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  • 1.
    Aaseth, Jan
    et al.
    Innlandet Hosp, Norway; Inland Norway Univ Appl Sci, Norway.
    Alexander, Jan
    Norwegian Inst Publ Hlth, Norway.
    Alehagen, Urban
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Tinkov, Alexey
    Yaroslavl State Univ, Russia; IM Sechenov First Moscow State Med Univ Sechenov, Russia.
    Skalny, Anatoly
    IM Sechenov First Moscow State Med Univ Sechenov, Russia; KG Razumovsky Moscow State Univ Technol & Managem, Russia.
    Larsson, Anders
    Uppsala Univ, Sweden.
    Crisponi, Guido
    Univ Cagliari, Italy.
    Nurchi, Valeria Marina
    Univ Cagliari, Italy.
    The Aging Kidney - As Influenced by Heavy Metal Exposure and Selenium Supplementation2021In: Biomolecules, E-ISSN 2218-273X, Vol. 11, no 8, article id 1078Article, review/survey (Refereed)
    Abstract [en]

    The aging process in the kidneys has been well studied. It is known that the glomerular filtration rate (GFR) declines with age in subjects older than 50-60 years. However, there is still insufficient knowledge regarding the response of the aged kidney to environmental toxicants such as mercury, cadmium, and lead. Here, we present a review on the functional decline and proposed mechanisms in the aging kidney as influenced by metal pollutants. Due to the prevalence of these toxicants in the environment, human exposure is nearly unavoidable. Further, it is well known that acute and chronic exposures to toxic metals may be detrimental to kidneys of normal adults, thus it may be hypothesized that exposure of individuals with reduced GFR will result in additional reductions in renal function. Individuals with compromised renal function, either from aging or from a combination of aging and disease, may be particularly susceptible to environmental toxicants. The available data appear to show an association between exposure to mercury, cadmium and/or lead and an increase in incidence and severity of renal disease in elderly individuals. Furthermore, some physiological thiols, as well as adequate selenium status, appear to exert a protective action. Further studies providing improved insight into the mechanisms by which nephrotoxic metals are handled by aging kidneys, as well as possibilities of therapeutic protection, are of utmost importance.

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  • 2.
    Abate, Ebba
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. University of Gondar, Ethiopia.
    Belayneh, Meseret
    University of Addis Ababa, Ethiopia.
    Idh, Jonna
    Vastervik Hospital, Sweden.
    Diro, Ermias
    University of Gondar, Ethiopia.
    Elias, Daniel
    University of Southern Denmark, Denmark.
    Britton, Sven
    Karolinska Hospital, Sweden.
    Aseffa, Abraham
    Armauer Hansen Research Institute, Ethiopia.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Sweden.
    Asymptomatic Helminth Infection in Active Tuberculosis Is Associated with Increased Regulatory and Th-2 Responses and a Lower Sputum Smear Positivity2015In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 9, no 8, article id e0003994Article in journal (Refereed)
    Abstract [en]

    Background The impact of intestinal helminth infection on the clinical presentation and immune response during active tuberculosis (TB) infection is not well characterized. Our aim was to investigate whether asymptomatic intestinal helminth infection alters the clinical signs and symptoms as well as the cell mediated immune responses in patients with active TB.

    Methodology Consecutive, newly diagnosed TB patients and healthy community controls (CCs) were recruited in North-west Ethiopia. TB-score, body mass index and stool samples were analyzed. Cells from HIV-negative TB patients (HIV-/TB) and from CCs were analyzed for regulatory T-cells (Tregs) and cytokine responses using flow cytometry and ELISPOT, respectively.

    Results A significantly higher ratio of helminth co-infection was observed in TB patients without HIV (Helm+/HIV-/TB) compared to HIV negative CCs, (40% (121/306) versus 28% (85/306), p = 0.003). Helm+/HIV-/TB patients showed significantly increased IL-5 secreting cells compared to Helm-/HIV-/TB (37 SFU (IQR:13-103) versus 2 SFU (1-50); p = 0.02, n = 30). Likewise, levels of absolute Tregs (9.4 (3.2-16.7) cells/mu l versus 2.4 (1.1-4.0) cells/mu l; p = 0.041) and IL-10 secreting cells (65 SFU (7-196) versus 1 SFU (0-31); p = 0.014) were significantly higher in Helm+/HIV-/TB patients compared to Helm-/HIV-/TB patients. In a multivariate analysis, a lower rate of sputum smear positivity for acid fast bacilli, lower body temperature, and eosinophilia were independently associated with helminth infection in TB patients.

    Conclusions Asymptomatic helminth infection is associated with increased regulatory T-cell and Th2-type responses and a lower rate of sputum smear positivity. Further studies are warranted to investigate the clinical and immunological impact of helminth infection in TB patients.

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  • 3.
    Abbas, Zaheer
    et al.
    Beijing Univ Chem Technol, Peoples R China.
    Soomro, Razium Ali
    Beijing Univ Chem Technol, Peoples R China; Beijing Univ Chem Technol, Peoples R China.
    Kalwar, Nazar Hussain
    Shah Abdul Latif Univ Khairpur, Pakistan.
    Tunesi, Mawada
    Beijing Univ Chem Technol, Peoples R China.
    Willander, Magnus
    Linköping University, Department of Science and Technology, Physics, Electronics and Mathematics. Linköping University, Faculty of Science & Engineering.
    Karakus, Selcan
    Istanbul Univ Cerrahpa Avcilar, Turkey.
    Kilislioglu, Ayben
    Istanbul Univ Cerrahpa Avcilar, Turkey.
    In Situ Growth of CuWO4 Nanospheres over Graphene Oxide for Photoelectrochemical (PEC) Immunosensing of Clinical Biomarker2020In: Sensors, E-ISSN 1424-8220, SENSORS, Vol. 20, no 1, article id 148Article in journal (Refereed)
    Abstract [en]

    Procalcitonin (PCT) protein has recently been identified as a clinical marker for bacterial infections based on its better sepsis sensitivity. Thus, an increased level of PCT could be linked with disease diagnosis and therapeutics. In this study, we describe the construction of the photoelectrochemical (PEC) PCT immunosensing platform based on it situ grown photo-active CuWO4 nanospheres over reduced graphene oxide layers (CuWO4@rGO). The in situ growth strategy enabled the formation of small nanospheres (diameter of 200 nm), primarily composed of tiny self-assembled CuWO4 nanoparticles (2-5 nm). The synergic coupling of CuWO4 with rGO layers constructed an excellent photo-active heterojunction for photoelectrochemical (PEC) sensing. The platform was then considered for electrocatalytic (EC) mechanism-based detection of PCT, where inhibition of the photocatalytic oxidation signal of ascorbic acid (AA), subsequent to the antibody-antigen interaction, was recorded as the primary signal response. This inhibition detection approach enabled sensitive detection of PCT in a concentration range of 10 pgmL(-1) to 50 ng.mL(-1) with signal sensitivity achievable up to 0.15 pgmL(-1). The proposed PEC hybrid (CuWO4@rGO) could further be engineered to detect other clinically important species.

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  • 4.
    Abdeldaim, Guma M. K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Strålin, Kristoffer
    Department of Infectious Diseases, Örebro University Hospital.
    Kirsebom, Leif A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Olcén, Per
    Department of Clinical Microbiology, Örebro University Hospital.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Herrmann, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Detection of Haemophilus influenzae in respiratory secretions from pneumonia patients by quantitative real-time polymerase chain reaction2009In: Diagnostic microbiology and infectious disease, ISSN 0732-8893, E-ISSN 1879-0070, Vol. 64, no 4, p. 366-373Article in journal (Refereed)
    Abstract [en]

    A quantitative real-time polymerase chain reaction (PCR) based on the omp P6 gene was developed to detect Haemophilus influenzae. Its specificity was determined by analysis of 29 strains of 11 different Haemophilus spp. and was compared with PCR assays having other target genes: rnpB, 16S rRNA, and bexA. The method was evaluated on nasopharyngeal aspirates from 166 adult patients with community-acquired pneumonia. When 104 DNA copies/mL was used as cutoff limit for the method, P6 PCR had a sensitivity of 97.5% and a specificity of 96.0% compared with the culture. Of 20 culture-negative but P6 PCR-positive cases, 18 were confirmed by fucK PCR as H. influenzae. Five (5.9%) of 84 nasopharyngeal aspirates from adult controls tested PCR positive. We conclude that the P6 real-time PCR is both sensitive and specific for identification of H. influenzae in respiratory secretions. Quantification facilitates discrimination between disease-causing H. influenzae strains and commensal colonization.

  • 5.
    Abdeldaim, Guma M. K.
    et al.
    Section of Clinical Bacteriology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Department of Clinical Mycobacteriology, National Center for Diseases Control, Benghazi, Libyan Arab Jamahiriya.
    Strålin, Kristoffer
    Department of Infectious Diseases, Örebro University Hospital, Örebro, Sweden; Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.
    Olcén, Per
    Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Blomberg, Jonas
    Section of Clinical Virology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Mölling, Paula
    Örebro University Hospital. Department of Laboratory Medicine.
    Herrmann, Björn
    Section of Clinical Bacteriology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Quantitative fucK gene polymerase chain reaction on sputum and nasopharyngeal secretions to detect Haemophilus influenzae pneumonia2013In: Diagnostic microbiology and infectious disease, ISSN 0732-8893, E-ISSN 1879-0070, Vol. 76, no 2, p. 141-146Article in journal (Refereed)
    Abstract [en]

    A quantitative polymerase chain reaction (PCR) for the fucK gene was developed for specific detection of Haemophilus influenzae. The method was tested on sputum and nasopharyngeal aspirate (NPA) from 78 patients with community-acquired pneumonia (CAP). With a reference standard of sputum culture and/or serology against the patient's own nasopharyngeal isolate, H. influenzae etiology was detected in 20 patients. Compared with the reference standard, fucK PCR (using the detection limit 10(5) DNA copies/mL) on sputum and NPA showed a sensitivity of 95.0% (19/20) in both cases, and specificities of 87.9% (51/58) and 89.5% (52/58), respectively. In a receiver operating characteristic curve analysis, sputum fucK PCR was found to be significantly superior to sputum P6 PCR for detection of H. influenzae CAP. NPA fucK PCR was positive in 3 of 54 adult controls without respiratory symptoms. In conclusion, quantitative fucK real-time PCR provides a sensitive and specific identification of H. influenzae in respiratory secretions.

  • 6.
    Abdelrahim, Nada A.
    et al.
    Department of Medical Microbiology, Faculty of Medical Laboratory Sciences, Nile University, Khartoum, Sudan.
    Mohamed, Nahla
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Fadl-Elmula, Imad M.
    Department of Pathology and Clinical Genetics, Faculty of Medicine, Al-Neelain University, Khartoum, Sudan; Assafa Academy, Kartoum, Sudan.
    Human herpes virus type-6 is associated with central nervous system infections in children in Sudan2022In: African Journal of Laboratory Medicine, ISSN 2225-2002, E-ISSN 2225-2010, Vol. 11, no 1, article id a1718Article in journal (Refereed)
    Abstract [en]

    Background: Human herpes virus type-6 (HHV-6) is increasingly recognised as a febrile agent in children. However, less is known in sub-Saharan African countries, including Sudan.

    Objective: We investigated the involvement of HHV-6 in paediatric central nervous system (CNS) infections in Khartoum, Sudan.

    Methods: Febrile patients aged up to 15 years with suspected CNS infections at Omdurman Hospital for Children from 01 December 2009 to 01 August 2010 were included. Viral DNA was extracted from leftover cerebrospinal fluid (CSF) specimens and quantitatively amplified by real-time polymerase chain reaction (PCR) at Umeå University in Sweden.

    Results: Of 503 CSF specimens, 13 (2.6%) were positive for HHV-6 (33.0% [13/40 of cases with proven infectious meningitis]). The median thermal cycle threshold for all HHV-6-positive specimens was 38 (range: 31.9-40.8). The median number of virus copies was 281.3/PCR run (1 × 105 copies/mL CSF; range: 30-44 × 103 copies/PCR run [12 × 103 - 18 × 106 copies/mL CSF]). All positive patients presented with fever and vomiting; 86.0% had seizures. The male-to-female ratio was 1:1; 50.0% were toddlers, 42.0% infants and 8.0% teenagers. Most (83.0%) were admitted in the dry season and 17.0% in the rainy season. Cerebrospinal fluid leukocytosis was seen in 33.0%, CSF glucose levels were normal in 86.0% and low in 14.0%, and CSF protein levels were low in 14.0% and high in 43.0%.

    Conclusion: Among children in Sudan with CNS infections, HHV-6 is common. Studies on the existence and spread of HHV-6 chromosomal integration in this population are needed.

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  • 7.
    Abdelrahim, Nada Abdelghani
    et al.
    Department of Pathology-Medical Microbiology, Faculty of Medicine, University of Medical Sciences and Technology, Khartoum, Sudan.
    Mohamed, Nahla
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Fadl-Elmula, Imad Mohammed
    Department of Pathology & Clinical Genetics, Al-Neelain University & Assafa Academy, Khartoum, Sudan.
    Viral meningitis in Sudanese children: differentiation, etiology and review of literature2022In: Medicine, ISSN 0025-7974, E-ISSN 1536-5964, Vol. 101, no 46, article id e31588Article, review/survey (Refereed)
    Abstract [en]

    Diagnosis of viral meningitis (VM) is uncommon practice in Sudan and there is no local viral etiological map. We therefore intended to differentiate VM using standardized clinical codes and determine the involvement of herpes simplex virus types-1 and 2 (HSV-1/2), varicella zoster virus, non-polio human enteroviruses (HEVs), and human parechoviruses in meningeal infections in children in Sudan. This is a cross-sectional hospital-based study. Viral meningitis was differentiated in 503 suspected febrile attendee of Omdurman Hospital for Children following the criteria listed in the Clinical Case Definition for Aseptic/Viral Meningitis. Patients were children age 0 to 15 years. Viral nucleic acids (DNA/RNA) were extracted from cerebrospinal fluid (CSF) specimens using QIAamp® UltraSens Virus Technology. Complementary DNA was prepared from viral RNA using GoScriptTM Reverse Transcription System. Viral nucleic acids were amplified and detected using quantitative TaqMan® Real-Time and conventional polymerase chain reactions (PCRs). Hospital diagnosis of VM was assigned to 0%, when clinical codes were applied; we considered 3.2% as having VM among the total study population and as 40% among those with proven infectious meningitis. Two (0.4%) out of total 503 CSF specimens were positive for HSV-1; Ct values were 37.05 and 39.10 and virus copies were 652/PCR run (261 × 103/mL CSF) and 123/PCR run (49.3 × 103/mL CSF), respectively. Other 2 (0.4%) CSF specimens were positive for non-polio HEVs; Ct values were 37.70 and 38.30, and the approximate virus copies were 5E2/PCR run (~2E5/mL CSF) and 2E2/PCR run (~8E4/mL CSF), respectively. No genetic materials were detected for HSV-2, varicella zoster virus, and human parechoviruses. The diagnosis of VM was never assigned by the hospital despite fulfilling the clinical case definition. Virus detection rate was 10% among cases with proven infectious meningitis. Detected viruses were HSV-1 and non-polio HEVs. Positive virus PCRs in CSFs with normal cellular counts were seen.

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  • 8.
    Abdel-Shafi, Seham
    et al.
    Botany and Microbiology Department, Faculty of Science, Zagazig University, Zagazig, Egypt.
    El-Serwy, Heba
    Botany and Microbiology Department, Faculty of Science, Zagazig University, Zagazig, Egypt.
    El-Zawahry, Yehia
    Botany and Microbiology Department, Faculty of Science, Zagazig University, Zagazig, Egypt.
    Zaki, Maysaa
    Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
    Sitohy, Basel
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sitohy, Mahmoud
    Biochemistry Department, Faculty of Agriculture, Zagazig University, Zagazig, Egypt.
    The Association between icaA and icaB Genes, Antibiotic Resistance and Biofilm Formation in Clinical Isolates of Staphylococci spp.2022In: Antibiotics, E-ISSN 2079-6382, Vol. 11, no 3, article id 389Article in journal (Refereed)
    Abstract [en]

    Sixty-six (66) Staphylococcus bacterial isolates were withdrawn from separate clinical samples of hospitalized patients with various clinical infections. Conventional bacteriological tests identified the species of all isolates, and standard microbiological techniques differentiated them into CoPS or CoNS. Their biofilm development was followed by an analysis via the MTP (microtiter tissue culture plates) technique, and we then investigated the presence/absence of icaA and icaB, which were qualified in the top-30 potent biofilm-forming isolates. Thirteen isolates (46.7%) showed the presence of one gene, six (20%) isolates exhibited the two genes, while ten (33.3%) had neither of them. The formation of staphylococci biofilms in the absence of ica genes may be related to the presence of other biofilm formation ica-independent mechanisms. CoPS was the most abundant species among the total population. S. aureus was the sole representative of CoPS, while S. epidermidis was the most abundant form of CoNS. Antibiotic resistance was developing against the most frequently used antimicrobial drugs, while vancomycin was the least-resisted drug. The totality of the strong and medium-strength film-forming isolates represented the majority proportion (80%) of the total investigated clinical samples. The biochemical pattern CoPS is associated with antibiotic resistance and biofilm formation and can be an alarming indicator of potential antibiotic resistance.

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  • 9.
    Abdulkarim, Farhad
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Molecular Biology.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Molecular Biology.
    Homologous recombination between the tuf genes of Salmonella typhimurium1996In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 260, no 4, p. 506-522Article in journal (Refereed)
    Abstract [en]

    The genes coding for the translation factor EF-Tu, tufA and tufB are separated by over 700 kb on the circular chromosome of Salmonella typhimurium. The coding regions of these genes have 99% identity at the nucleotide level in spite of the presumed ancient origin of the gene duplication. Sequence comparisons between S. typhimurium and Escherichiacoli suggest that within each species the two tuf genes are evolving inconcert. Here we show that each of the S. typhimurium tuf genes cantransfer genetic information to the other. In our genetic system thetransfers are seen as non-reciprocal, i.e. as gene conversion events.However, the mechanism of recombination could be reciprocal, with sisterchromosome segregation and selection leading to the isolation of aparticular class of recombinant. The amount of sequence informationtransferred in individual recombination events varies, but can be close tothe entire length of the gene. The recombination is RecABCD-dependent,and is opposed by MutSHLU mismatch repair. In the wild-type, this typeof recombination occurs at a rate that is two or three orders of magnitudegreater than the nucleotide substitution rate. The rate of recombinationdiffers by six orders of magnitude between a recA and a mutS strain.Mismatch repair reduces the rate of this recombination 1000-fold. The rateof recombination also differs by one order of magnitude depending onwhich tuf gene is donating the sequence selected for. We discuss threeclasses of model that could, in principle, account for the sequencetransfers: (1) tuf mRNA mediated recombination; (2) non-allelic reciprocalrecombination involving sister chromosomes; (3) non-allelic geneconversion involving sister chromosomes, initiated by a double-strandbreak close to one tuf gene. Although the mechanism remains to bedetermined, the effect on the bacterial cells is tuf gene sequencehomogenisation. This recombination phenomenon can account for theconcerted evolution of the tuf genes.

  • 10.
    Abdulkarim, Farhad
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Molecular Biology.
    Liljas, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Molecular Biology.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Molecular Biology.
    Mutations to kirromycin resistance occur in the interface of domains I and III of EF-Tu.GTP1994In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 352, p. 118-122Article in journal (Refereed)
    Abstract [en]

    The antibiotic kirromycin inhibits protein synthesis by binding to EF-Tu and preventing its release from the ribosome after GTP hydrolysis.We have isolated and sequenced a collection of kirromycin resistant tuf mutations and identified thirteen single amino acid substitutions at sevendifferent sites in EF-Tu. These have been mapped onto the 3D structures of EF-Tu’GTP and EF-Tu.GDP. In the active GTP form of EF-Tu themutations cluster on each side of the interface between domains I and III. We propose that this domain interface is the binding site for kirromycin.

  • 11.
    Abdulkarim, Farhad
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Molecular Biology.
    Tuohy, TMF
    Buckingham, RH
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Molecular Biology.
    Missense substitutions lethal to essential functions of EF-Tu1991In: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 73, no 12, p. 1457-1464Article in journal (Refereed)
    Abstract [en]

    We have used a simple selection and screening method to isolate function defective mutants of EF-Tu. From 28 mutants tested, 12 different missense substitutions, individually lethal to some essential function of EF-Tu, were identified by sequencing. In addition we found a new non-lethal missense mutation. The frequency of isolation of unique mutations suggests that this method can be used to easily isolate many more. The lethal mutations occur in all three structural domains of EF-Tu, but most are in domain II. We aim to use these mutants to define functional domains on EF-Tu.

  • 12.
    Abdurahman, Samir
    et al.
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Végvári, Akos
    Clinical Protein Science, Department of Electrical Measurements, Lund University, Lund, Sweden.
    Youssefi, Masoud
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Levi, Michael
    Tripep AB, Huddinge, Sweden .
    Höglund, Stefan
    Department of Biochemistry, Uppsala University, Uppsala, Sweden .
    Andersson, Elin
    Department of Clinical Virology, University of Göteborg, Göteborg, Sweden.
    Horal, Peter
    Department of Clinical Virology, University of Göteborg, Göteborg, Sweden.
    Svennerholm, Bo
    Department of Clinical Virology, University of Göteborg, Göteborg, Sweden.
    Balzarini, Jan
    Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
    Vahlne, Anders
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Activity of the small modified amino acid alpha-hydroxy glycineamide on in vitro and in vivo human immunodeficiency virus type 1 capsid assembly and infectivity2008In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 52, no 10, p. 3737-3744Article in journal (Refereed)
    Abstract [en]

    Upon maturation of the human immunodeficiency virus type 1 (HIV-1) virion, proteolytic cleavage of the Gag precursor protein by the viral protease is followed by morphological changes of the capsid protein p24, which will ultimately transform the virus core from an immature spherical to a mature conical structure. Virion infectivity is critically dependent on the optimal semistability of the capsid cone structure. We have reported earlier that glycineamide (G-NH(2)), when added to the culture medium of infected cells, inhibits HIV-1 replication and that HIV-1 particles with aberrant core structures were formed. Here we show that it is not G-NH(2) itself but a metabolite thereof, alpha-hydroxy-glycineamide (alpha-HGA), that is responsible for the antiviral activity. We show that alpha-HGA inhibits the replication of clinical HIV-1 isolates with acquired resistance to reverse transcriptase and protease inhibitors but has no effect on the replication of any of 10 different RNA and DNA viruses. alpha-HGA affected the ability of the HIV-1 capsid protein to assemble into tubular or core structures in vitro and in vivo, probably by binding to the hinge region between the N- and C-terminal domains of the HIV-1 capsid protein as indicated by matrix-assisted laser desorption ionization-mass spectrometry results. As an antiviral compound, alpha-HGA has an unusually simple structure, a pronounced antiviral specificity, and a novel mechanism of antiviral action. As such, it might prove to be a lead compound for a new class of anti-HIV substances.

  • 13.
    Abrahamsson, Annelie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Rzepecka, Anna
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Equal Pro-inflammatory Profiles of CCLs, CXCLs, and Matrix Metalloproteinases in the Extracellular Microenvironment In Vivo in Human Dense Breast Tissue and Breast Cancer2018In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 8, article id 1994Article in journal (Refereed)
    Abstract [en]

    The inflammatory microenvironment affects breast cancer progression. Proteins that govern the inflammatory response are secreted into the extracellular space, but this compartment still needs to be characterized in human breast tissues in vivo. Dense breast tissue is a major risk factor for breast cancer by yet unknown mechanisms and no non-toxic prevention for these patients exists. Here, we used the minimal invasive technique of microdialysis for sampling of extracellular proteins in live tissues in situ in breast cancers of women before surgery and in healthy women having dense or non-dense breast tissue on mammography. Proteins were profiled using a proximity extension assay. Out of the 32 proteins assessed, 26 exhibited similar profiles in breast cancers and dense breast tissues; CCL-4, -7, -8, -11, -15, -16, -22, -23, and -25, CXCL-5, -8, -9, -16 as well as sIL-6R, IL-18, vascular endothelial growth factor, TGF-a, fibroblast growth factor 19, matrix metalloproteinase (MMP)-1, -2, -3, and urokinase-type plasminogen activator were all increased, whereas CCL-3, CX3CL1, hepatocyte growth factor, and MMP-9 were unaltered in the two tissues. CCL-19 and -24, CXCL-1 and -10, and IL-6 were increased in dense breast tissue only, whereas IL-18BP was increased in breast cancer only. Our results provide novel insights in the inflammatory microenvironment in human breast cancer in situ and define potential novel therapeutic targets. Additionally, we show previously unrecognized similarities of the pro-inflammatory microenvironment in dense breast tissue and breast cancer in vivo suggesting that anti-inflammatory breast cancer prevention trials for women with dense breast tissue may be feasible.

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  • 14.
    Abrahamsson, Thomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Jakobsson, H.E.
    Karolinska Institute, Stockholm, Sweden.
    Andersson, A.F.
    KTH Royal Institute of Technology, Stockholm, Sweden.
    Björksten, B.
    Karolinska Institute, Stockholm, Sweden; Örebro University, Sweden .
    Engstrand, L.
    Karolinska Institute, Stockholm, Sweden; KTH Royal Institute of Technology, Stockholm, Sweden.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Low gut microbiota diversity in early infancy precedes asthma at school age2014In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 44, no 6, p. 842-850Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Low total diversity of the gut microbiota during the first year of life is associated with allergic diseases in infancy, but little is known how early microbial diversity is related to allergic disease later in school age.

    OBJECTIVE:

    To assess microbial diversity and characterize the dominant bacteria in stool during the first year of life in relation to the prevalence of different allergic diseases in school age, such as asthma, allergic rhinoconjunctivitis (ARC) and eczema.

    METHODS:

    The microbial diversity and composition was analysed with barcoded 16S rDNA 454 pyrosequencing in stool samples at 1 week, 1 month and 12 months of age in 47 infants which were subsequently assessed for allergic disease and skin prick test reactivity at 7 years of age (ClinicalTrials.gov ID NCT01285830).

    RESULTS:

    Children developing asthma (n = 8) had a lower diversity of the total microbiota than non-asthmatic children at 1 week (P = 0.04) and 1 month (P = 0.003) of age, whereas allergic rhinoconjunctivitis (n = 13), eczema (n = 12) and positive skin prick reactivity (n = 14) at 7 years of age did not associate with the gut microbiota diversity. Neither was asthma associated with the microbiota composition later in infancy (at 12 months). Children having IgE-associated eczema in infancy and subsequently developing asthma had lower microbial diversity than those that did not. There were no significant differences, however, in relative abundance of bacterial phyla and genera between children with or without allergic disease.

    CONCLUSION AND CLINICAL RELEVANCE:

    Low total diversity of the gut microbiota during the first month of life was associated with asthma but not ARC in children at 7 years of age. Measures affecting microbial colonization of the infant during the first month of life may impact asthma development in childhood.

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  • 15.
    Abrahamsson, Thomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping. University of Toronto, Canada.
    You Wu, Richard
    University of Toronto, Canada.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Gut microbiota and allergy: the importance of the pregnancy period2015In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 77, no 1, p. 214-219Article, review/survey (Refereed)
    Abstract [en]

    Limited microbial exposure is suggested to underlie the increase of allergic diseases in affluent countries, and bacterial diversity seems to be more important than specific bacteria taxa. Prospective studies indicate that the gut microbiota composition during the first months of life influences allergy development, and support the theory that factors influencing the early maturation of the immune system might be important for subsequent allergic disease. However, recent research indicates that microbial exposure during pregnancy may be even more important for the preventative effects against allergic disease. This review gives a background of the epidemiology, immunology, and microbiology literature in this field. It focuses on possible underlying mechanisms such as immune-regulated epigenetic imprinting and bacterial translocation during pregnancy, potentially providing the offspring with a pioneer microbiome. We suggest that a possible reason for the initial exposure of bacterial molecular patterns to the fetus in utero is to prime the immune system and/or the epithelium to respond appropriately to pathogens and commensals after birth.

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  • 16.
    Adamovic, Tatjana
    et al.
    Med Coll Wisconsin, Human & Mol Genet Ctr, Milwaukee, WI 53226 USA.
    Hamta, Achmad
    Univ Gothenburg, CMB Genet, Gothenburg, Sweden.
    Roshani, Leyla
    Univ Gothenburg, CMB Genet, Gothenburg, Sweden.
    Lü, Xuschun
    Univ Gothenburg, CMB Genet, Gothenburg, Sweden.
    Röhme, Dan
    Univ Gothenburg, CMB Genet, Gothenburg, Sweden.
    Helou, Khalil
    Univ Gothenburg, Dept Oncol, Gothenburg, Sweden.
    Klinga-Levan, Karin
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Levan, Göran
    Univ Gothenburg, CMB Genet, Gothenburg, Sweden.
    Rearrangement and allelic imbalance on chromosome 5 leads to homozygous deletions in the CDKN2A/2B tumor suppressor gene region in rat endometrial cancer2008In: Cancer Genetics and Cytogenetics, ISSN 0165-4608, E-ISSN 1873-4456, Vol. 184, no 1, p. 9-21Article in journal (Refereed)
    Abstract [en]

    The inbred BDII rat is a valuable experimental model for the genetic analysis of hormone-dependent endometrial adenocarcinoma (EAC). One common aberration detected previously by comparative genomic hybridization in rat EAC is loss affecting mostly the middle part of rat chromosome 5 (RNO5). First, we applied an RNO5-specific painting probe and four region-specific gene probes onto tumor cell metaphases from 21 EACs, and found that rearrangements involving RNO5 were common. The copy numbers of loci situated on RNO5 were found to be reduced, particularly for the CDKN2A/2B locus. Second, polymerase chain reaction analysis was performed with 22 genes and markers and homozygous deletions of the CDKN2A exon 1β and CDKN2B genes were detected in 13 EACs (62%) and of CDKN2A exon 1α in 12 EACs (57%) Third, the occurrence of allelic imbalance in RNO5 was analyzed using 39 microsatellite markers covering the entire chromosome and frequent loss of heterozygosity was detected. Even more intriguing was the repeated finding of allele switching in a narrow region of 7 Mb across the CDKN2A/2B locus. We conclude that genetic events affecting the middle part of RNO5 (including bands 5q31q33 and the CDKN2A locus) contribute to the development of EAC in rat, with the CDKN2A locus having a primary role.

  • 17.
    Adua, Eric
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Oteng Danso, Frank
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Mensah Boa-Amponsem, Oswald
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Adusei-Mensah, Frank
    University of Cape Coast, Ghana.
    Effect of Neutrophils on Nitric Oxide Production from Stimulated Macrophages2015In: Iranian Journal of Immunology, ISSN 1735-1383, E-ISSN 1735-367X, Vol. 12, no 2, p. 94-103Article in journal (Refereed)
    Abstract [en]

    Background: During the initial phase of an infection, there is an upregulation of inducible nitric oxide synthase in the macrophages for the production of nitric oxide. This is followed by the recruitment of polymorphonuclear leukocytes (neutrophils) which release arginase. Arginase competes with inducible nitric oxide synthase for a common substrate L-arginine. Objective: To investigate whether the entry of neutrophils and release of arginase can interfere with nitric oxide production from stimulated mouse macrophages. Methods: Neutrophils were isolated from human blood and stimulated with cytodex-3 beads. Cultured macrophages were stimulated with lipopolysaccharide and interferon gamma with or without N (G)-nitro-L-arginine methyl ester or N (omega)-hydroxy-nor-L-arginine. Measurement of NO2-/NO3- and urea were done using the spectrophotometer. Results: A significantly higher level of nitric oxide production from stimulated macrophages was observed compared to control. There was a decrease in nitric oxide production when stimulated macrophages were treated with the supernatant from activated neutrophils (pless than0.05). Conclusion: Arginase from neutrophils can modulate nitric oxide production from activated macrophages which may affect the course of infection by intracellular bacteria.

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  • 18.
    Afshar, Mastaneh
    et al.
    Department of Biomedicine, Aarhus University, Aarhus, Denmark.
    Poehlein, Anja
    Department of Genomic and Applied Microbiology, Institute of Microbiology and Genetics, University of Göttingen, Göttingen, Germany.
    Söderquist, Bo
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Brüggemann, Holger
    Department of Biomedicine, Aarhus University, Aarhus, Denmark.
    Complete Genome Sequences of Two Staphylococcus saccharolyticus Strains Isolated from Prosthetic Joint Infections2021In: Microbiology Resource Announcements, E-ISSN 2576-098X, Vol. 10, no 10, article id e00157-21Article in journal (Refereed)
    Abstract [en]

    Staphylococcus saccharolyticus is a human skin bacterium and is occasionally associated with prosthetic joint infections (PJIs). Here, we report the complete genome sequences of two strains that were isolated from shoulder and hip PJIs. The genomes show signs of reductive evolution; around 21% of all coding sequences are inactivated by frameshift mutations.

  • 19.
    Agerhäll, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Henrikson, Martin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Johansson Söderberg, Jenny
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sellin, Mats
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Tano, Krister
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Berggren, Diana
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    High prevalence of pharyngeal bacterial pathogens among healthy adolescents and young adults2021In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 129, no 12, p. 711-716Article in journal (Refereed)
    Abstract [en]

    The pharyngeal mucosa can be colonized with bacteria that have potential to cause pharyngotonsillitis. By the use of culturing techniques and PCR, we aimed to assess the prevalence of bacterial pharyngeal pathogens among healthy adolescents and young adults. We performed a cross-sectional study in a community-based cohort of 217 healthy individuals between 16 and 25 years of age. Samples were analyzed for Group A streptococci (GAS), Group C/G streptococci (SDSE), Fusobacterium necrophorum, and Arcanobacterium haemolyticum. Compared to culturing, the PCR method resulted in more frequent detection, albeit in most cases with low levels of DNA, of GAS (20/217 vs. 5/217; p < 0.01) and F. necrophorum (20/217 vs. 8/217; p < 0.01). Culturing and PCR yielded similar rates of SDSE detection (14/217 vs. 12/217; p = 0.73). Arcanobacterium haemolyticum was rarely detected (3/217), and only by PCR. Overall, in 25.3% (55/217) of these healthy adolescents and young adults at least one of these pathogens was detected, a rate that is higher than previously described. Further studies are needed before clinical adoption of PCR-based detection methods for pharyngeal bacterial pathogens, as our findings suggest a high incidence of asymptomatic carriage among adolescents and young adults without throat infections.

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  • 20.
    Aguilar Quiñones, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Impact of Viral Geometry and Cellular Lipid Environment on Virus-Endosome Fusion Kinetics2021Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
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  • 21.
    Ahlberg, Emelie
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Jenmalm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Tingö, Lina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Orebro Univ, Sweden.
    Evaluation of five column-based isolation kits and their ability to extract miRNA from human milk2021In: Journal of Cellular and Molecular Medicine (Print), ISSN 1582-1838, E-ISSN 1582-4934, Vol. 25, no 16, p. 7973-7979Article in journal (Refereed)
    Abstract [en]

    MicroRNA can be found in various body fluids, including breast milk. MicroRNA may be transferred from mother to infant via breast milk and potentially regulate the development of the infants immune system on a post-transcriptional level. This study aimed to determine the microRNA extraction efficiency of five RNA extraction kits from human skim milk samples. Their efficiency was determined by comparing microRNA concentrations, total RNA yield and purity. Furthermore, hsa-miR-148a-3p expression and the recovery of an exogenous control, cel-miR-39-3p, were quantified using qPCR. Each kit extracted different amounts of microRNA and total RNA, with one kit tending to isolate the highest amount of both RNA species. Based on these results, the extraction kit ReliaPrep (TM) miRNA Cell and Tissue Miniprep System from Promega was found to be the most appropriate kit for microRNA extraction from human skim milk. Moreover, further research is needed to establish a standardized protocol for microRNA extraction from breast milk.

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  • 22.
    Ahlstrand, Erik
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Medicine, Hematology, Örebro University Hospital, Örebro, Sweden.
    Bäckman, Anders
    Örebro University, School of Medical Sciences. Clinical Research Centre, Örebro University Hospital, Örebro, Sweden.
    Persson, Lennart
    Örebro University Hospital. Department of Infectious diseases, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Tidefelt, Ulf
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Söderquist, Bo
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Infectious diseases & Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Evaluation of a PCR method to determine the clinical significance of blood cultures with Staphylococcus epidermidis in patients with hematological malignancies2014In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 122, no 6, p. 539-544Article in journal (Refereed)
    Abstract [en]

    The aim was to investigate whether the detection and quantification of Staphylococcus epidermidis DNA in blood could distinguish S. epidermidis blood stream infections (BSIs) from blood culture contaminations in patients with hematological malignancies. The hld gene was chosen to identify S. epidermidis DNA and DNA in blood samples was detected by real-time PCR. Blood samples were obtained simultaneously with blood cultures positive for S. epidermidis (n = 30), during blood culture-negative episodes (n = 10) and episodes of bacteremia with other bacteria than S. epidermidis (n = 4) and from healthy blood donors (n = 10). In addition, DNA from S. epidermidis and a selection of other bacterial species were analyzed. Three different sets of criteria were used to classify episodes with positive blood cultures with S. epidermidis as BSIs or contaminations. All DNA preparations from S. epidermidis (n = 48) were hld-positive, but other bacterial species (n = 13) were negative. Sixteen (53%) of 30 blood samples from patients with blood cultures positive for S. epidermidis were hld-positive, but none of the controls. There was no clear association between a positive hld PCR and episodes interpreted as BSIs. In conclusion, hld PCR failed to distinguish S. epidermidis BSIs from blood culture contaminations in patients with hematological malignancies.

  • 23. Ahlstrand, Tuuli
    et al.
    Torittu, Annamari
    Elovaara, Heli
    Välimaa, Hannamari
    Pöllänen, Marja T.
    Kasvandik, Sergo
    Högbom, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ihalin, Riikka
    Interactions between the Aggregatibacter actinomycetemcomitans secretin HofQ and host cytokines indicate a link between natural competence and interleukin-8 uptake2018In: Virulence, ISSN 2150-5594, E-ISSN 2150-5608, Vol. 9, no 1, p. 1205-1223Article in journal (Refereed)
    Abstract [en]

    Naturally competent bacteria acquire DNA from their surroundings to survive in nutrient-poor environments and incorporate DNA into their genomes as new genes for improved survival. The secretin HofQ from the oral pathogen Aggregatibacter actinomycetemcomitans has been associated with DNA uptake. Cytokine sequestering is a potential virulence mechanism in various bacteria and may modulate both host defense and bacterial physiology. The objective of this study was to elucidate a possible connection between natural competence and cytokine uptake in A. actinomycetemcomitans. The extramembranous domain of HofQ (emHofQ) was shown to interact with various cytokines, of which IL-8 exhibited the strongest interaction. The dissociation constant between emHofQ and IL-8 was 43nM in static settings and 2.4M in dynamic settings. The moderate binding affinity is consistent with the hypothesis that emHofQ recognizes cytokines before transporting them into the cells. The interaction site was identified via crosslinking and mutational analysis. By structural comparison, relateda type I KH domain with a similar interaction site was detected in the Neisseria meningitidis secretin PilQ, which has been shown to participate in IL-8 uptake. Deletion of hofQ from the A. actinomycetemcomitans genome decreased the overall biofilm formation of this organism, abolished the response to cytokines, i.e., decreased eDNA levels in the presence of cytokines, and increased the susceptibility of the biofilm to tested -lactams. Moreover, we showed that recombinant IL-8 interacted with DNA. These results can be used in further studies on the specific role of cytokine uptake in bacterial virulence without interfering with natural-competence-related DNA uptake.

  • 24.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, AK 99508 USA.
    Bonnedahl, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Hosp, Sweden.
    Woksepp, Hanna
    Kalmar Cty Hosp, Sweden.
    Hernandez, Jorge
    Uppsala Univ, Sweden.
    Olsen, Bjorn
    Uppsala Univ, Sweden.
    Ramey, Andrew M.
    US Geol Survey, AK 99508 USA.
    Acquisition and dissemination of cephalosporin-resistant E.coli in migratory birds sampled at an Alaska landfill as inferred through genomic analysis2018In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 7361Article in journal (Refereed)
    Abstract [en]

    Antimicrobial resistance (AMR) in bacterial pathogens threatens global health, though the spread of AMR bacteria and AMR genes between humans, animals, and the environment is still largely unknown. Here, we investigated the role of wild birds in the epidemiology of AMR Escherichia coli. Using next-generation sequencing, we characterized cephalosporin-resistant E. coli cultured from sympatric gulls and bald eagles inhabiting a landfill habitat in Alaska to identify genetic determinants conferring AMR, explore potential transmission pathways of AMR bacteria and genes at this site, and investigate how their genetic diversity compares to isolates reported in other taxa. We found genetically diverse E. coli isolates with sequence types previously associated with human infections and resistance genes of clinical importance, including blaCTX-M and blaCMY. Identical resistance profiles were observed in genetically unrelated E. coli isolates from both gulls and bald eagles. Conversely, isolates with indistinguishable core-genomes were found to have different resistance profiles. Our findings support complex epidemiological interactions including bacterial strain sharing between gulls and bald eagles and horizontal gene transfer among E. coli harboured by birds. Results suggest that landfills may serve as a source for AMR acquisition and/or maintenance, including bacterial sequence types and AMR genes relevant to human health.

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  • 25.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, USA.
    Scott, Laura C.
    US Geol Survey, USA.
    Woksepp, Hanna
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Region Kalmar County, Sweden.
    Bonnedahl, Jonas
    Linköping University, Sweden;Region Kalmar County, Sweden.
    Ramey, Andrew M.
    US Geol Survey, USA.
    Environmental antimicrobial resistance gene detection from wild bird habitats using two methods: A commercially available culture-independent qPCR assay and culture of indicator bacteria followed by whole-genome sequencing2023In: Journal of Global Antimicrobial Resistance, ISSN 2213-7165, E-ISSN 2213-7173, Vol. 33, p. 186-193Article in journal (Refereed)
    Abstract [en]

    Objectives: A variety of methods have been developed to detect antimicrobial resistance (AMR) in differ-ent environments to better understand the evolution and dissemination of this public health threat. Com-parisons of results generated using different AMR detection methods, such as quantitative PCR (qPCR) and whole-genome sequencing (WGS), are often imperfect, and few studies have analysed samples in parallel to evaluate differences. In this study, we compared bacterial culture and WGS to a culture-independent commercially available qPCR assay to evaluate the concordance between methods and the utility of each in answering research questions regarding the presence and epidemiology of AMR in wild bird habitats.Methods: We first assessed AMR gene detection using qPCR in 45 bacterial isolates from which we had existing WGS data. We then analysed 52 wild bird faecal samples and 9 spatiotemporally collected water samples using culture-independent qPCR and WGS of phenotypically resistant indicator bacterial isolates.Results: Overall concordance was strong between qPCR and WGS of bacterial isolates, although concor-dance differed among antibiotic classes. Analysis of wild bird faecal and water samples revealed that more samples were determined to be positive for AMR via qPCR than via culture and WGS of bacterial isolates, although qPCR did not detect AMR genes in two samples from which phenotypically resistant isolates were found.Conclusions: Both qPCR and culture followed by sequencing may be effective approaches for characteris-ing AMR genes harboured by wild birds, although data streams produced using these different tools may have advantages and disadvantages that should be considered given the application and sample matrix.Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

  • 26.
    Ahlström, Stina
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Sweden.
    Ahlner, Johan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences.
    Jönsson, Anna K
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, S-58758 Linkoping, Sweden.
    Green, Henrik
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, S-58758 Linkoping, Sweden.
    The Importance of BHB Testing on the Post-Mortem Diagnosis of Ketoacidosis2022In: Biomolecules, E-ISSN 2218-273X, Vol. 12, no 1, article id 9Article in journal (Refereed)
    Abstract [en]

    Although beta-hydroxybutyrate (BHB) analysis has proved its importance in forensic pathology, its effects on cause-of-death diagnostics are unaddressed. Therefore, this study aims at evaluating the effects of BHB analysis on the number of deaths by DKA (diabetes ketoacidosis), AKA (alcoholic ketoacidosis), HHS (hyperosmolar hyperglycaemic state), hypothermia, diabetes, alcoholism, and acidosis NOS (not otherwise specified). All 2900 deaths from 2013 through 2019 in which BHB was analysed at the National Board of Forensic Medicine, and 1069 DKA, AKA, HHS, hypothermia, diabetes, alcoholism, and acidosis cases without BHB analysis were included. The prevalence of BHB-positive cases for each cause of death, and trends and proportions of different BHB concentrations, were investigated. The number of BHB analyses/year increased from 13 to 1417. AKA increased from three to 66 and acidosis from one to 20. The deaths from alcoholism, DKA, and hypothermia remained stable. It is unclear why death from alcoholism remained stable while AKA increased. The increase in unspecific acidosis deaths raises the question why a more specific diagnosis had not been used. In conclusion, BHB analysis is instrumental in detecting AKA and acidosis. The scientific basis for the diagnosis of DKA and hypothermia improved, but the number of cases did not change.

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  • 27.
    Ahmad, Irfan
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet; Department of Allied Health Sciences, University of Health Sciences.
    Cimdins, Annika
    Beske, Timo
    Römling, Ute
    Detailed analysis of c-di-GMP mediated regulation of csgD expression in Salmonella typhimurium2017In: BMC Microbiology, E-ISSN 1471-2180, Vol. 17, article id 27Article in journal (Refereed)
    Abstract [en]

    Background: The secondary messenger cyclic di-GMP promotes biofilm formation by up regulating the expression of csgD, encoding the major regulator of rdar biofilm formation in Salmonella typhimurium. The GGDEF/EAL domain proteins regulate the c-di-GMP turnover. There are twenty-two GGDEF/EAL domain proteins in the genome of S. typhimurium. In this study, we dissect the role of individual GGDEF/EAL proteins for csgD expression and rdar biofilm development. Results: Among twelve GGDEF domains, two proteins upregulate and among fifteen EAL domains, four proteins down regulate csgD expression. We identified two additional GGDEF proteins required to promote optimal csgD expression. With the exception of the EAL domain of STM1703, solely, diguanylate cyclase and phosphodiesterase activities are required to regulate csgD mediated rdar biofilm formation. Identification of corresponding phosphodiesterases and diguanylate cyclases interacting in the csgD regulatory network indicates various levels of regulation by c-di-GMP. The phosphodiesterase STM1703 represses transcription of csgD via a distinct promoter upstream region. Conclusion: The enzymatic activity and the protein scaffold of GGDEF/EAL domain proteins regulate csgD expression. Thereby, c-di-GMP adjusts csgD expression at multiple levels presumably using a multitude of input signals.

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  • 28.
    Ahmad, Irfan
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Institute of Biomedical and Allied Health Sciences, University of Health Sciences, Lahore, Pakistan.
    Karah, Nabil
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Nadeem, Aftab
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Analysis of colony phase variation switch in Acinetobacter baumannii clinical isolates2019In: PLOS ONE, E-ISSN 1932-6203, Vol. 14, no 1, article id e0210082Article in journal (Refereed)
    Abstract [en]

    Reversible switching between opaque and translucent colony formation is a novel feature of Acinetobacter baumannii that has been associated with variations in the cell morphology, surface motility, biofilm formation, antibiotic resistance and virulence. Here, we assessed a number of phenotypic alterations related to colony switching in A. baumannii clinical isolates belonging to different multi-locus sequence types. Our findings demonstrated that these phenotypic alterations were mostly strain-specific. In general, the translucent subpopulations of A. baumannii produced more dense biofilms, were more piliated, and released larger amounts of outer membrane vesicles (OMVs). In addition, the translucent subpopulations caused reduced fertility of Caenorhabditis elegans. When assessed for effects on the immune response in RAW 264.7 macrophages, the OMVs isolated from opaque subpopulations of A. baumannii appeared to be more immunogenic than the OMVs from the translucent form. However, also the OMVs from the translucent subpopulations had the potential to evoke an immune response. Therefore, we suggest that OMVs may be considered for development of new immunotherapeutic treatments against A. baumannii infections.

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  • 29.
    Ahmad, Irfan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Institute of Biomedical and Allied Health Sciences, University of Health Sciences, Lahore, Pakistan.
    Nadeem, Aftab
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Mushtaq, Fizza
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Institute of Biomedical and Allied Health Sciences, University of Health Sciences, Lahore, Pakistan.
    Zlatkov, Nikola
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Shahzad, Muhammad
    Department of Pharmacology, University of Health Sciences, Lahore, Pakistan.
    Zavialov, Anton V.
    Department of Biochemistry, University of Turku, Tykistökatu 6A, Turku, Finland.
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Csu pili dependent biofilm formation and virulence of Acinetobacter baumannii2023In: npj Biofilms and Microbiomes, E-ISSN 2055-5008, Vol. 9, no 1, article id 101Article in journal (Refereed)
    Abstract [en]

    Acinetobacter baumannii has emerged as one of the most common extensive drug-resistant nosocomial bacterial pathogens. Not only can the bacteria survive in hospital settings for long periods, but they are also able to resist adverse conditions. However, underlying regulatory mechanisms that allow A. baumannii to cope with these conditions and mediate its virulence are poorly understood. Here, we show that bi-stable expression of the Csu pili, along with the production of poly-N-acetyl glucosamine, regulates the formation of Mountain-like biofilm-patches on glass surfaces to protect bacteria from the bactericidal effect of colistin. Csu pilus assembly is found to be an essential component of mature biofilms formed on glass surfaces and of pellicles. By using several microscopic techniques, we show that clinical isolates of A. baumannii carrying abundant Csu pili mediate adherence to epithelial cells. In addition, Csu pili suppressed surface-associated motility but enhanced colonization of bacteria into the lungs, spleen, and liver in a mouse model of systemic infection. The screening of c-di-GMP metabolizing protein mutants of A. baumannii 17978 for the capability to adhere to epithelial cells led us to identify GGDEF/EAL protein AIS_2337, here denoted PdeB, as a major regulator of Csu pili-mediated virulence and biofilm formation. Moreover, PdeB was found to be involved in the type IV pili-regulated robustness of surface-associated motility. Our findings suggest that the Csu pilus is not only a functional component of mature A. baumannii biofilms but also a major virulence factor promoting the initiation of disease progression by mediating bacterial adherence to epithelial cells.

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  • 30.
    Ahmad, Irfan
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Institute of Biomedical and Allied Health Sciences, University of Health Sciences, Lahore, Pakistan.
    Nygren, Evelina
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Khalid, Fizza
    Myint, Si Lhyam
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    A Cyclic-di-GMP signalling network regulates biofilm formation and surface associated motility of Acinetobacter baumannii 179782020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 1991Article in journal (Refereed)
    Abstract [en]

    Acinetobacter baumannii has emerged as an increasing multidrug-resistant threat in hospitals and a common opportunistic nosocomial pathogen worldwide. However, molecular details of the pathogenesis and physiology of this bacterium largely remain to be elucidated. Here we identify and characterize the c-di-GMP signalling network and assess its role in biofilm formation and surface associated motility. Bioinformatic analysis revealed eleven candidate genes for c-di-GMP metabolizing proteins (GGDEF/EAL domain proteins) in the genome of A. baumannii strain 17978. Enzymatic activity of the encoded proteins was assessed by molecular cloning and expression in the model organisms Salmonella typhimurium and Vibrio cholerae. Ten of the eleven GGDEF/EAL proteins altered the rdar morphotype of S. typhimurium and the rugose morphotype of V. cholerae. The over expression of three GGDEF proteins exerted a pronounced effect on colony formation of A. baumannii on Congo Red agar plates. Distinct panels of GGDEF/EAL proteins were found to alter biofilm formation and surface associated motility of A. baumannii upon over expression. The GGDEF protein A1S_3296 appeared as a major diguanylate cyclase regulating macro-colony formation, biofilm formation and the surface associated motility. AIS_3296 promotes Csu pili mediated biofilm formation. We conclude that a functional c-di-GMP signalling network in A. baumannii regulates biofilm formation and surface associated motility of this increasingly important opportunistic bacterial pathogen.

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  • 31.
    Ahsan, Umaira
    et al.
    Institute of Biomedical and Allied Health Sciences, University of Health Sciences, Lahore, Pakistan; Department of Microbiology, University of Health Sciences, Lahore, Pakistan.
    Mushtaq, Fizza
    Institute of Biomedical and Allied Health Sciences, University of Health Sciences, Lahore, Pakistan.
    Saleem, Sidrah
    Department of Microbiology, University of Health Sciences, Lahore, Pakistan.
    Malik, Abdul
    Institute of Biomedical and Allied Health Sciences, University of Health Sciences, Lahore, Pakistan.
    Sarfaraz, Hira
    Institute of Biomedical and Allied Health Sciences, University of Health Sciences, Lahore, Pakistan.
    Shahzad, Muhammad
    Department of Pharmacology, University of Health Sciences, Lahore, Pakistan.
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ahmad, Irfan
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Institute of Biomedical and Allied Health Sciences, University of Health Sciences, Lahore, Pakistan.
    Emergence of high colistin resistance in carbapenem resistant Acinetobacter baumannii in Pakistan and its potential management through immunomodulatory effect of an extract from Saussurea lappa2022In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 13, article id 986802Article in journal (Refereed)
    Abstract [en]

    Carbapenem resistant Acinetobacter baumannii has emerged as one of the most difficult to treat nosocomial bacterial infections in recent years. It was one of the major causes of secondary infections in Covid-19 patients in developing countries. The polycationic polypeptide antibiotic colistin is used as a last resort drug to treat carbapenem resistant A. baumannii infections. Therefore, resistance to colistin is considered as a serious medical threat. The purpose of this study was to assess the current status of colistin resistance in Pakistan, a country where carbapenem resistant A. bumannii infections are endemic, to understand the impact of colistin resistance on virulence in mice and to assess alternative strategies to treat such infections. Out of 150 isolates collected from five hospitals in Pakistan during 2019–20, 84% were carbapenem resistant and 7.3% were additionally resistant to colistin. There were two isolates resistant to all tested antibiotics and 83% of colistin resistant isolates were susceptible to only tetracycline family drugs doxycycline and minocycline. Doxycycline exhibited a synergetic bactericidal effect with colistin even in colistin resistant isolates. Exposure of A. baumannii 17978 to sub inhibitory concentrations of colistin identified novel point mutations associated with colistin resistance. Colistin tolerance acquired independent of mutations in lpxA, lpxB, lpxC, lpxD, and pmrAB supressed the proinflammatory immune response in epithelial cells and the virulence in a mouse infection model. Moreover, the oral administration of water extract of Saussuria lappa, although not showing antimicrobial activity against A. baumannii in vitro, lowered the number of colonizing bacteria in liver, spleen and lung of the mouse model and also lowered the levels of neutrophils and interleukin 8 in mice. Our findings suggest that the S. lappa extract exhibits an immunomodulatory effect with potential to reduce and cure systemic infections by both opaque and translucent colony variants of A. baumannii.

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  • 32.
    Aili, Margareta
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Isaksson, Elin L
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Carlsson, Sara E
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wolf-Watz, Hans
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Rosqvist, Roland
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Francis, Matthew S
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Regulation of Yersinia Yop-effector delivery by translocated YopE2008In: International Journal of Medical Microbiology, ISSN 1438-4221, E-ISSN 1618-0607, Vol. 298, no 3-4, p. 183-192Article in journal (Refereed)
    Abstract [en]

    The bacterial pathogen Yersinia pseudotuberculosis uses a type III secretion (T3S) system to translocate Yop effectors into eukaryotic cells. Effectors are thought to gain access to the cytosol via pores formed in the host cell plasma membrane. Translocated YopE can modulate this pore formation through its GTPase-activating protein (GAP) activity. In this study, we analysed the role of translocated YopE and all the other known Yop effectors in the regulation of effector translocation. Elevated levels of Yop effector translocation into HeLa cells occurred by YopE-defective strains, but not those defective for other Yop effectors. Only Yersinia devoid of YopK exhibits a similar hyper-translocation phenotype. Since both yopK and yopE mutants also failed to down-regulate Yop synthesis in the presence of eukaryotic cells, these data imply that translocated YopE specifically regulates subsequent effector translocation by Yersinia through at least one mechanism that involves YopK. We suggest that the GAP activity of YopE might be working as an intra-cellular probe measuring the amount of protein translocated by Yersinia during infection. This may be a general feature of T3S-associated GAP proteins, since two homologues from Pseudomonas aeruginosa, exoenzyme S (ExoS) and exoenzyme T (ExoT), can complement the hyper-translocation phenotypes of the yopE GAP mutant.

  • 33.
    Aili, Margareta
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Telepnev, Max
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wolf-Watz, Hans
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rosqvist, Roland
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    In vitro GAP activity towards RhoA, Rac1 and Cdc42 is not a prerequisite for YopE induced HeLa cell cytotoxicity2003In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 34, no 6, p. 297-308Article in journal (Refereed)
    Abstract [en]

    The YopE cytotoxin of Yersinia is an essential virulence determinant that is translocated into the eukaryotic target cell via a plasmid-encoded type III secretion system. YopE possess a GTPase activating protein activity that in vitro has been shown to down regulate RhoA, Rac1, and Cdc42. Translocated YopE induces de-polymerisation of the actin microfilament structure in the eukaryotic cell which results in a rounding up of infected cells described as a cytotoxic effect. Here, we have investigated the importance of different regions of YopE for induction of cytotoxicity and in vitro GAP activity. Sequential removal of the N- and C-terminus of YopE identified the region between amino acids 90 and 215 to be necessary for induction of cytotoxicity. Internal deletions containing the essential arginine at position 144 resulted in a total loss of cytotoxic response. In-frame deletions flanking the arginine finger defined a region important for the cytotoxic effect to amino acids 166–183. Four triple-alanine substitution mutants in this region, YopE166-8A, 169-71A, 175-7A and 178-80A were still able to induce cytotoxicity on HeLa cells although they did not show any in vitro GAP activity towards RhoA, Rac1 or Cdc42. A substitution mutant in position 206-8A showed the same phenotype, ability to induce cytotoxic response but no in vitro GAP activity. We speculate that YopE may have additional unidentified targets within the eukaryotic cell.

  • 34.
    Aira, Naomi
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Andersson, Anna-Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Singh, Susmita K.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Mckay, Derek M.
    University of Calgary, Canada.
    Blomgran, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Species dependent impact of helminth-derived antigens on human macrophages infected with Mycobacterium tuberculosis: Direct effect on the innate anti-mycobacterial response2017In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 3, article id e0005390Article in journal (Refereed)
    Abstract [en]

    Background In countries with a high prevalence of tuberculosis there is high coincident of helminth infections that might worsen disease outcome. While Mycobacterium tuberculosis (Mtb) gives rise to a pro-inflammatory Th1 response, a Th2 response is typical of helminth infections. A strong Th2 response has been associated with decreased protection against tuberculosis. Principal findings We investigated the direct effect of helminth-derived antigens on human macrophages, hypothesizing that helminths would render macrophages less capable of controlling Mtb. Measuring cytokine output, macrophage surface markers with flow cytometry, and assessing bacterial replication and phagosomal maturation revealed that antigens from different species of helminth directly affect macrophage responses to Mtb. Antigens from the tapeworm Hymenolepis diminuta and the nematode Trichuris muris caused an anti-inflammatory response with M2-type polarization, reduced macrophage phagosome maturation and ability to activate T cells, along with increased Mtb burden, especially in T. muris exposed cells which also induced the highest IL-10 production upon co-infection. However, antigens from the trematode Schistosoma mansoni had the opposite effect causing a decrease in IL-10 production, M1-type polarization and increased control of Mtb. Conclusion We conclude that, independent of any adaptive immune response, infection with helminth parasites, in a species-specific manner can influence the outcome of tuberculosis by either enhancing or diminishing the bactericidal function of macrophages.

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  • 35.
    Ajab, Suad
    et al.
    Institute of Public Health, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates.
    Zoughbor, Sumaya
    Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates.
    Labania, Lena
    Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates.
    Olanda, Marie
    Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates.
    Östlundh, Linda
    National Medical Library, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates.
    Al Rasbi, Zakeya
    Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates.
    The role of microbiota in immunotherapy outcomes in colorectal cancer patients: A protocol for a systematic review2022In: PLOS ONE, E-ISSN 1932-6203, Vol. 17, no 8, article id e0273314Article, review/survey (Refereed)
    Abstract [en]

    In the human gut, there are many microbes, including bacteria, viruses and parasites. The imbalance in the numbers of each type of these microbes can translate into gastrointestinal disorders. Lately, different microbiota patterns have been associated with the levels of efficacy of immunotherapy in multiple cancer conditions. Studies have shown that patients with a more diverse gut microbiome respond better to immunotherapy than those with a homogeneous microbiome. This systematic review aims to identify and assess the available evidence on the efficacy of immunotherapy in treating colorectal cancer (CRC) patients and the effect of their microbiota on their treatment outcomes. The researchers will study the literature regarding CRC and immunotherapy outcomes to survey the different approaches employed to assess the treatment outcomes. A systematic search will be performed in five biomedical databases (PubMed, Scopus, Web of Science, Embase, and the Cochrane Library) in June-July, 2022. Also, open-access registers of clinical trials will be trawled. The search will be conducted without geographical or publication date restrictions; however, only papers published in the English language will be sought. Details regarding patients' diets, lifestyles, and characteristics will be assessed. We will define the primary outcome to compare CRC patients' immunotherapy responses with their gut microbiota composition. The systematic review methodology does not require ethics approval due to the nature of the study design. The systematic review results will be published in an open-access peer-reviewed journal.

    PROSPERO ID: CRD42021277691.

  • 36.
    Ajileye, Adebisi
    et al.
    Birmingham Heartlands Hospital, England.
    Alvarez, Nataly
    Corp Invest Biol, Colombia; University of Pontificia Bolivariana, Colombia.
    Merker, Matthias
    Research Centre Borstel, Germany; German Centre Infect Research, Germany.
    Walker, Timothy M.
    University of Oxford, England.
    Akter, Suriya
    Institute Trop Med, Belgium.
    Brown, Kerstin
    Birmingham Heartlands Hospital, England.
    Moradigaravand, Danesh
    Wellcome Trust Sanger Institute, England.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Sweden.
    Andres, Soenke
    Research Centre Borstel, Germany.
    Schleusener, Viola
    Research Centre Borstel, Germany.
    Omar, Shaheed V.
    Centre TB, South Africa.
    Coll, Francesc
    London School Hyg and Trop Med, England.
    Huang, Hairong
    Capital Medical University, Peoples R China.
    Diel, Roland
    University Hospital, Germany.
    Ismail, Nazir
    Centre TB, South Africa.
    Parkhill, Julian
    Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    de Jong, Bouke C.
    Institute Trop Med, Belgium.
    Peto, Tim E. A.
    University of Oxford, England.
    Crook, Derrick W.
    University of Oxford, England; Public Health England Microbiol Serv, England.
    Niemann, Stefan
    Research Centre Borstel, Germany; German Centre Infect Research, Germany.
    Robledo, Jaime
    Corp Invest Biol, Colombia; University of Pontificia Bolivariana, Colombia.
    Grace Smith, E.
    Birmingham Heartlands Hospital, England.
    Peacock, Sharon J.
    Wellcome Trust Sanger Institute, England; London School Hyg and Trop Med, England; University of Cambridge, England.
    Koeser, Claudio U.
    University of Cambridge, England.
    Some Synonymous and Nonsynonymous gyrA Mutations in Mycobacterium tuberculosis Lead to Systematic False-Positive Fluoroquinolone Resistance Results with the Hain GenoType MTBDRsl Assays2017In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, no 4, article id e02169-16Article in journal (Refereed)
    Abstract [en]

    In this study, using the Hain GenoType MTBDRsl assays (versions 1 and 2), we found that some nonsynonymous and synonymous mutations in gyrA in Mycobacterium tuberculosis result in systematic false-resistance results to fluoroquinolones by preventing the binding of wild-type probes. Moreover, such mutations can prevent the binding of mutant probes designed for the identification of specific resistance mutations. Although these mutations are likely rare globally, they occur in approximately 7% of multidrug-resistant tuberculosis strains in some settings.

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  • 37.
    Akaberi, Dario
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Identification of protease inhibitors against Flaviviruses and Coronaviruses2023Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Vector-borne flaviviruses and coronaviruses of zoonotic origins are important human pathogens and represent a serious threat to public health worldwide. Flaviviruses can be found on all continents, apart from Antarctica, where they are transmitted by arthropod vectors causing millions of infections every year. While most of the infections are mild or asymptomatic, flaviviruses like dengue and yellow fever viruses can cause potentially lethal hemorrhagic fever and shock syndrome. Neurotropic flaviviruses like West Nile, Japanese encephalitis, and Tick-borne encephalitis (TBEV) can cause meningoencephalitis with long-term symptoms.  Coronaviruses, and in particular betacoronaviruses of zoonotic origin like SARS (2003) and MERS (2012), have been periodically emerging since the early 2000s causing outbreaks of severe respiratory syndrome. The latest example is SARS-CoV-2 that after causing a cluster of infection in the Chinese city of Wuhan, spread all over the world causing at present over 6.9 million deaths. Although vaccines are essential in preventing infections or severe disease and hospitalization in the case of SARS-CoV-2, antivirals represent an extremely valuable tool for treatment and prevention of current and future flavivirus and coronavirus infections. In the work presented in this thesis we have used a combination of in silico and in vitro techniques to identify and test the activity of potential inhibitors of viral proteases. 

    In our first study (paper 1) we unexpectedly identified an HIV protease inhibitor with in vitro activity against ZIKV NS2B-NS3 protease. The inhibitor was identified by virtual screening of a library of known protease inhibitors, evaluated by molecular dynamics simulation and finally tested against recombinant ZIKV protease using a FRET-based enzymatic assay. The same combination of molecular docking and molecular dynamics simulations were also used to correctly predict the activity of a known pan-Flavivirus protease inhibitor against TBEV protease (paper 2). As a result, we were the first to report peptide-based compounds with in vitro activity against TBEV. 

    After the outbreak of the COVID-19 we switched our attention to SARS-CoV-2. We first tested the inhibitory effect of the broad-spectrum antiviral nitric oxide (NO) and found that the NO-releasing compound SNAP had a dose dependent inhibitory effect on SARS-CoV-2 replication in cell-based assays (paper 3). We speculated that SNAP could inhibit SARS-COV-2 protease by trans-nitration of the catalytic Cys145 of SARS-CoV-2 main protease and found that SNAP had a dose dependent inhibitory effect on recombinant SARS-CoV-2 Mpro protease activity in an in vitro enzymatic assay. In our last study (paper 4) we identified a new class of potent SARS-CoV-2 protease inhibitors through the affinity screening of DNA-encoded-chemical libraries containing 4.2 billion compounds. The identified compounds inhibited recombinant SARS-CoV-2 protease with IC50 as low as 25 nM and had a dose dependent antiviral effect in the low micromolar range in infected Calu-3 and Caco-2 cell lines. 

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  • 38.
    Akbaba, Yusuf
    et al.
    Erzurum Tech Univ, Fac Sci, Dept Basic Sci, Erzurum, Turkiye..
    Kaci, Fatma Necmiye
    Erzurum Tech Univ, Fac Sci, Dept Mol Biol & Genet, Erzurum, Turkiye.;St James Univ Hosp, Univ Leeds, Fac Med & Hlth, Leeds, England..
    Arslan, Mehmet Enes
    Erzurum Tech Univ, Fac Sci, Dept Mol Biol & Genet, Erzurum, Turkiye..
    Goksu, Suleyman
    Ataturk Univ, Fac Sci, Dept Chem, Erzurum, Turkiye..
    Mardinoglu, Adil
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology. Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London, England.;KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Turkez, Hasan
    Ataturk Univ, Fac Med, Dept Med Biol, Erzurum, Turkiye..
    Novel tetrahydronaphthalen-1-yl-phenethyl ureas: synthesis and dual antibacterial-anticancer activities2024In: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374, Vol. 39, no 1, article id 2286925Article in journal (Refereed)
    Abstract [en]

    Cancer and antibiotic-resistant bacterial infections are significant global health challenges. The resistance developed in cancer treatments intensifies therapeutic difficulties. In addressing these challenges, this study synthesised a series of N,N '-dialkyl urea derivatives containing methoxy substituents on phenethylamines. Using isocyanate for the efficient synthesis yielded target products 14-18 in 73-76% returns. Subsequently, their antibacterial and anticancer potentials were assessed. Cytotoxicity tests on cancer cell lines, bacterial strains, and a healthy fibroblast line revealed promising outcomes. All derivatives demonstrated robust antibacterial activity, with MIC values ranging from 0.97 to 15.82 mu M. Notably, compounds 14 and 16 were particularly effective against the HeLa cell line, while compounds 14, 15, and 17 showed significant activity against the SH-SY5Y cell line. Importantly, these compounds had reduced toxicity to healthy fibroblast cells than to cancer cells, suggesting their potential as dual-functioning agents targeting both cancer and bacterial infections.

  • 39. Akkaoui, Sanae
    et al.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Yagoubi, Maâmar
    Haubek, Dorte
    Aarhus University Denmark.
    El Hamidi, Adnane
    Mohammed V University in Rabat, Morocco.
    Rida, Sana
    Mohammed V University in Rabat, Morocco.
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Ennibi, OumKeltoum
    Mohammed V University in Rabat, Morocco.
    Chemical Composition, Antimicrobial activity, in Vitro Cytotoxicity and Leukotoxin Neutralization of Essential Oil from Origanum vulgare against Aggregatibacter actinomycetemcomitans2020In: Pathogens, E-ISSN 2076-0817, Vol. 9, no 3, article id 192Article in journal (Refereed)
    Abstract [en]

    In this study, the essential oil of Origanum vulgare was evaluated for putative antibacterial activity against six clinical strains and five reference strains of Aggregatibacter actinomycetemcomitans, in comparison with some antimicrobials. The chemical composition of the essential oil was analyzed, using chromatography (CG) and gas chromatography-mass spectrometry coupled (CG-MS). The major compounds in the oil were Carvacrol (32.36%), α-terpineol (16.70%), p-cymene (16.24%), and Thymol (12.05%). The antimicrobial activity was determined by an agar well diffusion test. A broth microdilution method was used to study the minimal inhibitory concentration (MIC). The minimal bactericidal concentration (MBC) was also determined. The cytotoxicity of the essential oil (IC50) was <125 µg/mL for THP-1 cells, which was high in comparison with different MIC values for the A. actinomycetemcomitans strains. O. vulgare essential oil did not interfere with the neutralizing capacity of Psidium guajava against the A. actinomycetemcomitans leukotoxin. In addition, it was shown that the O. vulgare EO had an antibacterial effect against A. actinomycetemcomitans on a similar level as some tested antimicrobials. In view of these findings, we suggest that O.vulgare EO may be used as an adjuvant for prevention and treatment of periodontal diseases associated to A. actinomycetemcomitans. In addition, it can be used together with the previously tested leukotoxin neutralizing Psidium guajava.

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  • 40. Akopyan, Karen
    et al.
    Edgren, Tomas
    Wang-Edgren, Helen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rosqvist, Roland
    Fahlgren, Anna
    Wolf-Watz, Hans
    Fallman, Maria
    Translocation of surface-localized effectors in type III secretion2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 4, p. 1639-1644Article in journal (Refereed)
    Abstract [en]

    Pathogenic Yersinia species suppress the host immune response by using a plasmid-encoded type III secretion system (T3SS) to trans- locate virulence proteins into the cytosol of the target cells. T3SS- dependent protein translocation is believed to occur in one step from the bacterial cytosol to the target-cell cytoplasm through a conduit created by the T3SS upon target cell contact. Here, we report that T3SS substrates on the surface of Yersinia pseudotuberculosis are translocated into target cells. Upon host cell contact, purified YopH coated on Y. pseudotuberculosis was specifically and rapidly trans- located across the target-cell membrane, which led to a physiological response in the infected cell. In addition, translocation of externally added YopH required a functional T3SS and a specific translocation domain in the effector protein. Efficient, T3SS-dependent transloca- tion of purified YopH added in vitro was also observed when using coated Salmonella typhimurium strains, which implies that T3SS- mediated translocation of extracellular effector proteins is conserved among T3SS-dependent pathogens. Our results demonstrate that polarized T3SS-dependent translocation of proteins can be achieved through an intermediate extracellular step that can be reconstituted in vitro. These results indicate that translocation can occur by a differ- ent mechanism from the assumed single-step conduit model.

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  • 41. Akyuz, Lalehan
    et al.
    Kaya, Murat
    Koc, Behlul
    Mujtaba, Muhammad
    Ilk, Sedef
    Labidi, Jalel
    Salaberria, Asier M.
    Cakmak, Yavuz Selim
    Yildiz, Aysegul
    Diatomite as a novel composite ingredient for chitosan film with enhanced physicochemical properties2017In: International Journal of Biological Macromolecules, ISSN 0141-8130, E-ISSN 1879-0003, Vol. 105, p. 1401-1411Article in journal (Refereed)
  • 42.
    Al Janabi, Jasmina
    et al.
    School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Tevell, Staffan
    Örebro University, School of Medical Sciences. Department of Infectious Diseases, Karlstad Hospital and Centre for Clinical Research and Education, Region Värmland, Karlstad, Sweden.
    Sieber, Raphael Niklaus
    Department of Bacteria, Parasites and Fungi, Statens Serum Institut, Copenhagen, Denmark.
    Stegger, Marc
    Örebro University, School of Medical Sciences. Department of Bacteria, Parasites and Fungi, Statens Serum Institut, Copenhagen, Denmark.
    Söderquist, Bo
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Emerging resistance in Staphylococcus epidermidis during dalbavancin exposure: a case report and in vitro analysis of isolates from prosthetic joint infections2023In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 78, no 3, p. 669-677Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Dalbavancin, a semisynthetic lipoglycopeptide with exceptionally long half-life and Gram-positive spectrum, is an attractive option for infections requiring prolonged therapy, including prosthetic joint infections (PJIs).

    OBJECTIVES: To investigate the prevalence of reduced susceptibility to dalbavancin in a strain collection of Staphylococcus epidermidis from PJIs, and to investigate genomic variation in isolates with reduced susceptibility selected during growth under dalbavancin exposure.

    METHODS: MIC determination was performed on S. epidermidis isolates from a strain collection (n = 64) and from one patient with emerging resistance during treatment (n = 4). These isolates were subsequently cultured on dalbavancin-containing agar and evaluated at 48 h; MIC determination was repeated if phenotypical heterogeneity was detected during growth. Population analysis profile (PAP-AUC) was performed in isolates where a  ≥ 2-fold increase in MIC was detected, together with corresponding parental isolates (n = 21). Finally, WGS was performed.

    RESULTS: All strains grew at 48 h on agar containing 0.125 mg/L dalbavancin. PAP-AUC demonstrated significant differences between parental and derived strains in four of the eight analysed groups. An amino acid change in the walK gene coinciding with emergence of phenotypic resistance was detected in the patient isolates, whereas no alterations were found in this region in the in vitro derived strains.

    CONCLUSIONS: Exposure to dalbavancin may lead to reduced susceptibility to dalbavancin through either selection of pre-existing subpopulations, epigenetic changes or spontaneous mutations during antibiotic exposure. Source control combined with adequate antibiotic concentrations may be important to prevent emerging reduced susceptibility during dalbavancin treatment.

  • 43.
    Alam, Athar
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Bröms, Jeanette E
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Kumar, Rajender
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    The Role of ClpB in Bacterial Stress Responses and Virulence2021In: Frontiers in Molecular Biosciences, E-ISSN 2296-889X, Vol. 8, article id 668910Article, review/survey (Refereed)
    Abstract [en]

    Bacterial survival within a mammalian host is contingent upon sensing environmental perturbations and initiating an appropriate counter-response. To achieve this, sophisticated molecular machineries are used, where bacterial chaperone systems play key roles. The chaperones are a prerequisite for bacterial survival during normal physiological conditions as well as under stressful situations, e.g., infection or inflammation. Specific stress factors include, but are not limited to, high temperature, osmolarity, pH, reactive oxidative species, or bactericidal molecules. ClpB, a member of class 1 AAA+ proteins, is a key chaperone that via its disaggregase activity plays a crucial role for bacterial survival under various forms of stress, in particular heat shock. Recently, it has been reported that ClpB also regulates secretion of bacterial effector molecules related to type VI secretion systems. In this review, the roles of ClpB in stress responses and the mechanisms by which it promotes survival of pathogenic bacteria are discussed.

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  • 44.
    Alam, Athar
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Golovliov, Igor
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Javed, Eram
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    ClpB mutants of Francisella tularensis subspecies holarctica and tularensis are defective for type VI secretion and intracellular replication2018In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 11324Article in journal (Refereed)
    Abstract [en]

    Francisella tularensis, a highly infectious, intracellular bacterium possesses an atypical type VI secretion system (T6SS), which is essential for the virulence of the bacterium. Recent data suggest that the HSP100 family member, ClpB, is involved in T6SS disassembly in the subspecies Francisella novicida. Here, we investigated the role of ClpB for the function of the T6SS and for phenotypic characteristics of the human pathogenic subspecies holarctica and tularensis. The Delta clpB mutants of the human live vaccine strain, LVS, belonging to subspecies holarctica, and the highly virulent SCHU S4 strain, belonging to subspecies tularensis, both showed extreme susceptibility to heat shock and low pH, severely impaired type VI secretion (T6S), and significant, but impaired intracellular replication compared to the wild-type strains. Moreover, they showed essentially intact phagosomal escape. Infection of mice demonstrated that both Delta clpB mutants were highly attenuated, but the SCHU S4 mutant showed more effective replication than the LVS strain. Collectively, our data demonstrate that ClpB performs multiple functions in the F. tularensis subspecies holarctica and tularensis and its function is important for T6S, intracellular replication, and virulence.

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  • 45.
    Alberti, Jean-Christophe
    et al.
    Univ Corse, Lab Biochim & Biol Mol Vegetales, CNRS SPE UMR6134, Campus Grimaldi,BP52, F-20250 Corte, France.;Univ Toulouse, INSA, UPS, INP,LISBP, 135 Ave Rangueil, F-31077 Toulouse, France..
    Mariani, Magali
    Univ Corse, Lab Biochim & Biol Mol Vegetales, CNRS SPE UMR6134, Campus Grimaldi,BP52, F-20250 Corte, France..
    de Caraffa, Virginie Brunini-Bronzini
    Univ Corse, Lab Biochim & Biol Mol Vegetales, CNRS SPE UMR6134, Campus Grimaldi,BP52, F-20250 Corte, France..
    Gambotti, Claude
    Univ Corse, Lab Biochim & Biol Mol Vegetales, CNRS SPE UMR6134, Campus Grimaldi,BP52, F-20250 Corte, France..
    Oliw, Ernst H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Berti, Liliane
    Univ Corse, Lab Biochim & Biol Mol Vegetales, CNRS SPE UMR6134, Campus Grimaldi,BP52, F-20250 Corte, France..
    Maury, Jacques
    Univ Corse, Lab Biochim & Biol Mol Vegetales, CNRS SPE UMR6134, Campus Grimaldi,BP52, F-20250 Corte, France..
    A functional role identified for conserved charged residues at the active site entrance of lipoxygenase with double specificity2016In: Journal of Molecular Catalysis B: Enzymatic, ISSN 1381-1177, E-ISSN 1873-3158, Vol. 123, p. 167-173Article in journal (Refereed)
    Abstract [en]

    Plant lipoxygenases (LOXs) are a class of widespread dioxygenases catalyzing the hydroperoxidation of free polyunsaturated fatty acids, producing 9-hydroperoxides or 13-hydroperoxides from linoleic and alpha-linolenic acids, and are called 9-LOX or 13-LOX, respectively. Some LOXs produce both 9- and 13- hydroperoxides. The models proposed to explain the reaction mechanism specificity fail to explain the "double specificity" character of these LOXs. In this study, we used the olive LOX1 with double specificity to investigate the implication of the charged residues R265, R268, and K283 in the orientation of the substrate into the active site. These residues are present in a conserved pattern around the entrance of the active site. Our results show that these residues are involved in the penetration of the substrate into the active site: this positive patch could capture the carboxylate end of the substrate, and then guide it into the active site. Due to its position on alpha 2 helix, the residue K283 could have a more important role, its interaction with the substrate facilitating the motions of residues constituting the "cork of lipoxygenases" or the alpha 2 helix, by disrupting putative hydrogen and ionic bonds.

  • 46. Alberto Diaz-Sanchez, Adrian
    et al.
    Corona-Gonzalez, Belkis
    Meli, Marina L.
    Obregon Alvarez, Dasiel
    Vega Canizares, Ernesto
    Fonseca Rodriguez, Osvaldo
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health. Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Centro Nacional de Sanidad Agropecuaria (CENSA), San José de las Lajas, Mayabeque, Cuba.
    Lobo Rivero, Evelyn
    Hofmann-Lehmann, Regina
    First molecular evidence of bovine hemoplasma species (Mycoplasma spp.) in water buffalo and dairy cattle herds in Cuba2019In: Parasites & Vectors, E-ISSN 1756-3305, Vol. 12, article id 78Article in journal (Refereed)
    Abstract [en]

    Background: Hemotropic mycoplasmas (aka hemoplasmas) are small bacteria which cause infectious anemia in several mammalian species including humans. Information on hemoplasma infections in Cuban bovines remains scarce and no studies applying molecular methods have been performed so far. The aim of the present study was to utilize real-time PCR and sequence analysis to investigate dairy cattle and buffalo from Cuba for the presence of bovine hemoplasma species.

    Results: A total of 80 blood samples from 39 buffalo and 41 dairy cattle were investigated for the presence of Mycoplasma wenyonii and Candidatus Mycoplasma haemobos using two species-specific real-time TaqMan PCR assays. PCR results revealed overall 53 (66.2%; 95% CI: 55.3-75.7%) positive animals for M. wenyonii and 33 (41.2%; 95% CI: 31.1-52.2%) for Ca. M. haemobos; the latter were all co-infections with M. wenyonii. The sample prevalences were similar in cattle and buffalo. Based on the sequence analysis of the nearly full-length 16S rRNA gene from two cattle and two buffalo, the presence of M. wenyonii and Ca. M. haemobos was confirmed. Statistical analysis revealed that buffalo and cattle one year of age or older were more frequently infected with M. wenyonii or Ca. M. haemobos than younger animals. PCR-positivity was not associated with anemia; however, the infection stage was unknown (acute infection versus chronic carriers).

    Conclusions: The high occurrence of bovine hemoplasma infections in buffalo and dairy cattle may have a significant impact on Cuban livestock production. To the best of our knowledge, this is the first molecular evidence of bovine hemoplasma species infection in dairy cattle and buffalo from Cuba and the Caribbean.

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  • 47. Aldick, Thomas
    et al.
    Bielaszewska, Martina
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Humpf, Hans-Ulrich
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Karch, Helge
    Vesicular stabilization and activity augmentation of enterohaemorrhagic Escherichia coli haemolysin2009In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 71, no 6, p. 1496-508Article in journal (Refereed)
    Abstract [en]

    Haemolysin from enterohaemorrhagic Escherichia coli (EHEC-Hly), a putative EHEC virulence factor, belongs to the RTX (repeat-in-toxin) family whose members rapidly inactivate themselves by self-aggregation. By investigating the status of EHEC-Hly secreted extracellularly, we found the toxin both in a free, soluble form and associated, with high tendency and independently of its acylation status, to outer membrane vesicles (OMVs) extruded by EHEC. We compared the interaction of both toxin forms with erythrocytes using scanning electron microscopy and binding assays. The OMV-associated toxin was substantially (80 times) more stable under physiological conditions than the free EHEC-Hly as demonstrated by prolonged haemolytic activity (half-life time 20 h versus 15 min). The haemolysis was preceded by calcium-dependent binding of OMVs carrying EHEC-Hly to erythrocytes; this binding was mediated by EHEC-Hly. We demonstrate that EHEC-Hly is a biologically active cargo in OMVs with dual roles: a cell-binding protein and a haemolysin. These paired functions produce a biologically potent form of the OMV-associated RTX toxin and augment its potential towards target cells. Our findings provide a general concept for stabilization of RTX toxins and open new insights into the biology of these important virulence factors.

  • 48.
    Alehagen, Urban
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Opstad, Trine B.
    Oslo Univ Hosp Ulleval, Norway; Univ Oslo, Norway.
    Alexander, Jan
    Norwegian Inst Publ Hlth, Norway.
    Larsson, Anders
    Uppsala Univ, Sweden.
    Aaseth, Jan
    Innlandet Hosp Trust, Norway; Inland Norway Univ Appl Sci, Norway.
    Impact of Selenium on Biomarkers and Clinical Aspects Related to Ageing. A Review2021In: Biomolecules, E-ISSN 2218-273X, Vol. 11, no 10, article id 1478Article, review/survey (Refereed)
    Abstract [en]

    Selenium (Se) is an essential dietary trace element that plays an important role in the prevention of inflammation, cardiovascular diseases, infections, and cancer. Selenoproteins contain selenocysteine in the active center and include, i.a., the enzymes thioredoxin reductases (TXNRD1-3), glutathione peroxidases (GPX1-4 and GPX6) and methionine sulfoxide reductase, involved in immune functions, metabolic homeostasis, and antioxidant defense. Ageing is an inevitable process, which, i.a., involves an imbalance between antioxidative defense and reactive oxygen species (ROS), changes in protein and mitochondrial renewal, telomere attrition, cellular senescence, epigenetic alterations, and stem cell exhaustion. These conditions are associated with mild to moderate inflammation, which always accompanies the process of ageing and age-related diseases. In older individuals, Se, by being a component in protective enzymes, operates by decreasing ROS-mediated inflammation, removing misfolded proteins, decreasing DNA damage, and promoting telomere length. Se-dependent GPX1-4 and TXNRD1-3 directly suppress oxidative stress. Selenoprotein H in the cell nucleus protects DNA, and selenoproteins residing in the endoplasmic reticulum (ER) assist in the removal of misfolded proteins and protection against ER stress. In this review, we highlight the role of adequate Se status for human ageing and prevention of age-related diseases, and further its proposed role in preservation of telomere length in middle-aged and elderly individuals.

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  • 49.
    Alexandra, Olivia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Potential Application of Multiplex Automated Genome Engineering (MAGE) and One-Step Curing Plasmid System for Environmental Cambodian Enterobacterial Isolates2021Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
    Abstract [en]

    Antimicrobial resistance (AMR) is concerning because it limits antimicrobial drug treatment options. AMR occurs by the overuse and misuse of antimicrobial drugs. In environmental settings, AMR can disseminate from places of high use, which leads to increased exposure to humans and animals. A previous study from our laboratory group showed extended-spectrum cephalosporinase-producing Escherichia coli/Klebsiella pneumoniae were isolated from fecal samples obtained in rural Cambodian community settings. Based on these isolates, this study has two aims. The first aim was characterization of selected Cambodian isolates with random amplification polymorphic DNA (RAPD) and antibiotic susceptibility test. From RAPD, the selected six isolates are diverse, except for C61 and C66 bacteria isolates with potential clonality. Additionally, the selected isolates are multidrug resistant (MDR) with reduced susceptibility to beta-lactams and fluoroquinolones. The second aim was to assess two developed methodologies, multiplex automated genome engineering (MAGE) and One-Step Curing Plasmid, by validation in bacteria laboratory strain and development for six Cambodian isolates. To modify AMR genetic elements, MAGE uses pMA7-SacB for homologous recombination with oligos for chromosomal gene disruption. Meanwhile, One-Step Curing Plasmid uses pFREE with the CRISPR/Cas9 system for plasmid and self-curing. Validation showed that MAGE can modify 8% of E. coli MG1655 with lacZ control screening oligos and almost 90% are cured from pFREE. Selected Cambodian isolates have antibiotic-resistance plasmids of IncR or IncFII replicon. For usage in Cambodian isolates, pFREE was modified to be pCAM-FREE by cloning IncR and IncFII plasmid as gRNA1 and gRNA5, respectively. Sequencing results showed pCAM-FREE have gRNA5. In conclusion, our study managed to characterize selected Cambodian isolates as MDR and diverse. In a laboratory strain, MAGE and One-Step Curing Plasmid are functional methods. Furthermore, pCAM-FREE was constructed to target IncFII and in the future, MAGE and pCAM-FREE could be tested in Cambodian isolates.  

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  • 50.
    Alfaifi, Sarah
    et al.
    Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
    Suliman, Rania
    Department of Clinical Laboratory Sciences, Prince Sultan Military College of Health Sciences, Dhahran, Saudi Arabia.
    Idriss, Mona Timan
    Department of Pharmaceutics, Faculty of Pharmacy, Imperial University College, Khartoum, Sudan; Department of Medical Sciences and Preparation Year, Northern College of Nursing, Arar, Saudi Arabia.
    Aloufi, Abeer S.
    Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
    Alolayan, Ebtesam
    Department of Zoology, King Saud University, Riyadh, Saudi Arabia.
    Awadalla, Maaweya
    Research Center, King Fahad Medical City, Riyadh, Saudi Arabia.
    Aodah, Alhassan
    Life Science & Environment Research Institute, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
    Asab, Omar Abu
    Life Science & Environment Research Institute, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
    Al-Qahtani, Jarallah
    Department of Histopathology, King Fahad Military Medical Complex, Dhahran, Saudi Arabia.
    Mohmmed, Nahla
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Alosaimi, Bandar
    Research Center, King Fahad Medical City, Riyadh, Saudi Arabia.
    In vivo Evaluation of the Antiviral Effects of Arabian Coffee (Coffea arabica) and Green Tea (Camellia sinensis) Extracts on Influenza A Virus2023In: International Journal of Biomedicine, ISSN 2158-0510, Vol. 13, no 3, p. 154-161Article in journal (Refereed)
    Abstract [en]

    This in vivo study was conducted to evaluate the antiviral activity of Arabian coffee (Coffea arabica) and green tea (Camellia sinensis) extracts against the influenza virus. High-performance liquid chromatography (HPLC) was used to determine the active components in each extract, and eighty experimental mice were treated. Electrophoresis was performed to detect protein expression, and reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze gene expression and quantify viral RNA. Lung tissue histopathology was processed to observe pathological signs. Oral administration of all extracts reduced the viral quantification in mice lungs by 61.6% in the early phase of infection, measured by PCR. From the extracts tested, unroasted green Arabica coffee (AC) extract in protective groups showed remarkable body weight stability of 16.76 g, a survival rate of 100%, and healthier lung tissue, compared to other groups. The antiviral effects of the tested AC and GT (green tea) revealed that AC extracts induced veridical effects, increased body weight, and improved survival rate. Those natural extracts may interfere with viral replication and reduce virus infection. The observed anti-influenza activity demonstrated by reduced symptoms and increased survival rate in animal models suggests that AC extracts might be used as a promising prophylactic agent against influenza viral infections. The active compound in the unroasted green AC extract requires further in vitro analysis as to which viral proteins are targeted by the natural extract and which molecular mechanism this antiviral inhibition is interfering with.

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