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Frank A. DeLano, Geert W. Schmid-Schönbein
PLoS One Infectious Diseases, 18.10.2024
Tilføjet 18.10.2024
by Frank A. DeLano, Geert W. Schmid-Schönbein The mechanism that triggers the progressive dysregulation of cell functions, inflammation, and breakdown of tissues during aging is currently unknown. We propose here a previously unknown mechanism due to tissue autodigestion by the digestive enzymes. After synthesis in the pancreas, these powerful enzymes are activated and transported inside the lumen of the small intestine to which they are compartmentalized by the mucin/epithelial barrier. We hypothesize that this barrier leaks active digestive enzymes (e.g. during meals) and leads to their accumulation in tissues outside the gastrointestinal tract. Using immune-histochemistry we provide evidence in young (4 months) and old (24 months) rats for significant accumulation of pancreatic trypsin, elastase, lipase, and amylase in peripheral organs, including liver, lung, heart, kidney, brain, and skin. The mucin layer density on the small intestine barrier is attenuated in the old and trypsin leaks across the tip region of intestinal villi with depleted mucin. The accumulation of digestive enzymes is accompanied in the same tissues of the old by damage to collagen, as detected with collagen fragment hybridizing peptides. We provide evidence that the hyperglycemia in the old is accompanied by proteolytic cleavage of the extracellular domain of the insulin receptor. Blockade of pancreatic trypsin in the old by a two-week oral treatment with a serine protease inhibitor (tranexamic acid) serves to significantly reduce trypsin accumulation in organs outside the intestine, collagen damage, as well as hyperglycemia and insulin receptor cleavage. These results support the hypothesis that the breakdown of tissues in aging is due to autodigestion and a side-effect of the fundamental requirement for digestion.
Læs mere Tjek på PubMedGarcia, Bruno; Ter Schiphorst, Benoit; Su, Fuhong; Picod, Adrien; Ikenna-Uba, Theo; Favory, Raphaël; Annoni, Filippo; Mebazaa, Alexandre; Vincent, Jean-Louis; Creteur, Jacques; Taccone, Fabio S.; Herpain, Antoine
Critical Care Explorations, 17.10.2024
Tilføjet 17.10.2024
OBJECTIVES: To analyze dynamic changes in the renin-angiotensin system (RAS) during septic shock, focusing on angiotensin-converting enzyme (ACE) activity and the balance between angiotensin peptides, using a mass spectrometry method. DESIGN: Experimental septic shock model induced by peritonitis in swine. SETTING: Experimental Laboratory, Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles. SUBJECTS: Forty time points from eight mechanically ventilated pigs. INTERVENTIONS: Septic shock was induced using intraperitoneal instillation of autologous feces, followed by standardized fluid resuscitation, norepinephrine infusion, antibiotic administration, and peritoneal lavage. MEASUREMENTS AND MAIN RESULTS: The induction of sepsis resulted in a significant increase in plasma renin activity and levels of angiotensin I and II, with a significant decrease in ACE activity observed from 4 hours post-resuscitation and a notable rise in the angiotensin I/angiotensin II ratio at 12 hours. Additionally, a shift toward the angiotensin-(1–7) axis was observed, evidenced by an increased angiotensin-(1–7)/angiotensin II ratio. CONCLUSIONS: The study highlighted dynamic shifts in the RAS during septic shock, characterized by reduced circulating ACE activity, elevated angiotensin I/II ratio, and a shift toward the angiotensin-(1–7) axis. These findings suggest an adaptive response within the RAS, potentially offering new insights into sepsis management and therapeutic targets.
Læs mere Tjek på PubMedChunyan Guo, Cuixiang Xu, Qing Feng, Xin Xie, Yan Li, Xiangrong Zhao, Jun Hu, Senbiao Fang, Lijun Shang
Journal of Medical Virology, 15.10.2024
Tilføjet 15.10.2024
Anne GreifenhagenHannes RuweVictoria ZimmerJana MesserschmidtDurga Prasad Naik BhukyaHawi Deressa KeneaAndreas SchallerThomas SpallekaDepartment of Plant Physiology and Biochemistry, University of Hohenheim, Stuttgart 70599, GermanybPlant Biotic Interactions Group, Albrecht-von-Haller Institute of Plant Sciences, Göttinger Zentrum für Molekulare Biowissenschaften (GZMB), University of Göttingen, Göttingen 37077, Germany
Proceedings of the National Academy of Sciences, 12.10.2024
Tilføjet 12.10.2024
Proceedings of the National Academy of Sciences, Volume 121, Issue 42, October 2024.
Læs mere Tjek på PubMedJournal of Infectious Diseases, 12.10.2024
Tilføjet 12.10.2024
Abstract Background Rising incidence of invasive beta-haemolytic streptococcal (iBHS) infections has prompted consideration of vaccination as a preventative strategy for at-risk populations. The benefits of a vaccine targeting Lancefield group A (Streptococcus pyogenes; Strep A) would increase if cross-species immunity against Lancefield groups C/G (Streptococcus dysgalactiae subspecies equisimilis; SDSE) and B (Streptococcus agalactiae; GBS) was demonstrated.Methods A prospective, observational study of adult patients with iBHS infections due to Strep A, SDSE or GBS. Antibody responses to six Strep A candidate antigens were assayed on acute and convalescent sera. A serological response was defined as an increase of >0.2log10 arbitrary units/mL (AU/mL).Results Sixty-seven participants were enrolled. Thirty-three participants were included in the final analysis (12, 11 and 10 with Strep A, SDSE and GBS, respectively). The median serological response for participants with Strep A was significant for all tested antigens (median >0.2log10 difference between acute and convalescent samples; P
Læs mere Tjek på PubMedOkegbe, Tishina; Bishop, Kristina Monroe; Rose, Jessica; Srivastava, Meena; Baptiste, Anne Jean
Journal of Acquired Immune Deficiency Syndromes, 10.10.2024
Tilføjet 10.10.2024
Introduction: Adolescents 10-19 years account for a growing proportion of people living with HIV (PLHIV). In 2023, 140,000 adolescents were diagnosed with HIV, yet knowledge of HIV status and uptake of testing services remain critically low. Index testing – offering testing to contacts of PLHIV – is an important case-finding strategy. In 2021, PEPFAR expanded guidance to explicitly include older adolescents 15 to 19 years. We reviewed index testing data to assess uptake and case-finding trends among biological adolescent-aged children and siblings of PLHIV 10-19 years. Methods: Routinely collected programmatic data from 27 USAID-supported PEPFAR country and regional programs were analyzed for fiscal years (FY) 2017 through FY2022 (October 2016 - September 2022). We compared the volume of index testing and subsequent new diagnoses across FYs and countries among biological adolescent-aged children and siblings of PLHIV, and disaggregated by age, 10-14 and 15-19 years, and sex. Results: Index testing among adolescents 10-19 years increased from FY17 to FY22, nearly doubling from 147,088 to 291,534. Similarly, new diagnoses among adolescents increased between FY17 and FY22 (3,721 vs 10,730). Overall, across FYs, index testing uptake and case-finding were higher among females than males, and the gap in testing uptake between sexes was larger for older than younger adolescents. Conclusion: Index testing uptake has increased substantially among adolescents over time, with rebounded gains for adolescents 15-19 years noted beginning in FY21. However, uptake across age and sex remained uneven, highlighting an opportunity to ensure targeted testing strategies are employed to reach adolescents 15-19 years and males. Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.
Læs mere Tjek på PubMedSorum, M. E., Gang, A. O., Tholstrup, D. M., Gudbrandsdottir, S., Kissow, H., Kornblit, B., Müller, K., Knop, F. K.
BMJ Open, 10.10.2024
Tilføjet 10.10.2024
IntroductionCancer treatment with high-dose chemotherapy damages the mucosal barrier of the gastrointestinal (GI) tract and is associated with severe toxicity involving mucositis, severe inflammation and organ dysfunction. Currently, there is no effective prophylaxis against this. Glucagon-like peptide 1 (GLP-1), a well-known regulator of blood glucose, has been suggested in mouse studies to possess trophic effects on gut epithelial cells as well as anti-inflammatory properties. In line with this, endogenous GLP-1 levels have been shown to be inversely correlated with toxicities after haematopoietic stem cell transplantation (HSCT) and treatment with a GLP-1 receptor agonist (GLP-1RA) was shown to limit chemotherapy-induced mucositis in rodents. This present study investigates the effects of the GLP-1RA semaglutide on GI mucositis severity score in patients with lymphoma undergoing high-dose chemotherapy followed by autologous (auto) HSCT. Methods and analysisThis is a randomised, double-blind, placebo-controlled, two-centre investigator-initiated clinical study. Forty adult patients with malignant lymphoma referred for auto-HSCT will be randomised in a 1:1 manner to receive either semaglutide or placebo once-weekly for 8 weeks. This includes a run-in period of 3–4 weeks with semaglutide 0.25 mg prior to high-dose chemotherapy treatment followed by a period of 4–5 weeks with semaglutide 0.5 mg including the 1 week of high-dose chemotherapy treatment. Clinical assessment of endpoint measurements and safety will be performed weekly during treatment and in a follow-up period of 10 weeks. The primary endpoint is GI mucositis severity (mean severity grade (0–II) during week 1–4 after auto-HSCT). Secondary endpoints include C-reactive protein increment, quality of life and safety. Fever, bacteraemia, antibiotic use, weight loss, morphine consumption, duration of hospitalisation, use of parenteral nutrition, change in muscle mass and clinical and laboratory evidence of organ toxicities will also be assessed. Ethics and disseminationThe study complies with Danish and European Union legislation and is approved by the Danish Medicines Agency, the Danish National Medical Research Ethics Committee (EU CT #2022-502139-20-00) and the Danish Data Protection Agency. The study is monitored by the Capital Region of Denmark’s good clinical practice unit. All results, positive, negative and inconclusive, will be disseminated at national and international scientific meetings and in peer-reviewed scientific journals. Trial registration numberNCT06449625
Læs mere Tjek på PubMedAbraham O. OluwoleNeha V. KalmankarMichela GuidaJack L. BennettGiovanna PoceJani R. BollaCarol V. RobinsonaDepartment of Chemistry, University of Oxford, Oxford OX1 3QZ, United KingdombThe Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, United KingdomcDepartment of Chemistry and Technologies of Drug, Sapienza University of Rome, Rome 00185, ItalydDepartment of Biology, University of Oxford, Oxford OX1 3RB, United Kingdom
Proceedings of the National Academy of Sciences, 10.10.2024
Tilføjet 10.10.2024
Proceedings of the National Academy of Sciences, Volume 121, Issue 41, October 2024.
Læs mere Tjek på PubMedNatalie Pach, Michael Basler
Frontiers in Immunology, 8.10.2024
Tilføjet 8.10.2024
BackgroundDefective ribosomal products (DRiPs) are non-functional proteins rapidly degraded during or after translation being an essential source for MHC class I ligands. DRiPs are characterized to derive from a substantial subset of nascent gene products that degrade more rapidly than their corresponding native retiree pool. So far, mass spectrometry analysis revealed that a large number of HLA class I peptides derive from DRiPs. However, a specific viral DRiP on protein level was not described. In this study, we aimed to characterize and identify DRiPs derived from a viral protein.MethodsUsing the nucleoprotein (NP) of the lymphocytic choriomeningitis virus (LCMV) which is conjugated N–terminally to ubiquitin, or the ubiquitin-like modifiers FAT10 or ISG15 the occurrence of DRiPs was studied. The formation and degradation of DRiPs was monitored by western blot with the help of a FLAG tag. Flow cytometry and cytotoxic T cells were used to study antigen presentation.ResultsWe identified several short lived DRiPs derived from LCMV-NP. Of note, these DRiPs could only be observed when the LCMV–NP was modified with ubiquitin or ubiquitin-like modifiers, but not in the wild type form. Using proteasome inhibitors, we could show that degradation of LCMV-NP derived DRiPs were proteasome dependent. Interestingly, the synthesis of DRiPs could be enhanced when cells were stressed with the help of FCS starvation. An enhanced NP118–126 presentation was observed when the LCMV-NP was modified with ubiquitin or ubiquitin-like modifiers, or under FCS starvation.ConclusionTaken together, we visualize for the first time DRiPs derived from a viral protein. Furthermore, DRiPs formation, and therefore MHC-I presentation, is enhanced under cellular stress conditions. Our investigations on DRiPs in MHC class I antigen presentation open up new approaches for the development of vaccination strategies.
Læs mere Tjek på PubMedMichel Siegel, Aman Padamsey, Anna-Lena Bolender, Patrick Hargreaves, Johannes Fraidling, Axel Ducret, Katharina Hartman, Cary M. Looney, Cristina Bertinetti-Lapatki, Olivier Rohr, Timothy P. Hickling, Thomas E. Kraft, Céline Marban-Doran
Frontiers in Immunology, 8.10.2024
Tilføjet 8.10.2024
IntroductionImmunogenicity refers to the ability of a substance, such as a therapeutic drug, to elicit an immune response. While beneficial in vaccine development, undesirable immunogenicity can compromise the safety and efficacy of therapeutic proteins by inducing anti-drug antibodies (ADAs). These ADAs can reduce drug bioavailability and alter pharmacokinetics, necessitating comprehensive immunogenicity risk assessments starting at early stages of drug development. Given the complexity of immunogenicity, an integrated approach is essential, as no single assay can universally recapitulate the immune response leading to the formation of anti-drug antibodies.MethodsTo better understand the Dendritic Cell (DC) contribution to immunogenicity, we developed two flow cytometry-based assays: the DC internalization assay and the DC activation assay. Monocyte-derived dendritic cells (moDCs) were generated from peripheral blood mononuclear cells (PBMCs) and differentiated over a five-day period. The internalization assay measured the accumulation rate of therapeutic antibodies within moDCs, while the activation assay assessed the expression of DC activation markers such as CD40, CD80, CD86, CD83, and DC-SIGN (CD209). To characterize these two assays further, we used a set of marketed therapeutic antibodies.ResultsThe study highlights that moDCs differentiated for 5 days from freshly isolated monocytes were more prone to respond to external stimuli. The internalization assay has been shown to be highly sensitive to the molecule tested, allowing the use of only 4 donors to detect small but significant differences. We also demonstrated that therapeutic antibodies were efficiently taken up by moDCs, with a strong correlation with their peptide presentation on MHC-II. On the other hand, by monitoring DC activation through a limited set of activation markers including CD40, CD83, and DC-SIGN, the DC activation assay has the potential to compare a series of compounds. These two assays provide a more comprehensive understanding of DC function in the context of immunogenicity, highlighting the importance of both internalization and activation processes in ADA development.DiscussionThe DC internalization and activation assays described here address key gaps in existing immunogenicity assessment methods by providing specific and reliable measures of DC function. The assays enhance our ability to pre-clinically evaluate the immunogenic potential of biotherapeutics, thereby improving their safety and efficacy. Future work should focus on further validating these assays and integrating them into a holistic immunogenicity risk assessment framework.
Læs mere Tjek på PubMedMiriana d’Alessandro, Paolo Cameli, Caroline V. Cotton, Janine A. Lamb, Laura Bergantini, Sara Gangi, Sarah Sugden, Lisa G. Spencer, Bruno Frediani, Robert P. New, Hector Chinoy, Elena Bargagli, Edoardo Conticini
PLoS One Infectious Diseases, 3.10.2024
Tilføjet 3.10.2024
by Miriana d’Alessandro, Paolo Cameli, Caroline V. Cotton, Janine A. Lamb, Laura Bergantini, Sara Gangi, Sarah Sugden, Lisa G. Spencer, Bruno Frediani, Robert P. New, Hector Chinoy, Elena Bargagli, Edoardo Conticini Background Interstitial lung disease (ILD) may complicate the course of systemic autoimmune rheumatic disease (SARD) and diagnostic biomarkers are needed. Krebs von den Lungen-6 (KL-6), ferritin (FER) and interleukin 6 (IL-6) have been involved in the ILD development. Our study aimed to compare KL-6, FER, IL-6 and soluble mesothelin-related peptide (SMRP) concentrations in a cohort of idiopathic and SARD-ILD. Methods 3169 patients were enrolled in the “UK Biomarkers in Interstitial Lung Disease (UK-BILD) Study”. We selected patients affected by SARD-ILD and idiopathic ILD (usual interstitial pneumonia-idiopathic pulmonary fibrosis and fibrotic non-specific interstitial pneumonia). Serum marker concentrations were measured through chemiluminescent assays (Fujirebio Europe, Ghent, Belgium). Results 1013 patients were selected for the study: 520 (51.3%) had idiopathic ILD and 493 (48.7%) SARD-ILD. Idiopathic ILD patients displayed higher KL-6 values than SARD-ILD (p = 0.0002). FER and SMRP, though within normal ranges, were significantly higher in idiopathic ILD (p
Læs mere Tjek på PubMedBMC Infectious Diseases, 3.10.2024
Tilføjet 3.10.2024
Abstract Background The prevalence of Helicobacter pylori (H. pylori) infection and its potential relationship to various diseases is currently a focus of attention. The aim of this study is to investigate the association between current and past H. pylori infections and elevated levels of microalbuminuria in type 2 diabetic patients. Methods Two hundred patients with type 2 diabetes mellitus were tested for the presence of H. pylori infection. They were divided into three groups: 52 had a current H. pylori infection, 38 had a past H. pylori infection, and 110 had no H. pylori infection. All study participants underwent assessments of plasma glucose levels, glycated hemoglobin (HbA1c), albuminuria levels, inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), as well as other relevant investigations. Results The prevalence of H. pylori infection (current and past) was detected in 90 out of 200 diabetic patients (45%). There was no statistically significant difference between the three groups in terms of age, diabetes duration, family history of DM, family history of hypertension, residence, or dyspeptic symptoms, indicating that current or past infection with H. pylori has no association with these variables. The current H. pylori infection group showed the highest levels of inflammatory markers, ESR and CRP, which were significantly different from those in the non-infected group (p = 0.013 and p
Læs mere Tjek på PubMedBMC Infectious Diseases, 3.10.2024
Tilføjet 3.10.2024
Abstract Background and objective To diagnose tuberculosis infection (TBI), whole blood is incubated with M.tuberculosis (Mtb)-specific peptides and the release of interferon-γ (IFN-γ) is measured in IFN-γ-release assays (IGRAs). Hyperglycaemia and fluctuations in blood glucose may modulate IFN-γ-release. Here, we investigated if glucose intake affects IFN-γ-release or IGRA results in IGRAs taken during an oral glucose tolerance test (OGTT). Methods Persons with TB disease (TB) or TBI underwent a standard 75-g OGTT at the start and end of treatment for TB or TBI. Blood for the IGRA QuantiFERON-TB Gold Plus (QFT) containing Mtb-specific tubes (TB1 and TB2), a non-specific mitogen tube (MIT) and an empty control tube (NIL) was drawn at sample-timepoints -15 (baseline), 60, 90, 120 and 240 min during the OGTT. Blood glucose was measured in parallel at all timepoints. IFN-γ-release (after subtraction of NIL) at each timepoint was compared with baseline using linear-mixed-model analysis. Results Twenty-four OGTTs from 14 participants were included in the final analysis. Compared to baseline, IFN-γ-release was increased at sample-timepoint 240 min for TB1; geometric mean (95% confidence interval) 3.0 (1.5–6.2) vs 2.5 (1.4–4.4) IU/mL (p = 0.047), and MIT; 182.6 (103.3–322.9) vs 146.0 (84.0–254.1) IU/mL (p = 0.002). Plasma glucose levels were not associated with IFN-γ-release and the QFT test results were unaffected by the OGTT. Conclusion Ingestion of glucose after a 10-h fast was associated with increased IFN-γ-release after 240 min in the MIT tube. However, there was no association between plasma glucose levels at the QFT sampling timepoint and IFN-γ-release. Furthermore, the QFT test results were not affected by glucose intake. The overall effect of an OGTT and prevailing plasma glucose levels on IFN-γ-release in IGRAs seem limited. Trial registration Trial registration ID: NCT04830462 (https://clinicaltrials.gov/study/NCT04830462). Registration date: 05-Apr-2021.
Læs mere Tjek på PubMedBMC Infectious Diseases, 2.10.2024
Tilføjet 2.10.2024
Abstract Background The prevalence of Helicobacter pylori (H. pylori) infection and its potential relationship to various diseases is currently a focus of attention. The aim of this study is to investigate the association between current and past H. pylori infections and elevated levels of microalbuminuria in type 2 diabetic patients. Methods Two hundred patients with type 2 diabetes mellitus were tested for the presence of H. pylori infection. They were divided into three groups: 52 had a current H. pylori infection, 38 had a past H. pylori infection, and 110 had no H. pylori infection. All study participants underwent assessments of plasma glucose levels, glycated hemoglobin (HbA1c), albuminuria levels, inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), as well as other relevant investigations. Results The prevalence of H. pylori infection (current and past) was detected in 90 out of 200 diabetic patients (45%). There was no statistically significant difference between the three groups in terms of age, diabetes duration, family history of DM, family history of hypertension, residence, or dyspeptic symptoms, indicating that current or past infection with H. pylori has no association with these variables. The current H. pylori infection group showed the highest levels of inflammatory markers, ESR and CRP, which were significantly different from those in the non-infected group (p = 0.013 and p
Læs mere Tjek på PubMedRoxana Hossain, Glenda Willems, Niels Wynant, Simon Borgolte, Kristof Govaerts, Mark Varrelmann
PLoS One Infectious Diseases, 2.10.2024
Tilføjet 2.10.2024
by Roxana Hossain, Glenda Willems, Niels Wynant, Simon Borgolte, Kristof Govaerts, Mark Varrelmann Beet yellows virus (BYV), one of the causal agents of virus yellows (VY) disease in sugar beet (Beta vulgaris subsp. vulgaris), induces economically important damage to the sugar production in Europe. In the absence of effective natural resistance traits, a deeper understanding of molecular reactions in plants to virus infection is required. In this study, the transcriptional modifications in a BYV susceptible sugar beet genotype following aphid-mediated inoculation on mature leaves were studied at three early infection stages [6, 24 and 72 hours post inoculation (hpi)] using RNA sequencing libraries. On average, 93% of the transcripts could be mapped to the B. vulgaris reference genome RefBeet-1.2.2. In total, 588 differentially expressed genes (DEGs) were identified across the three infection stages. Of these, 370 were up- regulated and 218 down-regulated when individually compared to mock-aphid inoculated leaf samples at the same time point, thereby eliminating the effect of aphid feeding itself. Using MapMan ontology for categorisation of sugar beet transcripts, early differential gene expression identified importance of the BIN categories “enzyme classification”, “RNA biosynthesis”, “cell wall organisation” and “phytohormone action”. A particularly high transcriptional change was found for diverse transcription factors, cell wall regulating proteins, signalling peptides and transporter proteins. 28 DEGs being important in “nutrient uptake”, “lipid metabolism”, “phytohormone action”, “protein homeostasis” and “solute transport”, were represented at more than one infection stage. The RT-qPCR validation of thirteen selected transcripts confirmed that BYV is down-regulating chloroplast-related genes 72 hpi, putatively already paving the way for the induction of yellowing symptoms characteristic for the disease. Our study provides deeper insight into the early interaction between BYV and the economically important crop plant sugar beet and opens up the possibility of using the knowledge of identified proviral plant factors as well as plant defense-related factors for resistance breeding.
Læs mere Tjek på PubMedBMC Infectious Diseases, 1.10.2024
Tilføjet 1.10.2024
Abstract Background and objective To diagnose tuberculosis infection (TBI), whole blood is incubated with M.tuberculosis (Mtb)-specific peptides and the release of interferon-γ (IFN-γ) is measured in IFN-γ-release assays (IGRAs). Hyperglycaemia and fluctuations in blood glucose may modulate IFN-γ-release. Here, we investigated if glucose intake affects IFN-γ-release or IGRA results in IGRAs taken during an oral glucose tolerance test (OGTT). Methods Persons with TB disease (TB) or TBI underwent a standard 75-g OGTT at the start and end of treatment for TB or TBI. Blood for the IGRA QuantiFERON-TB Gold Plus (QFT) containing Mtb-specific tubes (TB1 and TB2), a non-specific mitogen tube (MIT) and an empty control tube (NIL) was drawn at sample-timepoints -15 (baseline), 60, 90, 120 and 240 min during the OGTT. Blood glucose was measured in parallel at all timepoints. IFN-γ-release (after subtraction of NIL) at each timepoint was compared with baseline using linear-mixed-model analysis. Results Twenty-four OGTTs from 14 participants were included in the final analysis. Compared to baseline, IFN-γ-release was increased at sample-timepoint 240 min for TB1; geometric mean (95% confidence interval) 3.0 (1.5–6.2) vs 2.5 (1.4–4.4) IU/mL (p = 0.047), and MIT; 182.6 (103.3–322.9) vs 146.0 (84.0–254.1) IU/mL (p = 0.002). Plasma glucose levels were not associated with IFN-γ-release and the QFT test results were unaffected by the OGTT. Conclusion Ingestion of glucose after a 10-h fast was associated with increased IFN-γ-release after 240 min in the MIT tube. However, there was no association between plasma glucose levels at the QFT sampling timepoint and IFN-γ-release. Furthermore, the QFT test results were not affected by glucose intake. The overall effect of an OGTT and prevailing plasma glucose levels on IFN-γ-release in IGRAs seem limited. Trial registration Trial registration ID: NCT04830462 (https://clinicaltrials.gov/study/NCT04830462). Registration date: 05-Apr-2021.
Læs mere Tjek på PubMedReid, Michael J A; Bunnell, Rebecca; Davis, Marie; Carter, Hillary; Bartee, Maureen; Marrufo, Tatiana; Nkengasong, John
AIDS, 28.09.2024
Tilføjet 28.09.2024
Yousheng Peng, Chenchen Li, Xueke Hui, Xiaoning Huo, Nigus Abebe Shumuyed, Zhong Jia
PLoS One Infectious Diseases, 28.09.2024
Tilføjet 28.09.2024
by Yousheng Peng, Chenchen Li, Xueke Hui, Xiaoning Huo, Nigus Abebe Shumuyed, Zhong Jia Tuberculosis has posed a serious threat to human health. It is imperative to investigate the geographic prevalence of tuberculosis and medication resistance, as this information is essential for informing strategies for its prevention and treatment. Drug resistance was identified using a proportion method. Drug-resistant genes and pathways were predicted using whole genome sequencing. The drug resistance range of bedaquiline was identified using the microporous plate two-fold dilution method, and drug resistance genes were studied using sequencing. The study revealed that 19.99% of the tuberculosis cases had multidrug resistance. The genes of M. tuberculosis are predominantly involved in the synthesis of ABC transporters, two-component systems, and bacterial secretion systems, as well as in energy production and conversion, and lipid transport and metabolism. The genes encode for 82.45% of carbohydrate-related enzymes such as glycoside hydrolases, glycosyl transferases, and carbohydrate esterases. The minimum inhibitory concentration (MIC) of bedaquiline against clinical strains was approximately 0.06 μg/mL, with identified mutations in drug-resistant genes Rv0678, atpE, and pepQ, specifically V152A, P62A, and T222N, respectively. The multidrug resistance tuberculosis development was attributed to the strong medication resistance exhibited. It was concluded that tuberculosis had presented a high level of drug resistance. Phenotypic resistance was related to genes, existing potential genetic resistance in M. tuberculosis. Bedaquiline was found to possess effective antibacterial properties against M. tuberculosis.
Læs mere Tjek på PubMedEdouard Tuaillon, Mwiya Mwyia, Karine Bollore, Amandine Pisoni, Pierre-Alain Rubbo, Matthias Richard, Laurent Kremer, Maria M.W. Tonga, Duncan M. Chanda, Marianne Peries, Roselyne Vallo, Sabrina Eymard-Duvernay, Morgana D'Ottavi, Chipepo Kankasa, Philippe Van de Perre, Jean-Pierre Moles, Nicolas Nagot
International Journal of Infectious Diseases, 27.09.2024
Tilføjet 27.09.2024
This study suggests that supplementing the QuantiFERON assay with a combination of serological and T-cell markers could enhance childhood TB screening regardless of the HIV status and age. Further validation among the target population is necessary to confirm the performance of this scoring system.
Læs mere Tjek på PubMedCunxi Wang, Meiying Zheng, Chandler Est, Remi Lawal, Wenguang Liang, David A. Korasick, Michael J. Rau, Scott A. Saracco, Virginia Johnson, Yanfei Wang, Tommi White, Wenze Li, Jun Zhang, Xin Gu, Flora Liu-Gontarek
PLoS One Infectious Diseases, 27.09.2024
Tilføjet 27.09.2024
by Cunxi Wang, Meiying Zheng, Chandler Est, Remi Lawal, Wenguang Liang, David A. Korasick, Michael J. Rau, Scott A. Saracco, Virginia Johnson, Yanfei Wang, Tommi White, Wenze Li, Jun Zhang, Xin Gu, Flora Liu-Gontarek Transgenic soybean, cotton, and maize tolerant to protoporphyrinogen IX oxidase (PPO)-inhibiting herbicides have been developed by introduction of a bacterial-derived PPO targeted into the chloroplast. PPO is a membrane-associated protein with an intrinsic tendency for aggregation, making expression, purification, and formulation at high concentrations difficult. In this study, transgenic PPO expressed in three crops was demonstrated to exhibit up to a 13 amino acid sequence difference in the N-terminus due to differential processing of the chloroplast transit peptide (CTP). Five PPO protein variants were produced in and purified from E. coli, each displaying equivalent immunoreactivity and functional activity, with values ranging from 193 to 266 nmol min-1 mg-1. Inclusion of an N-terminal 6xHis-tag or differential processing of the CTP peptide does not impact PPO functional activity. Additionally, structural modeling by Alphafold, ESMfold, and Openfold indicates that these short N-terminal extensions are disordered and predicted to not interfere with the mature PPO structure. These results support the view that safety studies on PPO from various crops can be performed from a single representative variant. Herein, we report a novel and robust method for large-scale production of PPO, enabling rapid production of more than 200 g of highly active PPO protein at 99% purity and low endotoxin contamination. We also present a formulation that allows for concentration of active PPO to > 75 mg/mL in a buffer suitable for mammalian toxicity studies.
Læs mere Tjek på PubMedHairong Jia, Wenhao Su, Jiaqi Zhang, Zhaoyang Wei, Pepertual Tsikwa, Yanru Wang
PLoS One Infectious Diseases, 27.09.2024
Tilføjet 27.09.2024
by Hairong Jia, Wenhao Su, Jiaqi Zhang, Zhaoyang Wei, Pepertual Tsikwa, Yanru Wang Introduction Type 2 diabetes mellitus (T2DM) is a frequent chronic condition among the elderly, which increasing their susceptibility to infection. Urinary tract infection (UTI) is one of the most prevalent infections among older people with T2DM. However, the association between geriatric T2DM and the risk of UTI has not been thoroughly researched and is still contentious. Consequently, this protocol describes a systematic review to pinpoint the primary risk factors for UTI among elderly T2DM. Our goal is to improve recommendations for the creation of targeted treatment interventions by examining risk factors for UTI in elderly individuals with T2DM. Methods and analysis We will search 4 English literature databases (PubMed, Embase, Web of Science, and Cochrane Library) and 3 major Chinese databases (CNKI, WanFang, and VIP) from the establishment of the database to June 20, 2024. Systematic evaluation and meta-analysis will be conducted on cohort and case-control studies exploring the occurrence and risk determinants of UTI in individuals diagnosed with T2DM. The main focus will be on identifying the risk factors for UTI in elderly diabetic patients. Two researchers will independently review articles, collect data, and evaluate the quality and potential bias of study inclusion. We will use RevMan V.5.4 software to analyze the data. The quality of the included studies will be assessed using the Newcastle-Ottawa scale. In addition, the GRADE (Grade of Recommendations, Assessment, Development, Evaluation) method will be used to examine the quality of evidence for each exposure and outcome of interest. Discussion This study aims to illuminate the various risk factors associated with UTI in older patients diagnosed with T2DM. By this thorough investigation, we hope to provide a more comprehensive reference for medical professionals and researchers, thereby supporting the implementation of effective preventive strategies against UTI and improving overall nursing outcomes for this specific patient population. Trail registration PROSPERO (CRD42024559129).
Læs mere Tjek på PubMedFacundo Maiorana, Magali Neschuk, María Virginia Caronia, Karina Elizondo, María Laura Robledo, Adolfo Schneider, Georgina Veron, Pedro Dario Zapata, Fernando Javier Barreyro
PLoS One Infectious Diseases, 24.09.2024
Tilføjet 24.09.2024
by Facundo Maiorana, Magali Neschuk, María Virginia Caronia, Karina Elizondo, María Laura Robledo, Adolfo Schneider, Georgina Veron, Pedro Dario Zapata, Fernando Javier Barreyro Background Recent studies have suggested an association between H. pylori and metabolic-disfunction associated fatty liver disease (MASLD). However, epidemiologic studies have yielded inconsistent results. We aim to evaluate the association of H. pylori and G-allele PNPLA3 in MASLD diagnosis, and markers of severity. Methods A multi-center cross-sectional study was conducted. A total 224 functional dyspepsia (FD) patients cohort who underwent gastroscopy was selected. Biochemical, clinical parameters, ultrasound, FIB-4 score, LSM by VCTE, gastric biopsies, H. pylori status, and rs738409 PNPLA3 were evaluated. A second retrospective cohort of 86 patients with biopsy-proven MASLD who underwent gastroscopy with gastric biopsies was analyzed. Results In the FD cohort MASLD was observed in 52%, and H. pylori-positive in 51%. H. pylori infection was associated with MASLD prevalence, but in multivariate analyses adjusted for G-allele PNPLA3, it became not significant. Then in MASLD-only dyspeptic cohort, H. pylori infection was significantly linked to elevated serum AST levels and increased liver stiffness measurements, suggesting a potential role in liver injury and fibrosis. Histopathological analysis in biopsy-proven MASLD patients further supported these findings, showing a significant association between H. pylori infection and increased NAS score, fibrosis stage, and prevalence of MASH. Notably, the combination of H. pylori infection and G-allele PNPLA3 appeared to exacerbate MASLD severity beyond individual effects. Conclusions Our results suggest that H. pylori infection may play a role in the progression of liver injury and fibrosis in patients with MASLD, especially in those with specific genetic predispositions.
Læs mere Tjek på PubMedJournal of Infectious Diseases, 23.09.2024
Tilføjet 23.09.2024
Abstract HTLV-1 transforms primary CD4+ T cells in vitro within a short time; however, majority of infected individuals maintain an asymptomatic condition, suggesting there is an equilibrium between the infected cells and the host immunity. In this study, we identified a variation in a major viral antigen epitope, HTLV-1 Tax301-309, in HLA-A24-positive individuals. Mismatch in A24/Tax301-309 multimers impaired detection of anti-Tax CTLs. Notably, over half of the TCRs of the anti-Tax CTLs did not recognize mismatched Tax301-309 peptides. These findings highlighted the importance of matching the viral antigen epitope type in T-cell-based immunotherapy against ATL by using viral antigen Tax.
Læs mere Tjek på PubMedChenzhen Li, Xianghui Gao, Yunfeng Huo, Tahani A. Y. Asseri, Xueliang Tian, Kun Luo
PLoS One Infectious Diseases, 21.09.2024
Tilføjet 21.09.2024
by Chenzhen Li, Xianghui Gao, Yunfeng Huo, Tahani A. Y. Asseri, Xueliang Tian, Kun Luo A significant population of biocontrol microorganisms resides in the rhizosphere of plants, which can be utilized for plant disease control. To explore the potential of rhizosphere soil microorganisms as biocontrol agents against pepper blight, a bacterial strain Pa608 was screened from rhizosphere soil of pepper and identified as Pseudomonas aeruginosa through morphological characteristics and 16S rRNA sequences. The result showed that the strain Pa608 demonstrated antagonistic activity against Phytophthora capsici, effectively suppressing mycelial growth. The potted experiment showed a high control efficacy of 88.0%. Remarkably, the strain Pa608 also reduced the disease index of pepper blight in the field, resulting in control efficiencies of 74.9%. Moreover, the strain Pa608 also enhanced pepper plant height and yield. GC-MS analysis revealed the production of numerous secondary metabolites by the strain Pa608, with α-pinene displaying potent anti-oomycete activity by inhibiting P. capsici growth. In conclusion, P. aeruginosa Pa608 exhibited high biocontrol activity against P. capsici and can be utilized for the management of P. capsici in pepper cultivation.
Læs mere Tjek på PubMedMauro Bombaci, Enrico Mario Alessandro Fassi, Andrea Gobbini, Davide Mileto, Irene Cassaniti, Elisa Pesce, Emanuele Casali, Alessandro Mancon, Jose’ Sammartino, Alessandro Ferrari, Elena Percivalle, Romualdo Grande, Edoardo Marchisio, Maria Rita Gismondo, Sergio Abrignani, Fausto Baldanti, Giorgio Colombo, Renata Grifantini
Journal of Medical Virology, 20.09.2024
Tilføjet 20.09.2024
Yichen Zhong, Lorna Wilkinson-White, Esther Zhang, Biswaranjan Mohanty, Belinda B. Zhang, Madeline S. McRae, Rachel Luo, Thomas A. Allport, Anthony P. Duff, Jennifer Zhao, Serene El-Kamand, Mar-Dean Du Plessis, Liza Cubeddu, Roland Gamsjaeger, Sandro F. Ataide, Ann H. Kwan
PLoS One Infectious Diseases, 17.09.2024
Tilføjet 17.09.2024
by Yichen Zhong, Lorna Wilkinson-White, Esther Zhang, Biswaranjan Mohanty, Belinda B. Zhang, Madeline S. McRae, Rachel Luo, Thomas A. Allport, Anthony P. Duff, Jennifer Zhao, Serene El-Kamand, Mar-Dean Du Plessis, Liza Cubeddu, Roland Gamsjaeger, Sandro F. Ataide, Ann H. Kwan RNA-binding proteins (RBPs) are a major class of proteins that interact with RNAs to change their fate or function. RBPs and the ribonucleoprotein complexes they constitute are involved in many essential cellular processes. In many cases, the molecular details of RBP:RNA interactions differ between viruses, prokaryotes and eukaryotes, making prokaryotic and viral RBPs good potential drug targets. However, targeting RBPs with small molecules has so far been met with limited success as RNA-binding sites tend to be extended, shallow and dynamic with a mixture of charged, polar and hydrophobic interactions. Here, we show that peptide nucleic acids (PNAs) with nucleic acid-like binding properties and a highly stable peptide-like backbone can be used to target some RBPs. We have designed PNAs to mimic the short RNA stem-loop sequence required for the initiation of prokaryotic signal recognition particle (SRP) assembly, a target for antibiotics development. Using a range of biophysical and biochemical assays, the designed PNAs were demonstrated to fold into a hairpin structure, bind the targeted protein and compete with the native RNA hairpin to inhibit SRP formation. To show the applicability of PNAs against other RBPs, a PNA was also shown to bind Nsp9 from SARS-CoV-2, a protein that exhibits non-sequence-specific RNA binding but preferentially binds hairpin structures. Taken together, our results support that PNAs can be a promising class of compounds for targeting RNA-binding activities in RBPs.
Læs mere Tjek på PubMedDinghao Chen, Ziao Zhou, Nan Kong, Tengyan Xu, Juan Liang, Pingping Xu, Bingpeng Yao, Yu Zhang, Ying Sun, Ying Li, Bihan Wu, Xuejiao Yang, Huaimin Wang
Science Advances, 14.09.2024
Tilføjet 14.09.2024
Stoppelenburg, A. J., Schreibelt, G., Koeneman, B., Welsing, P., Breman, E.-J., Lammers, L., de Goede, A., Duiveman-de Boer, T., van Eden, W., Leufkens, P., de Vries, I. J. M., Broere, F., van Laar, J. M.
BMJ Open, 13.09.2024
Tilføjet 13.09.2024
IntroductionIn rheumatoid arthritis (RA), immunosuppressive therapies may achieve symptomatic relief, but do not induce long-term, drug-free remission. Meanwhile, the lifelong use of immunosuppressive drugs confers increased risk for malignancy and infections. As such, there is an unmet need for novel treatments that selectively target the pathogenic immune response in RA by inducing tolerance to autoantigens. Autologous cell therapy using antigen-loaded tolerogenic dendritic cells (tolDCs) aims to reinstate autoantigen-specific immunological tolerance in RA and could potentially meet this need. Methods and analysisWe report here the design of the phase I/II, investigator-initiated, open-label, dose-escalation trial TOLERANT. In this study, we will evaluate the intranodal administration of tolDCs in patients with RA that are in remission under immunosuppressive therapy. The tolDCs in this trial are loaded with the heat shock protein 70-derived peptide mB29a, which is an effective surrogate autoantigen in animal models of arthritis. Within this study, three dose-escalation cohorts (two intranodal injections of 5x106, 10x106 and 15x106 tolDCs), each consisting of three patients, are evaluated to identify the highest safe dose (recommended dose), and an extension cohort of nine patients will be treated with the recommended dose. The (co-)primary endpoints of this study are safety and feasibility, which we assess by the number of AEs and the successful production of tolDCs. The secondary endpoints include the immunological effects of the treatment, which we assess with a variety of high-dimensional and antigen-specific immunological assays. Clinical effects are exploratory outcomes. Ethics and disseminationEthical approval for this study has been obtained from the Netherlands Central Committee on Research Involving Human Subjects. The outcomes of the trial will be disseminated through publications in open-access, peer-reviewed scientific journals, scientific conferences and to patient associations. Trial registration numbersNCT05251870; 2019-003620-20 (EudraCT); NL71296.000.20 (CCMO register).
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