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Nature Communications Jun 2024Nanoscale flows of liquids can be revealed in various biological processes and underlie a wide range of nanofluidic applications. Though the integral characteristics of...
Nanoscale flows of liquids can be revealed in various biological processes and underlie a wide range of nanofluidic applications. Though the integral characteristics of these systems, such as permeability and effective diffusion coefficient, can be measured in experiments, the behaviour of the flows within nanochannels is still a matter of speculation. Herein, we used a combination of quadrupolar solid-state NMR spectroscopy, computer simulation, and dynamic vapour sorption measurements to analyse water diffusion inside peptide nanochannels. We detected a helical water flow coexisting with a conventional axial flow that are independent of each other, immiscible, and associated with diffusion coefficients that may differ up to 3 orders of magnitude. The trajectory of the helical flow is dictated by the screw-like distribution of ionic groups within the channel walls, while its flux is governed by external water vapour pressure. Similar flows may occur in other types of nanochannels containing helicoidally distributed ionic groups and be exploited in various nanofluidic lab-on-a-chip devices.
PubMed: 38951494
DOI: 10.1038/s41467-024-49878-7 -
Communications Biology Jul 2024Colistin remains an important antibiotic for the therapeutic management of drug-resistant Klebsiella pneumoniae. Despite the numerous reports of colistin resistance in...
Colistin remains an important antibiotic for the therapeutic management of drug-resistant Klebsiella pneumoniae. Despite the numerous reports of colistin resistance in clinical strains, it remains unclear exactly when and how different mutational events arise resulting in reduced colistin susceptibility. Using a bioreactor model of infection, we modelled the emergence of colistin resistance in a susceptible isolate of K. pneumoniae. Genotypic, phenotypic and mathematical analyses of the antibiotic-challenged and un-challenged population indicates that after an initial decline, the population recovers within 24 h due to a small number of "founder cells" which have single point mutations mainly in the regulatory genes encoding crrB and pmrB that when mutated results in up to 100-fold reduction in colistin susceptibility. Our work underlines the rapid development of colistin resistance during treatment or exposure of susceptible K. pneumoniae infections having implications for the use of cationic antimicrobial peptides as a monotherapy.
Topics: Klebsiella pneumoniae; Colistin; Anti-Bacterial Agents; Bioreactors; Drug Resistance, Bacterial; Klebsiella Infections; Microbial Sensitivity Tests; Humans
PubMed: 38951173
DOI: 10.1038/s42003-024-06378-0 -
BMJ Open Jul 2024Novel antidiabetes medications with proven cardiovascular or renal benefit, such as sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide 1...
OBJECTIVES
Novel antidiabetes medications with proven cardiovascular or renal benefit, such as sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA), have been introduced to the market. This study explored the 4-year trends of antidiabetes medication use among medical hospitalisations with type 2 diabetes (T2D).
DESIGN
Retrospective cohort study.
SETTING
Tertiary care hospital in Switzerland.
PARTICIPANTS
4695 adult hospitalisations with T2D and prevalent or incident use of one of the following antidiabetes medications (metformin, dipeptidyl peptidase-4 inhibitors (DPP-4i), sulfonylureas, GLP-1 RA, SGLT-2i, short-acting insulin or long-acting insulin), identified using electronic health record data. Quarterly trends in use of antidiabetes medications were plotted overall and stratified by cardiovascular disease (CVD) and chronic kidney disease (CKD).
RESULTS
We observed a stable trend in the proportion of hospitalisations with T2D who received any antidiabetes medication (from 77.6% during 2019 to 78% in 2022; p for trend=0.97). In prevalent users, the largest increase in use was found for SGLT-2i (from 7.4% in 2019 to 21.8% in 2022; p for trend <0.01), the strongest decrease was observed for sulfonylureas (from 11.4% in 2019 to 7.2% in 2022; p for trend <0.01). Among incident users, SGLT-2i were the most frequently newly prescribed antidiabetes medication with an increase from 26% in 2019 to 56.1% in 2022 (p for trend <0.01). Between hospital admission and discharge, SGLT-2i also accounted for the largest increase in prescriptions (+5.1%; p<0.01).
CONCLUSIONS
These real-world data from 2019 to 2022 demonstrate a significant shift in antidiabetes medications within the in-hospital setting, with decreased use of sulfonylureas and increased prescriptions of SGLT-2i, especially in hospitalisations with CVD or CKD. This trend aligns with international guidelines and indicates swift adaptation by healthcare providers, signalling a move towards more effective diabetes management.
Topics: Humans; Diabetes Mellitus, Type 2; Retrospective Studies; Hypoglycemic Agents; Male; Female; Hospitalization; Aged; Middle Aged; Switzerland; Sodium-Glucose Transporter 2 Inhibitors; Dipeptidyl-Peptidase IV Inhibitors; Renal Insufficiency, Chronic; Sulfonylurea Compounds; Cardiovascular Diseases; Adult; Metformin
PubMed: 38950998
DOI: 10.1136/bmjopen-2024-084526 -
BMJ Open Jul 2024Children and adolescents with recent-onset type 1 diabetes (T1D) commonly maintain a certain level of insulin production during the remission phase, which can last...
INfluenza VaccInation To mitigate typE 1 Diabetes (INVITED): a study protocol for a randomised, double-blind, placebo-controlled clinical trial in children and adolescents with recent-onset type 1 diabetes.
INTRODUCTION
Children and adolescents with recent-onset type 1 diabetes (T1D) commonly maintain a certain level of insulin production during the remission phase, which can last months to years. Preserving β-cell function can reduce T1D complications and improve glycaemic control. Influenza vaccination has pleiotropic effects and administration of the vaccine during the early phases of T1D may offer β-cell protection. This study aims to assess the effect of influenza vaccination on preserving β-cell function in children and adolescents with recent-onset T1D.
METHODS AND ANALYSIS
The INfluenza VaccInation To mitigate typE 1 Diabetes trial is a randomised, double-blind, placebo-controlled, multicentre trial in paediatric patients with recent-onset T1D aged 7-17 years. 100 participants will be randomised in a 1:1 ratio to receive either a standard inactivated quadrivalent influenza vaccine or a placebo within 14 days of diagnosis. The primary outcome is a difference in mean change (from baseline to 12 months) in C-peptide level between groups during a 2-hour mixed-meal tolerance test. Secondary outcomes include mean change (from baseline to 6 months) in C-peptide levels, haemoglobin A1c, ambulatory glucose profiles and insulin requirements. Exploratory outcomes are diabetes-related autoantibodies, inflammatory markers and serum haemagglutinin inhibition antibody titres against the influenza viruses. The current treatment for T1D is largely symptomatic, relying on insulin administration. There is a pressing need for novel pharmacological approaches aimed at modulating the immune system to preserve residual β-cell function. Existing immunotherapies are cost-prohibitive and associated with multiple side effects, whereas influenza vaccination is inexpensive and generally well tolerated. A positive outcome of this study holds potential for immediate implementation into standard care for children and adolescents with recent-onset T1D and may guide future research on immune modulation in T1D.
ETHICS AND DISSEMINATION
Ethical approval was obtained from Danish Health Authorities prior to participant enrollment. The trial results will be submitted to a peer-reviewed journal.
TRIAL REGISTRATION NUMBER
ClinicalTrials.gov NCT05585983 and EudraCT Number 2022-500906-17-01.
Topics: Humans; Diabetes Mellitus, Type 1; Adolescent; Child; Influenza Vaccines; Double-Blind Method; Female; Male; Influenza, Human; Glycated Hemoglobin; C-Peptide; Randomized Controlled Trials as Topic; Blood Glucose; Insulin; Vaccination; Insulin-Secreting Cells
PubMed: 38950997
DOI: 10.1136/bmjopen-2024-084808 -
ACR Open Rheumatology Jul 2024Rheumatoid arthritis (RA) has a "pre-RA" period in which multiple autoantibodies, including antibodies to citrullinated (cit) proteins (ACPA), rheumatoid factor (RF),...
OBJECTIVE
Rheumatoid arthritis (RA) has a "pre-RA" period in which multiple autoantibodies, including antibodies to citrullinated (cit) proteins (ACPA), rheumatoid factor (RF), anti-peptidyl arginine deiminase (anti-PAD), among others, have been described; however, few studies have tested all autoantibodies in a single pre-RA cohort. This study aims to evaluate the prevalence of multiple autoantibodies in pre-RA and potentially identify an autoantibody profile in pre-RA that indicates imminent onset of clinical RA.
METHODS
We evaluated 148 individuals with two pre- and one post-RA diagnosis samples available from the Department of Defense Serum Repository and matched controls. Samples were tested for immuglobulin (Ig) G anti-cyclic cit peptide-3 (anti-CCP3), five ACPA fine specificities, five anti-PAD isoforms, as well as RF IgA and RF IgM using commercial platforms; cutoffs were determined using levels present in <1% of controls.
RESULTS
Positivity of anti-CCP3, RF IgA and RF IgM, anti-PAD1, anti-cit-vimentin 2, anti-cit-fibrinogen, and anti-cit-histone 1 increased over time in pre-RA, although anti-PAD and ACPA fine specificities were predominately present within anti-CCP3-positive individuals. Within anti-CCP3-positive samples from the pre-RA period, positivity for RFs as well as anti-PAD and ACPA fine specificities classified samples as being closer to the time of RA diagnosis.
CONCLUSION
Multiple autoantibodies are present in pre-RA and increase in positivity as the time of RA diagnosis approaches. These results confirm previous findings predicting imminent RA and provide a pathway using commercial-grade assays to assess the risk for and timing of development of clinical RA.
PubMed: 38950890
DOI: 10.1002/acr2.11704 -
The Journal of Clinical Investigation Jun 2024Glucose plays a key role in shaping pancreatic β cell function. Thus, deciphering the mechanisms by which this nutrient stimulates β cells holds therapeutic promise...
Glucose plays a key role in shaping pancreatic β cell function. Thus, deciphering the mechanisms by which this nutrient stimulates β cells holds therapeutic promise for combating β cell failure in type 2 diabetes (T2D). β Cells respond to hyperglycemia in part by rewiring their mRNA metabolism, yet the mechanisms governing these changes remain poorly understood. Here, we identify a requirement for the RNA-binding protein PCBP2 in maintaining β cell function basally and during sustained hyperglycemic challenge. PCBP2 was induced in primary mouse islets incubated with elevated glucose and was required to adapt insulin secretion. Transcriptomic analysis of primary Pcbp2-deficient β cells revealed impacts on basal and glucose-regulated mRNAs encoding core components of the insulin secretory pathway. Accordingly, Pcbp2-deficient β cells exhibited defects in calcium flux, insulin granule ultrastructure and exocytosis, and the amplification pathway of insulin secretion. Further, PCBP2 was induced by glucose in primary human islets, was downregulated in islets from T2D donors, and impacted genes commonly altered in islets from donors with T2D and linked to single-nucleotide polymorphisms associated with T2D. Thus, these findings establish a paradigm for PCBP2 in governing basal and glucose-adaptive gene programs critical for shaping the functional state of β cells.
Topics: RNA-Binding Proteins; Animals; Insulin-Secreting Cells; Mice; Humans; Glucose; Diabetes Mellitus, Type 2; Insulin; Insulin Secretion; Mice, Knockout; Male; Adaptation, Physiological
PubMed: 38950317
DOI: 10.1172/JCI172436 -
PloS One 2024Co-infections are a common reality but understanding how the immune system responds in this context is complex and can be unpredictable. Heligmosomoides bakeri...
Heligmosomoides bakeri and Toxoplasma gondii co-infection leads to increased mortality associated with changes in immune resistance in the lymphoid compartment and disease pathology.
Co-infections are a common reality but understanding how the immune system responds in this context is complex and can be unpredictable. Heligmosomoides bakeri (parasitic roundworm, previously Heligmosomoides polygyrus) and Toxoplasma gondii (protozoan parasite) are well studied organisms that stimulate a characteristic Th2 and Th1 response, respectively. Several studies have demonstrated reduced inflammatory cytokine responses in animals co-infected with such organisms. However, while general cytokine signatures have been examined, the impact of the different cytokine producing lymphocytes on parasite control/clearance is not fully understood. We investigated five different lymphocyte populations (NK, NKT, γδ T, CD4+ T and CD8+ T cells), five organs (small intestine, Peyer's patches, mesenteric lymph nodes, spleen and liver), and 4 cytokines (IFN©, IL-4, IL-10 and IL-13) at two different time points (days 5 and 10 post T. gondii infection). We found that co-infected animals had significantly higher mortality than either single infection. This was accompanied by transient and local changes in parasite loads and cytokine profiles. Despite the early changes in lymphocyte and cytokine profiles, severe intestinal pathology in co-infected mice likely contributed to early mortality due to significant damage by both parasites in the small intestine. Our work demonstrates the importance of taking a broad view during infection research, studying multiple cell types, organs/tissues and time points to link and/or uncouple immunological from pathological findings. Our results provide insights into how co-infection with parasites stimulating different arms of the immune system can lead to drastic changes in infection dynamics.
Topics: Animals; Coinfection; Toxoplasma; Mice; Cytokines; Nematospiroides dubius; Strongylida Infections; Toxoplasmosis; Female; Toxoplasmosis, Animal; Spleen; Parasite Load; Lymphoid Tissue
PubMed: 38950025
DOI: 10.1371/journal.pone.0292408 -
PLoS Pathogens Jul 2024Oropharyngeal candidiasis (OPC) is the most common human fungal infection, arising typically from T cell immune impairments. IL-17 and IL-22 contribute individually to...
Oropharyngeal candidiasis (OPC) is the most common human fungal infection, arising typically from T cell immune impairments. IL-17 and IL-22 contribute individually to OPC responses, but here we demonstrate that the combined actions of both cytokines are essential for resistance to OPC. Mice lacking IL-17RA and IL-22RA1 exhibited high fungal loads in esophagus- and intestinal tract, severe weight loss, and symptoms of colitis. Ultimately, mice succumbed to infection. Dual loss of IL-17RA and IL-22RA impaired expression of small proline rich proteins (SPRRs), a class of antimicrobial effectors not previously linked to fungal immunity. Sprr2a1 exhibited direct candidacidal activity in vitro, and Sprr1-3a-/- mice were susceptible to OPC. Thus, cooperative actions of Type 17 cytokines mediate oral mucosal anti-Candida defenses and reveal a role for SPRRs.
Topics: Animals; Interleukin-22; Mice; Candidiasis, Oral; Interleukins; Interleukin-17; Mice, Knockout; Mice, Inbred C57BL; Candida albicans; Receptors, Interleukin; Receptors, Interleukin-17
PubMed: 38949991
DOI: 10.1371/journal.ppat.1012302 -
ELife Jul 2024Secreted chemokines form concentration gradients in target tissues to control migratory directions and patterns of immune cells in response to inflammatory stimulation;...
Secreted chemokines form concentration gradients in target tissues to control migratory directions and patterns of immune cells in response to inflammatory stimulation; however, how the gradients are formed is much debated. Heparan sulfate (HS) binds to chemokines and modulates their activities. In this study, we investigated the roles of HS in the gradient formation and chemoattractant activity of CCL5 that is known to bind to HS. CCL5 and heparin underwent liquid-liquid phase separation and formed gradient, which was confirmed using CCL5 immobilized on heparin-beads. The biological implication of HS in CCL5 gradient formation was established in CHO-K1 (wild-type) and CHO-677 (lacking HS) cells by Transwell assay. The effect of HS on CCL5 chemoattractant activity was further proved by Transwell assay of human peripheral blood cells. Finally, peritoneal injection of the chemokines into mice showed reduced recruitment of inflammatory cells either by mutant CCL5 (lacking heparin-binding sequence) or by addition of heparin to wild-type CCL5. Our experimental data propose that co-phase separation of CCL5 with HS establishes a specific chemokine concentration gradient to trigger directional cell migration. The results warrant further investigation on other heparin-binding chemokines and allows for a more elaborate insight into disease process and new treatment strategies.
Topics: Chemokine CCL5; Animals; Heparitin Sulfate; Humans; Cricetulus; CHO Cells; Mice; Chemotaxis; Heparin; Phase Separation
PubMed: 38949655
DOI: 10.7554/eLife.93871 -
Translational Vision Science &... Jul 2024We sought to evaluate the efficacy of growth differentiation factor (GDF)-15 treatment for suppressing epithelial-mesenchymal transition (EMT) and alleviating...
PURPOSE
We sought to evaluate the efficacy of growth differentiation factor (GDF)-15 treatment for suppressing epithelial-mesenchymal transition (EMT) and alleviating transforming growth factor β2 (TGFβ2)-induced lens opacity.
METHODS
To test whether GDF-15 is a molecule that prevents EMT, we pretreated the culture with GDF-15 in neural progenitor cells, retinal pigment epithelial cells, and lens epithelial cells and then treated with factors that promote EMT, GDF-11, and TGFβ2, respectively. To further investigate the efficacy of GDF-15 on alleviating lens opacity, we used mouse lens explant culture to mimic secondary cataracts. We pretreated the lens culture with GDF-15 and then added TGFβ2 to develop lens opacity (n = 3 for each group). Western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to measure EMT protein and gene expression, respectively.
RESULTS
In cell culture, GDF-15 pretreatment significantly attenuated EMT marker expression in cultured cells induced by treatment with GDF-11 or TGFβ2. In the lens explant culture, GDF-15 pretreatment also reduced mouse lens opacity induced by exposure to TGFβ2.
CONCLUSIONS
Our results indicate that GDF-15 could alleviate TGFβ2-induced EMT and is a potential therapeutic agent to slow or prevent posterior capsular opacification (PCO) progression after cataract surgery.
TRANSLATIONAL RELEVANCE
Cataracts are the leading cause of blindness worldwide, with the only current treatment involving surgical removal of the lens and replacement with an artificial lens. However, PCO, also known as secondary cataract, is a common complication after cataract surgery. The development of an adjuvant that slows the progression of PCO will be beneficial to the field of anterior complications.
Topics: Animals; Epithelial-Mesenchymal Transition; Transforming Growth Factor beta2; Growth Differentiation Factor 15; Cataract; Mice; Lens, Crystalline; Mice, Inbred C57BL; Cells, Cultured; Disease Models, Animal; Epithelial Cells; Blotting, Western; Retinal Pigment Epithelium
PubMed: 38949633
DOI: 10.1167/tvst.13.7.2