Plant Introduction
Not a member yet
60263 research outputs found
Sort by
Retraction for Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation
No full textTDP-43-mediated alternative polyadenylation is associated with a reduction in VPS35 and VPS29 expression in frontotemporal dementia
No full textTAR DNA-binding protein 43 (TDP-43) dysfunction is a hallmark of several neurodegenerative diseases, including frontotemporal dementia, amyotrophic lateral sclerosis, and Alzheimer's disease. Although cryptic exon inclusion is a well-characterized consequence of TDP-43 loss of function, emerging evidence reveals broader roles in RNA metabolism, notably in the regulation of alternative polyadenylation (APA) of disease-relevant transcripts. In the present study, we examined 3' untranslated region lengthening events in the brains of individuals with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), focusing on the functional impact of APA dysregulation. To investigate whether TDP-43-mediated APA events occur in the postmortem brain, we measured the 3' untranslated region length of the retromer component vacuolar protein sorting 35 (VPS35) and the ETS transcription factor (ELK1) in the frontal cortex of a large cohort of FTLD-TDP patients and of healthy controls, and evaluated if these APA events are associated with FTLD-TDP clinical characteristic, markers of TDP-43 pathology [e.g., hyperphosphorylated TDP-43 and cryptic stathmin-2 RNA], or the expression of VPS35 and VPS29 proteins, the latter being essential to the retromer complex. We identified robust 3' untranslated region lengthening of VPS35 and ELK1 in FTLD-TDP, which strongly associated with markers of TDP-43 pathology, and ELK1 APA also associated with an earlier age of disease onset. Functionally, VPS35 APA was associated with reduced VPS35 and VPS29 protein expression, and lower VPS35 levels were associated with increased hyperphosphorylated TDP-43 and cryptic stathmin-2 RNA. Together, these data implicate APA dysregulation as a critical downstream consequence of TDP-43 dysfunction and suggest that TDP-43 loss may contribute to retromer impairment through APA-mediated repression of retromer subunits. Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication
Sources of Subseasonal Predictability for Precipitation in South America Based on Model Experiments
No full textThis study investigates the sources of predictability underlying subseasonal precipitation skill over South America in existing subseasonal prediction systems. Using subseasonal re‐forecasts from the NCAR‐CESM2 model, we demonstrate that significant skill persists even when interannual variability is removed. The highest skill occurs during austral summer and spring. To isolate sources of predictability, we analyze a novel set of re‐forecast experiments initialized with climatological atmosphere, land and ocean states. Results indicate that atmospheric initial conditions are essential for achieving skill, while ocean initializations contribute to skill containing interannual variability and land initializations contribute minimally to skill. Canonical correlation analysis is used to identify the most skillful spatial patterns and associated time series during the high‐skill seasons. The most skillful patterns in December–February are not independent of the South American dipole but also contain additional skill beyond the dipole. This additional skill is not associated with propagating tropical convection or sea surface temperature anomalies indicating that the Madden–Julian Oscillation, El Niño–Southern Oscillation, or South Atlantic SST variability are not the sources of predictability. Instead, a wave‐train‐like structure extends across the South Pacific, resembling a Rossby wave response. Idealized experiments using a simplified atmospheric general circulation model show that this pattern can be reproduced by stationary tropical heating over the Maritime Continent, suggesting a dynamical link between tropical heating and South American precipitation variability on subseasonal timescales independent of ENSO and the MJO. Plain Language Summary This study explores why some weather models are able to skillfully predict rainfall over South America a few weeks in advance—a time range known as the subseasonal timescale. Using a model from the National Center for Atmospheric Research (NCAR‐CESM2), we find that this prediction skill is strongest during the Southern Hemisphere's summer and spring months. Interestingly, the skill remains even when large‐scale climate patterns like El Niño are removed, suggesting that other sources of predictability are at play. To understand what drives this skill, we tested different parts of the model's starting conditions. We found that the state of the atmosphere at the beginning of the forecast is the most important factor, while land and ocean conditions matter much less. We also identified specific rainfall patterns that the model predicts most accurately. In spring, these patterns match known climate features, but in summer, a pattern appears that is only partially linked to well‐known precipitation variability in SA. Wave‐like activity in the atmosphere, possibly triggered by heating in the tropical region near Indonesia appears to contribute to this pattern. This finding could help improve forecasts and our understanding of rainfall variability in South America. Key Points The MJO and ENSO are not the primary sources of subseasonal precipitation skill in South America Skill comes from the South American Dipole and from Rossby waves generated from the Maritime Continent region Atmospheric initial conditions are necessary to realize this skill while land and ocean conditions are no
Wound Healing Property of a Novel Thermo‐Reversible Wound Gel With Lasting Antimicrobial and Antibiofilm Activity
No full textThis study investigated the efficacy and safety of a novel thermo‐reversible antimicrobial wound gel (TRG, revyve Antimicrobial Wound Gel) designed to combat biofilm‐related infections in wounds. The TRG was evaluated for its ability to disrupt biofilms, sustain antimicrobial activity and promote wound healing. The gel exhibited thermo‐reversible properties, transitioning from a less viscous liquid ≤ 18°C to a highly viscous solid gel at wound temperature which would facilitate easy application and removal. Antimicrobial testing demonstrated that TRG effectively inactivated a broad range of wound‐related pathogens, including Staphylococcus aureus and Pseudomonas aeruginosa , with a 99.99%–99.9999% reduction in bacterial counts within 30 min. The TRG also maintained its antimicrobial efficacy after multiple inoculations with high microbial load (107 CFU/mL) over 7 days. In vitro biofilm assays showed effectiveness against biofilm bacteria with a reduction of ≥ 99.99% bacterial counts with one application over the course of 7 days. Biocompatibility testing confirmed that TRG was safe, with no signs of tissue necrosis or signs of tissue damage and no impact on wound healing in a porcine wound model. TRG's ability to reduce both planktonic and biofilm‐based bacteria without compromising wound healing makes it a promising candidate for treating both chronic and acute wounds. Thermo‐reversible properties of wound gel, transitioning from a low‐viscosity form at low temperature to a high‐viscosity gel at wound temperature, make the gel form‐fitting to the wound upon application and remain in place during treatment, while its lower viscosity upon cooling facilitated painless removal without damaging healing tissue.TRG was effective against both planktonic and biofilm forms of wound‐related pathogens and this effectiveness can be sustained over 7 days, minimising the need for frequent dressing changes.Safety and potential cytotoxic effect on wound healing of TRG was confirmed using biocompatibility and porcine wound study
Swimming performance, maximum O2 consumption, EPOC, post-exercise recovery, and tissue metabolites after fatigue by U crit versus chase protocols in mahi-mahi ( Coryphaena hippurus ), a high-performance pelagic teleost
No full textCarangiform fishes are highly active pelagic teleosts, but there have been relatively few studies of their swimming physiology. Recent evidence in other species suggests that swimming to exhaustion using a critical swimming speed (Ucrit) protocol may yield higher maximum O2 consumption rates (ṀO2max) than chase methodologies. However, there has been little work comparing the internal physiological disturbances and recovery processes resulting from the two methods. We compared these two protocols in young adult mahi-mahi (∼254 g, 26°C, 32 ppt). ṀO2maxafter chasing (20 min) was 30% lower than during Ucrit swimming (20-min speed increments). Absolute and factorial aerobic scopes were 42% and 30% lower, respectively, by chasing. Post-exercise recovery was much slower in chased fish, a > 1.8-fold higher excess post-exercise O2 consumption (EPOC) than in Ucrit fish. 60% of the total O2 cost of swimming to fatigue in the Ucrit protocol was incurred during swimming (i.e., extra ṀO2 above resting O2 consumption rate (ṀO2rest) and 40% during recovery (i.e., EPOC). Tissue-specific profiles of metabolites were very different between the two protocols, with the Ucrit treatment causing greater lactate accumulation in red muscle, and chasing causing greater lactate accumulation in the liver and intracellular pH (pHi) depression in both the red and white muscle at exhaustion, with other differences during recovery. Overall, the results suggest a much greater anaerobic contribution to exercise metabolism caused by chasing. The two protocols yield vastly different results, reflecting different processes. We conclude that the Ucrit protocol provides a much better profile of aerobic capacity
Changes in the 6th edition of the World Health Organization classification of tumours of the digestive system
No full textThe 6th Edition of the WHO Classification of Digestive System Tumours represents a significant update to the 5th edition. It integrates pathological, new molecular, and clinical insights to refine the taxonomy of digestive system neoplasms. The revised classification continues to emphasise standardisation in terminology, coding, and diagnostic criteria to facilitate global consistency in diagnosis, treatment, epidemiological reporting and research. Structural reorganisation of book chapters describes epithelial tumours by anatomical site, while separating neuroendocrine, mesenchymal and haematolymphoid tumours into dedicated chapters that are aligned with other WHO tumour volumes. Genetic tumour syndromes are classified by mechanisms, pathways and genes, whereas metastatic disease is comprehensively covered under other tumours and metastases. Key structural and diagnostic refinements include consolidation of gastric dysplasia entities; separation of duodenal/ampullary from jejuno-ileal tumours; clearer categorisation of colorectal serrated polyps and novel carcinoma grading; introduction of small- and large-duct intrahepatic cholangiocarcinoma as separate entities, and redefinition of undifferentiated carcinoma to include 'carcinoma with mesenchymal differentiation'. Several new entities are introduced, including oesophageal epidermoid metaplasia, colorectal intramucosal adenocarcinoma, low-grade tubuloglandular adenocarcinoma and lymphoglandular complex-like adenocarcinoma, intraductal tubulopapillary and intraductal oncocytic papillary neoplasms of the bile ducts and sonic hedgehog hepatocellular adenoma. The concept of amphicrine-like carcinoma (ALC) is distinguished from MiNEN and broadens the understanding of tumours with dual neuroendocrine-non-neuroendocrine differentiation. Grading systems are simplified to two-tier classifications (low/high grade) across precursor lesions, with enhanced criteria for neuroendocrine tumour grading. Anal canal neoplasia terminology is harmonised with human papillomavirus (HPV) related Lower Anogenital Squamous Terminology (LAST) and mass-forming biliary and gallbladder cancer precursors share similar terminology. Finally, carcinoma of unknown primary (CUP) is included in a separate section for the first time, classified by molecular and immunophenotypic profiles to guide therapy. Overall, the 6th edition strengthens tumour diagnostic precision and molecular alignment across the digestive system
Barriers to expeditious post-operative chemotherapy for patients with glioblastoma
No full textConsiderable effort has been dedicated to finding direct therapeutic treatments to improve prognosis for glioblastoma (GBM). Social determinants of health (SDoH) are known to affect the access patients have to obtaining specialist care. One such metric is the time to initiation of post-operative care, specifically timing to chemotherapy.
We conducted a retrospective analysis of patients with histopathologically confirmed GBM who received chemotherapy at our institution with complete follow-up. The primary outcome was time-to-chemotherapy initiation, and the cohort was divided into expeditious chemotherapy (within 28 days or less) or delayed chemotherapy (28 days or more). We evaluated the impact of race and ethnicity, insurance status (private, public, combination or none), and distance from the hospital, on the likelihood of patients receiving expeditious or delayed care. A mixture of Chi-square, Fisher’s, and Mann-Whitney U tests, as well as adjusted multivariate analyses, were used to analyze statistical significance.
Across 124 patients, those with Medicare and Private secondary insurance had an increased likelihood of experiencing expeditious care (LR: χ²(5)= 11.75, p = 0.038). Multivariate regression analysis further re-affirmed this with finding (OR=0.339, 95 %CI:0.122–0.942, p = 0.039). Race/ethnicity and distance from the hospital both proved to be insignificant as predictors of expeditious and delayed care on univariate (p = 0.926, p = 0.801, respectively) and multivariate analyses (p = 0.593, p = 0.521, respectively).
Patients with primary Medicare alongside secondary Private insurance coverage had the highest likelihood of experiencing expeditious care in the post-operative period. None of the predictors predicted delayed care. We are reassured that neither race nor distance from hospital impact care significantly at our institution.
•Insurance status predicts time to chemotherapy after GBM resection.•Medicare with secondary private insurance linked to expeditious chemotherapy.•Race, ethnicity, and distance are not predictors of delayed care
Prolonged stability of 1% 5-FU eye drops as topical chemotherapy for ocular surface squamous neoplasia
No full textTargeting Melanoma-Associated Fibroblasts to Overcome Cancer Stem Cell-Driven Drug Resistance
No full textAcquired resistance to BRAF V600E inhibitors remains a major obstacle in melanoma treatment. We hypothesized that melanoma-initiating cells (MICs), regulated by cancer-associated fibroblasts (CAFs) in the tumor microenvironment, mediate drug resistance through stromal Notch1 signaling.
Patient-derived melanoma-associated fibroblasts (MAFs) were engineered to activate Notch1 signaling (MAF N1IC-GFP) via lentiviral transduction. Drug resistance was assessed using BRAF inhibitor-resistant melanoma cells (451LuBR) in 3D spheroid co-culture assays with PLX4720 treatment.In vivo efficacy was evaluated in NSG mice co-grafted with 451LuBR cells and MAF N1IC-GFP or control MAF GFP (n=8/group). Primary endpoints included tumor growth, angiogenesis, and CD271⁺ MIC populations assessed by immunofluorescence and quantitative imaging.
In vitro, MAF N1IC-GFP suppressed drug-resistant melanoma spheroid formation across PLX4720 concentrations (1-100 μM, P <0.01). In vivo, MAF N1IC-GFP co-grafting reduced tumor growth by 50% (mean tumor weight, P <0.01) and bioluminescence signal (P <0.05). Mechanistically, MAF N1IC-GFP selectively depleted CD271⁺ MICs (~50% reduction in fluorescence intensity, P<0.01), decreased their proliferation (P <0.01), and induced apoptosis (P <0.01).
Activating Notch1 signaling in melanoma-associated fibroblasts overcomes BRAF inhibitor resistance by disrupting cancer stem cell niches. This stromal-targeted approach represents a novel therapeutic strategy to complement surgical and systemic therapies in melanoma patients with drug-resistant disease
