bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heat Shock-Induced PI(4)P Increase Drives HSPA1A Translocation to the Plasma Membrane in Cancer and Stressed Cells through PI4KIII Alpha Activation
Authors: Arce Alberto , Altman Rachel , Badolian Allen , Low Jensen , Cuaresma Azalea Blythe , Keshet Uri , Fiehn Oliver , Stahelin Robert V. , Nikolaidis Nikolas 
Published: February 2025

AbstractHSPA1A, a major heat shock protein, is known to translocate to the plasma membrane (PM) in response to cellular stress and cancer, where it plays protective roles in membrane integrity and stress resistance. Although phosphatidylinositol 4-phosphate [PI(4)P] is essential in this translocation, the signals that trigger and facilitate HSPA1A’s movement remain undefined.Given that membrane lipid composition dynamically shifts during stress, we hypothesized that heat shock-induced PI(4)P changes are crucial for HSPA1A’s PM localization. To test this hypothesis, we investigated the mechanisms driving PI(4)P changes and HSPA1A PM localization under heat shock. Lipidomic analysis, enzyme-linked immunosorbent assay (ELISA), and confocal imaging revealed a rapid PI(4)P increase at the PM post-heat shock, with levels peaking at 0 hours and declining by 8 hours. RNA sequencing and protein quantification indicated no transcriptional increase in PI4KIII alpha, the kinase responsible for PI(4)P synthesis, suggesting an alternative regulatory mechanism. Hypothesizing that heat shock enhances PI4KIII alpha activity, we performed ELISA coupled with immunoprecipitation, confirming a significant rise in PI4KIII alpha activity following heat shock. Functional analyses further demonstrated that RNAi-mediated PI4KIII alpha depletion or pharmacological PI(4)P reduction, using GSK-A1, impairs HSPA1A’s localization to the PM, confirming that HSPA1A translocation is PI(4)P-dependent. Our findings identify PI4KIII alpha activity as a key regulator of PI(4)P accumulation and subsequent HSPA1A recruitment to the PM in stressed and cancer cells. This lipid-mediated response offers new insights into stress adaptation and potentially modifiable pathways for therapeutic interventions to control HSPA1A function in cancer.
Self-Supervised Learning Can Distinguish Myelodysplastic Neoplasms from Clinical Mimics Using Bone Marrow Biopsies
Authors: Mehrtash Vahid , Le Hortense , Jafarzadeh Bita , Loghavi Sanam , Garcia-Manero Guillermo , Tsirigos Aristotelis , Park Christopher Y. 
Published: February 2025

AbstractThe diagnosis of myelodysplastic neoplasms (MDS) requires examination of the bone marrow for morphologic evidence of dysplasia. We sought to determine if a self-supervised learning (SSL) AI image analysis approach may be utilized to reliably distinguish MDS from its clinically relevant mimics using bone marrow biopsies (BMBx). Whole slide images (WSIs) of H&E- and reticulin-stained BMBx sections from 243 unique patients (89 MDS, 55 non-MDS cytopenic controls [NMCC], and 99 negative control [NC] cases) were segmented into tiles and analyzed. These tiles were then processed using the Barlow Twins SSL model to generate histomorphologic phenotype clusters (HPCs). Review of the HPCs revealed the clusters enriched in MDS captured known histopathologic features of MDS including hypercellularity, dysplastic and clustered megakaryocytes, increased immature hematopoietic cells, increased vascularity, fibrosis, and cell streaming patterns. Assessment of 95 MDS BMBx images from a second institution showed consistent HPC enrichment patterns, validating the robustness of the model. The trained ensemble model using H&E- and reticulin-stained slides distinguished MDS from NCs with an AUC of 0.89, and from age-matched, NMCCs with an AUC of 0.84. These findings demonstrate the potential of SSL approaches to capture diagnostically relevant morphologic patterns and to improve the reproducibility of MDS diagnosis.
Long term consequences of Total Ankle Replacement versus Ankle Fusion; a 25 year national population study of 41,000 patients
Authors: Hennessy Conor , Abram Simon , Brown Rick , Loizou Constantinos , Sharp Robert , Kendal Adrian 
Published: February 2025

AbstractAimsDefinitive and successful treatment of end stage ankle arthritis is either Total Ankle Replacement (TAR) or Ankle Fusion (AF). Both options place patients on an irreversible pathway that risks harm from further surgery. AF may predispose patients to subsequent hindfoot joint fusion and TAR is associated with high rates of complex revision surgery. The aim is to improve decision making by investigating the risks of further surgery, adjacent joint surgery and rare but serious complications of AF versus TAR.MethodsAn England population cohort study was performed using the Hospital Episode Statistics database, linked to ONS mortality data (19982023). The primary outcome was Kaplan Meier curve analysis of revision surgery free survival of TAR versus AF. Secondary outcome measures were the rates of adjacent joint/hindfoot fusion, any further reintervention to the ankle, perioperative mortality, 90 day complications, and serious adverse events.Results10,335 TAR and 30,704 AF were analysed. The AF revision rate was significantly lower than TAR at all time points including; 5 years (2% vs 6.1%, RR 0.12; 95% CI 0.10 to 0.16), 10 years (2.5% vs 10.2%, RR 0.12; 95% CI 0.08 to 0.18) and 20 years (3.1% vs 13.55%, RR 0.12; 95% CI 0.01 to 0.23).There was no significant difference in 25 year risk of adjacent joint fusion following AF (8.64%, 95% CI 7.79% to 9.58%) versus TAR (6.82%; 95% CI 5.36% to 8.66%). TAR was associated with higher risks of intra operative fracture (0.42% vs 0.10%, RR = 4.35) and reintervention for wound infection (0.26% vs 0.15%, RR 1.74) but fewer pulmonary emboli (0.23% vs 0.58%, RR = 0.40).ConclusionBoth TAR and AF are safe definitive treatments of ankle arthritis with low perioperative risk. TAR is associated with a significantly higher rate of further revision surgery than AF. AF does not predispose patients to hindfoot fusion surgery.
Human milk-derived extracellular vesicle treatment promotes the heat shock response in neonates with perinatal high fat diet exposure
Authors: Storm Jasmyne A. , Lu Jueqin , Obtial Mon Francis , Wijenayake Sanoji 
Published: February 2025

AbstractMaternal consumption of a high-fat diet (mHFD) during perinatal life (the collective prenatal and postnatal periods) influences neonatal development, initiates hypothalamic-pituitary-adrenal (HPA) axis activation, and impacts the long-term physiological and metabolic health of offspring. Milk-derived extracellular vesicles (MEVs) are lipid-coated nanovesicles found in mammalian milk that survive intestinal degradation and cross complex biological barriers, including the blood-brain barrier. MEVs have known cytoprotective activity in peripheral organs; however, their pro-survival functions in response to chronic pro-inflammation stemming from early life nutrient stress remain unknown in the neonatal brain. Further, sex differences resulting from MEV treatment require investigation, as male and female neonates illicit variable responses to early life nutrient stress. We investigated whether MEVs promote the heat shock response (HSR), a principal pro-survival mechanism responsible for refolding or degrading misfolded protein aggregates through the action of heat shock protein (HSP) chaperones. We investigated the interaction between MEVs and the HSR in the liver, hypothalamus, and prefrontal cortex in male and female neonatal rats exposed to perinatal mHFD within the stress hyporesponsive period at postnatal day 11. MEV treatment robustly modulated the HSR in female neonates with the largest response recorded in the prefrontal cortex. Specifically, in the prefrontal cortex, MEV treatment led to an upregulation of the main transcription factor (HSF1), while downregulating the negative regulators of HSF1 (Hsp70 and Hsp90). These results suggest that MEVs may influence pro-survival outcomes in the prefrontal cortex by activating HSF1-mediated pro-survival in a sex specific manner in response to mHFD.
Exploring the Impact of Volumetric Additive Manufacturing of Photo-crosslinkable Gelatin on Mesenchymal Stromal Cell Behavior and Differentiation
Authors: Pien Nele , Bogaert Bryan , Meeremans Marguerite , Popovici Cezar-Stefan , Dubruel Peter , De Schauwer Catharina , Van Vlierberghe Sandra 
Published: February 2025

AbstractThis study explores the application of photo-crosslinkable gelatin hydrogels (constituting GelSH and GelNB) for biofabrication using volumetric additive manufacturing (VAM). Three GelSH variants were prepared, yielding degree of substitutions (DS) of 39%, 54%, and 63%, and GelNB with a DS of 60%, alongside GelNB-GelSH formulations at concentrations of 5, 7.5, and 10% (w/v). Physico-chemical analyses confirmed that these variations led to differences in mass swelling ratio and mechanical properties. VAM enabled the fabrication of complex, high-fidelity 3D structures from the optimized GelNB-GelSH formulations, demonstrating its capacity to encapsulate mesenchymal stromal cells (MSCs) within a biomimetic matrix. Compared to the film casted constructs, the VAM-printed scaffolds exhibited significantly higher ALP activity and calcium deposition, confirming effective osteogenesis. Conversely, chondrogenic and adipogenic differentiation were more pronounced in the film casted groups due to their lower crosslinking density and lower compressive elastic modulus, emphasizing the role of the mechanical environment role in guiding cell differentiation. This study highlights the potential of VAM to produce complex and functional hydrogel scaffolds for tissue engineering, and lays the groundwork for future work on finetuning bioresin formulations to enhance differentiation across multiple lineages for various tissue engineering applications, including softer tissues.Abstract FigureThis study investigates photo-crosslinkable gelatin hydrogels (GelSH and GelNB) for volumetric additive manufacturing (VAM) in biofabrication. Different formulations influenced swelling and mechanical properties. VAM produced complex 3D scaffolds encapsulating mesenchymal stromal cells, enhancing osteogenesis compared to film-cast constructs. The findings highlight VAM’s potential for tissue engineering and optimizing bioresins for multi-lineage differentiation, including softer tissues.
Impact of nephrotoxins and oxidants on survival and transport function of hiPSC-derived renal proximal tubular cells
Authors: Mboni-Johnston Isaac Musong , Hartmann Sören , Kroll Christian , Berndt Carsten , Adjaye James , Schupp Nicole 
Published: February 2025

AbstractDue to their role in excretion, renal proximal tubule cells are susceptible to damage by toxic metabolites and xenobiotics. The regenerative capacity of the kidney allows for the replacement of damaged cells, a process involving differentiation programs. However, kidney function tends to decline, suggesting that the replacement cells may not achieve full functionality. To understand possible causes of this decline, we investigated effects of nephrotoxins and oxidants on the differentiation of induced pluripotent stem cells (iPSC) into proximal tubular epithelial-like cells (PTELC). Proliferation, apoptosis, senescence and expression of oxidative defense genes were analyzed in iPSCs, differentiating and differentiated cells treated with cisplatin (CisPt, up to 45 µM), cyclosporin A (CycA, up to 12 µM) and the oxidants menadione (Mena, up to 50 µM) and tert-butylhydroquinone (tBHQ, up to 50 µM). We found that differentiating cells were most sensitive to oxidants and showed increased sensitivity to CisPt, whereas all differentiation stages showed similar sensitivity to CycA. Both oxidative stress and CisPt triggered apoptosis in all differentiation stages, whereas CycA mainly induced senescence. Treatment during differentiation resulted in long-term effects on gene expression in differentiated cells. While oxidants had no effect on transport function of differentiated cells, CisPt and CycA impaired albumin uptake. Our data suggest a substantial sensitivity of differentiating cells to nephrotoxins and oxidants, an aspect that could potentially interfere with regenerative processes.
Dynamic regulation of NeuroD1 expression level by a novel viral construct during astrocyte-to-neuron reprogramming
Authors: Mseis-Jackson Natalie , Jiang Mei , Sharma Mehek , Ranchod Arya , Williams Christine , Chen Xuanyu , Li Hedong 
Published: February 2025

AbstractAstrocyte-to-neuron reprogramming presents a viable approach for regenerative medicine. The reprogramming factor NeuroD1 has demonstrated capability of neuronal reprogramming with high efficiency both in culture and in the injured central nervous system. High level of NeuroD1 expression is required to break down the cellular identity barrier for a successful reprogramming, and yet persistence of this high level drives the reprogrammed neurons primarily to glutamatergic subtype. This is consistent with the critical role of NeuroD1 in determination of glutamatergic neuronal lineage during development. However, diversified neuronal subtypes are needed to establish appropriate neuronal connectivity in disease/injury conditions. We reason that continuously high level of NeuroD1 expression forces the reprogrammed neurons into glutamatergic subtype, and that reducing NeuroD1 level after reprogramming may allow generation of neurons with diversified subtypes. For this purpose, we engineered a novel viral expression vector by which NeuroD1 expression can be dynamically regulated during the reprogramming process. Specifically, the target site of a neuron-specific microRNA (miR-124) is incorporated in the expression system. Therefore, this novel construct would still achieve a high NeuroD1 expression level in astrocytes for reprogramming to occur and yet reduce its level in the reprogrammed neurons by suppression of endogenous miR-124. In this study, we demonstrated that this construct elicits a dynamic gene expression pattern with much reduced level of NeuroD1 at later stages of neuronal reprogramming. We also showed that this construct still retains relatively high reprogramming efficiency and can generate mature neurons with an enhanced GABAergic neuronal phenotype.
Bridging the Nutrition Education Gap: From Theory to Practice- A Scalable Model for Nutrition Practicums in Medical Training
Authors: John Anjum , Reshma V.R , El-Hazimy Khadija 
Published: February 2025

AbstractBackgroundWith Kerala’s rising burden of non-communicable diseases (NCDs), it is crucial to strengthen nutrition education for medical students to equip future physicians’ with the ability to provide evidence-based dietary guidance. This study examined the effectiveness of incorporating practical demonstrations into the nutrition curriculum of a private medical college in Kerala, Southern India. This aims to enhance student engagement, deepen understanding of dietetic principles through practical application, and improve confidence in providing dietary counseling.MethodsThe study incorporated practical demonstrations such as meal planning, dietary assessments, and food label interpretation into the nutrition curriculum for third year medical students. Student feedback was collected through open-ended discussions and reflective exercises to assess their engagement and perceptions of the perceived learning outcomes.ResultsQualitative feedback indicated that students found practical demonstrations highly engaging, improving their confidence in applying nutritional knowledge. Thematic analysis identified key benefits such as enhanced experiential learning, increased ability to interpret nutrition labels, and improved patient counseling skills. However, challenges included limited time for hands-on activities, variability in prior nutrition knowledge, and limited faculty expertise in nutrition education.ConclusionsPractical demonstrations are an effective strategy for integrating nutrition education into medical curricula in Kerala as underscored by this study. By aligning with the National Medical Commission’s emphasis on integrated, application-based learning, and Kerala’s goals of addressing its rising burden of non-communicable diseases linked to malnutrition, this study offers a scalable model to strengthen clinical nutrition education, ultimately contributing to better public health outcomes nationwide.
Influence of Sex and Race/ Ethnicity on Major Adverse Cardiovascular Outcomes Following Coronary Artery Bypass Surgery in a Large Integrated Healthcare System
Authors: Yang Janine Y. , Stram Douglas , Doan John , Fairman Alix P. , Merchant Maqdooda , Triplett Cynthia , Sheikh Ahmad Y. , Ha Richard V. , Pursnani Seema K. 
Published: February 2025

AbstractBackgroundWe aimed to evaluate the influence of sex and race/ ethnicity on major adverse cardiovascular events (MACE) following coronary artery bypass grafting (CABG) in our integrated healthcare system.MethodsThis was a retrospective study of Kaiser Permanente Northern California members who underwent CABG from 2008-2019, evaluating odds of MACE (MI, stroke, serial percutaneous intervention (PCI), repeat CABG, death) at 30 days, 1 year, and up to 12 years follow-up using multivariable logistic and Cox proportional regression analyses. We adjusted for demographic, clinical, socioeconomic risk factors, and surgical characteristics.ResultsCohort included n=7405, mean age 65.2 yrs, 47% diabetic, 62% hypertensive, 20% with prior revascularization (PCI or CABG). There were n=6082 males and n=1323 females with 2179 (35.8%) and 639 (48.3%) MACE, respectively. MACE occurred in 40.4% of White, 38.1% of Hispanic, 32.9% of Filipino, 27.9% of South Asian, 29.1% of Other Asian/ Pacific Islander, 47.0% of Black, and 42.3% of Other Race/ Ethnicity patients (p<0.001). Older age, higher HbA1c, diabetes, end-stage renal disease, lower hemoglobin, higher creatinine, smoking, lack of cardiopulmonary bypass, and use of non-arterial graft were significant predictors of long-term MACE. Female sex was associated with an increased odds of MACE at 30 days (OR 1.62, 95% CI, 1.19-2.21) and 1-year (HR 1.24, 95% CI, 1.02-1.51). Asian race/ ethnicity was associated with lower 12-year hazard of MACE (HR Filipino 0.72; 95% CI, 0.60-0.87; South Asian 0.72, 95% CI, 0.50-1.03; Other Asian 0.71, 95% CI, 0.58-0.87).ConclusionFemale, Black, and Other Race/ Ethnicity groups had the greatest incidence of MACE at up to 12 years follow-up post CABG. These differences are largely driven by increased risk factor burden in these groups, and Black and Other race/ ethnicity were not independently associated with long-term CABG risk in multivariable modeling. Further understanding of the mechanisms for these sex and race/ethnic differences is required to improve upstream preventive efforts.
Environmental and geographic drivers of global bat phylogenetic diversity
Authors: Green Abigail E. , Calderón-Acevedo Camilo A. , Soto-Centeno J. Angel , Pelletier Tara A. 
Published: February 2025

AbstractAimUnderstanding patterns of biodiversity is vital to conserving species. We aimed to combine open-source genetic, environmental, and geographic information to analyze patterns of bat phylogenetic diversity (PD) in continuous ecoregions across the globe. This information is important for developing bat conservation strategies, and our methodology can work with any taxa that has sufficient georeferenced genetic data available.LocationGlobal.Time periodLast Interglacial to Present Day.Major taxa studiedChiroptera.MethodsAfter curating a global dataset containing 14,037 COI DNA sequences from 343 described species of bats, we calculated PD for two sets of continuous ecoregions at different spatial scales. To avoid the possible difficulties of using current species names, we used genetic OTUs identified by a single-locus species delimitation method to calculate PD. We then estimated a lineage through time plot and used random forest predictive modeling to identify the environmental and geographic predictors of PD.ResultsWe found that temperature variables were most closely associated with PD. In addition to temperature during the present, temperature during the last glacial maxima and temperature changes since the last interglacial were deemed important. However, when looking at different spatial scales, top variables differed slightly. Southeast Asia and South America had the highest levels of PD, along with some parts of Africa and the Himalayas. We demonstrate that, regardless of spatial scale and uneven sampling across the globe, single-locus genetic data is enough to reflect species diversity gradients.Main conclusionsWe show that publicly available, single-locus data can be used to analyze large-scale evolutionary patterns and inform effective and efficient conservation efforts. Additionally, choice of biodiversity measure and spatial scale matter when assessing species patterns. When looking at bats, temperature variables with a historical component are most important for predicting PD.
Functional interaction of electrical coupling and H-current and its putative impact on inhibitory transmission
Authors: Trigo Federico F. , Alcamí Pepe , Curti Sebastian 
Published: February 2025

AbstractThe flow of information within neural circuits depends on the communication between neurons, primarily taking place at chemical and electrical synapses. The coexistence of these two modalities of synaptic transmission and their dynamical interaction with voltage-gated membrane conductances enables a rich repertoire of complex functional operations. One such operation, coincidence detection, allows electrically coupled neurons to respond more strongly to simultaneous synaptic inputs than to temporally dispersed ones. Using the mesencephalic trigeminal (MesV) nucleus—a structure composed of large, somatically coupled neurons—as an experimental model, we first demonstrate that electrical coupling strength in the hyperpolarized voltage range is highly time-dependent due to the involvement of the IH current. We then show how this property influences the coincidence detection of hyperpolarizing signals. Specifically, simultaneous hyperpolarizing inputs induce larger membrane potential changes, resulting in stronger IH current activation. This, in turn, shortens the temporal window for coincidence detection. We propose that this phenomenon may be crucial for networks dynamics in circuits of electrically coupled neurons that receive inhibitory synaptic inputs and express the IH current. In particular, molecular layer interneurons (MLIs) of the cerebellar cortex provide an ideal model for studying coincidence detection of inhibitory synaptic inputs, and how this operation is shaped by the voltage-dependent conductances like the IH current, potentially impacting on motor coordination and learning.
Common tandem repeat variants associated with glaucoma risk in individuals of African ancestry
Authors: Pham Kenneth , Lee Roy , Di Rosa Isabel , Salowe Rebecca , Jin Fangming , Bradford Yuki , Ying Gui-Shuang , Phillips-Cremins Jennifer E. , Setia-Verma Shefali , O’Brien Joan 
Published: February 2025

AbstractThe contribution of common tandem repeats (TR) variants to common, complex disease remains unknown, especially in populations historically underrepresented in genetic research. We identified common TR variants associated with risk of primary open-angle glaucoma (POAG) in individuals of African ancestry. The POAG-associated TR variants were predominantly found at Alu poly(A) tail elements, regions, retinal development enhancers, and harbor binding sites of a POAG-associated transcription factor, LMX1B, suggesting a convergent mechanism of how common TR variation arises and contributes to POAG pathophysiology.