bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term Course of Kidney Function in Uterus Transplant Recipients Under Treatment With Tacrolimus and After Transplantectomy: Results of the First Clinical Cohort
Authors: Ekberg Jana , Hjelmberg Marie , Norén Åsa , Brännström Mats , Herlenius Gustaf , Baid-Agrawal Seema 
Published: September 2023

Background.
Chronic kidney disease is common after non-renal solid organ transplantation, mainly secondary to calcineurin inhibitors toxicity. Uterus transplantation (UTx) is an innovative treatment for women with absolute uterine factor infertility. UTx is exclusive because it is transient with the absence of lifelong immunosuppression and is performed in young healthy participants. Therefore, UTx provides a unique setting for evaluating the effect of time-limited calcineurin inhibitors treatment on recipients’ kidney function.

Methods.
In the first UTx cohort worldwide, we studied kidney function using estimated glomerular filtration rate (eGFR) in 7 women over a median follow-up of 121 (119–126) mo.

Results.
Median eGFR (mL/min/1.73 m2) of the cohort was 113 at UTx, which declined to 74 during month 3, 71 at months 10–12, 76 at hysterectomy (HE), and 83 at last follow-up. Median duration of tacrolimus exposure was 52 (22–83) mo, and median trough levels (µg/L) were 10 during month 3 and 5.8 at HE. Between UTx and month 3, decline in kidney function was observed in all 7 participants with a median eGFR slope for the whole cohort of −24 mL/min/1.73 m2, which declined further by −4 mL/min/1.73 m2 until months 10–12. Thereafter, eGFR slope improved in 3 participants, remained stable in 3, and worsened in 1 until HE/tacrolimus discontinuation, after which it improved in 2. Eventually, between UTx and last follow-up, 4 of 7 participants had a decline in their eGFR, the median annual eGFR slope being negative at −1.9 mL/min/1.73 m2/y for the whole group.

Conclusions.
Kidney function declined in all recipients early after UTx followed by a persistent long-term decrease in majority, despite transplantectomy and discontinuation of immunosuppression. Thus, UTx may incur an increased risk of chronic kidney disease even in this young and healthy population, highlighting the importance of close surveillance of kidney function and minimization of tacrolimus exposure.
Sex-Related Differences in Long-term Outcomes across the Spectrum of Ejection Fraction in Heart Failure Patients
Authors: Kawai Akane , Nagatomo Yuji , Yukino-Iwashita Midori , Ikegami Yukinori , Takei Makoto , Goda Ayumi , Kohno Takashi , Mizuno Atsushi , Kitamura Mitsunobu , Nakano Shintaro , Sakamoto Munehisa , Shiraishi Yasuyuki , Kohsaka Shun , Adachi Takeshi , Yoshikawa Tsutomu ,   WET-HF investigators
Published: September 2023

AbstractBackgroundRecently, patients with supra-normal left ventricular ejection fraction (snLVEF) are reported to have high risk of adverse outcomes, especially in women. We sought to evaluate sex-related differences in the association between LVEF and long-term outcomes in heart failure (HF) patients.MethodsThe multicenter WET-HF Registry enrolled all patients hospitalized for acute decompensated HF (ADHF). We analyzed 3,943 patients (age 77 years; 59.8% male) registered from 2006 to 2017. According to LVEF the patients were divided into the 3 groups: HF with reduced EF (HFrEF), mildly reduced EF (HFmrEF) and preserved EF (HFpEF). The primary endpoint was defined as the composite of cardiac death and ADHF rehospitalization after discharge.ResultsImplementation of guideline-directed medical therapy (GDMT) such as renin-angiotensin-system inhibitor (RASi), β-blocker and their combination at discharge was significantly lower in women than men in HFmrEF. Lower prescription of RASi + β-blocker combination in female HFmrEF was noted even after adjustment for covariates (p=0.007). There were no such sex-related differences in HFrEF. Female sex was associated with higher incidence of the primary endpoint and ADHF rehospitalization after adjustment for covariates exclusively in HFmrEF. Restricted cubic spline analysis demonstrated a U-shaped relationship between LVEF and the hazard ratio of the primary endpoint in women, but such relationship was not observed in men (pfor interaction=0.037).ConclusionsIn women, not only lower LVEF but also snLVEF were associated with worse long-term outcomes. Additionally, sex-related differences in the GDMT implementation for HFmrEF highlight the need for sex-specific guidelines to optimize HF management.
Patient Perception of Endoscopic and Medical Therapies for Weight Loss
Authors: Saumoy Monica , Gao Yinglin , Allison Kelly , Cronholm Peter F. , Pickett-Blakely Octavia , Kochman Michael L. , Thiruvengadam Nikhil R. 
Published: September 2023

AbstractBackgroundFor weight management, patient choice has increasingly driven therapeutic options, with less than 1% of eligible patients choosing bariatric surgery. The aim of this survey was to understand patient perceptions of endoscopic bariatric therapies (EBTs) and obesity-based pharmacotherapy.MethodsAn anonymously collected 7-question survey was distributed to gastroenterology patients undergoing screening colonoscopy.ResultsA total of 184 patients participated in the survey. Participants demonstrated a greater lack of knowledge of EBTs (78.2% unaware) compared to pharmacotherapy (35.9% unaware). 40.8% of respondents perceived that EBTs were not available in the United States. Only 15.8% of respondents recognized that pharmacotherapy requires long-term treatment to maintain weight loss. Disparities were noted in primarily Spanish-speaking patients demonstrating a lower awareness of the availability of EBTs in the US (57.6% unaware) and pharmacotherapy (62.1% unaware) compared to those with English as the primary language.ConclusionsPatient knowledge and preference are key to engaging in weight loss therapies. Knowledge gaps regarding weight-loss options, particularly EBTs, can limit the utilization of all options for the care of patients with obesity.
Quantitative trait loci mapping of circulating metabolites in cerebrospinal fluid to uncover biological mechanisms involved in brain-related phenotypes
Authors: Reus Lianne M. , Boltz Toni , Francia Marcelo , Bot Merel , Ramesh Naren , Koromina Maria , Pijnenburg Yolande A.L. , den Braber Anouk , van der Flier Wiesje M. , Visser Pieter Jelle , van der Lee Sven J. , Tijms Betty M. , Teunissen Charlotte E. , Loohuis Loes Olde , Ophoff Roel A. 
Published: September 2023

AbstractGenomic studies of molecular traits have provided mechanistic insights into complex disease, though these lag behind for brain-related traits due to the inaccessibility of brain tissue. We leveraged cerebrospinal fluid (CSF) to study neurobiological mechanismsin vivo, measuring 5,543 CSF metabolites, the largest panel in CSF to date, in 977 individuals of European ancestry. Individuals originated from two separate cohorts including cognitively healthy subjects (n=490) and a well-characterized memory clinic sample, the Amsterdam Dementia Cohort (ADC, n=487). We performed metabolite quantitative trait loci (mQTL) mapping on CSF metabolomics and found 126 significant mQTLs, representing 65 unique CSF metabolites across 51 independent loci. To better understand the role of CSF mQTLs in brain-related disorders, we performed a metabolome-wide association study (MWAS), identifying 40 associations between CSF metabolites and brain traits. Similarly, over 90% of significant mQTLs demonstrated colocalized associations with brain-specific gene expression, unveiling potential neurobiological pathways.
A Reinforcement Learning Model with Choice Traces for a Progressive Ratio Schedule
Authors: Ihara Keiko , Shikano Yu , Kato Sae , Yagishita Sho , Tanaka Kenji F. , Takata Norio 
Published: September 2023

AbstractThe progressive ratio (PR) lever-press task serves as a benchmark for assessing goal-oriented motivation. However, a well-recognized limitation of the PR task is that only a single data point, known as the breakpoint, is obtained from an entire session as a barometer of motivation. Because the breakpoint is defined as the final ratio of responses achieved in a PR session, variations in choice behavior during the PR task cannot be captured. We addressed this limitation by constructing four reinforcement learning models: a Simple Q- learning model, an Asymmetric model with two learning rates, a Perseverance model with choice traces, and a Perseverance model without learning. These models incorporated three behavioral choices: reinforced and non-reinforced lever presses and void magazine nosepokes (MNPs), because we noticed that mice performed frequent MNPs during PR tasks. The best model was the Perseverance model, which predicted a gradual reduction in amplitudes of reward prediction errors (RPEs) upon void MNPs. We confirmed the prediction experimentally with fiber photometry of extracellular dopamine (DA) dynamics in the ventral striatum of mice using a fluorescent protein (genetically encoded GPCR activation-based DA sensor: GRABDA2m). We verified application of the model by acute intraperitoneal injection of low-dose methamphetamine (METH) before a PR task, which increased the frequency of MNPs during the PR session without changing the breakpoint. The Perseverance model captured behavioral modulation as a result of increased initial action values, which are customarily set to zero and disregarded in reinforcement learning analysis. Our findings suggest that the Perseverance model reveals effects of psychoactive drugs on choice behaviors during PR tasks.
Septins Enable T Cell Contact GuidanceviaAmoeboid-Mesenchymal Switch
Authors: Zhovmer Alexander S. , Manning Alexis , Smith Chynna , Wang Jian , Ma Xuefei , Tsygankov Denis , Dokholyan Nikolay V. , Cartagena-Rivera Alexander X. , Singh Rakesh K. , Tabdanov Erdem D. 
Published: September 2023

ABSTRACTLymphocytes exit circulation and enter in-tissue guided migration toward sites of tissue pathologies, damage, infection, or inflammation. By continuously sensing and adapting to the guiding chemo-mechano-structural properties of the tissues, lymphocytes dynamically alternate and combine their amoeboid (non-adhesive) and mesenchymal (adhesive) migration modes. However, which mechanisms guide and balance different migration modes are largely unclear. Here we report that suppression of septins GTPase activity induces an abrupt amoeboid-to-mesenchymal transition of T cell migration mode, characterized by a distinct, highly deformable integrin-dependent immune cell contact guidance. Surprisingly, the T cell actomyosin cortex contractility becomes diminished, dispensable and antagonistic to mesenchymal-like migration mode. Instead, mesenchymal-like T cells rely on microtubule stabilization and their non-canonical dynein motor activity for high fidelity contact guidance. Our results establish septin’s GTPase activity as an important on/off switch for integrin-dependent migration of T lymphocytes, enabling their dynein-driven fluid-like mesenchymal propulsion along the complex adhesion cues.SIGNIFICANCE STATEMENTDeciphering mechanisms of guided lymphocyte migration paves the way towards effective immunotherapies for the extracellular matrix-rich tissues, such as solid tumors. Here we demonstrate that T cell septins’ GTPase activity regulates both actomyosin and microtubules, alternately enhancing either of these two major motor systems. Surprisingly, the suppression of septin GTPase activity also induces a highly guided integrin-dependent mesenchymal-like migration directed by the extracellular matrix proteins. The phenomenon of guided mesenchymal-like migration of T cells relies on the microtubules and microtubule-based dynein motors that are responsible for the force generation, powering guided T cell motility. This finding opens a new perspective for future studies of septin GTPases in a context of the optimisation of T cell-based immunotherapies for the solid tissues.
DISTINCT METABOLIC STATES DIRECT RETINAL PIGMENT EPITHELIUM CELL FATE DECISIONS
Authors: Perez-Estrada J. Raúl , Tangeman Jared A. , Proto-Newton Maeve , Sanaka Harshavardhan , Smucker Byran , Del Rio-Tsonis Katia 
Published: September 2023

ABSTRACTDuring tissue regeneration, proliferation, dedifferentiation, and reprogramming are necessary to restore lost structures. However, it is not fully understood how metabolism intersects with these processes. Chicken embryos can regenerate their retina through retinal pigment epithelium (RPE) reprogramming when treated with fibroblast factor 2 (FGF2). Using transcriptome profiling, we uncovered extensive regulation of gene sets pertaining to proliferation, neurogenesis, and glycolysis throughout RPE-to-neural retina reprogramming. By manipulating cell media composition, we determined that glucose, glutamine, or pyruvate are sufficient to support RPE reprogramming identifying glycolysis as a requisite. Conversely, the induction of oxidative metabolism by activation of pyruvate dehydrogenase induces Epithelial-to-mesenchymal transition (EMT), while simultaneously blocking the activation of neural retina fate. We also identify that EMT is partially driven by an oxidative environment. Our findings provide evidence that metabolism controls RPE cell fate decisions and provide insights into the metabolic state of RPE cells, which are prone to fate changes in regeneration and pathologies, such as proliferative vitreoretinopathy.
Gene transfer among viruses substantially contributes to gene gain of giant viruses
Authors: Wu Junyi , Meng Lingjie , Gaïa Morgan , Hikida Hiroyuki , Okazaki Yusuke , Endo Hisashi , Ogata Hiroyuki 
Published: September 2023

AbstractHorizontal gene transfers (HGTs) integrate all forms of life and viruses into a vast network of gene flow, which facilitates the transmission of genes beyond vertical inheritance and enhances genomic evolution. HGT is known to occur between closely related viruses. We hypothesized that there is frequent HGT among nucleocytoviruses, a group of diverse but evolutionarily related DNA viruses encoding hundreds to thousands of genes. However, the frequency of viral HGT (vHGT) has not been systematically investigated for nucleocytoviruses. We reconciled over 4,700 gene trees with a robust viral species tree that contains 195 reference viral genomes mainly from cultivation as a reference to infer evolutionary events, including gene gains (gene duplication, origination, and vHGT) and losses. The inferred evolutionary scenarios revealed that the genomes of these viruses have undergone numerous gene gain and loss events, with vHGT representing 28% to 42% of gene gain events in each viral order. By integrating the evolutionary paths of multiple viruses, our data suggest that vHGT is crucial for nucleocytovirus evolution.
5-hydroxymethylcytosines regulate gene expression as a passive DNA demethylation resisting epigenetic mark in proliferative somatic cells
Authors: Wei Alex , Zhang Hongjie , Qiu Qi , Fabyanic Emily B. , Hu Peng , Wu Hao 
Published: September 2023

SUMMARYEnzymatic erasure of DNA methylation in mammals involves iterative 5-methylcytosine (5mC) oxidation by the ten-eleven translocation (TET) family of DNA dioxygenase proteins. As the most abundant form of oxidized 5mC, the prevailing model considers 5-hydroxymethylcytosine (5hmC) as a key nexus in active DNA demethylation that can either indirectly facilitate replication-dependent depletion of 5mC by inhibiting maintenance DNA methylation machinery (UHRF1/DNMT1), or directly be iteratively oxidized to 5-formylcytosine (5fC) and 5-carboxycytosine (5caC) and restored to cytosine (C) through thymine DNA glycosylase (TDG)-mediated 5fC/5caC excision repair. In proliferative somatic cells, to what extent TET-dependent removal of 5mC entails indirect DNA demethylation via 5hmC-induced replication-dependent dilution or direct iterative conversion of 5hmC to 5fC/5caC is unclear. Here we leverage a catalytic processivity stalling variant of human TET1 (TET1.var: T1662E) to decouple the stepwise generation of 5hmC from subsequent 5fC/5caC generation, excision and repair. By using a CRISPR/dCas9-based epigenome-editing platform, we demonstrate that 5fC/5caC excision repair (by wild-type TET1, TET1.wt), but not 5hmC generation alone (by TET1.var), is requisite for robust restoration of unmodified cytosines and reversal of somatic silencing of the methylation-sensitive, germline-specificRHOXF2Bgene promoter. Furthermore, integrated whole-genome multi-modal epigenetic sequencing reveals that hemi-hydroxymethylated CpG dyads predominantly resist replication-dependent depletion of 5mC on the opposing strand in TET1.var-expressing cells. Notably, TET1.var-mediated 5hmC generation is sufficient to induce similar levels of differential gene expression (compared to TET1.wt) without inducing major changes in unmodified cytosine profiles across the genome. Our study suggests 5hmC alone plays a limited role in driving replication-dependent DNA demethylation in the presence of functional DNMT1/UHRF1 mechanisms, but can regulate gene expression as abona fideepigenetic mark in proliferative somatic cells.
The potential health and economic impacts of new tuberculosis vaccines under varying delivery strategies in Delhi and Gujarat, India: a modelling study
Authors: Clark Rebecca A , Portnoy Allison , Weerasuriya Chathika K , Sumner Tom , Bakker Roel , Harris Rebecca C , Rade Kirankumar , Mattoo Sanjay Kumar , Tumu Dheeraj , Menzies Nicolas A , White Richard G 
Published: September 2023

AbstractBackgroundIndia has the largest tuberculosis burden globally, but this burden varies nationwide. All-age tuberculosis prevalence in 2021 ranged from 747/100,000 in Delhi to 137/100,000 in Gujarat. Previous modelling has demonstrated the benefits and costs of introducing novel tuberculosis vaccines in India overall. However, no studies have compared the potential impact of tuberculosis vaccines in regions within India with differing tuberculosis disease and infection prevalence. We used mathematical modelling to investigate how the health and economic impact of two potential tuberculosis vaccines, M72/AS01Eand BCG-revaccination, could differ in Delhi and Gujarat under varying delivery strategies.MethodsWe applied a compartmental tuberculosis model separately for Delhi (higher disease and infection prevalence) and Gujarat (lower disease and infection prevalence), and projected epidemiological trends to 2050 assuming no new vaccine introduction. We simulated M72/AS01Eand BCG-revaccination scenarios varying target ages and vaccine characteristics. We estimated cumulative cases, deaths, and disability-adjusted life years averted between 2025–2050 compared to the no-new-vaccine scenario and compared incremental cost-effectiveness ratios to three cost-effectiveness thresholds.ResultsM72/AS01Eaverted a higher proportion of tuberculosis cases than BCG-revaccination in both regions (Delhi: 16.0% vs 8.3%, Gujarat: 8.5% vs 5.1%) and had higher vaccination costs (Delhi: USD$118 million vs USD$27 million, Gujarat: US$366 million vs US$97 million). M72/AS01Ein Delhi could be cost-effective, or even cost-saving, for all modelled vaccine characteristics. M72/AS01Ecould be cost-effective in Gujarat, unless efficacy was assumed only for those with current infection at vaccination. BCG-revaccination could be cost-effective, or cost-saving, in both regions for all modelled vaccine scenarios.DiscussionM72/AS01Eand BCG-revaccination could be impactful and cost-effective in Delhi and Gujarat. Differences in impact, costs, and cost-effectiveness between vaccines and regions, were determined partly by differences in disease and infection prevalence, and demography. Age-specific regional estimates of infection prevalence could help to inform delivery strategies for vaccines that may only be effective in people with a particular infection status. Evidence on the mechanism of effect of M72/AS01Eand its effectiveness in uninfected individuals, which were important drivers of impact and cost-effectiveness, particularly in Gujarat, are also key to improve estimates of population-level impact.
A Window into Mammalian Basement Membrane Development: Insights from themTurq2-Col4a1Mouse Model
Authors: Jones Rebecca A. , Trejo Brandon , Sil Parijat , Little Katherine A. , Pasolli H. Amalia , Joyce Bradley , Posfai Eszter , Devenport Danelle 
Published: September 2023

AbstractBasement membranes (BMs) are specialized sheets of extracellular matrix that underlie epithelial and endothelial tissues. BMs regulate traffic of cells and molecules between compartments, and participate in signaling, cell migration and organogenesis. The dynamics of mammalian BMs, however, are poorly understood, largely due to a lack of models in which core BM components are endogenously labelled. Here, we describe themTurquoise2-Col4a1mouse, in which we fluorescently tag collagen IV, the main component of BMs. Using an innovative Planar-Sagittal live imaging technique to visualize the BM of developing skin, we directly observe BM deformation during hair follicle budding and basal progenitor cell divisions. The BM’s inherent pliability enables dividing cells to remain attached to and deform the BM, rather than lose adhesion as generally thought. Using FRAP, we show BM collagen IV is extremely stable, even during periods of rapid epidermal growth. These findings demonstrate the utility of themTurq2-Col4a1mouse to shed new light on mammalian BM developmental dynamics.
p38-MAPK is prerequisite for the synthesis of SARS-CoV-2 protein
Authors: Mittal Priyasi , Khandelwal Nitin , Chander Yogesh , Verma Assim , Kumar Ram , Putatunda Chayanika , Barua Sanjay , Gulati Baldev Raj , Kumar Naveen 
Published: September 2023

AbstractThe inhibition of p38 mitogen-activated protein kinase (p38-MAPK) by small molecule chemical inhibitors was previously shown to impair severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) replication, however, mechanisms underlying antiviral activity remains unexplored. In this study, reduced growth of SARS-CoV-2 in p38-α knockout Vero cells, together with enhanced viral yield in cells transfected with construct expressing p38α, suggested that p38-MAPK is essential for the propagation of SARS-CoV-2. The SARS-CoV-2 was also shown to induce phosphorylation (activation) of p38, at time when transcription/translational activities are considered to be at the peak levels. Further, we demonstrated that p38 supports viral RNA/protein synthesis without affecting viral attachment, entry, and budding in the target cells. In addition, we demonstrated that long-term culture of SARS-CoV-2 in the presence of p38 inhibitor SB203580 does not easily select resistant viral mutants. In conclusion, we provide mechanistic insights on the regulation of SARS-CoV-2 replication by p38 MAPK.