bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-effectiveness of a 4 days-a-week triple therapy in persons living with HIV: an ancillary study of the ANRS 170 QUATUOR noninferiority trial
Authors: Hejblum Gilles , Daher Samih , Moulaire Paul , Amat Karine , Lambert-Niclot Sidonie , Allavena Clotilde , Katlama Christine , Lacombe Karine , Ponscarme Diane , Ghosn Jade , Gibowski Severine , Alvarez Jean-Claude , Capeau Jacqueline , Morand-Joubert Laurence , Costagliola Dominique , De Truchis Pierre , Landman Roland , Assoumou Lambert 
Published: September 2024

ABSTRACTBackgroundANRS 170 QUATUOR study (NCT03256422) demonstrated the noninferiority of a triple antiretroviral therapy (ART) taken 4 days a week (4/7-days) compared to a triple therapy taken 7 days a week (7/7-days) for persons living with HIV and with suppressed viremia. We aimed at investigating corresponding cost-effectiveness issues.MethodsAll persons involved in the primary analysis of the QUATUOR noninferiority trial were considered (N=636, 318 per arm) in this cost-effectiveness study. Time horizon was the first 48 weeks of the trial. Effectiveness was considered as the noninferiority of the 4/7-days strategy, main criterion of the trial primary analysis. Direct health resource costs (year2022€) were considered and included costs for ART, laboratory tests, co-medications, hospitalizations, and medical consultations. Analyses were based on 10,000 simulations replicating the trial. Additional analyses explored the national impact of spreading the 4/7-days strategy all over France. Sensitivity analyses included considering treatment success as effectiveness, and various proportions of persons adopting the 4/7-days strategy.FindingsThe mean individual total costs amounted to € 5,049 [95% confidence interval: 4,798–5,345] and € 8,089 [7,706–8,527] in the 4/7-days and 7/7-days arm, respectively. Corresponding ART costs were € 3,678 [3,593–3,763] and € 6,450 [6,301–6,596], respectively (p<0.0001), and constituted the single cost element with a statistical difference between the two strategies. Considering noninferiority as the effectiveness criterion in a health economic perspective, the 4/7-day strategy provided average savings of € 3,013 [2829–3196] in ART costs per individual and per year. Adopting the 4/7-days regimen in 20% of the potential recipients in France was estimated to provide annual savings of € 61,752,467 [61,569,005; 61,925,136].InterpretationThe 4/7-day strategy dominates the 7/7-day strategy since it spares substantial ART costs while maintaining treatment effectiveness. Study results support generalizing the adoption of 4/7-days triple ART regimens in France, when possible.
Pruritus and its Association with Cancer and Mortality in Dermatomyositis and Polymyositis: A Nationwide Cohort Study in Taiwan from 2005 to 2022
Authors: Huang Der-Jr , Shao Yu-Hsuan Joni , Shih Yi-Hsien , Lee Woan-Ruoh , Huang Ling-Ya , Kuo Yu-Min , Pham Quoc Thao Trang , Weng Hao-Jui 
Published: September 2024

AbstractBackgroundPruritus is the most common initial symptom reported by patients with dermatomyositis and polymyositis. However, there is limited data regarding the impact of pruritus on cancer and mortality in patients with dermatomyositis and polymyositis.ObjectiveTo investigate the associations of pruritus to cancer and mortality in patients with dermatomyositis and polymyositis.MethodsThis nationwide, population-based retrospective cohort study included adult dermatomyositis and polymyositis patients from Taiwan’s National Health Insurance Research Database between 2005 and 2022. Sex- and age-matched pruritic patients, identified by over six weeks of antipruritic medication use, and nonpruritic patients were analyzed. The primary outcome was cancer occurrence or all-cause mortality.ResultsAmong 919 matched pairs of pruritic and non-pruritic patients, cancer was observed in 19.96% in the long-term pruritic group, 14.63% in the short-term pruritic group, and 10.34% in the nonpruritic group (p<0.0001). All-cause mortality was documented at 30.37% in the long-term pruritic group, 29.69% in the short-term pruritic group, and 37.76% in the nonpruritic group (p<0.0001). Pruritus was associated with an increased risk of cancer (hazard ratio 1.492, 95% confidence interval 1.093-2.036), and a lower risk of all-cause mortality (hazard ratio 0.489, 95% confidence interval 0.419-0.571).ConclusionThis population-based study revealed pruritus appeared to be associated with increased cancer risk and decreased all-cause mortality. Thus, pruritus may serve as a pragmatic factor for risk stratification and tailored treatment strategies in dermatomyositis and polymyositis. Comprehensive cancer screening is recommended for patients with dermatomyositis or polymyositis, particularly those presenting with pruritus, whereas patients without pruritus may require vigilant management for potentially life-threatening complications and comorbidities.Key pointsPrevious single-institutional studies and studies with small cohorts reported conflicting data regarding the impact of pruritus on cancer and mortality in patients with dermatomyositis and polymyositisPruritus in dermatomyositis and polymyositis appeared to be associated with increased cancer risk and decreased all-cause mortality.Our findings suggest that pruritus may serve as a pragmatic factor for risk stratification and tailored treatment strategies in dermatomyositis and polymyositis.
Properties of rhythmogenic currents in spinal Shox2 interneurons across postnatal development
Authors: Singh Shayna , Yao Lihua , Shevtsova Natalia A. , Rybak Ilya A. , Dougherty Kimberly J. 
Published: September 2024

AbstractLocomotor behaviors are performed by organisms throughout life, despite developmental changes in cellular properties, neural connectivity, and biomechanics. The basic rhythmic activity in the central nervous system that underlies locomotion is thought to be generated via a complex balance between network and intrinsic cellular properties. Within mature mammalian spinal locomotor circuitry, we have yet to determine which properties of spinal interneurons (INs) are critical to rhythmogenesis and how they change during development. Here, we combined whole cell patch clamp recordings, immunohistochemistry, and RNAscope targeting lumbar Shox2 INs in mice, which are known to be involved in locomotor rhythm generation. We focused on the properties of putatively rhythmogenic ionic currents and the expression of corresponding ion channels across postnatal time points in mice. We show that subsets of Shox2 INs display voltage-sensitive conductances, in addition to respective ion channels, which may contribute to or shape rhythmic bursting. Persistent inward currents, M-type potassium currents, slow afterhyperpolarization, and T-type calcium currents are enhanced with age. In contrast, the hyperpolarization-activated and A-type potassium currents were either found with low prevalence in subsets of neonatal, juvenile, and adult Shox2 INs or did not developmentally change. We show that Shox2 INs become more electrophysiologically diverse by juvenile and adult ages, when locomotor behavior is weight-bearing. These results suggest a developmental shift in the magnitude of rhythmogenic ionic currents and the expression of corresponding ion channels that may be important for mature, weight-bearing locomotor behavior.
Regulation of alternative polyadenylation isoforms ofTimp2is an effector event of RAS signaling in cell transformation
Authors: Ai Yuxi , Ding Qingbao , Wan Zezhong , Tyagi Sanjay , Indeglia Alexandra , Murphy Maureen , Tian Bin 
Published: September 2024

SUMMARYAlternative polyadenylation (APA) generates mRNA isoforms with different lengths of the 3’ untranslated region (3’ UTR). The tissue inhibitor of metalloproteinase 2 (TIMP2) plays a key role in extracellular matrix remodeling under various developmental and disease conditions. Both human and mouse genes encoding TIMP2 contain two highly conserved 3’UTR APA sites, leading to mRNA isoforms that differ substantially in 3’UTR size. APA ofTimp2is one of the most significantly regulated events in multiple cell differentiation lineages. Here we show thatTimp2APA is highly regulated in transformation of NIH3T3 cells by the oncogene HRASG12V. Perturbations of isoform expression with long 3’UTR isoform-specific knockdown or genomic removal of the alternative UTR (aUTR) region indicate that the long 3’UTR isoform contributes to the secreted Timp2 protein much more than the short 3’UTR isoform. The short and long 3’UTR isoforms differ in subcellular localization to endoplasmic reticulum (ER). Strikingly,Timp2aUTR enhances secreted protein expression but no effect on intracellular proteins in reporter assays. Furthermore, downregulation ofTimp2long isoform mitigates gene expression changes elicited by HRASG12V. Together, our data indicate that regulation of Timp2 protein expression through APA isoform changes is an integral part of RAS-mediated cell transformation and 3’UTR isoforms ofTimp2can have distinct impacts on expression of secreted vs. intracellular proteins.
A binding site for the antibiotic GE81112 in the ribosomal mRNA channel
Authors: Schedlbauer Andreas , Han Xu , van Bakel Wouter , Kaminishi Tatsuya , Ochoa-Lizarralde Borja , Iturrioz Idoia , Çapuni Retina , Parry Ransford , Zegarra Ronny , Gil-Carton David , López-Alonso Jorge P. , Sanz Kristina Barragan , Brandi Letizia , Gualerzi Claudio O. , Fucini Paola , Connell Sean R. 
Published: September 2024

ABSTRACTThe initiation phase is the rate-limiting step of protein synthesis (translation) and is finely regulated, making it an important drug target. In bacteria, initiation is guided by three initiation factors and involves positioning the start site on the messenger RNA within the P-site on the small ribosomal subunit (30S), where it is decoded by the initiator tRNA. This process can be efficiently inhibited by GE81112, a natural hydrophilic, noncyclic, nonribosomal tetrapeptide. It is found in nature in three structural variants (A, B and B1 with molecular masses of 643-658 Da). Previous biochemical and structural characterisation of GE81112 indicates that the primary mechanism of action of this antibiotic is to (1) prevent the initiator tRNA from binding correctly to the P-site and (2) block conformational rearrangements in initiation factor IF3, resulting in anunlocked30S preICstate. In this study, using cryoEM, we have determined the binding site of GE81112 in initiation complexes (3.2-3.7Å) and on empty ribosomes (2.09 Å). This binding site is within the mRNA channel (E-site) but remote from the binding site of the initiation factors and initiator tRNA. This suggests that it acts allosterically to prevent the initiator tRNA from being locked into place. The binding mode is consistent with previous biochemical studies and recent work identifying the key pharmacophores of GE81112.
Single cell RNA-sequencing of malaria merozoites reveals that the parasite prepares for life within the red blood cell by activating a gene network
Authors: Piel Laura , Hernandez Celine , Jaszczyszyn Yan , Naquin Delphine , Santos Joana M. 
Published: September 2024

AbstractThe intraerythrocytic developmental cycle (IDC) during which the malaria parasitePlasmodium falciparummultiplies asexually within the human host red blood cell is the symptomatic stage of the life cycle. The IDC initiates when parasite stages called merozoites are released into the bloodstream, following schizont rupture, and invade the host red blood cells. The merozoite is the less studied stage of the IDC, despite its importance for the establishment of infection. We did the first transcriptional profiling of merozoites throughout development inside the schizont and after egress. Merozoites within the schizont, activate a series of tightly regulated gene expression programs, each encoding for proteins implicated in a specific process required for invasion and life within the host. After schizont egress, free merozoites still express some of these programs. Upon invasion, ring cells have a distinct transcriptional profile. The gene expression programs are regulated by specific transcription factors and chromatin accessibility as well as post-transcriptional mechanisms. Our work gains unprecedent insight into gene expression prior to and during host cell invasion and identifies potential new antimalarial targets.Author SummaryThe malaria parasitePlasmodium falciparum, which causes the death of over half a million people each year, has a complex life cycle but symptoms only arise when the parasite invades and develops inside the host red blood cells. The merozoites are responsible for invading the human red blood cells but because they are only briefly extracellular, their gene expression profile had yet to be determined. Here we used single cell RNA-sequencing to establish the gene expression program of merozoites throughout development inside schizonts and once free, prior to host cell invasion. We found that, in order to prepare for invasion and life within the host cell, merozoites activate a series of gene expression programs, each encoding for proteins implicated in a specific process. While some of the genes expressed by merozoites during maturation are still expressed in free merozoites, these transcripts are no longer detected after host cell invasion. This implicates tight regulation of gene expression. We suggest that regulation implicates binding of specific transcription factors, epigenetics as well as post-transcriptional mechanisms.
Heavy-tailed statistics of cortical representational drift are advantageous for stabilised downstream readouts
Authors: Micou Charles , O’Leary Timothy 
Published: September 2024

AbstractNeural representations of familiar environments and mastered tasks continue to change despite no further refinements to task performance or encoding efficiency. Downstream brain regions that depend on a steady supply of information from a neural population subject to this representational drift face a challenge: they must stabilise their readout using only statistical regularities in neural activity. Recent studies have described how representational drift induces deterioration in the accuracy of fixed decoders. Here, we highlight that while a variety of underlying statistics of drift at the level of individual neurons can produce comparable deterioration of a fixed decoder, these different statistics result in dramatically different deterioration rates in adaptive decoders. We describe an adaptive decoding strategy that can read out from a model drifting population long after fixed decoders degrade completely, and demonstrate that in simulated models this strategy is better-suited to heavy-tailed drift statistics, in which individual neurons make sudden and large changes in tuning. We investigate the extent to which these advantageous statistics manifest in experimental in-vivo measurements of drift by considering two existing and well-studied datasets that observe drift in the posterior parietal cortex and the visual cortex. We find preliminary support for sudden jumps in neural tuning that would allow a downstream observer to more easily distinguish changes in representation from noise. These observations are a step towards refining the larger picture of mechanisms underpinning the robustness of information transfer between brain regions that can function in spite of changes in representation driven both by drift and by the learning of new information.
Plasminogen Activator Inhibitor-1 is internalized by endothelial cells via macropinocytosis to evade degradation
Authors: McAdow Molly , Ahmetaj Gjina , Hauschel Rachel , Eichmann Anne , Sessa William 
Published: September 2024

AbstractPlasminogen activator inhibitor1 (PAI1) promotes hemostasis and is a biomarker of cardiovascular disease but accumulating evidence supports a role for PAI1 in intracellular biology. Recently, we found that PAI1 directly inhibits endothelial nitric oxide synthase (eNOS) and that exogenous PAI1 is internalized and traffics to eNOS. However, prior work has demonstrated that when PAI1 is internalized via LRP1 and uPAR on the cell surface and is internalized and degraded. Our objective was to identify the mechanism by which PAI1 is internalized and evades degradation. Here, we show that PAI1 is internalized by endothelial cells in an energy-dependent manner and persists in the cell for at least 6 hours. Entry is independent of LRP1, uPAR, or clathrin-mediated endocytosis. It is internalized in large vesicles, is inhibited by amiloride and nocodazole, and is partially dependent on CDC42, consistent with macropinocytosis. We propose that following internalization by macropinocytosis, PAI1 evades degradation, permitting eNOS inhibition.
Identification of Human Pathways Acting on Nuclear Non-Coding RNAs Using the Mirror Forward Genetic Approach
Authors: Che Rui , Panah Monireh , Mirani Bhoomi , Knowles Krista , Ostapovich Anastacia , Majumdar Debarati , Chen Xiaotong , DeSimone Joseph , White William , Noonan Megan , Luo Hong , Alexandrov Andrei 
Published: September 2024

SUMMARYDespite critical roles in diseases, human pathways acting on strictly nuclear non-coding RNAs have been refractory to forward genetics. To enable their forward genetic discovery, we developed a single-cell approach that “Mirrors” activities of nuclear pathways with cytoplasmic fluorescence. Application of Mirror to two nuclear pathways targeting MALAT1’s 3′ end, the pathway of its maturation and the other, the degradation pathway blocked by the triple-helical Element for Nuclear Expression (ENE), identified nearly all components of three complexes: Ribonuclease P and the RNA Exosome, including nuclear DIS3, EXOSC10, and C1D, as well as the Nuclear Exosome Targeting (NEXT) complex. Additionally, Mirror identified DEAD-box helicase DDX59 associated with the genetic disorder Oral-Facial-Digital syndrome (OFD), yet lacking known substrates or roles in nuclear RNA degradation. Knockout of DDX59 exhibits stabilization of the full-length MALAT1 with a stability-compromised ENE and increases levels of 3′-extended forms of small nuclear RNAs. It also exhibits extensive retention of minor introns, including in OFD-associated genes, suggesting a mechanism for DDX59 association with OFD. Mirror efficiently identifies pathways acting on strictly nuclear non-coding RNAs, including essential and indirectly-acting components, and, as a result, uncovers unexpected links to human disease.
Adult choline supplementation in a Down syndrome model reduces co-morbidities and improves cognition
Authors: Tallino Savannah , Etebari Rachel , McDonough Ian , Leon Hector , Sepulveda Isabella , Winslow Wendy , Bartholomew Samantha , Perez Sylvia E. , Mufson Elliott J. , Velazquez Ramon 
Published: September 2024

ABSTRACTDown syndrome (DS) is the most common cause of early-onset Alzheimer’s disease (AD). Dietary choline has been proposed as a modifiable factor to improve cognitive and pathological outcomes of AD, especially as many do not reach adequate daily intake levels. Perinatal choline supplementation (Ch+) in the Ts65Dn mouse model of DS protects offspring against AD-relevant pathology and improves cognition, and dietary Ch+ in adult AD models also ameliorates pathology and improves cognition. However, dietary Ch+ in adult Ts65Dn mice has not yet been explored. To test whether Ch+ in adulthood improves DS co-morbidities, we fed trisomic Ts65Dn mice and disomic littermate controls with either choline normal (ChN; 1.1 g/kg) or Ch+ (5 g/kg) diets from 4.5-14 months of age. We found that Ch+ improved cognitive flexibility in a reverse place preference task and reduced weight gain and peripheral inflammation in female mice, whereas Ch+ improved glucose metabolism in male mice. In conclusion, we found that adulthood Ch+ benefits behavioral and biological factors important for general well-being in DS and related to AD risk.
Evidence of genetic isolation and differentiation among historically fragmented British populations of common juniper,Juniperus communisL.
Authors: Baker J. , Cottrell J. , Ennos R. , Perry A. , A’Hara S. , Green S. , Cavers S. 
Published: September 2024

AbstractHabitat fragmentation and populations isolation pose a threat to the genetic diversity and adaptability of many species. The common juniper, Juniperus communis L., a keystone species for juniper scrub habitat and one of only three conifers that are native to the UK, has been in decline for more than a century in the UK and across its European range. Remnant UK juniper populations are now highly fragmented and often small, which has raised concerns for their resilience, especially in the face of climate change and the introduction of novel pathogens, such as Phytophthora austrocedri. This work presents a baseline genetic survey of native UK juniper populations and compares patterns of diversity between populations and among three population centres in southern England, the Lake District, and Scotland using both Single Nucleotide Polymorphism (SNP) and Simple Sequence Repeat (SSR) genetic markers. The aim was to evaluate the standing genetic diversity of native juniper stands, the impacts of habitat fragmentation, and to determine whether juniper populations are genetically isolated from one another. We found that juniper populations, while not completely isolated from one another, face substantial barriers to gene flow, especially between the three population centres. These centres also show different patterns of genetic diversity, indicating varying levels of internal gene flow and inbreeding. Our findings can form a baseline from which to monitor the effectiveness of conservation activities, prioritize populations of concern, and guide genetic rescue efforts.