bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-effectiveness of broadly neutralizing antibodies for infant HIV prophylaxis in settings with high HIV burdens: a simulation modeling study
Authors: Alba Christopher , Malhotra Shelly , Horsfall Stephanie , Barnhart Matthew E. , Bekker Adrie , Chapman Katerina , Cunningham Coleen K. , Fast Patricia E. , Fouda Genevieve G. , Freedberg Kenneth A. , Goga Ameena , Ghazaryan Lusine R. , Leroy Valériane , Mann Carlyn , McCluskey Margaret M. , McFarland Elizabeth J. , Muturi-Kioi Vincent , Permar Sallie R. , Shapiro Roger , Sok Devin , Stranix-Chibanda Lynda , Weinstein Milton C. , Ciaranello Andrea L. , Dugdale Caitlin M. 
Published: November 2023

ABSTRACTIntroductionApproximately 130 000 infants acquire HIV annually despite global maternal antiretroviral therapy scale-up. We evaluated the potential clinical impact and cost-effectiveness of offering long-acting, anti-HIV broadly neutralizing antibody (bNAb) prophylaxis to infants in three distinct settings.MethodsWe simulated infants in Côte d’Ivoire, South Africa, and Zimbabwe using the Cost-Effectiveness of Preventing AIDS Complications-Pediatric (CEPAC-P) model. We modeled strategies offering a three-bNAb combination in addition to WHO-recommended standard-of-care oral prophylaxis to infants: a) with known, WHO-defined high-risk HIV exposure at birth (HR-HIVE); b) with known HIV exposure at birth (HIVE); or c) with or without known HIV exposure (ALL). Modeled infants received1-dose,2-doses, orExtended(every 3 months through 18 months) bNAb dosing. Base case model inputs included 70% bNAb efficacy (sensitivity analysis range: 10-100%), 3-month efficacy duration/dosing interval (1-6 months), and $20/dose cost ($5-$100/dose). Outcomes included pediatric HIV infections, life expectancy, lifetime HIV-related costs, and incremental cost-effectiveness ratios (ICERs, in US$/year-of-life-saved [YLS], assuming a<50% GDP per capita cost-effectiveness threshold).ResultsThe base case model projects that bNAb strategies targetingHIVEandALLinfants would prevent 7-26% and 10-42% additional pediatric HIV infections, respectively, compared to standard-of-care alone, ranging by dosing approach.HIVE-Extendedwould be cost-effective (cost-saving compared to standard-of-care) in Côte d’Ivoire and Zimbabwe;ALL-Extendedwould be cost-effective in South Africa (ICER: $882/YLS). BNAb strategies targetingHR-HIVEinfants would result in greater lifetime costs and smaller life expectancy gains thanHIVE-Extended. Throughout most bNAb efficacies and costs evaluated in sensitivity analyses, targetingHIVEinfants would be cost-effective in Côte d’Ivoire and Zimbabwe, and targetingALLinfants would be cost-effective in South Africa.DiscussionAdding long-acting bNAbs to current standard-of-care prophylaxis would be cost-effective, assuming plausible efficacies and costs. The cost-effective target population would vary by setting, largely driven by maternal antenatal HIV prevalence and postpartum incidence.
Compare SGLT2I versus non-SGLT2I users in type-2 diabetic mellitus patients on GLP-1 receptor agonist: A population-based and machine learning causal inference analysis
Authors: Luo Zhiyao , Chou Oscar Hou-In , Ng Zita Man Wai , Chung Cheuk To Skylar , Chan Jeffrey Shi Kai , Chan Raymond Ngai Chiu , Lu Lei , Zhu Tingting , Cheung Bernard Man Yung , Liu Tong , Tse Gary , Zhou Jiandong 
Published: November 2023

AbstractBackgroundBoth sodium-glucose cotransporter-2 (SGLT2) inhibitors and GLP-1 receptor agonists (GLP1a) demonstrated benefits against cardiovascular diseases in type 2 diabetes (T2D). However, the effects of SGLT2I amongst patients already on GLP1a users remain unknown.ObjectiveThis real-world study compared the risks of cardiovascular diseases with and without exposure to SGLT2I amongst GLP1a users.MethodsThis was a retrospective population-based cohort study of patients with type-2 diabetes mellitus (T2DM) on GLP1a between 1st January 2015 and 31st December 2020 using a territory-wide registry from Hong Kong. The primary outcomes were new-onset myocardial infarction, atrial fibrillation, heart failure, and stroke/transient ischaemic attack (TIA). The secondary outcome was all-cause mortality. Propensity score matching (1:2 ratio) using the nearest neighbour search was performed. Multivariable Cox regression was used to identify significant associations. The machine learning causal inference analysis was used to estimate the treatment effect.ResultsThis cohort included 2526 T2DM patients on GLP1a (median age: 52.5 years old [SD: 10.9]; 57.34 % males). The SGLT2I users and non-SGLT2I users consisted of 1968 patients and 558 patients, respectively. After matching, non-SGLT2I users were associated with high risks of myocardial infarction (Hazard ratio [HR]: 2.91; 95% Confidence Interval [CI]: 1.30-6.59) and heart failure (HR: 2.49; 95% CI: 1.22-5.08) compared to non-SGLT2I users after adjusting for demographics, comorbidities, medications, renal function, and glycaemic tests. However, non-SGLT2I users were not associated with the risks of atrial fibrillation (HR: 1.52; 95% CI: 0.65-3.53) and stroke/TIA (HR: 1.72; 95% CI: 0.70-4.24). The results remained consistent in the competing risk and the sensitivity analyses.ConclusionsSGLT2I non-users was associated with higher risks of myocardial infarction and heart failure when compared to SGLT2I users after adjustments amongst T2DM patients on GLP1a. The result remained consistent in the machine learning causal inference analysis.Graphical abstract
Genomic insights into the evolution of secondary metabolism ofEscovopsisand its allies, specialized fungal symbionts of fungus-farming ants
Authors: Berasategui Aileen , Salem Hassan , Moller Abraham G. , Christopher Yuliana , Vidaurre-Montoya Quimi , Conn Caitlin , Read Timothy D. , Rodrigues Andre , Ziemert Nadine , Gerardo Nicole 
Published: November 2023

AbstractThe metabolic intimacy of symbiosis often demands the work of specialists. Natural products and defensive secondary metabolites can drive specificity by ensuring infection and propagation across host generations. But in contrast to bacteria, little is known about the diversity and distribution of natural product biosynthetic pathways among fungi and how they evolve to facilitate symbiosis and adaptation to their host environment. In this study, we define the secondary metabolism ofEscovopsisand closely related genera, members of which are specialized, diverse ascomycete fungi best known as mycoparasites of the fungal cultivars grown by fungus-growing ants. We ask how the gain and loss of various biosynthetic pathways corresponds to divergent lifestyles. Long-read sequencing allowed us to define the chromosomal features of representativeEscovopsisstrains, revealing highly reduced genomes (21.4-38.3 Mb) composed of 7-8 chromosomes.Escovopsisgenomes are highly co-linear, with genes localizing not only in the same chromosome, but also in the same order. Macrosynteny is high withinEscovopsisclades, and decreases with increasing phylogenetic distance, while maintaining a high degree of mesosynteny. To explore the evolutionary history of biosynthetic pathways in this group of symbionts relative to their encoding lineages, we performed an ancestral state reconstruction analysis, which revealed that, while many secondary metabolites are shared with non-ant associated sordariomycetes, 56 pathways are unique to the symbiotic genera. Reflecting adaptation to diverging ant agricultural systems, we observe that the stepwise acquisition of these pathways mirrors the ecological radiations of attine ants and the dynamic recruitment and replacement of their fungal cultivars. As different clades encode characteristic combinations of biosynthetic gene clusters, these delineating profiles provide important insights into the possible mechanisms underlying specificity between these symbionts and their hosts. Collectively, our findings shed light on the evolutionary dynamic nature of secondary metabolism inEscovopsisand its allies, reflecting adaptation of the symbionts to an ancient agricultural system.
The puzzling case of the 3p25 homozygous deletion: the target is notVHLbutVGLL4andATG7
Authors: Muller Florian , Behr Eliot 
Published: November 2023

AbstractThe 3p25 locus experiences recurrent homozygous deletions in diverse carcinomas. A validated tumor suppressor gene (TSG),VHLhas long been assumed to be the target of this deletion.Here, we show that homozygous deletions at the 3p25 locus are common in renal clear cell carcinoma (RCC) and squamous cell carcinomas but that these do not center onVHLbut on two nearby overlapping genes,VGLL4andATG7. While hypomorphic mutations ofVHLcoupled with heterozygous deletions are undoubtedly a driver in RCC, DepMap CRISPR data indicate that the complete absence ofVHLis broadly detrimental to cancer cells. Re-examination of TCGA and PDX data calls into question whetherVHLis ever homozygous deleted, even in RCC.Instead, multiple lines of evidence support the homozygous deletion ofVGLL4as a driver event in squamous cell carcinomas and the homozygous deletion ofATG7as a driver in RCC, with important implication for precision oncology. VGLL4 is the major negative regulator of the YAP/TEAD complex, with elimination of VGLL4 leading to hyperactive oncogenic YAP-dependent transcriptional activity which could be targeted by clinically emerging YAP/TEAD inhibitors. ATG7 is a critical regulator of autophagy, limiting proliferation in conditions of nutrient limitation and its deletion may open novel vulnerabilities for synthetic lethality.
Single cell transcriptional profiling of benign prostatic hyperplasia reveals a progenitor-like luminal epithelial cell state within an inflammatory microenvironment
Authors: Unno Rei , Akutagawa Jon , Song Hanbing , Hui Keliana , Chen Yih-An , Pham Julia , Yang Heiko , Huang Franklin W. , Chi Thomas 
Published: November 2023

AbstractBenign prostatic hyperplasia (BPH) is characterized by excessive cell proliferation and inflammation and affects most aging men. The development of new therapies for BPH requires a deeper understanding of the underlying pathophysiology and cellular components of BPH. Here, we characterize at single cell resolution the cellular states of BPH and identify cell populations enriched in BPH that contribute to cell proliferation and inflammation. Single-cell RNA-sequencing was performed on prostate tissue from 15 patients undergoing holmium laser enucleation of the prostate for treatment of BPH. Clustering and differential expression analysis on aligned single cell RNA-seq data was performed to annotate all cell types. Pseudotime, gene set enrichment, gene ontology, and ligand-receptor analyses were performed. 16,234 cells were analyzed and specific stromal, epithelial, and immune subgroups were found to be strongly associated with inflammation. A rare luminal subgroup was identified and pseudotime analysis indicated this luminal subgroup was more closely related to club and basal cells. Using a gene set derived from epithelial stem cells, we found that this luminal subgroup had a significantly higher stem cell signature score than all other epithelial subgroups, suggesting this subgroup is a luminal precursor state. Ligand-receptor interactions between stromal, epithelial, and immune cells were explored with CellPhoneDB. Unique interactions highlighting MIF, a pro-inflammatory cytokine that promotes epithelial cell growth and inflammation in the prostate, were found between fibroblasts and the progenitor luminal subgroup. This luminal subgroup also interacted with neutrophils and macrophages through MIF. Our single-cell profiling of BPH provides a roadmap for inflammation-linked cell subgroups and highlights a novel luminal progenitor subgroup interacting with other cell groups via MIF that may contribute to the inflammation and cell proliferation phenotype associated with BPH.
Understanding Age-Related Changes in Proprioception through Active and Passive Tasks
Authors: Carranza Erick , Franovic Sreten , Boos Amy , Pirondini Elvira 
Published: November 2023

AbstractVoluntary control of motor actions requires precise regulation of proprioceptive and somatosensory functions. While aging has demonstrated to decline sensory processing functions, the effect of age on proprioception remains less clear. Indeed, previous studies contradict on whether passive proprioception (i.e., during externally driven movements) is affected over age. Moreover, no studies explored age-related modifications in active proprioception (i.e., during voluntary movements). Understanding these changes is critical to identify and prevent possible causes of reduced movement performances and mobility, in particular in age-related neurological conditions such as stroke or Parkinson disease. Here, we first refined a robotic protocol to assess upper-limb active proprioception and demonstrated the robustness and reliability of outcome measures over sessions. We then compared performances between young and elderly subjects during active and passive proprioceptive tasks. We found that while the two populations of subjects performed similarly in passive proprioception, elderly subjects’ acuity declined during active proprioception. Importantly, we confirmed that the decline could not be explained by impairments in voluntary motor control. Our data and robotic protocols further elucidate the debate over proprioception in elderly subjects and provide evidence that robust proprioceptive assessments should be an essential measurement in clinical settings.New & NoteworthyUpper limb position sense has been previously evaluated using passive matching protocols with the contralateral arm. These studies have found contradicting results regarding a possible decline in passive proprioception over age. Here we replicated this passive protocol and compared it to its active counterpart. Our results suggest that aging has an effect only in the active condition, leading to the hypothesis of a potential role of the cortico-spinal and cerebellar pathways in proprioception decline.
Inhibition of mitochondrial protein import and proteostasis by a pro-apoptotic lipid
Authors: Fita-Torró Josep , Garrido-Huarte José Luis , López-Gil Lucía , Michel Agnès H. , Kornmann Benoît , Pascual-Ahuir Amparo , Proft Markus 
Published: November 2023

AbstractMitochondria-mediated cell death is critically regulated by bioactive lipids derived from sphingolipid metabolism. The lipid aldehyde trans-2-hexadecenal (t-2-hex) induces mitochondrial dysfunction from yeast to humans. Here we apply unbiased transcriptomic, functional genomics and chemoproteomic approaches in the yeast model to uncover the principal mechanisms and biological targets underlying this lipid-induced mitochondrial inhibition. We find that loss of Hfd1 fatty aldehyde dehydrogenase function efficiently sensitizes cells for t-2-hex inhibition and apoptotic cell death. Excess of t-2-hex causes a profound transcriptomic response with characteristic hallmarks of impaired mitochondrial protein import like activation of mitochondrial and cytosolic chaperones or proteasomal function and severe repression of translation. We confirm that t-2-hex stress induces rapid accumulation of mitochondrial pre-proteins and protein aggregates and subsequent activation of Hsf1- and Rpn4-dependent gene expression. By saturated transposon mutagenesis we find that t-2-hex tolerance requires an efficient heat shock response and specific mitochondrial and ER functions and that mutations in ribosome, protein and amino acid biogenesis are beneficial upon t-2-hex stress. We further show that genetic and pharmacological inhibition of protein translation causes t-2-hex resistance indicating that loss of proteostasis is the predominant consequence of the pro-apoptotic lipid. Several TOM subunits, including the central Tom40 channel, are lipidated by t-2-hexin vitroand mutation of accessory subunits Tom20 or Tom70 confers t-2-hex tolerance. Moreover, the Hfd1 gene dose determines the strength of t-2-hex mediated inhibition of mitochondrial protein import and Hfd1 co-purifies with Tom70. Our results indicate that transport of mitochondrial precursor proteins through the outer mitochondrial membrane is sensitively inhibited by the pro-apoptotic lipid and thus represents a hotspot for pro- and anti-apoptotic signaling.
Energy of functional brain states correlates with cognition in adolescent-onset schizophrenia and healthy persons
Authors: Theis Nicholas , Bahuguna Jyotika , Rubin Jonathan E. , Banerjee Shubha Sankar , Muldoon Brendan , Prasad Konasale M. 
Published: November 2023

AbstractAdolescent-onset schizophrenia (AOS) is rare, under-studied, and associated with more severe cognitive impairments and poorer outcomes than adult-onset schizophrenia. Neuroimaging has shown altered regional activations (first-order effects) and functional connectivity (second-order effects) in AOS compared to controls. The pairwise maximum entropy model (MEM) integrates first- and second-order factors into a single quantity called energy, which is inversely related to probability of occurrence of brain activity patterns. We take a combinatorial approach to study multiple brain-wide MEMs of task-associated components; hundreds of independent MEMs for various sub-systems are fit to 7 Tesla functional MRI scans. Acquisitions were collected from 23 AOS individuals and 53 healthy controls while performing the Penn Conditional Exclusion Test (PCET) for executive function, which is known to be impaired in AOS. Accuracy of PCET performance was significantly reduced among AOS compared to controls. A majority of the models showed significant negative correlation between PCET scores and the total energy attained over the fMRI. Across all instantiations, the AOS group was associated with significantly more frequent occurrence of states of higher energy, assessed with a mixed effects model. An example MEM instance was investigated further using energy landscapes, which visualize high and low energy states on a low-dimensional plane, and trajectory analysis, which quantify the evolution of brain states throughout this landscape. Both supported patient-control differences in the energy profiles. Severity of psychopathology was correlated positively with energy. The MEM’s integrated representation of energy in task-associated systems can help characterize pathophysiology of AOS, cognitive impairments, and psychopathology.
Protein interaction kinetics delimit the performance of phosphorylation-driven protein switches
Authors: Winter Daniel L. , Wairara Adelgisa R. , Bennett Jack L. , Donald William A. , Glover Dominic J. 
Published: November 2023

AbstractPost-translational modifications (PTMs) such as phosphorylation and dephosphorylation can rapidly alter protein surface chemistry and structural conformation which can, in turn, switch protein-protein interactions (PPIs) within signaling networks. Recently,de novodesigned phosphorylation-responsive protein switches have been created that harness kinase- and phosphatase-mediated phosphorylation that modulate PPIs. PTM-driven protein switches could be useful for investigating PTM dynamics in living cells, developing biocompatible nanodevices, and engineering signaling pathways to program cell behavior. However, little is known about the physical and kinetic constraints of PTM-driven protein switches, which limits their practical application. In this study, we present a theoretical framework to evaluate two-component PTM-driven protein switches based on four performance metrics: effective concentration, dynamic range, response time, and reversibility. Our computational models reveal an intricate relationship between the binding kinetics, phosphorylation kinetics, and switch concentration that governs the sensitivity and reversibility of PTM-driven protein switches. Building upon the insights of our theoretical investigation, we built and evaluated two novel phosphorylation-driven protein switches consisting of phosphorylation-sensitive coiled coils as sensor domains fused to fluorescent proteins as actuator domains. By modulating the phosphorylation state of the switches with a specific protein kinase and phosphatase, we demonstrate fast, reversible transitions between easily differentiated “on” and “off” states. The response of the switches linearly correlated to the concentration of the kinase, demonstrating its potential as a biosensor for kinase measurements in real time. As intended, both switches responded to specific kinase activity with an increase in fluorescence signal and our model could be used to distinguish between two mechanisms of switch activation: dimerization or a structural rearrangement. In summary, the protein switch kinetics model presented here should be useful to guide the design of PTM-driven switches and tune their performance towards concrete applications.
EEG covariance patterns detects global cortical activity distribution following weak tactile inputs
Authors: Mellbin Astrid , Rongala Udaya , Jörntell Henrik , Bengtsson Fredrik 
Published: November 2023

SummaryMany studies have suggested that the neocortex operates as a global network of functionally interconnected neurons, indicating that any sensory input could shift activity distributions across the whole brain. A tool assessing the activity distribution across cortical regions with high temporal resolution could then potentially detect subtle changes that may pass unnoticed in regionalized analyses. We used eight-channel, distributed electrocorticogram (ECoG) recordings to analyze changes in global activity distribution caused by single pulse electrical stimulations of the paw. We analyzed the temporally evolving covariance patterns of the activity distributions using principal component analysis (PCA). We found that localized tactile stimulation caused clearly measurable changes in global ECoG activity distribution. These changes in signal covariance patterns were detectable across a small number of ECoG channels, even when not including the somatosensory cortex, suggesting that the method has high sensitivity, potentially making it applicable to human EEG for detection of pathological changes.
Induction of immortal-like and functional CAR-T cells by defined factors
Authors: Wang Lixia , Jin Gang , Zhou Qiuping , Liu Yanyan , Zhao Xiaocui , Li Zhuoyang , Yin Na , Peng Min 
Published: November 2023

AbstractLong-term antitumor efficacy of chimeric antigen receptor (CAR)-T cells depends on their functional persistence in vivo. T cells with stem-like property show better persistence, but factors conferring T cells bona fide stemness remain to be determined. Here, we demonstrate the induction of CAR-T cells into an immortal-like and functional state, termed TIF. The induction of CAR-TIF cells depends on repression of two factors: BCOR and ZC3H12A, and requires antigen or CAR tonic signaling. The reprogrammed CAR-TIF cells possess almost infinite stemness resembling induced pluripotent stem cells but retain functionality of mature T cells, which exhibit superior antitumor effect. CAR-TIF cells enter a metabolically dormant state after elimination of target cells, which persist in vivo with a saturable niche and mediate memory protection. CAR-TIF cells represent a novel state of T cells with unprecedented stemness conferring long-term functional persistence of CAR-T cells in vivo, which have broad potentials in T cell therapies.