bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microglia determine ß-amyloid plaque burden but are non-essential for downstream pathology
Authors: Li Mosi , Holt Kris , Ridley Katherine , Qiu Jing , Haddow Kirsty , Vasoya Deepali , He Xin , Tulloch Jane , King Declan , Hume David A , Pridans Clare , Dando Owen R , Spires-Jones Tara L , Hardingham Giles E 
Published: August 2024

AbstractEvidence points to a role for microglia in Alzheimer’s disease (AD) risk, although their position in the pathological cascade is incompletely understood, prompting us to generate a model of ß-amyloidopathy lacking microglia. We find evidence that microglia promote plaque formation and creation of an Aß fibril-rich zone surrounding the plaque core. However, plaque-proximal reactive astrogliosis, synapse loss, and neurite dystrophy are still observed in the absence of microglia.
Single-egg Comet Assay: a protocol to quantify DNA damage in aquatic dormant stages
Authors: Salimraj Rejin , Perotti Alessio , Wojewodzic Marcin W. , Frisch Dagmar 
Published: August 2024

AbstractThe comet assay (CA) was originally developed as toxicity test and quantifies DNA integrity from the distribution of DNA across an electric field. Compromised DNA moves across electric fields faster than intact DNA strands, leaving a quantifiable signature that resembles a comet tail. The dimensions of this comet tail reflect relative DNA damage.We optimized the CA protocol for individual dormant propagules (Single-egg Comet Assay or SE-CA) to inform downstream analyses such as DNA sequencing, of the DNA quality contained in natural genetic archives of past populations. As a model we used dormant eggs of the microcrustaceanDaphnia.We tested the SE-CA protocol on impact of processing and storage conditions for dormant eggs and used it to assess DNA damage related to aging of eggs retrieved from recently deposited to centuries-old lake sediment. The SE-CA successfully determined the degree of DNA damage in individual eggs frozen in liquid nitrogen, or at -80°C as well as damage caused by bleaching and historical egg age.In conclusion, our protocol provides a cost-effective method of assessing DNA damage in sedimentary propagules such as dormantDaphniaeggs. More generally, the SE-CA can be applied to test DNA integrity in individual propagules prior to genome sequencing or to quantify environmental impacts on natural sedimentary biobanks.
High-Resolution Genome Assembly and Population Genetic Study of the Endangered MapleAcer pentaphyllum(Sapindaceae): Implications for Conservation Strategies
Authors: Li Xiong , Jiang Li-Sha , Deng Heng-Ning , Yu Qi , Ju Wen-Bin , Feng Yu , Xu Bo 
Published: August 2024

SummaryAcer pentaphyllumDiels (Sapindaceae), a highly threatened maple endemic to dry-hot valleys of the Yalong River in western Sichuan, China, requires urgent conservation efforts due to its extremely rarity and restricted distribution. In this study, we present a high-quality chromosome-level reference genome ofA. pentaphyllum(626 Mb, 2n = 26), comprising 70.64% repetitive sequences and 38,540 protein-coding genes. Phylogenetic analysis shows thatA. pentaphyllumdiverged from a clade consisting ofA. yangbienseandA. saccharumin the late Eocene (∼37.83 Ma). In the genome ofA. pentaphyllum, genes involved in responding to external environmental change have undergone expansion and positive selection, potentially reflecting its adaptive strategies. While no recent independent whole-genome duplication events were detected, a recent rapid amplification of transposable elements was observed. Population genomic analysis of 227 individuals from 28 populations revealed low genetic diversity (1.04 ± 0.97 × 10−3) compared to other woody species. Phylogeographic patterns suggest an upstream colonization along the Yalong River, with two severe population bottlenecks correlating with major Pleistocene climatic transitions. In addition, most populations exhibit high inbreeding and genetic load, particularly those at range edges (TKX, CDG, TES). Based on these genomic insights, we propose targeted conservation strategies, including genetic rescue measures, to safeguard this unique maple species. These findings not only contribute to the preservation ofA. pentaphyllumbut also enhance our understanding of plant adaptation to extreme environments and the impacts of climate change on species with restricted distributions.
Diminished social memory and hippocampal correlates of social interactions in chronic social defeat stress susceptibility
Authors: Larosa Amanda , Zhang Tian Rui , Wong Alice S. , Cyrus Y. H. Fung , Long Xiong Ling Yun (Jenny) , Fung Benjamin C. M. , Wong Tak Pan 
Published: August 2024

AbstractBackgroundThe susceptibility to chronic stress has been associated with depression, a mood disorder which highly implicates the hippocampus. Hippocampal contribution to stress susceptibility has been supported by findings in mice following chronic social defeat stress (CSDS). However, little is known of the role of hippocampal activity in determining the development of stress susceptibility.MethodsWe used the UCLA miniscope to longitudinally measure the activity of dorsal CA1 hippocampal neurons across CSDS. Apart from examining the representation of social information by these neurons, we also compared social memory in mice that were susceptible or resilient to CSDS.ResultsWe observed more stable dCA1 correlates of social interaction and social memory in CSDS resilience. Such changes were absent in CSDS susceptible mice and accompanied by greater social memory impairments.ConclusionsCSDS susceptibility may be supported by hippocampal social cognitive processes, reflected in diminished hippocampal representations of social information and a greater impairment in social memory.
Neural basis of concurrent deliberation toward a choice and degree of confidence
Authors: Vivar-Lazo Miguel , Fetsch Christopher R. 
Published: August 2024

ABSTRACTDecision confidence plays a key role in flexible behavior and (meta)cognition, but its underlying neural mechanisms remain elusive. To uncover the latent dynamics of confidence formation at the level of population activity, we designed a decision task for nonhuman primates that measures choice, reaction time, and confidence with a single eye movement on every trial. Monkey behavior was well fit by a bounded accumulator model instantiating parallel processing of evidence, rejecting a serial model in which the choice is resolved first followed by post-decision accumulation for confidence. Neurons in area LIP reflected concurrent accumulation, exhibiting covariation of choice and confidence signals across the population, and within-trial dynamics consistent with parallel updating at near-zero time lag. The results demonstrate that monkeys can process a single stream of evidence in service of two computational goals simultaneously—a categorical decision and associated level of confidence—and illuminate a candidate neural substrate for this ability.
Timing anti-PD-L1 checkpoint blockade immunotherapy to enhance tumor irradiation
Authors: Lee Steve Seung-Young , Pagacz Joanna , Averbek Sera , Scholten David , Liu Yue , Kron Stephen J. 
Published: August 2024

ABSTRACTBackgroundThe ability of radiotherapy (RT) to drive anti-tumor immunity is limited by adaptive resistance. While RT induces inflammation and recruits activated tumor-infiltrating lymphocytes (TILs) including cytotoxic T lymphocytes (CTLs), the resulting radiation- and IFNγ-dependent PD-L1 expression restores an immunosuppressed tumor microenvironment. Unleashing an effective anti-tumor response may require precise sequencing of RT and checkpoint blockade immunotherapy (CBI) to block PD-L1 signaling before it can mediate its suppressive effects.MethodsFlank tumors formed in BALB/c mice with syngeneic CT26 colon or 4T1 mammary carcinoma cells were treated with otherwise ineffective doses of ionizing radiation (10 Gy) followed by CBI (0.2 mg anti-PD-L1, i.v.) after 0, 1, 3, 5 or 7 days, comparing tumor response. Anti-PD-L1 delivery was measured by fluorescence, TILs by flow cytometry and immunofluorescence, PD-L1 expression by immunohistochemistry, and tumor size by calipers.ResultsIn both CT26 and 4T1 tumors, 10 Gy alone resulted in a transient growth delay associated with infiltrating CTLs peaking at 3 days and PD-L1 at 5 days. CTLs returned toward baseline by 7 days, consistent with adaptive resistance. Anti-PD-L1 failed to potentiate radiation except when injected 5 days after 10 Gy, which prevented CTL depletion and led to tumor elimination. Potentially contributing to compound effects, anti-PD-L1 penetrated tumors and bound PD-L1 more efficiently after irradiation.ConclusionsOptimal timing to exploit radiation-induced permeability to enhance CBI delivery and interrupt adaptive resistance by blocking PD-L1 as it peaks may offer a general strategy to enhance external beam radiotherapy by protecting activated TILs and potentiating anti-tumor immune response.
Rapid phenotypic and genotypic change in a laboratory schistosome population
Authors: Jutzeler Kathrin S. , Platt Roy N. , Li Xue , Morales Madison , Diaz Robbie , Le Clec’h Winka , Chevalier Frédéric D. , Anderson Timothy J.C. 
Published: August 2024

AbstractBackgroundGenomic analysis has revealed extensive contamination among laboratory-maintained microbes including malaria parasites,Mycobacterium tuberculosisandSalmonellaspp. Here, we provide direct evidence for recent contamination of a laboratory schistosome parasite population, and we investigate its genomic consequences. The BrazilianSchistosoma mansonipopulation SmBRE has several distinctive phenotypes, showing poor infectivity, reduced sporocysts number, low levels of cercarial shedding and low virulence in the intermediate snail host, and low worm burden and low fecundity in the vertebrate rodent host. In 2021 we observed a rapid change in SmBRE parasite phenotypes, with a ∼10x increase in cercarial production and ∼4x increase in worm burden.MethodsTo determine the underlying genomic cause of these changes, we sequenced pools of SmBRE adults collected during parasite maintenance between 2015 and 2023. We also sequenced another parasite population (SmLE) maintained alongside SmBRE without phenotypic changes.ResultsWhile SmLE allele frequencies remained stable over the eight-year period, we observed sudden changes in allele frequency across the genome in SmBRE between July 2021 and February 2023, consistent with expectations of laboratory contamination. (i) SmLE-specific alleles rose in the SmBRE population from 0 to 41-46% across the genome between September and October 2021, documenting the timing and magnitude of the contamination event. (ii) After contamination, strong selection (s= ∼0.23) drove replacement of low fitness SmBRE with high fitness SmLE alleles. (iii) Allele frequency changed rapidly across the whole genome, except for a region on chromosome 4 where SmBRE alleles remained at high frequency.ConclusionsWe were able to detect contamination in this case because SmBRE shows distinctive phenotypes. However, this would likely have been missed with phenotypically similar parasites. These results provide a cautionary tale about the importance of tracking the identity of parasite populations, but also showcase a simple approach to monitor changes within populations using molecular profiling of pooled population samples to characterize fixed single nucleotide polymorphisms. We also show that genetic drift results in continuous change even in the absence of contamination, causing parasites maintained in different labs (or sampled from the same lab at different times) to diverge.
Therapeutic targeting of Syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers
Authors: Takeda Mitsunobu , Theardy Madelaine S. , Sorokin Alexey , Coker Oluwadara , Kanikarla Preeti , Chen Shuaitong , Yang Zecheng , Nguyen Phuoc , Wei Yongkun , Yao Jun , Wang Xiaofei , Yan Liang , Jin Yanqing , Cai Yiming , Paku Masakatsu , Chen Ziheng , Li Kara Z. , Citron Francesca , Tomihara Hideo , Gao Sisi , Deem Angela K. , Zhao Jun , Wang Huamin , Hanash Samir , DePinho Ronald A , Maitra Anirban , Draetta Giulio F. , Ying Haoqiang , Kopetz Scott , Yao Wantong 
Published: August 2024

AbstractThe therapeutic benefit of recently developed mutant KRAS (mKRAS) inhibitors has been limited by the rapid onset of resistance. Here, we aimed to delineate the mechanisms underlying acquired resistance to mKRAS inhibition and identify actionable targets for overcoming this clinical challenge. Previously, we identified Syndecan-1 (SDC1) as a key effector for pancreatic cancer progression whose surface expression is driven by mKRAS. By leveraging both pancreatic and colorectal cancer models, we found that surface SDC1 expression was initially diminished upon mKRAS inhibition, but recovered in tumor cells that bypass mKRAS dependency. Functional studies showed that these tumors depended on SDC1 for survival, further establishing SDC1 as a driver for the acquired resistance to mKRAS inhibition. Mechanistically, we revealed that the YAP1-SDC1 axis was the major driving force for bypassing mKRAS dependency to sustain nutrient salvage machinery and tumor maintenance. Specifically, YAP1 activation mediated the recovery of SDC1 localization on cell surface that sustained macropinocytosis and enhanced the activation of multiple RTKs, promoting resistance to KRAS-targeted therapy. Overall, our study has provided the rationale for targeting the YAP-SDC1 axis to overcome resistance to mKRAS inhibition, thereby revealing new therapeutic opportunities for improving the clinical outcome of patients with KRAS-mutated cancers.
Neural mechanisms of credit assignment for delayed outcomes during contingent learning
Authors: Witkowski Phillip P. , Rondot Lindsay , Kurth-Nelson Zeb , Garvert Mona M. , Dolan Raymond J , Behrens Timothy E. J. , Boorman Erie D. 
Published: August 2024

SummaryAdaptive behavior in complex environments critically relies on the ability to appropriately link specific choices or actions to their outcomes. However, the neural mechanisms that support the ability to credit only those past choices believed to have caused the observed outcomes remain unclear. Here, we leverage multivariate pattern analyses of functional magnetic resonance imaging (fMRI) data and an adaptive learning task to shed light on the underlying neural mechanisms of such specific credit assignment. We find that the lateral orbitofrontal cortex (lOFC) and hippocampus (HC) code for the causal choice identity when credit needs to be assigned for choices that are separated from outcomes by a long delay, even when this delayed transition is punctuated by interim decisions. Further, we show when interim decisions must be made, learning is additionally supported by lateral frontopolar cortex (lFPC). Our results indicate that lFPC holds previous causal choices in a “pending” state until a relevant outcome is observed, and the fidelity of these representations predicts the fidelity of subsequent causal choice representations in lOFC and HC during credit assignment. Together, these results highlight the importance of the timely reinstatement of specific causes in lOFC and HC in learning choice-outcome relationships when delays and choices intervene, a critical component of real-world learning and decision making.
Therapeutic potential of red blood cell-derived extracellular vesicles in reducing neuroinflammation and protecting against retinal degeneration
Authors: Sekar Rakshanya , Cioanca Adrian V. , Yang Yilei (Evelyn) , Kamath Karthik Shantharam , Carroll Luke , Natoli Riccardo , Wooff Yvette 
Published: August 2024

AbstractNeuroinflammation is a pathological process mediated through immune cell activation and pro-inflammatory cytokine release, resulting in neuronal cell death. In the central nervous system (CNS), neuroinflammation is a characteristic feature underlying the onset and progression of retinal and neurodegenerative diseases. Targeting neuroinflammation to reduce neuronal cell death and protect against visual and cognitive declines is therefore a key therapeutic strategy. However, due to the complex and multi-faceted nature of these diseases, to date there has been little therapeutic success with single target approaches insufficient to tackle widespread and multi-pathway inflammatory cascades. Furthermore, as the retina and brain reside within immune-privileged environments, a major challenge in treating these diseases is producing and delivering a therapeutic that, in itself, does not exacerbate inflammation. Extracellular vesicles (EV), derived from red blood cells (RBC EV), present a promising solution to overcome these hurdles, due to their innate ability to cross blood-tissue barriers, biocompatible nature, and their broad anti-inflammatory properties to modulate complex neuroinflammatory pathways.This study therefore investigated the therapeutic potential of RBC EV in mediating neuroinflammation using anin-vivophoto-oxidative damage model of retinal degeneration as a model for CNS neuroinflammation. In this work, we developed a novel incubation pipeline using N1 medium supplement and superoxide dismutase (SOD) supplementation to promote the production of safe, neuroprotective, and anti-inflammatory RBC EV. Delivery of RBC EVin vivo, was shown to be safe with strong penetration across all retinal layers. Further, therapeutic administration of RBC EV via local intravitreal injection significantly reduced inflammation and cell death and preserved retinal function. Notably, strong safety and therapeutic efficacy was also demonstrated in the retina following systemic (intraperitoneal) administration, highlighting a potential game-changing approach for less-invasive therapeutic delivery to the CNS. Finally, multi-omic analyses andin vitrofindings supported an anti-inflammatory mechanism-of-action, with RBC EV modulating pro-inflammatory cytokine release, including those known to be involved in the pathogenesis of retinal and neurodegenerative diseases.Taken together, these findings highlight the broad applicability of RBC EV in treating neuroinflammation in the CNS, presenting a scalable and effective treatment approach for these currently untreatable diseases.
PLSKO: a robust knockoff generator to control false discovery rate in omics variable selection
Authors: Yang Guannan , Menkhorst Ellen , Dimitriadis Evdokia , Lê Cao Kim-Anh 
Published: August 2024

AbstractThe knockoff framework, combined with variable selection procedure, controls false discovery rate (FDR) without the need for calculatingp−values. Hence, it presents an attractive alternative to differential expression analysis of high-throughput biological data. However, current knockoff variable generators make strong assumptions or insufficient approximations that lead to FDR inflation when applied to biological data.We propose Partial Least Squares Knockoff (PLSKO), an efficient and assumption-free knockoff generator that is robust to varying types of biological omics data. We compare PLSKO with a wide range of existing methods. In simulation studies, we show that PLSKO is the only method that controls FDR with sufficient statistical power in complex non-linear cases. In semi-simulation studies based on real data, we show that PLSKO generates valid knockoff variables for different types of biological data, including RNA-seq, proteomics, metabolomics and microbiome. In preeclampsia multi-omics case studies, we combined PLSKO with Aggregation Knockoff to address the randomness of knockoffs and improve power, and show that our method is able to select variables that are biologically relevant.
Sequential mosaic variants inKRASandSTAT5Bassociated with a mixed phenotype of two acquired errors of immunity
Authors: Forkgen Julia , Masle-Farquhar Etienne , Fontaine Yves , Russell Amanda , Ji Shannon , Peters Timothy J , Qiao Zhen , Geaghan Michael , Jackson Katherine JL , Hammond Jillian M , Deveson Ira W , David Clementine , Lemberg Daniel A , Gupta Nitin , Fuentes-Bolanos Noemi , Mustjoki Satu , Hwa Vivian , Tangye Stuart G , Gray Paul E , Siggs Owen M 
Published: August 2024

AbstractMosaic genetic variation has been implicated in the pathogenesis of both malignant and non-malignant immunological disease. Here, we report a unique case of postnatal acquisition of a gain-of-function (GoF)KRASvariant, with an additional GoFSTAT5Bvariant, in a woman with inflammatory bowel disease, splenomegaly, thrombocytopenia, bronchiectasis, monocytosis, and eosinophilia. Targeted amplicon sequencing revealed widespread distribution of both variants in key immune cell populations, and in historical blood and tissue samples, with the emergence of both variants coinciding with the time of clinical presentation. Short- and long-read single cell RNA sequencing of patient cells highlighted a unique population of monocytes, with a broad distribution of both variants, and dysregulated cytokine signaling pathways. Flow cytometry revealed dysregulated STAT signaling, and the presence of a distinct population of highly granular CD24+ cells. Taken together with the clinical presentation, these findings led to a diagnosis of combined RAS-associated autoimmune leukoproliferative disorder (RALD) and non-clonalSTAT5BGoF disease. To our knowledge, this is the first reported combination of two distinct acquired errors of immunity causing a mixed clinical phenotype, and highlights the importance of considering acquired monogenic diseases within a broader genomic context.
Rare but elevated incidence of hematological malignancy after clozapine use in schizophrenia: a population cohort study
Authors: Hu Yuqi , Gao Le , Zhou Lingyue , Liu Wenlong , Wei Cuiling , Liu Boyan , Sun Qi , Tian Wenxin , Chu Rachel Yui Ki , Song Song , Cheng Franco Wing Tak , Chan Joe Kwun Nam , Ng Amy Pui Pui , Lo Heidi Ka Ying , Lee Krystal Chi Kei , Chang Wing Chung , Wong William Chi Wai , Chan Esther Wai Yin , Wong Ian Chi Kei , Chai Yi , Lai Francisco Tsz Tsun 
Published: August 2024

ABSTRACTBackgroundRecent disproportionality analyses and nationwide case-control studies suggested a potential association between clozapine use and hematological malignancy (HM). Nevertheless, the absolute rate difference is unclear due to the absence of cohort studies.MethodsWe extracted data from a territory-wide public healthcare database in Hong Kong to build a retrospective cohort of anonymized patients aged 18+ with a diagnosis of schizophrenia who used clozapine or olanzapine (drug comparator with highly similar chemical structure and pharmacological mechanisms) for 90+ days, with at least two prior other antipsychotic use records within both groups. Weighted by inverse probability of treatment based on propensity scores, Poisson regression was used to estimate the incidence rate ratio (IRR) of HM between clozapine and olanzapine users. The absolute rate difference was also estimated.ResultsIn total, 9,965 patients were included, with 834 clozapine users, who had a significant IRR of 2.22 (95% CI 1.52, 3.34) for HM compared to olanzapine users. Absolute rate difference was estimated to be 57.40 (95% CI 33.24, 81.55) per 100,000 person-years. Findings were consistent across sub-groups by age and sex in terms of effect size, although the IRR was non-significant for those aged 65 or older. Sensitivity analyses all supported the robustness of the results and showed good specificity to HM but no other cancers.ConclusionAbsolute rate difference in HM incidence was very small although there is a twofold elevated rate. Pharmacotherapies with clozapine may consider this potential rare risk in addition to known side effects.