bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic encoding of biological motion information in macaque medial superior temporal area
Authors: Feng Tingting , Zhang Bo , Tang Qin , Han Wenhao , Liu Jingxuan , Jiang Yi , Zhang Tao 
Published: November 2023

AbstractThe ability to decipher biological motion information is an essential brain function that develops early in life and is evolutionarily conserved across many species. However, the neuronal encoding of biological motion information remains unclear due to the scarce electrophysiological evidence. In the current study, we tackled this issue by examining whether and how neurons in the monkey medial superior temporal cortex (MST) extract form from biological motion and encode spatial transformations in biological motion. Results revealed that MST neurons are capable of encoding form information and discriminating the horizontal and the vertical mirror transformations of biological motion. More importantly, BM information is dynamically encoded in the modulation strength of evoked spike trains rather than the average firing rate during stimulus presentation. Furthermore, the ability of MST neurons to detect various biological motion features is closely linked with the neuronal selectivity for optic flow patterns.
Intraneuronal binding of amyloid beta with reelin - implications for the onset of Alzheimer’s disease
Authors: Kobro-Flatmoen Asgeir , Omholt Stig W. 
Published: November 2023

AbstractIt was recently shown that in anteriolateral entorhinal cortex layer II neurons (ECLII neurons) in McGill-R-Thy1-APP homozygous transgenic rats (a model commonly used to study Alzheimer’s disease (AD)), the glycoprotein reelin and intracellular amyloid-β(Aβ) engage in a direct protein–protein interaction. Numerous studies of the human brain supported by experimental results from rodent and cell models point to a role for intracellular oligomeric Aβin the onset of AD. If reelin functions as a sink for intracellular Aβand if the binding to reelin makes Aβphysiologically inert, it implies that reelin may prevent the neuron from being exposed to the detrimental effects typically associated with oligomeric Aβ. Considering that reelin expression is extraordinarily high in the major subset of ECLII neurons compared to most other cortical neurons, such a protective role appears very difficult to reconcile with the fact that ECLII is clearly a major cradle for the onset of AD in humans. Here we show that this conundrum may be resolved if ECLII neurons have a much higher maximum production capacity of Aβthan neurons expressing low levels of reelin. We provide a rationale for why this difference has evolved, and argue that the higher maximum production capacity of Aβin ECLII neurons may in a senescent Aβ-inducing physiology predispose these neurons to initiate AD development.Author summaryAmyloid-βis a small peptide that is widely recognized as one of the main culprits involved in the development of Alzheimer’s disease. It was recently shown that in the major subset of neurons in entorhinal cortex layer II, which expresses high levels of the protein reelin, amyloid-βand reelin bind to each other. These neurons, which are strongly involved in memory formation, are among the first to die in subjects with Alzheimer’s disease. If intracellular amyloid-β, which is clearly involved in the onset of the disease, becomes physiologically inert when it binds to reelin, it implies that reelin can prevent the neuron from being exposed to the detrimental effects of increased levels of amyloid-β. Considering that reelin expression is extraordinarily high in ECLII neurons compared to most other cortical neurons, such a protective role appears very difficult to reconcile with the fact that ECLII constitute the predominant cortical site for initiation of Alzheimer’s disease. Here, we show that this paradox may be resolved if ECLII neurons have a much higher maximum amyloid-βproduction capacity than neurons expressing low levels of reelin. We provide reasons why this difference has evolved and argue that it, in a senescent physiology, predisposes ECLII neurons to initiate the development of Alzheimer’s disease.
Gene and allele specific expression underlying the electric signal divergence in African weakly electric fish
Authors: Cheng Feng , Dennis Alice B. , Baumann Otto , Kirschbaum Frank , Abdelilah-Seyfried Salim , Tiedemann Ralph 
Published: November 2023

AbstractIn the African weakly electric fish genusCampylomormyrus, electric organ discharge (EOD) signals are strikingly different in shape and duration among closely related species, contribute to pre-zygotic isolation and may have triggered an adaptive radiation. We performed mRNA sequencing on electric organs (EOs) and skeletal muscles (SMs; from which the EOs derive) from three species with short (0.4 ms), medium (5 ms), and long (40 ms) EODs and two different cross-species hybrids. We identified 1,444 up-regulated genes in EO shared by all five species/hybrids cohorts, rendering them candidate genes for EO-specific properties inCampylomormyrus. We further identified several candidate genes, includingKCNJ2andKLF5, their up-regulation may contribute to increased EOD duration. Hybrids between a short (C. compressirostris) and a long (C. rhynchophorus) discharging species exhibit EODs of intermediate duration and showed imbalanced expression ofKCNJ2alleles, pointing towards a cis-regulatory difference at this locus, relative to EOD duration.KLF5is a transcription factor potentially balancing potassium channel gene expression, a crucial process for the formation of an EOD. Unraveling the genetic basis of the species-specific modulation of the EOD inCampylomormyrusis crucial for understanding the adaptive radiation of this emerging model taxon of ecological (perhaps even sympatric) speciation.
WTAP, transcriptionally regulated by p65, promotes inflammation through m6A modification and phase separation
Authors: Ge Yong , Chen Rong , Ling Tao , Liu Biaodi , Huang Jingrong , Cheng Youxiang , Lin Yi , Chen Hongxuan , Xie Xiongmei , Xia Guomeng , Luo Guanzheng , Yuan Shaochun , Xu Anlong 
Published: November 2023

AbstractEmerging evidence has linked dysregulation ofN6-methyladenosine (m6A) to inflammation and inflammatory diseases, but the underlying mechanism still needs investigation. Here, we found that high m6A modification in a variety of hyperinflammatory states is p65-dependent, because Wilms tumor 1 associated protein (WTAP), a key component of the writer complex, is transcriptionally regulated by p65 and its overexpression can lead to higher m6A modification. Mechanistically, upregulated WTAP is more prone to phase separation to facilitate the aggregation of “writer” complex to nuclear speckles and the deposition of m6A marks onto transcriptionally active inflammatory transcripts, thereby accelerating proinflammatory response. Furthermore, myeloid deficiency of WTAP attenuates the severity of LPS-induced sepsis and DSS-induced IBD. Thus, the proinflammatory effect of WTAP is a general risk-increasing mechanism, and interrupting the assembly of m6A writer complex by targeting the phase separation of WTAP to reduce the global m6A level may be a potential and promising therapeutic strategy for alleviating hyperinflammation.
Asymmetric roles for M2-M3 linkers of specific GABAAreceptor subunits in the intrinsic closed-open equilibrium and its modulation by the benzodiazepine diazepam
Authors: Nors Joseph W. , Endres Zachary , Goldschen-Ohm Marcel P. 
Published: November 2023

AbstractGABAAreceptors (GABAARs) are neurotransmitter-gated ion channels critical for inhibitory synaptic transmission as well as the molecular target for benzodiazepines (BZDs), one of the most widely prescribed class of psychotropic drugs today. Despite structural insight into the conformations underlying functional channel states, the detailed molecular interactions involved in conformational transitions and the physical basis for their modulation by BZDs are not fully understood. We previously identified that alanine substitution at the central residue in the α1 subunit M2-M3 linker (V279A) enhances the efficiency of linkage between the BZD site and the pore gate. Here, we expand on this work by investigating the effect of alanine substitutions at the analogous positions in the M2-M3 linkers of β2 (I275A) and γ2 (V290A) subunits, which together with α1 comprise typical heteromeric α1β2γ2 synaptic GABAARs. We find that these mutations confer subunit-specific effects on the intrinsic pore closed-open equilibrium and its modulation by the BZD diazepam (DZ). The mutations α1(V279A) or γ2(V290A) bias the channel toward a closed conformation, whereas β2(I275A) biases the channel toward an open conformation to the extent that the channel becomes leaky and opens spontaneously in the absence of agonist (e.g., GABA). In contrast, only α1(V279A) enhances the efficiency of DZ-to-pore linkage, whereas mutations in the other two subunits have no effect. These observations show that the central residue in the M2-M3 linkers of distinct subunits in synaptic α1β2γ2 GABAARs contribute asymmetrically to the intrinsic closed-open equilibrium and its modulation by DZ.
Stability of DNA-Methylation Profiles of Biological Aging in Children and Adolescents
Authors: deSteiguer Abby J. , Raffington Laurel , Sabhlok Aditi , Tanksley Peter , Tucker-Drob Elliot M. , Harden K. Paige 
Published: November 2023

AbstractBackground and ObjectivesMethylation profile scores (MPSs) index biological aging and aging-related disease in adults and are cross-sectionally associated with social determinants of health in childhood. MPSs thus provide an opportunity to trace how aging-related biology responds to environmental changes in early life. Information regarding the stability of MPSs in early life is currently lacking.MethodWe use longitudinal data from children and adolescents ages 8-18 (N = 428, M age = 12.15 years) from the Texas Twin Project. Participants contributed two waves of salivary DNA-methylation data (mean lag = 3.94 years), which were used to construct four MPSs reflecting multi-system physiological decline and mortality risk (PhenoAgeAccel and GrimAgeAccel), pace of biological aging (DunedinPACE), and cognitive function (Epigenetic-g). Furthermore, we exploit variation among participants in whether they were exposed to the COVID-19 pandemic during the course of study participation, in order to test how a historical period characterized by environmental disruption might affect children’s aging-related MPSs.ResultsAll MPSs showed moderate longitudinal stability (test-retestrs = 0.42, 0.44, 0.46, 0.51 for PhenoAgeAccel, GrimAgeAccel, and Epigenetic-g, and DunedinPACE, respectively). No differences in the stability of MPSs were apparent between those whose second assessment took place after the onset of the COVID-19 pandemic vs. those for whom both assessments took place prior to the pandemic.ConclusionsAging-related DNA-methylation patterns are less stable in childhood than has been previously observed in adulthood. Further developmental research on the methylome is necessary to understand which environmental perturbations in childhood impact trajectories of biological aging and when children are most sensitive to those impacts.Article SummaryMethylation profiles of biological aging are less stable in childhood than has been previously observed in adulthood.What’s Known on This SubjectMethylation profile scores (MPSs) index biological aging in adults and are cross-sectionally associated with social determinants of health in childhood. Aging-related MPSs in adulthood show very high test-retest stability but data on longitudinal stability of MPSs in childhood is sparse.What This Study AddsChildren’s methylation profiles of biological aging are moderately stable across an approximately four-year period. Methylation profiles are less stable in childhood than in adulthood, suggesting that aging-related biology in childhood might be more responsive to environmental changes than in adulthood.
Tumor microenvironment-induced FOXM1 regulates ovarian cancer stemness
Authors: Battistini Chiara , Kenny Hilary A. , Nieddu Valentina , Melocchi Valentina , Decio Alessandra , Gatto Alessia , Ghioni Mariacristina , Porta Francesca M. , Giavazzi Raffaella , Colombo Nicoletta , Bianchi Fabrizio , Lengyel Ernst , Cavallaro Ugo 
Published: November 2023

SummaryIn ovarian tumors, the omental microenvironment profoundly influences the behavior of cancer cells and sustains the acquisition of stem-like traits, with major impacts on tumor aggressiveness and relapse. Here, we exploit a patient-derived platform of organotypic cultures to study the crosstalk between the tumor microenvironment and ovarian cancer stem cells. The pro-tumorigenic transcription factor FOXM1 is specifically induced by the microenvironment in ovarian cancer stem cells, through activation of FAK/YAP signaling. The microenvironment-induced FOXM1 sustains stemness, and its inactivation reduces cancer stem cells survival in the omental niche and enhances their response to the PARP inhibitor Olaparib. By unveiling the novel role of FOXM1 in ovarian cancer stemness, our findings highlight patient-derived organotypic co-cultures as a powerful tool to capture clinically relevant mechanisms of the microenvironment/stem cells crosstalk, contributing to the identification of tumor vulnerabilities.
Decoding Heterogenous Single-cell Perturbation Responses
Authors: Song Bicna , Liu Dingyu , Dai Weiwei , McMyn Natalie , Wang Qingyang , Yang Dapeng , Krejci Adam , Vasilyev Anatoly , Untermoser Nicole , Loregger Anke , Song Dongyuan , Williams Breanna , Rosen Bess , Cheng Xiaolong , Chao Lumen , Kale Hanuman T. , Zhang Hao , Diao Yarui , Bürckstümmer Tilmann , Siliciano Jenet M. , Li Jingyi Jessica , Siliciano Robert , Huangfu Danwei , Li Wei 
Published: November 2023

AbstractUnderstanding diverse responses of individual cells to the same perturbation is central to many biological and biomedical problems. Current methods, however, do not precisely quantify the strength of perturbation responses and, more importantly, reveal new biological insights from heterogeneity in responses. Here we introduce the perturbation-response score (PS), based on constrained quadratic optimization, to quantify diverse perturbation responses at a single-cell level. Applied to single-cell transcriptomes of large-scale genetic perturbation datasets (e.g., Perturb-seq), PS outperforms existing methods for quantifying partial gene perturbation responses. In addition, PS presents two major advances. First, PS enables large-scale, single-cell-resolution dosage analysis of perturbation, without the need to titrate perturbation strength. By analyzing the dose-response patterns of over 2,000 essential genes in Perturb-seq, we identify two distinct patterns, depending on whether a moderate reduction in their expression induces strong downstream expression alterations. Second, PS identifies intrinsic and extrinsic biological determinants of perturbation responses. We demonstrate the application of PS in contexts such as T cell stimulation, latent HIV-1 expression, and pancreatic cell differentiation. Notably, PS unveiled a previously unrecognized, cell-type-specific role of coiled-coil domain containing 6 (CCDC6) in guiding liver and pancreatic lineage decisions, where CCDC6 knockouts drive the endoderm cell differentiation towards liver lineage, rather than pancreatic lineage. The PS approach provides an innovative method for dose-to-function analysis and will enable new biological discoveries from single-cell perturbation datasets.One sentence summaryWe present a method to quantify diverse perturbation responses and discover novel biological insights in single-cell perturbation datasets.
Utility of AlphaMissense predictions in Asparagine Synthetase deficiency variant classification
Authors: Staklinski Stephen J. , Scheben Armin , Siepel Adam , Kilberg Michael S. 
Published: November 2023

AbstractAlphaMissense is a recently developed method that is designed to classify missense variants into pathogenic, benign, or ambiguous categories across the entire human proteome. Asparagine Synthetase Deficiency (ASNSD) is a developmental disorder associated with severe symptoms, including congenital microcephaly, seizures, and premature death. Diagnosing ASNSD relies on identifying mutations in the asparagine synthetase (ASNS) gene through DNA sequencing and determining whether these variants are pathogenic or benign. Pathogenic ASNS variants are predicted to disrupt the protein’s structure and/or function, leading to asparagine depletion within cells and inhibition of cell growth. AlphaMissense offers a promising solution for the rapid classification of ASNS variants established by DNA sequencing and provides a community resource of pathogenicity scores and classifications for newly diagnosed ASNSD patients. Here, we assessed AlphaMissense’s utility in ASNSD by benchmarking it against known critical residues in ASNS and evaluating its performance against a list of previously reported ASNSD-associated variants. We also present a pipeline to calculate AlphaMissense scores for any protein in the UniProt database. AlphaMissense accurately attributed a high average pathogenicity score to known critical residues within the two ASNS active sites and the connecting intramolecular tunnel. The program successfully categorized 78.9% of known ASNSD-associated missense variants as pathogenic. The remaining variants were primarily labeled as ambiguous, with a smaller proportion classified as benign. This study underscores the potential role of AlphaMissense in classifying ASNS variants in suspected cases of ASNSD, potentially providing clarity to patients and their families grappling with ongoing diagnostic uncertainty.
Differential effects of aging on regional corpus callosum microstructure and the modifying influence of pulse pressure
Authors: Kraft Jessica N , Matijevic Stephanie , Hoagey David A , Kennedy Kristen M , Rodrigue Karen 
Published: November 2023

AbstractThe corpus callosum is composed of several subregions, distinct in cellular and functional organization. This organization scheme may render these subregions differentially vulnerable to the aging process. Callosal integrity may be further compromised by vascular risk factors, which negatively influence white matter health. Here, we test for heterochronicity of aging, hypothesizing an anterior-to-posterior gradient of vulnerability to aging that may be altered by effects of vascular health. In 174 healthy adults across the adult lifespan (mean age=53.56 ± 18.90, range=20-94 years old, 58.62% women), measures of pulse pressure and diffusion-weighted imaging were conducted. A deterministic tractography approach was utilized to extract fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD) from each of five callosal subregions, serving as estimates of microstructural health. General linear models tested effects of age, hypertension, and pulse pressure on these metrics. We observed no significant effect of hypertensive diagnosis on callosal microstructure. We found a significant main effect of age and an age x pulse pressure interaction whereby older age and elevated pulse pressure were associated with poorer FA, AD, and RD. Age effects revealed non-linear components and occurred along an anterior-posterior gradient of severity in the callosum. This gradient disappeared when pulse pressure was considered. These results indicate that age-related deterioration across the callosum is regionally variable, and that pulse pressure, a proxy of arterial stiffness, alters this aging pattern.Significance StatementAging is associated with microstructural changes in the corpus callosum, the largest white matter tract in the brain. Additionally, vascular factors, such as hypertension and pulse pressure, affect corpus callosum microstructure. However, it is unclear whether these factors uniformly impact the corpus callosum throughout aging. The current study aimed to characterize patterns of aging and assess the role of hypertension and pulse pressure across different subregions of the corpus callosum. We found an age-related gradient on corpus callosum microstructure, with the most pronounced impact on anterior regions. However, this gradient was not found when pulse pressure was considered. These findings suggest that subregions are differentially sensitive to age-related decline, and pulse pressure modifies and exacerbates these declines.
Gains in soil C storage under anthropogenic N deposition are rapidly lost following its cessation
Authors: Propson Brooke E. , Zak Donald R. , Classen Aimée T. , Burton Andrew J. , Freedman Zachary B. 
Published: November 2023

ABSTRACTAnthropogenic nitrogen (N) deposition enhanced the global terrestrial carbon (C) sink and partially offset anthropogenic CO2emissions. This was driven by the suppression of microbial activity associated with the breakdown of soil organic matter. However, since the implementation of emission abatement policies in the 1970’s, atmospheric N deposition has declined globally, and the consequences of this decline are unknown. Here, we assessed the response of soil C storage, and associated microbial activities, in a long-term field study that experimentally increased N deposition for 24-years. We measured soil C and N, parameters of microbial activity, and compared effect sizes of soil C in response to, and in recovery from, the N deposition treatment across the history of our experiment (1994-2022). Our results demonstrate that the accumulated C in the organic horizon has been lost and exhibit additional deficits 5-years post-termination of the N deposition treatment. These findings, in part, arise from mechanistic changes in microbial activity. Soil C in the mineral soil was less responsive thus far in recovery. If these organic horizon C dynamics are similar in other temperate forests, the Northern Hemisphere C sink will be reduced and climate warming will be enhanced.
TaxaNorm: a novel taxa-specific normalization approach for microbiome data
Authors: Wang Ziyue , Lloyd Dillon , Zhao Shanshan , Motsinger-Reif Alison 
Published: November 2023

AbstractBackgroundIn high-throughput sequencing studies, sequencing depth, which quantifies the total number of reads, varies across samples. Unequal sequencing depth can obscure true biological signals of interest and prevent direct comparisons between samples. To remove variability due to differential sequencing depth, taxa counts are usually normalized before downstream analysis. However, most existing normalization methods scale counts using size factors that are sample specific but not taxa specific, which can result in over- or under-correction for some taxa.ResultsWe developed TaxaNorm, a novel normalization method based on a zero-inflated negative binomial model. This method assumes the effects of sequencing depth on mean and dispersion vary across taxa. Incorporating the zero-inflation part can better capture the nature of microbiome data. We also propose two corresponding diagnosis tests on the varying sequencing depth effect for validation. We find that TaxaNorm achieves comparable performance to existing methods in most simulation scenarios in downstream analysis and reaches a higher power for some cases. Specifically, it has a well balance on power and false discoveries control. When applying the method in a real dataset, TaxaNorm has improved performance when correcting technical bias.ConclusionTaxaNorm considers correcting both sample- and taxon-specific bias by introducing an appropriate regression framework in the microbiome data, which aids in data interpretation and visualization. The ‘TaxaNorm’ R package is freely available through the CRAN repositoryhttps://CRAN.R-project.org/package=TaxaNormand the source code can be downloaded athttps://github.com/wangziyue57/TaxaNorm.