bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single nucleus multiomics identifies ZEB1 and MAFB as candidate regulators of Alzheimer’s disease-specific cis regulatory elements
Authors: Anderson A. G. , Rogers B. B. , Loupe J. M. , Rodriguez-Nunez I. , Roberts S. C. , White L. M. , Brazell J. N. , Bunney W. E. , Bunney B. G. , Watson S. J. , Cochran J. N. , Myers R. M. , Rizzardi L. F. 
Published: October 2022

SummaryCell type-specific transcriptional differences between brain tissues from donors with Alzheimer’s disease (AD) and unaffected controls have been well-documented, but few studies have rigorously interrogated the regulatory mechanisms responsible for these alterations. We performed single nucleus multiomics (snRNA-seq+snATAC-seq) on 105,332 nuclei isolated from cortical tissues from 7 AD and 8 unaffected donors to identify candidate cis-regulatory elements (CREs) involved in AD-associated transcriptional changes. We detected 319,861 significant correlations, or links, between gene expression and cell type-specific transposase accessible regions enriched for active CREs. Among these, 40,831 were unique to AD tissues. Validation experiments confirmed the activity of many regions, including several candidate regulators of APP expression. We identified ZEB1 and MAFB as candidate transcription factors playing important roles in AD-specific gene regulation in neurons and microglia, respectively. Microglial links were globally enriched for heritability of AD risk and previously identified active regulatory regions.
Artificial neural network language models predict human brain responses to language even after a developmentally realistic amount of training
Authors: Hosseini Eghbal A. , Schrimpf Martin , Zhang Yian , Bowman Samuel , Zaslavsky Noga , Fedorenko Evelina 
Published: October 2022

AbstractArtificial neural networks have emerged as computationally plausible models of human language processing. A major criticism of these models is that the amount of training data they receive far exceeds that of humans during language learning. Here, we use two complementary approaches to ask how the models’ ability to capture human fMRI responses to sentences is affected by the amount of training data. First, we evaluate GPT-2 models trained on 1 million, 10 million, 100 million, or 1 billion words against an fMRI benchmark. We consider the 100-million-word model to be developmentally plausible in terms of the amount of training data given that this amount is similar to what children are estimated to be exposed to during the first 10 years of life. Second, we test the performance of a GPT-2 model trained on a 9-billion-token dataset to reach state-of-the-art next-word prediction performance on the human benchmark at different stages during training. Across both approaches, we find that (i) the models trained on a developmentally plausible amount of data already achieve near-maximal performance in capturing fMRI responses to sentences. Further, (ii) lower perplexity—a measure of next-word prediction performance—is associated with stronger alignment with human data, suggesting that models that have received enough training to achieve sufficiently high next-word prediction performance also acquire representations of sentences that are predictive of human fMRI responses. In tandem, these findings establish that althoughsometraining is necessary for the models’ predictive ability, a developmentally realistic amount of training (∼100 million words) may suffice.
The genome-wide mutational consequences of DNA hypomethylation
Authors: Besselink Nicolle , Keijer Janneke , Vermeulen Carlo , Boymans Sander , de Ridder Jeroen , van Hoeck Arne , Cuppen Edwin , Kuijk Ewart 
Published: October 2022

AbstractDNA methylation is important for establishing and maintaining cell identity and for genomic stability. This is achieved by regulating the accessibility of regulatory and transcriptional elements and the compaction of subtelomeric, centromeric, and other inactive genomic regions. Carcinogenesis is accompanied by a global loss in DNA methylation, which facilitates the transformation of cells. Cancer hypomethylation may also cause genomic instability, for example through interference with the protective function of telomeres and centromeres. However, understanding the role(s) of hypomethylation in tumor evolution is incomplete because the precise mutational consequences of global hypomethylation have thus far not been systematically assessed. Here we made genome-wide inventories of all possible genetic variation that accumulates in single cells upon the long-term global hypomethylation by CRISPR/CAS9-mediated conditional knockdown of DNMT1. Depletion of DNMT1 results in a genomewide reduction in DNA methylation levels. Hypomethylated cells show reduced proliferation rates, reactivation of the inactive X-chromosome and abnormal nuclear morphologies. Prolonged hypomethylation is accompanied by increased chromosomal instability. However, there is no increase in mutational burden, enrichment for certain mutational signatures or structural changes to the genome. We conclude that the primary consequence of global hypomethylation is chromosomal instability and does not necessarily lead to other small-scale or structural mutational effects.
Pseudomonas apudapuassp. nov.,Pseudomonas fontissp. nov.,Pseudomonas idahonensissp. nov., andPseudomonas rubrasp. nov. isolated from in, and around, a rainbow trout farm
Authors: Testerman Todd , Varga Jackie , Donohue Hailey , Da Silva Caroline Vieira , Graf Joerg 
Published: October 2022

ABSTRACTDuring a large-scale bacterial culturing effort of biofilms in the vicinity of a rainbow trout aquaculture facility in Idaho, USA, ten isolates were identified as having pathogen inhibiting activity and were characterized further. These isolates were shown to be Gram negative, rod-shaped bacteria belonging to the genusPseudomonas. Whole genome comparisons and multi-locus sequence analysis using four housekeeping genes (16S rDNA,gyrA, rpoB, rpoD) showed that these 10 isolates clustered into four distinct species groups. These comparisons also indicated that these isolates were below the established species cutoffs for the genusPseudomonas. Further phenotypic characterization using API 20NE, API ZYM, and BioLog GENIII assays and chemotaxonomic analysis of cellular fatty acids were carried out. Based on the genomic, physiological, and chemotaxonomic properties of these isolates, we concluded that these strains composed four novel species ofPseudomonas. The proposed names are:Pseudomonas apudapuassp. nov. consisting of strains ID233, ID386T, and ID387 with ID386T(DSM 114641) as the type strain;Pseudomonas rubrasp. nov. consisting of strains ID291T, ID609, and ID1025 with ID291T(DSM 114640) as the type strain;Pseudomonas idahonensissp. nov. consisting of strains ID357Tand ID1048 with ID357T(DSM 114609) as the type strain; andPseudomonas fontissp. nov. consisting of strains ID656Tand ID681 with ID656T(DSM 114610) as the type strain.
Particle fusion of Single Molecule Localization Microscopy data reveals dimer structure of Nup96 in Nuclear Pore Complex
Authors: Wang Wenxiu , Jakobi Arjen , Wu Yu-Le , Ries Jonas , Stallinga Sjoerd , Rieger Bernd 
Published: October 2022

AbstractSingle molecule localization microscopy offers nowadays resolution nearly down to the molecular level with specific molecular labelling, thereby being a promising tool for structural biology. In practice, however, the actual value to this field is limited primarily by incomplete fluorescent labeling of the structure. This missing information can be completed by merging information from many structurally identical particles equivalent to cryo-EM single-particle analysis. In this analysis, we present particle averaging of fluorescently labelled Nup96 in the Nuclear Pore Complex followed by data analysis to show that Nup96 occurs as a dimer with in total 32 copies per pore. We use Artificial Intelligence assisted modeling in Alphafold to extend the existing cryo-EM model of Nup96 to accurately pinpoint the positions of the fluorescent labels and show the accuracy of the match between fluorescent and cryo-EM data to be better than 3 nm in-plane and 5 nm out-of-plane.
Heterosynaptic Plasticity of the Visuo-auditory Projection Requires Cholecystokinin released from Entorhinal Cortex Afferents
Authors: Sun Wenjian , Wu Haohao , Peng Yujie , Tang Peng , Zhao Ming , Zheng Xuejiao , Feng Hemin , Li Hao , Liang Ye , Li Jing , Su Junfeng , Chen Xi , Hökfelt Tomas , He Jufang 
Published: October 2022

AbstractThe entorhinal cortex is involved in establishing enduring visuo-auditory associative memory in the neocortex. Here we explored the mechanisms underlying this synaptic plasticity related to projections from the visual and entorhinal cortices to the auditory cortex, using optogenetics of dual pathways. High-frequency laser stimulation (HFLS) of the visuo-auditory projection did not induce long-term potentiation (LTP). However, after pairing with sound stimulus, the visuo-auditory inputs were potentiated following either infusion of cholecystokinin (CCK) or HFLS of the entorhino-auditory CCK-expressing projection. Combining retrograde tracing and RNAscope in situ hybridization, we show that CCK expression is higher in entorhinal cortex neurons projecting to the auditory cortex than in those originating from the visual cortex. In the presence of CCK, potentiation in the neocortex occurred when the pre-synaptic input arrived 200 ms before post-synaptic firing, even after just five trials of pairing. Behaviorally, inhibition of CCK signaling blocked the generation of associative memory. Our results indicate that neocortical visuo-auditory association is formed through heterosynaptic plasticity, which depends on release of CCK in the neocortex mostly from entorhinal afferents.
Nuclear autophagy interactome unveils WSTF as a constitutive nuclear inhibitor of inflammation
Authors: Wang Yu , Eapen Vinay V. , Kournoutis Athanasios , Onorati Angelique , Li Xianting , Zhou Xiaoting , Cetinbas Murat , Wang Lu , Liu Jihe , Bretz Corey , Zhou Zhuo , Ho Sui Shannan J. , Saladi Srinivas Vinod , Sadreyev Ruslan I. , Adams Peter D. , Kingston Robert E. , Yue Zhenyu , Johansen Terje , Dou Zhixun 
Published: October 2022

AbstractMacroautophagy (hereafter referred to as autophagy) degrades a variety of cellular components. A poorly understood area is autophagic degradation of nuclear substrates, or “nuclear autophagy”. It remains unclear what can be degraded by autophagy from the mammalian nuclei. We began our study by investigating the nuclear binding partners of ATG8 family proteins that play important roles in recognizing autophagy substrates. We systematically evaluated the ATG8 nuclear interactome in primary human cells and in mouse brain, identifying hundreds of novel interactions. We continued our study by evaluating the nuclear proteomes of cellular senescence, a stable form of cell cycle arrest program associated with inflammation, in which nuclear autophagy is involved. Combined with the ATG8 nuclear interactome data, we identified WSTF, a component of the ISWI chromatin remodeling complex, as a novel substrate of nuclear autophagy. The degradation of WSTF, mediated by a direct interaction with the GABARAP isoform of ATG8, promotes chromatin accessibility of inflammatory genes and induces senescence-associated inflammation. Furthermore, WSTF directly binds the p65 subunit of NF-κB and inhibits its acetylation, thus blocking inflammatory gene expression in the setting of senescence, cancer, and pathogen infection. In addition, we show that loss of WSTF is required for the immuno-surveillance of oncogenic Ras in mouse liver; forced expression of WSTF inhibited tumor-suppressive inflammation and led to the development of liver tumors. Taken together, our study provides a global view of mammalian nuclear autophagy and reveals a novel nuclear inhibitor of inflammation implicated in diverse pathological contexts. Targeting WSTF may be broadly valuable as therapeutic intervention of inflammatory diseases.
Structural Analysis of Phosphorylation Proteoforms in a Dynamic Heterogeneous System Using Flash Oxidation Coupled In-Line with Ion Exchange Chromatography
Authors: Cheng Zhi , Misra Sandeep K. , Shami Anter , Sharp Joshua S. 
Published: October 2022

ABSTRACTProtein post-translational modifications (PTMs) are key modulators of protein structure and function that often change in a dynamic fashion in response to cellular stimuli. Dynamic post-translational modifications are very challenging to structurally characterize using modern techniques, including covalent labeling methods, due to the presence of multiple proteoforms and conformers together in solution. Here, we have coupled ion exchange HPLC with a flash oxidation system (IEX LC-FOX) to successfully elucidate structural changes among three phosphoproteoforms of ovalbumin (OVA) during dephosphorylation with alkaline phosphatase (AP). Real-time dosimetry indicates no difference in effective radical dose between peaks or across the peak, demonstrating both the lack of scavenging of the NaCl gradient and the lack of a concentration effect on radical dose between peaks of different intensities. The use of IEX LC-FOX allows us to structurally probe each phosphoproteoform as it elutes from the column, capturing structural data before the dynamics of the system reintroduce heterogeneity. We found significant differences in residue-level oxidation between the hydroxyl radical footprint of non-phosphorylated, mono-phosphorylated and di-phosphorylated ovalbumin. Not only were our data consistent with the previously reported stabilization of ovalbumin structure by phosphorylation, but local structural changes were also consistent with the measured order of dephosphorylation of Ser344 being removed first. These results demonstrate the utility of IEX LC-FOX for measuring the structural effects of PTMs, even in dynamic systems.
Three-dimensional genome re-wiring in loci with Human Accelerated Regions
Authors: Keough Kathleen C. , Whalen Sean , Inoue Fumitaka , Przytycki Pawel F. , Fair Tyler , Deng Chengyu , Steyert Marilyn , Ryu Hane , Lindblad-Toh Kerstin , Karlsson Elinor ,   Zoonomia Consortium, Nowakowski Tomasz , Ahituv Nadav , Pollen Alex , Pollard Katherine S. 
Published: October 2022

AbstractHuman Accelerated Regions (HARs) are conserved genomic loci that evolved at an accelerated rate in the human lineage and may underlie human-specific traits. We generated HARs and chimpanzee accelerated regions with the largest alignment of mammalian genomes to date. To facilitate exploration of accelerated evolution in other lineages, we implemented an open-source Nextflow pipeline that runs on any computing platform. Combining deep-learning with chromatin capture experiments in human and chimpanzee neural progenitor cells, we discovered a significant enrichment of HARs in topologically associating domains (TADs) containing human-specific genomic variants that change three-dimensional (3D) genome organization. Differential gene expression between humans and chimpanzees at these loci in multiple cell types suggests rewiring of regulatory interactions between HARs and neurodevelopmental genes. Thus, comparative genomics together with models of 3D genome folding revealed enhancer hijacking as an explanation for the rapid evolution of HARs.One-Sentence SummaryHuman-specific changes to 3D genome organization may have contributed to rapid evolution of mammalian-conserved loci in the human genome.
The nuclear Argonaute HRDE-1 directs target gene re-localization and shuttles to nuage to promote small RNA mediated inherited silencing
Authors: Ding Yue-He , Ochoa Humberto , Ishidate Takao , Mello Craig C. 
Published: October 2022

AbstractArgonaute small-RNA pathways engage heterochromatin-silencing co-factors to promote transgenerational inheritance in animals. However, little is known about how heterochromatin and small-RNA pathways interact to transmit silencing. Here we show that the induction of heterochromatin silencing in C. elegans by RNAi or by artificially tethering pathway components to target RNA correlates with the co-localization of the target alleles in pachytene nuclei. Tethering the nuclear Argonaute WAGO-9/HRDE-1 induces heterochromatin formation, but also functions independently to induce small-RNA amplification. We show that HRDE-1 shuttles to nuage domains called mutator foci where amplification is thought to occur. Tethering a heterochromatin-silencing factor, NRDE-2, induces heterochromatin silencing and also induces the de-novo synthesis of HRDE-1 guide RNAs, and through HRDE-1 acts to further amplify downstream small-RNA silencing. Our findings support a model in which HRDE-1 functions both upstream, to initiate heterochromatin silencing, and downstream, to stimulate small-RNA amplification, establishing a self-enforcing mechanism that propagates silencing to offspring.
Atypical NMDA Receptors Limit Synaptic Plasticity in the Adult Ventral Hippocampus
Authors: Hurley Emily P. , Mukherjee Bandhan , Fang Lisa , Barnes Jocelyn R. , Nafar Firoozeh , Hirasawa Michiru , Parsons Matthew P. 
Published: October 2022

AbstractN-methyl-D-aspartate receptors (NMDARs) assemble as functionally diverse heterotetramers. Incorporation of the GluN3A subunit into NMDARs alters conventional NMDAR properties by reducing both magnesium sensitivity and calcium permeability. GluN1 together with GluN3A can also form functional receptors that lack a glutamate binding site and instead serve as excitatory glycine receptors (eGlyRs). GluN3A expression is high in early development but naturally declines to low levels in most brain regions by adulthood. Interestingly, GluN3A expression remains elevated in the CA1 of the adult ventral hippocampus (VH), but not in the dorsal hippocampus (DH). The DH and VH are now well-understood to play very different functional roles, with the DH being primarily involved in cognitive functions and the VH in emotional processing. Why GluN3A persists in the adult VH, and the impact its presence has on glutamatergic neurotransmission in the VH is currently unknown. Here, we show that GluN3A remains elevated both at synaptic and extrasynaptic locations in the adult VH, assembling as GluN1/GluN2/GluN3A NMDARs with reduced magnesium sensitivity, as well as GluN1/GluN3A eGlyRs. By comparing various synaptic properties in the DH and VH of wild-type (WT) and GluN3A knockout (KO) mice, we demonstrate that GluN3A persistence in the VH attenuates glutamate release, limits postsynaptic calcium influx through NMDARs, and reduces the magnitude of NMDAR-dependent long-term potentiation. In comparison, GluN3A KO had relatively little effect on these same properties in the DH. In all, our data demonstrate that GluN3A persistence in the VH represents a key modulator of VH excitability and therefore may play a central role in emotional processing.
Distinct effects of disease-associated TREM2 R47H/+ and T66M mutations on iPSC-derived microglia
Authors: Penney Jay , Ralvenius William T , Loon Anjanet , Cerit Oyku , Dileep Vishnu , Milo Blerta , Woolf Hannah , Tsai Li-Huei 
Published: October 2022

AbstractGenetic findings have highlighted key roles for microglia in the pathology of neurodegenerative conditions such as Alzheimer’s disease (AD). Distinct mutations in the microglial protein TREM2 (triggering receptor expressed on myeloid cells 2) are associated with different forms of neurodegeneration in humans; R47H/+ mutations increase AD risk, while loss-of-function mutations such as TREM2 T66M result in more severe forms of neurodegeneration. We employed gene editing and stem cell models to gain insight into the effects of these mutations on human iPSC-derived microglia. We found divergent effects of TREM2 R47H/+ and T66M mutations on gene expression, with R47H/+ cells exhibiting a pro-inflammatory gene expression signature. Both the TREM2 R47H/+ and T66M mutations caused similar impairments in microglial movement and the uptake of multiple substrates, while R47H/+ microglia were hyper-responsive to inflammatory stimuli, consistent with their gene expression signature. We developed an in vitro laser-induced injury model in neuron-microglia co-cultures, finding an impaired injury response by TREM2 R47H/+ microglia. Furthermore, in xenotransplantation experiments, mouse brains transplanted with TREM2 R47H/+ microglia exhibited reduced synaptic density. Consistently, we observed upregulation of multiple complement cascade components in TREM2 R47H/+ microglia, suggesting that inappropriate synaptic pruning may underlie the effect. Thus, these findings identify shared and distinct effects of these two TREM2 mutations on microglial gene expression and function. While the TREM2 T66M mutation impairs microglial movement and uptake processes, the TREM2 R47H/+ mutation additionally confers multiple potentially detrimental effects on human microglia, likely to underlie its association with AD.
Employees' adoption of HR analytics – a theoretical framework based on career construction theory
Authors: Dhankhar Kiran , Singh Abhishek 
Published: October 2022

PurposeDrawing upon the career construction theory, the present study aims to propose and test a mediation model exploring the association among technology readiness, adoption of human resource (HR) analytics by HR professionals, and organizational career growth.Design/methodology/approachA survey has been conducted to collect data from HR professionals (N = 347) working in various industrial sectors in India. The data collected is analyzed for mediation using SPSS PROCESS Macro (Model 4).FindingsThe study provided evidence about the mediating role of individual adoption of HR analytics between technology readiness (motivators, inhibitors) and organization career growth (career goal progress, professional ability development, promotion speed and remuneration growth).Research limitations/implicationsFirstly, the results provide evidence in relation to the career construction theory with respect to adoption of human resource analytics by HR professionals. Secondly, the study findings validate the technology readiness model in the context of adopting HR analytics. Thirdly and most significantly, the study proposes a novel theoretical framework for adoption of HR analytics by HR professionals in organizations.Practical implicationsThe findings imply that HR professionals' technology readiness (motivators and inhibitors) can facilitate better adoption of HR analytics in organizations. Moreover, the adoption of HR analytics shall promote better career growth for HR professionals.Originality/valueThe present study builds and tests a theoretical framework based on technology readiness, individual adoption of HR analytics, and organization career growth. The study is the first of its kind to the best of the authors' knowledge.