bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Jacob/nsmf gene knockout does not protect against hypoxia- and NMDA-induced neuronal cell death
Authors: Gomes Guilherme M. , Bär Julia , Karpova Anna , Kreutz Michael R. 
Published: December 2022

ABSTRACTJacob is a synapto-nuclear messenger protein that encodes and transduces the origin of synaptic and extrasynaptic NMDA receptor signals to the nucleus. The protein assembles a signalosome that differs in case of synaptic or extrasynaptic NMDAR activation. Following nuclear import Jacob docks these signalosomes to the transcription factor CREB. We have recently shown that amyloid-beta and extrasynaptic NMDAR activation triggers the translocation of a Jacob signalosome that results in inactivation of the transcription factor CREB, a phenomenon termed Jacob-induced CREB shut-off (JaCS). JaCS contributes to early Alzheimer’s disease pathology and a gene knockout of nsmf, the gene encoding Jacob, protects against amyloid pathology. Given that extrasynaptic activity is also involved in acute excitotoxicity, like in stroke, we asked whether nsmf gene knockout will also protect against acute insults, like oxygen and glucose deprivation and excitotoxic NMDA stimulation. Here we show that organotypic hippocampal slices from wild-type and nsmf-/-mice display similar degrees of degeneration when exposed to either oxygen glucose deprivation or 50 µM NMDA incubation. This lack of neuroprotection indicates that JaCS is mainly relevant in conditions of low level chronic extrasynaptic NMDAR activation that results in cellular degeneration induced by alterations in gene transcription.
Myristoyl’s dual role in allosterically regulating and localizing Abl kinase
Authors: de Buhr Svenja , Gräter Frauke 
Published: December 2022

Abstractc-Abl kinase, a key signalling hub in many biological processes ranging from cell development to proliferation, is tightly regulated by two inhibitory Src homology domains. An N-terminal myristoyl-modification can bind to a hydrophobic pocket in the kinase C-lobe, which stabilizes the auto-inhibitory assembly. Activation is triggered by myristoyl release. We used molecular dynamics simulations to show how both myristoyl and the Src homology domains are required to impose the full inhibitory effect on the kinase domain, and reveal the allosteric transmission pathway at residue-level resolution. Importantly, we find myristoyl insertion into a membrane to thermodynamically compete with binding to c-Abl. Myristoyl thus not only localizes the protein to the cellular membrane, but membrane attachment at the same time enhances activation of c-Abl by stabilizing its pre-activated state. Our data put forward a model in which lipidation tightly couples kinase localization and regulation, a scheme that currently appears to be unique for this non-receptor tyrosine kinase.
Identification of quiescent FOXC2+spermatogonial stem cells in adult mammals
Authors: Wang Zhipeng , Jin Cheng , Li Pengyu , Li Yiran , Tang Jielin , Yu Zhixin , Jiao Tao , Ou Jinhuan , Wang Han , Zou Dingfeng , Li Mengzhen , Mang Xinyu , Liu Jun , Lu Yan , Li Kai , Zhang Ning , Yu Jia , Miao Shiying , Wang Linfang , Song Wei 
Published: December 2022

AbstractIn adult mammals, spermatogenesis embodies the complex developmental process from spermatogonial stem cells (SSCs) to spermatozoa. At the top of this developmental hierarchy lie a series of SSC subpopulations. Their individual identities as well as the relationships with each other, however, remain largely elusive. Using single-cell analysis and lineage tracing, we discovered both in mice and humans the quiescent adult SSC subpopulation marked specifically by forkhead box protein C2 (FOXC2). All spermatogenic progenies can be derived from FOXC2+SSCs and the ablation of FOXC2+SSCs led to the depletion of the undifferentiated spermatogonia pool. During germline regeneration, FOXC2+SSCs were activated and able to completely restore the process. Germ cell specificFoxc2knockout resulted in an accelerated exhaustion of SSCs and eventually led to male infertility. Furthermore, FOXC2 prompts the expressions of negative regulators of cell cycle thereby ensures the SSCs reside in quiescence. Thus, this work proposes that the quiescent FOXC2+SSCs are essential for maintaining the homeostasis and regeneration of spermatogenesis in adult mammals.
Abundant pleiotropy across neuroimaging modalities identified through a multivariate genome-wide association study
Authors: Tissink E.P. , Shadrin A.A. , van der Meer D. , Parker N. , Hindley G. , Roelfs D. , Frei O. , Fan C.C. , Nagel M. , Nærland T. , Budisteanu M. , Djurovic S. , Westlye L. T. , van den Heuvel M.P. , Posthuma D. , Kaufmann T. , Dale A.M. , Andreassen O.A. 
Published: December 2022

AbstractGenetic pleiotropy is abundant across spatially distributed brain characteristics derived from one neuroimaging modality (e.g. structural, functional or diffusion MRI). A better understanding of pleiotropy across modalities could inform us on the integration of brain function, micro- and macrostructure. Here we show extensive genetic overlap across neuroimaging modalities at a locus and gene level in the UK Biobank (N=34,029) and ABCD Study (N=8,607). When jointly analysing phenotypes derived from structural, functional and diffusion MRI with the Multivariate Omnibus Statistical Test (MOSTest), we boost the discovery of loci and genes beyond previously identified effects for each modality individually. Cross-modality genes are involved in fundamental biological processes and predominantly expressed during prenatal brain development. We additionally boost prediction of psychiatric disorders by conditioning independent GWAS on our multimodal multivariate GWAS. These findings shed light on the shared genetic mechanisms underlying variation in brain morphology, functional connectivity, and tissue composition.Graphical abstract
Likelihood-based docking of models into cryo-EM maps
Authors: Millán Claudia , McCoy Airlie J. , Terwilliger Thomas C. , Read Randy J. 
Published: December 2022

AbstractOptimized docking of models into cryo-EM maps requires exploiting an understanding of the signal expected in the data to minimize the calculation time while maintaining sufficient signal. The likelihood-based rotation function used in crystallography can be employed to establish plausible orientations in a docking search. A phased likelihood translation function yields scores for the placement and rigid-body refinement of oriented models. Optimised strategies for choices of the resolution of data from the cryo-EM maps to use in the calculations and the size of search volumes are based on expected log-likelihood-gain scores, computed in advance of the search calculation. Tests demonstrate that the new procedure is fast, robust and effective at placing models into even challenging cryo-EM maps.SynopsisExploiting analogies to crystallographic molecular replacement, a strategy for docking into cryo-EM maps is informed by calculations of expected log-likelihood-gain scores.
Anatomy of the complete mouse eye vasculature in development and pathology explored by light-sheet fluorescence microscopy
Authors: Krimpenfort Luc , Garcia-Collado Maria , van Leeuwen Tom , Locri Filippo , Luik Anna-Liisa , Queiro-Palou Antonio , Kanatani Shigeaki , André Helder , Uhlén Per , Jakobsson Lars 
Published: December 2022

AbstractEye development and function rely on precise establishment, regression and maintenance of its many sub-vasculatures. These crucial vascular properties have been extensively investigated in eye development and disease utilizing genetic and experimental mouse models. However, due to technical limitations, individual studies have often restricted their focus to one specific sub-vasculature. Here, we apply a workflow that allows for visualisation of complete vasculatures of mouse eyes of various developmental stages. Through tissue depigmentation, immunostaining, clearing and light-sheet fluorescence microscopy (LSFM) entire vasculatures of the retina, vitreous (hyaloids) and uvea were simultaneously imaged at high resolution. In silico dissection provided detailed information on their 3D architecture and interconnections. By this method we describe remodelling of the postnatal iris vasculature following its disconnection to the feeding hyaloid vasculature. In addition, we demonstrate examples of conventional and LSFM-mediated analysis of choroidal neovascularisation after laser-induced wounding, showing added value of the presented workflow in analysis of modelled eye disease. These advancements in visualisation and analysis of the respective eye vasculatures in development and complex eye disease open for novel observations of their functional interplay at a whole-organ level.
SAFB associates with nascent RNAs to promote gene expression in mouse embryonic stem cells
Authors: Cherney Rachel E. , Eberhard Quinn E. , Mills Christine A. , Porrello Alessandro , Zhang Zhiyue , White David , Herring Laura E. , Calabrese J. Mauro 
Published: December 2022

AbstractScaffold Attachment Factor B (SAFB) is a conserved RNA Binding Protein (RBP) that is essential for early mammalian development. However, the RNAs that associate with SAFB in mouse embryonic stem cells have not been characterized. Here, we addressed this unknown using RNA-seq and SAFB RNA immunoprecipitation followed by RNA-seq (RIP-seq) in wild-type ESCs and in ESCs in which SAFB and SAFB2 were knocked out. SAFB predominantly associated with introns of protein-coding genes through purine-rich motifs. The transcript most enriched in SAFB association was the lncRNAMalat1, which also contains a purine-rich region in its 5′end. Knockout of SAFB/2 led to down- and upregulation of approximately 1,000 genes associated with multiple biological processes, including genes that are regulated by Polycomb and genes involved in apoptosis, cell division, and cell migration. The spliced and nascent transcripts of many downregulated genes associated with high levels of SAFB in wild-type cells, implying that SAFB binding promotes their expression. Reintroduction of SAFB into double-knockout cells restored gene expression towards wild-type levels, an effect that was again observable at the level of spliced and nascent transcripts. Proteomics analysis revealed a significant enrichment of nuclear speckle-associated and RS-domain containing proteins among SAFB interactors. Our findings suggest that among other potential functions in mouse embryonic stem cells, SAFB promotes the expression of a subset of genes through its ability to bind purine regions in nascent RNA.
Contribution of Notch/Wnt signaling modulation in reactive astrocyte reparative response after brain injury
Authors: Delgado-Garcia Lina Maria , Benincasa Julia C. , Courbassier Natália Rodrigues , Ribeiro Tais Novaki , Porcionatto Marimélia 
Published: December 2022

AbstractAfter a Traumatic Brain Injury (TBI), the neural network activates a reparative response seeking to restore homeostasis. Astrocyte reactivation is an essential component of this response. The injury creates a temporal microenvironment where neurogenic signaling molecules regulate cell fate decisions of neocortical neural progenitors. Likewise, astrocyte reactivation triggers a transcriptional-proliferative program where neurogenic signaling molecules play crucial roles. However, precise molecular mechanisms are context-specific and are not fully understood. Here we studied cellular and molecular aspects of reactive astrocytes response after Notch-Wnt neurogenic signaling modulation. Our results provide new evidence of cortical Notch-Wnt signaling activation after TBI. Reactive astrocytes in the core of Notch signaling showed a differential aggregated distribution.In vitro, Notch inhibition promoted a neural precursor profile and might increase the number of cells committed in a proliferative response. Finally, we found an indirect co-regulation of Wnt-Shh signaling in BHLH-Notch target genes and a Notch-supportive effect in Wnt-Shh signaling activation.
Identification of S1PR4 as an immune modulator for favourable prognosis in HNSCC through unbiased machine learning
Authors: Huang Chenshen , Zhu Fengshuo , Wang Ning , Huang Qi 
Published: December 2022

AbstractAs the largest family of membrane proteins, G protein-coupled receptors (GPCRs) are the most prominent family of pharmacological targets. However, only a few GPCRs have been well-defined in terms of their physiological and pathological functions. Thus, an efficient way to identify key GPCRs involved in tumour formation is urgently needed. In this study, patients with head and neck squamous cell carcinoma (HNSCC) were classified into two different subtypes based on the characteristics of GPCRs using an unbiased machine learning method. Notably, these two subtypes showed significant differences in prognosis, gene expression, and immune microenvironment, especially in the infiltration of CD8+T cells. Based on these differences, we screened three potential key regulators (S1PR4, S1PR5, and GPR87) from all GPCRs and constructed a prognostic nomogram for patients with HNSCC. We identified S1PR4 as the key GPCR in determining the two subtypes for positive correlation with the proportion and cytotoxicity of CD8+T cells in HNSCC and was mainly expressed in a subset of CX3CR1+CD8+T cells. We also demonstrated that S1PR4 is an immune modulator for the favourable prognosis of HNSCC patients. We found that S1PR4 was highly expressed in CD8+T cells from the tumours of HNSCC patients, which was significantly associated with better prognosis, and S1PR4 expression was accompanied by higher T cell cytotoxic marker expression (IFNG and GZMB). Notably, S1PR4 co-localised with CX3CR1, which has been identified as the most cytotoxic marker of CD8+T cells. Furthermore, S1PR4 upregulation could significantly increase T cell function in CAR-T cell therapy, indicating its great potential in cancer immunotherapy. Therefore, these results identified S1PR4 as a key indicator of cytotoxicity and the proportion of tumour-infiltrating CD8+T cells and confirmed the prognostic value of S1PR4 in HNSCC. Our findings contribute to the knowledge of S1PR4 in anti-tumour immunity, providing a potential GPCR-targeted therapeutic option for future HNSCC treatment.
AIRRSHIP: simulating human B cell receptor repertoire sequences
Authors: Sutherland Catherine , Cowan Graeme J M 
Published: December 2022

SummaryAdaptive Immune Receptor Repertoire Sequencing is a rapidly developing field that has advanced understanding of the role of the adaptive immune system in health and disease. Numerous tools have been developed to analyse the complex data produced by this technique but work to compare their accuracy and reliability has been limited. Thorough, systematic assessment of their performance is dependent on the ability to produce high quality simulated datasets with known ground truth. We have developed AIRRSHIP, a flexible and fast Python package that produces synthetic human B cell receptor sequences. AIRRSHIP uses a comprehensive set of reference data to replicate key mechanisms in the immunoglobulin recombination process, with a particular focus on junctional complexity. Repertoires generated by AIRRSHIP are highly similar to published data and all steps in the sequence generation process are recorded. These data can be used to not only determine the accuracy of repertoire analysis tools but can also, by tuning of the large number of user-controllable parameters, give insight into factors that contribute to inaccuracies in results.Availability and ImplementationAIRRSHIP is implemented in Python. It is available viahttps://github.com/Cowanlab/airrshipand on PyPI athttps://pypi.org/project/airrship/. Documentation can be found athttps://airrship.readthedocs.io.Contactgraeme.cowan@ed.ac.uk
Network-Guided Sparse Subspace Clustering on Single-Cell Data
Authors: Yuan Chenyang , Jiang Shunzhou 
Published: December 2022

AbstractWith the rapid development of single-cell RNA sequencing (scRNA-seq) technology, people are able to investigate gene expression at the individual cell level. Identification of cell types via unsupervised clustering is one of the fundamental issues in analyzing single-cell data. However, due to the high dimensionality of expression profiles, traditional clustering methods are difficult to generate satisfactory results. To address this problem, we designed NetworkSSC, a network-guided sparse subspace clustering (SSC) approach. NetworkSSC is based on a similar assumption in SSC that the expression of cells within the same type lies in the same subspace. Moreover, it integrates an additional regularization term to include the gene network’s Laplacian matrix, so as to utilize the network information. The comparison results of 5 scRNA-seq data sets show that NetworkSSC outperforms ordinary SSC and other clustering methods in most cases.
TheFLOWERING LOCUS T LIKE 2-1gene ofChenopodiumtriggers precocious flowering in Arabidopsis seedlings
Authors: Abeyawardana Oushadee A. J. , Moravec Tomáš , Krüger Manuela , Belz Claudia , Gutierrez-Larruscain David , Vondráková Zuzana , Eliášová Kateřina , Štorchová Helena 
Published: December 2022

ABSTRACTTheFLOWERING LOCUS T(FT)gene is the essential integrator of flowering regulatory pathways in angiosperms. The paralogs of theFTgene may perform antagonistic functions, as exemplified byBvFT1, that suppresses flowering inBeta vulgaris, unlike the paralogous activatorBvFT2. The roles ofFTgenes in other amaranths were less investigated. Here, we transformedArabidopsis thalianawith theFLOWERING LOCUS T like(FTL) genes ofChenopodiumand found, that bothFTL1andFTL2-1accelerated flowering, despite having been the homologs of theBeta vulgarisfloral promoter and suppressor, respectively. The floral promotive effect ofFTL2-1was so strong that it caused lethality when overexpressed under the35Spromoter.FTL2-1placed in inducible cassette accelerated flowering after the induction with methoxyphenozide. The occasional expression ofFTL2-1led to precocious flowering in some primary transformants even without chemical induction. After theFTLgene duplication in Amaranthaceae, theFTL1copy maintained the role of floral activator. The second copyFTL2underwent subsequent duplication and functional diversification, which enabled to control the onset of flowering in amaranths to adapt to variable environments.HIGHLIGHTTheFLOWERING LOCUS T like 2-1(FTL 2-1) gene ofChenopodiumacts as a strong activator of flowering in Arabidopsis, despite being a homolog of floral repressorBvFT1.
CAbiNet: Joint visualization of cells and genes based on a gene-cell graph
Authors: Zhao Yan , Kohl Clemens , Rosebrock Daniel , Hu Qinan , Hu Yuhui , Vingron Martin 
Published: December 2022

AbstractIn routine single-cell RNA-sequencing (scRNA-seq) analysis workflows, cells are commonly visualized in 2D to show the patterns in the data. However, these visualization approaches do not give any information about the genes that define the cell groups or clusters. It is therefore desirable to display cells and genes simultaneously such that by their relative position to each other information about the genes’ expression in a cluster can be obtained. Here we propose “Correspondence Analysis based Biclustering on Networks” (CAbiNet) as a novel approach to jointly visualize cells and genes by a non-linear embedding approach, called biMAP. The biMAP allows for easy and interactive exploration of cells and their corresponding marker genes in a single plot. CabiNet additionally offers an intuitive way to perform biclustering jointly on cells and genes, providing a simplified workflow to annotate cell types on the biMAP. CAbiNet is accessible through GitHub as an R package.
Nature Notes: Spatiotemporal variation in the competitive environment, with implications for how climate change may affect a species with parental care
Authors: Potticary Ahva L. , Otto Hans W. , McHugh Joseph V. , Moore Allen J. 
Published: December 2022

AbstractBurying beetles of the genusNicrophorushave become a model for studying the evolution of complex parental care in a laboratory.Nicrophorusspecies depend on small vertebrate carcasses to breed, which they process and provision to their begging offspring. However, vertebrate carcasses are highly sought after by a wide variety of species and so competition is expected to be critical to the evolution of parental care. Despite this, the competitive environment forNicrophorusis rarely characterized in the wild and remains a missing factor in laboratory studies. Here, we performed a systematic sampling ofNicrophorus orbicollisliving near the southern extent of their range at Whitehall Forest in Clarke County, Georgia, USA. We determined the density ofN. orbicollisand other necrophilous species that may affect the availability of this breeding resource through interference or exploitation competition. In addition, we characterize body size, a key trait involved in competitive ability, for allNicrophorusspecies at Whitehall Forest throughout the season. Finally, we compare our findings to other published natural history data for Nicrophorines. We document a significantly longer active season than was observed twenty years previously at Whitehall Forest for bothN. orbicollisandNicrophorus tomentosus, potentially due to climate change. As expected, the adult body size ofN. orbicolliswas larger thanN. tomentosus, the only otherNicrophorusspecies that was captured in 2022 at Whitehall Forest. The other most prevalent interspecific insects captured included species in the families Staphylinidae, Histeridae, Scarabaeidae, and Elateridae, which may act as competitors or predators ofNicrophoruseggs and larvae. Together, our results indicate significant variation in intra- and interspecific competition relative to populations within theN. orbicollisrange. These findings suggest that the competitive environment varies extensively over space and time, which help to inform the role of ecology in the evolution of parental care in this species.
Alcohol and Cannabinoid Binges and Daily Exposure to Nicotine in Adolescent/Young Adult Rats induce Sex-Dependent Long-Term Learning and Motivation Alterations
Authors: Abela Norbert , Haywood Katie , Di Giovanni Giuseppe 
Published: December 2022

AbstractAdolescence is a critical developmental period, concerning anatomical, neurochemical and behavioral changes. Moreover, adolescents are more sensitive to the long-term deleterious effects of drug abuse. Binge-like consumption of alcohol and marijuana, along with tobacco smoking, is a dangerous pattern often observed in adolescents during weekends. Nevertheless, the long-term effect of their adolescent co-exposure has not been experimentally investigated yet.Long-Evans adolescent male (n = 20) and female (n = 20) rats from postnatal day 30 (P30) until P60 were daily treated with nicotine (0.3 mg/kg, i.p.), and, on two consecutive ‘binging days’ per week (for a total of eight times), received an intragastric ethanol solution (3 g/kg) and an intraperitoneal (i.p.) dose of cannabinoid 1/2 receptor agonist WIN55,212-2 (1.2 mg/kg). These rats were tested after treatment discontinuation at >P90 for associative food-rewarded operant learning in the two-lever conditioning chambers for six consecutive days on a fixed ratio 1 (FR1) schedule followed by another six days of daily FR2 schedule testing, after 45 days rest. We found the main effects of sex x treatment interactions in FR1 but not in FR2 experiments. Treated females show attenuated operant responses for food pellets during all FR1 and the FR2 schedule, whilst the treated males show an impairment in FR2 but not in the FR1 schedule. Moreover, the treated females’ percentage of learners was significantly lower than female controls in FR1 while treated males and females were lower than controls in FR2.Our findings suggest that intermittent adolescent abuse of common drugs, such as alcohol and marijuana, and chronic tobacco exposure can cause significant long-term effects on motivation for natural reinforcers later in adulthood in both sexes. Females appear to be more sensitive to the deleterious effects of adolescent polydrug abuse with both sexes having an increased likelihood of developing lifelong brain alterations.