bluuebunny/crossref_metadata_2025_split huggingface dataset:
Highly diverse and unknown viruses may enhance Antarctic endoliths’ adaptability
Authors: Ettinger Cassandra L. , Saunders Morgan , Selbmann Laura , Delgado-Baquerizo Manuel , Donati Claudio , Albanese Davide , Roux Simon , Tringe Susannah , Pennacchio Christa , del Rio Tijana G. , Stajich Jason E. , Coleine Claudia 
Published: December 2022

AbstractRock-dwelling microorganisms are key players in ecosystem functioning of Antarctic ice free-areas. Yet, little is known about their diversity and ecology. Here, we performed metagenomic analyses on rocks from across Antarctica comprising >75,000 viral operational taxonomic units (vOTUS). We found largely undescribed, highly diverse and spatially structured virus communities potentially influencing bacterial adaptation and biogeochemistry. This catalog lays the foundation for expanding knowledge of the virosphere in extreme environments.
Mechanistic implications of the interaction of the soluble substrate-binding protein with a type II ABC importer
Authors: Zhu Lingwei , Kim Jinrang , Leng Kun , Ramos John E. , Kinz-Thompson Colin D. , Karpowich Nathan K. , Gonzalez Ruben L. , Hunt John F. 
Published: December 2022

ATP-BindingCassette (ABC) Transporters employ homologous ATPase domains to drive transmembrane transport of diverse substrates ranging from small molecules to large polymers. Bacterial ABC importers require an extramembranoussubstratebindingprotein (SBP) to deliver the transport substrate to the extracellular side of the transporter complex. Previous studies suggest significant differences in the transport mechanisms of type Ivs. type II bacterial ABC importers, which contain unrelated transmembrane domains. We herein use ensemble fluorescence resonance energy transfer (FRET) experiments to characterize the kinetics of SBP interaction in theE. coliBtuCD-F complex, a canonical type II ABC importer that transports vitamin B12. We demonstrate that, in the absence of B12, BtuF (the SBP) forms a ‘locked’ (kinetically hyper-stable) complex with nanodisc-reconstituted BtuCD that can only be dissociated by ATP hydrolysis, which represents a futile reaction cycle. Notably, no type I importer has been observed to form an equivalent locked complex. We also show that either ATP or vitamin B12binding substantially slows formation of the locked BtuCD-F complex, which will limit the occurrence of futile hydrolysis under physiological conditions.Mutagenesis experiments demonstrate that efficient locking requires concerted interaction of BtuCD with residues on both sides of the B12binding pocket in BtuF. Combined with the kinetic inhibition of locking by ATP binding, these observations imply that the transition state for the locking reaction involves a global alteration in the conformation of BtuCD that extends from its BtuF binding site in the periplasm to its ATP-binding sites on the opposite side of the membrane in the cytoplasm. These observations suggest that locking, which seals the extracellular B12entry site of the transporter, may help push B12through the transporter and directly contribute to the transport mechanism in type II ABC importers.
Localized assembly for long reads enables genome-wide analysis of repetitive regions at single-base resolution in human genomes
Authors: Ikemoto Ko , Fujimoto Hinano , Fujimoto Akihiro 
Published: December 2022

AbstractBackgroundLong-read sequencing technologies have the potential to overcome the limitations of short reads and provide a comprehensive picture of the human genome. However, it remains hard to characterize repetitive sequences by reconstructing genomic structures at high resolution solely from long reads. Here, we developed a localized assembly method (LoMA) that constructs highly accurate consensus sequences (CSs) from long reads.MethodsWe first developed LoMA, by combining minimap2, MAFFT, and our algorithm, which classifies diploid haplotypes based on structural variants and constructs CSs. Using this tool, we analyzed two human samples (NA18943 and NA19240) sequenced with the Oxford Nanopore sequencer. We defined target regions in each genome based on mapping patterns and then constructed a high-quality catalog of the human insertion solely from the long-read data.ResultsThe assessment of LoMA showed high accuracy of CSs (error rate < 0.3%) compared with raw data (error rate > 8%) and superiority to the previous study. The genome-wide analysis of NA18943 and NA19240 identified 5,516 and 6,542 insertions (ζ 100 bp) respectively. Most insertions (∼80%) were derived from the tandem repeat and transposable elements. We also detected processed pseudogenes, insertions in transposable elements, and long insertions (> 10 kbp). Further, our analysis suggested that short tandem duplications were association with gene expression and transposons.ConclusionsOur analysis showed that LoMA constructs high-quality sequences from long reads with substantial errors. This study revealed the true structures of insertions with high accuracy and inferred mechanisms for the insertions. Our approach contributes to the future human genome studies. LoMA is available at our GitHub page:https://github.com/kolikem/loma.
Dynamics of repurposing synthetic and natural compounds against WNT/β-Catenin signaling in glioma- Anin vivoapproach
Authors: S Daisy Precilla , Kuduvalli Shreyas S , Biswas Indrani , K Bhavani , B Agiesh Kumar , Thomas Jisha Mary , T. S Anitha 
Published: December 2022

ABSTRACTBackgroundGlioblastomas arise from multistep tumorigenesis of the glial cells and are associated with poor prognosis. Despite the current state-of-art treatment, tumor recurrence is inevitable. Thus, there exists a desperate need for effective therapeutic alternatives to improve glioblastoma outcome. Among the innovations blooming up, drug repurposing could provide a profound premises for glioblastoma treatment enhancement. While considering this strategy, the efficacy of the repurposed drugs as monotherapies were not up to par; hence, the focus has now shifted to investigate the multi-drug combinations to target glioblastomas. In line with this concept, we investigated the efficacy of a quadruple-combinatorial treatment comprising temozolomide (the benchmark drug) along with chloroquine (a synthetic drug), naringenin (a flavonoid) and phloroglucinol (a marine derivative) in an orthotopic glioma-induced xenograft model.MethodsAnti-proliferative effect of the drugs was assessed by immunostaining. The expression profiles of WNT/β-catenin and apoptotic markers were evaluated by qRT-PCR, immunoblotting and ELISA. Patterns of mitochondrial depolarization was determined by flow cytometry. TUNEL assay was performed to affirm apoptosis induction.In vivodrug detection study was carried out by ESI-Q-TOF MS analysis.ResultsThe quadruple-drug treatment had significantly hampered GB proliferation and had induced apoptosis by modulating the WNT/β-catenin signalling. Flow cytometric analysis revealed that the induction of apoptosis was associated with mitochondrial depolarization. Further the quadruple-drug cocktail, had breached the blood brain barrier and was detected in the brain tissue and plasma samples from various experimental groups.ConclusionThe quadruple-drug combination served as a promising adjuvant therapy to combat glioma lethalityin vivoand can be probed for translation from bench to bedside.
A cortical circuit for orchestrating oromanual food manipulation
Authors: An Xu , Matho Katherine , Li Yi , Mohan Hemanth , Xu X. Hermione , Whishaw Ian Q. , Kepecs Adam , Huang Z. Josh 
Published: December 2022

ABSTRACTCooperative forelimb and mouth movements during eating contribute to diet selection among vertebrates including the oromanual manipulatory skills in rodents and primates. Whereas spinal and brainstem circuits implement forelimb and orofacial actions, whether there is a specialized cortical circuit that flexibly assembles these to achieve cross-body and oromanual coordination for skilled manipulation remains unclear. Here we discover a cortical region and its cell-type-specific circuitry that orchestrates body postures and oromanual coordination for food manipulation in mice. An optogenetic screen of cortical areas and projection neuron types identified a rostral forelimb-orofacial area (RFO), wherein activation of pyramidal tract (PTFezf2) and intratelencephalic (ITPlxnD1) neurons induced concurrent posture, forelimb and orofacial eating-like movements. In a pasta-eating behavior, RFO PTFezf2and ITPlxnD1activity were closely correlated with picking up the pasta, adopting a sitting posture, oromanual manipulation, and hand-assisted biting. RFO inactivation and inhibition of RFO PTsFezf2and ITsPlxnD1impaired posture and oromanual coordination, leading to deficient pasta manipulation and biting. RFO is reciprocally connected to forelimb and orofacial sensorimotor areas as well as insular and visceral areas. Within this network, ITsPlxnD1project bilaterally to the entire network and the ventrolateral striatum and PTsFezf2project to multiple subcortical areas associated with forelimb and orofacial control. These results suggest that ITsPlxnD1select and coordinate the feeding program involving multiple body parts and PTsFezf2implement the fine details of movements. Our study reveals a neural circuit basis of hand-mouth coordination for object manipulation.
Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease
Authors: Serrano-Pozo Alberto , Li Zhaozhi , Woodbury Maya E. , Muñoz-Castro Clara , Wachter Astrid , Jayakumar Rojashree , Bryant Annie G. , Noori Ayush , Welikovitch Lindsay A. , Hu Miwei , Zhao Karen , Liao Fan , Lin Gen , Pastika Timothy , Tamm Joseph , Abdourahman Aicha , Kwon Taekyung , Bennett Rachel E. , Talanian Robert V. , Biber Knut , Karran Eric H. , Hyman Bradley T. , Das Sudeshna 
Published: December 2022

ABSTRACTAstrocytes play a critical role in brain homeostasis and normal functions but their changes along the spatiotemporal progression of Alzheimer’s disease (AD) neuropathology remain largely unknown. Here we performed single-nucleus RNA-sequencing on brain regions along the stereotypical progression of AD pathology from donors ranging the entire normal aging-AD continuum comprising 628,943 astrocyte nuclei from 32 donors across 5 brain regions. We discovered temporal gene-expression-trajectories with gene sets differentially activated at various disease stages. Surprisingly, a gene set enriched in proteostasis and energy metabolism, was upregulated in late-stage but unexpectedly returned to baseline levels in end-stage, suggesting exhaustion of response in “burnt-out” astrocytes. The spatial gene-expression-trajectories revealed that astrocytic genes of tripartite synapses are dysregulated in parallel to the stereotypical progression of tangle pathology across regions. We identified astrocyte heterogeneity across brain regions with a continuum from homeostatic to reactive cells through “intermediate” transitional states. These findings suggest complex astrocytic dysfunction in AD neurodegeneration.
The impact of genetically controlled splicing on exon inclusion and protein structure
Authors: Einson Jonah , Minaeva Mariia , Rafi Faiza , Lappalainen Tuuli 
Published: December 2022

AbstractCommon variants affecting mRNA splicing are typically identified though splicing quantitative trait locus (sQTL) mapping and have been shown to be enriched for GWAS signals by a similar degree to eQTLs. However, the specific splicing changes induced by these variants have been difficult to characterize, making it more complicated to analyze the effect size and direction of sQTLs, and to determine downstream splicing effects on protein structure.In this study, we catalogue sQTLs using exon percent spliced in (PSI) scores as a quantitative phenotype. PSI is an interpretable metric for identifying exon skipping events and has some advantages over other methods for quantifying splicing from short read RNA sequencing. In our set of sQTL variants, we find evidence of selective effects based on splicing effect size and effect direction, as well as exon symmetry. Additionally, we utilize AlphaFold2 to predict changes in protein structure associated with sQTLs overlapping GWAS traits, highlighting a potential new use-case for this technology for interpreting genetic effects on traits and disorders.
Systematic evaluation of anatomical details on transcranial electric stimulation and transcranial magnetic stimulation induced electric fields in a non-human primate model
Authors: Mantell Kathleen E. , Shirinpour Sina , Puonti Oula , Xu Ting , Zimmermann Jan , Heilbronner Sarah R. , Thielscher Axel , Opitz Alexander 
Published: December 2022

AbstractNon-human primates (NHPs) have become key for translational research in noninvasive brain stimulation (NIBS). However, in order to create comparable stimulation conditions to humans it is vital to evaluate and match electric fields across species. Numerical models to simulate electric fields are an important tool for experimental planning in NHPs and translation to human studies. It is thus essential to evaluate how anatomical details in NHP models affect NIBS electric fields. Here, we create a highly accurate head model of a non-human primate (NHP) from 10.5 T MR data. We systematically evaluate how muscle tissue and head size (due to different MRI fields of view) affect simulation results in transcranial electric and magnetic stimulation (TES and TMS). Our findings indicate that the inclusion of muscle can affect TES electric field strength up to 29.5% while TMS is largely unaffected. Additionally, comparing a full head model to a cropped head model illustrates the impact of head size on electric fields for both TES and TMS. We find opposing effects between TES and TMS with an increase up to 13.5% for TES and a decrease up to 21.5% for TMS for the cropped head model compared to the full head model. Our results provide important insights into the level of anatomical detail needed for NHP head models and can inform future translational efforts for NIBS studies.HighlightsWe created a high resolution non-human primate FEM head model from 10.5 T MR data.We ran transcranial electric and magnetic stimulation (TES and TMS) simulations to evaluate the effects of muscle and head size on the induced electric field in the brain.We simulated both isotropic and anisotropic muscle conductivities.Muscle tissue can greatly affect simulation results for TES (increase electric field strength by up to 29.5%), but not for TMS.There are opposing, but large effects of using a full head model versus a cropped head model for both TES (increase up to 13.5%) and TMS (decrease of up to 21.5%)
Genetic tagging uncovers a robust, selective activation of the thalamic paraventricular nucleus by adverse experiences early in life
Authors: Kooiker Cassandra L. , Chen Yuncai , Birnie Matthew T. , Baram Tallie Z. 
Published: December 2022

AbstractBackgroundEarly-life adversity (ELA) is associated with increased risk for mood disorders including depression and substance use disorders. These are characterized by impaired reward-related behaviors, suggesting compromised operations of reward-related brain circuits. However, the brain regions engaged by ELA that mediate these enduring consequences of ELA remain largely unknown. In an animal model of ELA, we have identified aberrant reward-seeking behaviors, a discovery that provides a framework for assessing the underlying circuits.MethodsEmploying TRAP2 male and female mice, in which neurons activated within a defined timeframe are permanently tagged, we compared ELA and control-reared mice, assessing the quantity and distribution of ELA-related neuronal activation. After validating the TRAP2 results using native cFos labeling, we defined the molecular identity of this population of activated neurons.ResultsWe uniquely demonstrate that the TRAP2 system is feasible and efficacious in neonatal mice. Surprisingly, the paraventricular nucleus of the thalamus (PVT) is robustly and almost exclusively activated by ELA and is the only region distinguishing ELA from typical rearing. Remarkably, a large proportion of ELA-activated PVT neurons express CRFR1, the receptor for the stress-related peptide, corticotropin-releasing hormone (CRH), but these neurons do not express CRH itself.ConclusionsWe show here that the PVT, an important component of reward circuits which is known to encode remote, emotionally salient experiences to influence future motivated behaviors, encodes adverse experiences as remote as those occurring during the early postnatal period and is thus poised to contribute to the enduring deficits in reward-related behaviors consequent to ELA.
Heterologous boosting of neutralizing activity against Delta and Omicron SARS-CoV-2 variants in CoronaVac-primed adults; a randomized study with SCB-2019 vaccine
Authors: Roa Camilo C. , de Los Reyes Mari Rose A. , Plennevaux Eric , Smolenov Igor , Hu Branda , Gao Faith , Ilagan Hannalyn , Ambrosino Donna , Siber George , Clemens Ralf 
Published: December 2022

ABSTRACTBackgroundThe global COVID-19 pandemic has peaked but some countries such as China are reporting serious infectious outbreaks due to SARS-CoV-2 variants. Waning vaccine-derived immunogenicity and mutations in variants allowing vaccine evasion require new booster immunization approaches. We compared homologous and heterologous boosting in adults previously fully primed with a whole-virus inactivated COVID-19 vaccine.MethodsAt multiple sites in the Philippines we enrolled 430 adults (18-72 years) immunized with two doses of CoronaVac at least 3 months previously and randomly assigned them to receive homologous (CoronaVac, n = 216) or heterologous (recombinant protein vaccine, SCB-2019, n = 214) booster doses. Non-inferiority/superiority of the neutralizing antibody (NAb) response 15 days after boosting was measured by microneutralization against prototype SARS-CoV-2, and Delta and Omicron variants in subsets (50 per arm). Participants recorded solicited local and systemic adverse events for 7 days, unsolicited AEs until Day 29, and serious adverse events until Day 60.ResultsNAb geometric mean titers (GMT) against prototype on Day 15 were 744 (95% CI: 669-828) and 164 (143-189) in heterologous and homologous groups, respectively, with a heterologous/homologous GMT ratio of 4.63 (3.95-5.41), meeting both pre-defined non-inferiority and superiority criteria. Similarly, geometric mean-fold rises for NAb against Delta and Omicron BA.1, BA.2, BA.4 and BA.5 variants were superior after heterologous SCB-2019 (range 3.01-4.66) than homologous CoronaVac (range 0.85-1.6) in an exploratory analysis. Reactogenicity and safety measures were evenly balanced between groups; the most frequent local reaction was mild or moderate injection site pain; mild or moderate headache and fatigue were the most frequent systemic adverse events. No vaccine-related serious adverse events were reported.ConclusionHeterologous boosting of CoronaVac-immunized adults with SCB-2019 was well tolerated with superior immunogenicity than homologous boosting, particularly for newly emerged variants, supporting use of SCB-2019 for booster vaccination.
Secreted ADAMTS-like 2 promotes myoblast differentiation by potentiating Wnt signaling
Authors: Taye Nandaraj , Singh Mukti , Baldock Clair , Hubmacher Dirk 
Published: December 2022

AbstractThe formation of multinucleated contractile myofibers from muscle stem cells during myogenesis is indispensable for skeletal muscle formation. Myogenesis is governed by myogenic regulatory transcription factors, including MYOD. However, very few MYOD- regulated effector proteins were shown to be sufficient to promote myogenesis. Here, we identified an unexpected role for the secreted matricellular protein ADAMTS-like 2 (ADAMTSL2) as a rheostat for Wnt signaling during myogenesis downstream of MYOD. ADAMTSL2 expression was induced during myoblast differentiation and ADAMTSL2 was required for myoblast differentiation. ADAMTSL2 ablation in myogenic precursor cells resulted in aberrant muscle architecture in vivo. The pro-myogenic ADAMTSL2 function was dependent on WNT ligands. Mechanistically, ADAMTSL2 potentiated WNT signaling by binding to WNT ligands and WNT receptors. Finally, we identified a WNT-binding ADAMTSL2 peptide that was sufficient to promote myogenesis. Since ADAMTSL2 was previously described as a negative regulator of TGFβ signaling in fibroblasts, ADAMTSL2 now emerges as a signaling node that could integrate and fine-tune WNT, TGFβ and potentially other signaling pathways within the dynamic microenvironment of differentiating myoblasts during skeletal muscle development and regeneration.
Epileptiform activity influences theta-burst induced LTP in the adult hippocampus: a role for lipid raft dynamics in early metaplasticity
Authors: Carvalho-Rosa JD , Rodrigues NC , Silva-Cruz A , Vaz SH , Cunha-Reis D 
Published: December 2022

AbstractNon-epileptic seizures are identified as a common epileptogenic trigger. Early metaplasticity following seizures may contribute to epileptogenesis by abnormally altering synaptic strength and homeostatic plasticity. We now studied howin vitroepileptiform activity triggers early changes in CA1 long-term potentiation (LTP) induced by theta-burst stimulation (TBS) in rat hippocampal slices and the involvement of lipid rafts in these early metaplasticity events. Two forms of epileptiform activity (EA) were induced: 1) interictal-like EA triggered by withdrawal of Mg2+and K+elevation to 6mM in the superfusion medium or 2) ictal-like EA induced by bicuculine (10μM) delivery. LTP induced 30 min post EA was impaired, an effect more pronounced after ictal-like EA. LTP recovered to control levels 60 min post interictal-like EA but was still impaired 60 min after ictal-like EA. The synaptic molecular events underlying this altered LTP were investigated 30 min post EA. Synaptosomes isolated from parallel slices showed enhanced AMPA GluA1 Ser831 phosphorylation but decreased Ser 845 phosphorylation and a marked decrease in GluA1/GluA2 ratio. A marked decrease in flotillin-1 and caveolin-1 levels concomitantly with a moderate increase in PSD-95 and marked increase in gephyrin levels.Altogether, EA differentially influences hippocampal CA1 LTP thorough regulation of GluA1/GluA2 levels and AMPA GluA1 phosphorylation suggesting altered LTP post-seizures may be a relevant target of antiepileptogenic therapies. In addition, this metaplasticity is also associated with marked alterations in classic and synaptic lipid raft markers, suggesting these may also constitute promising targets in epileptogenesis prevention.
Sleep-related consolidation and generalizability of motor skills learned by physical practice, motor imagery and action observation
Authors: Conessa Adrien , Debarnot Ursula , Siegler Isabelle , Boutin Arnaud 
Published: December 2022

AbstractSleep benefits the consolidation of motor skills learned by physical practice, mainly through periodic thalamocortical sleep spindle activity. However, motor skills can be learned without overt movement through motor imagery or action observation. Here, we investigated whether sleep spindle activity also supports the consolidation of non-physically learned movements. Forty-five electroencephalographic sleep recordings were collected during a daytime nap after motor sequence learning by physical practice, motor imagery or action observation. Our findings reveal that a temporal cluster-based organization of sleep spindles underlies motor memory consolidation in all groups, albeit with distinct behavioral outcomes. A daytime nap offers an early sleep window promoting the retention of motor skills learned by physical practice and motor imagery, and its generalizability towards the inter-manual transfer of skill after action observation. Findings may further have practical impacts with the development of non-physical rehabilitation interventions for patients having to remaster skills following peripherical or brain injury.