bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cerebrospinal fluid neurofilament light improves accurate distinction between neurodegenerative and psychiatric disorders at a cognitive neuropsychiatry service
Authors: Kang Matthew , Eratne Dhamidhu , Dobson Hannah , Malpas Charles B , Keem Michael , Lewis Courtney , Grewal Jasleen , Tsoukra Vivian , Dang Christa , Mocellin Ramon , Kalincik Tomas , Santillo Alexander F , Zetterberg Henrik , Blennow Kaj , Stehmann Christiane , Varghese Shiji , Li Qiao-Xin , Masters Colin L , Collins Steven , Berkovic Samuel F , Evans Andrew , Kelso Wendy , Farrand Sarah , Loi Samantha M , Walterfang Mark , Velakoulis Dennis 
Published: September 2022

ABSTRACTObjectivePeople with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown.MethodsWe collected longitudinal diagnostic information (mean=36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other), and PSY. We pre-specified NfL>582pg/mL as indicative of ND/MCI/other.ResultsDiagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone.ConclusionsCSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.
The effects of COVID-19 on child mental and social health: biannual assessments up to April 2022 in a clinical and two general population samples
Authors: Zijlmans Josjan , Tieskens Jacintha M. , van Oers Hedy A. , Alrouh Hekmat , Luijten Michiel A.J. , de Groot Rowdy , van der Doelen Daniël , Klip Helen , van der Lans Rikkert M. , de Meyer Ronald , van der Mheen Malindi , Ruisch I. Hyun , van den Berg Germie , Bruining Hilgo , Buitelaar Jan , van der Rijken Rachel , Hoekstra Pieter J. , Kleinjan Marloes , Lindauer Ramón J.L. , Oostrom Kim J. , Staal Wouter , Vermeiren Robert , Cornet Ronald , Haverman Lotte , Popma Arne , Bartels Meike , Polderman Tinca J. C. 
Published: September 2022

AbstractBackgroundThe COVID-19 pandemic has had an acute impact on child mental and social health, but long-term effects are still unclear. We examined how child mental health has developed since the start of the COVID-19 pandemic up to two years into the pandemic (April 2022).MethodsWe included children (age 8-18) from two general population samples (N = 222-1,333 per measurement and N = 2,401-13,362 for pre-covid data) and one clinical sample receiving psychiatric care (N = 334-748). Behavioral questionnaire data were assessed five times from April 2020 till April 2022 and pre-pandemic data were available for both general population samples. We collected parent-reported data on internalizing and externalizing problems with the Brief Problem Monitor and self-reported data on Anxiety, Depressive symptoms, Sleep-related impairments, Anger, Global health, and Peer relations with the Patient-Reported Outcomes Measurement Information System (PROMIS®).ResultsIn all samples, parents reported overall increased internalizing problems, but no increases in externalizing problems, in their children. Children from the general population self-reported increased mental health problems from before to during the pandemic on all six PROMIS domains, with generally worst scores in April 2021, and scores improving towards April 2022 but not to pre-pandemic norms. Children from the clinical sample reported increased mental health problems throughout the pandemic, with generally worst scores in April 2021 or April 2022 and no improvement. We found evidence of minor age effects and no sex effects.ConclusionsChild mental health in the general population has deteriorated during the first phase of the COVID-19 pandemic, has improved since April 2021, but has not yet returned to pre-pandemic levels. Children in psychiatric care show worsening of mental health problems during the pandemic, which has not improved since. Changes in child mental health should be monitored comprehensively to inform health care and policy.
The Neuroscience Multi-Omic Archive: A BRAIN Initiative resource for single-cell transcriptomic and epigenomic data from the mammalian brain
Authors: Ament Seth A. , Adkins Ricky S. , Carter Robert , Chrysostomou Elena , Colantuoni Carlo , Crabtree Jonathan , Creasy Heather H. , Degatano Kylee , Felix Victor , Gandt Peter , Garden Gwenn A. , Giglio Michelle , Herb Brian R. , Khajouei Farzaneh , Kiernan Elizabeth , McCracken Carrie , McDaniel Kennedy , Nadendla Suvarna , Nickel Lance , Olley Dustin , Orvis Joshua , Receveur Joseph P. , Schor Mike , Tickle Timothy L. , Way Jessica , Hertzano Ronna , Mahurkar Anup A. , White Owen R 
Published: September 2022

ABSTRACTScalable technologies to sequence the transcriptomes and epigenomes of single cells are transforming our understanding of cell types and cell states. The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative Cell Census Network (BICCN) is applying these technologies at unprecedented scale to map the cell types in the mammalian brain. In an effort to increase data FAIRness (Findable, Accessible, Interoperable, Reusable), the NIH has established repositories to make data generated by the BICCN and related BRAIN Initiative projects accessible to the broader research community. Here, we describe the Neuroscience Multi-Omic Archive (NeMO Archive; nemoarchive.org), which serves as the primary repository for genomics data from the BRAIN Initiative. Working closely with other BRAIN Initiative researchers, we have organized these data into a continually expanding, curated repository, which contains transcriptomic and epigenomic data from over 50 million brain cells, including single-cell genomic data from all of the major regions of the adult and prenatal human and mouse brains, as well as substantial single-cell genomic data from non-human primates. We make available several tools for accessing these data, including a searchable web portal, a cloud-computing interface for large-scale data processing (implemented on Terra, terra.bio), and a visualization and analysis platform, NeMO Analytics (nemoanalytics.org).KEY POINTSThe Neuroscience Multi-Omic Archive serves as the genomics data repository for the BRAIN Initiative.Genomic data from >50 million cells span all the major regions of the brains of humans and mice.We provide a searchable web portal, a cloud-computing interface, and a data visualization platform.
Identification of the Metaphyseal Skeletal Stem Cell
Authors: Yang Guan , He Qi , Guo Xiaoxiao , Li Rong-Yu , Lin Jingting , Tao Wanyu , Liu Wenjia , Lin Huisang , Tang Mingchuan , Xing Shilai , Qi Yini , Peng Yanli , Dong Lei , Han Jingdong , Zhou Bin , Teng Yan , Yang Xiao 
Published: September 2022

SUMMARYIdentification of novel regional skeletal stem cells (SSCs) will provide a new cellular paradigm for bone physiology and dysfunction. Several populations of SSCs have been identified at distinct skeletal sites. However, a bona fide SSC population has not yet been formally characterized in the bone marrow. Here, we identify a metaphyseal SSCs (mpSSCs) population whose transcriptional landscape is distinct from other bone mesenchymal stromal cells (bMSCs) in the bone marrow. These mpSSCs emerge at the postnatal stage and reside just underneath the growth plate, consistent with the fact that these mpSSCs are exclusively derived from hypertrophic chondrocytes (HCs). These mpSSCs possess SSC properties such as self-renewal and multipotencyin vitroandin vivo, stand at the top of the HC de-differentiation path, and produce most HC progeny. Genetic block of the conversion from HCs to mpSSCs significantly compromises trabecular bone formation and bone regeneration. Thus, metaphysis houses a unique HC-derived SSC population, which is a major source of osteoblasts and bMSCs supporting postnatal trabecular bone formation.
Oncogenic YAP mediates changes in chromatin accessibility and activity that drive cell cycle gene expression and cell migration
Authors: Fetiva Maria Camila , Liss Franziska , Gertzmann Dörthe , Thomas Julius , Gantert Benedikt , Vogl Magdalena , Sira Nataliia , Weinstock Grit , Kneitz Susanne , Ade Carsten P. , Gaubatz Stefan 
Published: September 2022

ABSTRACTYAP, the key protein effector of the Hippo pathway, is a transcriptional co-activator that controls the expression of cell cycle genes, promotes cell growth and proliferation and regulates organ size. YAP modulates gene transcription by binding to distal enhancers, but the mechanisms of gene regulation by YAP-bound enhancers remain poorly understood. Here we show that constitute active YAP5SA leads to widespread changes in chromatin accessibility in untransformed MCF10A cells. Newly accessible regions include YAP-bound enhancers that mediate activation of cycle genes regulated by the Myb-MuvB (MMB) complex. By CRISPR-interference we identify a role for YAP-bound enhancers in phosphorylation of Pol II at Ser5 at MMB-regulated promoters, extending previously published studies that suggested YAP primarily regulates the pause-release step and transcriptional elongation. YAP5SA also leads to less accessible “closed” chromatin regions, which are not directly YAP-bound but which contain binding motifs for the p53 family of transcription factors. Diminished accessibility at these regions is, at least in part, a consequence of reduced expression and chromatin-binding of the p53 family member ΔNp63 resulting in downregulation of ΔNp63-target genes and promoting YAP-mediated cell migration. In summary, our studies uncover changes in chromatin accessibility and activity that contribute to the oncogenic activities of YAP.
Rapid, DNA-induced interface swapping by DNA gyrase
Authors: Germe Thomas , Bush Natassja G. , Baskerville Victoria , Saman Dominik , Benesch Justin , Maxwell Anthony 
Published: September 2022

ABSTRACTDNA gyrase, a ubiquitous bacterial enzyme, is a type IIA topoisomerase formed by heterotetramerisation of 2 GyrA subunits and 2 GyrB subunits, to form the active complex. GyrA is usually found as a dimer in solution, whereas GyrB can exist as a monomer. DNA gyrase is able to loop DNA around the C-terminal domains (CTDs) of GyrA and pass one DNA duplex through a transient double-strand break (DSB) established in another duplex. This results in the conversion of a positive loop into a negative one, thereby introducing negative supercoiling into the bacterial genome, an activity essential for DNA replication and transcription. The strong protein interface in the GyrA dimer must be broken to allow passage of the transported DNA segment and it is generally assumed that the interface is usually stable and only opens when DNA is transported, to prevent the introduction of deleterious DSBs in the genome. In this paper we show that DNA gyrase can exchange its DNA-cleaving interfaces between two active heterotetramers. This so-called interface “swapping” or “exchange” (IS) can occur within a few minutes in solution. We also show that bending of DNA by gyrase is essential for cleavage but not for DNA bindingper seand favors IS. interface swapping is also favored by DNA wrapping and an excess of GyrB. We suggest that proximity, promoted by GyrB oligomerization and binding and wrapping along a length of DNA, between two heterotetramers favors rapid interface exchange. This exchange does not require ATP, can occur in the presence of fluoroquinolones, and raises the possibility of non-homologous recombination solely through gyrase activity. The ability of gyrase to undergo interface swapping also explains how gyrase heterodimers, containing a single active-site tyrosine, can carry out double-strand passage reactions and therefore suggests an alternative explanation to the recently proposed “swivelling” mechanism for DNA gyrase (Gubaev, Weidlich, and Klostermeier 2016).
Cytomotive actins and tubulins share a polymerisation switch mechanism conferring robust dynamics
Authors: Wagstaff James Mark , Planelles-Herrero Vicente José , Sharov Grigory , Alnami Aisha , Kozielski Frank , Derivery Emmanuel , Löwe Jan 
Published: September 2022

SummaryProtein filaments are used in myriads of ways to organise other molecules in space and time within cells. Some filament-forming proteins couple the hydrolysis of nucleotides to their polymerisation cycle, thus powering the directed movement of other molecules. These filaments are termed cytomotive. Only members of the actin and tubulin protein superfamilies are known to form cytomotive filaments. We sought to examine the basis of cytomotivity via structural studies of the polymerisation cycles of actin and tubulin homologues from across the tree of life. We analysed published data and performed new structural experiments designed to disentangle functional components of these complex filament systems. In sum, our analysis demonstrates the existence of shared subunit polymerisation switches amongst both cytomotive actins and tubulins, i.e. the conformation of subunits switches upon assembly into filaments. Such cytomotive switches explain filament robustness, by enabling the coupling of kinetic and structural polarities required for useful cytomotive behaviours, and by ensuring that single cytomotive filaments do not fall apart.
Complementary environmental analysis and functional characterization of a plastid diatom lower glycolytic-gluconeogenesis pathway
Authors: Dorrell Richard G. , Zhang Youjun , Liang Yue , Gueguen Nolwenn , Nonoyama Tomomi , Croteau Dany , Penot Mathias , Adiba Sandrine , Bailleul Benjamin , Gros Valérie , Karlusich Juan José Pierella , Zweig Nathanaël , Fernie Alisdair R. , Jouhet Juliette , Maréchal Eric , Bowler Chris 
Published: September 2022

AbstractOrganic carbon fixed in chloroplasts through the Calvin Cycle can be diverted towards different metabolic fates, including cytoplasmic and mitochondrial respiration; gluconeogenesis; and synthesis of diverse plastid metabolites via the pyruvate hub. In plants, pyruvate is principally produced via cytoplasmic glycolysis, although a plastid-targeted lower glycolytic pathway is known in non-photosynthetic tissue. Here, we characterize a lower plastid glycolytic-gluconeogenesis pathway in diatoms, ecologically important marine algae distantly related to plants. We show that two reversible enzymes required to complete diatom plastid glycolysis-gluconeogenesis, Enolase and PGAM (bis-phospho-glycerate mutase), originated through duplications of mitochondria-targeted respiratory isoforms. Through CRISPR-Cas9 mutagenesis, integrative ‘omic analyses, and measured kinetics of expressed enzymes in the diatomPhaeodactylum tricornutum, we present evidence that this pathway diverts plastid glyceraldehyde-3-phosphate into the pyruvate hub, and may also function in the gluconeogenic direction. Considering experimental data, we show that this pathway has different roles dependent in particular on day length and environmental temperature, and show that it is expressed at elevated levels in high latitude oceans where diatoms are abundant. Our data provide evolutionary, meta-genomic and functional insights into a poorly understood yet evolutionarily recurrent plastid metabolic pathway.
Potentiation of Adipogenesis by Reactive Oxygen Species is a Unifying Mechanism in the Pro-adipogenic Properties of Bisphenol A and its New Structural Analogues
Authors: Singh Radha D. , Wager Jessica L. , Scheidl Taylor B , Connors Liam T. , Easson Sarah , Callaghan Mikyla A. , Alatorre-Hinojosa Samuel , Swift Lucy H. , Colarusso Pina , Jadli Anshul , Shutt Timothy E. , Patel Vaibhav , Thompson Jennifer A. 
Published: September 2022

ABSTRACTAimsStructural analogues of bisphenol A (BPA), including BPS and BPF, are emerging environmental toxicants as their presence in the environment is rising since new regulatory restrictions were placed on BPA-containing infant products. The adipogenesis-enhancing effect of bisphenols may explain the link between human exposure and metabolic disease; however, underlying molecular pathways remain unresolved.ResultsExposure to BPS, BPF, BPA or ROS generators enhanced lipid droplet formation and expression of adipogenic markers after induction of differentiation in adipose-derived progenitors isolated from mice. RNAseq analysis in BPS-exposed progenitors revealed modulation in pathways regulating adipogenesis and responses to oxidative stress. ROS was higher in bisphenol-exposed cells, while co-treatment with antioxidants attenuated adipogenesis and abolished the effect of BPS. There was a loss of mitochondria membrane potential in BPS-exposed cells and mitochondria-derived ROS contributed to potentiation of adipogenesis by BPS and its analogues. Male mice exposed to BPS during gestation had higher whole-body adiposity, as measured by TD-NMR, while postnatal exposure had no impact on adiposity in either sex.InnovationThese findings support existing evidence showing a role for ROS in regulating adipocyte differentiation and are the first to highlight ROS as a unifying mechanism that explains the pro-adipogenic properties of BPA and its structural analogues.ConclusionROS act as signaling molecules in the regulation of adipocyte differentiation and mediate bisphenol-induced potentiation of adipogenesis.
Real-time visualization of phagosomal pH manipulation by Cryptococcus neoformans in an immune signal-dependent way
Authors: Santiago-Burgos Emmanuel J. , Stuckey Peter V. , Santiago-Tirado Felipe H. 
Published: September 2022

AbstractUnderstanding of how intracellular pathogens survive in their host cells is important to improve management of their diseases. This has been fruitful for intracellular bacteria but it is an understudied area in fungal pathogens. Here we start elucidating and characterizing the strategies used by one of the commonest fungal pathogens, Cryptococcus neoformans, to survive intracellularly. The ability of the fungus to survive inside host cells is one of the main drivers of disease progression, yet it is unclear whether C. neoformans resides in a fully acidified, partially acidic, or neutral phagosome. Using a dye that only fluoresce under acidic conditions to stain C. neoformans, a hypha-defective Candida albicans mutant, and the nonpathogenic Saccharomyces cerevisiae, we characterized the fungal behaviors in infected macrophages by live microscopy. The main behavior in the C. albicans mutant strain and S. cerevisiae-phagosomes was rapid acidification after internalization, which remained for the duration of the imaging. In contrast, a significant number of C. neoformans-phagosomes exhibited alternative behaviors distinct from the normal phagosomal maturation: some phagosomes acidified with subsequent loss of acidification, and other phagosomes never acidified. Moreover, the frequency of these behaviors was affected by the immune status of the host cell. We applied the same technique to a flow cytometry analysis and found that a substantial percentage of C. neoformans-phagosomes showed impaired acidification, whereas almost 100% of the S. cerevisiae-phagosomes acidify. Lastly, using a membrane-damage reporter, we show phagosome permeabilization correlates with acidification alterations, but it is not the only strategy that C. neoformans uses to manipulate phagosomal acidification. The different behaviors described here provide an explanation to the confounding literature regarding cryptococcal-phagosome acidification and the methods can be applied to study other intracellular fungal pathogens.
Activity of EGFR transmembrane region variants indicates specific transmembrane dimers are not required for EGFR activity
Authors: Bartzoka Foteini , Gonzalez-Magaldi Monica , Byrne Patrick O. , Callery Nicole I. , Hristova Kalina , Leahy Daniel J. 
Published: September 2022

AbstractThe Epidermal Growth Factor Receptor (EGFR) is a Receptor Tyrosine Kinase that mediates cell proliferation and differentiation events during development and maintenance of complex organisms. Formation of specific, ligand-dependent EGFR dimers is a key step in stimulating EGFR signaling, and crystal structures of active, dimeric forms of isolated EGFR extracellular regions and kinase domains have revealed much about how dimer interactions regulate EGFR activity. The nature and role of the transmembrane region in regulating EGFR activity remains less clear, however. Proposed roles for the transmembrane region range from nonspecific but energetically favorable interactions to specific transmembrane dimer conformations being associated with active, inactive, or activity-modulated states of EGFR. To investigate the role of specific transmembrane dimers in modulating EGFR activity we generated thirteen EGFR variants with altered transmembrane sequences designed to favor or disfavor specific types of transmembrane region interactions. We show using FRET microscopy that EGFR transmembrane regions have an intrinsic propensity to associate in mammalian cell membranes that is counteracted by the extracellular region. We show using cell-based assays that each of the EGFR transmembrane variants except the Neu variant, which results in constitutive receptor phosphorylation, is able to autophosphorylate and stimulate phosphorylation of downstream effectors Erk and Akt. Our results indicate that many transmembrane sequences, including polyleucine, are compatible with EGFR activity and provide no evidence for specific transmembrane dimers regulating EGFR function.
Identification of a chemical probe for lipid kinase phosphatidylinositol-5-phosphate 4-kinase gamma (PI5P4Kγ)
Authors: Drewry David H. , Potjewyd Frances M. , Smith Jeffery L. , Howell Stefanie , Axtman Alison D. 
Published: September 2022

ABSTRACTPhosphatidylinositol-5-phosphate 4-kinase gamma (PI5P4Kγ), which phosphorylates phosphatidylinositol-5-monophosphate (PI(5)P), is a human lipid kinase with intriguing roles in inflammation, T cell activation, autophagy regulation, immunity, heart failure, and several cancers. To provide a high-quality chemical tool that would enable additional characterization of this protein, we designed and evaluated a potent, selective, and cell-active inhibitor of human PI5P4Kγ. We describe the use of the PI5P4Kγ NanoBRET assay to generate structure–activity relationships (SAR), support chemical probe (2) design, and identify a structurally related negative control (4). We have characterized the binding of our chemical probe to PI5P4Kγ using orthogonal assay formats reliant on competition with an ATP-competitive reagent. Based on our results in these assays, we hypothesize that 2 binds in the ATP active site of PI5P4Kγ. Kinome-wide profiling complemented by further off-target profiling confirmed the selectivity of both our chemical probe and negative control. When a breast cancer cell line (MCF-7) was treated with compound 2, increased mTORC1 signaling was observed, demonstrating that efficacious binding of 2 to PI5P4Kγ in cells results in activation of a negative feedback loop also reported in PI5P4Kγ knockout mice.