bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic stratification of clozapine prescription patterns using schizophrenia polygenic scores
Authors: Kappel Djenifer B. , Legge Sophie E. , Hubbard Leon , Willcocks Isabella R. , King Adrian , Jansen John , Helthuis Marinka , Owen Michael J. , O’Donovan Michael C. , Walters James T.R. , Pardiñas Antonio F. 
Published: February 2022

ABSTRACTBACKGROUNDTreatment-resistant schizophrenia (TRS) affects ∼30% of individuals with the disorder. Clozapine is the medication of choice in TRS but optimizing administration and dose titration are complex. The identification of predictive factors that influence clozapine prescription and response, including genetics, is of clinical interest in a precision psychiatry framework. We aimed to determine if a polygenic risk score (PRS) for schizophrenia is associated with the highest drug dose an individual received during clozapine treatment.METHODSWe used generalized linear regression models accounting for demographic, pharmacological, and clinical covariates to determine the relationship between PRS and highest daily dose of clozapine. We used two independent multi-ancestry samples of individuals from the UK from a clozapine monitoring system, CLOZUK2 (N= 3133) and CLOZUK3 (N= 909). Schizophrenia PRS were calculated using the latest available GWAS summary statistics from the Psychiatric Genomics Consortium. In a secondary analysis of the two merged cohorts, logistic regression models were used to estimate the relationship between schizophrenia PRS and clozapine doses classified as low, standard, or high (>600 mg/day).RESULTSAfter controlling for relevant available covariates, schizophrenia PRS were correlated with the highest clozapine dose ever prescribed, in both CLOZUK2 (β= 12.217, s.e= 3.776, P= 0.001) and CLOZUK3 (β= 12.730, s.e= 5.987, P= 0.034). In the secondary analysis, the schizophrenia PRS was specifically associated with taking a clozapine dose greater than 600 mg/day (OR= 1.279, P= 0.006).CONCLUSIONSSchizophrenia PRS is associated with the highest clozapine dose ever prescribed in two independent multi-ancestry samples from the UK, suggesting that the genetic liability to schizophrenia might index factors associated with therapeutic decisions in TRS cohorts.
Inducing synthetic lethality for selective targeting of acute myeloid leukemia cells harboring STAG2 mutations
Authors: Subramaniam Agatheeswaran , Sandén Carl , Moura-Castro Larissa , Žemaitis Kristijonas , Schmiderer Ludwig , Bäckström Alexandra , Arvidsson Elin , Hultmark Simon , Miharada Natsumi , Paulsson Kajsa , Fioretos Thoas , Larsson Jonas 
Published: February 2022

AbstractTargeted therapies exploiting selective vulnerabilities of malignant cells are highly desired for clinical applications. The cohesin protein complex comprises of RAD21, SMC3, SMC1A as well as a fourth subunit that consists of either STAG1 or STAG2 and is essential for proper chromosomal segregation during mitosis. STAG2 loss-of-function mutations are recurrent driver events in acute myeloid leukemia (AML) and appear relatively early during leukemogenesis. Studies in cell lines have shown that STAG2 deficient cells are uniquely vulnerable to STAG1 perturbation, and this vulnerability could thus be exploited to selectively eliminate STAG2 null AML cells. Here we show that partial perturbation of STAG1 is well tolerated by normal human hematopoietic stem cells and does not affect their functionality. By contrast, STAG1 knockdown is lethal to STAG2 null human HSCs by inducing major mitotic defects. Moreover, STAG1 knockdown induced synthetic lethality in primary human AML cells harboring a STAG2 mutation and completely abrogated leukemia progression in xenograft models. Overall, our study provides proof-of-concept demonstration of a synthetic lethal approach to selectively target primary human cancer cells with STAG2 mutations
Controlling microbial co-culture based on substrate pulsing can lead to stability through differential fitness advantages
Authors: Martinez J.Andres , Delvenne Matheo , Henrion Lucas , Moreno Fabian , Telek Samuel , Dusny Christian , Delvigne Frank 
Published: February 2022

AbstractMicrobial consortia are an exciting alternative for increasing the performances of bioprocesses for the production of complex metabolic products. However, the functional properties of microbial communities remain challenging to control, considering the complex interaction mechanisms occurring between co-cultured microbial species. Indeed, microbial communities are highly dynamic and can adapt to changing environmental conditions through complex mechanisms, such as phenotypic diversification. We focused on stabilizing a co-culture ofSaccharomyces cerevisiaeandEscherichia coliin continuous cultures. Our preliminary data pointed out that transient diauxic shifts could lead to stable co-culture by providing periodic fitness advantages to the yeast. Based on a computational toolbox called MONCKS (for MONod-type Co-culture Kinetic Simulation), we were able to predict the dynamics of diauxic shift for both species based on a cybernetic approach. This toolbox was further used to predict the frequency of diauxic shift to be applied to reach co-culture stability. These simulations were successfully reproduced experimentally in continuous bioreactors with glucose pulsing. Finally, based on a bet-hedging reporter, we observed that the yeast population exhibited an increased phenotypic diversification process in co-culture compared with mono-culture, suggesting that this mechanism could be the basis of the metabolic fitness of the yeast.
Long noncoding RNA MEG3 activates neuronal necroptosis in Alzheimer’s disease
Authors: Balusu Sriram , Horré Katrien , Thrupp Nicola , Snellinx An , Serneels Lutgarde , Chrysidou Iordana , Arranz Amaia M. , Sierksma Annerieke , Simrén Joel , Karikari Thomas K. , Zetterberg Henrik , Chen Wei-Ting , Thal Dietmar Rudolf , Salta Evgenia , Fiers Mark , Strooper Bart De 
Published: February 2022

Abstract/SummaryNeuronal cell loss is a defining feature of Alzheimer’s disease (AD), but it remains unclear how neurons die and how this relates to other defining characteristics of the disease1. Existing in vivo AD models only partially recapitulate the neuropathology of AD with very mild or no neuronal cell loss. Here we demonstrate that human neurons xenografted in mouse brain exposed to amyloid pathology develop sarkosyl-insoluble tau filaments, positive Gallyas silver staining, release phosphorylated tau (P-tau181) into the blood, and display considerable neuronal cell loss, providing a model for the induction of full Tau pathology by simple exposure to amyloid pathology in AD. The alterations are specific to human neurons and contrast with the mild effects exhibited in mouse neurons. A core transcriptional program in the human neurons is characterized by strong upregulation of MEG3, a neuron-specific long noncoding RNA. MEG3 is also strongly upregulated in neurons from AD patients in situ. MEG3 expression alone is sufficient to induce necroptosis in human neurons in vitro. Orally administered small molecule receptor-interacting protein (RIP) kinase -1 and -3 inhibitors rescued the neuronal cell loss in this novel AD model. Thus, xenografted human neurons are uniquely sensitive to amyloid pathology, recapitulate all the defining neuropathological features of AD, and ultimately die by necroptosis.
Description of Life History and Reproductive Size Thresholds in Three High ElevationPuya(Bromeliaceae)
Authors: Veldhuisen Leah , Garcia Lino Mary Carolina , Bodine Erin , Aguirre-Santoro Julián , Jabaily Rachel 
Published: February 2022

AbstractThe Andes are a hotspot for biodiversity and high species endemism for both plants and animals. The genusPuya(Bromeliaceae) lives throughout the Andes, including puna and the páramo ecosystems above 3500m. Here, we studied the life history and reproductive size thresholds in three species ofPuya(P. raimondii, P. cryptanthaandP. goudotiana):P. raimondiiin the Bolivian puna, andP. cryptanthaandP. goudotianain the Colombian páramo. We collected data on threshold size at flowering and clonal reproduction. All three species were found to have a consistent minimum size at flowering, while onlyP. cryptanthademonstrated a minimum size for clonal reproduction. No such evidence was found forP. goudotiana. We also found a positive correlation between leaf length and fruit number forP. goudotianaandP. cryptantha. Our data supported thatP. raimondiiis fully semelparous and indicated thatP. goudotianaandP. cryptanthamay be semi-semelparous.
Deletion of the microglial transmembrane immune signaling adaptor TYROBP ameliorates Huntington’s disease mouse phenotype
Authors: Creus-Muncunill Jordi , Mattei Daniele , Bons Joanna , Ramirez-Jimenez Angie V. , Hamilton B. Wade , Corwin Chuhyon , Chowdhury Sarah , Schilling Birgit , Ellerby Lisa , Ehrlich Michelle E. 
Published: February 2022

ABSTRACTBACKGROUNDHuntington’s disease (HD) is a fatal neurodegenerative disorder caused by an expansion of the CAG trinucleotide repeat in the huntingtin gene. Immune activation is abundant in the striatum of HD patients. Detection of active microglia at presymptomatic stages suggests that microgliosis is a key early driver of neuronal dysfunction and degeneration. Recent studies showed that deletion of Tyrobp, a microglial-enriched protein, ameliorates neuronal function in Alzheimer’s disease amyloid and tauopathy mouse models while decreasing components of the complement subnetwork, thus raising the possibility that Tyrobp deletion can be beneficial for HD.METHODSTo test the hypothesis that Tyrobp deficiency would be beneficial in a HD model, we placed the Q175 HD mouse model on a Tyrobp-null background. We characterized these mice with a combination of behavioral testing, immunohistochemistry, transcriptomic and proteomic profiling. Further, we evaluated the Q175 microglia-specific gene signature, with and without Tyrobp, by purifying microglia from these mice for transcriptomics.RESULTSComprehensive analysis of publicly available transcriptomic HD human data revealed that TYROBP network is overactivated in HD putamen. The Q175 mice showed morphologic microglial activation, reduced levels of post-synaptic density-95 protein and motor deficits at 6 and 9 months of age, all of which were ameliorated on the Tyrobp-null background. Gene expression analysis revealed that lack of Tyrobp in the Q175 model does not prevent the decrease in the expression of striatal neuronal genes but reduces pro-inflammatory pathways that are specifically active in HD human brain. Integration of transcriptomic and proteomic data identified that astrogliosis and complement system pathway were reduced after Tyrobp deletion. Results were further validated by immunofluorescence analysis. Microglia-specific HD gene dysregulation, characterized by overexpression of neuronal genes, was also not corrected by Tyrobp deletion.CONCLUSIONSOur data provide molecular and functional support demonstrating that Tyrobp deletion prevents many of the abnormalities in the Q175 HD mouse model, in the absence of correction of striatal neuronal gene expression, suggesting that the Tyrobp pathway is a potential therapeutic candidate for Huntington’s disease.
Measuring brain beats: cardiac-aligned fast fMRI signals
Authors: Hermes Dora , Wu Hua , Kerr Adam B. , Wandell Brian 
Published: February 2022

AbstractBlood and cerebrospinal fluid (CSF) pulse and flow throughout the brain, driven by the cardiac cycle. These fluid dynamics, which are essential to healthy brain function, are characterized by several noninvasive magnetic resonance imaging (MRI) methods. Recent developments in fast MRI, specifically simultaneous multislice (SMS) acquisition methods, provide a new opportunity to rapidly and broadly assess cardiac-driven flow, including CSF spaces, surface vessels and parenchymal vessels. We use these techniques to assess blood and CSF flow dynamics in brief (3.5 minute) scans on a conventional 3T MRI scanner. Cardiac pulses are measured with a photoplethysmograph (PPG) on the index finger, along with fMRI signals in the brain. We retrospectively analyze the fMRI signals gated to the heart beat. Highly reliable cardiac-gated fMRI temporal signals are observed in CSF and blood on the timescale of one heartbeat (test-retest reliability within subjects R2>0.50). Cardiac pulsations with a local minimum following systole are observed in blood vessels, with earlier extrema in the carotid and basilar arteries and in branches of the anterior, posterior and middle cerebral arteries and extrema ∼200 ms later in the superior sagittal, transverse and straight sinuses. CSF spaces in the ventricles and subarachnoid space showed cardiac pulsations with a local maximum following systole instead. Similar responses are observed, with less temporal detail, in slower resting state scans with slice timing retrospectively aligned to the cardiac pulse in the same manner. The SMS measurements rapidly, noninvasively and reliably sample brain-wide fMRI signal pulsations aligned to the heartbeat. The measurements estimate the amplitude and phase of cardiac driven fMRI pulsations in the CSF relative to those in the arteries, which is thought to be an estimate of the local intracranial impedance. Cardiac aligned fMRI signals can provide new insights about fluid dynamics or diagnostics for diseases where these dynamics are important.
Self-organization, quality control, and preclinical studies of human iPSC-derived retinal sheets for tissue-transplantation therapy
Authors: Watari Kenji , Yamasaki Suguru , Tu Hung-Ya , Shikamura Masayuki , Kamei Tatsuya , Adachi Hideki , Tochitani Tomoaki , Kita Yasuyuki , Nakamura Aya , Ueyama Kazuki , Ono Keiichi , Morinaga Chikako , Matsuyama Take , Sho Junki , Nakamura Miyuki , Fujiwara Masayo , Hori Yoriko , Tanabe Anna , Hirai Rina , Terai Orie , Ohno Osamu , Ohara Hidetaka , Hayama Tetsuya , Ikeda Atsushi , Nukaya Daiki , Matsushita Keizo , Takahashi Masayo , Kishino Akiyoshi , Kimura Toru , Kawamata Shin , Mandai Michiko , Kuwahara Atsushi 
Published: February 2022

AbstractThree-dimensional retinal organoids (3D-retinas) are a promising graft source for transplantation therapy. We previously developed self-organizing culture for 3D-retina generation from human pluripotent stem cells (hPSCs). Here we present a quality control method and preclinical studies for tissue-sheet transplantation. Self-organizing hPSCs differentiated into both retinal and off-target tissues. Gene expression analyses identified the major off-target tissues as eye-related, cortex-like, and spinal cord-like tissues. For quality control, we developed a qPCR-based test in which each hPSC-derived neuroepithelium was dissected into two tissue-sheets: inner-central sheet for transplantation and outer-peripheral sheet for qPCR to ensure retinal tissue selection. During qPCR, tissue-sheets were stored for 3–4 days using a newly developed preservation method. In a rat tumorigenicity study, no transplant-related adverse events were observed. In retinal degeneration model rats, retinal transplants differentiated into mature photoreceptors and exhibited light responses in electrophysiology assays. These results demonstrate our rationale toward self-organizing retinal sheet transplantation therapy.
Resolving drug selection and migration in an inbred South American Plasmodium falciparum population with identity-by-descent analysis
Authors: Carrasquilla Manuela , Early Angela M , Taylor Aimee R , Knudson Angélica , Echeverry Diego F , Anderson Timothy JC , Mancilla Elvira , Aponte Samanda , Cárdenas Pablo , Buckee Caroline O , Rayner Julian C , Sáenz Fabián E , Neafsey Daniel E , Corredor Vladimir 
Published: February 2022

AbstractThe human malaria parasite Plasmodium falciparum is globally widespread, but its prevalence varies significantly between and even within countries. Most population genetic studies in P. falciparum focus on regions of high transmission where parasite populations are large and genetically diverse, such as sub-Saharan Africa. Understanding population dynamics in low transmission settings, however, is of particular importance as these are often where drug resistance first evolves. Here, we use the Pacific Coast of Colombia and Ecuador as a model for understanding the population structure and evolution of Plasmodium parasites in small populations harboring low genetic diversity. The combination of low transmission and a high proportion of monoclonal infections means there are few outcrossing events and clonal lineages persist for long periods of time. Yet despite this, the population is evolutionarily labile and has successfully adapted to multiple drug regimes. Using 166 newly sequenced whole genomes, we measure relatedness between parasites, calculated as identity by descent (IBD), and find 17 distinct but highly related clonal lineages, six of which have persisted in the region for at least a decade. This inbred population structure is captured in more detail with IBD than with other common population structure analyses like PCA, ADMIXTURE, and distance-based trees. We additionally use patterns of intra-chromosomal IBD and an analysis of haplotypic variation to explore the role of recombination in spreading drug resistance mutations throughout the region. Two genes associated with chloroquine resistance, crt and aat1, show evidence of hard selective sweeps, while selection appears soft and/or incomplete at three other key resistance loci (dhps, mdr1, and dhfr). Overall, this work highlights the strength of IBD analyses for studying parasite population structure and resistance evolution in regions of low transmission, and emphasizes that drug resistance can evolve and spread in extremely small populations, as will occur in any region nearing malaria elimination.
Complete sequences of the velvet worm slime proteins reveal that slime formation is enabled by disulfide bonds and intrinsically disordered regions
Authors: Lu Yang , Sharma Bhargy , Soon Wei Long , Shi Xiangyan , Zhao Tianyun , Lim Yan Ting , Sobota Radoslaw M. , Hoon Shawn , Pilloni Giovanni , Usadi Adam , Pervushin Konstantin , Miserez Ali 
Published: February 2022

AbstractThe slime of velvet worms (Onychophora) is a strong and fully biodegradable protein material, which upon ejection undergoes a fast liquid-to-solid transition to ensnare prey. However, the molecular mechanisms of slime self-assembly are still not well understood, notably because the primary structures of slime proteins are yet unknown. Combining transcriptomic and proteomic studies, we have obtained the complete primary sequences of slime proteins and identified key features for slime self-assembly. The high molecular weight slime proteins contain Cys residues at the N- and C-termini that mediate the formation of multi-protein complexes via disulfide bonding. Low complexity domains in the N-termini were also identified and their propensity for liquid-liquid phase separation established, which may play a central role for slime biofabrication. Using solid-state nuclear magnetic resonance, rigid and flexible domains of the slime proteins were mapped to specific peptide domains. The complete sequencing of major slime proteins is an important step towards sustainable fabrication of polymers inspired by the velvet worm slime.
Human regulatory T-cells locally differentiate and are functionally heterogeneous within the inflamed arthritic joint
Authors: Lutter Lisanne , van der Wal M. Marlot , Brand Eelco C. , Maschmeyer Patrick , Vastert Sebastiaan , Mashreghi Mir-Farzin , van Loosdregt Jorg , van Wijk Femke 
Published: February 2022

AbstractObjectiveTregs are crucial for immune regulation, and environment-driven adaptation of effector (e)Tregs is essential for local functioning. However, the extent of human Treg heterogeneity in inflammatory settings is unclear.MethodsWe combined single-cell RNA- and TCR-sequencing on Tregs derived from 4-6 patients with juvenile idiopathic arthritis (JIA) to investigate the functional heterogeneity of human synovial fluid (SF)-derived Tregs from inflamed joints. Confirmation and suppressive function of the identified Treg clusters was assessed by flow cytometry.ResultsFour Treg clusters were identified; incoming, activated eTregs with either a dominant suppressive or cytotoxic profile, and GPR56+CD161+CXCL13+ Tregs. Pseudotime analysis showed differentiation towards either classical eTreg profiles or GPR56+CD161+CXCL13+ Tregs supported by TCR data. Despite its most differentiated phenotype GPR56+CD161+CXCL13+ Tregs were shown to be suppressive. Furthermore, BATF was identified as an overarching eTreg regulator, with the novel Treg-associated regulon BHLHE40 driving differentiation towards GPR56+CD161+CXCL13+ Tregs, and JAZF1 towards classical eTregs.ConclusionOur study reveals a heterogeneous population of Tregs at the site of inflammation in JIA. SF Treg differentiate to a classical eTreg profile with a more dominant suppressive or cytotoxic profile that share a similar TCR repertoire, or towards GPR56+CD161+CXCL13+ Tregs with a more distinct TCR repertoire. Genes characterizing GPR56+CD161+CXCL13+ Tregs were also mirrored in other T-cell subsets in both the tumor and autoimmune setting. Finally, the identified key regulators driving SF Treg adaptation may be interesting targets for autoimmunity or tumor interventions.
ERROR MODELLED GENE EXPRESSION ANALYSIS (EMOGEA) PROVIDES A SUPERIOR OVERVIEW OF TIME COURSE RNA-SEQ MEASUREMENTS AND LOW COUNT GENE EXPRESSION
Authors: Karakach Tobias K. , Taverna Federico , Barra Jasmine 
Published: February 2022

ABSTRACTSerial RNA-seq studies of bulk samples are widespread and provide an opportunity for improved understanding of gene regulation during e.g., development or response to an incremental dose of a pharmacotherapeutic. In addition, the widely popular single cell RNA-seq (scRNA-seq) data implicitly exhibit serial characteristics because measured gene expression values recapitulate cellular transitions. Unfortunately serial RNA-seq data continue to be analyzed by methods that ignore this ordinal structure and yield results that are difficult to interpret. Here, we present Error Modelled Gene Expression Analysis (EMOGEA), a principled framework for analyzing RNA-seq data that incorporates measurement uncertainty in the analysis, while introducing a special formulation for modelling data that are acquired as a function of time or other continuous variable. By incorporating uncertainties in the analysis, EMOGEA is specifically suited for RNA-seq studies in which low-count transcripts with small fold-changes lead to significant biological effects. Such transcripts include signaling mRNAs and non-coding RNAs (ncRNA) that are known to exhibit low levels of expression. Through this approach, missing values are handled by associating with them disproportionately large uncertainties which makes it particularly useful for single cell RNA-seq data. We demonstrate the utility of this framework by extracting a cascade of gene expression waves from a well-designed RNA-seq study of zebrafish embryogenesis and, a scRNA-seq study of mouse pre-implantation and provide unique biological insights into the regulation of genes in each wave. For non-ordinal measurements, we show that EMOGEA has a much higher rate of true positive calls and a vanishingly small rate for false negative discoveries compared to common approaches. Finally, we provide an R package (https://github.com/itikadi/EMOGEA) that is self-contained and easy to use.
Graphical Abstract:Graphical representation of EMOGEA indicating the incorporation of measurement errors in modeling RNA-seq data to generate superior results in exploratory analysis, differential gene expression analyses and, scRNA-seq and Time Course analyses.