bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bayesian Differential Analysis of Cell Type Proportions
Authors: Karagiannis Tanya T. , Monti Stefano , Sebastiani Paola 
Published: January 2023

SUMMARYThe analysis of cell type proportions in a biological sample should account for the compositional nature of the data but most analyses ignore this characteristic with the risk of producing misleading conclusions. The recent method scCODA appropriately incorporates these constraints by using a Bayesian Multinomial-Dirichlet model that requires a reference cell type to normalize the distribution of all cell types. However, a reference cell type that is stable across biological conditions may not always be available. Here, we present an approach that uses a Bayesian multinomial regression for the analysis of single cell distribution data without the need for a reference cell type. We show an implementation example using the rjags package within the R software.
Molecular Imaging with Fibroblast Activation Protein Tracers depicts Inflammatory Joint Damage and its Transition to Resolution of Inflammation
Authors: Rauber Simon , Mohammadian Hashem , Schmidkonz Christian , Atzinger Armin , Soare Alina , Maschauer Simone , Treutlein Christoph , Angeli Mario , Raimondo Maria Gabriella , Xu Cong , Yang Kai-Ting , Lu Le , Labinsky Hannah , Kampylafka Eleni , Knitza Johannes , Maric Hans , Distler Jörg H.W. , Bäuerle Tobias , Kuwert Torsten , Prante Olaf , Cañete Juan , Schett Georg , Ramming Andreas 
Published: January 2023

ABSTRACTJoint fibroblasts play an important role in the transition from joint inflammation to irreversible joint damage. There is no established clinical method to measure fibroblast activation during inflammation and their phenotypic dynamics upon therapy to date. Here we show that upon treatment with IL-17A/TNF-blocking antibodies fibroblasts change their phenotype from a destructive IL-6+/MMP3+THY1+to a CD200+DKK3+subtype, actively inducing resolution of inflammation. This phenotypic switch can be visualized due to so far unexplored different capacities of fibroblast subtypes with regard to receptor internalization of small molecular tracers with high affinity to FAP. Although FAP expression levels are comparable between fibroblast subtypes in the joint, FAP internalisation rate correlates with the destructive potential of fibroblasts and resolving fibroblasts have a lower FAP internalisation rate, providing a valuable imaging tool to visualize the transition from joint damage to resolution of inflammation.
GEARBOCS: An Adeno Associated Virus Tool forIn VivoGene Editing in Astrocytes
Authors: Sivadasan Bindu Dhanesh , Savage Justin T. , Brose Nicholas , Bradley Luke , Dimond Kylie , Tan Christabel Xin , Eroglu Cagla 
Published: January 2023

SummaryCRISPR/Cas9-based genome engineering enables rapid and precise gene manipulations in the CNS. Here, we developed a non-invasive astrocyte-specific method utilizing a single AAV vector, which we named GEARBOCS (Gene Editing in AstRocytes Based On CRISPR/Cas9 System). We verified GEARBOCS’ specificity to mouse cortical astrocytes and demonstrated its utility for three types of gene manipulations: knockout (KO); tagging (TagIn); and reporter knock-in (GeneTrap) strategies. Next, we deployed GEARBOCS in two test cases. First, we determined that astrocytes are a necessary source of the synaptogenic factor Sparcl1 for thalamocortical synapse maintenance in the mouse primary visual cortex. Second, we determined that cortical astrocytes express the synaptic vesicle associated Vamp2 protein and found that it is required for maintaining excitatory and inhibitory synapse numbers in the visual cortex. These results show that the GEARBOCS strategy provides a fast and efficient means to study astrocyte biologyin vivo.MotivationAstrocytes are indispensable for brain development, function, and health. However, molecular tools to study astrocyte biology and functionin vivohave been largely limited to genetically modified mice. Here, we developed a CRISPR/Cas9-based gene editing strategy within a single AAV vector that enables efficient genome manipulations in astrocytes. We designed and optimized this easy-to-use viral tool to understand gene expression, protein localization and function in astrocytesin vivo.
Metacognitive Judgments during Visuomotor Learning Reflect the Integration of Error History
Authors: Hewitson Christopher L. , Al-Fawakhiri Naser , Forrence Alexander D. , McDougle Samuel D. 
Published: January 2023

ABSTRACTPeople form metacognitive representations of their own abilities across a range of tasks. How these representations are influenced by errors during learning is poorly understood. Here we ask how metacognitive confidence judgments of performance during motor learning are shaped by the learner’s recent history of errors. Across four motor learning experiments, our computational modeling approach demonstrated that people’s confidence judgments are best explained by a recency-weighted averaging of visually observed errors. Moreover, in the formation of these confidence estimates, people appear to re-weight observed motor errors according to a subjective cost function. Confidence judgments were adaptive, incorporating recent motor errors in a manner that was sensitive to the volatility of the learning environment, integrating a shallower history when the environment was more volatile. Finally, confidence tracked motor errors in the context of both implicit and explicit motor learning, but only showed evidence of influencing behavior in the latter. Our study thus provides a novel descriptive model that successfully approximates the dynamics of metacognitive judgments during motor learning.NEW & NOTEWORTHYThis study examined how, during visuomotor-learning, people’s confidence in their performance is shaped by their recent history of errors. Using computational modeling, we found that confidence incorporated recent error-history, tracked subjective error-costs, was sensitive to environmental volatility, and in some contexts may influence learning. Together, these results provide a novel model of metacognitive judgments during motor-learning that could be applied to future computational and neural studies at the interface of higher-order cognition and motor control.
Energetics of the Microsporidian Polar Tube Invasion Machinery
Authors: Chang Ray , Davydov Ari , Jaroenlak Pattana , Budaitis Breane , Ekiert Damian C. , Bhabha Gira , Prakash Manu 
Published: January 2023

AbstractMicrosporidia are eukaryotic, obligate intracellular parasites that infect a wide range of hosts, leading to health and economic burdens worldwide. Microsporidia use an unusual invasion organelle called the polar tube (PT), which is ejected from a dormant spore at ultra-fast speeds, to infect host cells. The mechanics of PT ejection are impressive.Anncaliia algeraemicrosporidia spores (3-4µm in size) shoot out a 100-nm-wide PT at a speed of 300µm/sec, creating a shear rate of 3000 sec−1. The infectious cargo, which contains two nuclei, is shot through this narrow tube for a distance of ∼60-140µm (Jaroenlak et al., 2020) and into the host cell. Considering the large hydraulic resistance in an extremely thin tube and the low-Reynolds-number nature of the process, it is not known how microsporidia can achieve this ultrafast event. In this study, we use Serial Block-Face Scanning Electron Microscopy to capture 3-dimensional snapshots ofA. algeraespores in different states of the PT ejection process. Grounded in these data, we propose a theoretical framework starting with a systematic exploration of possible topological connectivity amongst organelles, and assess the energy requirements of the resulting models. We perform PT ring experiments in media of varying viscosity, and use the results to rank our proposed hypotheses based on their predicted energy requirement. We also present a possible mechanism for cargo translocation, and quantitatively compare our predictions to experimental observations. Our study provides a comprehensive biophysical analysis of the energy dissipation of microsporidian infection process and demonstrates the extreme limits of cellular hydraulics.Statement of SignicanceMicrosporidia are a group of spore-forming, intracellular parasites that infect a wide range of hosts (including humans). Once triggered, microsporidian spores (3-4µm in size) shoot out a specialized organelle called the polar tube (PT) (60-140µm long, 100 nm wide) at ultrafast speed (300µm/sec), penetrating host cells and acting as a conduit for the transport of infectious cargo. Although this process has fascinated biologists for a century, the biophysical mechanisms underlying PT extrusion are not understood. We thus take a data-driven approach to generate models for the physical basis of PT ring and cargo transport through the PT. Our approach here demonstrates the extreme limits of cellular hydraulics and the potential applications of biophysical approaches to other cellular architectures.
Discovery of highly potent small molecule pan-coronavirus fusion inhibitors
Authors: Curreli Francesca , Chau Kent , Tran Thanh-Thuy , Nicolau Isabella , Ahmed Shahad , Das Pujita , Hillyer Christopher D. , Premenko-Lanier Mary , Debnath Asim K. 
Published: January 2023

ABSTRACTThe unprecedented pandemic of COVID-19, caused by a novel coronavirus, SARS-CoV-2, has led to massive human suffering, death, and economic devastation worldwide. The virus is mutating fast to more transmissible and infectious variants. The Delta variant (B.1.617.2), initially identified in India, and the omicron variant (BA.4 and BA.5) have spread worldwide. In addition, recently alarming antibody evasive SARS-CoV-2 subvariants, BQ and XBB, have been reported. These new variants may pose a substantial challenge to controlling the spread of this virus. Therefore, the continued development of novel drugs having pan-coronavirus inhibition to treat and prevent infection of COVID-19 is urgently needed. These drugs will be critically important in dealing with new pandemics that will emerge in the future. We report the discovery of several highly potent small molecule pan-coronavirus inhibitors. One of which, NBCoV63, showed low nM potency against SARS-CoV-2 (IC50: 55 nM), SARS-CoV (IC50: 59 nM), and MERS-CoV (IC50: 75 nM) in pseudovirus-based assays with excellent selectivity indices (SI: as high as > 900) demonstrating its pan-coronavirus inhibition. NBCoV63 showed equally effective antiviral potency against SARS-CoV-2 mutant (D614G) and several variants of concerns (VOCs) such as B.1.617.2 (Delta), B.1.1.529/BA.1 and BA.4/BA.5 (Omicron) and K417T/E484K/N501Y (Gamma). NBCoV63 also showed similar efficacy profiles to Remdesivir against authentic SARS-CoV-2 (Hong Kong strain) and two of its variants (Delta and Omicron) by plaque reduction in Calu3 cells. Additionally, we show that NBCoV63 inhibits virus-mediated cell-to-cell fusion in a dose-dependent manner. Furthermore, the Absorption, distribution, metabolism, and excretion (ADME) data of NBCoV63 demonstrated drug-like properties.
The STEMRI trial: magnetic resonance spectroscopy imaging can define tumor areas enriched in glioblastoma-initiating cells
Authors: Lemarié Anthony , Lubrano Vincent , Delmas Caroline , Lusque Amélie , Cerapio Juan-Pablo , Perrier Marion , Siegfried Aurore , Arnauduc Florent , Nicaise Yvan , Dahan Perrine , Filleron Thomas , Mounier Muriel , Toulas Christine , Moyal Elizabeth Cohen-Jonathan 
Published: January 2023

ABSTRACTBACKGROUNDGlioblastoma (GB) gold standard treatment combines maximally-safe surgical resection of the contrast-enhanced (CE) central tumor area, as defined by MRI, and chemo-radiotherapy. However, most patients relapse within one year in non-CE peritumoral FLAIR regions. Spectroscopy MRI (MRSI) can discriminate metabolic tumor areas with higher recurrence potential. We showed that regions with Choline/N-acetyl-aspartate index >2 (CNI+) were predictive of relapse sites post-radiotherapy in CE and FLAIR areas. As relapses are mainly imputed to a subpopulation of aggressive and resistant tumor stem-like cells, called GB-initiating cells (GIC), this suggests that CNI+ areas might be enriched in GIC.METHODSWe conducted a prospective trial in 16 eligible GB patients subjected to preoperative MRSI/MRI and subsequent surgery/chemo-radiotherapy to investigate GIC enrichment of CNI+ versus CNI− areas, based on biopsies in CE and FLAIR. We combined in vitro/vivo biological characterization of biopsies and derived GIC lines with biopsy RNAseq analyses.RESULTSBiopsy characterization by FACS and RNAseq revealed that FLAIR/CNI+ areas showed an enrichment in GIC-population and in stem-related gene signature, but also in pathways related to DNA repair, adhesion/migration and mitochondrial bioenergetics. More, FLAIR/CNI+ samples gave rise to GIC-enriched neurospheres faster than CNI− counterparts. Finally, parameters assessing Biopsy GIC Content and Time to Neurosphere formation in FLAIR/CNI+ areas were associated with worse patient outcome.CONCLUSIONPreoperative MRI/MRSI combination would certainly allow better resection and targeting of CNI+ areas in FLAIR, as their GIC-enrichment can predict worse outcome in GB patients.TRIAL REGISTRATIONClinicalTrials.govNCT01872221.FUNDINGRITC (RECF1929), GRICR and Plan Cancer 2016 (HTE).
Tailoring Human Sleep: selective alteration through Brainstem Arousal Circuit Stimulation
Authors: Deli Alceste , He Shenghong , Duchet Benoit , Huang Yongzhi , Martin Sean , Sanrangmat Nagaraja , Denison Timothy , Tan Huiling , Vyazovskiy Vladyslav V. , Green Alexander 
Published: January 2023

AbstractBrainstem nuclei, such as the pedunculopontine nucleus, send activating projections to cortex, modulating states of sleep, wakefulness and arousal levels. Surgical modulation of subcortical activity using deep brain stimulation (DBS) is utilised in the management of pain and movement disorders. DBS of brainstem arousal circuits in a state-dependent manner could offer an attractive alternative in severe pharmacoresistant cases of hypersomnia and in disorders of consciousness, where behavioural activation is desired.We wanted to investigate if we can selectively induce wakefulness and/or alter sleep state through DBS of the PPN region (PPNR). To this end, we used the opportunity of implanted PPNR electrodes in stimulation-naïve patients with multiple systems atrophy. PPNR activity was recorded during both slow wave sleep (SWS) and quiet wakefulness with simultaneous cortical EEG, in order to identify differences in brainstem oscillatory patterns during different states of excitability. PPNR DBS in two gamma frequency protocols (40Hz and 100Hz) was delivered during SWS of the same sleep stage and with comparable pre-trial levels of slow wave activity.Additionally, SHAM trials were used as a control where no stimulation was applied. We examined changes in cortical oscillatory power, changes in functional connectivity (coherence and causality) from pre- to post-stimulation and phase-locking of cortical oscillations with DBS frequencies and their sub-harmonics during stimulation. We also evaluated connectivity changes induced by DBS and corresponding differences in circuit dynamics between SWS and wakefulness.Beta and gamma PPNR oscillatory power increased when wake was compared to sleep. We saw clear PPNR power modulation by the phase of EEG slow wave, with significant increase in gamma compared to beta power during the ‘excitable’ part of the slow-wave cycle. Gamma PPNR DBS induced transitions to wakefulness and REM, while it truncated sleep time compared to baseline. The 40Hz stimulation protocol was more efficient in reducing slow wave activity and increasing cortical beta power, compared to PPNR DBS at 100Hz. Furthermore, intrinsic cortical rhythms phase-locked with 40 Hz PPNR DBS to a significantly higher degree compared to the 100Hz protocol, with regional differences in phase-locking, suggesting a complex biological phenomenon. Finally, functional connectivity changes induced by PPNR DBS were consistent with differences in circuit dynamics between SWS and wakefulness. Overall, these results highlight the possibility of using DBS of brainstem arousal circuits to promote arousal and wakefulness, which opens new perspectives for using closed-loop approaches to modulate vigilance states in humans for therapeutic benefit.
An Exploratory Systematic Review and Meta-analysis on Period Poverty
Authors: Delanerolle Gayathri , Yang Xiaojie , Cavalini Heitor , Kurmi Om , Rostivik Camilla , Shetty Ashish , Saraswat Lucky , Taylor Julie , Sajid Sana , Rathod Shanaya , Shi Jian Qing , Phiri Peter 
Published: January 2023

AbstractBackgroundPeriod povertyis a global health and social issue that needs to be addressed. The primary aim of this study was to provide a comprehensive understanding on period poverty, including outcomes associated menstruation.MethodsAll observational and randomised clinical trials reporting menstruation challenges, menstrual poverty and menstrual products were included. Our search strategy included multiple electronic databases of PubMed, Web of Science, ScienceDirect, ProQuest and EMBASE. Studies published in a peer review journal in English between the 30thof April 1980 and the 30thof April 2022 were included. The Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias (RoB) of the systematic included studies. Pooled odds ratios (ORs) together with 95% confidence intervals (CIs) are reported overall and for sub-groups.ResultsA total of 80 studies were systematically selected, where 38 were included in the meta-analysis. Of the 38 studies, 28 focused on children and young girls (i.e., 10-24 years old) and 10 included participants with a wider age range of 15-49 years. The prevalence of using disposable sanitary pads was 45% (95% CI = [0.35,0.58]). The prevalence of menstrual education pre-menarche was 68% (95% CI = [0.56, 0.82]). The prevalence of good MHM was 39% (95% CI = [0.25, 0.61]). Women in rural area (OR = 0.30, 95% CI = [0.13, 0.69]) were 0.70 times less likely to have good MHM practices than those living in urban area.DiscussionThere was a lack of evidence, especially from low- and middle-income countries. Further research to better understand the scope and prevalence of period poverty should be considered. This will enable the development of improved policies to increase access to menstrual products and medical support where necessary.FundingNot ApplicableRegistrationA systematic methodology was developed and published (CRD42022339536).
A systematic review and meta-analysis of the diagnostic accuracy of endometrial sampling tests for detecting endometrial cancer
Authors: Sakna Noha , Elgendi Marwa , Salama Mohamed , Zeinhom Ahmed , Labib Somia , Nabhan Ashraf 
Published: January 2023

AbstractObjectivesto determine the diagnostic accuracy of different endometrial sampling tests for detecting endometrial carcinoma.Designa systematic review and meta-analysis of studies of diagnostic accuracy.Eligibility criteriaWe included published diagnostic test accuracy studies of women, of all ages, who had an endometrial sampling for preoperatively detecting endometrial cancer with verification using histopathology of hysterectomy specimens as the reference standard. We excluded case control and case series studies.Information sourcesWe searched the Cochrane library, MEDLINE/PubMed, CINAHL, Web of Science, and Scopus from the date of inception of the databases to January 18, 2023. We did not apply any restrictions on language or date of publication. We searched the references of included studies and other systematic reviews.Risk of biasWe extracted study data and assessed study quality using the revised quality assessment tool for diagnostic accuracy studies (QUADAS-2).Synthesis of resultsWe used bivariate diagnostic random-effects meta-analysis and presented the results in a summary receiver operating characteristic curve. We assessed the certainty of evidence as recommended by the GRADE approach.ResultsTwelve included studies, published between 1986 and 2022, recruited 1607 participants. Seven studies were low risk of bias in all domains and all studies had low applicability concerns. The most examined index tests were Pipelle and conventional dilation and curettage. For diagnosing endometrial carcinoma, the sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio (95% confidence intervals), for Pipelle were 0.774 (0.565, 0.900), 0.985 (0.927, 0.997), 97.000 (14.000, 349.000), and 0.241 (0.101, 0.442)and for conventional dilation and curettage were 0.773 (0.333, 0.959), 0.987 (0.967, 0.995), 62.300 (18.600, 148.000), and 0.268 (0.042, 0.676); respectively.ConclusionHigh certainty evidence indicates that pre-operative endometrial sampling particularly using Pipelle or conventional curettage is accurate in diagnosing endometrial cancer. Studies assessing other endometrial sampling tests were sparse.Systematic review registrationCenter for Open Science, osf.io/h8e9z
p53 modulates kinase inhibitor resistance and lineage plasticity in NF1-related MPNSTs
Authors: Grit Jamie L. , McGee Lauren E. , Tovar Elizabeth A. , Essenburg Curt J. , Wolfrum Emily , Beddows Ian , Williams Kaitlin , Sheridan Rachael , Schipper Josh , Adams Marie , Arumugam Menusha , Woude Thomas Vander , Gurunathan Sharavana , Field Jeffrey M. , Wulfkuhle Julia , Petricoin Emanuel F. , Graveel Carrie R. , Steensma Matthew R. 
Published: January 2023

AbstractMalignant peripheral nerve sheath tumors (MPNSTs) are chemotherapy resistant sarcomas that are a leading cause of death in neurofibromatosis type 1 (NF1). Although NF1-related MPNSTs derive from neural crest cell origin, they also exhibit intratumoral heterogeneity.TP53mutations are associated with significantly decreased survival in MPNSTs, however the mechanisms underlyingTP53-mediated therapy responses are unclear in the context ofNF1-deficiency. We evaluated the role of two commonly altered genes,METandTP53, in kinome reprograming and cellular differentiation in preclinical MPNST mouse models. We previously showed thatMETamplification occurs early in human MPNST progression and thatTrp53loss abrogated MET-addiction resulting in MET inhibitor resistance. Here we demonstrate a novel mechanism of therapy resistance whereby p53 alters MET stability, localization, and downstream signaling leading to kinome reprogramming and lineage plasticity.Trp53loss also resulted in a shift from RAS/ERK to AKT signaling and enhanced sensitivity to MEK and mTOR inhibition. In response to MET, MEK and mTOR inhibition, we observed broad and heterogeneous activation of key differentiation genes inTrp53-deficient lines suggestingTrp53loss also impacts lineage plasticity in MPNSTs. These results demonstrate the mechanisms by which p53 loss alters MET dependency and therapy resistance in MPNSTS through kinome reprogramming and phenotypic flexibility.