bluuebunny/crossref_metadata_2025_split huggingface dataset:
Super-delta2: An Enhanced Differential Expression Analysis Procedure for Multi-Group Comparisons of RNA-seq Data
Authors: Cui Zihan , Liu Yuhang , Zhang Jinfeng , Qiu Xing 
Published: February 2021

AbstractBackgroundWe developedsuper-delta2, a differential gene expression analysis pipeline designed for multi-group comparisons for RNA-seq data. It includes a customized one-way ANOVA F-test and a post-hoc test for pairwise group comparisons; both are designed to work with a multivariate normalization procedure to reduce technical noise. It also includes a trimming procedure with bias-correction to obtain robust and approximately unbiased summary statistics used in these tests. We demonstrated the asymptotic applicability ofsuper-delta2to log-transformed read counts in RNA-seq data by large sample theory based on Negative Binomial Poisson (NBP) distribution.ResultsWe comparedsuper-delta2with three commonly used RNA-seq data analysis methods: limma/voom, edgeR, and DESeq2 using both simulated and real datasets. In all three simulation settings,super-delta2not only achieved the best overall statistical power, but also was the only method that controlled type I error at the nominal level. When applied to a breast cancer dataset to identify differential expression pattern associated with multiple pathologic stages,super-delta2selected more enriched pathways than other methods, which are directly linked to the underlying biological condition (breast cancer).ConclusionsBy incorporating trimming and bias-correction in the normalization step,super-delta2was able to achieve tight control of type I error. Because the hypothesis tests are based on asymptotic normal approximation of the NBP distribution,super-delta2does not require computationally expensive iterative optimization procedures used by methods such as edgeR and DESeq2, which occasionally have convergence issues.
CSF Aβ38 levels are associated with Alzheimer-related decline: implications for γ-secretase modulators
Authors: Cullen Nicholas C. , Janelidze Shorena , Palmqvist Sebastian , Stomrud Erik , Mattsson-Carlgren Niklas , Hansson Oskar 
Published: February 2021

AbstractObjectiveShorter Aβ species might modulate disease progression in Alzheimer’s disease (AD). Here we studied whether Aβ38 levels in cerebrospinal fluid (CSF) are associated with risk of developing AD dementia and cognitive decline.MethodsCSF Aβ38 levels were measured in 656 individuals across two clinical cohorts – the Swedish BioFINDER study and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Cox regression models were used to evaluate the association between baseline Aβ38 levels and risk of AD dementia in AD-biomarker positive individuals (AD+; determined by CSF P-tau/Aβ42 ratio) with subjective cognitive decline (SCD) or mild cognitive impairment (MCI). Linear mixed effects models were used to evaluate the association between baseline Aβ38 levels and cognitive decline as measured by MMSE in AD+ participants with SCD, MCI or AD dementia.ResultsIn the BioFINDER cohort, high Aβ38 levels were associated with slower decline in MMSE (β = 0.30 points / sd., P = 0.001) and with lower risk of conversion. To AD dementia (HR = 0.83 per sd., P = 0.03). In the ADNI cohort, higher Aβ38 levels were associated with less decline in MMSE (β = 0.27, P = 0.01), but not risk of conversion to AD dementia (P = 0.66). Aβ38 levels in both cohorts remained significantly associated with both outcomes when adjusted for CSF P-tau levels and remained associated with cognition when adjusted for CSF Aβ42 levels.ConclusionsHigher CSF Aβ38 levels are associated with lower risk of AD-related changes in two independent clinical cohorts. These findings may have implications for γ-secretase modulators as potential disease-altering therapy.
Language impairment in motor neuron disease phenotypes different from classical amyotrophic lateral sclerosis: a review
Authors: Sbrollini Benedetta , Preti Alice Naomi , Zago Stefano , Papagno Costanza , Appollonio Ildebrando Marco , Nicolò Aiello Edoardo 
Published: February 2021

AbstractBackgroundUp to 35-40% of patients with amyotrophic lateral sclerosis (ALS) present with language deficits falling within the spectrum of frontotemporal degeneration (FTD). It is currently debated whether frontotemporal involvement occurs or not in motor neuron disease (MND) phenotypes that differ from classical ALS (i.e., both non-ALS MNDs and non-classical ALS endo-phenotypes) - this stance being supported by the notion of a common pathology underlying MNDs. To investigate whether language dysfunctions also occur in patients with different-from-classical-ALS MNDs can; a) help determine whether the MND-FTDcontinuumcould be broadened at a neuropsychological level; b) convey relevant entailments to cognitive diagnostics in these populations.AimsThe present study thus aimed at reviewing evidence regarding language impairment in different-from-classical-ALS MND patients. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were consulted to implement and report the present review. Studies were included if a) language was quantitatively assessed b) in patients diagnosed with different-from-classical-ALS MND phenotypes. Studies assessing demented patients only were excluded. From an originalN=1117 contributions,N=20 group studies were finally included. Secondary outcomes were taken into account for qualitatively assessing potential biases in generalizing results.Main contributionStudies were divided into those assessing predominant-upper vs. - lower MND patients (UMND/LMND). Language dysfunctions appeared to be more prevalent and severe in UMND patients. Language screeners were able to detect language deficits in both groups. Lexical-semantic deficits appeared to be highly prevalent in both groups and a selective difficulty in action-vs. object-naming was systematically detected. Morpho-syntactic deficits were seldom reported in both groups. Phonological deficits and central dysgraphic features were found in UMND patients only.ConclusionPatients with different-from-classical-ALS MND phenotypes display language deficits similar to those of classical ALS patients (as far as both prevalence and type are concerned) and thus could be validly included in the MND-FTDcontinuumat a neuropsychological level. A greater cortical involvement might account for language deficits being more severe in UMND patients. Consistently with guidelines for cognitive assessment in ALS patients, action-naming tasks might represent a valid and sensitive tool for assessing language in UMND/LMND patients too.
Immuno-fibrotic drivers of impaired lung function in post-acute sequelae of SARS-CoV-2 infection (PASC)
Authors: Chun Hyung J. , Coutavas Elias , Pine Alexander , Lee Alfred I. , Yu Vanessa , Shallow Marcus , Giovacchini Coral X. , Mathews Anne , Stephenson Brian , Que Loretta G. , Lee Patty J. , Kraft Bryan D. 
Published: February 2021

ABSTRACTIntroductionSubjects recovering from COVID-19 frequently experience persistent respiratory ailments; however, little is known about the underlying biological factors that may direct lung recovery and the extent to which these are affected by COVID-19 severity.MethodsWe performed a prospective cohort study of subjects with persistent symptoms after acute COVID-19, collecting clinical data, pulmonary function tests, and plasma samples used for multiplex profiling of inflammatory, metabolic, angiogenic, and fibrotic factors.ResultsSixty-one subjects were enrolled across two academic medical centers at a median of 9 weeks (interquartile range 6-10) after COVID-19 illness: n=13 subjects (21%) mild/non-hospitalized, n=30 (49%) hospitalized/non-critical, and n=18 subjects (30%) hospitalized/intensive care (“ICU”). Fifty-three subjects (85%) had lingering symptoms, most commonly dyspnea (69%) and cough (58%). Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and diffusing capacity for carbon monoxide (DLCO) declined as COVID-19 severity increased (P<0.05), but did not correlate with respiratory symptoms. Partial least-squares discriminant analysis of plasma biomarker profiles clustered subjects by past COVID-19 severity. Lipocalin 2 (LCN2), matrix metalloproteinase-7 (MMP-7), and hepatocyte growth factor (HGF) identified by the model were significantly higher in the ICU group (P<0.05) and inversely correlated with FVC and DLCO (P<0.05), and were confirmed in a separate validation cohort (n=53).ConclusionsSubjective respiratory symptoms are common after acute COVID-19 illness but do not correlate with COVID-19 severity or pulmonary function. Host response profiles reflecting neutrophil activation (LCN2), fibrosis signaling (MMP-7), and alveolar repair (HGF) track with lung impairment and may be novel therapeutic or prognostic targets.FundingThe study was funded in part by the NHLBI (K08HL130557 to BDK and R01HL142818 to HJC), the DeLuca Foundation Award (AP), a donation from Jack Levin to the Benign Hematology Program at Yale, and Divisional/Departmental funds from Duke University.
Cellular substrates of functional network integration and memory in temporal lobe epilepsy
Authors: Douw Linda , Nissen Ida A. , Fitzsimmons Sophie M.D.D. , Santos Fernando A.N. , Hillebrand Arjan , van Straaten Elisabeth C.W. , Stam Cornelis J. , De Witt Hamer Philip C. , Baayen Johannes C. , Klein Martin , Reijneveld Jaap C. , Heyer Djai B. , Verhoog Matthijs B. , Wilbers René , Hunt Sarah , Mansvelder Huibert D. , Geurts Jeroen J.G. , de Kock Christiaan P.J. , Goriounova Natalia A. 
Published: February 2021

AbstractTemporal lobe epilepsy (TLE) patients are at risk of memory deficits, which have been linked to functional network disturbances, particularly of integration of the default mode network (DMN). However, the cellular substrates of functional network integration are unknown. We leverage a unique cross-scale dataset of therapy-resistant TLE patients, who underwent fMRI, MEG and/or neuropsychological testing before neurosurgery. fMRI and MEG underwent atlas-based connectivity analyses. Functional network centrality of the lateral middle temporal gyrus, part of the DMN, was used as a measure of local network integration. Subsequently, non-pathological cortical tissue from this region was used for single cell morphological and electrophysiological patch-clamp analysis, assessing integration in terms of total dendritic length and action potential rise speed. As could be hypothesized, greater network centrality related to better memory performance. Moreover, greater network centrality correlated with more integrative properties at the cellular level across patients. We conclude that individual differences in cognitively relevant functional network integration of a DMN region are mirrored by differences in cellular integrative properties of this region in TLE patients. These findings connect previously separate scales of investigation, increasing translational insight into focal pathology and large-scale network disturbances in TLE.
Crystal structure determination of the armadillo repeat domain ofDrosophilaSARM1 using MIRAS phasing
Authors: Gu Weixi , Luo Zhenyao , Vonrhein Clemens , Jia Xinying , Ve Thomas , Nanson Jeffrey D. , Kobe Boštjan 
Published: February 2021

AbstractWe describe the crystal structure determination of the ARM domain ofDrosophilaSARM1 (dSARM1ARM), which required combination of a number of sources of phase information in order to obtain interpretable electron density maps. SARM1 is a central executioner of the process of axon degeneration, a common feature of the early phase of a range of neurodegenerative diseases. SARM1 is held in the inactive state in healthy axons by its N-terminal auto-inhibitory ARM domain, and is activated to cleave NAD+upon injury, triggering the subsequent axon degeneration. To characterize the molecular mechanism of SARM1 activation, we sought to determine the crystal structure of the SARM1 ARM domain. Here we describe the recombinant production and crystallization of dSARM1ARM, as well as unconventional process used for structure determination. Crystals were obtained in the presence of NMN, a precursor of NAD+and a potential activator of SARM1, only afterin situproteolysis of the N-terminal 63 residues. After molecular replacement attempts failed, we determined the crystal structure of dSARM1ARMat 1.65 Å resolution using the MIRAS phasing technique with the program autoSHARP, combining data from the native, SeMet-labelled, and Br-soaked crystals. The structure will further our understanding of the regulation of SARM1.
AMycobacterium tuberculosiseffector targets mitochondrion, controls energy metabolism and limits cytochrome c exit
Authors: Martin Marianne , deVisch Angelique , Boudehen Yves-Marie , Barthe Philippe , Gutierrez Claude , Turapov Obolbek , Aydogan Talip , Heriaud Laurène , Gracy Jerome , Neyrolles Olivier , Mukamolova Galina V. , Letourneur François , Cohen-Gonsaud Martin 
Published: February 2021

AbstractHost metabolism reprogramming is a key feature ofMycobacterium tuberculosis (Mtb)infection that enables the survival of this pathogen within phagocytic cells and modulates the immune response facilitating the spread of the tuberculosis disease. Here, we demonstrate that a previously uncharacterized secreted protein fromMtb,Rv1813c manipulates the host metabolism by targeting mitochondria. When expressed in eukaryotic cells, the protein is delivered to the mitochondrial intermembrane space and promotes the enhancement of host ATP production by boosting the oxidative phosphorylation metabolic pathway. Furthermore, the release of cytochrome c from mitochondria, an early apoptotic event in response to short-term oxidative stress, is delayed in Rv1813c expressing cells. This study reveals a novel class of mitochondria targeting effectors fromMtbwhich might participate in host cells metabolic reprogramming and apoptosis control duringMtbinfections.
Independent duplications of the Golgi phosphoprotein 3 oncogene in birds
Authors: Opazo Juan C. , Vandewege Michael W. , Gutierrez Javier , Zavala Kattina , Vargas-Chacoff Luis , Morera Francisco J. , Mardones Gonzalo A. 
Published: February 2021

AbstractGolgi phosphoprotein 3 (GOLPH3) was the first reported oncoprotein of the Golgi apparatus. It was identified as an evolutionarily conserved protein upon its discovery about 20 years ago, but its function remains puzzling in normal and cancer cells. The GOLPH3 gene is part of a group of genes that also includes the GOLPH3L gene. Because cancer has deep roots in multicellular evolution, studying the evolution of the GOLPH3 gene family in non-model species represents an opportunity to identify new model systems that could help better understand the biology behind this group of genes. The main goal of this study is to explore the evolution of the GOLPH3 gene family in birds as a starting point to understand the evolutionary history of this oncoprotein. We identified a repertoire of three GOLPH3 genes in birds. We found duplicated copies of the GOLPH3 gene in all main groups of birds other than paleognaths, and a single copy of the GOLPH3L gene. We suggest there were at least three independent origins for GOLPH3 duplicates. Amino acid divergence estimates show that most of the variation is located in the N-terminal region of the protein. Our transcript abundance estimations show that one paralog is highly and ubiquitously expressed, and the others were variable. Our results are an example of the significance of understanding the evolution of the GOLPH3 gene family, especially for unraveling its structural and functional attributes.
Genomic Considerations for FHIR; eMERGE Implementation Lessons
Authors: Murugan Mullai , Babb Lawrence J. , Taylor Casey Overby , Rasmussen Luke V. , Freimuth Robert R. , Venner Eric , Yan Fei , Yi Victoria , Granite Stephen J. , Zouk Hana , Aronson Samuel J. , Power Kevin , Fedotov Alex , Crosslin David R. , Fasel David , Jarvik Gail P. , Hakonarson Hakon , Bangash Hana , Kullo Iftikhar J. , Connolly John J. , Nestor Jordan G. , Caraballo Pedro J. , Wei WeiQi , Wiley Ken , Rehm Heidi L. , Gibbs Richard A. 
Published: February 2021

AbstractStructured representation of clinical genetic results is necessary for advancing precision medicine. The Electronic Medical Records and Genomics (eMERGE) Network’s Phase III program initially used a commercially developed XML message format for standardized and structured representation of genetic results for electronic health record (EHR) integration. In a desire to move towards a standard representation, the network created a new standardized format based upon Health Level Seven Fast Healthcare Interoperability Resources (HL7 FHIR), to represent clinical genomics results. These new standards improve the utility of HL7 FHIR as an international healthcare interoperability standard for management of genetic data from patients. This work advances the establishment of standards that are being designed for broad adoption in the current health information technology landscape.
TheGiardialamellipodium-like ventrolateral flange supports attachment and rapid cytokinesis
Authors: Hardin William R. , Alas Germain C. M. , Taparia Nikita , Thomas Elizabeth B. , Steele-Ogus Melissa , Hvorecny Kelli L. , Halpern Aaron R. , Tůmová Pavla , Kollman Justin M. , Vaughan Joshua C. , Sniadecki Nathan J. , Paredez Alexander R. 
Published: February 2021

AbstractAttachment to the intestinal epithelium is critical to the lifestyle of the ubiquitous parasiteGiardia lamblia. The microtubule cytoskeleton plays a well characterized role in attachment via the ventral adhesive disc, whereas the role of the unconventional actin cytoskeleton is controversial. We identified a novel actin associated protein with putative WH2-like actin binding domains we named Flangin. Flangin complexes withGiardiaactin and is enriched in the ventrolateral flange (VLF), a lamellipodium-like membrane protrusion at the interface between parasites and attached surfaces. Live imaging revealed that the VLF grows to ~1 μm in width after cytokinesis, then remains size-uniform in interphase, grows during mitosis, and is resorbed during cytokinesis. A Flangin truncation mutant stabilizes the VLF and blocks cytokinesis, indicating that the VLF is a membrane reservoir supporting rapid myosin-independent cytokinesis inGiardia. Rho family GTPases are important regulators of membrane protrusions,GlRac, the sole Rho family GTPase inGiardia, was localized to the VLF. Knockdown of Flangin, actin, andGlRac result in VLF formation defects indicating a conserved role forGlRac andactin in forming membrane protrusions, despite the absence of canonical actin binding proteins that link Rho GTPase signaling to lamellipodia formation. Flangin-depleted parasites challenged with fluid shear force in flow chambers had a reduced ability to remain attached, indicating a role for the VLF in attachment. This secondary attachment mechanism complements the microtubule based adhesive ventral disc, a feature that is particularly important during mitosis when the parental ventral disc begins disassembly in preparation for cytokinesis.ImportanceThe ventrolateral flange (VLF) is a lamellipodium-like structure found at the host-parasite interface that has long been thought to be involved in parasite attachment. The proteins responsible for building the VLF have remained unidentified precluding manipulation of the VLF to determine its role inGiardiabiology. We identified Flangin, a novel actin associated protein that localizes to the VLF, implicatingGiardiaactin in VLF formation. We demonstrate that: 1.) Flangin, actin, andGlRac are required for VLF formation, 2.) the VLF serves as a membrane reservoir to supportGiardia’sincredibly fast cytokinesis, and 3) the VLF augments attachment, which is critical to parasitism. The microtubule-based adhesive ventral disc and the actin-based ventrolateral flange represent redundant means of maintaining attachment, the presence of redundant systems illustrate the importance of attachment to the lifestyle of this ubiquitous parasite.
β-importins Tnpo-SR and Cadmus and the small GTPase Ran promote ovarian cyst formation inDrosophila
Authors: Beachum Allison N. , Hinnant Taylor D. , Williams Anna E. , Powell Amanda M. , Ables Elizabeth T. 
Published: February 2021

ABSTRACTGerm cells undergo mitotic expansion via incomplete cytokinesis, forming cysts of undifferentiated cells that remain interconnected prior to meiotic initiation, through mechanisms that are not well-defined. In somatic cells, Ras-related nuclear protein (Ran) spatiotemporally regulates mitotic spindle assembly, cleavage furrow formation and abscission. Here, we identify Ran and β-importins as critical regulators of cyst development in theDrosophilaovary. Depletion ofRanor the β-importinsTnpo-SRandcadmusdisrupts oocyte selection and results in egg chambers with variable numbers of germ cells, suggesting abnormal cyst development and cyst fragmentation. We demonstrate that Ran, Tnpo-SR, and Cadmus regulate key cellular processes during cyst formation, including cell cycle dynamics, fusome biogenesis, and ring canal stability, yet do so independently of mitotic spindle assembly. Further, Tnpo-SR and Cadmus control cyclin accumulation and suppress cytokinesis independent of Ran-GTP, suggesting that β-importins sequester protein cargos that normally promote the mitotic-to-meiotic transition. Our data demonstrates that Ran and β-importins are critical for germ cell cyst formation, a role that is likely conserved in other organisms.SUMMARY STATEMENTRan and two β-importins function coordinately to promote oocyte selection and cyst development in theDrosophilaovary.
A topological characterization of DNA sequences based on chaos geometry and persistent homology
Authors: Nguyen Dong Quan Ngoc , Le Phuong Dong Tan , Xing Lin , Lin Lizhen 
Published: February 2021

AbstractMethods for analyzing similarities among DNA sequences play a fundamental role in computational biology, and have a variety of applications in public health, and in the field of genetics. In this paper, a novel geometric and topological method for analyzing similarities among DNA sequences is developed, based on persistent homology from algebraic topology, in combination with chaos geometry in 4-dimensional space as a graphical representation of DNA sequences. Our topological framework for DNA similarity analysis is general, alignment-free, and can deal with DNA sequences of various lengths, while proving first-of-the-kind visualization features for visual inspection of DNA sequences directly, based on topological features of point clouds that represent DNA sequences. As an application, we test our methods on three datasets including genome sequences of different types of Hantavirus, Influenza A viruses, and Human Papillomavirus.