bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intellectual disability and cerebellar hypoplasia in autism reported by associative learning
Authors: Welsh John P. , Munson Jeffrey , John Tanya St. , Meehan Christina N. , Tran Elise N. , Begay K. Kawena , Dager Stephen R. , Estes Annette M. 
Published: March 2021

ABSTRACTObjectiveTo determine how impairments in associative learning in autism spectrum disorder (ASD) relate to intellectual disability (ID) and early-childhood cerebellar hypoplasia.MethodsTrace and long-delay eye blink conditioning (EBC) were performed in 62 children age 11.2 years having: 1) ASD with ID (ASD+ID); 2) ASD without ID (ASD-noID); or 3) typical development (TD). The sub-second timing of conditioned eye-blink responses (CRs) acquired to a tone paired with a corneal air puff was related to brain structure at age 2 years and clinical measures across ages 2-12 years. Because CR timing is influenced strongly by cerebellar function, EBC was used to test hypotheses relating cerebellar hypoplasia to ASD.ResultsChildren with ASD+ID showed early-onset CRs during trace EBC that were related to early-childhood hypoplasia of the cerebellum but not of the cerebral cortex, hippocampus, or amygdala. Children with ASD-noID showed early-onset CRs only during long-delay EBC without cerebellar hypoplasia. Using EBC measures, logistic regression detected ASD with 81% sensitivity and 79% specificity while linear discriminant analysis separated ASD subgroups based on ID but not ASD severity. MRI of additional 2-year-olds with ASD indicated that early-onset CRs during trace EBC revealed ASD+ID more readily than cerebellar hypoplasia, per se.ConclusionsEarly-childhood cerebellar hypoplasia occurs in children with ASD+ID that demonstrate early-onset CRs during trace EBC. Trace EBC reveals the relationship between cerebellar hypoplasia and ASD+ID likely by engaging cerebro-cerebellar circuits involved in intellect. We emphasize that the cerebellum optimizes sensory-motor processing at sub-second intervals, impairments of which may contribute to ID.
Estimating COVID-19 cases and deaths prevented by non-pharmaceutical interventions, and the impact of individual actions: a retrospective model-based analysis
Authors: Fair Kathyrn R , Karatayev Vadim A , Anand Madhur , Bauch Chris T 
Published: March 2021

AbstractSimulation models from the early COVID-19 pandemic highlighted the urgency of applying non-pharmaceutical interventions (NPIs), but had limited empirical data. Here we use data from 2020-2021 to retrospectively model the impact of NPIs in Ontario, Canada. Our model represents age groups and census divisions in Ontario, and is parameterised with epidemiological, testing, demographic, travel, and mobility data. The model captures how individuals adopt NPIs in response to reported cases. We compare a scenario representing NPIs introduced within Ontario (closures of workplaces/schools, reopening of schools/workplaces with NPIs in place, individual-level NPI adherence) to counterfactual scenarios wherein alternative strategies (e.g. no closures, reliance on individual NPI adherence) are adopted to ascertain the extent to which NPIs reduced cases and deaths. Combined school/workplace closure and individual NPI adoption reduced the number of deaths in the best-case scenario for the case fatality rate (CFR) from 178548 [CI: 171845, 185298] to 3190 [CI: 3095, 3290] in the Spring 2020 wave. In the Fall 2020/Winter 2021 wave, the introduction of NPIs in workplaces/schools reduced the number of deaths from 20183 [CI: 19296, 21057] to 4102 [CI: 4075, 4131]. Deaths were several times higher in the worst-case CFR scenario. Each additional 9−16 (resp. 285−578) individuals who adopted NPIs in the first wave prevented one additional infection (resp., death). Our results show that the adoption of NPIs prevented a public health catastrophe. A less comprehensive approach, employing only closures or individual-level NPI adherence, would have resulted in a large number of cases and deaths.
Assessment of serological assays for identifying high titer convalescent plasma
Authors: Farnsworth Christopher W. , Case James Brett , Hock Karl , Chen Rita E. , O’Halloran Jane A. , Presti Rachel , Goss Charles W. , Rauseo Adriana M. , Ellebedy Ali , Theel Elitza S. , Diamond Michael S. , Henderson Jeffrey P. 
Published: March 2021

ABSTRACTThe COVID-19 pandemic has been accompanied by the largest mobilization of therapeutic convalescent plasma (CCP) in over a century. Initial identification of high titer units was based on dose-response data using the Ortho VITROS IgG assay. The proliferation of SARS-CoV-2 serological assays and non-uniform application has led to uncertainty about their interrelationships. The purpose of this study was to establish correlations and analogous cutoffs between commercially available serological tests (Ortho, Abbott, Roche), a spike ELISA, and a virus neutralization assay using convalescent plasma from a cohort of 79 donors from April 2020. Relationships relative to FDA-approved cutoffs under the CCP EUA were identified by linear regression and receiver operator characteristic curves. Relative to the Ortho VITROS assay, the r2 of the Abbott, Roche, the anti-Spike ELISA and the neutralizing assay were 0.58, 0.5, 0.82, and 0.44, respectively. The best correlative index for establishing high-titer units was 3.82 S/C for the Abbott, 10.89 COI for the Roche, 1:1,202 for the anti-Spike ELISA, and 1:200 by the neutralization assay. The overall agreement using derived cutoffs compared to the CCP EUA Ortho VITROS cutoff of 9.5 was 92.4% for Abbott, 84.8% for Roche, 87.3% for the anti-S ELISA and 78.5% for the neutralization assay. Assays based on antibodies against the nucleoprotein (Roche, Abbott) and neutralizing antibody tests were positively associated with the Ortho assay, although their ability to distinguish FDA high-titer specimens was imperfect. The resulting relationships help reconcile results from the large body of serological data generated during the COVID-19 pandemic.
In vivoregulation of fluorescent fusion proteins by engineered kinases
Authors: Lepeta Katarzyna , Roubinet Chantal , Kanca Oguz , Ochoa-Espinosa Amanda , Bieli Dimitri , Cabernard Clemens , Affolter Markus , Caussinus Emmanuel 
Published: March 2021

AbstractReversible protein phosphorylation by kinases in extensively used to control a plethora of processes essential for proper development and homeostasis of multicellular organisms. One main obstacle in studying the role of a defined kinase-substrate interaction is that kinases form complex signaling networks and most often phosphorylate multiple substrates involved in various cellular processes. In recent years, several new approaches have been developed to control the activity of a given kinase. However, most of them fail to regulate a single protein target, likely hiding the effect of a unique kinase-substrate by pleiotropic effects. To overcome this limitation, we have created protein binder-based engineered kinases for direct, robust and tissue-specific phosphorylation of target fluorescent protein fusionsin vivo. We show that synthetic Rok kinases, based on theDrosophilaortholog of Rho-associated protein kinase (ROCK), are functional enzymes and can activate myosin II through phosphorylation of Sqh::GFP or Sqh::mCherry in different morphogenetic processes in a developing fly embryo. We next use the system to study the impact of actomyosin activation specifically in the developing tracheal branches and showed that ectopic activation of actomyosin with engineered Rok kinase did not prevent cell intercalation nor the formation of autocellular junctions. We assume that this approach can be adapted to other kinases and targets in various eukaryotic genetic systems.
Identification and prediction of developmental enhancers in sea urchin embryos
Authors: Arenas-Mena César , Miljovska Sofija , Rice Edward J. , Gurges Justin , Shashikant Tanvi , Ercan Sevinç , Danko Charles G. 
Published: March 2021

AbstractBackgroundThe transcription of developmental regulatory genes is often controlled by multiple cis-regulatory elements. The identification and functional characterization of distal regulatory elements remains challenging, even in tractable model organisms like sea urchins.ResultsWe evaluate the use of chromatin accessibility, transcription and RNA Polymerase II for their ability to predict enhancer activity of genomic regions in sea urchin embryos. ATAC-seq, PRO-seq, and Pol II ChIP-seq from early and late blastula embryos are manually contrasted with experimentalcis-regulatory analyses available in sea urchin embryos, with particular attention to common developmental regulatory elements known to have enhancer and silencer functions differentially deployed among embryonic territories. Using the three functional genomic data types, machine learning models are trained and tested to classify and quantitatively predict the enhancer activity of several hundred genomic regions previously validated with reporter constructs invivo.ConclusionsOverall, chromatin accessibility and transcription have substantial power for predicting enhancer activity. For promoter-overlapping cis-regulatory elements in particular, the distribution of Pol II is the best predictor of enhancer activity in blastula embryos. Furthermore, ATAC- and PRO-seq predictive value is stage dependent for the promoter-overlapping subset. This suggests that the sequence of regulatory mechanisms leading to transcriptional activation have distinct relevance at different levels of the developmental gene regulatory hierarchy deployed during embryogenesis.
Antidepressants stimulate lipoprotein(a) macropinocytosis via serotonin-enhanced cell surface binding
Authors: Deo Nikita , Siddiqui Halima , Madani Golnoush , Rutledge Malcolm , Williams Michael JA , McCormick Sally PA , Redpath Gregory MI 
Published: March 2021

AbstractWe recently found that plasminogen receptors regulate the plasma membrane binding and uptake of Lp(a) via macropinocytosis. In this study, we sought to further define lipoprotein(a) [Lp(a)] macropinocytosis, discovering an unexpected role for antidepressants and serotonin in the regulation of this process. We found that the tricyclic antidepressant imipramine enhanced Lp(a) uptake, in contradiction of its published role as a macropinocytosis inhibitor. Extending these experiments to the commonly used serotonin uptake inhibitors (SSRIs) citalopram and sertraline, we found that citalopram stimulated, while sertraline inhibited, Lp(a) uptake. Imipramine and citalopram enhanced cell surface binding of Lp(a) rather than upregulating macropinocytosis. Consistent with imipramine and citalopram boosting extracellular serotonin levels, serotonin itself also enhanced Lp(a) surface binding and uptake. Imipramine and serotonin increased expression of the plasminogen receptor with a C-terminal lysine (PlgRKT), a receptor known to enhance cell surface binding of Lp(a), likely accounting for their effects on Lp(a) uptake. Finally, imipramine and citalopram increased Lp(a) delivery into Rab11 recycling endosomes, but not degradative pathways in the cell. These findings indicate citalopram and imipramine may have utility as a potential Lp(a)-lowering therapeutic in people suffering from depression who often have elevated Lp(a) levels and an increased risk of cardiovascular disease.
High content 3D imaging method for quantitative characterization of organoid development and phenotype
Authors: Beghin Anne , Grenci Gianluca , Rajendiran Harini , Delaire Tom , Mohamad Raffi Saburnisha Binte , Blanc Damien , Mets Richard de , Ong Hui Ting , Acharya Vidhyalakshmi , Sahini Geetika , Racine Victor , Galland Remi , Sibarita Jean-Baptiste , Viasnoff Virgile 
Published: March 2021

ABSTRACTQuantitative analysis on a large number of organoids can provide meaningful information from the morphological variability observed in 3D organotypic cultures, called organoids. Yet, gathering statistics of growing organoids is currently limited by existing imaging methods and subsequent image analysis workflows that are either restricted to 2D, limited in resolution, or with a low throughput. Here, we present an automated high content imaging platform synergizing high density organoid cultures with 3D live light-sheet imaging. The platform is an add-on to a standard inverted microscope. We demonstrate our capacity to collect libraries of 3D images at a rate of 300 organoids per hour, enabling training of artificial intelligence-based algorithms to quantify the organoid morphogenetic organization at multiple scales with subcellular resolution. We validate our approach on different organotypic cell cultures (stem, primary, and cancer), and quantify the development of hundreds of neuroectoderm organoids (from human Embryonic Stem Cells) at cellular, multicellular and whole organoid scales.
Transcriptome-based phylogeny and whole-genome duplication in Theaceae
Authors: Zhang Qiong , Zhao Lei , Zhao Jian-Li , Folk Ryan A. , Zamora Nelson , Soltis Pamela S. , Soltis Douglas E. , Yang Shi-Xiong , Gao Lian-Ming , Peng Hua , Yu Xiang-Qin 
Published: March 2021

AbstractTheaceae, with three tribes and nine genera, is a family of great economic and ecological importance. Recent phylogenetic analyses based on plastid genome resolved the relationship among three tribes and the intergeneric relationships within Gordonieae and Stewartieae. However, generic level relationships within the largest tribe Theeae were not fully resolved and potential hybridization among genera within Theeae revealed previously also remains to be tested further. Here we conducted a comprehensive phylogenomic study of Theaceae based on transcriptomes and low-depth whole-genome sequencing of 57 species as well as additional plastome sequence data from previous work. Phylogenetic analyses suggested that Stewartieae was the first-diverging clade in Theaceae, consistent with previous study using plastomic data. Within Theeae, the highly supportedApterosperma-Laplaceaclade grouped withPyrenariawith maximum support based on the partitioned and unpartitioned concatenation analyses using the 610 low-copy nuclear genes, leavingCamelliaandPolysporaas another sister genera in the tribe. PhyloNet analyses suggested one reticulation event withinCamelliaandPyrenariarespectively, but no intergeneric reticulations were detected in Theeae. Another introgression was found betweenGordonia lasianthusand the common ancestor of Gordonieae during the Late Oligocene. The existing land bridges (e.g. Bering land bridge) might have facilitated this ancient introgression. Further researches need to be conducted to uncover the interspecific introgression pattern withinCamellia.Ks distribution analyses supported the tea family shared one whole-genome duplication (WGD) event Ad-β, which was recently mapped to the clade containing core Ericales, Primuloids, Polemonioids and Lecythidaceae.
Genomic analysis of response to neoadjuvant chemotherapy in esophageal adenocarcinoma
Authors: Izadi Fereshteh , Sharpe Benjamin P. , Breininger Stella P. , Secrier Maria , Gibson Jane , Walker Robert , Rahman Saqib , Devonshire Ginny , Lloyd Megan A , Walters Zoë S. , Fitzgerald Rebecca C. , Rose-Zerilli Matthew J. J. , Underwood Tim J. 
Published: March 2021

AbstractNeoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (<20%), as is the overall survival benefit at 5 years (5%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1-2 (n=27) and non-responders classified as TRG4-5 (n=38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs 1.70/Mb,P=0.036) and elevated copy number variation in non-responders (282 vs 136/patient,P<0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note,NAV3mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.
Regulatory FOXP3+ T cells in uterine sarcomas are associated with favorable prognosis, low extracellular matrix expression and reduced YAP activation
Authors: Gultekin Okan , Gonzalez-Molina Jordi , Hardell Elin , Moyano-Galceran Lidia , Mitsios Nicholas , Mulder Jan , Kokaraki Georgia , Isaksson Anders , Sarhan Dhifaf , Lehti Kaisa , Carlson Joseph W. 
Published: March 2021

AbstractPurposeUterine sarcomas are rare but deadly malignancies without effective treatment. The goal of this study was to characterize and identify potential mechanisms underlying observed variations in the immune microenvironment of different sarcoma subtypes, using integrated clinicopathological and molecular methods.Experimental designFifty-eight cases of uterine sarcoma with full clinicopathological annotation were analyzed for their immune landscape in the tumor microenvironment, gene, and protein expression. Cases included leiomyosarcoma (LMS; n=13), low-grade endometrial stromal sarcoma (ESS; n=16), undifferentiated uterine sarcoma (UUS; n=26), and YWHAE-FAM22 translocation-bearing ESS (YFAM; n=3). Image analysis was used to quantify immune cells and immune regulatory proteins. Gene ontology and network enrichment analysis of matching transcriptomic data was used to relate over- and under expressed genes to pathways and further to the immune phenotype and clinicopathological findings.ResultsImmune cell characterization revealed overall prevalence of regulatory T cells and the pro-tumor M2-like macrophages. Cytotoxic T cells were only found in ESS and UUS tumors. Expression of immune regulatory proteins was heterogeneous, with PD-L1 being undetectable. Hierarchical clustering of patients showed four immune signatures independent of tumor type, where infiltration of non-exhausted FOXP3+cells and M1-like macrophages were associated with greater overall survival. High CD8+/FOXP3+ratio in UUS and ESS was associated with poor survival and upregulation of extracellular matrix (ECM)-related genes and proteins and YAP nuclear localization.ConclusionsUterine sarcomas present distinct immune signatures with prognostic value, independent of tumor type. This study suggests that the ECM is a potential regulator of the immune microenvironment in uterine sarcomas.
Quantifying evolutionary constraints on the intronic branch point sequence in the bovine and human genome
Authors: Kadri Naveen Kumar , Mapel Xena Marie , Pausch Hubert 
Published: March 2021

AbstractThe branch point sequence is a cis-acting intronic motif required for mRNA splicing. Despite their functional importance, branch point sequences are not routinely annotated. Here we predict branch point sequences in 179,476 bovine introns and investigate their variability using a catalogue of 29.4 million variants detected in 266 cattle genomes. We localize the bovine branch point within a degenerate heptamer “nnyTrAy”. An adenine residue at position 6, that acts as branch point, and a thymine residue at position 4 of the heptamer are more strongly depleted for mutations than coding sequences suggesting extreme purifying selection. We provide evidence that mutations affecting these evolutionarily constrained residues lead to alternative splicing. We confirm evolutionary constraints on branch point sequences using a catalogue of 115 million SNPs established from 3,942 human genomes of the gnomAD database.
Verticillium dahliaeeffector VDAL protects MYB6 from degradation by interacting with PUB25/26 E3 ligases for enhancing Verticillium wilt resistance inArabidopsis
Authors: Ma Aifang , Zhang Dingpeng , Wang Guangxing , Wang Kai , Li Zhen , Gao Yuanhui , Li Hengchang , Bian Chao , Cheng Jinkui , Han Yinan , Yang Shuhua , Gong Zhizhong , Qi Junsheng 
Published: March 2021

ABSTRACTVerticillium wilt is a severe plant disease that causes massive losses in multiple crops. Increasing the plant resistance to Verticillium wilt is a critical challenge worldwide. Here, we report that the hemibiotrophicVerticillium dahliae(V. dahliae)-secreted Asp f2-like protein VDAL causes leaf wilting when applied to cotton leavesin vitro,but enhances the resistance toV. dahliaewhen overexpressed inArabidopsisor cotton without affecting the plant growth and development. VDAL protein interacts withArabidopsisE3 ligases PUB25 and PUB26 (PUBs) and is ubiquitinated by PUBsin vitro. However, VDAL is not degraded by PUB25 or PUB26in planta. Besides, thepub25 pub26double mutant shows higher resistance toV. dahliaethan the wild type. PUBs interact with the transcription factor MYB6 in a yeast two-hybrid screen. MYB6 promotes plant resistance to Verticillium wilt while PUBs ubiquitinate MYB6 and mediate its degradation. VDAL competes with MYB6 for binding to PUBs, and the role of VDAL in increasing Verticillium wilt resistance depends on MYB6. Taken together, these results suggest that plants evolute a strategy to utilize the invaded effector protein VDAL to resist theV. dahliaeinfection without causing a hypersensitive response (HR), Alternatively, in order to take nutrients from host cells, hemibiotrophic pathogens may use some effectors to keep plant cells alive during its infection in order to take nutrients from host cells. This study provides the molecular mechanism for plants increasing disease resistance when overexpressing some effector proteins without inducing HR, and may promote searching for more genes from pathogenic fungi or bacteria to engineer plant disease resistance.One-sentence summaryEctopically expressed VDAL inArabidopsisalleviates the degradation of a positive disease response factor MYB6 through its interaction with PUB25/26 E3 ligases.
RNA polymerase II depletion from the inactive X chromosome territory is not mediated by physical compartmentalization
Authors: Collombet Samuel , Rall Isabell , Dugast-Darzacq Claire , Heckert Alec , Halavatyi Aliaksandr , Le Saux Agnes , Dailey Gina , Darzacq Xavier , Heard Edith 
Published: March 2021

AbstractSub-nuclear compartmentalization has been proposed to play an important role in gene regulation by segregating active and inactive parts of the genome in distinct physical and biochemical environments, where transcription and epigenetic factors are either concentrated or depleted. The inactive X chromosome offers a paradigm for studying sub-nuclear compartmentalization. When the non-codingXistRNA coats the X chromosome, it recruits repressors and chromatin factors that trigger gene silencing, and forms a dense body of heterochromatin from which the transcription machinery appears to be excluded. Phase separation has been proposed to be involved in X-chromosome inactivation (XCI) and might explain exclusion of the transcription machinery by preventing its diffusion into theXist-coated territory. Here, using quantitative fluorescence microscopy and single particle tracking, we show that RNA polymerase II (RNAPII) freely accesses theXistterritory during initiation of XCI, and that its diffusion is not prevented by biophysical constraints. Instead, the apparent depletion of RNAPII is due to the loss of its chromatin bound fraction. These findings demonstrate that initial exclusion of RNA Pol2 from the inactive X is a consequence of its reduced binding rate at the chromatin and gene level, rather than the biophysical compartmentalization of the inactive X heterochromatin domain. The Xist silent compartment is thus a biochemical rather than a biophysical compartment, at least during initiation of XCI.