bluuebunny/crossref_metadata_2025_split huggingface dataset:
Snake Fungal Disease Caused by the Fungal Pathogen Ophidiomyces ophidiicola in Texas
Authors: Lizarraga Alan , Hart Lezley , Nolen Michele , Williams Lance , Glavy Joseph 
Published: April 2022

AbstractThe pathogen Ophidiomyces ophidiicola (O.o.), widely known as the primary cause of snake fungal disease (SFD) has been detected in Texas’s naïve snakes. Our team set out to begin to characterize O. ophidiicola’s spread in east Texas. From July 2019 until October 2021, we sampled 176 snakes across east Texas and detected 27 positives cases (qPCR confirmed 27/176). From a ribbon snake with clear clinical display, we isolated and cultured what we believe to be the Texas isolate of O. ophidiicola. With over 1/10 snakes that may be infected in East Texas, gives credence to the onset of SFD in Texas.
A combinatorial anticancer drug screen identifies off-target effects of epigenetic chemical probes
Authors: Barghout Samir H. , Mann Mandeep K. , Yu Yifan , Schimmer Aaron D. , Schapira Matthieu , Arrowsmith Cheryl H. , Barsyte-Lovejoy Dalia 
Published: April 2022

AbstractAnticancer drug response is determined by genetic and epigenetic mechanisms. To identify the epigenetic regulators of anticancer drug response, we conducted a chemical epigenetics screen using chemical probes that target different epigenetic modulators. In this screen, we tested 31 epigenetic probes in combination with 14 mechanistically diverse anticancer agents and identified 8 epigenetic probes that significantly potentiate the cytotoxicity of TAK-243, a first-in-class ubiquitin-activating enzyme (UBA1) inhibitor evaluated in several solid and hematologic malignancies. These probes are TP-472, GSK-864, A-196, UNC1999, SGC-CBP30 and PFI-4 (and its related analogs GSK6853 and GSK5959), and they target BRD9/7, mutant IDH1, SUV420H1/2, EZH2/1, p300/CBP and BRPF1B, respectively. In contrast to epigenetic probes, negative control compounds did not have a significant impact on TAK-243 cytotoxicity. Potentiation of TAK-243 cytotoxicity was associated with reduced ubiquitylation and induction of apoptosis. Mechanistically, epigenetic probes exerted their potentiation by inhibiting the efflux transporter ABCG2 without inducing significant changes in the ubiquitylation pathways or ABCG2 expression levels. The identified probes shared chemical scaffold similarities with TAK-243 and could potentially interact with ABCG2 as assessed by docking analysis. Based on these data, we have developed a cell-based assay that can quantitatively evaluate ABCG2 inhibition by drug candidates. In conclusion, our study identifies epigenetic chemical probes that profoundly potentiate TAK-243 cytotoxicity through off-target ABCG2 inhibition. We also provide experimental evidence that several negative control compounds cannot exclude a subset of off-target effects of chemical probes. Finally, potentiation of TAK-243 cytotoxicity can serve as a quantitative measure of ABCG2-inhibitory activity.
Ganglioside enriched phospholipid vesicles induce cooperative Aβ oligomerization and membrane disruption
Authors: Saha Jhinuk , Bose Priyankar , Dhakal Shailendra , Ghosh Preetam , Rangachari Vijayaraghavan 
Published: April 2022

ABSTRACTA major hallmark of Alzheimer disease (AD) is the accumulation of extracellular aggregates of amyloid-β (Aβ). Structural polymorphism observed among Aβ fibrils in AD brains seem to correlate with the clinical sub-types suggesting a link between fibril polymorphism and pathology. Since fibrils emerge from a templated growth of low-molecular weight oligomers, understanding the factors affecting oligomer generation is important. The membrane lipids are key factors that influence early stages of Aβ aggregation and oligomer generation, and cause membrane disruption. We have previously demonstrated that conformationally discrete Aβ oligomers can be generated by modulating the charge, composition, chain length of lipids and surfactants. Here, we extend our studies into liposomal models by investigating Aβ oligomerization on large unilamellar vesicles (LUVs) of total brain extracts (TBE), reconstituted lipid rafts (LRs) or 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). Specifically, we varied the vesicle composition by varying the amount of GM1 gangliosides added as a constituent. We found that liposomes enriched in GM1 induce the formation of toxic, low-molecular weight oligomers that are isolable in a lipid-complexed form. Importantly, the data indicate that oligomer formation and membrane disruption are highly cooperative processes. Numerical simulations on the experimental data confirm cooperativity and reveal that GM1-enriched liposomes form twice as many numbers of pores as those without GM1. Overall, this study uncovers mechanisms of cooperativity between oligomerization and membrane disruption under controlled lipid compositional bias, and refocuses the significance of the early stages of Aβ aggregation in polymorphism, propagation, and toxicity in AD.TOC figure
BioAct: Biomedical Knowledge Base Construction using Active Learning
Authors: Wright Dustin , Gentile Anna Lisa , Faux Noel , Beck Kristen L. 
Published: April 2022

AbstractCreating and curating knowledge resources has been a paramount activity in the biomedical domain. In recent years, automated methods for knowledge base construction have flourished and have enabled large scale construction and curation of such resources. In the biological domain, techniques such as next generation sequencing produce new data at exponential rate, making mere manual curation of knowledge resources simply unfeasible. The major technology to automate knowledge base construction is Information Extraction — specifically tasks such as Named Entity Recognition or Relation Extraction. The major hurdle for IE methods is the availability of labelled data for training, which can be prohibitively expensive and challenging to obtain due to the need of domain experts. Active learning aims at minimizing the cost of manual labelling by only requiring it for smaller and more useful portions of the data. With this motivation, we devised a method to quickly construct highly curated datasets to enable biomedical knowledge base construction. The method, named BioAct, is based on a partnership between automatic annotation methods (leveraging SciBERT with other machine learning models) and subject matter experts and uses active learning to create training datasets in the biological domain. The main contribution of this work is twofold; in addition to the BioAct method itself, we publicly release an annotated dataset on antimicrobial resistance, produced by a team of subject matter experts using BioAct. Additionally, we simulate a knowledge base construction task using the MegaRes and CARD knowledge bases to provide insight and lessons learned about the usefulness of the annotated dataset for this task.
Unilateral Perforant Path Transection Does Not Alter Lateral Entorhinal Cortical or Hippocampal CA3 Arc Expression
Authors: Cooper Tara L. , Thompson John J. , Turner Sean M. , Watson Cory , Lubke Katelyn N. , Logan Carly N. , Maurer Andrew P. , Burke Sara N. 
Published: April 2022

ABSTRACTIt is well established that degradation of perforant path fibers is associated with age-related cognitive dysfunction and CA3 hyperactivity. Whether this fiber loss triggers a cascade of other functional changes within the hippocampus circuit has not been causatively established, however. Thus, the current study evaluated the effect of perforant path fiber loss on neuronal activity in CA3 and layer II of the lateral entorhinal cortex (LEC) in relation to mnemonic similarity task performance. Expression of the immediate early gene Arc was quantified in rats that received a unilateral right hemisphere transection of the perforant path or sham surgery that cut the cortex but left the fibers intact. Behavior-related expression of Arc mRNA was measured to test the hypothesis that fiber loss leads to elevated activation of CA3 and LEC neurons, as previously observed in aged rats that were impaired on the mnemonic similarity task. Transection of perforant path fibers, which has previously been shown to lead to a decline in mnemonic similarity task performance, did not alter Arc expression. Arc expression in CA3, however, was correlated with task performance on the more difficult discrimination trials across both surgical groups. These observations further support a link between CA3 activity and mnemonic similarity task performance but suggest the reduced input from the entorhinal cortex to the hippocampus, as observed in old age, does not causatively elevate CA3 activity.
A landscape of differentiated biological processes involved in the initiation of sex differentiation in zebrafish
Authors: Ye Ding , Tu Yi-Xuan , Wang Houpeng , He Mudan , Wang Yaqing , Chen Zhengfang , Chen Zhen-Xia , Sun Yonghua 
Published: April 2022

ABSTRACTZebrafish (Danio rerio) has been used as a promising animal model to study gonadal development and gametogenesis. Although previous studies have identified critical molecules participating in zebrafish gonad differentiation, a landscape view of the biological processes involved in this process is still lacking. Here we isolated intact zebrafish differentiating gonads, at 25 days post-fertilization (dpf) and 30 dpf, and conducted RNA-seq analysis between the juvenile gonads that tended to develop into ovaries or testes. Our study demonstrates that the juvenile ovary and testis at 25 dpf and 30 dpf are different at the level of biological process. During ovary differentiation, the biological processes related to metabolic activities in production of energy and maternal substances, RNA degradation, and DNA repair were enriched. During testis differentiation, the biological processes related to cell proliferation, differentiation, and morphogenesis were enriched, with a total of 15 signaling pathways. Notably, we reveal that the immune-related processes are extensively involved in the regulation of testis development. Overall, this study provides a landscape of differentiated biological processes and novel insights into the initiation of sex differentiation in zebrafish.
The AKT Forkhead box O transcription factor axis regulates human cytomegalovirus replication
Authors: Zhang Hongbo , Domma Anthony J. , Goodrum Felicia D. , Moorman Nathaniel J. , Kamil Jeremy P. 
Published: April 2022

ABSTRACTThe serine/threonine protein kinase AKT is a critical mediator of growth factor signaling that broadly impacts mRNA translation, metabolism, programmed cell death and stress responses. Human cytomegalovirus (HCMV), a large dsDNA virus in the herpesvirus family, dramatically remodels host cell signaling pathways during lytic infection. Here, we show that AKT accumulates in an inactive form during HCMV infection, as indicated by hypo-phosphorylation at Thr308 and Ser473, as well as nuclear localization of FOXO3a. Moreover, we find that expression of constitutively active myristoylated AKT (myr-AKT) causes a 1-log defect in viral replication, accompanied by defects in viral DNA synthesis and viral late gene expression. These findings suggest that HCMV shutoff of AKT is not merely incidental to viral factors such as pUL38 that maintain high levels of mTORC1 activity independently of extracellular growth factor signals. Short interfering RNA knockdown of FOXO3a, but not FOXO1, phenocopied the replication defects seen during expression of myr-AKT, corroborating a role for FOXO3a during HCMV infection. Accordingly, a chimeric FOXO3a-estrogen receptor fusion protein, whose nuclear localization is regulated by the small molecule ligand 4-hydroxytamoxifen instead of AKT activity, rescues virtually all the replication defects induced by myr-AKT expression. Taken together, our results argue that HCMV dampens AKT signaling to promote nuclear localization of FOXO transcription factors, which are required for efficient viral replication.IMPORTANCEEvidence from a diverse herpesvirus infection models suggests that the PI3K / AKT signaling pathway suppresses reactivation from latency, and that inactivation of the pathway stimulates viral lytic replication. Here, we show that AKT accumulates in an inactive state during HCMV infection of lytically permissive cells while the presence of constitutive AKT activity causes substantial viral replication defects. Although AKT phosphorylates a diverse array of cellular substrates, we identify an important role for the Forkhead box class O transcription factors. Our findings show that when FoxO3a nuclear localization is decoupled from its negative regulation by AKT, the viral replication defects observed in the presence of constitutively active AKT are reversed. Collectively, our results reveal that HCMV inactivates AKT to promote the nuclear localization of FOXO transcription factors, which strongly implies that FOXOs play critical roles in transactivating cellular and/or viral genes during infection.
Novel CSF biomarkers of GLUT1 deficiency syndrome: implications beyond the brain’s energy deficit
Authors: Peters Tessa M.A. , Merx Jona , Kooijman Pieter C. , Noga Marek , de Boer Siebolt , van Gemert Loes A. , Salden Guido , Engelke Udo F.H. , Lefeber Dirk J. , van Outersterp Rianne E. , Berden Giel , Boltje Thomas J. , Artuch Rafael , Pías Leticia , García-Cazorla Ángeles , Barić Ivo , Thöny Beat , Oomens Jos , Martens Jonathan , Wevers Ron A. , Verbeek Marcel M. , Coene Karlien L.M. , Willemsen Michèl A.A.P. 
Published: April 2022

AbstractWe used next-generation metabolic screening to identify new biomarkers for improved diagnosis and pathophysiological understanding of glucose transporter type 1 deficiency syndrome (GLUT1DS), comparing metabolic CSF profiles from 11 patients to those of 116 controls. This confirmed decreased CSF glucose and lactate levels in patients with GLUT1DS and increased glutamine at group level. We identified three novel biomarkers significantly decreased in patients, namely gluconic + galactonic acid, xylose-α1-3-glucose and xylose-α1-3-xylose-α1-3-glucose, of which the latter two have not previously been identified in body fluids. CSF concentrations of gluconic + galactonic acid may be reduced as these metabolites could serve as alternative substrates for the pentose phosphate pathway. Xylose-α1-3-glucose and xylose-α1-3-xylose-α1-3-glucose may originate from O-glycosylated proteins; their decreased levels are hypothetically the consequence of insufficient glucose, one of two substrates for O-glucosylation. Since many proteins are O-glucosylated, this deficiency may affect cellular processes and thus contribute to GLUT1DS pathophysiology. The novel CSF biomarkers have the potential to improve the biochemical diagnosis of GLUT1DS. Our findings imply that brain glucose deficiency in GLUT1DS may cause disruptions at the cellular level that go beyond energy metabolism, underlining the importance of developing treatment strategies that directly target cerebral glucose uptake.
mRNA-1273 but not BNT162b2 induces antibodies against polyethylene glycol (PEG) contained in mRNA-based vaccine formulations
Authors: Carreño Juan Manuel , Singh Gagandeep , Tcheou Johnstone , Srivastava Komal , Gleason Charles , Muramatsu Hiromi , Desai Parnavi , Aberg Judith A. , Miller Rachel L. ,   PARIS study group, Pardi Norbert , Simon Viviana , Krammer Florian 
Published: April 2022

AbstractTwo messenger RNA (mRNA)-based vaccines are widely used globally to prevent coronavirus disease 2019 (COVID-19). Both vaccine formulations contain PEGylated lipids in their composition, in the form of polyethylene glycol [PEG] 2000 dimyristoyl glycerol for mRNA-1273, and 2 [(polyethylene glycol)-2000]-N,N-ditetradecylacetamide for BNT162b2. It is known that some PEGylated drugs and products for human use that contain PEG, are capable of eliciting immune responses, leading to detectable PEG-specific antibodies in serum. In this study, we determined if any of the components of mRNA-1273 or BNT162b2 formulations elicited PEG-specific antibody responses in serum by enzyme linked immunosorbent assay (ELISA). We detected an increase in the reactivity to mRNA vaccine formulations in mRNA-1273 but not BNT162b2 vaccinees’ sera in a prime-boost dependent manner. Furthermore, we observed the same pattern of reactivity against irrelevant lipid nanoparticles from an influenza virus mRNA formulation and found that the reactivity of such antibodies correlated well with antibody levels against high and low molecular weight PEG. Using sera from participants selected based on the vaccine-associated side effects experienced after vaccination, including delayed onset, injection site or severe allergic reactions, we found no obvious association between PEG antibodies and adverse reactions. Overall, our data shows a differential induction of anti-PEG antibodies by mRNA-1273 and BNT162b2. The clinical relevance of PEG reactive antibodies induced by administration of the mRNA-1273 vaccine, and the potential interaction of these antibodies with other PEGylated drugs remains to be explored.
Stepwise origin and evolution of a transcriptional activator and repressor system integrating nutrient signaling in plants
Authors: Jamsheer K Muhammed , Gazara Rajesh Kumar , Jindal Sunita , Kumar Manoj 
Published: April 2022

AbstractPlants possess a unique transcriptional regulatory system in which two related MYB-related transcription factors (TFs) coordinate gene expression according to phosphate (Pi) and nitrogen (N) availability. The Phosphorus Starvation Response (PSR) type TFs are transcriptional activators integrating the cellular Pi sensing machinery and gene regulation majorly under Pi starvation. The Hypersensitivity To Low Pi-Elicited Primary Root Shortening (HRS) type TFs are transcriptional repressors integrating the Pi and N availability signals through different feedback loops. They are highly connected through multiple signaling loops to finetune the transcriptional responses according to nutrient availability. Molecular functions of these TFs are fairly uncovered in model systems; however, how plants evolved this activator-repressor system is currently unknown. In this study, using sensitive evolutionary analysis, we identified a stepwise origin of the PSR-HRS regulatory system in plants. The PSR TFs were originated before the split of Prasinodermophyta and Chlorophyta. The HRS TFs were originated later in the Streptrophycean algae. We also identified the asymmetric expansion of this TF repertoire in land plants majorly shaped by genome duplication and triplication events. The phylogenetic reconstruction coupled with motif analysis revealed that the origin of the specific accessory motifs is a major contributing factor in the functional divergence which led to the evolution of different sub-families preceding the angiosperm radiation. The spatiotemporal gene expression analysis in different developmental stages and nutrient availability conditions in angiosperms identified a critical role of expression divergence in shaping the functions of these TF families which is essential for adaptive plasticity of plants.
Chlamydia trachomatis effector Dre1 interacts with dynactin to reposition host organelles during infection
Authors: Sherry Jessica , Dolat Lee , McMahon Eleanor , Swaney Danielle L. , Bastidas Robert J. , Johnson Jeffrey R. , Valdivia Raphael H. , Krogan Nevan J. , Elwell Cherilyn A. , Engel Joanne N. 
Published: April 2022

AbstractChlamydia trachomatis is an obligate intracellular pathogen that replicates within a specialized membrane-bound compartment, called the inclusion. Chlamydia species express a unique class of effectors, Incs, which are translocated from the bacteria by a Type III secretion system and are inserted into the inclusion membrane where they modulate the host-bacterium interface. C. trachomatis repositions specific host organelles during infection to acquire nutrients and evade host cell surveillance, however the bacterial and host proteins controlling these processes are largely unknown. Here, we identify an interaction between the host dynactin complex and the C. trachomatis Inc CT192 (CTL0444), hereafter named Dre1 for Dynactin Recruiting Effector 1. We show that dynactin is recruited to the inclusion in a Dre1-dependent manner and that loss of Dre1 diminishes the recruitment of specific host organelles, including the centrosome, mitotic spindle, and Golgi apparatus to the inclusion. Inactivation of Dre1 results in decreased C. trachomatis fitness in cell-based assays and in a mouse model of infection. By targeting particular functions of the versatile host dynactin complex, Dre1 facilitates re-arrangement of certain organelles around the growing inclusion. Our work highlights how C. trachomatis employs a single effector to evoke specific, large-scale changes in host cell organization that establish an intracellular replicative niche without globally inhibiting host cellular function.
Performance Comparison Of Agilent New SureSelect All Exon v8 Probes With v7 Probes For Exome Sequencing
Authors: Belova Vera , Shmitko Anna , Pavlova Anna , Afasizhev Robert , Cheranev Valery , Tabanakova Anastasia , Ponikarovskaya Natalya , Rebrikov Denis , Korostin Dmitriy 
Published: April 2022

AbstractExome sequencing may become routine in health care it increases the chance of pinpointing the genetic cause of an individual patient’s condition and thus making an accurate diagnosis. It is important for facilities providing genetic services to keep track of changes in the technology of exome capture in order to maximize throughput while reducing cost per sample. In this study, we focused on comparing the newly released exome probe set Agilent SureSelect Human All Exon v8 and the previous probe set v7. In preparation for higher throughput of exome sequencing using the DNBSEQ-G400, we evaluated target design, coverage statistics, and variants across these two different exome capture products. Although the target size of the v8 design has not changed much compared to the v7 design (35.24 Mb vs 35.8 Mb), the v8 probe design allows you to call more of SNVs (+3.06%) and indels (+8.49%) with the same number of raw reads per sample on the common target regions (34.84 Mb). Our results suggest that the new Agilent v8 probe set for exome sequencing yields better data quality than the current Agilent v7 set.
Parallel lipid-carried epitope pillars enhance stimulation of chimeric antigen receptor T cells
Authors: Tong Jiao , Lai Hanyu , Wang Jingxia , Zhu Chenxi , Mai Xinjia , Zhou Dapeng 
Published: April 2022

AbstractChimeric antigen receptor T cells are genetically engineered to express a specific T cell receptor of interest, such as to target a cancer-specific antigen. Signaling events in chimeric antigen receptor T cells are essential for their proliferation, survival, and function. To achieve optimal antitumor efficacy, signaling motifs as well as the structure of the transmembrane domain of the chimeric antigen receptor have to be carefully designed. However, it remains unclear whether the arrangement, and therefore the movement and elasticity, of tumor antigens influence their stimulation of chimeric antigen receptor T cells. Here we show that MUC1 molecules tethered to a glycosylphosphatidylinositol anchor drastically increased its stimulation of chimeric antigen receptor T cells. In particular, MUC1 molecules containing one tandem repeat sequence showed significantly greater stimulatory activity than five tandem repeat sequences. Thus glycosylphosphatidylinositol-anchored, tumor antigen epitope pillars in parallel are attractive targets for the design of chimeric antigen receptor T cells. These novel findings, which we propose as the parallel lipid-carried epitope model, emphasize the importance of epitope arrangement in selecting highly effective chimeric antigen receptor T cells, potentially revolutionizing the applicability of this therapy. Furthermore, our data have implications for the necessity of methodologies to measure the elasticity, movement, and density of antigen pillars in parallel, as key tools to guide future chimeric antigen receptor T cell therapy.