bluuebunny/crossref_metadata_2025_split huggingface dataset:
TAD hierarchy restricts poised LTR activation and loss of TAD hierarchy promotes LTR co-option in cancer
Authors: Wong Elissa W. P. , Sahin Merve , Yang Rui , Lee UkJin , Zhan Yingqian A. , Misra Rohan , Tomas Fanny , Alomran Nawaf , Polyzos Alexander , Lee Cindy J. , Trieu Tuan , Fundichely Alexander M. , Wiesner Thomas , Rosowicz Andrew , Cheng Shuyuan , Liu Christina , Lallo Morgan , Merghoub Taha , Hamard Pierre-Jacques , Koche Richard , Khurana Ekta , Apostolou Effie , Zheng Deyou , Chen Yu , Leslie Christina S. , Chi Ping 
Published: June 2024

AbstractTransposable elements (TEs) are abundant in the human genome, and they provide the sources for genetic and functional diversity. The regulation of TEs expression and their functional consequences in physiological conditions and cancer development remain to be fully elucidated. Previous studies suggested TEs are repressed by DNA methylation and chromatin modifications. The effect of 3D chromatin topology on TE regulation remains elusive. Here, by integrating transcriptome and 3D genome architecture studies, we showed that haploinsufficient loss ofNIPBLselectively activates alternative promoters at the long terminal repeats (LTRs) of the TE subclasses. This activation occurs through the reorganization of topologically associating domain (TAD) hierarchical structures and recruitment of proximal enhancers. These observations indicate that TAD hierarchy restricts transcriptional activation of LTRs that already possess open chromatin features. In cancer, perturbation of the hierarchical chromatin topology can lead to co-option of LTRs as functional alternative promoters in a context-dependent manner and drive aberrant transcriptional activation of novel oncogenes and other divergent transcripts. These data uncovered a new layer of regulatory mechanism of TE expression beyond DNA and chromatin modification in human genome. They also posit the TAD hierarchy dysregulation as a novel mechanism for alternative promoter-mediated oncogene activation and transcriptional diversity in cancer, which may be exploited therapeutically.
Data rescue in high-motion youth cohorts for robust and reproducible brain-behavior relationships
Authors: Ramduny Jivesh , Vanderwal Tamara , Kelly Clare 
Published: June 2024

AbstractRecognition of the detrimental impact of participant motion on functional connectivity measures has led to the adoption of increasingly stringent quality control standards to minimize potential motion artifacts. These stringent standards can lead to the exclusion of many participants, creating a tension with a countervailing requirement for large sample sizes that can provide adequate statistical power, particularly for brain-behavior association studies. Here, we test and validate two techniques aimed at mitigating the impact of head motion on functional connectivity estimates, and show that these techniques enable the retention of a substantial proportion of participants who would otherwise be excluded based on motion criteria, such as a minimum mean framewise displacement (FD) threshold. Specifically, we first show that functional connectomes computed using time series data that have been ordered according to motion (i.e., framewise displacement — FD) and (1) subsetted to include the lowest-motion time points (“motion ordered”) or (2) subsetted and resampled (“bagged”) are reproducible, in that they enable the successful identification of an individual from a group using functional connectome fingerprinting. Second, we demonstrate that motion-ordered and bagged functional connectomes yield robust brain-behavior associations, which, when examined as a function of sample size, are comparable to those obtained using the standard full time series. Finally, we show that the utility of both approaches lies in maximizing participant inclusivity by allowing for the retention of high-motion participants that would otherwise be discarded. Given equivalent performance of the two approaches across these tests of reproducibility, validity, and utility, we conclude by recommending motion-ordering to enable data rescue, maximize inclusivity, and address the need for adequately powered samples in functional connectivity research, while maintaining stringent data quality standards. While our findings were reproducible across different head motion thresholds and edges in the functional connectome, we outline possibilities for further validation and assessment of generalization using other behavioral phenotypes and consortia datasets.
Preclinical study of the human recombinant Erythropoietin (GBPD002) compared with Eprex®
Authors: Nag Kakon , Mohiuddin Mohammad , Khan Maksudur Rahman , Kumar Samir , Sarker Enamul Haq , Roy Rony , Biswas Bipul Kumar , Barman Uttam , Haq Sheik Rejaul , Bachar Sitesh Chandra , Sultana Naznin 
Published: June 2024

AbstractErythropoietin (EPO) is a glycoprotein that an essential growth factor for erythroid progenitors at the bone marrow, which appears in blood as a response to hypoxia. It is produced mainly by the kidneys; and its biosynthesis and release are stimulated by the reduction of tissue oxygenation and/or the reduction of the mass of erythrocytes. Here, we report the results of the preclinical evaluation of the safety of ‘GBPD002’ a recombinant human erythropoietin (rhEPO) developed by the Globe Biotech Limited, Bangladesh, through a comparative study of acute toxicity with Eprex®, a commercial homologue from Janssen, UK. The product was administered subcutaneously into Wistar rats, at 500 lU/kg of therapeutic dose (TD) and 3 times of TD for the single dose toxicity study on 14 consecutive days and 125 UL/kg, 250 UL/kg, 500 UL/kg, 750 UL/kg, 1000 UL/kg, 1250 UL/kg and 1500 UL/kg of GBPD002 and Eprex®on 7 consecutive days respectively for the repeated dose toxicity study. Hematological and biochemical parameters were measured for all test subjects before first dose injection and the day after last dose injection of the both studies. Necropsy and histopathology of representative subjects from each group were also observed to find any pathological significance like degeneration or cellular necrosis in internal organs such as kidney, liver, lung and spleen of any rat under experiment. Both GBPD002 and Eprex®comparative toxicology studies revealed similar pharmacologically driven mechanisms of toxicity, which is statistically insignificant (p>0.05). Though hematology parameter values stayed within the normal range during the assay period but the high count of hemoglobin and high hematocrit (P<0.05), together with the decrease in white blood cell, confirm the therapeutic effect of Erythropoietin in both studies. Moreover, in both studies, the initial and final values of aspartate aminotransferase, alanine aminotransferase and blood urea nitrogen were also found similar (p>0.05) for both GBPD002 and Eprex®in the study. The study clearly established that the toxicological profile of “GBPD002” and Eprex®, administered subcutaneously, were similar and related to the known pharmacology of erythropoietin alfa; hereby, demonstrating the proof of ‘totality’ and ‘no residual uncertainty’ between “GBPD002” and Eprex®. Therefore, “GBPD002” and Eprex®shall be administered interchangeably in relevant indications.
Antiviral Drug Discovery with an Optimized Biochemical Dengue Protease Assay: Improved Predictive Power for Antiviral Efficacy
Authors: Lang Johannes , Dutta Sudip Kumar , Reichert Lisa , Kühl Nikos , Martina Byron , Klein Christian D. 
Published: June 2024

AbstractThe viral NS2B-NS3 protease is a promising drug target to combat dengue virus (DENV) and other emerging flaviviruses. The discovery of novel DENV protease inhibitors with antiviral efficacy is hampered by the low predictive power of biochemical assays. We herein present a comparative evaluation of biochemical DENV protease assay conditions and their benchmarking against antiviral efficacy and a protease-specific reporter gene assay. Variations were performed with respect to pH, type of detergent, buffer, and substrate. The revised assay conditions were applied in a medicinal chemistry effort aimed at phenylglycine protease inhibitors. This validation study demonstrated a considerably improved predictive power for antiviral efficacy in comparison to previous approaches. An extensive evaluation of phenylglycine-based DENV protease inhibitors with highly diverseN-terminal caps indicates further development potential in this structural region. Furthermore, the phenylglycine moiety may be less essential than previously assumed, providing a development option towards reduced lipophilicity and thereby an improved pharmacokinetic and toxicity profile.Graphical Abstract
A New Halogenated Solvent For Ex Vivo Magnetic Resonance Imaging
Authors: Honnorat Nicolas , Mojtabai Mariam , Li Jinqi , Smith Morgan , Seshadri Sudha , Bieniek Kevin , Habes Mohamad 
Published: June 2024

AbstractMagnetic Resonance Imaging (MRI) is a prominent non-invasive imaging technique. Structural MRI, the most common MRI modality, interacts with the hydrogen nuclei in samples, also called protons. When using structural MRI to scan ex vivo tissues, the biological samples are often placed in proton-free liquids containing no hydrogen atoms to obtain clean images that do not require background removal. Several proton-free liquids have been used during the last two decades, but they are all per- and polyfluoroalkyl substances (PFAS), and PFAS have recently been recognized as a significant environmental concern. To find replacement solutions, new families of proton-free liquids without fluorine atoms will need to be investigated for stability and safety and to check potential effects on subsequent tissue staining. The present work is a preliminary step in that direction. We validate the MRI properties of a broadly used, affordable, non-PFAS, proton-free solvent that has, as far as we know, never been considered for ex vivo MRI scanning.
How the Tulip Breaking Virus Creates Striped Tulips
Authors: Wong Aidan , Carrero Gustavo , Hillen Thomas 
Published: June 2024

AbstractThe beauty of tulips has enchanted mankind for centuries. The striped variety has attracted particular attention for its intricate and unpredictable patterns. A good understanding of the mechanism that drives the striped pattern formation of thebroken tulipshas been missing since the 17th century. It is known since 1928 that these patterned tulips suffer from a viral infection by thetulip breaking virus. Here, we present a mathematical model to understand how a virus infection of the petals can lead to stripes, thereby solving a 350 year old mystery. The model, which describes the viral inhibition of pigment expression (anthocyanins) and their interaction with viral reproduction, incorporates a pattern formation mechanism identified as anactivator-substratemechanism, similar to the well-known Turing instability, working together with a Wolpert’s positional information mechanism. The model is solved on a growing tulip petal shaped domain, whereby we introduce a new method to describe the tulip petal growth explicitly. This work contributes to the theory of pattern formation of reaction-diffusion systems on growing domains applied to the fields of virology and botany.
Joint estimation of the effective reproduction number and daily incidence in the presence of aggregated and missing data
Authors: Conway Eamon , Mueller Ivo 
Published: June 2024

AbstractDisease surveillance is an integral component of government policy, allowing public health professionals to monitor transmission of infectious diseases and appropriately apply interventions. To aid with surveillance efforts, there has been extensive development of mathematical models to help inform policy decisions, However, these mathematical models rely upon data streams that are expensive and often only practical for high income countries. With a growing focus on equitable public health tools there is a dire need for development of mathematical models that are equipped to handle the data stream challenges prevalent in low and middle income countries, where data is often incomplete and subject to aggregation. To address this need, we develop a mathematical model for the joint estimation of the effective reproduction number and daily incidence of an infectious disease using incomplete and aggregated data. Our investigation demonstrates that this novel mathematical model is robust across a variety of reduced data streams, making it suitable for application in diverse regions.Author summaryMonitoring the transmission of infectious diseases is an important part of government policy that is often hindered by limitations in data streams. This is especially true in low and middle income countries where health sectors have less funding. In this work we develop a mathematical model to enhance disease surveillance by overcoming these data limitations, providing accurate inferences of relevant epidemiological parameters.
Immunoglobulin A Carries SulfatedN-glycans Primarily at the Tailpiece Site – An Oxonium-Ion-Guided Approach for Site-SpecificN-glycan Identification
Authors: Zuniga-Banuelos Frania J. , Lemke Greta , Hoffmann Marcus , Reichl Udo , Rapp Erdmann 
Published: June 2024

AbstractSulfatedN-glycans from human immunoglobulin A (IgA) were recently discovered via glycomic approaches. However, their site-specific description is still pending. CertainN-glycan structures at specificN-glycosylation sites in IgA are crucial for microbial neutralization and effector functions. For instance, sialylatedN-glycans on the C-terminal tailpiece mediate anti-viral activity by interfering with sialic-acid-binding viruses. SulfatedN-glycan epitopes can be ligands for viral proteins and thus play a role in the immune response. In this study, we performed a site-specific screening for sulfatedN-glycans in two commercially available human serum IgA samples employing an in-depthN-glycoproteomic approach, previously developed by us. We found evidence of complex-type and hybrid-typeN-glycans containing sulfatedN-acetylhexosamine (sulfated HexNAc) attached to theN-glycosylation sites in the tailpiece and the CH2 domain of both IgA subclasses. A detailed comparison of theN-glycosylation profiles of human serum IgA samples from two suppliers showed suchN-glycans with sulfated HexNAc consistently in higher abundance in the tailpiece region. Surprisingly, also complex-typeN-glycan compositions bearingO-acetylated sialic acid were identified in the tailpiece. These findings have not been described before for a site-specific glycopeptide analysis. Overall, our work provides a methodology for performing a dedicated site-specific search for sulfated andO-acetylatedN-glycans that can be easily transferred, e.g. to human IgA derived from mucosal tissues, milk, or saliva. Our future aim is to include sulfatedN-glycans into longitudinal studies of IgAN-glycosylation and to investigate their role as a biomarker and a treatment option.Abstract Figure
Analyses of trait evolution and diversification reveal multiple adaptive periods in the fungal orderHymenochaetales
Authors: Wang Xue-Wei , Varga Torda , Li Qiu-Shi , Nagy László G. , Zhou Li-Wei 
Published: June 2024

AbstractMushroom-forming fungi (Agaricomycetes) represent one of the most speciose and morphologically diverse life forms, which radiated into most niches on Earth and evolved diverse morphologies and life histories. The orderHymenochaetalescomprises a species-rich group of important wood decayers and tree parasites, however, patterns of macroevolution across the order and thus the origins of key traits, such as pathogenicity are currently unknown. Here, using a novel, nearly comprehensive phylogeny of theHymenochaetales, we show that its evolution has been shaped by an early adaptive period, followed by a general rate slowdown interrupted by local rapid radiations in the Cretaceous. We inferred that the ancestor of the order has undergone rapid phenotypic diversification into a range of morphologies and lifestyles, of which crust-like morphologies and ‘pileate-sessile’ forms typical of bracket-fungi became dominant among extant taxa. Net diversification rate showed significant correlations with paleoclimate, morphological and ecological traits, however, teasing apart the contributions of individual clades revealed that these were mostly driven by the Mid-late Cretaceous rapid radiation of the genusPhylloporia, a diverse group of plant parasites. Together, this study unraveled a complex evolutionary history of theHymenochaetalesand uncovered novel patterns of phenotype evolution and diversification in mushroom-forming fungi.
A Pluripotent Stem Cell Platform for in Vitro Systems Genetics Studies of Mouse Development
Authors: Glenn Rachel A. , Do Stephanie C. , Guruvayurappan Karthik , Corrigan Emily K. , Santini Laura , Medina-Cano Daniel , Singer Sarah , Cho Hyein , Liu Jing , Broman Karl , Czechanski Anne , Reinholdt Laura , Koche Richard , Furuta Yasuhide , Kunz Meik , Vierbuchen Thomas 
Published: June 2024

SUMMARYThe directed differentiation of pluripotent stem cells (PSCs) from panels of genetically diverse individuals is emerging as a powerful experimental system for characterizing the impact of natural genetic variation on developing cell types and tissues. Here, we establish new PSC lines and experimental approaches for modeling embryonic development in a genetically diverse, outbred mouse stock (Diversity Outbred mice). We show that a range of inbred and outbred PSC lines can be stably maintained in the primed pluripotent state (epiblast stem cells -- EpiSCs) and establish the contribution of genetic variation to phenotypic differences in gene regulation and directed differentiation. Using pooledin vitrofertilization, we generate and characterize a genetic reference panel of Diversity Outbred PSCs (n = 230). Finally, we demonstrate the feasibility of pooled culture of Diversity Outbred EpiSCs as “cell villages”, which can facilitate the differentiation of large numbers of EpiSC lines for forward genetic screens. These data can complement and inform similar efforts within the stem cell biology and human genetics communities to model the impact of natural genetic variation on phenotypic variation and disease-risk.
Signal transduction pathways controllingIns2gene activity and beta cell state transitions
Authors: Chu Chieh Min Jamie , Sabbineni Bhavya , Cen Haoning Howard , Hu Xiaoke , Sun WenQing Grace , Brownrigg George P. , Xia Yi Han , Rogalski Jason , Johnson James D. 
Published: June 2024

SummaryPancreatic β cells exist in low and high insulin gene activity states that are dynamic on a scale of hours to days. Here, we used live 3D imaging, mass spectrometry proteomics, and targeted perturbations of β cell signaling to comprehensively investigateIns2(GFP)HIGHandIns2(GFP)LOWβ cell states. We identified the twoIns2gene activity states in intact isolated islets and showed that cells in the same state were more likely to be nearer to each other. We report the proteomes of pure β cells to a depth of 5555 proteins and show that β cells with highIns2gene activity had reduced β cell immaturity factors, as well as increased translation. We identified activators of cAMP signaling (GLP1, IBMX) as powerful drivers of transitions fromIns2(GFP)LOWto theIns2(GFP)HIGHstates. Okadaic acid and cyclosporine A had the opposite effects. This study provides new insight into the proteomic profiles and regulation of β cell states.
Single nucleus transcriptomics, pharmacokinetics, and pharmacodynamics of combined CDK4/6 and mTOR inhibition in a phase 0/1 trial of recurrent high-grade glioma
Authors: Johnson Kevin C. , Tien An-Chi , Jiang Jun , McNamara James , Chang Yu-Wei , Montgomery Chelsea , DeSantis Anita , Elena-Sanchez Leonel , Fujita Yoko , Kim Seongho , Spitzer Avishay , Gabriel Paul , Flynn William F. , Courtois Elise T. , Hong Amy , Harmon Jocelyn , Umemura Yoshie , Tovmasyan Artak , Li Jing , Mehta Shwetal , Verhaak Roel , Sanai Nader 
Published: June 2024

ABSTRACTOutcomes for adult patients with a high-grade glioma continue to be dismal and new treatment paradigms are urgently needed. To optimize the opportunity for discovery, we performed a phase 0/1 dose-escalation clinical trial that investigated tumor pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics following combined ribociclib (CDK4/6 inhibitor) and everolimus (mTOR inhibitor) treatment in recurrent high-grade glioma. Patients with a recurrent high-grade glioma (n = 24) harboring 1)CDKN2A/Bdeletion orCDK4/6amplification, 2)PTENloss orPIK3CAmutations, and 3) wild-type retinoblastoma protein (Rb) were enrolled. Patients received neoadjuvant ribociclib and everolimus treatment and no dose-limiting toxicities were observed. The median unbound ribociclib concentrations in Gadolinium non-enhancing tumor regions were 170 nM (range, 65 – 1770 nM) and 634 nM (range, 68 – 2345 nM) in patients receiving 5 days treatment at the daily dose of 400 and 600 mg, respectively. Unbound everolimus concentrations were below the limit of detection (< 0.1 nM) in both enhancing and non-enhancing tumor regions at all dose levels. We identified a significant decrease in MIB1 positive cells suggesting ribociclib-associated cell cycle inhibition. Single nuclei RNAseq (snRNA) based comparisons of 17 IDH-wild-type on-trial recurrences to 31 IDH-wild-type standard of care treated recurrences data demonstrated a significantly lower fraction of cycling and neural progenitor-like (NPC-like) malignant cell populations. We validated the CDK4/6 inhibitor-directed malignant cell state shifts using three patient-derived cell lines. The presented clinical trial highlights the value of integrating pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics to assess treatment effects in phase 0/1 surgical tissues, including malignant cell state shifts.ClinicalTrials.govidentifier:NCT03834740.
γ-secretase facilitates retromer-mediated retrograde transport
Authors: Takeo Yuka , Crite Mac , DiMaio Daniel 
Published: June 2024

AbstractThe retromer complex mediates retrograde transport of protein cargos from endosomes to the trans-Golgi network (TGN). γ-secretase is a multisubunit protease that cleaves the transmembrane domain of its target proteins. Mutations in genes encoding subunits of retromer or γ-secretase can cause familial Alzheimer disease (AD) and other degenerative neurological diseases. It has been reported that retromer interacts with γ-secretase, but the consequences of this interaction are not known. Here, we report that retromer-mediated retrograde protein trafficking in cultured human epithelial cells is impaired by inhibition of γ-secretase activity or by genetic elimination of γ-secretase. γ-secretase inhibitor XXI and knockout of PS1, the catalytic subunit of γ-secretase, inhibit endosome to TGN trafficking of retromer-dependent retrograde cargos, divalent metal transporter 1 isoform II (DMT1-II), cation-independent mannose-6-phosphate receptor (CIMPR), and shiga toxin. Trafficking of retromer-independent cargos, such as cholera toxin and a CIMPR mutant that does not bind to retromer was not affected by γ-secretase inhibition. XXI treatment and PS1 KO inhibit interaction of γ-secretase with retromer but do not inhibit the association of cargo with retromer or with γ-secretase in intact cells. Similarly, these treatments do not affect the level of Rab7-GTP, which regulates retromer-cargo interaction. These results suggest that the γ-secretase-retromer interaction facilitates retromer-mediated retrograde trafficking.