bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nonlinear effect of light intensity on normal axial development of rhesus monkeys
Authors: Hu Ying-Zhou , Yang Hua , Wu Jing , Li Hao , Lv Long-Bao , Zhu Zhu , Zhou Lu-Yao , Zhang Yu-Hua , Yan Fang-Fang , Fan Shu-Han , Li Cheng-Yu , Wang Shu-Xiao , Zhao Jian-Ping , Qi Qiang , Huang Chang-Bing , Hu Xin-Tian 
Published: July 2022

AbstractPurposeTo investigate the effects of different indoor lighting intensity (500 lx, 750 lx and 1,000 lx) on normal ocular axial length growth by using juvenal rhesus monkeys.MethodsTwenty-four juvenile monkeys were exposed continuously to normal intensity light (NIL, 500 lx, n=16), medium intensity light (MIL, 750 lx, n=8) and high intensity light (HIL, 1 000 lx, n=8), with a same CCT value (about 3000 K) for 246 days. Axial length, anterior chamber depth, corneal curvature radius were measured at about a monthly interval.ResultsAfter 246 days of light exposure, the growth of axial length of the MIL group (750 lx) were 0.151 ± 0.081 mm and 0.139 ± 0.070 mm in the right and left eyes, respectively, and significantly larger in comparison with the NIL group (500lx, OD: 0.068 ± 0.055 mm, OS: 0.074 ± 0.057 mm) and the HIL group (1000lx,OD:0.063 ± 0.093 mm, OS: 0.084 ± 0.052 mm) monkeys. This effect was stable and robust during the whole experimental period.ConclusionThe effects of different intensity lighting on normal ocular axial development was not linear as most people currently think. We must be cautious when it comes to elevate light intensity in classrooms. Whether this conclusion is correct under lights of other CCT value needs further study.
Meiotic resetting of the cellular Sod1 pool is driven by protein aggregation, degradation, and transient LUTI-mediated repression
Authors: Wende Helen M. Vander , Gopi Mounika , Onyundo Megan , Medrano Claudia , Adanlawo Temiloluwa , Brar Gloria A. 
Published: July 2022

ABSTRACTGametogenesis requires packaging of the cellular components needed for the next generation. In budding yeast, this process includes degradation of many mitotically stable proteins, followed by their resynthesis. Here, we show that one such case—Superoxide dismutase 1 (Sod1), a protein that commonly aggregates in human ALS patients—is regulated by an integrated set of events, beginning with the formation of pre-meiotic Sod1 aggregates. This is followed by degradation of a subset of the prior Sod1 pool and clearance of Sod1 aggregates. As degradation progresses, Sod1 protein production is transiently blocked during mid-meiotic stages by transcription of an extended and poorly translated SOD1 mRNA isoform, SOD1LUTI. Expression of SOD1LUTI is induced by the Unfolded Protein Response, and it acts to repress canonical SOD1 mRNA expression. SOD1LUTI is no longer expressed following the meiotic divisions, enabling a resurgence of canonical mRNA and synthesis of new Sod1 protein such that gametes inherit a full complement of this important enzyme that is essential for gamete viability. Altogether, this work reveals meiosis to be an unusual cellular context in which Sod1 levels are tightly regulated. Our findings also suggest that further investigation of Sod1 during yeast gametogenesis could shed light on conserved aspects of its aggregation and degradation that could have implications for our understanding of human disease.
Single-Cell RNA-seq of Heart Reveals Intercellular Communication Drivers of Myocardial Fibrosis in Diabetic Mice
Authors: Li Wei , Lou Xinqi , Zha Yingjie , Zha Jun , Hong Lei , Xie Zhanli , Yang Shudi , Wang Chen , An Jianzhong , Zhang Zhenhao , Qiao Shigang 
Published: July 2022

AbstractDiabetes-induced cardiomyopathy is characterized by myocardial fibrosis as a main pathology. In-depth study of cardiac heterogeneity and cell-to-cell interactions will help to reveal the pathogenesis of diabetic myocardial fibrosis and provide potential targets for the treatment of this disease. Here, we insighted into the intercellular communication drivers underlying myocardial fibrosis in mouse heart with high-fat-diet (HFD)/streptozotocin (STZ)-induced diabetes at single-cell resolution. Intercellular and protein-protein interaction networks of fibroblasts and macrophages, endothelial cells, as well as fibroblasts and epicardial cells reveal critical changes in ligand-receptor interactions such as Pdgf(s)-Pdgfra and Efemp1-Egfr, which promote the development of a profibrotic microenvironment during diabetes progression and confirm that specific inhibition of Pdgfra axis can significantly improve diabetic myocardial fibrosis. We further identified the phenotypically distinct Hrchi and Postnhi fibroblast subpopulations that are associated with pathological extracellular matrix remodeling, of which Hrchi fibroblasts are the most profibrogenic under diabetic conditions. Finally, we validated the role of Itgb1 hub gene mediated intercellular communication drivers of diabetic myocardial fibrosis in Hrchi fibroblasts, and confirmed the result by AAV9-mediated Itgb1 knockdown in the heart of diabetic mice. In summary, cardiac cell mapping provides novel insights into intercellular communication drivers underlying pathological extracellular matrix remodeling during diabetic myocardial fibrosis.
Imaginal disc growth factors areDrosophilaChitinase-like Proteins with roles in morphogenesis and CO2response
Authors: Sustar Anne , Strand Liesl , Zimmerman Sandra , Berg Celeste 
Published: July 2022

AbstractChitinase-like proteins (CLPs) are members of the family 18 glycosyl hydrolases, which include chitinases and the enzymatically inactive CLPs. A mutation in the enzyme’s catalytic site, conserved in vertebrates and invertebrates, allowed CLPs to evolve independently with functions that do not require chitinase activity. CLPs normally function during inflammatory responses, wound healing, and host defense, but when they persist at excessive levels at sites of chronic inflammation and in tissue-remodeling disorders, they correlate positively with disease progression and poor prognosis. However, little is known about their physiological function.Drosophila melanogasterhas six CLPS, termed Imaginal disc growth factors (Idgfs), encoded byIdgf1,Idgf2,Idgf3,Idgf4,Idgf5, andIdgf6. In this study we developed tools to facilitate characterization of the physiological roles of the Idgfs by deleting each of theIdgfgenes using the CRISPR/Cas9 system and assessing loss-of-function phenotypes. Using null lines, we showed that loss-of-function for all six Idgf proteins significantly lowers fertility and viability and compromises germ cell migration. We also showed that Idgfs play roles in epithelial morphogenesis, maintaining proper epithelial architecture and cell shape, regulating E-cadherin and cortical Actin, and protecting these tissues against CO2exposure. Defining the normal molecular mechanisms of CLPS is key to understanding how deviations tip the balance from a physiological to a pathological state.
Structural changes in chromosomes driven by multiple condensin motors during mitosis
Authors: Dey Atreya , Shi Guang , Takaki Ryota , Thirumalai D. 
Published: July 2022

AbstractWe created a computational framework that describes the loop extrusion (LE) by multiple condensin I and II motors in order to investigate the changes in chromosome organization during mitosis. The theory accurately reproduces the experimentally measured contact probability profiles for the mitotic chromosomes in HeLa and DT40 cells. The rate of loop extrusion is smaller at the start of mitosis and increases as the cells approach the metaphase. The mean loop size generated by condensin II is about six times larger than the ones created by condensin I. The loops, which overlap with each other, are stapled to a central dynamically changing helical scaffold formed by the motors during the LE process. The structures of the mitotic chromosomes, using a data-driven method that uses the Hi-C contact map as input, are best described as random helix perversion (RHP) in which the handedness changes randomly along the scaffold. The extent of propagation in the RHP structures is less in HeLa cells than in the DT40 chromosomes.
Diversity and prevalence ofClostridium innocuumin the human gut microbiota
Authors: Bhattacharjee Disha , Flores Clara , Woelfel-Monsivais Christine , Seekatz Anna M. 
Published: July 2022

ABSTRACTClostridia are a polyphyletic group of Gram-positive, spore-forming anaerobes in the Firmicutes phylum that significantly impact metabolism and functioning of human gastrointestinal tract. Recently, Clostridia were divided into two separate classes, Clostridia and Erysipelotrichia, based on phenotypic and 16S rRNA gene-based differences. While Clostridia include many well-known pathogenic bacteria, Erysipelotrichia remain relatively uncharacterized, particularly regarding their role as a pathogen vs. commensal. Despite wide recognition as a commensal, the Erysipelotrichial species,Clostridium innocuum, has recently been associated with various disease states. To further understand the ecological and potential virulent role ofC. innocuum, we conducted a genomic comparison across 38C. innocuumisolates and 75 publicly available genomes. Based on colony morphology, we isolated multipleC. innocuumcultivars from the feces of healthy human volunteers (n=5). Comparison of the 16S rRNA gene of our isolates against publicly available microbiota datasets in healthy individuals suggests a high prevalence ofC. innocuumacross the human population (> 80%). Analysis of single nucleotide polymorphisms (SNPs) across core genes and average nucleotide identify (ANI) revealed the presence of 4 clades among all available unique genomes (n=108 total). Investigation of carbohydrate and protein utilization pathways, including comparison against the carbohydrate-activating-enzyme (CAZyme) database, demonstrated inter-and intra-clade differences that were further substantiatedin vitro. Collectively, these data indicate genetic variance within theC. innocuumspecies that may help clarify its role in human disease and health.IMPORTANCEClostridia are a group of medically important anaerobes as both commensals and pathogens. Recently, a new class of Erysipelotrichia containing a number of re-assigned Clostridial species has emerged, includingClostridium innocuum. Recent studies have implicatedC. innocuumas a potential causative agent of diarrhea in patients from whomClostridioides difficilecould not be isolated. Using genomic andin vitrocomparison, this study sought to characterizeC. innocuumin the healthy human gut. Our analyses suggest thatC. innocuumis a highly prevalent and diverse species, demonstrating clade-specific differences in metabolism and potential virulence. Collectively, this study is the first investigation into a broader description ofC. innocuumas a human gut inhabitant.
Suspected Adverse Drug Reactions of the Type 2 Antidiabetic Drug Class Dipeptidyl-Peptidase IV inhibitors (DPP4i): Can polypharmacology help explain?
Authors: Jones Lauren , Jones Alan M. 
Published: July 2022

AbstractTo interpret the relationship between the polypharmacology of dipeptidyl-peptidase IV inhibitors (DPP4i) and their suspected adverse drug reaction (ADR) profiles using a national registry.A retrospective investigation into the suspected ADR profile of four licensed DPP4i in the United Kingdom using the National MHRA Yellow Card Scheme and OpenPrescribing databases. Experimental data from the ChEMBL database alongside physiochemical (PC) and pharmacokinetic (PK) profiles were extracted and interpreted.DPP4i show limited polypharmacology alongside low suspected ADR rates. We found minimal statistical difference between the unique ADR profiles ascribed to the DPP4i except for total ADRs (χ2;p<.05). Alogliptin consistently showed the highest suspected ADR rate per 1,000,000 items prescribed. Saxagliptin showed the lowest suspected ADR rate across all organ classes but did not reach statistical difference (χ2;p>.05). We also confirmed the Phase III clinical trial data that showed gastrointestinal and skin reactions are the most reported ADR across the class and postulated underlying mechanisms for this based on possible drug interactions.We have proposed underlying mechanisms behind the reported suspected ADRs and their polypharmacology. The main pharmacological mechanism behind the ADRs is attributed to interactions with DPP4 activity and/or structure homologue (DASH) proteins which augment the immune-inflammatory modulation of DPP4.
Loss of polarity regulators initiates gasdermin E mediated pyroptosis in human maternal fetal interface trophoblasts
Authors: Patel Khushali , Nguyen Jasmine , Shaha Sumaiyah , Brightwell Amy , Duan Wendy , Zubkowski Ashley , Riddell Meghan 
Published: July 2022

AbstractThe syncytiotrophoblast is the placental epithelial cell that forms the maternal surface of the human placenta, acting as a barrier and facilitating exchange between mother and fetus. Syncytiotrophoblast dysfunction is a feature of pregnancy pathologies, like preeclampsia. Dysfunctional syncytiotrophoblast display a loss of microvilli, a marker of aberrant apical-basal polarization, but little data exists about the regulation of syncytiotrophoblast polarity. Atypical protein kinase-c (aPKC) isoforms are conserved polarity regulators. Thus, we hypothesized that aPKC isoforms regulate syncytiotrophoblast polarity. Using human placental explant culture and primary trophoblasts, we found that loss of aPKC activity or expression induces syncytiotrophoblast gasdermin E dependent pyroptosis. We also establish that TNF-α induces an isoform specific decrease in aPKC expression and gasdermin E dependent pyroptosis. Therefore, aPKCs are homeostatic regulators of syncytiotrophoblast function and a pathogenically relevant pro-inflammatory signal leads to a highly pro-inflammatory form of cell death at the maternal-fetal interface. Therefore, our results have important implications for the pathobiology of placental disorders.
Cholesterol-mediated tight junction formation
Authors: Shigetomi Kenta , Ikenouchi Junichi 
Published: July 2022

AbstractLipids have the ability to self-organize but the significance of this phenomenon in the assembly of membrane structures is unknown. We previously reported that cholesterol enrichment directs the formation of tight junctions (TJs), adhesion structures responsible for the epithelial barrier (Shigetomi et al., 2018). However, it is unclear how cholesterol accumulates and informs TJ formation. Cholesterol typically accumulates in the vicinity of apical cell junctions (Shigetomi et al., 2018). Surprisingly, cholesterol distribution is unaltered in an epithelial cell line that lacks TJs, generated by suppressing the expression of claudins, membrane proteins that determine the barrier properties of TJs. Assembly of claudin into hallmark ‘strands’ is canonically thought to require binding to Zonula occludens (ZO) proteins but a claudin mutant that cannot bind to ZO proteins still form strands. These results suggest a novel mechanism for TJ formation that is dependent on cholesterol and reveal an unexpected role of ZO proteins as organizers of the cholesterol domain.
Convergence of two global regulators to coordinate expression of essential virulence determinants of Mycobacterium tuberculosis
Authors: Khan Hina , Paul Partha , Sevalkar Ritesh Rajesh , Kachhap Sangita , Singh Balvinder , Sarkar Dibyendu 
Published: July 2022

AbstractCyclic AMP (cAMP) is known to function as a global regulator of M. tuberculosis gene expression. Sequence-based transcriptomic profiling identified the mycobacterial regulon controlled by the cAMP receptor protein, CRP. In this study, we identified a new subset of CRP-associated genes including virulence determinants which are also under the control of a major regulator, PhoP. Our results suggest that PhoP as a DNA binding transcription factor, impacts expression of these genes, and phosphorylated PhoP promotes CRP recruitment at the target promoters. Further, we uncover a distinct regulatory mechanism involving CRP and PhoP on transcriptional control of these genes. While both these regulators influence gene expression, we show that activation of these genes requires direct recruitment of both PhoP and CRP at their target promoters. The most fundamental biological insight is derived from the inhibition of CRP binding at the regulatory regions in a PhoP-deleted strain owing to CRP-PhoP protein-protein interactions. Based on these results, a model is proposed suggesting how CRP and PhoP function as co-activators and contribute to activation of the essential pathogenic determinants. Together, these results uncover a novel mechanism where two interacting virulence factors impact expression of virulence determinants, have significant implications on TB pathogenesis.
Elevated FOXG1 supports exit from quiescence in neural stem cells through FoxO6
Authors: Ferguson Kirsty M , Blin Carla , Garcia-Diaz Claudia , Bulstrode Harry , Bressan Raul Bardini , McCarten Katrina , Pollard Steven M. 
Published: July 2022

SummaryThe molecular mechanisms controlling the balance of quiescence and proliferation in adult neural stem cells (NSCs) are often deregulated in brain cancers such as glioblastoma (GBM). Previously, we reported that FOXG1, a forebrain-restricted neurodevelopmental transcription factor, is frequently upregulated in glioblastoma stem cells (GSCs) and limits the effects of cytostatic pathways, in part by repression of the tumour suppressor Foxo3. Here, we show that increased FOXG1 upregulates FoxO6, a more recently discovered FoxO family member with potential oncogenic functions. Although genetic ablation of FoxO6 in proliferating NSCs has no effect on the cell cycle or entry into quiescence, we find that FoxO6-null NSCs can no longer efficiently exit quiescence following FOXG1 elevation. Increased FoxO6 results in the formation of large acidic vacuoles, reminiscent of Pak1-regulated macropinocytosis. Consistently, Pak1 expression is upregulated by FOXG1 overexpression and downregulated upon FoxO6 loss in proliferative NSCs. These data suggest a pro-oncogenic role for FoxO6 in controlling the exit from quiescence in NSCs, and shed light on the functions of this underexplored FoxO family member.Research highlightsFoxO6 is a downstream effector of elevated FOXG1 in mouse NSCs and GSCs.Upregulation of FoxO6 is necessary for FOXG1 to drive efficient quiescence exit of NSCs.FoxO6 overexpression stimulates macropinocytosis, a process regulated by the actin cytoskeleton regulator Pak1.Pak1 is upregulated by FOXG1 overexpression and downregulated upon FoxO6 loss.
RPG interacts with E3-ligase CERBERUS to mediate rhizobial infection in Lotus japonicus
Authors: Li Xiaolin , Liu Miaoxia , Cai Min , Chiasson David , Groth Martin , Heckmann Anne B. , Wang Trevor L. , Parniske Martin , Downie J. Allan , Xie Fang 
Published: July 2022

ABSTRACTSymbiotic interactions between rhizobia and legumes result in the formation of root nodules, which fix nitrogen that can be used for plant growth. Rhizobia usually invade legume roots through a plant-made tunnel-like structure called an infection thread (IT). Rhizobium-directed polar growth (RPG) encodes a coiled-coil protein that was identified in Medicago truncatula as required for root nodule infection, but the function of RPG remains poorly understood. In this study, we identified and characterized RPG in Lotus japonicus and determined that it is required for IT formation. RPG was induced by Mesorhizobium loti or purified Nodulation factor and displayed an infection-specific expression pattern. Nodule inception (NIN) bound to the RPG promoter and induced its expression. A GFP-RPG protein was localized in puncta subcellular localization in L. japonicus root protoplasts and in root hairs infected by M. loti. The N-terminal predicted C2 lipid-binding domain of RPG was not required for this subcellular localization or for function. CERBERUS, a U-box E3 ligase which is also required for rhizobial infection, was found to be localized in similar puncta. RPG co-localized and directly interacted with CERBERUS at the early endosomes (TGN/EE) compartment and near the nuclei in root hairs after rhizobia inoculation. Our study sheds light on that a RPG-CERBERUS protein complex that is involved in an exocytotic pathway mediating IT polarity growth which is driven by nuclear migration.One sentence summaryPuncta localization RPG-CERBERUS protein complex promote polarity growth of ITs driven by nuclear migration.
Experimental considerations for study ofC. eleganslysosomal proteins
Authors: Clancy John C. , Vo An A. , Myles Krista M. , Levenson Max T. , Ragle James Matthew , Ward Jordan D. 
Published: July 2022

ABSTRACTLysosomes are an important organelle required for the degradation of a range of cellular components. Lysosome function is critical for development and homeostasis as dysfunction can lead to inherited genetic disorders, cancer, and neurodegenerative and metabolic disease. The acidic and protease-rich environment of lysosomes poses experimental challenges. Many fluorescent proteins are quenched or degraded, while specific red fluorescent proteins can be cleaved from translational fusion partners and accumulate. While studying MLT-11, aC. elegansmolting factor that localizes to lysosomes and the cuticle, we sought to optimize several experimental parameters. We found that, in contrast to mNeonGreen fusions, mScarlet fusions to MLT-11 missed cuticular and rectal epithelial localization. Rapid sample lysis and denaturation was critical for preventing MLT-11 fragmentation while preparing lysates for western blots. Using a model lysosomal substrate (NUC-1) we found that rigid polyproline linkers and truncated mCherry constructs do not prevent cleavage of mCherry from NUC-1. We provide evidence that extended localization in lysosomal environments prevents the detection of FLAG epitopes in western blots. Finally, we optimize an acid-tolerant green fluorescent protein (Gamillus) for use inC. elegans. These experiments provide important experimental considerations and new reagents for the study ofC. eleganslysosomal proteins.
Molecular mechanism of plasmid-borne resistance to sulfonamides
Authors: Venkatesan Meenakshi , Fruci Michael , Verellen Lou Ann , Skarina Tatiana , Mesa Nathalie , Stogios Peter J. , Savchenko Alexei 
Published: July 2022

AbstractThe sulfonamides (sulfas) are the oldest class of synthetic antibacterial that target the essential, conserved dihydropteroate synthase (DHPS) enzyme, encoded by folP, through chemical mimicry of its substrate p-aminobenzoic acid (pABA). Resistance has complicated their clinical utility and is widespread in pathogenic species. Resistance is mediated by acquisition of sul genes on mobile genetic elements, which code for the so-called Sul enzymes that are divergent DHPS enzymes with intrinsic sulfa-insensitivity. Even decades after the discovery of this resistance mechanism, its molecular details have not been understood. In this study, we elucidate the molecular basis for intrinsic resistance of Sul enzymes using x-ray crystallography, enzymology, mutagenesis, intrinsic tryptophan fluorescence, antibiotic susceptibility of a contemporary ΔfolP strain, and adaptive laboratory evolution of folP. We show that the active sites of Sul enzymes possess a modified pABA-interaction region based on insertion of a Phe-Gly sequence. This insertion is necessary for discrimination between pABA and sulfonamides, more than 1000-fold loss in binding affinity of sulfas to Sul enzymes, and robust pan-sulfonamide resistance. We detect no fitness cost due to this active site modification, as it does not compromise the rate of dihydropteroate biosynthesis and complements the thymidine-auxotrophy of an E. coli folP deletion strain. Lab-evolved sulfa-resistance folP recapitulated this mechanism through the same active site insertion. Finally, we show that this insertion and a nearby loop confer increased active site flexibility of Sul enzymes relative to DHPS. These results provide a molecular foundation for revisiting DHPS-targeted antibacterials to evade resistance.