bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictors and long-term outcomes of oropharyngeal dysphagia in Persons with Multiple Sclerosis: A systematic review protocol
Authors: Sadeghi Zahra , Afshar Mohamadreza , Memarian Asefeh , Flowers Heather L. 
Published: June 2023

AabstractBackgroundOropharyngeal dysphagia (OPD) can be functionally debilitating in persons with multiple sclerosis (pwMS). OPD induces alterations in safety and efficacy of food and/or liquid ingestion and may incur negative sequalae such as aspiration pneumonia or malnutrition/dehydration. Early detection and timely management of OPD in pwMS could prevent such complications and reduce mortality rates. Identifying predictors of OPD relative to its onset or repeat manifestation will enable the development of care pathways that target early assessment and sustained management. The aims of this systematic review are to compile, evaluate, and summarise the existing literature reporting potential predictors and associated long-term outcomes (e.g., aspiration pneumonia, malnutrition, dehydration, and/or death) of OPD in pwMS.MethodsWe will undertake a systematic review to identify studies that describe patterns and complications of OPD in pwMS. Variables of interest include predictors of OPD along with long-term outcomes. We will search MEDLINE, EMBASE, CINAHL, AMED, the Cochrane Library, Web of Science, and Scopus. We will consider studies for inclusion if they involve at least 30 adult participants with MS and report risk factors of OPD and/or its long-term outcomes. Studies will be excluded if they refer to esophageal or oropharyngeal dysphagia induced by causes other than multiple sclerosis. Study selection and data extraction will be performed by two independent assessors for abstract and full article review. We will present study characteristics in tables and document research findings for dysphagia-related risk factors or its complications via a narrative format or meta-analysis if warranted (e.g., mean difference and/or risk ratios measurements). All included studies will undergo risk of bias assessment conducted independently by two authors with consensus on quality ratings.ConclusionThere is a lacune with respect to systematic reviews involving predictors and long-term outcomes of dysphagia in in pwMS to date. Our systematic review will provide the means to develop accurate and efficient management protocols for careful monitoring and evaluation by dysphagia experts. The results of this systematic review will be published in a peer-reviewed journal.Systematic review registrationPROSPERO CRD42022340625
Structure of full-length cobalamin-dependent methionine synthase and cofactor loading capturedin crystallo
Authors: Mendoza Johnny , Purchal Meredith , Yamada Kazuhiro , Koutmos Markos 
Published: June 2023

AbstractCobalamin-dependent methionine synthase (MS) is a key enzyme in methionine and folate one-carbon metabolism. MS is a large multi-domain protein capable of binding and activating three substrates: homocysteine, folate,S-adenosylmethionine for methylation. Achieving three chemically distinct methylations necessitates significant domain rearrangements to facilitate substrate access to the cobalamin cofactor at the right time. The distinct conformations required for each reaction have eluded structural characterization as its inherently dynamic nature renders structural studies difficult. Here, we use a thermophilic MS homolog (tMS) as a functional MS model. Its exceptional stability enabled characterization of MS in the absence of cobalamin, marking the first studies of a cobalamin-binding protein in its apoenzyme state. More importantly, we report the first high-resolution full-length MS structure, ending a multi-decade quest. We also captured cobalamin loadingin crystallo, providing structural insights into holoenzyme formation. Our work paves the way for unraveling how MS orchestrates large-scale domain rearrangements crucial for achieving challenging chemistries.
Direct Regulation of the Voltage Sensor of HCN Channels by Membrane Lipid Compartmentalization
Authors: Handlin Lucas J. , Dai Gucan 
Published: June 2023

ABSTRACTIon channels function within a membrane environment characterized by dynamic lipid compartmentalization. Limited knowledge exists regarding the response of voltage-gated ion channels to transmembrane potential within distinct membrane compartments. By leveraging fluorescence lifetime imaging microscopy (FLIM) and Förster resonance energy transfer (FRET), we visualized the localization of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in membrane domains. HCN4 exhibits a greater propensity for incorporation into ordered lipid domains compared to HCN1. To investigate the conformational changes of the S4 helix voltage sensor of HCN channels, we used dual stop-codon suppression to incorporate different noncanonical amino acids, orthogonal click chemistry for site-specific fluorescence labeling, and transition metal FLIM-FRET. Remarkably, altered FRET levels were observed between VSD sites within HCN channels upon disruption of membrane domains. We propose that the voltage-sensor rearrangements, directly influenced by membrane lipid domains, can explain the heightened activity of pacemaker HCN channels when localized in cholesterol-poor, disordered lipid domains, leading to membrane hyperexcitability and diseases.
Inhibition of Retinoic Acid Signaling in Proximal Tubular Epithelial cells Protects against Acute Kidney Injury by Enhancing Kim-1-dependent Efferocytosis
Authors: Yang M. , Lopez L.N. , Brewer M. , Delgado R. , Menshikh A. , Clouthier K. , Zhu Y. , Vanichapol T. , Yang H. , Harris R. , Gewin L. , Brooks C. , Davidson A. , de Caestecker M.P. 
Published: June 2023

Retinoic acid receptor (RAR) signaling is essential for mammalian kidney development, but in the adult kidney is restricted to occasional collecting duct epithelial cells. We now show there is widespread reactivation of RAR signaling in proximal tubular epithelial cells (PTECs) in human sepsis-associated acute kidney injury (AKI), and in mouse models of AKI. Genetic inhibition of RAR signaling in PTECs protects against experimental AKI but is associated with increased expression of the PTEC injury marker, Kim-1. However, Kim-1 is also expressed by de-differentiated, proliferating PTECs, and protects against injury by increasing apoptotic cell clearance, or efferocytosis. We show that the protective effect of inhibiting PTEC RAR signaling is mediated by increased Kim-1 dependent efferocytosis, and that this is associated with de-differentiation, proliferation, and metabolic reprogramming of PTECs. These data demonstrate a novel functional role that reactivation of RAR signaling plays in regulating PTEC differentiation and function in human and experimental AKI.Graphical abstract
Platelet-Localized ST6Gal1 Does Not Impact IgG Sialylation
Authors: Glendenning Leandre M. , Zhou Julie Y. , Kukan Emily N. , Gao Chao , Cummings Richard D. , Joshi Smita , Whiteheart Sidney W. , Cobb Brian A. 
Published: June 2023

AbstractThe IgG antibody class forms an important basis of the humoral immune response, conferring reciprocal protection from both pathogens and autoimmunity. IgG function is determined by the IgG subclass, as defined by the heavy chain, as well as the glycan composition at N297, the conserved site of N-glycosylation within the Fc domain. For example, lack of core fucose promotes increased antibody-dependent cellular cytotoxicity, whereas α2,6-linked sialylation by the enzyme ST6Gal1 helps to drive immune quiescence. Despite the immunological significance of these carbohydrates, little is known about how IgG glycan composition is regulated. We previously reported that mice with ST6Gal1-deficient B cells have unaltered IgG sialylation. Likewise, ST6Gal1 released into the plasma by hepatocytes does not significantly impact overall IgG sialylation. Since IgG and ST6Gal1 have independently been shown to exist in platelet granules, it was possible that platelet granules could serve as a B cell-extrinsic site for IgG sialylation. To address this hypothesis, we used a platelet factor 4 (Pf4)-Cre mouse to delete ST6Gal1 in megakaryocytes and platelets alone or in combination with an albumin-Cre mouse to also remove it from hepatocytes and the plasma. The resulting mouse strains were viable and had no overt pathological phenotype. We also found that despite targeted ablation of ST6Gal1, no change in IgG sialylation was apparent. Together with our prior findings, we can conclude that in mice, neither B cells, the plasma, nor platelets have a substantial role in homeostatic IgG sialylation.
Structure of mechanically activated ion channel OSCA2.3 reveals mobile elements in the transmembrane domain
Authors: Jojoa-Cruz Sebastian , Burendei Batuujin , Lee Wen-Hsin , Ward Andrew B. 
Published: June 2023

SummaryMembers of the OSCA/TMEM63 are mechanically activated ion channels and structures of some OSCA members have revealed the architecture of these channels and structural features that are potentially involved in mechanosensation. However, these structures are all in a similar state and information about the motion of different elements of the structure is limited, preventing a deeper understanding of how these channels work. Here, we used cryo-electron microscopy to determine high resolution structures ofArabidopsis thalianaOSCA1.2 and OSCA2.3 in peptidiscs. The structure of OSCA1.2 resembles previous structures of the same protein in different environments. Yet, in OSCA2.3 the TM6a-TM7 linker constricts the pore on its cytoplasmic side, revealing conformational heterogeneity within the OSCA family. Furthermore, coevolutionary sequence analysis uncovered a conserved interaction between TM6a-TM7 linker and the Beam-Like Domain. Our results support the involvement of TM6a-TM7 in mechanosensation and potentially in the diverse response of OSCA channels to mechanical stimuli.
Evolution of ion channels in cetaceans: A natural experiment in the Tree of life
Authors: Uribe Cristóbal , Nery Mariana F. , Zavala Kattina , Mardones Gonzalo A. , Riadi Gonzalo , Opazo Juan C. 
Published: June 2023

AbstractCetaceans could be seen as a natural experiment within the tree of life in which a mammalian lineage changed from terrestrial to aquatic habitats. This shift involved extensive phenotypic modifications, which represent an opportunity to explore the genetic bases of phenotypic diversity. Furthermore, the availability of whole genome sequences in representative species of all main cetacean groups means that we are in a golden age for such studies. Among the different molecular systems that maintain cellular homeostasis, ion channels are crucial for the proper physiological functioning of all living species. This study aims to explore the evolution of ion channels during the evolutionary history of cetaceans. To do so, we created a bioinformatic pipeline to annotate the repertoire of ion channels in the genome of the species included in our sampling. Our main results show that cetaceans have on average, fewer protein-coding genes and a higher percentage of annotated ion channels than non-cetacean mammals. Signals of positive selection were detected in ion channels related to the heart, locomotion, visual and neurological phenotypes. Interestingly, we predict that the NaV1.5 ion channel of most toothed whales (odontocetes) is sensitive to tetrodotoxin (TTX), similar to NaV1.7, given the presence of tyrosine instead of cysteine, in a specific position of the ion channel. Finally, the gene turnover rate of the cetacean crown group is more than three times faster than non-cetacean mammals.
Title: β Cell microRNAs Function as Molecular Hubs of Type 1 Diabetes Pathogenesis and as Biomarkers of Diabetes Risk
Authors: Syed Farooq , Krishnan Preethi , Chang Garrick , Langlais Sarah R. , Hati Sumon , Yamada Kentaro , Lam Anh K. , Talware Sayali , Liu Xiaowen , Sardar Rajesh , Liu Jing , Mirmira Raghavendra G. , Evans-Molina Carmella 
Published: June 2023

AbstractMicroRNAs (miRNAs) are small non-coding RNAs that play a crucial role in modulating gene expression and are enriched in cell-derived extracellular vesicles (EVs). We investigated whether miRNAs from human islets and islet-derived EVs could provide insight into β cell stress pathways activated during type 1 diabetes (T1D) evolution, therefore serving as potential disease biomarkers. We treated human islets from 10 cadaveric donors with IL-1β and IFN-γ to model T1Dex vivo. MicroRNAs were isolated from islets and islet-derived EVs, and small RNA sequencing was performed. We found 20 and 14 differentially expressed (DE) miRNAs in cytokine-versus control-treated islets and EVs, respectively. Interestingly, the miRNAs found in EVs were mostly different from those found in islets. Only two miRNAs, miR-155-5p and miR-146a-5p, were upregulated in both islets and EVs, suggesting selective sorting of miRNAs into EVs. We used machine learning algorithms to rank DE EV-associated miRNAs, and developed custom label-free Localized Surface Plasmon Resonance-based biosensors to measure top ranked EVs in human plasma. Results from this analysis revealed that miR-155, miR-146, miR-30c, and miR-802 were upregulated and miR-124-3p was downregulated in plasma-derived EVs from children with recent-onset T1D. In addition, miR-146 and miR-30c were upregulated in plasma-derived EVs of autoantibody positive (AAb+) children compared to matched non-diabetic controls, while miR-124 was downregulated in both T1D and AAb+ groups. Furthermore, single-molecule fluorescence in situ hybridization confirmed increased expression of the most highly upregulated islet miRNA, miR-155, in pancreatic sections from organ donors with AAb+ and T1D.One Sentence SummarymiRNA expression patterns in human pancreatic islets and EVs change under inflammatory conditions and can be leveraged to inform biomarkers strategies for T1D.
Two subtypes of GTPase-activating proteins coordinate tip growth and cell size regulation inPhyscomitrium patens
Authors: Ruan Jingtong , Lai Linyu , Ou Hongxin , Yi Peishan 
Published: June 2023

AbstractThe establishment of cell polarity is a prerequisite for many developmental processes. However, how it is achieved during tip growth in plants remains elusive. Here, we show that the RHO OF PLANTs (ROPs), ROP GUANINE NUCLEOTIDE EXCHANGE FACTORs (RopGEFs), and ROP GTPASE-ACTIVATING PROTEINs (RopGAPs) assemble into membrane domains in tip-growing cells of the mossPhyscomitrium patens. The confinement of membrane domains requires redundant global inactivation of ROPs by PpRopGAPs and the PLECKSTRIN HOMOLOGY (PH) domain-containing RenGAP PpREN. Unexpectedly, PpRopGAPs and PpREN exert opposing effects on domain size and cell width upon overexpression. Biochemical and functional analyses indicate that PpRopGAPs are recruited to the membrane by active ROPs to restrict domain size through clustering, whereas PpREN rapidly inactivates ROPs and inhibits PpRopGAP-induced clustering. We propose that the activity- and clustering-based domain organization by RopGAPs and RenGAPs is a general mechanism for coordinating polarized cell growth and cell size regulation in plants.SignificanceUsing the mossPhyscomitrium patens, we show that PpRopGAPs and PpRenGAP redundantly regulate tip growth by inactivating ROP GTPases and influencing their membrane organization. They display distinct GAP activities and binding capacities to ROPs and could oppositely regulate cell width when overexpressed. We propose that tip growth and cell size regulation are coordinated by two subtypes of GTPase-activating proteins that act together to maintain an optimal amount of active ROPs but reversely regulate the membrane clustering of ROPs. The involvement of functionally diverged GAPs in modulating ROP activity and localization may represent a general mechanism for cell morphology regulation in plants.
WBSCR16 Determines Metabolic Flexibility Via Regulating Mitochondrial 16S rRNA Maturation
Authors: Zhang Shengjie , Dong Zi , Feng Yang , Guo Wei , Zhang Chen , Shi Yifan , Zhao Zhiyun , Wang Jiqiu , Ning Guang , Huang Guorui 
Published: June 2023

AbstractMitochondria play significant roles in energy homeostasis by dissipating excess calories. However, the key proteins in mitochondrial govern metabolically flexibility remain poorly understand. Herein, we generated adipose specificWbscr16-/-mice and cells, both of which exhibited a preference for fat utilization and displayed dramatic mitochondrial changes. We demonstrated that WBSCR16 is essential for the specific cleavage of 16S rRNA-tRNALeu, leading to the production of maturated 16S rRNA, which in turn controls mitochondrial large ribosomal assembly. Importantly, WBSCR16 was identified as a 16S rRNA-binding protein that directly interacts with RNase P subunit MRPP3. Furthermore, evidence showed that WBSCR16 ablation promotes energy wasting via lipid cycling in BAT, leading to excess energy expenditure and resistance to obesity. Conversely, cells and mice with WBSCR16 overexpression preferred to glucose utilization. These findings suggest that WBSCR16 is the key mitochondrial switch protein between glucose and lipid metabolism, making it a promising target for the development of fat busting drug.
The activity ofengrailedimaginal disc enhancers is modulated epigenetically by chromatin and autoregulation
Authors: Cheng Yuzhong , Chan Fountane , Kassis Judith A. 
Published: June 2023

Abstractengrailed(en) encodes a homeodomain transcription factor crucial for the proper development of Drosophila embryos and adults. Like many developmental transcription factors,enexpression is regulated by many enhancers, some of overlapping function, that drive expression in spatially and temporally restricted patterns. Theenembryonic enhancers are located in discrete DNA fragments that can function correctly in small reporter transgenes. In contrast, theenimaginal disc enhancers (IDEs) do not function correctly in small reporter transgenes. En is expressed in the posterior compartment of wing imaginal disks; small IDE-reporter transgenes are expressed in the anterior compartment, the opposite of what is expected. Our data show that the En protein binds toenIDEs, and we suggest that En directly represses IDE function. We identified twoenIDEs, ‘O’ and ‘S’. Deletion of either of these IDEs from a 79kb HA-en rescue transgene (HAen79) caused a loss-of-functionenphenotype when theHAen79transgene was the sole source of En. In contrast, flies with a deletion of the same IDEs from the endogenousengene had no phenotype, suggesting a resiliency not seen in theHAen79rescue transgene. Inserting a gypsy insulator inHAen79betweenenregulatory DNA and flanking sequences strengthened the activity ofHAen79, giving better function in both the ON and OFF transcriptional states. Altogether our data show that theenIDEs stimulate expression in the entire imaginal disc, and that the ON/OFF state is set by epigenetic regulators. Further, the endogenous locus imparts a stability toenfunction not seen even in a large transgene, reflecting the importance of both positive and negative epigenetic influences that act over relatively large distances in chromatin.Author SummaryGenes that control development are often used at different times and places in a developing embryo. Transcription of these important genes must be tightly regulated; therefore, these genes often have large arrays of regulatory DNA. In Drosophila, discrete fragments of DNA (enhancers) can be identified that turn genes on in patterns in the early embryo. In cells where the genes are transcriptionally ON, there are active modifications on chromatin, setting later enhancers in a transcription-permission environment. In cells where the genes are OFF, repressive chromatin marks keep later enhancers inactive. In this paper we studied two late enhancers of the Drosophilaengene. We show that the correct activity of these enhancers is dependent on being next to other, earlier actingenenhancers. Our data also show that En can repress its own expression, likely directly by acting on these late enhancers. The chromatin-regulated activity of theseenlate enhancers is similar to what was described for a late enhancer of another Drosophila developmental gene,Ubx. We suggest that this mode of regulation is likely to be important for many late-acting developmental enhancers in many different organisms.
Nature and nurture: comparing mouse behavior in classic versus revised anxiety-like and social behavioral assays in genetically or environmentally defined groups
Authors: Ronquillo Janet , Nguyen Michael T. , Rothi Linnea , Bui-Tu Trung-Dan , Yang Jocelyn , Halladay Lindsay R. 
Published: June 2023

AbstractWidely used rodent anxiety assays like the elevated plus maze (EPM) and the open field test (OFT) are often conflated with rodents’ natural preference for dark over light environments or protected over open spaces. The EPM and OFT have been used for many decades, yet have also been criticized by generations of behavioral scientists. Several years ago, two revised anxiety assays were designed to improve upon the “classic” tests by excluding the possibility to avoid or escape aversive areas of each maze. The 3-D radial arm maze (3DR) and the 3-D open field test (3Doft) each consist of an open space connected to ambiguous paths toward uncertain escape. This introduces continual motivational conflict, thereby increasing external validity as an anxiety model. But despite this improvement, the revised assays have not caught on. One issue may be that studies to date have not directly compared classic and revised assays in the same animals. To remedy this, we contrasted behavior in a battery of assays (EPM, OFT, 3DR, 3Doft, and a sociability test) in mice defined either genetically by isogenic strain, or environmentally by postnatal experience. Findings indicate that the optimal assay to assess anxiety-like behavior may depend upon grouping variable (e.g. genetic versus environment). We argue that the 3DR may be the most ecologically valid of the anxiety assays tested, while the OFT and 3Doft provided the least useful information. Finally, exposure to multiple assays significantly affected sociability measures, raising concerns for designing and interpreting batteries of behavioral tests in mice.
Linguistic clustering and aggregate productive efficiency in Indonesia
Authors: Repkine Alexandre 
Published: June 2023

PurposeThe purpose of this study is to explore the link between aggregate production efficiency and the extent of linguistic clustering in Indonesia.Design/methodology/approachThe author draws on the stochastic frontier model and applies it to the data on Indonesian provinces to compute the effects of various determinants on these provinces' aggregate production efficiency. The key determinant is the spatial index of linguistic clustering that the author believes has never been applied before in this context.FindingsLinguistic clustering is an important determinant of aggregate production efficiency. Linguistic diversity is positively associated with productive efficiency if members of a specific linguistic group are not clustered beyond a certain level.Originality/valueTo the best of the author’s knowledge, this is the first study that links the spatial index of linguistic clustering (because of Massey and Danton) to production efficiency. In other words, the contribution of this study is to introduce a geographical dimension to the mainstream analysis of the association between ethnic diversity and economic performance.