bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of an amyloidogenic intermediate of transthyretin by NMR relaxation dispersion
Authors: Leach Benjamin I. , Ferguson James A. , Morgan Gareth , Sun Xun , Kroon Gerard , Oyen David , Dyson H. Jane , Wright Peter E. 
Published: February 2024

AbstractThe aggregation pathway of transthyretin (TTR) proceeds through rate-limiting dissociation of the tetramer and partial misfolding of the monomers, which assemble into amyloid structures through a downhill polymerization mechanism. The structural features of the aggregation-prone monomeric intermediate are poorly understood. Characterization of amyloidogenic intermediates is challenging due to their propensity to aggregate at concentrations necessary for structural studies. NMR relaxation dispersion offers a unique opportunity to characterize these intermediates when they exchange on favorable timescales with NMR-visible ground states. To characterize the structural transitions associated with tetramer dissociation, we have analyzed ground-state chemical shift differences between the native tetramer and an engineered monomer in which the critical F87 side chain is replaced by glutamate. The secondary structure and overall fold of the F87E monomer is similar to that of the tetramer except for β-strand H. This strand populates two conformations, where it is either docked on the protein core or is displaced from the edge of the β-sheet formed by β-strands D, A, G, and H (DAGH β-sheet) and is dynamically disordered. Chemical shift differences derived from analysis of1H/15N single, double and zero quantum relaxation dispersion data provide insights into the structure of a low-lying excited state that exchanges with the ground state of the F87E monomer at a rate of 3800 s-1. Disruption of the subunit interfaces of the TTR tetramer leads to destabilization of edge strands in both β-sheets of the F87E monomer. Conformational fluctuations are propagated through the entire hydrogen bonding network of the DAGH β-sheet, from the inner β-strand H, which forms the strong dimer interface in the TTR tetramer, to outer strand D which is unfolded in TTR fibrils. Fluctuations are also propagated from the AB loop in the weak dimer interface to the EF helix, which undergoes structural remodeling in fibrils. The conformational fluctuations in both regions are enhanced at acidic pH where amyloid formation is most favorable. The relaxation dispersion data provide insights into the conformational dynamics of the amyloidogenic state of monomeric TTR that predispose it for structural remodeling and progression to amyloid fibrils.
Elevated prevalence of the global panzootic chytrid strain in Ecuadorian anurans of the Amazonian lowlands
Authors: Smart Utpal , McCracken Shawn F. , Brunner Rebecca M. , Rivera Clarissa , Rodriguez David 
Published: February 2024

ABSTRACTConsiderable attention has been directed to studying the infection dynamics of the fungal pathogen,Batrachochytrium dendrobatidis(Bd), affecting amphibians in the high elevations of the Neotropics. Lowland forests of the same realm, on the other hand, remain relatively understudied in this context. Herein, an attempt to bridge this gap was made by investigating the occurrence ofBdin several anuran taxa inhabiting the Amazonian lowlands in the northeast of Ecuador. To this end, 207 anurans belonging to 10 different families, 25 different genera, and 55 distinct host species were sampled forBdDNA in 2008. Data on the taxonomy, morphology (i.e., weight and snout-vent length), and life-long aquatic dependency of hosts (i.e., aquatic index) were also collated to serve as potential predictors of infection prevalence. Genotyping via quantitative PCR revealed the presence of the global panzootic lineage ofBd(Bd-GPL) in the Ecuadorian Amazon. The overall infection prevalence ofBdwas determined to be 58%, which is a relatively high prevalence rate ofBdreported for any amphibian population from the lowlands of the Neotropics to date. A total of 88% of sampled anuran families tested positive for the infection at varying proportions. A logistic regression analysis showed a significant negative relationship between host weight and the proportion ofBdinfections (p < 0.05). However, no significant associations were observed between host taxonomy, aquatic dependency, or snout-vent length andBdprevalence. Our findings contribute to the understanding ofBddynamics in the Neotropical lowlands and emphasize the need for future research on the ecological factors influencingBdin the Amazon and their implications for amphibian conservation.
Lysosomal integrity suppresses TIR-1/SARM1 aggregation to restrain toxic propagation of p38 innate immunity
Authors: Tse-Kang Samantha Y. , Pukkila-Worley Read 
Published: February 2024

SUMMARYInnate immunity in bacteria, plants and animals requires the specialized subset of TIR-domain proteins that are NAD+hydrolases. Aggregation of these TIR proteins engages their enzymatic activity, but it is not known how this protein multimerization is regulated. Here, we discovered that TIR oligomerization is exquisitely controlled to prevent immune toxicity. We found that p38 propagates its own activation by promoting the feedforward expression and aggregation of the lone enzymatic TIR protein in the nematodeC. elegans, TIR-1/SARM1. We performed a forward genetic screen to determine how the p38 positive feedforward loop is regulated. We discovered that the integrity of the specific lysosomal sub-compartment that expresses TIR-1/SARM1 is actively maintained to limit inappropriate aggregation of this protein and restrain toxic p38 immune activation. Thus, innate immune defenses in intestinal epithelial cells are regulated by specific control of TIR-1/SARM1 multimerization.
Foam rolling intervention improves lactate clearance after high-intensity exercise
Authors: Kasahara Kazuki , Oneyama Keita , Ito Takeru , Nakamura Masatoshi , Ochi Genta 
Published: February 2024

AbstractPurposeThe effects foam rolling (FR) intervention on lactate clearance and the impaired executive function associated with fatigue after high-intensity exercise remain unclear. This study examined whether FR is an effective tool for fatigue recovery.MethodsEighteen healthy adults (10 males, 8 females; 21.8±1.7 years) without consistent exercise habits participated. The participants performed high-intensity exercises using an ergometer with a progressive load. Post-exercise FR intervention was compared with the control condition. Measurements included lactate, vigor/fatigue by the Profile of Mood States 2nd edition, cognitive function (cognitive task performance), and leg and body rating of perceived exertion (RPE) pre-and post-exercise, and post-intervention (5 min post-exercise).ResultsThe blood lactate concentration post-FR intervention (−7.3±3.0 mmol/L) was significantly reduced. Increased lactate clearance by FR correlated with faster recovery of executive function for those with greater lactate clearance, although cognitive fatigue was not observed after high-intensity exercise (P= .086,r= 0.41). Lactate clearance was not significantly correlated with RPE in the FR condition, whereas RPE decreased with increased lactate clearance for those with greater lactate clearance in the control condition (leg;r= 0.778, body;r= 0.669).ConclusionsThese results indicated FR intervention may be an effective recovery tool for exhausting exercises.
AIBP controls TLR4 inflammarafts and mitochondrial dysfunction in a mouse model of Alzheimer’s disease
Authors: Kim Yi Sak , Choi Soo-Ho , Kim Keun-Young , Navia-Pelaez Juliana M. , Perkins Guy A. , Choi Seunghwan , Kim Jungsu , Nazarenkov Nicolaus , Rissman Robert A. , Ju Won-Kyu , Ellisman Mark H. , Miller Yury I. 
Published: February 2024

ABSTRACTMicroglia-driven neuroinflammation plays an important role in the development of Alzheimer’s disease (AD). Microglia activation is accompanied by the formation and chronic maintenance of TLR4 inflammarafts, defined as enlarged and cholesterol-rich lipid rafts serving as an assembly platform for TLR4 dimers and complexes of other inflammatory receptors. The secreted apoA-I binding protein (APOA1BP or AIBP) binds TLR4 and selectively targets cholesterol depletion machinery to TLR4 inflammaraft expressing inflammatory, but not homeostatic microglia. Here we demonstrated that amyloid-beta (Aβ) induced formation of TLR4 inflammarafts in microglia in vitro and in the brain of APP/PS1 mice. Mitochondria in Apoa1bp-/-APP/PS1 microglia were hyperbranched and cupped, which was accompanied by increased ROS and the dilated ER. The size and number of Aβ plaques and neuronal cell death were significantly increased, and the animal survival was decreased in Apoa1bp-/-APP/PS1 compared to APP/PS1 female mice. These results suggest that AIBP exerts control of TLR4 inflammarafts and mitochondrial dynamics in microglia and plays a protective role in AD associated oxidative stress and neurodegeneration.
Gene expression plasticity of the mammalian brain circadian clock in response to photoperiod
Authors: Cox Olivia H. , Gianonni-Guzmán Manuel A. , Cartailler Jean-Philippe , Cottam Matthew A. , McMahon Douglas G. 
Published: February 2024

ABSTRACTSeasonal daylength, or circadian photoperiod, is a pervasive environmental signal that profoundly influences physiology and behavior. In mammals, the central circadian clock resides in the suprachiasmatic nuclei (SCN) of the hypothalamus where it receives retinal input and synchronizes, or entrains, organismal physiology and behavior to the prevailing light cycle. The process of entrainment induces sustained plasticity in the SCN, but the molecular mechanisms underlying SCN plasticity are incompletely understood. Entrainment to different photoperiods persistently alters the timing, waveform, period, and light resetting properties of the SCN clock and its driven rhythms. To elucidate novel molecular mechanisms of photoperiod plasticity, we performed RNAseq on whole SCN dissected from mice raised in Long (LD 16:8) and Short (LD 8:16) photoperiods. Fewer rhythmic genes were detected in Long photoperiod and in general the timing of gene expression rhythms was advanced 4-6 hours. However, a few genes showed significant delays, includingGem. There were significant changes in the expression clock-associated geneTimelessand in SCN genes related to light responses, neuropeptides, GABA, ion channels, and serotonin. Particularly striking were differences in the expression of the neuropeptide signaling genesProkr2andCck, as well as convergent regulation of the expression of three SCN light response genes,Dusp4,Rasd1, andGem. Transcriptional modulation ofDusp4andRasd1,and phase regulation ofGem,are compelling candidate molecular mechanisms for plasticity in the SCN light response through their modulation of the critical NMDAR-MAPK/ERK-CREB/CRE light signaling pathway in SCN neurons. Modulation ofProkr2andCckmay critically support SCN neural network reconfiguration during photoperiodic entrainment. Our findings identify the SCN light response and neuropeptide signaling gene sets as rich substrates for elucidating novel mechanisms of photoperiod plasticity.
Integrated multi-omics analyses reveal the pro-inflammatory and pro-fibrotic pulmonary macrophage subcluster in silicosis
Authors: Kang Hanyujie , Gu Xueqing , Cao Siyu , Tong Zhaohui , Song Nan 
Published: February 2024

AbstractBackgroundSilicosis is a lethal occupational disease caused by long-term exposure to respirable silica dust. Pulmonary macrophages play a crucial role in mediating the initiation of silicosis. However, the phenotypic and functional heterogeneities of pulmonary macrophages in silicosis have not been well-studied.MethodsThe silicosis mouse model was established by intratracheal administration of silica suspension. Bronchoalveolar lavage fluids (BALFs) of mice were collected for the multiplex cytokine analysis. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics were performed to reveal the heterogeneity and spatial localization of macrophages in the lung tissues. The formation of the fibrotic nodules was characterized by histology, hydroxyproline assay, and immunohistochemical staining, respectively. The expression of the pro-inflammatory or pro-fibrotic genes was investigated by quantitative polymerase chain reaction (qPCR).ResultsWe found that the level of pro-inflammatory cytokines and chemokines is significantly increased in the BALFs of silicosis mice. Apparent collagen deposition can also be observed in the silicotic lung tissues. By scRNA-seq, we have identified a subpopulation of Mmp12himacrophages significantly expanding in the lung tissues of mice with silicosis. Spatial transcriptomics analysis further confirmed that the Mmp12himacrophages are mainly enriched in silicosis nodules. Pseudotime trajectory showed that these Mmp12himacrophages, highly expressing both pro-inflammatory and pro-fibrotic genes are derived from Ly6c+monocytes. Additionally, 4-octyl itaconate (4-OI) treatment, which can alleviate pulmonary fibrosis in silicosis mice, also reduces the enrichment of the Mmp12himacrophages. Moreover, we found a subset of macrophages in BALFs derived from patients with silicosis exhibited similar characteristics of Mmp12himacrophages in silicosis mice models.ConclusionsOur study suggested that a group of Mmp12himacrophages highly express both pro-inflammatory and pro-fibrotic factors in silicosis mice, and thus may contribute to the progression of fibrosis. The findings have proposed new insights for understanding the heterogeneity of lung macrophages in silicosis, suggesting that the subset of Mmp12himacrophages may be a potential therapy target to further halt the progression of silicosis.
Nerve injury inhibitsOprd1andCnr1transcription through REST in primary sensory neurons
Authors: Subedi Ashok , Tiwari Aadhya , Etemad Asieh , Huang Yuying , Chatterjee Biji , McLeod Samantha M. , Lu Yungang , Gonzalez DiAngelo , Ghosh Krishna , Singh Sanjay K. , Ruiz Elisa , Grimm Sandra L. , Coarfa Cristian , Pan Hui-Lin , Majumder Sadhan 
Published: February 2024

AbstractThe transcription repressor REST in the dorsal root ganglion (DRG) is upregulated by peripheral nerve injury and promotes the development of chronic pain. However, the genes targeted by REST in neuropathic pain development remain unclear. The expression levels of 4 opioid receptor (Oprm1,Oprd1,Oprl1,Oprk1)and the cannabinoid CB1 receptor (Cnr1) genes in the DRG regulate nociception. In this study, we determined the role of REST in the control of their expression in the DRG induced by spared nerve injury (SNI) in both male and female mice. Transcriptomic analyses of male mouse DRGs followed by quantitative reverse transcription polymerase chain reaction analyses of both male and female mouse DRGs showed that SNI upregulated expression ofRestand downregulated mRNA levels of all 4 opioid receptor andCnr1genes, butOprm1was upregulated in female mice. Analysis of publicly available bioinformatic data suggested that REST binds to the promoter regions ofOprm1andCnr1. Chromatin immunoprecipitation analyses indicated differing levels of REST at these promoters in male and female mice. Full-lengthRestconditional knockout in primary sensory neurons reduced SNI-induced pain hypersensitivity and rescued the SNI-induced reduction in the expression ofOprd1andCnr1in the DRG in both male and female mice. Our results suggest that nerve injury represses the transcription ofOprd1andCnr1via REST in primary sensory neurons and that REST is a potential therapeutic target for neuropathic pain.
FECDO-Flexible and Efficient Coding for DNA Odyssey
Authors: Sun Fajia , Qian Long 
Published: February 2024

SummaryDNA has been pursued as a compelling medium for digital data storage during the past decade. While large-scale data storage and random access have been achieved in artificial DNA, the synthesis cost keeps hindering DNA data storage from popularizing into daily life. In this study, we proposed a more efficient paradigm for digital data compressing to DNA, while excluding arbitrary sequence constraints. Both standalone neural networks and pre-trained language models were used to extract the intrinsic patterns of data, and generated probabilistic portrayal, which was then transformed into constraint-free nucleotide sequences with a hierarchical finite state machine. Utilizing these methods, a 12%-26% improvement of compression ratio was realized for various data, which directly translated to up to 26% reduction in DNA synthesis cost. Combined with the progress in DNA synthesis, our methods are expected to facilitate the realization of practical DNA data storage.
Differential weighting of information during aloud and silent reading: Evidence from representational similarity analysis of fMRI data
Authors: Bailey Lyam M. , Matheson Heath E. , Fawcett Jonathon M. , Bodner Glen E. , Newman Aaron J. 
Published: February 2024

AbstractSingle word reading depends on multiple types of information processing: readers must process low-level visual properties of the stimulus, form orthographic and phonological representations of the word, and retrieve semantic content from memory. Reading aloud introduces an additional type of processing wherein readers must execute an appropriate sequence of articulatory movements necessary to produce the word. To date, cognitive and neural differences between aloud and silent reading have mainly been ascribed to articulatory processes. However, it remains unclear whether articulatory information is used to discriminate unique words, at the neural level, during aloud reading. Moreover, very little work has investigated how other types of information processing might differ between the two tasks. The current work used representational similarity analysis (RSA) to interrogate fMRI data collected while participants read single words aloud or silently. RSA was implemented using a whole-brain searchlight procedure to characterize correspondence between neural data and each of five models representing a discrete type of information. Both conditions elicited decodability of visual, orthographic, phonological, and articulatory information, though to different degrees. Compared with reading silently, reading aloud elicited greater decodability of visual, phonological, and articulatory information. By contrast, silent reading elicited greater decodability of orthographic information in right anterior temporal lobe. These results support an adaptive view of reading whereby information is weighted according to its task relevance, in a manner that best suits the reader’s goals.
MicroRNA-26b protects against MASH development in mice and can be efficiently targeted with lipid nanoparticles
Authors: Peters Linsey J.F. , Rakateli Leonida , Huchzermeier Rosanna , Bonnin-Marquez Andrea , Maas Sanne L. , Lin Cheng , Jans Alexander , Geng Yana , Gorter Alan , Gijbels Marion J. , Rensen Sander S. , Olinga Peter , Hendrikx Tim , Krawczyk Marcin , Brisbois Malvina , Jankowski Joachim , Bidzhekov Kiril , Weber Christian , Biessen Erik A.L. , Shiri-Sverdlov Ronit , Houben Tom , Döring Yvonne , Bartneck Matthias , van der Vorst Emiel P.C. 
Published: February 2024

AbstractBackground & AimsThe prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing, urging more research into the underlying mechanisms. MicroRNA-26b (miR-26b) might play a role in several MASH-related pathways. Therefore, we aimed to determine the role of miR-26b in MASH and its therapeutic potential using miR-26b mimic-loaded lipid nanoparticles (LNPs).MethodsApoe-/-Mir26b-/-,Apoe-/-LysMcreMir26bfl/flmice, and respective controls were fed a western-type diet to induce MASH. Plasma and liver samples were characterized regarding lipid metabolism, hepatic inflammation, and fibrosis. Additionally, miR-26b mimic-loaded LNPs were injected inApoe-/-Mir26b-/-mice to rescue the phenotype and key results were validated in human precision-cut liver slices. Finally, kinase profiling was used to elucidate underlying mechanisms.ResultsApoe-/-Mir26b-/-mice showed increased hepatic lipid levels, coinciding with increased expression of scavenger receptor a and platelet glycoprotein 4. Similar effects were found in mice lacking myeloid-specificmiR-26b. Additionally, hepatic TNF and IL-6 levels and amount of infiltrated macrophages were increased inApoe-/-Mir26b-/-mice. Moreover,Tgfbexpression was increased by themiR-26bdeficiency, leading to more hepatic fibrosis. A murine treatment model with miR-26b mimic-loaded LNPs reduced hepatic lipids, rescuing the observed phenotype. Kinase profiling identified increased inflammatory signaling uponmiR-26bdeficiency, which was rescued by LNP treatment. Finally, miR-26b mimic-loaded LNPs also reduced inflammation in human precision-cut liver slices.ConclusionsOverall, our study demonstrates that the detrimental effects ofmiR-26bdeficiency in MASH can be rescued by LNP treatment. This novel discovery leads to more insight into MASH development, opening doors to potential new treatment options using LNP technology.Graphical abstract
Epigallocatechin-3-gallate inhibit the protein arginine methyltransferase 5 and Enhancer of Zeste homolog 2 in breast cancer bothin vitroandin vivo
Authors: Nalla Kirankumar , Chatterjee Biji , Poyya Jagadeesh , Swain Aishwarya , Ghosh Krishna , Pan Archana , Joshi Chandrashekhar G , Manavathi Bramanandam , Kanade Santosh R 
Published: February 2024

AbstractHistone methyltransferases are selectively catalyzing the methylation of lysine or arginine residues of target histone and non-histone proteins, classified as lysine methyltransferases and arginine methyltransferases. The EZH2 and PRMT5 catalyze trimethylation of H3 at K27 and symmetric dimethylation of H4 at R3 respectively. These histone repressive marks have been considered as hallmarks in cancer. Both PRMT5 and EZH2 over expressed in several cancers and have been considered as important target of drug development. As a result, many synthetic molecules as inhibitors of both PRMT5 and EZH2 are at different level of preclinical and clinical phases. Cancer atlas data analysis revealed that both PRMT5 and EZH2 had shown more than 90% amplification in breast cancer alone. We screened an array of phytocompounds towards the inhibition of PRMT5 and EZH2 usingin silico, in vitroassays. Among them Epigallocatechin-3-gallate (EGCG) has interacted with human PRMT5: MEP50 and EZH2 efficiently. The EGCG interacted within the SAM binding site, with a π-cation interaction at Lys 333 and H-bonds with Tyr324, Tyr334, Gly365, Leu437, and Glu444. Surface plasmon resonance analysis revealed that EGCG has strong binding affinity in nanomolar concentrations with both PRMT5-MEP50 than EZH2. Further in vitro methylation and cell-based assays proved the inhibitory potential of EGCG by reducing the catalytic products of PRMT5 and EZH2 i.e., H4R3me2s & H3K27me3 respectively and showed that it induced autophagy and apoptosis. Furthermorein vivo, mouse xenografts studies demonstrated that oral dosage, reduced tumor size significantly with reduction in proliferation marker Ki67 and these histone repressive marks. Finally conclude that inhibition of PRMT5 and EZH2 by EGCG potentially can be used to develop combined therapeutic approaches.