bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cell-selective proteomics reveal novel effectors secreted by an obligate intracellular bacterial pathogen
Authors: Sanderlin Allen G. , Margolis Hannah K. , Meyer Abigail F. , Lamason Rebecca L. 
Published: November 2023

AbstractPathogenic bacteria secrete protein effectors to hijack host machinery and remodel their infectious niche.Rickettsiaspp. are obligate intracellular bacteria that can cause life- threatening disease, but their absolute dependence on the host cell environment has impeded discovery of rickettsial effectors and their host targets. We implemented bioorthogonal non-canonical amino acid tagging (BONCAT) duringR. parkeriinfection to selectively label, isolate, and identify secreted effectors. As the first use of BONCAT in an obligate intracellular bacterium, our screen more than doubles the number of experimentally validated effectors forR. parkeri. The novel secreted rickettsial factors (Srfs) we identified includeRickettsia-specific proteins of unknown function that localize to the host cytoplasm, mitochondria, and ER. We further show that one such effector, SrfD, interacts with the host Sec61 translocon. Altogether, our work uncovers a diverse set of previously uncharacterized rickettsial effectors and lays the foundation for a deeper exploration of the host-pathogen interface.
A meta-analysis of rice phosphoproteomics data to understand variation in cell signalling across the rice pan-genome
Authors: Ramsbottom Kerry A , Prakash Ananth , Riverol Yasset Perez , Camacho Oscar Martin , Sun Zhi , Kundu Deepti J. , Bowler-Barnett Emily , Martin Maria , Fan Jun , Chebotarov Dmytro , McNally Kenneth L , Deutsch Eric W , Vizcaíno Juan Antonio , Jones Andrew R 
Published: November 2023

AbstractPhosphorylation is the most studied post-translational modification, and has multiple biological functions. In this study, we have re-analysed publicly available mass spectrometry proteomics datasets enriched for phosphopeptides from Asian rice (Oryza sativa). In total we identified 15,522 phosphosites on serine, threonine and tyrosine residues on rice proteins.We identified sequence motifs for phosphosites, and link motifs to enrichment of different biological processes, indicating different downstream regulation likely caused by different kinase groups. We cross-referenced phosphosites against the rice 3,000 genomes, to identify single amino acid variations (SAAVs) within or proximal to phosphosites that could cause loss of a site in a given rice variety. The data was clustered to identify groups of sites with similar patterns across rice family groups, for example those highly conserved in Japonica, but mostly absent in Aus type rice varieties - known to have different responses to drought. These resources can assist rice researchers to discover alleles with significantly different functional effects across rice varieties.The data has been loaded into UniProt Knowledge-Base - enabling researchers to visualise sites alongside other data on rice proteins e.g. structural models from AlphaFold2, PeptideAtlas and the PRIDE database - enabling visualisation of source evidence, including scores and supporting mass spectra.
Predicting protein folding pathway using a novel folding force field model derived from known protein universe
Authors: Zhao Kailong , Zhao Pengxin , Wang Suhui , Xia Yuhao , Zhang Guijun 
Published: November 2023

AbstractThe protein folding problem has emerged as a new challenge with the significant advances in deep learning driven protein structure prediction methods. While the structures of almost all known proteins have been successfully predicted, the process by which they fold remains an enigma. Understanding the intricate folding mechanism is of paramount importance, as it directly impacts the stable expression and biological function of proteins. Here, we propose FoldPAthreader, a protein folding pathway prediction method that designs a novel folding force field model by exploring the intrinsic relationship between protein evolutionary history and folding mechanisms from the known protein universe. Further, the folding force field is used to guide Monte Carlo conformational sampling, driving the protein chain fold into its native state by exploring a series of transition states and potential intermediates. On the 30 targets we collected, FoldPAthreader can successfully predict 70% of the proteins whose folding pathway is consistent with wet-lab experimental data. The results show that the folding force field can capture key dynamic features of hydrogen bonding and hydrophobic interactions. Importantly, for the widely studied BPTI and TIM proteins, the folding pathway predicted by FoldPAthreader have the same microscopic dynamic properties as those simulated by molecular dynamics.Significance StatementProtein folding is the process by which a protein acquires its functional conformations by gradually transforming from random coils into a specific three-dimensional structure. In the post-Alphafold2 era, functional analysis of protein macromolecules should not only rely on the final state structure, but should pay more attention to the structural folding process, that is, the various intermediate states formed during the folding process. At present, there is no folding force field specifically used for protein folding pathway prediction in computational biology. Here we extracted folding information from 100-million-level structure database and designed a new folding force field for folding pathway prediction, proving a hypothesis that the protein evolutionary history implicitly contains folding information of individual protein. This study may provide new insights into the understanding of protein folding mechanisms, which is expected to advance drug discovery.
The thiol methyltransferase activity of TMT1A (METTL7A) is conserved across species
Authors: González Dalmasy José M. , Fitzsimmons Christina M. , Frye William J.E. , Perciaccante Andrew J. , Jewell Connor P. , Jenkins Lisa M. , Batista Pedro J. , Robey Robert W. , Gottesman Michael M. 
Published: November 2023

ABSTRACTAlthough few resistance mechanisms for histone deacetylase inhibitors (HDACis) have been described, we recently demonstrated that TMT1A (formerly METTL7A) and TMT1B (formerly METTL7B) can mediate resistance to HDACis with a thiol as the zinc-binding group by methylating and inactivating the drug. TMT1A and TMT1B are poorly characterized, and their normal physiological role has yet to be determined. As animal model systems are often used to determine the physiological function of proteins, we investigated whether the ability of these methyltransferases to methylate thiol-based HDACis is conserved across different species. We found that TMT1A was conserved across rats, mice, chickens, and zebrafish, displaying 85.7%, 84.8%, 60.7% and 51.0% amino acid sequence identity, respectively, with human TMT1A. Because TMT1B was not found in the chicken or zebrafish, we focused our studies on the TMT1A homologs. HEK-293 cells were transfected to express mouse, rat, chicken, or zebrafish homologs of TMT1A and all conferred resistance to the thiol-based HDACIs NCH-51, KD-5170 and romidepsin compared to empty vector-transfected cells. Additionally, all homologs blunted the downstream effects of HDACi treatment such as increased p21 expression, increased acetylated histone H3, and cell cycle arrest. Increased levels of dimethylated romidepsin were also found in the culture medium of cells transfected to express any of the TMT1A homologs after a 24 h incubation with romidepsin compared to empty-vector transfected cells. Our results indicate that the ability of TMT1A to methylate molecules is conserved across species. Animal models may therefore be useful in elucidating the role of these enzymes in humans.
Investigating the Effect of Visual Threat in Virtual Reality on Perceiving Postural Instability Onset
Authors: McIlroy Robert E , Barnett-Cowan Michael 
Published: November 2023

AbstractBackgroundSensory information processing plays a crucial role in monitoring the timing of external and internal events, including the control of balance. While previous research has investigated the role of vision in the perceived timing of postural instability onset with eyes closed and open, it is important to further explore the influence of visual context. Virtual reality offers a unique opportunity to manipulate visual information and assess its impact on balance control and the perceived timing of sensory events.Research QuestionDoes visual information, particularly visual threat presented in virtual reality, alter the perceived timing of postural instability onset?MethodsTwo temporal order judgment tasks were conducted using virtual reality to manipulate visual information. Participants were placed on a virtual skyscraper to induce visual threat. The experiments investigated the impact of visual information on the perceived onset of postural instability while manipulating the presence/absence of visual threat.ResultsWith vision available but without visual threat, the onset of a postural perturbation needed to occur 10.71-12.33 ms before a reference sound stimulus to be perceived as simultaneous. With visual threat, the onset needed to occur 4.45 ms before auditory cue onset to be perceived as simultaneous. While these delays were not significantly different from true simultaneity of perturbation and sound onset, participants were significantly more precise in their judgments when threatening visual information was present.SignificanceOur results show that visual context, particularly visual threat presented in virtual reality, may alter the perception of perturbation onset and the precision of judgments made. This has implications for understanding the role of vision in balance control and developing interventions to improve balance and prevent falls.
Targeted brain-specific tauopathy compromises peripheral skeletal muscle integrity and function
Authors: Alava Bryan , Hery Gabriela , Sidhom Silvana , Prokop Stefan , Esser Karyn , Abisambra Jose 
Published: November 2023

SummaryTauopathies are neurodegenerative disorders in which the pathological intracellular aggregation of the protein tau causes cognitive deficits. Additionally, clinical studies report muscle weakness in populations with tauopathy. However, whether neuronal pathological tau species confer muscle weakness, and whether skeletal muscle maintains contractile capacity in primary tauopathy remains unknown. Here, we identified skeletal muscle abnormalities in a mouse model of primary tauopathy, expressing human mutant P301L-tau using adeno-associated virus serotype 8 (AAV8). AAV8-P301L mice showed grip strength deficits, hyperactivity, and abnormal histological features of skeletal muscle. Additionally, spatially resolved gene expression of muscle cross sections were altered in AAV8-P301L myofibers. Transcriptional changes showed alterations of genes encoding sarcomeric proteins, proposing a weakness phenotype. Strikingly, specific force of the soleus muscle was blunted in AAV8-P301L tau male mice. Our findings suggest tauopathy has peripheral consequences in skeletal muscle that contribute to weakness in tauopathy.
A human immune/muscle xenograft model of FSHD muscle pathology
Authors: Daman Katelyn , Yan Jing , Burzenski Lisa M. , Kady Jamie , Shultz Leonard D. , Brehm Michael A. , Emerson Charles P. 
Published: November 2023

AbstractBackgroundFacioscapulohumeral muscular dystrophy (FSHD) disease progression is associated with muscle inflammation, although its role in FSHD muscle pathology is unknown.MethodsWe have developed a novel humanized mouse strain, NSG-SGM3-W41, that supports the co- engraftment of human hematopoietic stem cells (HSCs) and muscle myoblasts as an experimental model to investigate the role of innate immunity in FSHD muscle pathology.ResultsThe NSG-SGM3-W41 mouse supports the selective expansion of human innate immune cell lineages following engraftment of human HSCs and the co-engraftment and differentiation of patient-derived FSHD or control muscle myoblasts. Immunohistological and NanoString RNA expression assays establish that muscle xenografts from three FSHD subjects were immunogenic compared to those from unaffected first-degree relatives. FSHD muscle xenografts preferentially accumulated human macrophages and B cells and expressed early complement genes of the classical and alternative pathways including complement factor C3 protein, which is a mediator of early complement function through opsonization to mark damaged cells for macrophage engulfment. FSHD muscle xenografts also underwent immune donor dependent muscle turnover as assayed by human spectrin β1 immunostaining of muscle fibers and by NanoString RNA expression assays of muscle differentiation genes.ConclusionsThe NSG-SGM3-W41 mouse provides an experimental model to investigate the role of innate immunity and complement in FSHD muscle pathology and to develop FSHD therapeutics targeting DUX4 and the innate immunity inflammatory responses.
Poc1 is a basal body inner junction protein that promotes triplet microtubule integrity and interconnections
Authors: Ruehle Marisa D. , Li Sam , Agard David A. , Pearson Chad G. 
Published: November 2023

ABSTRACTBasal bodies (BBs) are conserved eukaryotic structures that organize motile and primary cilia. The BB is comprised of nine, cylindrically arranged, triplet microtubules (TMTs) that are connected to each other by inter-TMT linkages which maintain BB structure. During ciliary beating, forces transmitted to the BB must be resisted to prevent BB disassembly. Poc1 is a conserved BB protein important for BBs to resist ciliary forces. To understand how Poc1 confers BB stability, we identified the precise position of Poc1 binding in theTetrahymenaBB and the effect of Poc1 loss on BB structure. Poc1 binds at the TMT inner junctions, stabilizing TMTs directly. From this location, Poc1 also stabilizes inter-TMT linkages throughout the BB, including the cartwheel pinhead and the inner scaffold. Moreover, we identify a molecular response to ciliary forces via a molecular remodeling of the inner scaffold, as determined by differences in Fam161A localization. Thus, while not essential for BB assembly, Poc1 promotes BB interconnections that establish an architecture competent to resist ciliary forces.
Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging
Authors: Saeedi Saravi Seyed Soheil , Pugin Benoit , Constancias Florentin , Thomas Aurélien , Gludic Sylvain Le , Allemann Meret Sarah , Karsai Gergely , Lee Pratintip , Menni Cristina , Attaye Ilias , Beer Jürg H. 
Published: November 2023

AbstractEndothelial cell (EC) senescence plays a crucial role in the development of cardiovascular diseases in aging population. Gut microbiota alterations are emerging as significant factors present in cellular senescence associated with aging. However, little is known about how aging-related changes in gut microbiota are causally implicated in EC senescence. Here we show that gut microbiota-dependent phenylacetic acid (PAA) and its derivative, phenylacetylglutamine (PAGln), are elevated in a human aging cohort (TwinsUK, n=7,303) and in aged mice. Metagenomic analyses revealed a marked increase in the abundance of PAA-producing microbial pathways (PPFOR and VOR), which were positively associated with the abundance ofClostridiumsp. ASF356, higher circulating PAA concentrations, and endothelial dysfunction in old mice. We found that PAA potently induces EC senescence and attenuates angiogenesis. Mechanistically, PAA increases mitochondrial H2O2generation, which aggravates IL6-mediated HDAC4 translocation and thereby upregulates VCAM1. In contrast, exogenous acetate, which was reduced in old mice, rescues the PAA-induced EC senescence and restores angiogenic capacity through markedly alleviating the SASP and epigenetic alteration. Our studies provide direct evidence of PAA-mediated crosstalk between aging gut microbiota and EC senescence and suggest a microbiota-based therapy for promoting healthy aging.HighlightsAging-related gut microbiota alterations contribute to a marked elevation of plasma PAA and PAGln in humans and miceClostridiumsp. ASF356 contributes to PPFOR-mediated PAA formation in aged miceGut-derived PAA promotes endothelial senescence and impairs angiogenesisPAA induces mitochondrial H2O2generation, by which drives epigenetic alterations and SASP in ECsAcetate rescues PAA-induced EC senescence and mitochondrial dysfunctionAcetate improves angiogenesis by reducing HDAC4 phosphorylation and SASP
Differential responses of primary neuron-secreted MCP-1 and IL-9 to type 2 diabetes and Alzheimer’s disease-associated metabolites
Authors: Ball Brendan K. , Kuhn Madison K. , Fleeman Rebecca M. , Proctor Elizabeth A. , Brubaker Douglas K. 
Published: November 2023

ABSTRACTType 2 diabetes (T2D) is implicated as a risk factor for Alzheimer’s disease (AD), the most common form of dementia. In this work, we investigated neuroinflammatory responses of primary neurons to potentially circulating, blood-brain barrier (BBB) permeable metabolites associated with AD, T2D, or both. We identified nine metabolites associated with protective or detrimental properties of AD and T2D in literature (lauric acid, asparagine, fructose, arachidonic acid, aminoadipic acid, sorbitol, retinol, tryptophan, niacinamide) and stimulated primary mouse neuron cultures with each metabolite before quantifying cytokine secretion via Luminex. We employed unsupervised clustering, inferential statistics, and partial least squares discriminant analysis to identify relationships between cytokine concentration and disease-associations of metabolites. We identified MCP-1, a cytokine associated with monocyte recruitment, as differentially abundant between neurons stimulated by metabolites associated with protective and detrimental properties of AD and T2D. We also identified IL-9, a cytokine that promotes mast cell growth, to be differentially associated with T2D. Indeed, cytokines, such as MCP-1 and IL-9, released from neurons in response to BBB-permeable metabolites associated with T2D may contribute to AD development by downstream effects of neuroinflammation.
JUNmRNA Translation Regulation is Mediated by Multiple 5’ UTR and Start Codon Features
Authors: González-Sánchez Angélica M. , Castellanos-Silva Eimy A. , Díaz-Figueroa Gabriela , Cate Jamie H. D. 
Published: November 2023

ABSTRACTRegulation of mRNA translation by eukaryotic initiation factors (eIFs) is crucial for cell survival. In humans, eIF3 stimulates translation of theJUNmRNA which encodes the transcription factor JUN, an oncogenic transcription factor involved in cell cycle progression, apoptosis, and cell proliferation. Previous studies revealed that eIF3 activates translation of theJUNmRNA by interacting with a stem loop in the 5′ untranslated region (5′ UTR) and with the 5′ -7-methylguanosine cap structure. In addition to its interaction site with eIF3, theJUN5′ UTR is nearly one kilobase in length, and has a high degree of secondary structure, high GC content, and an upstream start codon (uAUG). This motivated us to explore the complexity ofJUNmRNA translation regulation in human cells. Here we find that JUN translation is regulated in a sequence and structure-dependent manner in regions adjacent to the eIF3-interacting site in theJUN5′ UTR. Furthermore, we identify contributions of an additional initiation factor, eIF4A, inJUNregulation. We show that enhancing the interaction of eIF4A withJUNby using the compound Rocaglamide A (RocA) repressesJUNtranslation. We also find that both the upstream AUG (uAUG) and the main AUG (mAUG) contribute toJUNtranslation and that they are conserved throughout vertebrates. Our results reveal additional layers of regulation forJUNtranslation and show the potential ofJUNas a model transcript for understanding multiple interacting modes of translation regulation.
Genome-wide assessment of runs of homozygosity in Sahiwal cattle of Pakistan
Authors: Sesay Abdul Rahman , Saif-ur-Rehman Mohammad , Ramzan Faisal , Awan Faisal Saeed 
Published: November 2023

AbstractRuns of homozygosity (ROH) are extensive stretches of homozygous genotypes present in an individual genome inherited from each of its parents. Selection pressures have been one of the core causes of a reduction in genetic diversity in some genomic regions, leading to an accumulation of ROH in these regions. An individual’s ROH can provide information about the past of his population, including the extent of inbreeding, recent bottlenecks, and positive selection. The study aimed to evaluate the degree of autozygosity throughout the genome in Sahiwal cattle to discern and describe ROH patterns. In addition, we also estimated the rate of inbreeding based on ROH in Sahiwal cattle. A sample of 98 Sahiwal bulls from various public institutional herds and private livestock farms in the Punjab province of Pakistan was used for this study. All animals were genotyped using the 140k BovineHD SNP chip. The study identified ROH in all animals. The mean ROH per animal was 29.71, with values extending from 2.35 to 85.31. The mean length of the ROH was 5.84 Mb, and the longest segment was 51.43 Mb (1,727 SNPs) found on BTA3. Results revealed that genome-wide ROH for Sahiwal was typically composed of many short and medium segments (2–4 Mb and 4–8 Mb), accounting for approximately 54.18% of all detected ROH. The inbreeding coefficient based on ROH (FROH) ranged from 0.016 to 0.057. The study revealed several genes, including STAT1, ATP1A1, OLR1, and CD4, which are known genes related to milk production. Thus, understanding ROH patterns, an inbreeding coefficient derived from ROH, and candidate genes associated with significant economic traits can help explain the mechanisms governing these traits in Sahiwal cattle.
Mass spectrometry imaging links interxylary cork formation with phytochemical distribution inScutellaria baicalensis
Authors: Huang Lieyan , Nie Lixing , Dong Jing , Yao Lingwen , Kang Shuai , Jin Hongyu , Wei Feng , Ma Shuangcheng 
Published: November 2023

AbstractInterxylary cork, an anomalous cork structure of plant, is occasionally seen in older roots ofScutellaria baicalensisGeorgi (Lamiaceae). Xylem tissues encircled by interxylary corks gradually decay. Efforts have been made to elucidate the development of interxylary cork inS. baicalensis, but the variation of phytochemical accumulation in different root tissues segmented by interxylary cork has not been studied. In this investigation, mass spectrometry imaging was employed to visualize thein situphytochemicals in the decayed root ofS. baicalensis(Kuqin). A special flavonoid was observed to show especially high mass intensity in the cork region, and its spatial distribution was regarded as a reflection of cork development. Interxylary corks were found to be successively formed in the root ofS. baicalensis. After the continuous formation of interxylary corks, root tissues were divided into different parts by interxylary corks, including the non-decayed part, slightly decayed part and severely decayed part. Interestingly, pharmaceutically important flavonoids presented different accumulation tendencies in tissues of different decaying degrees. Owing to the non-targeted analytical function of mass spectrometry imaging, the holistic difference of chemical composition of decayed and non-decayed tissues of Kuqin was deciphered. To our knowledge, this is the first experiment that maps out the successive formation of interxylary corks inS. baicalensisusing mass spectrometry imaging. Also, our research successfully correlates plant anatomy with the spatial distribution of phytochemicals, which sets a good example for the exploration of plant science from the dimension of spatial information.