bluuebunny/crossref_metadata_2025_split huggingface dataset:
Surface frustration re-patterning underlies the structural landscape and evolvability of fungal orphan candidate effectors
Authors: Derbyshire Mark C. , Raffaele Sylvain 
Published: January 2023

ABSTRACTPathogens secrete effector proteins to subvert host physiology and cause disease. Effectors are engaged in a molecular arms race with the host resulting in conflicting evolutionary constraints to manipulate host cells without triggering immune responses. The molecular mechanisms allowing effectors to be at the same time robust and evolvable remain largely enigmatic. Here, we show that 62 conserved structure-related families encompass the majority of fungal orphan effector candidates at the subphylum level. These effectors diversified through changes in patterns of thermodynamic frustration at surface residues. The underlying mutations tended to increase the robustness of the overall effector protein structure while switching potential binding interfaces. This mechanism could explain how conserved effector families maintained biological activity over long evolutionary timespans in different host environments and provides a model for the emergence of sequence-unrelated effector families with conserved structures.
High Throughput Single Cell Proteomic Analysis of Organ Derived Heterogeneous Cell Populations by Nanoflow Dual Trap Single Column Liquid Chromatography
Authors: Kreimer Simion , Binek Aleksandra , Chazarin Blandine , Cho Jae Hyung , Haghani Ali , Hutton Alexandre , Marbán Eduardo , Mastali Mitra , Meyer Jesse G , Mesquita Thassio , Song Yang , Van Eyk Jennifer , Parker Sarah 
Published: January 2023

AbstractIdentification and proteomic characterization of rare cell types within complex organ derived cell mixtures is best accomplished by label-free quantitative mass spectrometry. High throughput is required to rapidly survey hundreds to thousands of individual cells to adequately represent rare populations. Here we present parallelized nanoflow dual-trap single-column liquid chromatography (nanoDTSC) operating at 15 minutes of total run time per cell with peptides quantified over 11.5 minutes using standard commercial components, thus offering an accessible and efficient LC solution to analyze 96 single-cells per day. At this throughput, nanoDTSC quantified over 1,000 proteins in individual cardiomyocytes and heterogenous populations of single cells from aorta.For Table of Contents Only
Metabolite T1relaxation times differ across the adult lifespan
Authors: Murali-Manohar Saipavitra , Gudmundson Aaron T. , Hupfeld Kathleen E. , Zöllner Helge J. , Hui Steve C.N. , Song Yulu , Davies-Jenkins Christopher W. , Gong Tao , Wang Guangbin , Oeltzschner Georg , Edden Richard A.E. 
Published: January 2023

AbstractPurposeTo investigate the age-dependence of metaboliteT1relaxation times at 3T in both gray- and white-matter-rich voxels.MethodsThis manuscript analyzes publicly available metabolite and metabolite-nulled (single inversion recovery TI = 600 ms) spectra acquired at 3T using PRESS localization. Voxels were placed in posterior cingulate cortex and centrum semiovale in 102 healthy volunteers across 5 decades of life (20s to 60s). All spectra were analyzed in Osprey v2.4.0. To estimateT1relaxation times for tNAA2.0and tCr3.0, the ratio of modeled metabolite residual amplitudes in the metabolite-nulled spectrum to the full metabolite signal was calculated using the single inversion recovery signal equation. Correlations betweenT1and subject age were evaluated.ResultsSpearman correlations revealed that estimated T1relaxation times of tNAA2.0(rs= −0.43; p < 0.001) and tCr3.0(rs= −0.23; p = 0.021) decreased significantly with age in white-matter-rich CSO, and less steeply (and not significantly) for tNAA2.0(rs= −0.15; p = 0.136) and tCr3.0(rs= −0.10; p = 0.319) in gray-matter-rich PCC.ConclusionThe analysis harnessed a large publicly available cross-sectional dataset to test an important hypothesis, that metabolite T1relaxation times change with age. This preliminary study stresses the importance of further work to measure age-normed metabolite T1relaxation times for accurate quantification of metabolite levels in studies of aging.
Chromatin Remodeling Drives Immune-Fibroblast Crosstalk in Heart Failure Pathogenesis
Authors: Alexanian Michael , Padmanabhan Arun , Nishino Tomohiro , Travers Joshua G. , Ye Lin , Lee Clara Youngna , Sadagopan Nandhini , Huang Yu , Pelonero Angelo , Auclair Kirsten , Zhu Ada , Gonzalez Teran Barbara , Flanigan Will , Kim Charis Kee-Seon , Lumbao-Conradson Koya , Costa Mauro , Jain Rajan , Charo Israel , Haldar Saptarsi M. , Pollard Katherine S. , Vagnozzi Ronald J. , McKinsey Timothy A. , Przytycki Pawel F. , Srivastava Deepak 
Published: January 2023

AbstractChronic inflammation and tissue fibrosis are common stress responses that worsen organ function, yet the molecular mechanisms governing their crosstalk are poorly understood. In diseased organs, stress-induced changes in gene expression fuel maladaptive cell state transitions and pathological interaction between diverse cellular compartments. Although chronic fibroblast activation worsens dysfunction of lung, liver, kidney, and heart, and exacerbates many cancers, the stress-sensing mechanisms initiating the transcriptional activation of fibroblasts are not well understood. Here, we show that conditional deletion of the transcription co-activatorBrd4inCx3cr1-positive myeloid cells ameliorates heart failure and is associated with a dramatic reduction in fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancyin vivoinCx3cr1-positive cells identified a large enhancer proximal toInterleukin-1 beta (Il1b), and a series of CRISPR deletions revealed the precise stress-dependent regulatory element that controlled expression ofIl1bin disease. Secreted IL1B functioned non-cell autonomously to activate a p65/RELA-dependent enhancer near the transcription factorMEOX1, resulting in a profibrotic response in human cardiac fibroblasts.In vivo, antibody-mediated IL1B neutralization prevented stress-induced expression ofMEOX1, inhibited fibroblast activation, and improved cardiac function in heart failure. The elucidation of BRD4-dependent crosstalk between a specific immune cell subset and fibroblasts through IL1B provides new therapeutic strategies for heart disease and other disorders of chronic inflammation and maladaptive tissue remodeling.
A CheZ orthologue inCampylobacter jejuniplays a role in chemotaxis through conserved phosphatase activity
Authors: Jama Abdullahi S. , Ketley Julian M. 
Published: January 2023

AbstractThe major food-borne pathogenCampylobacter jejuniemploys chemotactic motility to colonise the avian gut, and also as a virulence mechanism in human diarrhoeal disease.InEscherichia coliCheY activity is modulated by CheZ, a phosphatase originally thought to be absent inC. jejuni. The Hp0170 protein ofHelicobacter pyloriis a distant homologue of CheZ and, asC. jejuniCj0700 is homologous to HP0170, Cj0700 could also act as a CheZ orthologue inCampylobacter. Both theC. jejuniCheV and CheA proteins also contain a response regulator (RR) domain that may be phosphorylated. Cj0700 would therefore be predicted to dephosphorylateC. jejuniCheY and possibly also the CheV and CheA RR domains.A mutant (Δcj0700)and complement (Δcj0700, cj0046::cj0700) were constructed inC.jejunistrains NCTC11168, NCTC11828 and 81-176. On semisolid agar the Δcj0700mutant strain showed reduced motility relative to wild-type and this phenotype was reversed in the complemented strain. In pull down and bacterial two hybrid assays, expressed Cj0700 was able to interact with CheY, CheA-RR and CheV.Cj0700 is able to dephosphorylate the RR domain of CheY and CheA-RR, but less efficiently, CheV. These findings verify that Cj0700 plays a role inC. jejunichemotaxis through phosphatase activity with respect to CheY, and is hence likely to be a CheZ orthologue. Cj0700 also partially modulates the phosphorylation level of the RR domain on CheA and CheV, although the functional consequences of this interaction require further investigation.
HiDDEN: A machine learning label refinement method for detection of disease-relevant populations in case-control single-cell transcriptomics
Authors: Goeva Aleksandrina , Dolan Michael-John , Luu Judy , Garcia Eric , Boiarsky Rebecca , Gupta Rajat M , Macosko Evan 
Published: January 2023

AbstractIn case-control single-cell RNA-seq studies, sample-level labels are transferred onto individual cells, labeling all case cells as affected, but only a small fraction of them may actually be perturbed. Here, using simulations, we demonstrate that the standard approach to single cell analysis fails to isolate the subset of affected case cells and their markers when either the affected subset is small, or when the strength of the perturbation is mild. To address this fundamental limitation, we introduce HiDDEN, a computational method that refines the case-control labels to accurately reflect the perturbation status of each cell. We show HiDDEN’s superior ability to recover biological signals missed by the standard analysis workflow in simulated ground truth datasets of cell type mixtures. When applied to a dataset of human multiple myeloma precursor conditions, HiDDEN recapitulates the expert manual annotation and discovers malignancy in previously considered healthy early stage samples. When applied to a mouse model of demyelination, HiDDEN identifies an endothelial subpopulation playing a role in early stage blood-brain barrier dysfunction. We anticipate that HiDDEN should find a wide usage in contexts which require the detection of subtle changes in cell types across conditions.
An axon – T cell feedback loop enhances inflammation and axon degeneration
Authors: Liu Tingting , Wang Huanhuan , Kutsovsky Daniel Y. , Ohn Christine Y.J. , Patel Nandan , Yang Jing , Simon David J. 
Published: January 2023

AbstractInflammation is closely associated with many neurodegenerative disorders. Yet whether inflammation causes or exacerbates neurodegeneration has been challenging to define because the two processes are so closely linked. Here we disentangle inflammation from the axon damage it causes by individually blocking cytotoxic T cell function and axon degeneration. We model inflammatory damage in mouse skin, a barrier tissue that, despite frequent inflammation, must maintain proper functioning of a dense array of axon terminals. We show that sympathetic axons control skin inflammation through release of norepinephrine, which suppresses activation of gamma delta T cells via the β2 adrenergic receptor. Strong inflammatory stimulation in the form of the toll like receptor 7 (TLR7) agonist imiquimod (IMQ) causes progressive gamma delta T cell-mediated, Sarm-1-dependent loss of these immunosuppressive sympathetic axons, a positive feedback loop that removes a physiological brake on T cells, resulting in enhanced inflammation and inflammatory axon damage.
Leaf decomposing fungi influenceSaccharomyces paradoxusgrowth across carbon environments
Authors: El-Khatib Samer , Lambert Madeleine G. , Reed Meghan N. , Goncalves Melane Brito , Boynton Primrose J. 
Published: January 2023

AbstractSaccharomyces paradoxusis a model organism in ecology and evolution. However, its metabolism in its native habitat remains mysterious: it is frequently found growing on leaf litter, a habitat with few carbon sources thatS. paradoxuscan metabolize. We hypothesized that leaf-decomposing fungi from the same habitat break down the cellulose in leaf litter extracellularly and release glucose, supportingS. paradoxusgrowth. We found that facilitation by leaf-decomposing fungi was possible on cellulose and inhibition was common on glucose, suggesting diverse interactions betweenS. paradoxusand other fungi that have the potential to supportS. paradoxusin nature.
C. elegansSMOC-1 interacts with both BMP and glypican to regulate BMP signaling
Authors: DeGroot Melisa S. , Williams Byron , Chang Timothy Y , Maas Gamboa Maria L. , Larus Isabel , Fromme J. Christopher , Liu Jun 
Published: January 2023

ABSTRACTSSecreted modular calcium binding (SMOC) proteins are conserved matricellular proteins found in organisms fromC. elegansto humans. SMOC homologs characteristically contain one or two extracellular calcium (EC) binding domain(s) and one or two thyroglobulin type-1 (TY) domain(s). SMOC proteins inDrosophilaand Xenopus have been found to interact with cell surface heparan sulfate protein glycans (HSPGs) to exert both positive and negative influences on the conserved bone morphogenetic protein (BMP) signaling pathway. In this study, we used a combination of biochemical, structural modeling, and molecular genetic approaches to dissect the functions of the sole SMOC protein inC. elegans. We showed that SMOC-1 binds LON-2/glypican, as well as the mature domain of DBL-1/BMP. Moreover, SMOC-1 can simultaneously bind LON-2/glypican and DBL-1/BMP. The interaction between SMOC-1 and LON-2/glypican is mediated by the EC domain of SMOC-1, while the interaction between SMOC-1 and DBL-1/BMP involves full-length SMOC-1. We further showed that while SMOC-1(EC) is sufficient to promote BMP signaling when overexpressed, both the EC and TY domains are required for SMOC-1 function at the endogenous locus. Finally, when overexpressed, SMOC-1 can promote BMP signaling in the absence of LON-2/glypican. Taken together, our findings led to a model where SMOC-1 functions both negatively in a LON-2-dependent manner and positively in a LON-2-independent manner to regulate BMP signaling. Our work provides a mechanistic basis for how the evolutionarily conserved SMOC proteins regulate BMP signaling.
Parallel reconstruction of the excitatory and inhibitory inputs received by single neurons reveals the synaptic basis of recurrent spiking
Authors: Bartram Julian , Franke Felix , Kumar Sreedhar Saseendran , Buccino Alessio Paolo , Xue Xiaohan , Gänswein Tobias , Schröter Manuel , Kim Taehoon , Kasuba Krishna Chaitanya , Hierlemann Andreas 
Published: January 2023

AbstractSelf-sustained recurrent activity in cortical networks is thought to be important for multiple crucial processes, including circuit development and homeostasis. Yet, the precise relationship between synaptic input patterns and the spiking output of individual neurons remains largely unresolved. Here, we developed, validated and applied a novel in vitro experimental platform and analytical procedures that provide – for individual neurons – simultaneous excitatory and inhibitory synaptic activity estimates during recurrent network activity. Our approach combines whole-network high-density microelectrode array (HD-MEA) recordings from rat neuronal cultures with patch clamping and enables a comprehensive mapping and characterization of active incoming connections to single postsynaptic neurons. We found that, during network states with excitation(E)-inhibition(I) balance, postsynaptic spiking often coincided with the maxima of fast fluctuations in the input E/I ratio. These spike-associated E/I ratio escalations were largely due to a rapid bidirectional change in synaptic inhibition that was modulated by the network-activity level. Our approach also uncovered the underlying circuit architecture and we show that individual neurons received a few key inhibitory connections – often from special hub neurons – that were instrumental in controlling postsynaptic spiking. Balanced network theory predicts dynamical regimes governed by small and rapid input fluctuation and featuring a fast neuronal responsiveness. Our findings – obtained in self-organized neuronal cultures – suggest that the emergence of these favorable regimes and associated network architectures is an inherent property of cortical networks in general.
Identification and Characterization of novel long non-coding RNAs in vascular smooth cells
Authors: Solomon Charles U. , McVey David G. , Andreadi Catherine , Gong Peng , Turner Lanka , Khemiri Sonja , Chamberlain Julie C. , Webb Tom R. , Samani Nilesh J. , Ye Shu 
Published: January 2023

AbstractA significant portion of the RNA produced from the human genome consists of long non-coding RNAs (lncRNAs). These molecules tend to have lower levels of expression, are more specific to certain tissues, and show greater variation in expression between individuals compared to protein-coding messenger RNAs (mRNAs). LncRNAs have been linked with regulatory roles in gene expression and genome architecture. There is growing evidence that lncRNAs play important roles in many biological processes and diseases, and a number of lncRNAs have been identified as potential therapeutic targets. Here, we report the identification and characterization of the lncRNA landscape of vascular smooth muscle cells (VSMC). We used an ensemble of bioinformatics tools to identify 329 novel lncRNAs from a large VSMC RNA-Seq dataset. We found that majority of the novel lncRNAs are natural antisense transcripts of protein-coding genes. In addition, we predicted cellular localization and potential miRNAs that targets the novel lncRNAs and found that most localize in the cytoplasm and that miRNA target site ranged from 2-889 sites on each novel lncRNA. Furthermore, we identified co-expressed lncRNAs that correlate with the proliferation, migration and apoptosis of vascular smooth muscle cells. These results suggest that we have identified a diverse set of previously unknown lncRNAs that may be involved in important regulatory pathways in vascular smooth muscle cells.
Genetic diversity of North American popcorn germplasm and the effect of population structure on nicosulfuron response
Authors: Sullivan Madsen , Williams Martin M. , Studer Anthony J. 
Published: January 2023

ABSTRACTPopcorn is an important crop in the United States; however, genetic analyses of popcorn are limited and tend to utilize relatively few markers that cannot capture the total genomic variation. To improve the genomic resources in popcorn, a panel of 362 popcorn accessions was evaluated using 417,218 single nucleotide polymorphisms generated using a genotyping-by-sequencing approach. Using this genomic data, a model-based clustering analysis identified two populations. The first comprised North American Yellow Pearl Popcorns and several accessions of the Chilean Curagua landrace. The second, the Pointed and Latin American Popcorns, included all remaining North American (pointed and early popcorns), Latin American, and global accessions. The two populations exhibited large differences in population structure and genetic diversity. The North American Yellow Pearl Popcorns constitute a highly inbred population with limited genetic diversity compared to the Pointed and Latin American Popcorns. Additionally, phenotypic differences between the two populations were observed in kernel color and nicosulfuron sensitivity. A filtered set of SNPs was curated and used for genome-wide association studies and popcorn-specific candidate genes for nicosulfuron tolerance were identified. The genomic characterization described here can be used by breeding programs to accelerate the rate of genetic gain and incorporate genetic diversity into elite popcorn germplasm.Core IdeasNorth American Popcorn is composed of two distinct populations that differ genetically and phenotypically.North American Yellow Pearl Popcorns contain limited genetic diversity and are highly inbred.Pointed and Latin American Popcorns exhibit considerable genetic diversity and rapid linkage disequilibrium decay.Kernel color does not affect nicosulfuron sensitivity and instead reflects differences between the populations.Popcorn-specific candidate genes for nicosulfuron tolerance are distinct from dent corn.
A biochemical analysis of Black Soldier fly (Hermetia illucens) larval frass plant growth promoting activity
Authors: Green Terrence 
Published: January 2023

AbstractBlack Soldier fly (Hermetia illucens) larval (BSFL) frass separated from BSFL processed catering waste, and that recovered directly from larvae, was examined for its nitrogen, phosphate and potassium (N:P205:K2O), phytohormone and biogenic amine content, its plant growth promoting activity, and screened to test the hypothesis that bacteria characteristic of the genusEnterococcus, present in the biome of decaying catering waste and the larval gut, pass freely through the gut and are excreted in viable form into their frass. Its plant growth promoting activity was measured by comparing the growth of winter wheat berry (Triticum aestivum) grown in frass treated soil relative to that measured in untreated (control) soil. Its N:P205:K2O, biogenic amine and phytohormone composition were determined by standard soil analysis, HPLC and HPLC/GC-MS methodologies, respectively, and found to be too low to account for its plant growth promoting activity which induced a 11% increase in arial mass and shoot length in treated plants over controls. Colonies ofEnterococcigrew out on streaking frass collected directly from larvae on standard bile-esculin azide agar culture plates, confirming the hypothesis that viableEnteroccociare excreted in their frass. SinceEnterococciare capable of colonizing the rhizosphere and boosting the growth of plants on amendment into soil, these findings lend further insight into the underlying mechanism(s) accounting for the increased growth of plants growing in frass treated soils.
High-parameter phenotypic characterization reveals a subset of human Th17 cells that preferentially produce IL17 againstM. tuberculosisantigen
Authors: Ogongo Paul , Tran Anthony , Marzan Florence , Gingrich David , Krone Melissa , Aweeka Francesca , Lindestam Arlehamn Cecilia S , Martin Jeffrey N. , Deeks Steven G. , Hunt Peter W. , Ernst Joel D. 
Published: January 2023

AbstractBackgroundInterleukin 17 producing CD4 T cells contribute to the control ofMycobacterium tuberculosis (Mtb)infection in humans; whether infection with Human Immunodeficiency Virus (HIV) disproportionately affects distinct Th17 cell subsets that respond toMtbis incompletely defined.MethodsWe performed high-definition characterization of circulatingMtb-specific Th17 cells by spectral flow cytometry in people with latent TB and treated HIV (HIV-ART). We also measured kynurenine pathway activity by LC/MS on plasma and tested the hypothesis that tryptophan catabolism influences Th17 cell frequencies in this context.ResultsWe identified two subsets of Th17 cells: subset 1 defined as CD4+Vα7.2-CD161+CD26+and subset 2 defined as CD4+Vα7.2-CCR6+CXCR3-cells of which subset 1 was significantly reduced in LTBI with HIV-ART, yetMtb-responsive IL17-producing CD4 T cells were preserved; we found that IL17-producing CD4 T cells dominate the response toMtbantigen but not CMV antigen or staphylococcal enterotoxin B (SEB); and tryptophan catabolism negatively correlates with both subset 1 and subset 2 Th17 cell frequencies.ConclusionsWe found differential effects of ART-suppressed HIV on distinct subsets of Th17 cells, that IL17-producing CD4 T cells dominate responses toMtbbut not CMV antigen or SEB, and that kynurenine pathway activity is associated with decreases of circulating Th17 cells that may contribute to tuberculosis immunity.