bluuebunny/crossref_metadata_2025_split huggingface dataset:
Layer-Specific Vulnerability is a Mechanism of Topographic Map Aging
Authors: Northall Alicia , Doehler Juliane , Weber Miriam , Vielhaber Stefan , Schreiber Stefanie , Kuehn Esther 
Published: May 2022

AbstractTopographic maps form a critical feature of cortical organization, yet are poorly described with respect to their microstructure in the living aging brain. We acquired quantitative structural and functional 7T-MRI data from younger and older adults to characterize layer-wise topographic maps of the primary motor cortex (M1). Using parcellation-inspired techniques, we show that qT1 and QSM values of the hand, face, and foot areas differ significantly, revealing microstructurally-distinct cortical fields in M1. We show that these fields are distinct in older adults, and that myelin borders between them do not degenerate. We further show that the output layer 5 of M1 shows a particular vulnerability to age-related increased iron, while layer 5 and the superficial layer show increased diamagnetic substance, likely reflecting calcifications. Taken together, we provide a novel 3D model of M1 microstructure, where body parts form distinct structural units, but layers show specific vulnerability towards increased iron and calcium in older adults. Our findings have implications for understanding sensorimotor organization and aging, in addition to topographic disease spread.
Expansion microscopy reveals subdomains in C. elegans germ granules
Authors: Suen Kin M. , Sheard Thomas M. D. , Lin Chi-Chuan , Milonaityte Dovile , Jayasinghe Izzy , Ladbury John E. 
Published: May 2022

AbstractMany membraneless organelles (MLOs) have been shown to form via liquid-liquid phase separation (LLPS). Light and electron microscopy techniques have been indispensable in the identification and characterization of LLPS MLOs. However, for complex MLOs such as the perinuclear germ granule in C. elegans, our understanding of how the organelle as a whole is regulated is hampered by 1) the technical limitations in confocal fluorescence imaging in which only a few granule protein markers can be examined at a time and 2) the inaccessibility of electron microscopy. In this study, we take advantage of the newly developed super-resolution method of expansion microscopy (ExM) and in-situ staining of the whole proteome to examine the C. elegans germ granule, the P granule. We show that in small RNA pathway mutants, the P granule is smaller compared with wild type animals. Furthermore, we investigate the relationship between the P granule and two other germ granules, mutator foci and Z granule, and show that they are located within the same protein-dense regions while occupying distinct subdomains within this ultrastructure. The experimental workflow developed here will serve as an important tool in our understanding of germ granule biology as well as the biological role of LLPS.
Prominent astrocytic alpha-synuclein pathology with unique post-translational modification signatures unveiled across Lewy body disorders
Authors: Altay Melek Firat , Liu Alan King Lun , Holton Janice L. , Parkkinen Laura , Lashuel Hilal A. 
Published: May 2022

ABSTRACTAlpha-synuclein (aSyn) is a pre-synaptic monomeric protein that can form aggregates in neurons in Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB), and in oligodendrocytes in multiple system atrophy (MSA). Although the accumulation of aSyn in astrocytes has previously been described in PD, PDD and DLB, the biochemical properties of aSyn in this type of pathology and its topographical distribution have not been studied in detail. Here, we present a systematic investigation of aSyn astrocytic pathology, using an expanded toolset of antibodies covering the entire sequence and known post-translational modifications (PTMs) of aSyn in Lewy body (LB) disorders, including sporadic PD, PDD, DLB, familial PD with SNCA G51D mutation and SNCA duplication, and in MSA. Astrocytic aSyn was mainly detected in the limbic cortical regions of LB disorders, but were absent in key pathological regions of MSA. These astrocytic aSyn accumulations were detected only with aSyn antibodies against the mid N-terminal and non-amyloid component (NAC) regions covering aSyn residues 34-99. The astroglial accumulations were negative to canonical aSyn aggregation markers, including p62, ubiquitin and aSyn pS129, but positive for phosphorylated and nitrated forms of aSyn at Tyrosine 39 (Y39), and mostly not resistant to proteinase K. Our findings suggest that astrocytic aSyn accumulations are a major part of aSyn pathology in LB disorders, and possess a distinct sequence and PTM signature that is characterized by both N- and C-terminal truncations and modifications at Y39. To the best of our knowledge, this is the first description of aSyn accumulation made solely from N- and C-terminally cleaved aSyn species and the first report demonstrating that astrocytic aSyn exists as a mixture of Y39 phosphorylated and nitrated species. These observations underscore the critical importance of systematic characterization of aSyn accumulation in different cell types as a necessary step to capturing the diversity of aSyn species and pathology in the brain. Our findings combined with further studies on the role of astrocytic pathology in the progression of LB disorders can pave the way towards identifying novel disease mechanisms and therapeutic targets.
Sweepstakes reproductive success via pervasive and recurrent selective sweeps
Authors: Árnason Einar , Koskela Jere , Halldórsdóttir Katrín , Eldon Bjarki 
Published: May 2022

AbstractHighly fecund natural populations characterized by high early mortality abound, yet our knowledge about their recruitment dynamics is somewhat rudimentary. This knowledge gap has implications for our understanding of genetic variation, population connectivity, local adaptation, and the resilience of highly fecund populations. The concept of sweepstakes reproductive success, which posits a considerable variance and skew in individual reproductive output, is key to understanding the distribution of individual reproductive success. However, it still needs to be determined whether highly fecund organisms reproduce through sweepstakes and, if they do, the relative roles of neutral and selective sweepstakes. Here we use coalescent-based statistical analysis of population genomic data to show that selective sweepstakes likely explain recruitment dynamics in the highly fecund Atlantic cod. We show that the Kingman coalescent (modeling no sweepstakes) and the Xi-Beta coalescent (modeling random sweepstakes), including complex demography and background selection, do not provide an adequate fit for the data. The Durrett-Schweinsberg coalescent, in which selective sweepstakes result from recurrent and pervasive selective sweeps of new mutations, offers greater explanatory power. Our results show that models of sweepstakes reproduction and multiple-merger coalescents are relevant and necessary for understanding genetic diversity in highly fecund natural populations. These findings have fundamental implications for understanding the recruitment variation of fish stocks and general evolutionary genomics of high-fecundity organisms.
2-hydroxyglutarate controls centromere and heterochromatin conformation and function in the male germline
Authors: Mayorek Nina , Schlossberg Miriam , Mansour Yousef , Pillar Nir , Stein Ilan , Mushasha Fatima , Baziza Guy , Medvedev Eleonora , Manevitch Zakhariya , Menzel Julia , Aizenshtein Elina , Sarvin Boris , Sarvin Nikita , Shlomi Tomer , Klutstein Michael , Pikarsky Eli 
Published: May 2022

Abstract2-hydroxyglutarate (2HG) is recognized as an epigenetic regulator in cancer and some transient biological processes. Of all organs, the testis harbors the highest baseline physiological levels of 2HG, yet it’s putative functions in germ cell biology are unknown. Here we show that 2HG is generated in specific stages of spermatogenesis by the testis specific lactate dehydrogenase C (LDHC), beginning at the last stages of prophase I. Unexpectedly LDHC enters nuclei and concentrates in centromeres. LDHC-generated L-2HG controls centromere condensation and pericentromeric heterochromatin organization through multiple effects including clustering of chromocenters, centromere and chromocenter condensation and expression of satellite RNAs. These effects are rapid and specific to L but not D-2HG.In vivodepletion of L-2HG causes centromere malfunction and activation of the spindle assembly checkpoint. Our findings reveal that 2HG can directly affect centromere and pericentromeric heterochromatin conformation and function and is necessary for licensing chromosome segregation.
Distinct architectural requirements for the parS centromeric sequence of the pSM19035 plasmid partition machinery
Authors: Volante Andrea , Alonso Juan C. , Mizuuchi Kiyoshi 
Published: May 2022

AbstractThree-component ParABS partition systems ensure stable inheritance of many bacterial chromosomes and low-copy-number plasmids. ParA localizes to the nucleoid through its ATP- dependent non-specific DNA binding activity, whereas centromere-like parS-DNA and ParB form partition complexes that activate ParA-ATPase to drive the system dynamics. The essential parS sequence arrangements vary among ParABS systems, reflecting the architectural diversity of their partition complexes. Here, we focus on the pSM19035 plasmid partition system that uses a ParBpSM of the ribbon-helix-helix (RHH) family. We show that parSpSM with four or more contiguous ParBpSM-binding sequence repeats is required to assemble a stable ParApSM-ParBpSM complex and efficiently activate the ParApSM-ATPase, stimulating complex disassembly. Disruption of the contiguity of the parSpSM sequence array destabilizes the ParApSM-ParBpSM complex and prevents efficient ATPase activation. Our findings reveal the unique architecture of the pSM19035 partition complex and how it interacts with nucleoid-bound ParApSM-ATP.
Two-Stage Multivariate Mendelian Randomization on Multiple Outcomes with Mixed Distributions
Authors: Deng Yangqing , Tu Dongsheng , O’Callaghan Chris J , Liu Geoffrey , Xu Wei 
Published: May 2022

SummaryIn clinical research, it is of importance to study whether certain clinical factors or exposures have causal effects on clinical and patient reported outcomes like toxicities, quality of life, and self-reported symptoms, which can help improve patient care. Usually, such outcomes are recorded as multiple variables with different distributions. Mendelian randomization is a commonly used technique for causal inference with the help of genetic instrumental variables to deal with observed and unobserved confounders. Nevertheless, the current methodology of Mendelian randomization on multiple outcomes only focuses on one outcome at a time, meaning that it does not consider the correlation structure of multiple outcomes, which may lead to loss of statistical power. In situations with multiple outcomes of interest, especially when there are mixed correlated outcomes with multiple distributions, it is much more desirable to jointly analyze them with a multivariate approach. Some multivariate methods have been proposed to model mixed outcomes, however, they do not incorporate instrumental variables and cannot handle unmeasured confounders. To overcome the above challenges, we propose a two-stage multivariate Mendelian Randomization Method (MRMO), that can perform multivariate analysis on mixed outcomes using instrumental variables. We demonstrate that our proposed MRMO algorithm can gain power over the existing univariate method through simulation studies and a clinical application on a randomized Phase III clinical trial study on colorectal cancer patients.
Chemical genetic screening identifies nalacin as an inhibitor of GH3 amido synthetase for auxin conjugation
Authors: Xie Yinpeng , Zhu Ying , Wang Na , Luo Min , Ohta Tsuyoshi , Guo Ruipan , Yu Zongjun , Aizezi Yalikunjiang , Zhang Linlin , Yan Yan , Zhang Yujie , Bao Hongyu , Wang Yichuan , Zhu Ziqiang , Huang Ancheng , Zhao Yunde , Asami Tadao , Huang Hongda , Guo Hongwei , Jiang Kai 
Published: May 2022

AbstractRoot system is critical for plant growth and development. To develop plant growth regulators functioning in root development, we performed a phenotype-based chemical screen in Arabidopsis and identified a chemical, nalacin, that mimicked the effects of auxin on root development. Genetic, pharmacological and biochemical approaches demonstrated that nalacin exerts its auxin-like activities by inhibiting indole-3-acetic acid (IAA) conjugation that is mediated by Gretchen Hagen 3 (GH3) acyl acid amido synthetases. The crystal structure of Arabidopsis GH3.6 in complex with D4 (a derivative of nalacin) together with docking simulation analysis revealed the molecular basis of the inhibition of group II GH3 by nalacin. Sequence alignment analysis indicated broad bioactivities of nalacin and D4 as inhibitors of GH3s in vascular plants, which were confirmed, at least, in tomato and rice. In summary, our work identifies nalacin as a potent inhibitor of IAA conjugation mediated by group II GH3 that plays versatile roles in hormone-regulated plant development and has potential applications in both basic research and agriculture.
Cytokinins induce prehaustoria coordinately with quinone and phenolic signals in the parasitic plant Striga hermonthica
Authors: Aoki Natsumi , Cui Songkui , Yoshida Satoko 
Published: May 2022

AbstractOrobanchaceae parasitic plants are major threats to global food security, causing severe agricultural damage worldwide. Parasitic plants derive water and nutrients from their host plants through multicellular organs called haustoria. The formation of a prehaustorium, a primitive haustorial structure, is provoked by host-derived haustorium-inducing factors (HIFs). Quinones, including 2,6-dimethoxy-p-benzoquinone (DMBQ), and phenolics, including syringic acid, are of most potent HIFs for various species in Orobanchaceae, but except non-photosynthetic holoparasites, Phelipanche and Orobanche spp. On the other hand, cytokinin phytohormones was reported to induce prehaustoria in Phelipanche ramosa. However, little is known about whether cytokinins act as HIFs in the other parasitic species. Moreover, the signaling pathways for quinones, phenolics and cytokinins in prehaustorium induction are not well understood. This study showed that cytokinins act as HIFs in Striga hermonthica but not in Phtheirospermum japonicum. Using chemical inhibitors for each type of HIF, we demonstrated that cytokinins activate prehaustorium formation through a signaling pathway that overlaps with the quinone and phenolic HIF pathways in S. hermonthica. Host root exudates activated S. hermonthica cytokinin biosynthesis and signaling genes, and inhibitors blocking any of three types of HIFs perturbed the prehaustorium-inducing activity of exudates, indicating that host root exudates include a mixture of HIFs. Our study reveals the importance of cytokinins for prehaustorium formation in obligate parasitic plants.
A Genetically Encodable and Chemically Disruptable System for Synthetic Post-Translational Modification Dependent Signaling
Authors: McMahan Jeffrey B. , Ngo John T. 
Published: May 2022

ABSTRACTWe describe an engineered “writer/reader” framework for programming post-translational control into synthetic mammalian signaling proteins. In this approach, a bacterially-derived biotin protein ligase (BirA) was used as a “writer” element for the modification of artificial receptors and transcription factors containing a biotin acceptor peptide (AP) fusion tag. To enable modification events to transmit biochemical information, we designed encodable “reader” modules using sequences from a biotinamide-binding antibody. Proteins fused to reader domains were able to interact with AP-tagged polypeptides in a biotinylation-dependent manner, and control over the timing and extent of these interactions could be modulated through both genetic and chemically-based strategies. Genetic and cell-specific control over AP-reader module interactions was achieved via regulated BirA expression, and the interaction states of both intra-and inter-cellular complexes could be modulated with biotinamide-based and bioorthogonally-functionalized compounds. The utility of this approach was demonstrated by installing post-translational and chemogenetic control into synthetic Notch (“SynNotch”)-based systems.
MATTE: anti-noise module alignment for phenotype-gene-related analysis
Authors: Cai Guoxin , Zhou Zhan , Gu Xun 
Published: May 2022

AbstractPurposeAlthough many transcriptome analysis methods find fundamental interactions or markers of some phenotypes, preservation of module or network is still a challenge.MethodsThe study developed a method to directly compare the transcriptome data of phenotypes and present the differences modularly, called Module Alignment of TranscripTomE(MATTE).ResultsMATTE performs better under high noise than differential co-expression(DC) clustering in the simulation experiments but still detects differential expression(DE) and DC genes. After subsequent annotation of cell types in single-cell data, MATTE obtained the best scores in both supervised and unsupervised learning, i. e. MATTE found meaningful markers. Finally, we apply MATTE in analyzing the transcriptome of Breast Cancer(BRCA). We have found five BRCA subtypes, and the characteristic of one subtype is detected in the form of a module network.ConclusionMATTE can find meaningful genes and modules, thus facilitating the downstream analysis task to obtain insight into biology.
Knowledge, attitude, and practice towards lymphatic filariasis among inhabitants of an endemic town in Oyo State, Nigeria
Authors: Jaiyeola Taiwo Mofadeke , Udoh Ekerette Emmanuel , Adebambo Abiola Basirat 
Published: May 2022

AbstractIntroductionThe burden of lymphatic Filariasis (LF) popularly called Ina orun in southwest Nigeria is of serious concern and it calls for urgent attention. The study aimed at assessing the knowledge attitude and practice of inhabitants of two communities endemic with LF in Ibadan south-west Local Government Area (IBSWLGA) of Oyo State, Nigeria.Materials and methodsA cross-sectional study was carried out using a semi-structured questionnaire.ResultsOut of 243 participants comprising of both male and female with a mean age of 35.01± 8.53 years, 35% reported ever hearing about LF. The majority (73.3%) of the participants had an overall poor knowledge of the disease, while only 26.7% have good knowledge of the disease. 26.3% of the participants knew the main cause of LF while 74.9% did not know the disease is communicable. About half (50.6%) and 42.4% of the participants did not know the symptoms and the prevention practices respectively. Only 27.2% knew that mosquitoes play a major role in LF transmission. 85.6% of the respondents were not aware of the Mass Drug Administration (MDA) program in the study area while 36.6% of participants did not know the role of MDA in preventing and controlling LF.ConclusionThese results indicate poor community knowledge, inadequate prevention practices, and a lack of awareness of available programmatic efforts that the population can benefit from to tackle continuous transmission of the lymphatic filariasis disease. In conclusion, with the present low status on the disease awareness and response, increased sensitization and community interventions on LF are necessary and this calls for urgent attention.
Immunomodulatory effects of Simvastatin in Toll-like receptor-2 stimulated Rheumatoid arthritis synoviocytes
Authors: Saeed Mohammad , Al-Karakooly Zeiyad , Ali Nawab , Ortmann Robert A. 
Published: May 2022

AbstractFibroblast-like synoviocytes (FLS) are major effector cells in Rheumatoid arthritis (RA). Toll-like receptor-2 (TLR2) activation of FLS plays a key role in RA pathogenesis. Recently, statins have been shown to modulate RA. We investigated the immunomodulatory effects of simvastatin (SMV) in vitro, in FLS cell lines from control and RA subjects, in the presence of TLR2 activation. Normal and RA FLS cultures (1×105 cells/well) were treated with SMV then activated with TLR2 ligand (Pam3CSK4 100μg/ml) for 24-hours. SMV caused dose-dependent cytotoxicity in both cell lines as assessed by Alamar-blue assay and increased ROS production measured by flow cytometry. Gene expression of anti-oxidants including GSR, TXNRD1, PRDX1, SOD2 and MT3 was upregulated. BNIP3 expression was increased 2200-fold in RA-FLS after SMV/TLR2 treatment pointing to apoptosis as a cause of observed cytotoxicity. Apoptosis increased in both cell lines with SMV to 25%. Akt decreased dose-dependently in RA FLS assessed by western blots. IP-1, IP-2 and IP3 decreased with SMV/TLR2 treatment indicating cell survival while IL-6 increased dose-dependently. Thus, SMV induces apoptosis in FLS by upregulating BNIP3 and inhibiting Akt. FLS react to survive by increasing IL-6, decreasing IP-1 and IP-2 and upregulating anti-oxidant genes. SMV has immunomodulatory properties and may be used in RA as adjunctive therapy in combination with other more potent disease-modifying medications.
A Bioinformatics Approach To Reveal Common Genes And Molecular Pathways Shared By Cutaneous Melanoma and Uveal Melanoma
Authors: Jayaraj Dr. Perumal , Sen Seema , Kaur Khushneet , Gupta Kritika , Taluja Shreya 
Published: May 2022

AbstractBackgroundMelanomas are highly aggressive in nature and are known for metastasis and death. Melanocytes that give rise to melanomas are neural crest progenitor-cells. Our research is primarily concerned with Uveal Melanoma (UM) and Cutaneous Melanoma (CM). Although they both share same melanocytic origin, but the biology of their respective is different.AimThe aim of our study is to recognize the common differentially expressed genes (DEGs) between UM and CM.MethodologyThe gene expression profile was downloaded from the GEO and analyzed by GEO2R for identification of DEGs. By applying DAVID, GO and KEGG, pathway enrichment analysis was performed. PPI of these DEGs was analyzed using STRING and visualized through Cytoscape and MCODE. Further, we utilized HPA and GEPIA to obtain Kaplan-Meier Graph for survival analysis in order to assess the prognostic value of hub genes.ResultsWe examined the UM and CM datasets and discovered three common upregulated and eight common downregulated DEGs for both the melanomas based on computational analysis. HMGCS1 and ELOVL5 were shown to be enriched in a variety of altered molecular pathways and pathways in cancer. Overexpression of HMGCS1 and ELOVL5 were linked to poor prognosis in CM.ConclusionOn computational evaluation, we found that HMGCS1 and ELOVL5 were upregulated in both of these melanomas. Enrichment analysis showed that these genes are involved in cancer metabolism pathway and associated with poor prognosis in CM. However, the molecular study of these genes in UM is limited. Therefore, a better understanding of the cancer metabolism pathways should be carried to pave the way for clinical benefits.