bluuebunny/crossref_metadata_2025_split huggingface dataset:
SMRT sequencing of theOryza rufipogongenome reveals the genomic basis of rice adaptation
Authors: Li Wei , Li Kui , Huang Ying , Shi Cong , Hu Wu-Shu , Zhang Yun , Zhang Qun-Jie , Xia En-Hua , Hutang Ge-Ran , Zhu Xun-Ge , Liu Yun-Long , Liu Yuan , Tong Yan , Zhu Ting , Huang Hui , Zhang Dan , Zhao Yuan , Jiang Wen-Kai , Yuan Jie , Niu Yong-Chao , Gao Cheng-Wen , Gao Li-Zhi 
Published: January 2020

AbstractAsian cultivated rice is believed to have been domesticated from an immediate ancestral progenitor,Oryza rufipogon, which provides promising sources of novel alleles for world rice improvement. Here we first present a high-qualityde novoassembly of the typicalO. rufipogongenome through the integration of single-molecule sequencing (SMRT), 10× and Hi-C technologies. This chromosome-based reference genome allows a multi-species comparative analysis of the annual selfingO. sativaand its two wild progenitors, the annual selfingO. nivaraand perennial outcrossingO. rufipogon, identifying massive numbers of dispensable genes that are functionally enriched in reproductive process. Comparative genomic analyses identified millions of genomic variants, of which large-effect mutations (e.g., SVs, CNV and PAVs) may affect the variation of agronomically significant traits. We demonstrate how lineage-specific expansion of rice gene families may have contributed to the formation of reproduction isolation (e.g., the recognition of pollen and male sterility), thus brightening the role in driving mating system evolution during the evolutionary process of recent speciation. We document thousands of positively selected genes that are mainly involved in flower development, ripening, pollination, reproduction and response to biotic- and abiotic stresses. We show that selection pressures may serve as crucial forces to govern substantial genomic alterations among the three rice species that form the genetic basis of rapid evolution of mating and reproductive systems under diverse habitats. This first chromosome-based wild rice genome in the genusOryzawill become powerful to accelerate the exploration of untapped genomic diversity from wild rice for the enhancement of elite rice cultivars.
LRP::FLAG reduces phosphorylated tau levels in Alzheimer’s Disease
Authors: Cuttler Katelyn , Bignoux Monique J. , Otgaar Tyrone C. , Chigumba Stephanie , Ferreira Eloise , Weiss Stefan F.T. 
Published: January 2020

AbstractAlzheimer’s disease (AD) is characterized by amyloid beta (Aβ) plaque and neurofibrillary tangle formation, respectively. Neurofibrillary tangles form as a result of the intracellular accumulation of hyperphosphorylated tau. Telomerase activity and levels of the human reverse transcriptase (hTERT) subunit of telomerase are significantly decreased in AD. Recently it has been demonstrated that the 37kDa/67kDa laminin receptor (LRP/LR) interacts with telomerase and is implicated in Aβ pathology. Here we show that LRP/LR co-localizes with tau in the perinuclear cell compartment and FRET confirmed a direct interaction between LRP/LR and tau in HEK-293 cells. Overexpression of LRP::FLAG in HEK-293 and SH-SY5Y cells decreased total and phosphorylated tau levels with a concomitant decrease in PrPclevels, a tauopathy-related protein. Additionally, LRP::FLAG overexpression resulted in increased hTERT levels. These data indicate for the first time a role of LRP/LR in tauopathy of Alzheimer’s Disease and recommend LRP::FLAG as a potential alternative therapeutic tool for Alzheimer’s Disease treatment through rescuing cells from Aβ induced cytotoxicity and, as shown in this report, decreased phosphorylated tau levels.
Genetic ablation of the mitochondrial ribosome inPlasmodium falciparumsensitizes the human malaria parasite to antimalarial drugs targeting mitochondrial functions
Authors: Ling Liqin , Mulaka Maruthi , Munro Justin , Dass Swati , Mather Michael W. , Riscoe Michael K. , Llinás Manuel , Zhou Jing , Ke Hangjun 
Published: January 2020

ABSTRACTThe mitochondrion of malaria parasites contains clinically validated drug targets. WithinPlasmodium spp., the mitochondrial DNA (mtDNA) is only 6 kb long, being the smallest mitochondrial genome among all eukaryotes. The mtDNA encodes only three proteins of the mitochondrial electron transport chain and ∼ 27 small, fragmented rRNA genes in length of 22-195 nucleotides. The rRNA fragments are thought to form a mitochondrial ribosome (mitoribosome), together with ribosomal proteins imported from the cytosol. The mitoribosome ofPlasmodium falciparumhas been shown to be essential for maintenance of the mitochondrial membrane potential and parasite viability. However, the role of mitoribosomes in sustaining the metabolic status of the parasite mitochondrion remains unknown. Here, among the 14 annotated mitoribosomal proteins of the small subunit ofP. falciparum, we verified the localization and tested the essentiality of three candidates (PfmtRPS12, PfmtRPS17, PfmtRPS18), employing a CRISPR/Cas9 mediated conditional knockdown tool. Using immuno-electron microscopy, we provided evidence that the mitoribosome is closely associated with the mitochondrial inner membrane in the parasite. Upon knockdown of the mitoribosome, the parasites became hypersensitive to inhibitors targeting thebc1complex, dihydroorotate dehydrogenase andF1FoATP synthase complex. Furthermore, knockdown of the mitoribosome blocked the pyrimidine biosynthesis pathway and reduced the pool of pyrimidine nucleotides. Together, our data suggest that disruption of theP. falciparummitoribosome compromises the metabolic capability of the mitochondrion, rendering the parasite hypersensitive to a panel of inhibitors targeting mitochondrial functions.
Negative regulation of the Rcs phosphorelay via IgaA contact with the RcsD phosphotransfer protein
Authors: Wall Erin A. , Majdalani Nadim , Gottesman Susan 
Published: January 2020

AbstractTwo-component systems and phosphorelays play central roles in the ability of bacteria to rapidly respond to changing environments. InE. coliand related enterobacteria, the complex Rcs phosphorelay is a critical player in changing bacterial behavior in response to antimicrobial peptides, beta-lactam antibiotics, and other challenges to the cell surface. The Rcs system is unusual in that IgaA, an inner membrane protein, is essential due to its negative regulation of the RcsC/RcsD/RcsB phosphorelay. While it has previously been shown that IgaA transduces signals from the outer membrane lipoprotein RcsF, how it interacts with the phosphorelay was unknown. Here we use in vivo interaction assays and genetic dissection of the critical proteins to demonstrate that IgaA interacts with the phosphorelay protein RcsD, and that this interaction is necessary for regulation. Interactions in periplasmic domains of these two proteins anchor repression of signaling. However, the signaling response depends on a weaker interaction between cytoplasmic loop 1 of IgaA and a truncated PAS domain in RcsD. A point mutation in the PAS domain increases interactions between the two proteins and is sufficient to abolish induction of this phosphorelay. RcsC, the histidine kinase that initiates phosphotransfer through the phosphorelay, appears to be indirectly regulated by IgaA via the contacts with RcsD. Unlike RcsD, and unlike many other histidine kinases, the periplasmic domain of RcsC is not necessary for the response to inducing signals. The multiple contacts between IgaA and RcsD form a poised sensing system, preventing over-activation of this apparently toxic phosphorelay but allowing it to be rapidly and quantitatively responsive to signals.Author SummaryThe Rcs phosphorelay plays a central role in allowing enterobacteria to sense and respond to antibiotics, host-produced antimicrobials, and interactions with surfaces. A unique negative regulator, IgaA, keeps signaling from this pathway under control when it is not needed, but how it controls the phosphorelay has been unclear. We define a set of critical interactions between IgaA and the phosphotransfer protein RcsD. A periplasmic contact between IgaA and RcsD provides a necessary inhibition of Rcs signaling, modulated further by regulated interactions in the cytoplasmic domains of each protein. This multipartite interaction provides a sensitive regulatory switch.
PD-L1 upregulation by IFN-α/γ-mediated Stat1 suppresses anti-HBV T cell response
Authors: Liu LanLan , Hou Junwei , Qin Lijuan , Liu Weiwei , Zhang Han , Li Yang , Chen Mi , Deng Mengmeng , Zhao Bao , Hu Jun , Zheng Huaguo , Meng Songdong 
Published: January 2020

AbstractProgrammed death ligand 1 (PD-L1) has been recently shown to be a major obstacle to antiviral immunity by binding to its receptor programmed death 1 (PD-1) on specific IFN-γ producing T cells in chronic hepatitis B. Currently, IFN-α is widely used to treat hepatitis B virus(HBV) infection, but its antiviral effect vary greatly and the mechanism is not totally clear. We found that IFN-α/γ induced a marked increase of PD-L1 expression in hepatocytes. Signal and activators of transcription (Stat1) was then identified as a major transcription factor involved in IFN-α/γ-mediated PD-L1 elevation bothin vitroand in mice. Blockage of the PD-L1/PD-1 interaction by a specific mAb greatly enhanced HBV-specific T cell activity by the gp96 adjuvanted therapeutic vaccine, and promoted HBV clearance in HBV transgenic mice. Our results demonstrate the IFN-α/γ-Stat1-PD-L1 axis plays an important role in mediating T cell hyporesponsiveness and inactivating liver-infiltrating T cells in the hepatic microenvironment. These data raise further potential interest in enhancing the anti-HBV efficacy of IFN-α and therapeutic vaccines.
Dynamin-like proteins are essential for vesicle biogenesis inMycobacterium tuberculosis
Authors: Gupta Shamba , Palacios Ainhoa , Khataokar Atul , Weinrick Brian , Lavín Jose L. , Sampedro Leticia , Gil David , Anguita Juan , Menendez M. Carmen , García M. Jesus , Dogra Navneet , Neiditch Matthew B. , Prados-Rosales Rafael , Rodríguez G. Marcela 
Published: January 2020

ABSTRACTMycobacterium tuberculosis (Mtb)secretes pathogenicity factors and immunologically active molecules via membrane vesicles. However, nothing is known about the mechanisms involved in mycobacterial vesicle biogenesis. This study investigates molecular determinants of membrane vesicle production inMtbby analyzingMtbcells under conditions of high vesicle production: iron limitation and VirR restriction. Ultrastructural analysis showed extensive cell envelope restructuring in association with vesicle release that correlated with downregulation of cell surface lipid biosynthesis and peptidoglycan alterations. Comparative transcriptomics showed common upregulation of theiniBACoperon in association with high vesicle production inMtbcells. Vesicle production analysis demonstrated that the dynamin-like proteins (DLPs) encoded by this operon, IniA and IniC, are necessary for release of EV byMtbin culture and in infected macrophages. Isoniazid, a first-line antibiotic, used in tuberculosis treatment, was found to stimulate vesicle release in a DLP-dependent manner. Our results provide a new understanding of the function of mycobacterial DLPs and mechanistic insights into vesicle biogenesis. The findings will enable further understanding of the relevance ofMtb-derived extracellular vesicles in the pathogenesis of tuberculosis and may open new avenues for therapeutic research.IMPORTANCEIron is an essential nutrient that promotes survival and growth ofM. tuberculosis, the bacterium that causes human tuberculosis (TB). Limited availability of iron, often encountered in the host environment, stimulatesM. tuberculosisto secrete membrane-bound extracellular vesicles containing molecules that may help it evade the immune system. Characterizing the bacterial factors and mechanisms involved in the production of mycobacterial vesicles is important for envisioning ways to interfere with this process. Here, we report the discovery of proteins required byM. tuberculosisfor vesicle biogenesis in culture and during host cell infection. We also demonstrate a connection between antibiotic response and extracellular vesicle production. The work provides insights into the mechanisms underlying vesicle biogenesis inM. tuberculosisand permits better understanding of the significance of vesicle production toM. tuberculosis-host interactions and antibiotic stress response.
A Temporal Quantitative Profiling of Newly Synthesized Proteins during Aβ Accumulation
Authors: Ma Yuanhui , McClatchy Daniel B. , Martínez-Bartolomé Salvador , Bamberger Casimir , Yates John R. 
Published: January 2020

ABSTRACTAccumulation of aggregated amyloid beta (Aβ) in the brain is believed to impair multiple cellular pathways and play a central role in Alzheimer’s disease pathology. But how this process is regulated remains unclear. In theory, measuring protein synthesis is the most direct way to evaluate a cell’s response to stimuli, but to date there have been few reliable methods to do this. To identify the protein regulatory network during the development of Aβ deposition in AD, we applied a new proteomic technique to quantitate newly synthesized protein (NSP) changes in the cerebral cortex and hippocampus of 2, 5 and 9-month-old APP/PS1 AD transgenic mice. This bioorthogonal non-canonical amino acid tagging (BONCAT) analysis combined PALM (Pulse Azidohomoalanine Labeling in Mammals) and HILAQ (Heavy Isotope Labeled AHA Quantitation) to reveal a comprehensive dataset of NSPs prior to and post Aβ deposition, including the identification of proteins not previously associated with AD, and demonstrated that the pattern of differentially expressed NSPs is age-dependent. We also found dysregulated vesicle transportation networks including endosomal subunits, coat protein complex I (COPI) and mitochondrial respiratory chain throughout all timepoints and two brain regions. These results point to a pathological dysregulation of vesicle transportation that occurs prior to Aβ accumulation and the onset of AD symptoms, which may progressively impact the entire protein network and thereby drive neurodegeneration. This study illustrates key pathway regulation responses to the development of AD pathogenesis by directly measuring the changes of protein synthesis and provides unique insights into the mechanisms that underlie AD.
Clustered γ-Protocadherins Regulate Cortical Interneuron Programmed Cell Death
Authors: Mancia Walter , Spatazza Julien , Rakela Benjamin , Chatterjee Ankita , Pande Viraj , Maniatis Tom , Hasenstaub Andrea R. , Stryker Michael P. , Alvarez-Buylla Arturo 
Published: January 2020

AbstractCortical function critically depends on inhibitory/excitatory balance. GABAergic cortical inhibitory interneurons (cINs) are born in the ventral forebrain. After completing their migration into cortex, their final numbers are adjusted-during a period of postnatal development - by programmed cell death (PCD). The mechanisms that regulate cIN elimination remain controversial. Here we show that genes in the protocadherin (Pcdh)-γ gene cluster, but not in the Pcdh-α or Pcdh-β clusters, are required for survival of cINs through a BAX-dependent mechanism. Surprisingly, the physiological and morphological properties of Pcdh-γ deficient and wild type cINs during PCD were indistinguishable. Co-transplantation of wild type and Pcdh-γ deficient interneuron precursor cells demonstrate that: 1) the number of mutant cINs eliminated was much higher than that of wild type cells, but the proportion of mutant or WT cells undergoing cell death was not affected by their density; 2) the presence of mutant cINs increases cell death among wild-type counterparts, and 3) cIN survival is dependent on the expression of Pcdh-γ C3, C4, and C5. We conclude that Pcdh-γ, and specifically γC3, γC4, and γC5, play a critical role in regulating cIN survival during the endogenous period of PCD.SignificanceGABAergic cortical inhibitory interneurons (cINs) in the cerebral cortex originate from the ventral embryonic forebrain. After a long migration, they come together with local excitatory neurons to form cortical circuits. These circuits are responsible for higher brain functions, and the improper balance of excitation/inhibition in the cortex can result in mental diseases. Therefore, an understanding of how the final number of cINs is determined is both biologically and, likely, therapeutically significant. Here we show that cell surface homophilic binding proteins belonging to the clustered protocadherin gene family, specifically three isoforms in the Pcdh-γ cluster, play a key role in the regulation cIN programmed cell death. Co-transplantation of mutant and wild-type cINs shows that Pcdh-γ genes have cell-autonomous and non-cell autonomous roles in the regulation of cIN cell death. This work will help identify the molecular mechanisms and cell-cell interactions that determine how the proper ratio of excitatory to inhibitory neurons is determined in the cerebral cortex.
Sponge Physioecology On Moorea, French Polynesia: Local Distribution And Filtration Efficiency OfLamellodysideaUnder Varying Temperatures
Authors: Leveque-Eichhorn Lily 
Published: January 2020

AbstractThis physio-ecological study investigated the physiology and distribution ofLamellodysidea sp.in Moorea, French Polynesia. Specifically, its distribution was described across three reef types—fringing, mid-barrier, and barrier reefs—as well as across sites between Cook’s Bay and Opunohu Bay. Additionally, filtration experiments were conducted to test how temperature impacts filtration efficiency. This is informative when predicting how future ocean temperatures are going to affect sponge’s success and distribution. Sponge abundance was found to decrease from the fringing reef out to the barrier reef, with the highest number of sponges in the fringing reef, less in the mid-barrier reef, and none found in the barrier reef. Sponges were also unevenly distributed across sites, with sponge abundance clearly increasing as you move away from Cook’s Bay. Together, these data show that sponges demonstrate habitat preference that is related to their physiological tolerances. Filtration data showed that over a 3-hour period sponges increase their physiological output when introduced to environments 3-6 degrees Celsius above normal. This suggests that as ocean temperatures warm, sponges are likely to increase their filtration efficiency, thus increasing their ecological role as filter feeders, or struggle to survive at this new level of physiological function.
Sampling artifacts in single-cell genomics cohort studies
Authors: Massoni-Badosa Ramon , Iacono Giovanni , Moutinho Catia , Kulis Marta , Palau Núria , Marchese Domenica , Rodríguez-Ubreva Javier , Ballestar Esteban , Rodriguez-Esteban Gustavo , Marsal Sara , Aymerich Marta , Colomer Dolors , Campo Elias , Julià Antonio , Martín-Subero José Ignacio , Heyn Holger 
Published: January 2020

AbstractRobust protocols and automation now enable large-scale single-cell RNA and ATAC sequencing experiments and their application on biobank and clinical cohorts. However, technical biases introduced during sample acquisition can hinder solid, reproducible results and a systematic benchmarking is required before entering large-scale data production. Here, we report the existence and extent of gene expression and chromatin accessibility artifacts introduced during sampling and identify experimental and computational solutions for their prevention.
Reduced PABPN1 levels causes cytoskeleton disorganization and aberrant differentiation
Authors: Olie Cyriel Sebastiaan , van der Wal Erik , Domagoj Cikes , Maton Loes , de Greef Jessica C. , Lin I-Hsuan , Chen Yi-Fan , Kareem Elsayad , Penninger Josef M. , Kessler Benedikt M. , Raz Vered 
Published: January 2020

AbstractThe polyadenylation binding protein nucleus 1 (PABPN1), a multifactorial regulator of mRNA processing, regulates muscle wasting and atrophy. Previously, we elucidated the PABPN1-dependent proteome and found that levels of structural proteins, sarcomeric and cytoskeletal, were highly altered. We identified MURC, a plasma membrane-associated protein, to be affected by the cytoskeletal stability and suggest that MURC is a novel marker for impaired regeneration in muscles. We also studied the spatial organization of muscle structural proteins in 2D and 3D cell models with reduced PABPN1 levels (named here as shPAB). We show that dysregulation of cytoskeletal proteins in the shPab proteome is associated with a cytoskeleton lacking a polarized organization in muscle cells. We show that consequently, the cell mechanical features as well as myogenic differentiation are significantly reduced. We then show that restoring cytoskeletal stability, by actin overexpression in shPAB was beneficial for cell fusion and for the expression of sarcomeric proteins in shPAB models. We suggest that poor cytoskeleton mechanical features are caused by altered expression levels and contribute to aging-associated muscle wasting and atrophy.
Genetic associations at regulatory phenotypes improve fine-mapping of causal variants for twelve immune-mediated diseases
Authors: Kundu Kousik , Mann Alice L. , Tardaguila Manuel , Watt Stephen , Ponstingl Hannes , Vasquez Louella , Morrell Nicholas W. , Stegle Oliver , Pastinen Tomi , Sawcer Stephen J. , Anderson Carl A. , Walter Klaudia , Soranzo Nicole 
Published: January 2020

AbstractThe identification of causal genetic variants for common diseases improves understanding of disease biology. Here we use data from the BLUEPRINT project to identify regulatory quantitative trait loci (QTL) for three primary human immune cell types and use these to fine-map putative causal variants for twelve immune-mediated diseases. We identify 340 unique, non major histocompatibility complex (MHC) disease loci that colocalise with high (>98%) posterior probability with regulatory QTLs, and apply Bayesian frameworks to fine-map associations at each locus. We show that fine-mapping applied to regulatory QTLs yields smaller credible set sizes and higher posterior probabilities for candidate causal variants compared to disease summary statistics. We also describe a systematic under-representation of insertion/deletion (INDEL) polymorphisms in credible sets derived from publicly available disease meta-analysis when compared to QTLs based on genome-sequencing data. Overall, our findings suggest that fine-mapping applied to disease-colocalising regulatory QTLs can enhance the discovery of putative causal disease variants and provide insights into the underlying causal genes and molecular mechanisms.