bluuebunny/crossref_metadata_2025_split huggingface dataset:
DksA controls the response of the Lyme disease spirochete Borrelia burgdorferi to starvation
Authors: Boyle William K. , Groshong Ashley M. , Drecktrah Dan , Boylan Julie A. , Gherardini Frank C. , Blevins Jon S. , Samuels D. Scott , Bourret Travis J. 
Published: September 2018

ABSTRACTThe pathogenic spirocheteBorrelia burgdorferisenses and responds to diverse environmental challenges, including changes in nutrient availability, throughout its enzootic cycle inIxodesspp. ticks and vertebrate hosts. This study examined the role of DnaK suppressor protein (DksA) in the transcriptional response ofB. burgdorferito starvation. Wild-type anddksAmutantB. burgdorferistrains were subjected to starvation by shifting mid-logarithmic phase cultures grown in BSK II medium to serum-free RPMI medium for 6 h under microaerobic conditions (5% CO2, 3% O2). Microarray analyses of wild-typeB. burgdorferirevealed that genes encoding flagellar components, ribosomal proteins, and DNA replication machinery were downregulated in response to starvation. DksA mediated transcriptomic responses to starvation inB. burgdorferias thedksA-deficient strain differentially expressed only 47 genes in response to starvation compared to the 500 genes differentially expressed in wild-type strains. Consistent with a role for DksA in the starvation response ofB. burgdorferi, fewer CFUs were observed fordksAmutant after prolonged starvation in RPMI medium compared to wild-typeB. burgdorferi. Transcriptomic analyses revealed a partial overlap between the DksA regulon and the regulon of RelBbu, the guanosine tetraphosphate and guanosine pentaphosphate [(p)ppGpp] synthetase that controls the stringent response; the DksA regulon also included many plasmid-borne genes. Additionally, thedksAmutant strain exhibited constitutively elevated (p)ppGpp levels compared to the wild-type strain, implying a regulatory relationship between DksA and (p)ppGpp. Together, these data indicate that DksA along with (p)ppGpp direct the stringent response to effectB. burgdorferiadaptation to its environment.IMPORTANCEThe Lyme disease bacteriumBorrelia burgdorferimust sense and respond to diverse environments as it cycles between its tick vectors and various vertebrate hosts.B. burgdorferimust withstand prolonged periods of starvation while it resides in unfedIxodesticks. In this study, the regulatory protein DksA is shown to play a pivotal role controlling the transcriptional responses ofB. burgdorferito starvation. The results of this study suggest that DksA gene regulatory activity impactsB. burgdorferimetabolism, virulence gene expression, and the ability of this bacterium to complete its natural life cycle.
Twin Study of Early-Onset Major Depression Finds DNA Methylation Enrichment for Neurodevelopmental Genes
Authors: Roberson-Nay Roxann , Wolen Aaron R. , Lapato Dana M. , Lancaster Eva E. , Webb Bradley T. , Verhulst Bradley , Hettema John M. , York Timothy P. 
Published: September 2018

AbstractMajor depression (MD) is a debilitating mental health condition with peak prevalence occurring early in life. Genome-wide examination of DNA methylation (DNAm) offers an attractive comple ment to studies of allelic risk given it can reflect the combined influence of genes and environment. The current study used a co-twin control design to identify differentially and variably methylated regions of the genome that distinguish monozygotic (MZ) twins with and without a lifetime history of early-onset MD. The sample included 150 Caucasian monozygotic twins (73% female;Mage=17.52SD=1.28) assessed during a developmental stage characterized by relatively dis tinct neurophysiological changes. All twins were generally healthy and currently free of medica tions with psychotropic effects. DNAm was measured in peripheral blood cells using the Infinium Human BeadChip 450K Array. MD associations were detected at 760 differentially and variably methylated probes/regions that mapped to 428 genes. Results indicated an association between early-onset MD and many genes and genomic regions involved in neural circuitry formation, pro jection, functioning, and plasticity. Gene enrichment analyses implicated genes related to neuron structures and neurodevelopmental processes including cell-cell adhesion genes (e.g.,CDHs, PCDHAs, PCDHA1C/2C). Genes previously implicated in mood and psychiatric disorders as well as chronic stress (e.g.,HDAC4, NRG1) also were identified. DNAm regions associated with MD where found to overlap genetic loci observed in the latest Psychiatric Genomics Consortium meta‐ analysis of depression. Understanding the time course of epigenetic influences during emerging adulthood may clarify developmental phases where genes modulate individual differences in MD risk.
Extrinsic Noise Suppression in Micro RNA mediated Incoherent Feedforward Loops
Authors: Carignano Alberto , Mukherjee Sumit , Singh Abhyudai , Seelig Georg 
Published: September 2018

AbstractMicroRNA mediated incoherent feed forward loops (IFFLs) are recurrent network motifs in mammalian cells and have been a topic of study for their noise rejection and buffering properties. Previous work showed that IFFLs can adapt to varying promoter activity and are less prone to noise than similar circuits without the feed forward loop. Furthermore, it has been shown that microRNAs are better at rejecting extrinsic noise than intrinsic noise. This work studies the biological mechanisms that lead to extrinsic noise rejection for microRNA mediated feed forward network motifs. Specifically, we compare the effects of microRNA-induced mRNA degradation and translational inhibition on extrinsic noise rejection, and identify the parameter regimes where noise is most efficiently rejected. In the case of static extrinsic noise, we find that translational inhibition can expand the regime of extrinsic noise rejection. We then analyze rejection of dynamic extrinsic noise in the case of a single-gene feed forward loop (sgFFL), a special case of the IFFL motif where the microRNA and target mRNA are co-expressed. For this special case, we demonstrate that depending on the time-scale of fluctuations in the extrinsic variable compared to the mRNA and microRNA decay rates, the feed forward loop can both buffer or amplify fluctuations in gene product copy numbers.
Sexual selection rewires reproductive protein networks
Authors: Karr Timothy L. , Southern Helen , Rosenow Matthew , Gossmann Toni I. , Snook Rhonda R. 
Published: September 2018

Polyandry drives postcopulatory sexual selection (PCSS), resulting in rapid evolution of male ejaculate traits. Critical to male and female fitness, the ejaculate is known to contain rapidly evolving seminal fluid proteins (SFPs) produced by specialized male secretory accessory glands. The evidence that rapid evolution of some SFPs is driven by PCSS, however, is indirect, based on either plastic responses to changes in the sexual selection environment or correlative macroevolutionary patterns. Moreover, such studies focus on SFPs that represent but a small component of the accessory gland proteome. Neither how SFPs function with other reproductive proteins, nor how PCSS influences the underlying secretory tissue adaptations and content of the accessory gland, has been addressed at the level of the proteome. Here we directly test the hypothesis that PCSS results in rapid evolution of the entire male accessory gland proteome and protein networks by taking a system-level approach, combining divergent experimental evolution of PCSS inDrosophila pseudoobscura (Dpse), high resolution mass spectrometry (MS) and proteomic discovery, bioinformatics and population genetic analyses. We demonstrate that PCSS influences the abundance of over 200 accessory gland proteins, including SFPs. A small but significant number of these proteins display molecular signatures of positive selection. Divergent PCSS also results in fundamental and remarkably compartmentalized evolution of accessory gland protein networks in which males subjected to strong PCSS invest in protein networks that serve to increase protein production whereas males subjected to relaxed PCSS alters protein networks involved in protein surveillance and quality. These results directly demonstrate that PCSS is a key evolutionary driver that shapes not only individual reproductive proteins, but rewires entire reproductive protein networks.The abbreviations used are:BLASTBasic Local Alignment Search ToolDpseDrosophila pseudoobscuraPCSSpostcopulatory sexual selectionSFPsseminal fluid proteinsDmelD. melanogasterSDSsodium dodecylsulfateSDS-PAGEsodium dodecylsulfate polyacrylamide gel electrophoresisMSmass spectrometryLC-MS/MSliquid chromatography-MS/MSAcgPaccessory gland proteomeFDRsFalse Discovery RatesAcgSaccessory gland secretomeexoPexoproteomeLFQlabel-free quantitationPpolyandryMmonandryGOgene ontologyCCcellular componentMFmolecular functionBPbiological processSTRINGSearch Tool for the Retrieval of Interacting Genes/ProteinsDIOPTDRSC Integrative Ortholog Prediction ToolsERendoplasmic reticulum
Genome wide association study in 3,173 outbred rats identifies multiple loci for body weight, adiposity, and fasting glucose
Authors: Chitre Apurva S. , Polesskaya Oksana , Holl Katie , Gao Jianjun , Cheng Riyan , Bimschleger Hannah , Martinez Angel Garcia , George Tony , Gileta Alexander F. , Han Wenyan , Horvath Aidan , Hughson Alesa , Ishiwari Keita , King Christopher P. , Lamparelli Alexander , Versaggi Cassandra L. , Martin Connor , Pierre Celine L. St. , Tripi Jordan A. , Wang Tengfei , Chen Hao , Flagel Shelly B. , Meyer Paul , Richards Jerry , Robinson Terry E. , Palmer Abraham A. , Solberg Woods Leah C. 
Published: September 2018

AbstractObjectiveObesity is influenced by genetic and environmental factors. Despite success of human genome wide association studies (GWAS), the specific genes that confer obesity remain largely unknown. The objective of this study was to use outbred rats to identify genetic loci underlying obesity and related morphometric and metabolic traits.MethodsWe measured obesity-relevant traits including body weight, body length, body mass index, fasting glucose, and retroperitoneal, epididymal, and parametrial fat pad weight in 3,173 male and female adult N/NIH heterogeneous stock (HS) rats across three institutions, providing data for the largest rat GWAS to date. Genetic loci were identified using a linear mixed model that accounted for the complex family relationships of the HS and covariate to account for differences among the three phenotyping centers.ResultsWe identified 32 independent loci, several of which contained only a single gene (e.g. Epha5, Nrg1 and Klhl14) or obvious candidate genes (Adcy3, Prlhr). There were strong phenotypic and genetic correlations among obesity-related traits, and extensive pleiotropy at individual loci.ConclusionsThese studies demonstrate utility of HS rats for investigating the genetics of obesity related traits across institutions and identify several candidate genes for future functional testing.
Rapid and highly-specific generation of targeted DNA sequencing libraries enabled by linking capture probes with universal primers
Authors: Pel Joel , Leung Amy , Choi Wendy W. Y. , Despotovic Milenko , Ung W. Lloyd , Shibahara Gosuke , Gelinas Laura , Marziali Andre 
Published: September 2018

AbstractTargeted Next Generation Sequencing (NGS) is being adopted increasingly broadly in many research, commercial and clinical settings. Currently used target capture methods, however, typically require complex and lengthy (sometimes multi-day) workflows that complicates their use in certain applications. In addition, small panels for high sequencing depth applications such as liquid biopsy typically have low on-target rates, resulting in unnecessarily high sequencing cost.We have developed a novel targeted sequencing library preparation method, named Linked Target Capture (LTC), which replaces typical multi-day target capture workflows with a single-day, combined ‘target-capture-PCR’ workflow. This approach uses physically linked capture probes and PCR primers and is expected to work with panel sizes from 100 bp to >10 Mbp. It reduces the time and complexity of the capture workflow, eliminates long hybridization and wash steps and enables rapid library construction and target capture. High on-target read fractions are achievable due to repeated sequence selection in the target-capture-PCR step, thus lowering sequencing cost.We have demonstrated this technology on sample types including cell-free DNA (cfDNA) and formalin-fixed, paraffin-embedded (FFPE) derived DNA, capturing a 35-gene pan-cancer panel, and therein detecting single nucleotide variants, copy number variants, insertions, deletions and gene fusions. With the integration of unique molecular identifiers (UMIs), variants as low as 0.25% abundance were detected, limited by input mass and sequencing depth. Additionally, sequencing libraries were prepared in less than eight hours from extracted DNA to loaded sequencer, demonstrating that LTC holds promise as a broadly applicable tool for rapid, cost-effective and high performance targeted sequencing.
STAT3 promotes melanoma metastasis by CEBP-induced repression of the MITF pigmentation pathway
Authors: Swoboda Alexander , Soukup Robert , Kinslechner Katharina , Wingelhofer Bettina , Schörghofer David , Sternberg Christina , Pham Ha T. T. , Vallianou Maria , Horvath Jaqueline , Stoiber Dagmar , Kenner Lukas , Larue Lionel , Poli Valeria , Beermann Friedrich , Yokota Takashi , Kubicek Stefan , Krausgruber Thomas , Rendeiro André F. , Bock Christoph , Zenz Rainer , Kovacic Boris , Aberger Fritz , Hengstschläger Markus , Petzelbauer Peter , Mikula Mario , Moriggl Richard 
Published: September 2018

AbstractMetastatic melanoma is hallmarked by its ability to switch oncogenic MITF expression. Here we tested the impact of STAT3 on melanoma onset and progression in association with MITF expression levels. We established a mouse melanoma model for deleting Stat3 specifically in melanocytes with specific expression of human hyperactive NRASQ61K in an Ink4a deficient background. Mice with tissue specific Stat3 deletion showed an early onset of disease, but displayed significantly diminished lung metastases. Whole genome expression profiling also revealed a reduced invasion phenotype, which was functionally confirmed in 3D melanoma model systems. Notably, loss or knockdown of STAT3 in mouse or human cells resulted in up-regulation of MITF and induction of cell proliferation. Mechanistically we show that STAT3 induced CEBPa/b expression was sufficient to suppress MITF transcription. Epigenetic analysis by ATAC-seq confirmed that STAT3 enabled CEBPa/b binding to the MITF enhancer region thereby silencing it. We conclude that STAT3 is a metastasis driver in melanoma able to antagonize the MITF oncogene via direct induction of CEBP family member transcription facilitating RAS-RAF-driven melanoma metastasis.List of AbbreviationsATAC-seq, Assay for Transposase-Accessible Chromatin using sequencing; CEBP, CAAT Box Enhancer Binding Protein; CRE, Cre recombinase; EGF, Epidermal Growth Factor; GEO, Gene Expression Omnibus; GSEA, Gene Set Enrichment Analysis; HSC70, Heat Shock 70 kDa protein; IHC, Immunohistochemistry; IL-6, Interleukin-6; JAK, Janus Kinase; MITF, Microphthalmia-Associated Transcription Factor; NSG, NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice; OSM, Oncostatin M; PDGF, Platelet-Derived Growth Factor; pS, phosphoserine; pY, phosphotyrosine; RAS, Rat Sarcoma; RAF, Rapidly Accelerated Fibrosarcoma; RTK, Receptor Tyrosine Kinase; RT-PCR, Reverse Transcription Polymerase Chain Reaction; S100b, Calcium Binding Protein S100 beta; shRNA, short hairpin RNA; SOX10, Sex Determining Region Y-10; STAT, Signal Transducer and Activator of Transcription; TCGA, The Cancer Genome Atlas; TMA, Tissue Micro Array
Eco-evolutionary processes underlying early warning signals of population declines
Authors: Baruah Gaurav , Clements Christopher F. , Ozgul Arpat 
Published: September 2018

AbstractEnvironmental change can impact the stability of populations and can cause rapid declines in abundance. Abundance-based warning signals have been proposed to predict such declines, but these have been shown to have limited success, leading to the development of warning signals based on the distribution of fitness-related traits such as body size.The dynamics of such traits in response to external environmental perturbations are controlled by a range of underlying factors such as reproductive rate, genetic variation, and plasticity. However, it remains unknown how such ecological and evolutionary factors affect the stability landscape of populations and the detectability of abundance and trait-based warning signals of population decline.Here, we apply a trait-based demographic approach and investigate both trait and population dynamics in response to gradual changes in the environment. We explore a range of ecological and evolutionary constraints under which the stability of a population may be affected.We show both analytically and with model-based simulations that strength of abundance-based early warning signals is significantly affected by ecological and evolutionary factors.Finally, we show that a unified approach, combining trait- and abundance-based information, significantly improves our ability to predict population declines. Our study suggests that the inclusion of trait dynamic information alongside generic warning signals should provide more accurate forecasts of the future state of biological systems.
Patient-specific logic models of signaling pathways from screenings on cancer biopsies to prioritize personalized combination therapies
Authors: Eduati Federica , Jaaks Patricia , Merten Christoph A. , Garnett Mathew J. , Rodriguez Julio Saez- 
Published: September 2018

AbstractMechanistic modeling of signaling pathways mediating patient-specific response to therapy can help to unveil resistance mechanisms and improve therapeutic strategies. Yet, creating such models for patients, in particular for solid malignancies, is challenging. A major hurdle to build these models is the limited material available, that precludes the generation of large-scale perturbation data. Here, we present an approach that couples ex vivo high-throughput screenings of cancer biopsies using microfluidics with logic-based modeling to generate patient-specific dynamic models of extrinsic and intrinsic apoptosis signaling pathways. We used the resulting models to investigate heterogeneity in pancreatic cancer patients, showing dissimilarities especially in the PI3K-Akt pathway. Variation in model parameters reflected well the different tumor stages. Finally, we used our dynamic models to efficaciously predict new personalized combinatorial treatments. Our results suggest our combination of microfluidic experiments and mathematical model can be a novel tool toward cancer precision medicine.
Characteristics of Interactions at Protein Segments External to Globular Domains in the Protein Data Bank
Authors: Kasahara Kota , Minami Shintaro , Aizawa Yasunori 
Published: September 2018

ABSTRACTThe principle of three-dimensional protein structure formation is a long-standing conundrum in structural biology. A globular domain of a soluble protein is formed by a network of atomic contacts among amino acid residues, but regions external to globular domains, like loop and linker, often do not have intramolecular contacts with globular domains. Although these regions can play key roles for protein function as interfaces for intermolecular interactions, their nature remains unclear. Here, we termed protein segments external to globular domains as floating segments and sought for them in tens of thousands of entries in the Protein Data Bank. As a result, we found that 0.72 % of residues are in floating segments. Regarding secondary structural elements, coil structures are enriched in floating segments, especially for long segments. Interactions with polypeptides and polynucleotides, but not small compounds, are enriched in floating segments. The amino acid preferences of floating segments are similar to those of surface residues, with exceptions; the small side chain amino acids, Gly and Ala, are preferred, and some charged side chains, Arg and His, are disfavored for floating segments compared to surface residues. Our comprehensive characterization of floating segments may provide insights into understanding protein sequence-structure-function relationships.
Chemerin Induced byTreponema pallidumPredicted Membrane Protein Tp0965 Mediates Endothelial Dysfunction via Activating MAPK Signaling Pathway
Authors: Zhang Rui-Li , Yang Li-Jia , Wang Qian-Qiu 
Published: September 2018

AbstractChemerin, a chemoattractant protein, is involved in endothelial dysfunction and vascular inflammation in pathological conditions. In a recent study, we observed the upregulation of chemerin in endothelial cells followingin vitrotreatment withT. pallidum. Here, we investigated the role of chemerin in endothelial cells dysfunction induced by theT. pallidumpredicted membrane protein Tp0965. Following stimulation of human umbilical vein endothelial cells (HUVECs) with Tp0965, chemerin and its ChemR23 receptor were up-regulated, companied with elevated expression of TLR2. Furthermore, chemerin from HUVECs activated endothelial cells via chemerin/ChemR23 signaling in an autocrine/paracrine manner, characterized by upregulated expression of ICAM-1, E-selectin and MMP-2. Activation of endothelial cells depended on the MAPK signaling pathway. In addition, Tp0965-induced chemerin promoted monocytes migration to endothelial cells, also via chemerin/ChemR23 pathway. The RhoA/ROCK signaling pathway was also involved in monocytes migration in response to chemerin/ChemR23. Our results highlight the role of Tp0965-induced chemerin in endothelial cells dysfunction, which contributes to the immunopathogenesis of vascular inflammation of syphilis.Author summaryTreponema pallidumis the spirochete of syphilis, which causes a chronic system inflammation. Endothelium damage caused by this bacterium is the key step in the systemic dissemination and pathophysiology of syphilis, particularly cardiovascular syphilis and neurosyphilis. In this study, we show a novel molecular mechanism of endothelium damage induce byTreponema pallidumpredicted membrane protein Tp0965. Chemerin is a recently identified adipocytokine and chemoattractant protein with a crucial role in endothelial dysfunction and vascular inflammation in pathological conditions. Our data show that Tp0965 up-regulated the expression of chemerin and its ChemR23 receptor by endothelial cells in vitro. Furthermore, chemerin from HUVECs activated endothelial cells via chemerin/ChemR23 signaling in an autocrine/paracrine manner and depended on the MAPK signaling pathway. In addition, Tp0965-induced chemerin promoted monocytes migration to endothelial cells, also via chemerin/ChemR23 pathway. The RhoA/ROCK signaling pathway was also involved in monocytes migration in response to chemerin/ChemR23. These findings contribute to the immunopathogenesis of vascular inflammation of syphilis.