bluuebunny/crossref_metadata_2025_split huggingface dataset:
Urine proteome changes in a chronic unpredictable mild stress (CUMS) mouse model of major depressive disorder
Authors: Huan Yuhang , Wei Jing , Su Tong , Gao Youhe 
Published: June 2020

AbstractBackgroundMajor depressive disorder (MDD) is a prevalent complex psychiatric disorder with a high prevalence rate. Because MDD is a systemic multifactorial disorder involving complex interactions and disturbances of various molecular pathways, there are no effective biomarkers for clinical diagnosis. Urine is not subjected to homeostatic control, allowing it to reflect the sensitive and comprehensive changes that occur in various diseases. In this study, we examined the urine proteome changes in a CUMS mouse model of MDD.MethodsMale C57BL/6 mice were subjected to chronic unpredictable mild stress for 5 weeks. The tail suspension test (TST) and sucrose consumption test (SCT) were then applied to evaluate depression-like behaviors. The urine proteomes on day 0 and day 36 in the CUMS group were profiled by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS).ResultsA total of 45 differential proteins were identified, 24 of which have been associated with the pathogenic mechanisms of MDD, while 10 proteins have been previously suggested as MDD biomarkers. There was an average of two differential proteins that were identified through 1048574 random combination statistical analyses, indicating that at least 95% of the differential proteins were reliable and not the result of random combination. The differential proteins were mainly associated with blood coagulation, inflammatory responses and central nervous system development.ConclusionsOur preliminary results indicated that the urine proteome can reflect changes associated with MDD in the CUMS model, which provides potential clues for the diagnosis of clinical MDD patients.
Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8
Authors: Qin Gong , Robinson Kim , Chenrui Xu , Jiawen Zhang , Zhi Boo Zhao , Thiam Teo Daniel Eng , Yaming Zhang , Yew Lim John Soon , Ing Goh Wah , Wright Graham , Zhong Franklin L. , Bin Wu , Reversade Bruno 
Published: June 2020

AbstractNod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related NLR proteins, NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, the molecular mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIINDUPA-CARD) of NLRP1 and CARD8 self-oligomerize to trigger the assembly of distinct inflammasome complexes. Recombinant FIINDUPA-CARD of NLRP1 forms a two-layered filament, with an inner core composed of oligomerized CARD domains and the outer layer consisting of FIINDUPArings. Biochemically, oligomerized NLRP1-CARD is sufficient to drive ASC speck formation in cultured human cells via filament formation-a process that is greatly enhanced by NLRP1-FIINDUPA, which forms ring-like oligomersin vitro. In addition, we report the cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments at 3.7 Å, which uncovers unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide unique structural insight into the mechanisms of activation for human NLRP1 and CARD8, uncovering an unexpected level of specificity in inflammasome signaling mediated by heterotypic CARD domain interactions.
Mitochondrial dsRNAs activate PKR and TLR3 to promote chondrocyte degeneration in osteoarthritis
Authors: Kim Sujin , Lee Keonyong , Choi Yong Seok , Ku Jayoung , Lee Yun Jong , Kim Yoosik 
Published: June 2020

ABSTRACTProtein kinase R (PKR) is an immune response protein that becomes activated by long double-stranded RNAs (dsRNAs). Several studies reported the misactivation of PKR in patients of degenerative diseases including primary osteoarthritis (OA). However, the molecular identity of PKR-activating dsRNAs remains unknown. Here, we investigate the role of mitochondrial dsRNAs (mt-dsRNAs) in the development of OA. We find that in response to OA-mimicking stressors, cytosolic efflux of mt-dsRNAs is increased, leading to PKR activation and subsequent induction of inflammatory cytokines and apoptosis. Moreover, mt-dsRNAs are exported to the extracellular space where they activate toll-like receptor 3. Elevated expression of mt-dsRNAs in the synovial fluids of OA patients further supports our data. Lastly, we show that autophagy protects chondrocytes from mitochondrial dysfunction partly by removing cytosolic mt-dsRNAs. Together, these findings establish the PKR-mt-dsRNA as a critical regulatory axis in OA development and suggest mt-dsRNAs as a potential target in fighting OA.
Premature commitment to uncertain beliefs during human NMDA receptor hypofunction
Authors: Salvador Alexandre , Arnal Luc H. , Vinckier Fabien , Domenech Philippe , Gaillard Raphaël , Wyart Valentin 
Published: June 2020

AbstractIn uncertain environments, accurate decision-making requires integrating ambiguous or conflicting signals – a cognitive inference process thought to require n-methyl-d-aspartate (NMDA) synaptic receptors. Here we characterized the causal impact of human NMDA receptor hypofunction on cognitive inference using placebo-controlled infusions of ketamine in a visual cue combination task. Participants tested under ketamine showed elevated uncertainty, together with impaired cognitive inference despite intact visual processing. This behavioral effect of ketamine was associated in patterns of electrical brain activity with degraded and unbalanced coding of presented cues in associative cortex, followed by premature response preparation in motor cortex. Through quantitative simulations, we propose that these cognitive alterations reflect an urge to explain away the elevated uncertainty triggered by ketamine. This compensatory mechanism may cause the emergence of psychotic symptoms observed under chronic NMDA receptor dysfunction, but also forge unusually strong beliefs when confronted with uncertainty in everyday life.
Entelon®(vitis viniferaseed extract) reduces inflammation and calcification in a beagle dog model of intravascular bovine pericardium implantation
Authors: Choi Gab-Chol , Kim Sokho , Rahman Mahbubur , Oh Ji Hyun , Cho Yun Seok , Shin Hong Ju 
Published: June 2020

AbstractObjectiveInflammation and calcification are major factors responsible for failure of bioprosthetic valve and other substitute heart valve implantations. The objective of this study was to evaluate the anti-inflammatory and anti-calcification effects of Entelon150®(consisting of grape-seed extract) in a beagle dog model of intravascular bovine pericardium implantation.MethodsIn total, 8 healthy male beagle dogs were implanted with a bovine pericardium bilaterally in the external jugular veins and divided into two groups. Animals in the Entelon150®group (n = 4) were treated with 150 mg of Entelon150®twice daily for six weeks after surgery. The negative control (NC) group (n = 4) was treated with 5 ml of saline using the same method. After six weeks, we measured the calcium content, performed histological examination, and performed molecular analysis.ResultsThe calcium content of implanted tissue in the Entelon150®group (0.56±0.14 mg/g) was significantly lower than that in the NC group (1.48±0.57 mg/g) (p < 0.05). Histopathological examination showed that infiltration of chronic inflammatory cells, such as fibroblasts and macrophages, occurred around the graft in all groups; however, the inflammation level of the implanted tissue in the Entelon150®group was significantly lower than that in the NC group. Both immunohistochemical and western blot analyses revealed that bone morphogenetic protein 2 expression was significantly attenuated in the Entelon150®group.ConclusionsOur results indicate that Entelon150®significantly attenuates post-implantation inflammation and degenerative calcification of the bovine pericardium in dogs. Therefore, Entelon150®may increase the longevity of the bovine pericardium after intravascular implantation.
Detecting new allies: Modifier screen identifies a genetic interaction betweenImaginal disc growth factor 3and a Rho-kinase substrate during dorsal appendage tube formation inDrosophila
Authors: Espinoza Claudia Y. , Berg Celeste A. 
Published: June 2020

ABSTRACTBiological tube formation underlies organ development, and when disrupted, can cause severe birth defects. To investigate the genetic basis of tubulogenesis, we study the formation ofDrosophila melanogastereggshell structures, called dorsal appendages, which are produced by epithelial tubes. Previously we found that precise levels ofDrosophilaChitinase-like proteins (CLPs), encoded by theImaginal disc growth factor (Idgf)gene family, are needed to regulate dorsal-appendage tube closure and tube migration. To identify factors that act in theIdgfpathway, we developed a genetic modifier screen based on the finding that overexpressingIdgf3causes dorsal appendage defects with ∼50% frequency. Using a library of partially overlapping heterozygous deficiencies, we scanned chromosome 3L and found regions that enhanced or suppressed theIdgf3-overexpression phenotype. Using smaller deletions, RNAi, and mutant alleles, we further mapped five regions and refined the interactions to 58 candidate genes. Importantly, mutant alleles identifiedcombover (cmb), a substrate of Rho-kinase (Rok) and a component of the Planar Cell Polarity (PCP) pathway, as anIdgf3-interacting gene: loss of function enhanced while gain of function suppressed the dorsal appendage defects. Since PCP drives cell intercalation in other systems, we asked ifcmb/+affected cell intercalation in our model, but we found no evidence of its involvement in this step. Instead, we found that loss ofcmbdominantly enhanced tube defects associated withIdgf3overexpression by expanding the apical area of dorsal appendage cells. Apical surface area determines tube volume and shape; in this way,Idgf3andcmbregulate tube morphology.
Trophic cooperation promotes bacterial survival ofStaphylococcus aureusandPseudomonas aeruginosa
Authors: Camus Laura , Briaud Paul , Bastien Sylvère , Elsen Sylvie , Doléans-Jordheim Anne , Vandenesch François , Moreau Karen 
Published: June 2020

AbstractIn the context of infection,Pseudomonas aeruginosaandStaphylococcus aureusare frequently co-isolated, particularly in cystic fibrosis (CF) patients. Within lungs, the two pathogens exhibit a range of competitive and coexisting interactions. In the present study, we explored the impact ofS. aureuson the physiology ofP. aeruginosain the context of coexistence. Transcriptomic analyses showed thatS. aureussignificantly and specifically affects the expression of numerous genes involved inP. aeruginosacarbon and amino acid metabolism. In particular, 65% of the strains presented considerable overexpression of the genes involved in the acetoin catabolic (aco) pathway. We demonstrated that acetoin is (i) produced by clinicalS. aureusstrains, (ii) detected in sputa from CF patients, and (iii) involved inP. aeruginosa’s acosystem induction. Furthermore, acetoin is catabolized byP. aeruginosa, a metabolic process that improves the survival of both pathogens by providing a new carbon source forP. aeruginosaand avoiding the toxic accumulation of acetoin onS. aureus. Due to its beneficial effects on both bacteria, acetoin catabolism could testify to the establishment of trophic cooperation betweenS. aureusandP. aeruginosain the CF lung environment, thus promoting their persistence.
CRISPR-Cas-amplified urine biomarkers for multiplexed and portable cancer diagnostics
Authors: Hao Liangliang , Zhao Renee T. , Ngambenjawong Chayanon , Fleming Heather E. , Bhatia Sangeeta N. 
Published: June 2020

AbstractSynthetic biomarkers, exogenous probes that generate molecular reporters, represent an emerging paradigm in precision diagnostics with applications across infectious and noncommunicable diseases. In order to achieve their promise, these methods reply on multiplexing strategies to provide tools that are both sensitive and specific. However, the field of synthetic biomarkers has not benefited from molecular strategies such as DNA-barcoding due to the susceptibility of nucleic acidsin vivo. Herein, we exploit chemically-stabilized DNAs to tag synthetic biomarkers and produce diagnostic signalsviaCRISPR nucleases. Our strategy capitalizes on disease-associated, protease-activated release of nucleic acid barcodes and polymerase-amplification-free, CRISPR-Cas-mediated barcode detection in unprocessed biofluids. In murine cancer models, we show that the DNA-encoded urine biomarkers can noninvasively detect and monitor disease progression, and demonstrate that nuclease amplification can be harnessed to convert the readout to a point-of-care tool. This technique combines specificity with ease of use to offer a new platform to study human disease and guide therapeutic decisions.
A pathway for error-free non-homologous end joining of resected meiotic double-strand breaks
Authors: Hatkevich Talia , Miller Danny E. , Turcotte Carolyn A. , Miller Margaret C. , Sekelsky Jeff 
Published: June 2020

ABSTRACTProgrammed DNA double-strand breaks (DSBs) made during meiosis are repaired by recombination with the homologous chromosome to generate, at selected sites, reciprocal crossovers that are critical for the proper separation of homologs in the first meiotic divisions. Backup repair processes can compensate when the normal meiotic recombination processes are non-functional. We describe a novel backup repair mechanism that occurs when the homologous chromosome is not available inDrosophila melanogastermeiosis. In the presence of a previously described mutation (Mcm5A7) that disrupts chromosome pairing, DSB repair is initiated by homologous recombination but is completed by non-homologous end joining (NHEJ). Remarkably, this process yields precise repair products. Our results provide support for a recombination intermediate recently discovered in mouse meiosis, in which an oligonucleotide bound to the Spo11 protein that catalyzes DSB formation remains bound after resection. We propose that this oligonucleotide functions as a primer for fill-in synthesis to allow scarless repair by NHEJ.
Embryonic stem cells commit to differentiation by symmetric divisions following a variable lag period
Authors: Strawbridge Stanley E , Blanchard Guy B , Smith Austin , Kugler Hillel , Martello Graziano 
Published: June 2020

ABSTRACTMouse embryonic stem (ES) cells are derived from the epiblast of the preimplantation embryo and retain the capacity to give rise to all embryo lineages. ES cells can be released into differentiation from a near-homogeneous maintenance condition. Exit from the ES cell state can be accurately monitored using the Rex1-GFPd2 transgenic reporter, providing a powerful system for examining a mammalian cell fate transition. Here, we performed live-cell imaging and tracking of ES cells during entry into differentiation for 48 hours in defined conditions. We observed a greater cell surface area and a modest shortening of the cell cycle prior to exit and subsequently a reduction in cell size and increase in motility. We did not see any instance of cells regaining ES cell identity, consistent with unidirectional developmental progression. Transition occurred asynchronously across the population but genealogical tracking revealed a high correlation in cell-cycle length and Rex1-GFPd2 expression between daughter cells. A population dynamics model was consistent with symmetric divisions during exit from naive pluripotency. Collapse of ES cell identity occurred acutely in individual cells but after a variable delay. The variation in lag period can extend up to three generations, creating marked population asynchrony.
The effect of hybridization on transposable element accumulation in an undomesticated fungal species
Authors: Hénault Mathieu , Marsit Souhir , Charron Guillaume , Landry Christian R. 
Published: June 2020

AbstractTransposable elements (TEs) are mobile genetic elements that can profoundly impact the evolution of genomes and species. A long-standing hypothesis suggests that hybridization could deregulate TEs and trigger their accumulation, although it received mixed support from studies in plants and animals. Here, we tested this hypothesis in fungi using incipient species of the undomesticated yeastSaccharomyces paradoxus. Population genomic data revealed no signature of higher transposition in natural hybrids. As we could not rule out the elimination of past transposition increase signatures by natural selection, we performed a laboratory evolution experiment on a panel of artificial hybrids to measure TE accumulation in the near absence of selection. Changes in TE copy numbers were not predicted by the level of evolutionary divergence between the parents of a hybrid genotype. Rather, they were highly dependent on the individual hybrid genotypes, showing that strong genotype-specific deterministic factors govern TE accumulation in yeast hybrids.
Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding
Authors: Starr Tyler N. , Greaney Allison J. , Hilton Sarah K. , Crawford Katharine H.D. , Navarro Mary Jane , Bowen John E. , Tortorici M. Alejandra , Walls Alexandra C. , Veesler David , Bloom Jesse D. 
Published: June 2020

AbstractThe receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein mediates viral attachment to ACE2 receptor, and is a major determinant of host range and a dominant target of neutralizing antibodies. Here we experimentally measure how all amino-acid mutations to the RBD affect expression of folded protein and its affinity for ACE2. Most mutations are deleterious for RBD expression and ACE2 binding, and we identify constrained regions on the RBD’s surface that may be desirable targets for vaccines and antibody-based therapeutics. But a substantial number of mutations are well tolerated or even enhance ACE2 binding, including at ACE2 interface residues that vary across SARS-related coronaviruses. However, we find no evidence that these ACE2-affinity enhancing mutations have been selected in current SARS-CoV-2 pandemic isolates. We present an interactive visualization and open analysis pipeline to facilitate use of our dataset for vaccine design and functional annotation of mutations observed during viral surveillance.
The costs of networking in nonwork domains: a resource-based perspective
Authors: Wolff Hans-Georg , Kim Sowon 
Published: June 2020

PurposeWhile studies have established that networking is an investment in an individual's career that pays off, recent research has begun to examine the potential costs of networking. This study suggests that prior research is limited in scope, as it remains focused on the work domain. Drawing upon the work home resources model (Ten Brummelhuis and Bakker, 2012), the authors broaden this perspective and develop a framework of negative consequences in nonwork domains. The paper proposes that networking generates costs in nonwork domains, because it requires the investment of finite energy resources in the work domain, and people lack these resources in other domains.Design/methodology/approachThis study uses structural equation modeling of multisource data from N = 306 individuals and their partners to examine how networking affects two distinct nonwork outcomes: work–family conflict and work–life balance.FindingsAnalyses support the general framework: networking is related to time- and strain-based work–family conflict, and work time mediates the relationship between networking and these forms of conflict. Moreover, networking exhibits an inverted U-shaped relationship with work–life balance, indicating that excessive networking as well as a lack of networking decrease work–life balance.Originality/valueThis study adds to the emergent literature on the negative consequences of networking. The findings suggest that employees and organizations should adopt a broader and more balanced perspective on networking: one that takes the well-known benefits – but also potential costs in work and nonwork domains – into account.
Impact of product innovativeness on technology switching in global market
Authors: AL-Kwifi Osama Sam , Ongsakul Viput , Abu Farha Allam K. , Zafar Ahmed U. , Karasneh Mahmoud 
Published: June 2020

PurposeThe purpose of this paper is to explore the relationship between product innovativeness and the process of technology switching. This issue is important for two reasons: (1) in mature markets, the only way to increase market share is through consumers' switching from competitor firms and (2) it is essential to determine whether the product innovation strategy can meet users' needs in high-technology markets.Design/methodology/approachResearch centers (university hospitals) specializing in magnetic resonance imaging (MRI) are the lead users of the MRI market. In this market, the technology switching process was tracked using an annual conference database. Interviews with industry experts and lead users were conducted in order to determine the relationship between product innovativeness and technology switching.FindingsThe findings reveal that in the lead users' segment, technology switching is occurring at a significant level. The interviews emphasized the influence of product innovativeness on technology switching in the global MRI market, as well as the importance of adopting an open innovation process as a strategy to enhance product innovativeness.Practical implicationsThe results can be generalized to industries with similar characteristics, such as high rates of technological change and technology heterogeneity. In high-technology markets, managers should monitor switching behavior. They should also study the influence of product innovativeness on such behavior in order to determine the correct product innovation strategy and meet users' preferences effectively.Originality/valueThe literature reports considerable research that investigates switching behavior, but most publications use data from a short time period and cover a limited geographical region. This is the first study that uses data to track the switching behavior of high-technology products on a global scale over a 22-year period.
Understanding nascent women entrepreneurs: an exploratory investigation into their entrepreneurial intentions
Authors: Wannamakok Wisuwat , Chang Yu-Yu 
Published: June 2020

Purpose
Women entrepreneurs are having increasingly profound impacts on the global economic landscape, although little is known about what supports or restricts women’s entrepreneurial attempts. The purpose of this paper is to explore the perceptual (i.e. presence of role models and fear of failure) and cognitive (i.e. opportunity recognition and entrepreneurial knowledge) mechanisms that influence a women’s choice of an entrepreneurial career.

Design/methodology/approach
A transnational sample of 9,716 women participating in global entrepreneurship monitor (GEM) survey was examined using logistical regression analysis.

Findings
The results indicate that role models, opportunity discovery and entrepreneurial knowledge have a significant and positive influence on female respondents’ entrepreneurial intentions. Interestingly, fear of failure is not related to their entrepreneurial intention, which challenges the prevailing assumption that the worries about new venture outcomes are the primary suppressor of women’s entrepreneurship.

Originality/value
This study sheds new light on the intention of becoming women entrepreneurs, which has multiple implications for originality/value. This study sheds new light on the intention of becoming women entrepreneurs, which has many implications for policymakers. Moreover, theoretical contributions and directions for future research are discussed.