bluuebunny/crossref_metadata_2025_split huggingface dataset:
PXN/Paxillin Phase Separation Promotes Focal Adhesion Assembly and Integrin Signaling
Authors: Liang Peigang , Wu Yuchen , Zheng Shanyuan , Zhang Jiaqi , Yang Shuo , Wang Jinfang , Ma Suibin , Zhang Mengjun , Gu Zhuang , Liu Qingfeng , Jiang Wenxue , Xing Qiong , Wang Bo 
Published: December 2022

AbstractFocal adhesions (FAs) are transmembrane protein assemblies mediating cell-matrix connection. Tools to manipulate the compositionally intricate and dynamic FAs are currently limited, rendering many fundamental hypotheses untestable. Although protein liquid-liquid phase separation (LLPS) has been tied to the organization and dynamics of FAs, the underlying mechanisms remain unclear. Here, we experimentally tune the LLPS of PXN/Paxillin, an essential scaffold protein of FAs, by utilizing light-inducible Cry2 system. In addition to nucleating FA components, light-triggered PXN LLPS potently activates integrin signaling and subsequently accelerates cell spreading. PXN favors homotypic interaction-driven LLPSin vitro. In cells, PXN condensates are associated with plasma membrane, and modulated by actomyosin contraction and client proteins of FAs. Interestingly, non-specific weak inter-molecular interactions, together with specific molecular interactions, underlie the multicomponent condensation of PXN, and are efficient to promote FA assembly and integrin signaling. Thus, our data establish an active role of PXN phase transition into a condensed membrane-associated compartment in promoting assembly/maturation of FAs.
Significantly reduced inflammatory foreign-body-response to neuroimplants and improved recording performance in young compared to adult rats
Authors: Sharon Aviv , Jankowski Maciej M. , Shmoel Nava , Erez Hadas , Spira Micha E. 
Published: December 2022

AbstractThe multicellular inflammatory encapsulation of implanted intracortical multielectrode arrays (MEA) is associated with severe deterioration of their field potentials’ (FP) recording performance, which thus limits the use of brain implants in basic research and clinical applications. Therefore, extensive efforts have been made to identify the conditions in which the inflammatory foreign body response (FBR) is alleviated, or to develop methods to mitigate the formation of the inflammatory barrier. Here, for the first time, we show that (1) in young rats (74±8 gr, 4 weeks old at the onset of the experiments), cortical tissue recovery following MEA implantation proceeds with ameliorated inflammatory scar as compared to adult rats (242 ±18 gr, 9 weeks old at the experimental onset); (2) in contrast to adult rats in which the Colony Stimulating factor 1 Receptor (CSF1R) antagonist chow eliminated ~95% of the cortical microglia but not microglia adhering to the implant surfaces, in young rats the microglia adhering to the implant were eliminated along with the parenchymal microglia population. The removal of microglia adhering to the implant surfaces was correlated with improved recording performance by in-house fabricated Perforated Polyimide MEA Platforms (PPMP). These results support the hypothesis that microglia adhering to the surface of the electrodes, rather than the multicellular inflammatory scar, is the major underlying mechanism that deteriorates implant recording performance, and that young rats provide an advantageous model to study months-long, multisite electrophysiology in freely behaving rats.
Soluble NS1 antagonizes IgG- and IgA-mediated monocytic phagocytosis of DENV infected cells
Authors: Waldran Mitchell J. , Wegman Adam D. , Bahr Lauren E. , Currier Jeffrey R. , Waickman Adam T. 
Published: December 2022

AbstractDengue virus (DENV) is endemic in over 100 countries, infecting an estimated 400 million individuals every year. Infection with DENV raises a significant antibody response, primarily consisting of antibodies targeting viral (structural) proteins. However, not all DENV antigens are part of the virion itself, as the DENV genome encodes several non-structural (NS) proteins. One of these, NS1, has been shown to be antigenic and is expressed on the membrane of DENV-infected cells. IgG and IgA isotype antibodies that bind NS1 are detectable in serum following DENV infection and are also capable of interacting with Fc receptors expressed on professional phagocytes. Our study aims to determine if NS1-binding IgG and IgA isotype antibodies contribute to the clearance of DENV-infected cells by professional phagocytes through antibody mediated phagocytosis/trogocytosis. Using an in vitro model of trogocytosis we observed that both IgG and IgA isotype antibodies can facilitate facilitating monocytic uptake of DENV NS1 expressing plasma membrane in an additive fashion. This process was dependent on the expression of FcγRI (CD64) and FcαR (CD89) for IgG and IgA mediated membrane uptake, respectively. Furthermore, this process was antagonized by the presence of soluble NS1, suggesting that the production of soluble NS1 by infected cells may serve as an immunological chaff, thereby antagonizing opsonization and clearance of infected cells by NS1-specific IgG and IgA isotype antibodies.
WRNIP1 PREVENTS G4/R-LOOP-ASSOCIATED GENOMIC INSTABILITY
Authors: Valenzisi Pasquale , Marabitti Veronica , Petrai Stefano , Giardinelli Francesca Rita , Pichierri Pietro , Franchitto Annapaola 
Published: December 2022

ABSTRACTMaintenance of genome integrity is essential for cell viability and depends on complete and accurate DNA replication. However, G4/R-loops may provide significant obstacles for DNA replication, as they can cause collisions between replication fork and the transcription machinery. Hence, cells require mechanisms to counteract the presence of persistent G4/R-loops, most of which remain poorly understood. Here, we demonstrate an involvement of the Werner helicase-interacting protein 1 (WRNIP1) in preventing DNA damage induced by G4/R-loop-associated transcription-replication conflicts. We discovered that the ubiquitin-binding domain of WRNIP1 is required to efficiently avoid pathological persistence of G4/R-loops upon replication stress. Also, we observed that G4s reside within R-loops and that WRNIP1 colocalises with these structures. Furthermore, WRNIP1 plays a role in restarting replication from transcription-induced fork stalling. More importantly, we characterized the interplay between WRNIP1 and the DNA helicase FANCJ in counteracting R-loop-dependent G4 formation in response to replication stress. Collectively, our findings propose a mechanisms whereby WRNIP1, contributing to stabilise FANCJ to G4 sites, mitigates the G4/R-loop-mediated transcription-replication conflicts and protects against DNA damage accumulation.
Targeted Kinase Degradation via the KLHDC2 Ubiquitin E3 Ligase
Authors: Kim Younghoon , Seo Christina , Jeon Eunhye , You Inchul , Hwang Kyubin , Kim Namkyoung , Choi Ha-Soon , Hinshaw Stephen M. , Gray Nathanael S. , Sim Taebo 
Published: December 2022

AbstractChemically induced protein degradation is a powerful strategy for perturbing cellular biochemistry. The predominant mechanism of action for protein degrader drugs involves induced proximity between the cellular ubiquitin conjugation machinery and the target. Unlike traditional small molecule enzyme inhibition, targeted protein degradation can clear an undesired protein from cells. We demonstrate here the use of peptide ligands for Kelch-Like Homology Domain Containing protein 2 (KLHDC2), a substrate adaptor protein and member of the cullin-2 (CUL2) ubiquitin ligase complex, for targeted protein degradation. Peptide-based bivalent compounds that can induce proximity between KLHDC2 and target proteins cause degradation of the targeted factors. The cellular activity of these compounds depends on KLHDC2 binding. This work demonstrates the utility of KLHDC2 for targeted protein degradation and exemplifies a strategy for the rational design of new peptide-based ligands useful for this purpose.
Heritability of de novo germline mutation reveals a contribution from paternal but not maternal genetic factors
Authors: Hwang Seongwon , Neville Matthew D. C. ,   Genomics England Research Consortium, Day Felix R. , Scally Aylwyn 
Published: December 2022

AbstractDe novo mutations (DNMs) in the germline have long been identified as a key element in the causes of developmental and other genetic disorders. Previous attempts to investigate genetic factors affecting DNMs have suffered from a lack of statistical power, due to the difficulty of obtaining a sufficient number of parent-offspring trios. Thus, the rare disease cohort of the UK’s 100k Genomes Project (100kGP), comprising more than 10,000 trios, represents an unprecedented opportunity to investigate the genetics of germline mutation. Here we estimate SNP heritability of DNM count in offspring, as a measure of the relative contribution of genetic factors to the variance of the trait, in a PCA-selected subset of the 100kGP cohort. We estimate separate SNP heritabilities for paternally and maternally transmitted mutations (based on parentally phased DNMs in offspring), computed using parental genetic variants at a range of minimum frequencies and a variety of methodologies. We estimate a heritability of 10-20% for paternal DNMs; by contrast, for maternal DNMs we find no significant evidence for non-zero heritability. We investigated the partitioning of heritability among genes with different expression profiles in different tissue or cell states, and found a relative heritability enrichment for genes expressed in gonadal tissues, particularly testis. Among germ cells in adult testes we observed relative enrichment of heritability in genes associated with the (undifferentiated) spermatogonial stem cell state.
Vocal learning-associated convergent evolution in mammalian proteins and regulatory elements
Authors: Wirthlin Morgan E. , Schmid Tobias A. , Elie Julie E. , Zhang Xiaomeng , Shvareva Varvara A. , Rakuljic Ashley , Ji Maria B. , Bhat Ninad S. , Kaplow Irene M. , Schäffer Daniel E. , Lawler Alyssa J. , Annaldasula Siddharth , Lim Byungkook , Azim Eiman ,   Zoonomia Consortium, Meyer Wynn K. , Yartsev Michael M. , Pfenning Andreas R. 
Published: December 2022

AbstractVocal learning, the ability to modify vocal behavior based on experience, is a convergently evolved trait in birds and mammals. To identify genomic elements associated with vocal learning, we integrated new experiments conducted in the brain of the Egyptian fruit bat with analyses of the genomes of 222 placental mammals. We first identified an anatomically specialized region of the bat motor cortex containing direct monosynaptic projections to laryngeal motoneurons. Using wireless neural recordings of this brain region in freely vocalizing bats, we verified that single neuron activity in this region relates to vocal production. We profiled the open chromatin of this vocal-motor region, which we used to train machine learning models to identify enhancers associated with vocal learning across mammals. We found 201 proteins and 45 candidate enhancers that display convergent evolution associated with vocal learning, many of which overlapped loci associated with human speech disability. One such locus contains the neurodevelopmental transcription factorsTSHZ3andZNF536and multiple candidate vocal learning-associated enhancers, suggesting the co-evolution of protein and regulatory sequences underlying vocal learning.One-Sentence SummaryAnalyses of bat neural activity and epigenomic data in a brain region involved in vocal behavior were used to identify proteins and regulatory elements associated with vocal learning in mammals.
Coevolutionary dynamics via adaptive feedback in collective-risk social dilemma game
Authors: Liu Linjie , Chen Xiaojie , Szolnoki Attila 
Published: December 2022

AbstractHuman society and natural environment form a complex giant ecosystem, where human activities not only lead to the change of environmental states, but also react to them. By using collective-risk social dilemma game, some studies have already revealed that individual contributions and the risk of future losses are inextricably linked. These works, however, often use an idealistic assumption that the risk is constant and not affected by individual behaviors. We here develop a coevolutionary game approach that captures the coupled dynamics of cooperation and risk. In particular, the level of contributions in a population affects the state of risk, while the risk in turn influences individuals’ behavioral decision-making. Importantly, we explore two representative feedback forms describing the possible effect of strategy on risk, namely, linear and exponential feedbacks. We find that cooperation can be maintained in the population by keeping at a certain fraction or forming an evolutionary oscillation with risk, independently of the feedback type. However, such evolutionary outcome depends on the initial state. Taken together, a two-way coupling between collective actions and risk is essential to avoid the tragedy of the commons. More importantly, a critical starting portion of cooperators and risk level is what we really need for guiding the evolution toward a desired direction.
An approach to rapid distributed manufacturing of broad spectrum anti-viral griffithsin using cell-free systems to mitigate pandemics
Authors: Borhani Shayan G. , Levine Max Z. , Krumpe Lauren H. , Wilson Jennifer , Henrich Curtis J. , O’Keefe Barry R. , Lo Donald , Sittampalam G. Sitta , Godfrey Alexander G. , Lunsford R. Dwayne , Mangalampalli Venkata , Tao Dingyin , LeClair Christopher A. , Thole Aaron , Frey Douglas , Swartz James , Rao Govind 
Published: December 2022

AbstractThis study describes the cell-free biomanufacturing of a broad-spectrum antiviral protein, griffithsin (GRFT) such that it can be produced with consistent purity and potency in less than 24 hours. We demonstrate GRFT production using two independent cell-free systems, one plant and one microbial. Griffithsin purity and quality were verified using standard regulatory metrics. Efficacy was demonstratedin vitroagainst SARS-CoV-2 and HIV-1 and was nearly identical to that of GRFT expressedin vivo. The proposed production process is efficient and can be readily scaled up and deployed anywhere in the world where a viral pathogen might emerge. The current emergence of viral variants has resulted in frequent updating of existing vaccines and loss of efficacy for front-line monoclonal antibody therapies. Proteins such as GRFT with its efficacious and broad virus neutralizing capability provide a compelling pandemic mitigation strategy to promptly suppress viral emergence at the source of an outbreak.
Beta-triggered adaptive deep brain stimulation during reaching movement in Parkinson’s disease
Authors: He Shenghong , Baig Fahd , Merla Anca , Torrecillos Flavie , Perera Andrea , Wiest Christoph , Debarros Jean , Benjaber Moaad , Hart Michael G , Morgante Francesca , Hasegawa Harutomo , Samuel Michael , Edwards Mark , Denison Timothy , Pogosyan Alek , Ashkan Keyoumars , Pereira Erlick , Tan Huiling 
Published: December 2022

AbstractSubthalamic nucleus (STN) beta-triggered adaptive deep brain stimulation (ADBS) has been shown to provide clinical improvement comparable to conventional continuous DBS (CDBS) in people with Parkinson’s disease (PD) with less energy delivered to the brain and less stimulation induced side-effects. However, several questions remain unanswered. First, there is a normal physiological reduction of STN beta band power just prior to and during voluntary movement. ADBS systems will therefore reduce or cease stimulation during movement and could therefore compromise motor performance compared to CDBS. Second, beta power was smoothed and estimated over time periods of 400ms or longer in most previous ADBS studies. A shorter smoothing period could have the advantage of being more sensitive to changes in beta power which could enhance motor performance. In this study, we addressed these two questions by evaluating the effectiveness of STN beta-triggered ADBS using a standard 400ms and a shorter 200ms smoothing window during reaching movements. Results from 13 people with PD showed that STN beta-triggered ADBS is effective in improving motor performance during reaching movements as it better preserves gamma oscillation than CDBS in people with PD, and that shortening the smoothing window does not result in any additional behavioural benefit. ADBS significantly improved tremor compared with no DBS but was not as effective as CDBS. When developing ADBS systems for PD, it might not be necessary to track very fast beta dynamics; combining beta, gamma, and motor decoding might be more beneficial with additional biomarkers needed for optimal treatment of tremor.
Diagnostic yield of genetic screening in a diverse, community-ascertained cohort
Authors: Rao Nandana D. , Kaganovsky Jailanie , Malouf Emily , Coe Sandy , Huey Jenna , Tsinajinne Darwin , Hassan Sajida , King Kristine , Fullerton Stephanie M. , Chen Annie T. , Shirts Brian H. 
Published: December 2022

AbstractBackgroundPopulation screening for genetic risk of adult-onset preventable conditions has been proposed as an attractive public health intervention. Screening unselected individuals can identify many individuals who will not be identified through current genetic testing guidelines.MethodsWe sought to evaluate enrollment in and diagnostic yield of population genetic screening in a resource-limited setting among a diverse population. We developed a low-cost, short-read next-generation sequencing panel of 25 genes that had 98.4% sensitivity and 99.98% specificity compared to diagnostic panels. We used email invitations to recruit a diverse cohort of patients in the University of Washington Medical Center system unselected for personal or family history of hereditary disease. Participants were sent a saliva collection kit in the mail with instructions on kit use and return. Results were returned using a secure online portal. Enrollment and diagnostic yield were assessed overall, and across race and ethnicity groups.ResultsOverall, 40,857 people were invited and 2,899 (7.1%) enrolled. Enrollment varied across race and ethnicity groups, with the lowest enrollment among African American individuals (3.3%) and the highest among Multiracial or Other Race individuals (13.0%). Of 2,864 enrollees who received screening results, 106 actionable variants were identified in 103 individuals (3.6%). Of those who screened positive, 30.1% already knew about their results from prior genetic testing. The diagnostic yield was 74 new, actionable genetic findings (2.6%). The addition of more recently identified cancer risk genes increased the diagnostic yield of screening.ConclusionsPopulation screening can identify additional individuals that could benefit from prevention, but challenges in recruitment and sample collection will reduce actual enrollment and yield. These should not be overlooked in intervention planning or in cost and benefit analysis.
Temperature and depth dependence of the spatial distribution of snow crab
Authors: Choi Jae S. , Cameron Brent , Christie Kate , Glass Amy , MacEachern Ellen 
Published: December 2022

AbstractThe cascading effects of rapid climate change is a reality with which all biota are challenged. In this context, we examine the spatiotemporal probability of occurrence of snow crab as a means to express viable habitat. This is attempted for three demographic components, morphometrically mature males and females and immature adolescent crab in the Scotian Shelf region of the northwest Atlantic, Canada. We use a robust approach, known as Conditional AutoRegressive models, to define viable habitat. Further, we focus upon viable habitat, conditioned on the marginal influence of temperature and depth as they are known to be important constraints on snow crab. We observe some niche partitioning in terms of depth and temperature. We also note declines in viable habitat marginal to depth and temperature since 2010 for all demographic groups. This population representing the southern-most distribution of snow crab in the northwest Atlantic are vulnerable to degradation of viable habitat attributable to rapid climate change.One-Sentence SummaryRapid climate change and a decadal scale change in the viable habitat of snow crab of the Scotian Shelf ecosystem.
High-throughput functional characterization of combinations of transcriptional activators and repressors
Authors: Mukund Adi X. , Tycko Josh , Allen Sage J. , Robinson Stephanie A. , Andrews Cecelia , Ludwig Connor H. , Spees Kaitlyn , Bassik Michael C. , Bintu Lacramioara 
Published: December 2022

AbstractDespite growing knowledge of the functions of individual human transcriptional effector domains, much less is understood about how multiple effector domains within the same protein combine to regulate gene expression. Here, we measure transcriptional activity for 8,400 effector domain combinations by recruiting them to reporter genes in human cells. In our assay, weak and moderate activation domains synergize to drive strong gene expression, while combining strong activators often results in weaker activation. In contrast, repressors combine linearly and produce full gene silencing, and repressor domains often overpower activation domains. We use this information to build a synthetic transcription factor whose function can be tuned between repression and activation independent of recruitment to target genes by using a small molecule drug. Altogether, we outline the basic principles of how effector domains combine to regulate gene expression and demonstrate their value in building precise and flexible synthetic biology tools.
Likelihood-based signal and noise analysis for docking of models into cryo-EM maps
Authors: Read Randy J. , Millán Claudia , McCoy Airlie J. , Terwilliger Thomas C. 
Published: December 2022

AbstractFast, reliable docking of models into cryo-EM maps requires understanding of the errors in the maps and the models. Likelihood-based approaches to errors have proven to be powerful and adaptable in experimental structural biology, finding applications in both crystallography and cryo-EM. Indeed, previous crystallographic work on the errors in structural models is directly applicable to likelihood targets in cryo-EM. Likelihood targets in Fourier space are derived here to characterise, based on the comparison of half-maps, the direction- and resolution-dependent variation in the strength of both signal and noise in the data. Because the signal depends on local features, the signal and noise are analysed in local regions of the cryo-EM reconstruction. The likelihood analysis extends to prediction of the signal that will be achieved in any docking calculation for a model of specified quality and completeness. A related calculation generalises a previous measure of the information gained by making the cryo-EM reconstruction.