bluuebunny/crossref_metadata_2025_split huggingface dataset:
Large-Scale Deep Multi-Layer Analysis of Alzheimer’s Disease Brain Reveals Strong Proteomic Disease-Related Changes Not Observed at the RNA Level
Authors: Johnson Erik C.B. , Carter E. Kathleen , Dammer Eric B. , Duong Duc M. , Gerasimov Ekaterina S. , Liu Yue , Liu Jiaqi , Betarbet Ranjita , Ping Lingyan , Yin Luming , Serrano Geidy E. , Beach Thomas G. , Peng Junmin , De Jager Philip L. , Haroutunian Vahram , Zhang Bin , Gaiteri Chris , Bennett David A. , Gearing Marla , Wingo Thomas S. , Wingo Aliza P. , Lah James J. , Levey Allan I. , Seyfried Nicholas T. 
Published: April 2021

AbstractThe biological processes that are disrupted in the Alzheimer’s disease (AD) brain remain incompletely understood. We recently performed a proteomic analysis of >2000 brains to better understand these changes, which highlighted alterations in astrocytes and microglia as likely key drivers of disease. Here, we extend this analysis by analyzing >1000 brain tissues using a tandem mass tag mass spectrometry (TMT-MS) pipeline, which allowed us to nearly triple the number of quantified proteins across cases. A consensus protein co-expression network analysis of this deeper dataset revealed new co-expression modules that were highly preserved across cohorts and brain regions, and strongly altered in AD. Nearly half of the protein co-expression modules, including modules significantly altered in AD, were not observed in RNA networks from the same cohorts and brain regions, highlighting the proteopathic nature of AD. Two such AD-associated modules unique to the proteomic network included a module related to MAPK signaling and metabolism, and a module related to the matrisome. Analysis of paired genomic and proteomic data within subjects showed that expression level of the matrisome module was influenced by theAPOE ε4allele, but was not related to the rate of cognitive decline after adjustment for neuropathology. In contrast, the MAPK/metabolism module was strongly associated with the rate of cognitive decline. Disease-associated modules unique to the proteome are sources of promising therapeutic targets and biomarkers for AD.
Inversions maintain differences between migratory phenotypes of a songbird
Authors: Lundberg Max , Mackintosh Alexander , Petri Anna , Bensch Staffan 
Published: April 2021

AbstractLong-distance migration requires adaptations in a suite of behavioral, physiological and morphological traits. However, almost nothing is known about the genetic basis of these adaptations. The willow warblerPhylloscopus trochilusoccurs in Europe with a northern and southern subspecies that show drastically different migration routes and wintering areas. Previous studies have demonstrated that the subspecies are genetically extremely similar except for three divergent chromosome regions, of which two are associated with the differences in migratory phenotypes and one is associated with an environmental gradient. Here we use a combination of long-read sequencing, linked-read sequencing and optical mapping to construct more complete and contiguous assemblies for both of the subspecies. We find evidence for inversions in each of the three divergent regions, which range from 0.4 to 13 Mb in size, and that breakpoints are associated with tandem repeat arrays or segmental duplications. The divergence times between inverted and non-inverted haplotypes are similar across the regions (∼1.2 Myrs), which is compatible with a scenario where the inversions arose in either of two allopatric populations that subsequently hybridized. The improved genome assemblies and annotation also allowed us to detect additional functional differences in the divergent regions that provide candidate genes for migration and local adaptations to environmental gradients.
Introducing conflict resolution and negotiation training into a biomedical sciences graduate curriculum
Authors: Schaller Michael D. , Gatesman-Ammer Amanda 
Published: April 2021

AbstractAnalysis of the biomedical workforce and graduate education have produced recommendations for modifications of pre-doctoral training to broadly prepare trainees for wider ranging scientific careers. Increased exposure to career opportunities and development of training in professional skills is widely recommended, but details of implementation are not widely available. In alignment with these recommendations, we have incorporated professional skills training into the biomedical science graduate curriculum at West Virginia University. An important component of the training is developing conflict resolution and negotiation skills. This training will provide useful skills for academic careers, non-academic careers and life situations outside of the workplace. Conflict resolution/negotiation skills are also relevant in managing issues in diversity, equity and inclusivity. We report our experience in developing this component of the training program, provide an overview of the approach to delivery and practice of skills, and provide an analysis of the reception and effectiveness of the training.
GNPS Dashboard: Collaborative Analysis of Mass Spectrometry Data in the Web Browser
Authors: Petras Daniel , Phelan Vanessa V. , Acharya Deepa , Allen Andrew E. , Aron Allegra T. , Bandeira Nuno , Bowen Benjamin P. , Belle-Oudry Deirdre , Boecker Simon , Cummings Dale A. , Deutsch Jessica M , Fahy Eoin , Garg Neha , Gregor Rachel , Handelsman Jo , Navarro-Hoyos Mirtha , Jarmusch Alan K. , Jarmusch Scott A. , Louie Katherine , Maloney Katherine N. , Marty Michael T. , Meijler Michael M. , Mizrahi Itzhak , Neve Rachel L , Northen Trent R. , Molina-Santiago Carlos , Panitchpakdi Morgan , Pullman Benjamin , Puri Aaron W. , Schmid Robin , Subramaniam Shankar , Thukral Monica , Vasquez-Castro Felipe , Dorrestein Pieter C , Wang Mingxun 
Published: April 2021

AbstractAccess to web-based platforms has enabled scientists to perform research remotely. A critical aspect of mass spectrometry data analysis is the inspection, analysis, and visualization of the raw data to validate data quality and confirm statistical observations. We developed the GNPS Dashboard, a web-based data visualization tool, to facilitate synchronous collaborative inspection, visualization, and analysis of private and public mass spectrometry data remotely.
Multi-Scale Coarse Grained Model for the Stepping of Molecular Motors with application to Kinesin
Authors: Goldtzvik Yonathan , Thirumalai D. 
Published: April 2021

AbstractConventional kinesin, a motor protein that transports cargo within cells, walks by taking multiple steps towards the plus end of the microtubule (MT). While significant progress has been made in understanding the details of the walking mechanism of kinesin there are many unresolved issues. From a computational perspective, a central challenge is the large size of the system, which limits the scope of time scales accessible in standard computer simulations. Here, we create a general multi-scale coarse-grained model for motors that enables us to simulate the stepping process of motors on polar tracks (actin and MT) with focus on kinesin. Our approach greatly shortens the computation times without a significant loss in detail, thus allowing us to better describe the molecular basis of the stepping kinetics. The small number of parameters, which are determined by fitting to experimental data, allows us to develop an accurate method that may be adopted to simulate stepping in other molecular motors. The model enables us to simulate a large number of steps, which was not possible previously. We show in agreement with experiments that due to the docking of the neck linker (NL) of kinesin, sometimes deemed as the power stroke, the space explored diffusively by the tethered head is severely restricted allowing the step to be in a tens of microseconds. We predict that increasing the interaction strength between the NL and the motor head, achievable by mutations in the NL, decreases the stepping time but reaches a saturation value. Furthermore, the full 3-dimensional dynamics of the cargo are fully resolved in our model, contributing to the predictive power and allowing us to study the important aspects of cargo-motor interactions.
SARS-CoV-2 Vaccines Elicit Durable Immune Responses in Infant Rhesus Macaques
Authors: Garrido Carolina , Curtis Alan D. , Dennis Maria , Pathak Sachi H. , Gao Hongmei , Montefiori David , Tomai Mark , Fox Christopher B. , Kozlowski Pamela A. , Scobey Trevor , Munt Jennifer E. , Mallroy Michael L. , Saha Pooja T. , Hudgens Michael G. , Lindesmith Lisa C. , Baric Ralph S. , Abiona Olubukola M. , Graham Barney , Corbett Kizzmekia S. , Edwards Darin , Carfi Andrea , Fouda Genevieve , Van Rompay Koen K. A. , De Paris Kristina , Permar Sallie R. 
Published: April 2021

AbstractEarly life SARS-CoV-2 vaccination has the potential to provide lifelong protection and achieve herd immunity. To evaluate SARS-CoV-2 infant vaccination, we immunized two groups of 8 infant rhesus macaques (RMs) at weeks 0 and 4 with stabilized prefusion SARS-CoV-2 S-2P spike (S) protein, either encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or mixed with 3M-052-SE, a TLR7/8 agonist in a squalene emulsion (Protein+3M-052-SE). Neither vaccine induced adverse effects. High magnitude S-binding IgG and neutralizing infectious dose 50 (ID50) >103were elicited by both vaccines. S-specific T cell responses were dominated by IL-17, IFN-γ, or TNF-α. Antibody and cellular responses were stable through week 22. The S-2P mRNA-LNP and Protein-3M-052-SE vaccines are promising pediatric SARS-CoV-2 vaccine candidates to achieve durable protective immunity.One-Sentence SummarySARS-CoV-2 vaccines are well-tolerated and highly immunogenic in infant rhesus macaques
CRISPRpas: Programmable regulation of alternative polyadenylation by dCas9
Authors: Shin Jihae , Ding Qingbao , Baljinnyam Erdene , Wang Ruijia , Tian Bin 
Published: April 2021

ABSTRACTWell over half of human mRNA genes produce alternative polyadenylation (APA) isoforms that differ in mRNA metabolism due to 3’ UTR size changes or have variable coding potentials when coupled with alternative splicing. Aberrant APA is implicated in a growing number of human diseases. A programmable tool for APA regulation, hence, would be instrumental for understanding how APA events impact biological processes. Here, using a catalytically dead Cas9 (dCas9), we developed a method, named CRISPRpas, to alter cleavage and polyadenylation site (PAS) usage in 3’ UTRs or introns. We present key features that facilitate CRISPRpas, including targeting DNA strand, distance between PAS and targeting sequence, and strength of the PAS. For intronic PAS, we additionally analyze strengths of 5’ splice site and target location in intron. Our analyses implicate a dynamic competition between PAS usage and nascent RNA decay when RNA polymerase II elongation is blocked. We show modulation of APA of multiple endogenous genes including a gene that contains a single nucleotide polymorphism (SNP) that affects APA in the human population. CRISPRpas expands the CRISPR toolkit for perturbation of gene expression.
Joint representation of working memory and uncertainty in human cortex
Authors: Li Hsin-Hung , Sprague Thomas C. , Yoo Aspen H. , Ma Wei Ji , Curtis Clayton E. 
Published: April 2021

AbstractNeural representations of visual working memory (VWM) are noisy, and thus, decisions based on VWM are inevitably subject to uncertainty. However, the mechanisms by which the brain simultaneously represents the content and uncertainty of memory remain largely unknown. Here, inspired by the theory of probabilistic population codes, we test the hypothesis that the human brain represents an item maintained in VWM as a probability distribution over stimulus feature space, thereby capturing both its content and uncertainty. We used a neural generative model to decode probability distributions over memorized locations from fMRI activation patterns. We found that the mean of the probability distribution decoded from retinotopic cortical areas predicted memory reports on a trial-by-trial basis. Moreover, in several of the same mid-dorsal stream areas the spread of the distribution predicted subjective trial-by-trial uncertainty judgments. These results provide evidence that VWM content and uncertainty are jointly represented by probabilistic neural codes.
Novel human cell expression method reveals the role and prevalence of posttranslational modification in non-muscle tropomyosins
Authors: Carman Peter J. , Barrie Kyle R. , Dominguez Roberto 
Published: April 2021

AbstractBiochemical studies require large protein quantities, which are typically obtained using bacterial expression. However, the folding machinery of bacteria is inadequate for many mammalian proteins, which additionally undergo posttranslational modifications (PTMs) that bacteria, yeast, or insect cells cannot perform. Many proteins also require native N- and C-termini and cannot tolerate extra tag amino acids for function. Tropomyosin, a coiled coil that decorates most actin filaments in cells, requires both native N- and C-termini and PTMs, specifically N-terminal acetylation, to polymerize along actin filaments. Here, we describe a new method that combines native protein expression in human cells with an intein-based purification tag that can be precisely removed after purification. Using this method, we expressed several non-muscle tropomyosin isoforms. Mammalian cell-expressed tropomyosins are functionally different from theirE. coli-expressed counterparts, display multiple types of PTMs, and can form heterodimers. This method can be extended to other proteins, as demonstrated here for α-synuclein.
The Okur-Chung Neurodevelopmental Syndrome (OCNDS) mutation CK2K198Rleads to a rewiring of kinase specificity
Authors: Caefer Danielle M , Phan Nhat Q , Liddle Jennifer C , Balsbaugh Jeremy L , O’Shea Joseph P , Tzingounis Anastasios V , Schwartz Daniel 
Published: April 2021

AbstractOkur-Chung Neurodevelopmental Syndrome (OCNDS) is caused by heterozygous mutations to the CSNK2A1 gene, which encodes the alpha subunit of casein kinase II (CK2). The most frequently occurring mutation is lysine 198 to arginine (K198R). To investigate the impact of this mutation, we first generated a high-resolution phosphorylation motif of CK2WT, including the first characterization of specificity for tyrosine phosphorylation activity. A second high resolution motif representing CK2K198Rsubstrate specificity was also generated. Here we report for the first time the impact of the OCNDS associated CK2K198Rmutation. Contrary to prior speculation, the mutation does not result in a loss of function, but rather shifts the substrate specificity of the kinase. Broadly speaking the mutation leads to 1) a decreased preference for acidic residues in the +1 position, 2) a decreased preference for threonine phosphorylation, 3) an increased preference for tyrosine phosphorylation, and 4) an alteration of the tyrosine phosphorylation specificity motif. To further investigate the result of this mutation we have developed a probability-based scoring method, allowing us to predict shifts in phosphorylation in the K198R mutant relative to the wild type kinase. As an initial step we have applied the methodology to the set of axonally localized ion channels in an effort to uncover potential alterations of the phosphoproteome associated with the OCNDS disease condition.
Early life Western diet-induced memory impairments and gut microbiome changes in female rats are long-lasting despite healthy dietary intervention
Authors: Tsan Linda , Sun Shan , Bridi Lana , Chirala Lekha S. , Noble Emily E. , Fodor Anthony A. , Kanoski Scott E. 
Published: April 2021

AbstractObjectiveConsumption of a Western diet during adolescence results in hippocampus (HPC)-dependent memory impairments and gut microbiome dysbiosis. Whether these adverse outcomes are reversible in adulthood following intervention with a healthy diet is unknown. Here we assessed the short- and long-term effects of adolescent consumption of a Western diet enriched with either sugar alone, or sugar and fat on metabolic outcomes, HPC-dependent memory, and gut microbiota.MethodsAdolescent female rats (PN 26) were fed a standard chow diet (CTL), a chow diet with access to 11% sugar solution (SUG), or a junk food cafeteria-style diet (CAF) containing a variety of fat- and/or sugar-enriched foods. During adulthood (PN 65+), metabolic outcomes, HPC-dependent memory, and gut microbial populations were evaluated both before and after a 5-week dietary intervention period where all groups were fed a diet of water standard chow.ResultsPrior to the dietary intervention both the CAF and SUG groups demonstrated impaired HPC-dependent memory, increased adiposity, and altered gut microbial populations relative to controls. However, impaired peripheral glucose regulation was only observed in the SUG group. The dietary intervention reversed the metabolic dysfunction in both the CAF and SUG groups, whereas HPC-dependent memory impairments were reversed in the SUG, but not the CAF group. The composition of the gut microbiota remained distinct from controls in both groups after dietary intervention.ConclusionsWhile the metabolic impairments associated with adolescent cafeteria diet consumption are reversible in adulthood with dietary intervention, the HPC-dependent memory impairments and the gut microbiome dysbiosis persist.
Exploiting Family History in Aggregation Unit-based Genetic Association Tests
Authors: Wang Yanbing , Chen Han , Peloso Gina Marie , DeStefano Anita , Dupuis Josée 
Published: April 2021

AbstractThe development of sequencing technology calls for new powerful methods to detect disease associations and lower the cost of sequencing studies. Family history (FH) contains information on disease status of relatives, adding valuable information about the probands’ health problems and risk of diseases. Incorporating data from FH is a cost-effective way to improve statistical evidence in genetic studies, and moreover, overcomes limitations in study designs with insufficient cases or missing genotype information for association analysis. We proposed family history aggregation unit-based test (FHAT) and optimal FHAT (FHAT-O) to exploit available FH for rare variant association analysis. Moreover, we extended liability threshold model of case-control status and FH (LT-FH) method in aggregated unit-based methods and compared that with FHAT and FHAT-O. The computational efficiency and flexibility of the FHAT and FHAT-O were demonstrated through both simulations and applications. We showed that FHAT, FHAT-O and LT-FH method offer reasonable control of the type I error unless case/control ratio is extremely unbalanced, in which case they result in smaller inflation than that observed with conventional methods excluding FH. We also demonstrated that FHAT and FHAT-O are more powerful than LT-FH method and conventional methods in many scenarios. By applying FHAT and FHAT-O to the analysis of all cause dementia and hypertension using the exome sequencing data from the UK Biobank, we showed that our methods can improve significance for known regions. Furthermore, we replicated the previous associations in all cause dementia and hypertension and detected novel regions through the exome-wide analysis.
Interspecies recombination has driven the macroevolution of cassava mosaic begomoviruses
Authors: Crespo-Bellido Alvin , Steen Hoyer J. , Dubey Divya , Jeannot Ronica B. , Duffy Siobain 
Published: April 2021

ABSTRACTBegomoviruses (familyGeminiviridae, genusBegomovirus) significantly hamper crop production and threaten food security around the world. The frequent emergence of new begomovirus genotypes is facilitated by high mutation frequencies and the propensity to recombine and reassort. Homologous recombination has been especially implicated in the emergence of novel cassava mosaic begomovirus (CMB) genotypes, which cause cassava mosaic disease (CMD). Cassava (Manihot esculenta) is a staple food crop throughout Africa, and an important industrial crop in Asia, two continents where production is severely constrained by CMD. The CMD species complex is comprised of 11 bipartite begomovirus species with ample distribution throughout Africa and the Indian subcontinent. While recombination is regarded as a frequent occurrence for CMBs, a revised, systematic assessment of recombination and its impact on CMB phylogeny is currently lacking. We assembled datasets of all publicly available, full-length DNA-A (n=880) and DNA-B (n=369) nucleotide sequences from the 11 recognized CMB species. Phylogenetic networks and complementary recombination detection methods revealed extensive recombination among the CMB sequences. Six out of the eleven species have descended from unique interspecies recombination events. Estimates of recombination and mutation rates revealed that all species experience mutation more frequently than recombination, but measures of population divergence indicate that recombination is largely responsible for the genetic differences between species. Our results support that recombination has significantly impacted the CMB phylogeny and is driving speciation in the CMD species complex.IMPORTANCECassava mosaic disease (CMD) is a significant threat to cassava production throughout Africa and Asia. CMD is caused by a complex comprised of 11 recognized virus species exhibiting accelerated rates of evolution, driven by high frequencies of mutation and genetic exchange. Here, we present a systematic analysis of the contribution of genetic exchange to cassava mosaic virus diversity. Most of these species emerged as a result of genetic exchange. This is the first study to report the significant impact of genetic exchange on speciation in a group of viruses.
Unraveling the host-selective toxic interaction of cassiicolin with lipid membranes and its cytotoxicity
Authors: Ngo Kien Xuan , Quoc Nguyen Bao , Nguyen Phuong Doan N. , Furusho Hirotoshi , Miyata Makoto , Shimonaka Tomomi , Chau Nguyen Ngoc Bao , Vinh Nguyen Phuong , Nghia Nguyen Anh , Mohammed Tareg Omer , Ichikawa Takehiko , Kodera Noriyuki , Konno Hiroki , Fukuma Takeshi , Ando Toshio 
Published: April 2021

AbstractCassiicolin (Cas), a toxin produced byCorynespora cassiicola, is responsible for corynespora leaf fall disease in rubber trees. Currently, the molecular mechanism of the cytotoxicity of Cas and its host selectivity have not been fully elucidated. Here, we analyzed the binding of Cas1 and Cas2 to membranes consisting of different plant lipids and their membrane-disruption activities. Using high-speed atomic force microscopy and confocal microscopy, we reveal that the binding and disruption activities of Cas1 and Cas2 on lipid membranes are strongly dependent on the specific plant lipids. The negative phospholipids, glycerolipids, and sterols are more susceptible to membrane damage caused by Cas1 and Cas2 than neutral phospholipids and betaine lipids. Cytotoxicity tests on rubber leaves of RRIV 1, RRIV 4, and PB 255 clones suggest that the toxins cause necrosis of rubber leaves, except for the strong resistance of PB 255 against Cas2. Cryo- SEM analyses of necrotic leaf tissues exposed to Cas1 confirm that cytoplasmic membranes are vulnerable to the toxin. Thus, the host selectivity of Cas toxin is attained by the lipid-dependent binding activity of Cas to the membrane, and the cytotoxicity of Cas arises from its ability to form biofilm-like structures and disrupt specific membranes.Graphic AbstractHighlightsCas1 and Cas2 directly damage and cause necrosis in the leaves of specific rubber clones.Cas1 and Cas2 can form biofilm-like structures on specific lipid membranes (negative phospholipids, glycerolipids, and sterols). The biofilm-like formation of Cas toxin plays an important role in selective disruption on lipid membranes.Vulnerability of the specific cytoplasmic membranes to the selective Cas toxin that is the most remarkable feature of cytotoxicity of Cas toxin on plant cells.