bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-Level DBSCAN: A Hierarchical Density-Based Clustering Method for Analyzing Molecular Dynamics Simulation Trajectories
Authors: Liu Song , Cao Siqin , Suarez Michael , Goonetillek Eshani C. , Huang Xuhui 
Published: June 2021

AbstractMolecular Dynamic (MD) simulations have been extensively used as a powerful tool to investigate dynamics of biological molecules in recent decades. Generally, MD simulations generate high-dimensional data that is very hard to visualize and comprehend. As a result, clustering algorithms have been commonly used to reduce the dimensionality of MD data with the key benefit being their ability to reduce the dimensionality of MD data without prior knowledge of structural details or dynamic mechanisms. In this paper, we propose a new algorithm, the Multi-Level Density-Based Spatial Clustering of Applications with Noise (ML-DBSCAN), which combines the clustering results at different resolution of density levels to obtain the hierarchical structure of the free energy landscape and the metastable state assignment. At relatively low resolutions, the ML-DBSCAN can efficiently detect high population regions that contain all metastable states, while at higher resolutions, the ML-DBSCAN can find all metastable states and structural details of the free energy landscape. We demonstrate the powerfulness of the ML-DBSCAN in generating metastable states with a particle moving in a Mexican hat-like potential, and four peptide and protein examples are used to demonstrate how hierarchical structures of free energy landscapes can be found. Furthermore, we developed a GPU implementation of the ML-DBSCAN, which allows the algorithm to handle larger MD datasets and be up to two orders of magnitude faster than the CPU implementation. We demonstrate the power of the ML-DBSCAN on MD simulation datasets of five systems: a 2D-potential, alanine dipeptide, β-hairpin Tryptophan Zipper 2 (Trpzip2), Human Islet Amyloid Polypeptide (hIAPP), and Maltose Binding Protein (MBP). Our code is available at https://github.com/liusong299/ML-DBSCAN.
Detection ofNeisseria meningitidisin Saliva and Oropharyngeal Samples from College Students
Authors: Miellet Willem R. , Mariman Rob , Pluister Gerlinde , de Jong Lieke J. , Grift Ivo , Wijkstra Stijn , van Logchem Elske , van Veldhuizen Janieke , Immink Marie-Monique , Wijmenga-Monsuur Alienke J. , Rots Nynke Y. , Sanders Elisabeth A.M. , Bosch Thijs , Trzciński Krzysztof 
Published: June 2021

ABSTRACTObjectivesSince conjugated polysaccharide vaccines reduce carriage of vaccine-typeNeisseria meningitidisstrains, meningococcal carriage is an accepted endpoint in monitoring vaccine effects. We have assessed vaccine-type genogroup carriage prevalence in students at the time of MenACWY vaccine introduction in The Netherlands. In addition, we evaluated the feasibility of saliva sampling and qPCR-based detection method for the surveillance of meningococcal carriage.MethodsPaired saliva and oropharyngeal samples, collected from 299 students, were cultured for meningococcus. The DNA extracted from all bacterial growth was subjected to qPCRs quantifying meningococcal presence and genogroup-specific genes. Samples negative by culture yet positive for qPCR were cultured again for meningococcus. Results for saliva were compared with oropharyngeal samples.ResultsAltogether 74 (25% of 299) students were identified as meningococcal carrier by any method used. Sixty-one students (20%) were identified as carriers with qPCR. The difference between number of qPCR-positive oropharyngeal (n=59) and saliva (n=52) samples was not significant (McNemar’s test,p=0.07). Meningococci were cultured from 72 students (24%), with a significantly higher (p<0.001) number of oropharyngeal (n=70) compared with saliva (n=54) samples. The prevalence of genogroups A, B, C, W, and Y was none, 9%, 1% and 6%, respectively, and 8% of students carried MenACWY vaccine-type genogroup meningococci.ConclusionsWe show that the detected prevalence of meningococcal carriage between oropharyngeal and saliva samples was nondifferent with qPCR and moreover, detection with both samples was highly concordant. Saliva is easy to collect and when combined with qPCR detection can be considered for meningococcal carriage studies.
Emerging single cell endothelial heterogeneity supports sprouting tumour angiogenesis and growth
Authors: Matsumoto Ken , Rambow Florian , Stanchi Fabio , Mathivet Thomas , Qian Junbin , Giese Wolfgang , He Liqun , Lambrechts Diether , Zhou Bin , Betsholtz Christer , Marine Jean-Christophe , Gerhardt Holger 
Published: June 2021

SUMMARYBlood vessels supplying tumors are often dysfunctional and generally heterogeneous. The mechanisms underlying this heterogeneity remain poorly understood. Here, using multicolor lineage tracing, in vivo time-lapse imaging and single cell RNA sequencing in a mouse glioma model, we identify tumour-specific blood endothelial cells that originate from cells expressing the receptor for colony stimulating factor 1, Csf1r, a cytokine which controls macrophage biology. These Csf1r lineage endothelial cells (CLECs) form up to 10% of the tumour vasculature and express, besides classical blood endothelial cell markers, a gene signature that is distinct from brain endothelium but shares similarities with lymphatic endothelial cell populations. in silico analysis of pan-cancer single cell RNAseq datasets highlights the presence of a comparable subpopulation in the endothelium of a wide spectrum of human tumours. We show that CLECs actively contribute to sprouting and remodeling of tumour blood vessels and that selective depletion of CLECs reduces vascular branching and tumour growth. Our findings indicate that a non-tumour resident Csf1r-positive population is recruited to tumours, differentiates into blood endothelial cells to contribute to vascularization and, thereby, tumour growth.
Neutralizing antibodies elicited by the Ad26.COV2.S COVID-19 vaccine show reduced activity against 501Y.V2 (B.1.351), despite protection against severe disease by this variant
Authors: Moore Penny L , Moyo-Gwete Thandeka , Hermanus Tandile , Kgagudi Prudence , Ayres Frances , Makhado Zanele , Sadoff Jerald , Le Gars Mathieu , van Roey Griet , Crowther Carol , Garrett Nigel , Bekker Linda-Gail , Morris Lynn , Schuitemaker Hanneke , Gray Glenda 
Published: June 2021

AbstractThe emergence of SARS-CoV-2 variants, such as 501Y.V2, with immune evasion mutations in the spike has resulted in reduced efficacy of several COVID-19 vaccines. However, the efficacy of the Ad26.COV2.S vaccine, when tested in South Africa after the emergence of 501Y.V2, was not adversely impacted. We therefore assessed the binding and neutralization capacity of n=120 South African sera (from Day 29, post-vaccination) from the Janssen phase 3 study, Ensemble. Spike binding assays using both the Wuhan-1 D614G and 501Y.V2 Spikes showed high levels of cross-reactivity. In contrast, in a subset of 27 sera, we observed significantly reduced neutralization of 501Y.V2 compared to Wuhan-1 D614G, with 22/27 (82%) of sera showing no detectable neutralization of 501Y.V2 at Day 29. These data suggest that even low levels of neutralizing antibodies may contribute to protection from moderate/severe disease. In addition, Fc effector function and T cells may play an important role in protection by this vaccine against 501Y.V2.
Diversification of ergot alkaloids and heritable fungal symbionts in morning glories
Authors: Beaulieu Wesley T. , Panaccione Daniel G. , Quach Quynh N. , Smoot Katy L. , Clay Keith 
Published: June 2021

AbstractHeritable microorganisms play critical roles in life cycles of many macro-organisms but their prevalence and functional roles are unknown for most plants. Bioactive ergot alkaloids produced by heritablePeriglandulafungi occur in some morning glories (Convolvulaceae), similar to ergot alkaloids in grasses infected with related fungi. Ergot alkaloids have been of longstanding interest given their toxic effects, psychoactive properties, and medical applications. Here we show that ergot alkaloids are concentrated in four morning glory clades exhibiting differences in alkaloid profiles and are more prevalent in species with larger seeds than those with smaller seeds. Further, we found a phylogenetically-independent, positive correlation between seed mass and alkaloid concentrations in symbiotic species. Our findings suggest that heritable symbiosis has diversified among particular clades by vertical transmission through seeds combined with host speciation, and that ergot alkaloids are particularly beneficial to species with larger seeds. Our results are consistent with the defensive symbiosis hypothesis where bioactive ergot alkaloids fromPeriglandulasymbionts protect seeds and seedlings from natural enemies, and provide a framework for exploring microbial chemistry in other plant-microbe interactions.
A light tunable differentiation system for the creation and control of consortia in yeast
Authors: Aditya Chetan , Bertaux François , Batt Gregory , Ruess Jakob 
Published: June 2021

AbstractArtificial microbial consortia seek to leverage division-of-labour to optimize function and possess immense potential for bioproduction. Co-culturing approaches, the preferred mode of generating a consortium, remain limited in their ability to give rise to stable consortia having finely tuned compositions. Here, we present an artificial differentiation system in budding yeast capable of generating stable microbial consortia with custom functionalities from a single strain at user-defined composition in space and in time based on optogenetically-driven genetic rewiring. Owing to fast, reproducible, and light-tunable dynamics, our system enables dynamic control of consortia composition in continuous cultures for extended periods. We further demonstrate that our system can be extended in a straightforward manner to give rise to consortia with multiple subpopulations. Our artificial differentiation strategy establishes a novel paradigm for the creation of complex microbial consortia that are simple to implement, precisely controllable, and versatile to use.
Quantitative and population genomics suggest a broad role of staygreen loci in the drought adaptation of sorghum
Authors: Faye Jacques M. , Akata Eyanawa A. , Sine Bassirou , Diatta Cyril , Cisse Ndiaga , Fonceka Daniel , Morris Geoffrey P. 
Published: June 2021

SUMMARYDrought is a major constraint on plant productivity globally. Sorghum (Sorghum bicolor) landraces have evolved in drought-prone regions, but the genetics of their adaptation is not yet understood. Loci underlying stay-green post-flowering drought tolerance (Stg), have been identified in a temperate breeding line, but their role in drought adaptation of tropical sorghum is to be elucidated.We phenotyped 590 diverse sorghum accessions from West Africa under field-based managed drought stress, pre-flowering (WS1) and post-flowering (WS2) over several years and conducted genome-wide association studies (GWAS).Broad-sense heritability for grain and biomass yield components was high (33-92%) across environments. There was a significant correlation between stress tolerance index (STI) for grain weight across WS1 and WS2. GWAS revealed thatSbZfl1andSbCN12, orthologs of maize flowering genes, likely underlie flowering time variation under these conditions. GWAS further identified associations (n = 134) for STI and drought effects on yield components, including 16 putative pleiotropic associations. Thirty of the associations colocalized withStg1–4loci and had large effects. Seven lead associations, including some withinStg1, overlapped with positive selection outliers.Our findings reveal natural genetic variation for drought tolerance-related traits, and suggest a broad role ofStgloci in drought adaptation of sorghum.
Myofilament Glycation in Diabetes Reduces Contractility by Inhibiting Tropomyosin Movement, is Rescued by cMyBPC Domains
Authors: Papadaki Maria , Kampaengsri Theerachat , Barrick Samantha K. , Campbell Stuart G. , von Lewinski Dirk , Rainer Peter P. , Harris Samantha P. , Greenberg Michael J. , Kirk Jonathan A. 
Published: June 2021

AbstractDiabetes doubles the risk of developing heart failure (HF). As the prevalence of diabetes grows, so will HF unless the mechanisms connecting these diseases can be identified. Methylglyoxal (MG) is a glycolysis by-product that forms irreversible modifications on lysine and arginine, called glycation. We previously found that myofilament MG glycation causes sarcomere contractile dysfunction and is increased in patients with diabetes and HF. The aim of this study was to discover the molecular mechanisms by which MG glycation of myofilament proteins cause sarcomere dysfunction and to identify therapeutic avenues to compensate. In humans with type 2 diabetes without HF, we found increased glycation of sarcomeric actin compared to non-diabetics and it correlated with decreased calcium sensitivity. Depressed calcium sensitivity is pathogenic for HF, therefore myofilament glycation represents a promising therapeutic target to inhibit the development of HF in diabetics. To identify possible therapeutic targets, we further defined the molecular actions of myofilament glycation. Skinned myocytes exposed to 100 μM MG exhibited decreased calcium sensitivity, maximal calcium-activated force, and crossbridge kinetics. Replicating MG’s functional affects using a computer simulation of sarcomere function predicted simultaneous decreases in tropomyosin’s blocked-to-closed rate transition and crossbridge duty cycle were consistent with all experimental findings. Stopped-flow experiments and ATPase activity confirmed MG decreased the blocked-to-closed transition rate. Currently, no therapeutics target tropomyosin, so as proof-of-principal, we used a n-terminal peptide of myosin-binding protein C, previously shown to alter tropomyosin’s position on actin. C0C2 completely rescued MG-induced calcium desensitization, suggesting a possible treatment for diabetic HF.
BacPROTACs mediate targeted protein degradation in bacteria
Authors: Morreale Francesca Ester , Kleine Stefan , Leodolter Julia , Ovchinnikov Stepan , Kley Juliane , Kurzbauer Robert , Hoi David M. , Meinhart Anton , Hartl Markus , Haselbach David , Kaiser Markus , Clausen Tim 
Published: June 2021

SummaryHijacking the cellular protein degradation system offers unique opportunities for drug discovery, as exemplified by proteolysis targeting chimeras (PROTACs). Despite their superior properties over classical inhibitors, it has so far not been possible to reprogram the bacterial degradation machinery to interfere with microbial infections. Here, we develop small-molecule degraders, so-called BacPROTACs, that bind to the substrate receptor of the ClpC:ClpP protease, priming neo-substrates for degradation. In addition to their targeting function, BacPROTACs activate ClpC, transforming the resting unfoldase into its functional state. The induced higher-order oligomer was visualized by cryo-EM analysis, providing a structural snapshot of activated ClpC unfolding a protein substrate. Finally, degradation assays performed in mycobacteria demonstrate in vivo activity of BacPROTACs, highlighting the potential of the technology to provide next generation antibiotics.
VSTseed: periodic spaced seeds for reads with substitutions
Authors: Titarenko Valeriy , Titarenko Sofya 
Published: June 2021

AbstractMotivationTechnical progress in computer hardware made it possible to access and process large amounts of data even on budget workstations. Therefore new or existing alignment algorithms may use large index files to increase performance. Spaced seeds with large weights reduce the number of possible locations of a read within a reference sequence. Optimal patterns for spaced seeds may guarantee to align reads even with several substitutions.ResultsFor reads of 64–200 bp periodic spaced seeds of 32, 40, 48, 56, 64 weights are found that guarantee to locate all positions within a reference sequence for a specified number of point mutations. SIMD instructions to convert masked reads into 64, 80, 96, 112, 128-bit numbers are provided.AvailabilityC codes to generate spaced seeds and find optimal SIMD instructions for them are freely available under MIT license at https://github.com/vtman/VSTseed
Allele-specific gene editing rescues pathology in a human model of Charcot-Marie-Tooth disease type 2E
Authors: Feliciano Carissa M. , Wu Kenneth , Watry Hannah L. , Marley Chiara B.E. , Ramadoss Gokul N. , Ghanim Hana Y. , Liu Angela Z. , Zholudeva Lyandysha V. , McDevitt Todd C. , Saporta Mario A. , Conklin Bruce R. , Judge Luke M. 
Published: June 2021

ABSTRACTMany neuromuscular disorders are caused by dominant missense mutations that lead to dominant-negative or gain-of-function pathology. This category of disease is challenging to address via drug treatment or gene augmentation therapy because these strategies may not eliminate the effects of the mutant protein or RNA. Thus, effective treatments are severely lacking for these dominant diseases, which often cause severe disability or death. The targeted inactivation of dominant disease alleles by gene editing is a promising approach with the potential to completely remove the cause of pathology with a single treatment. Here, we demonstrate that allele-specific CRISPR gene editing in a human model of axonal Charcot-Marie-Tooth (CMT) disease rescues pathology caused by a dominant missense mutation in the neurofilament light chain gene (NEFL, CMT type 2E). We utilized a rapid and efficient method for generating spinal motor neurons from human induced pluripotent stem cells (iPSCs) derived from a patient with CMT2E. Diseased motor neurons recapitulated known pathologic phenotypes at early time points of differentiation, including aberrant accumulation of neurofilament light chain protein in neuronal cell bodies. We selectively inactivated the disease NEFL allele in patient iPSCs using Cas9 enzymes to introduce a frameshift at the pathogenic N98S mutation. Motor neurons carrying this allele-specific frameshift demonstrated an amelioration of the disease phenotype comparable to that seen in an isogenic control with precise correction of the mutation. Our results validate allele-specific gene editing as a therapeutic approach for CMT2E and as a promising strategy to silence dominant mutations in any gene for which heterozygous loss-of-function is well tolerated. This highlights the potential for gene editing as a therapy for currently untreatable dominant neurologic diseases.
Land-use planning for health: Tradeoffs and nonlinearities govern how land-use change impacts vector-borne disease risk
Authors: Kain Morgan P , MacDonald Andrew J , Mordecai Erin A , Mandle Lisa 
Published: June 2021

Patterns of land-use can affect the transmission of many infectious diseases with human health implications; yet, applied ecosystem service models have rarely accounted for disease transmission risk. A mechanistic understanding of how land-use changes alter infectious disease transmission would help to target public health interventions and to minimize human risk of disease with either ecosystem degradation or restoration. Here, we present a spatially explicit model of disease transmission on heterogeneous landscapes that is designed to serve as a road map for modeling the multifaceted impacts of land-use on disease transmission. We model the transmission of three vector-borne diseases with distinct transmission dynamics (parameterized using published literature to represent dengue, yellow fever, and malaria) on simulated landscapes of varying spatial heterogeneity in tree cover and urban area. Overall, we find that these three diseases depend on the biophysical landscape in different nonlinear ways, leading to tradeoffs in disease risk across the landscape; rarely do we predict disease risk to be high for all three diseases in a local setting. We predict that dengue risk peaks in areas of high urban intensity and human population density, yellow fever risk peaks in areas with low to moderate human population density and high tree cover, and malaria risk peaks where patchy tree cover abuts urban area. To examine how this approach can inform land use planning, we applied the model to a small landscape to the northwest of Bogotá, Colombia under multiple restoration scenarios. We predict that in an area inhabited by both Aedes aegypti and Ae. albopictus, any increase in overall tree cover would increase dengue and yellow fever risk, but that risk can be minimized by pursuing a large contiguous reforestation project as opposed to many small, patchy projects. A large contiguous reforestation project is also able to both reduce overall malaria risk and the number of malaria hotspots. As sustainable development goals make ecosystem restoration and biodiversity conservation top priorities, it is imperative that land use planning account for potential impacts on both disease transmission and other ecosystem services.Open Research statementAll data and code used in this study are available in the online supplemental material. Code and data are also hosted at: https://github.com/morgankain/Land-Use_Disease_Model.
Scalable and Automated CRISPR-Based Strain Engineering Using Droplet Microfluidics
Authors: Iwai Kosuke , Wehrs Maren , Garber Megan , Sustarich Jess , Washburn Lauren , Costello Zachary , Kim Peter W. , Ando David , Gaillard William R. , Hillson Nathan J. , Adams Paul D. , Mukhopadhyay Aindrila , Martin Hector Garcia , Singh Anup K. 
Published: June 2021

ABSTRACTWe present a droplet-based microfluidic system that enables CRISPR-based gene editing and high-throughput screening on chip. The microfluidic device contains a 10 x 10 element array, each element containing sets of electrodes for two electric field actuated operations-electrowetting for merging droplets to mix reagents and electroporation for transformation. It can perform up to 100 genetic modifications in parallel, providing a scalable platform for generating the large number of engineered strains required for combinatorial optimization of genetic pathways and predictable bioengineering. We demonstrate the system’s capabilities through CRISPR-based engineering of two test cases-1) disruption of the function of enzyme galactokinase (galK) in E. coli and 2) targeted engineering of glutamine synthetase gene (glnA) and blue-pigment synthetase (bpsA) enzyme to improve indigoidine production in E. coli.