bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of antibodies neutralizing historical and emerging SARS-CoV-2 strains using a thermodynamically coupled de novo biosensor system
Authors: Zhang Jason Z. , Yeh Hsien-Wei , Walls Alexandra C. , Wicky Basile I.M. , Sprouse Kaiti , VanBlargan Laura A. , Treger Rebecca , Quijano-Rubio Alfredo , Pham Minh N. , Kraft John C. , Haydon Ian C. , Yang Wei , DeWitt Michelle , Chow Cameron , Carter Lauren , Wener Mark H. , Stewart Lance , Veesler David , Diamond Michael S. , Baker David 
Published: June 2021

AbstractWith global vaccination efforts against SARS-CoV-2 underway, there is a need for rapid quantification methods for neutralizing antibodies elicited by vaccination and characterization of their strain dependence. Here, we describe a designed protein biosensor that enables sensitive and rapid detection of neutralizing antibodies against wild type and variant SARS-CoV-2 in serum samples. More generally, our thermodynamic coupling approach can better distinguish sample to sample differences in analyte binding affinity and abundance than traditional competition based assays.
Hierarchical control of microbial community assembly
Authors: Pontrelli Sammy , Szabo Rachel , Pollak Shaul , Schwartzman Julia , Ledezma-Tejeida Daniela , Cordero Otto X. , Sauer Uwe 
Published: June 2021

AbstractMetabolic processes that fuel the growth of heterotrophic microbial communities are initiated by specialized biopolymer degraders that decompose complex forms of organic matter. It is unclear, however, to what extent degraders control the downstream assembly of the community that follows polymer breakdown. Investigating a model marine microbial community that degrades chitin, we show that chitinases secreted by different degraders produce oligomers of specific chain lengths that not only select for specialized consumers but also influence the metabolites secreted by these consumers into a shared resource pool. Each species participating in the breakdown cascade exhibits unique hierarchical preferences for substrates, which underlies the sequential colonization of metabolically distinct groups as resource availability changes over time. By identifying the metabolic underpinnings of microbial community assembly, we reveal a hierarchical crossfeeding structure that allows biopolymer degraders to shape the dynamics of community assembly.One sentence summarySpecialized biopolymer degraders direct the trajectory of microbial community assembly through interconnected modes of nutrient crossfeeding.
A multiscale approach for computing gated ligand binding from molecular dynamics and Brownian dynamics simulations
Authors: Sadiq S. Kashif , Chicharro Abraham Muñiz , Friedrich Patrick , Wade Rebecca C. 
Published: June 2021

AbstractWe develop an approach to characterise the effects of gating by a multi-conformation protein consisting of macrostate conformations that are either accessible or inaccessible to ligand binding. We first construct a Markov state model of the apo-protein from atomistic molecular dynamics simulations from which we identify macrostates and their conformations, compute their relative macrostate populations and interchange kinetics, and structurally characterise them in terms of ligand accessibility. We insert the calculated first-order rate constants for conformational transitions into a multi-state gating theory from which we derive a gating factorγthat quantifies the degree of conformational gating. Applied to HIV-1 protease, our approach yields a kinetic network of three accessible (semi-open, open and wide-open) and two inaccessible (closed and a newly identified, ‘parted’) macrostate conformations. The ‘parted’ conformation sterically partitions the active site, suggesting a possible role in product release. We find that the binding kinetics of drugs and drug-like inhibitors to HIV-1 protease falls in the slow gating regime. However, becauseγ=0.75, conformational gating only modestly slows ligand binding. Brownian dynamics simulations of the diffusional association of eight inhibitors to the protease - that have a wide range of experimental association constants (~104- 1010M−1s−1) - yields gated rate constants in the range ~0.5-5.7 × 108M−1s−1. This indicates that, whereas the association rate of some inhibitors could be described by the model, for many inhibitors either subsequent conformational transitions or alternate binding mechanisms may be rate-limiting. For systems known to be modulated by conformational gating, the approach could be scaled computationally efficiently to screen association kinetics for a large number of ligands.Graphical TOC Entry
Forward genetics combined with unsupervised classifications identified zebrafish mutants affecting biliary system formation
Authors: Singh Divya Jyoti , Tuscano Kathryn M. , Ortega Karen L. , Dimri Manali , Tae Kevin , Lee William , Muslim Muslim A. , Liu Jay L. , Pierce Lain X. , McClendon Allyson , Naegele Gregory , Gibson Isabel , Livesay Jodi , Sakaguchi Takuya F. 
Published: June 2021

AbstractImpaired formation of the biliary network can lead to congenital cholestatic liver diseases; however, the genes responsible for proper biliary system formation and maintenance have not been fully identified. Combining computational network structure analysis algorithms with a zebrafish forward genetic screen, we identified 24 new zebrafish mutants that display impaired intrahepatic biliary network formation. Complementation tests suggested that these 24 mutants affect 24 different genes. We applied unsupervised clustering algorithms to classify the recovered mutants into three classes unbiasedly. Further computational analyses revealed that each of the recovered mutations in these three classes shows a unique effect on node subtype composition and connection property distribution of the intrahepatic biliary network. Besides, we found that most recovered mutations are viable. In those mutant fish, biliary network phenotypes persist into adulthood, which themselves are good animal models to study chronic cholestatic liver diseases. Altogether, this study provides unique genetic and computational toolsets that advance our understanding of the molecular pathways leading to biliary system malformation and cholestatic liver diseases.
Evidence for widespread alterations in cortical microstructure after 32 hours of sleep deprivation
Authors: Voldsbekk Irene , Bjørnerud Atle , Groote Inge , Zak Nathalia , Roelfs Daniel , Maximov Ivan I. , Geier Oliver , Due-Tønnessen Paulina , Bøen Erlend , Kuiper Yvonne S. , Løkken Lise-Linn , Strømstad Marie , Blakstvedt Taran Y. , Bjorvatn Bjørn , Malt Ulrik F. , Westlye Lars T. , Elvsåshagen Torbjørn , Grydeland Håkon 
Published: June 2021

AbstractCortical microstructure is influenced by circadian rhythm and sleep deprivation, yet the precise underpinnings of these effects remain unclear. The ratio between T1-weighted and T2-weighted magnetic resonance images (T1w/T2w ratio) has been linked to myelin levels and dendrite density and may offer novel insight into the intracortical microstructure of the sleep deprived brain. Here, we examined intracortical T1w/T2w ratio in 41 healthy young adults (26 women) before and after 32 hours of either sleep deprivation (n = 18) or a normal sleep-wake cycle (n = 23). Linear models revealed significant group differences in T1w/T2w ratio change after 32 hours in four clusters, including bilateral effects in the insular, cingulate, and superior temporal cortices, comprising regions involved in attentional, auditory and pain processing. Across clusters, the sleep deprived group showed an increased T1w/T2w ratio, while the normal sleep-wake group exhibited a reduced ratio. These changes were not explained by in-scanner head movement, and 95% of the effects across clusters remained significant after adjusting for cortical thickness and hydration. Compared with a normal sleep-wake cycle, 32 hours of sleep deprivation yields intracortical T1w/T2w ratio increases. While the intracortical changes detected by this study could reflect alterations in myelin or dendritic density, or both, histological analyses are needed to clarify the precise underlying cortical processes.
Distinct MUNC lncRNA structural domains regulate transcription of different promyogenic factors
Authors: Przanowska Roza K. , Weidmann Chase A. , Saha Shekhar , Cichewicz Magdalena A. , Jensen Kate N. , Przanowski Piotr , Irving Patrick S. , Guertin Michael J. , Weeks Kevin M. , Dutta Anindya 
Published: June 2021

SummaryMany lncRNAs have been discovered using transcriptomic data, however, it is broadly unclear what fraction of lncRNAs are functional and what structural properties affect their phenotype. MUNC lncRNA, also known as DRReRNA, stimulates skeletal muscle differentiation. The prevailing hypothesis is that MUNC stimulates the Myod1 gene in cis as an enhancer RNA and stimulates expression of several other promyogenic genes in trans by recruiting the cohesin complex to their promoters. Experimental probing of the RNA structure revealed that MUNC contains multiple structural domains not detected by RNA structure prediction algorithms in the absence of experimental information. We discovered that these specific and structurally distinct domains are required for induction of different promyogenic genes, for binding at different genomic sites to regulate the expression of adjacent genes, and for binding the cohesin complex. Moreover, we found that induction of Myod1 or interaction with cohesin comprise only a subset of the broad regulatory impact of this lncRNA. Our study thus reveals unexpectedly complex, structure-driven functions for the MUNC lncRNA and emphasizes the importance of experimentally determined structures for understanding structure-function relationships in lncRNAs.
Point-of-care analyte quantification and digital readout via lysate-based cell-free biosensors interfaced with personal glucose monitors
Authors: Zhang Yan , Steppe Paige L. , Kazman Maxwell W. , Styczynski Mark P. 
Published: June 2021

AbstractField-deployable diagnostics based on cell-free systems have advanced greatly, but on-site quantification of target analytes remains a challenge. Here we demonstrate that Escherichia coli lysate-based cell-free biosensors coupled to a personal glucose monitor (PGM) can enable on-site analyte quantification, with the potential for straightforward reconfigurability to diverse types of analytes. We show that analyte-responsive regulators of transcription and translation can modulate production of the reporter enzyme β-galactosidase, which in turn converts lactose into glucose for PGM quantification. Because glycolysis is active in the lysate and would readily deplete converted glucose, we decoupled enzyme production and glucose conversion to increase endpoint signal output. This lysate metabolism did, however, allow for one-pot removal of glucose present in complex samples (like human serum) without confounding target quantification. Taken together, we show that integrating lysate-based cell-free biosensors with PGMs enables accessible target detection and quantification at the point of need.Table of Contents Graphic
A method for three-dimensional single-cell chronic electrophysiology from developing brain organoids
Authors: Le Floch Paul , Li Qiang , Liu Ren , Tasnim Kazi , Zhao Siyuan , Lin Zuwan , Jiang Han , Liu Jia 
Published: June 2021

AbstractHuman induced pluripotent stem cell-derived brain organoids have shown great potential for studies of human brain development and neurological disorders. However, quantifying the evolution and development of electrical functions in brain organoids is currently limited by measurement techniques that cannot provide long-term stable three-dimensional (3D) bioelectrical interfaces with brain organoids during development. Here, we report a cyborg brain organoid platform, in which 2D progenitor or stem cell sheets can fold “tissue-like” stretchable mesh nanoelectronics through organogenesis, distributing stretchable electrode arrays across 3D organoids. The tissue-wide integrated stretchable electrode arrays show no interruption to neuronal differentiation, adapt to the volume and morphological changes during organogenesis, and provide long-term stable electrical contacts with neurons within brain organoids during development. The seamless and non-invasive coupling of electrodes to neurons enables a 6-month continuous recording of the same brain organoids and captures the emergence of single-cell action potentials from early-stage brain organoid development.
metaMIC: reference-free Misassembly Identification and Correction of de novo metagenomic assemblies
Authors: Lai Senying , Pan Shaojun , Coelho Luis Pedro , Chen Wei-Hua , Zhao Xing-Ming 
Published: June 2021

AbstractEvaluating the quality of metagenomic assemblies is important for constructing reliable metagenome-assembled genomes and downstream analyses. Here, we present metaMIC (https://github.com/ZhaoXM-Lab/metaMIC), a machine-learning based tool for identifying and correcting misassemblies in metagenomic assemblies. Benchmarking results on both simulated and real datasets demonstrate that metaMIC outperforms existing tools when identifying misassembled contigs. Furthermore, metaMIC is able to localize the misassembly breakpoints, and the correction of misassemblies by splitting at misassembly breakpoints can improve downstream scaffolding and binning results.
Hypothalamic effective connectivity at rest is associated with body weight and energy homeostasis
Authors: Voigt Katharina , Andrews Zane B. , Harding Ian H. , Razi Adeel , Verdejo-Garcia Antonio 
Published: June 2021

AbstractHunger and satiety states drive eating behaviours via changes in brain function. The hypothalamus is a central component of the brain networks that regulate food intake. Animal research parsed the roles of the lateral hypothalamus (LH) and the medial hypothalamus (MH) in hunger and satiety respectively. Here, we examined how hunger and satiety change information flow between human LH and MH brain networks, and how these interactions are influenced by body mass index. Forty participants (15 overweight/obese) underwent two resting-state functional MRI scans: after overnight fasting (fasted state) and following a standardised meal (sated state). The direction and valence (excitatory/inhibitory influence) of information flow between the MH and LH was modelled using spectral dynamic causal modelling. Our results revealed two core networks interacting across homeostatic state and weight status: subcortical bidirectional connections between the LH, MH and the substantia nigra pars compacta (prSN), and cortical top-down inhibition from frontoparietal and temporal areas. During fasting relative to satiety, we found higher inhibition between the LH and prSN, whereas the prSN received greater top-down inhibition from across the cortex. Individuals with higher BMI showed that these network dynamics occur irrespective of fasted or satiety states. Our findings reveal fasting affects brain dynamics over a distributed hypothalamic-midbrain-cortical network. This network is less sensitive to state-related fluctuations among people with obesity.
Ultrashort treatment with telacebec alone and with companion drugs in immunocompetent and immunosuppressed mouse footpad models of Buruli ulcer
Authors: Komm Oliver , Almeida Deepak V. , Converse Paul J. , Omansen Till F. , Nuermberger Eric L. 
Published: June 2021

ABSTRACTThe antimicrobial treatment of Mycobacterium ulcerans infection, or Buruli ulcer (BU), has a long duration and is therefore burdensome and linked to indirect costs for affected patients. The new antimycobacterial drug telacebec (Q203) has previously shown promising treatment-shortening potential in mouse models of BU. In the present study, we investigated the potential of Q203 to reduce the treatment duration further. The first experiment investigated the possibility of cure by one, three or five doses of Q203 (2 mg/kg) with or without a companion drug (bedaquiline, BDQ, clofazimine, CFZ, or clarithromycin, CLR) in immunocompetent BALB/c mice. The second experiment assessed the effect of five doses of Q203 with or without BDQ or CFZ on Mycobacterium ulcerans infection of immunocompromised SCID-beige mice with the aim to evaluate the contribution of host immunity to treatment efficacy. In BALB/c mice, a treatment duration as short as 3 days was sufficient to prevent relapse in nearly all footpads and a single dose of Q203 with or without BDQ or CFZ prevented relapse in approximately 50% of footpads. Unlike in BALB/c mice, a small percentage of SCID-beige mouse footpads were culture-positive after a treatment duration of five days, highlighting an important role of host immunity for M. ulcerans clearance. Our results confirm the marked potency and prolonged bactericidal and sterilizing effects of Q203, even in immunocompromised SCID-beige mice.
A selective adenylyl cyclase 1 inhibitor relieves pain without causing tolerance
Authors: Giacoletti Gianna , Price Tatum , Hoelz Lucas V.B , Msdi Abdulwhab Shremo , Vazquez-Falto Katerina , Amorim Fernandes Tácio V. , Santos de Pontes Vinícius , Wang Hongbing , Boechat Nubia , Nornoo Adwoa , Brust Tarsis F. 
Published: June 2021

AbstractAdenylyl cyclases (ACs) catalyze the production of the second messenger cyclic adenosine monophosphate from adenosine triphosphate. Among the ten different AC isoforms, studies with knockout animals indicate that inhibition of AC1 can relieve pain and reduce behaviors linked to opioid dependence. We previously identified ST034307 as a selective inhibitor of AC1. The development of an AC1-selective inhibitor now provides the opportunity to further study the therapeutic potential of inhibiting this protein in pre-clinical animal models of pain and related adverse reactions. In the present study we have shown that ST034307 relieves pain in mouse models of formalin-induced inflammatory pain, acid-induced visceral pain, and acid-depressed nesting. In addition, ST034307 did not cause analgesic tolerance after chronic dosing. We also show that the compound is restricted to the periphery following subcutaneous injections and report the predicted molecular interaction between ST034307 and AC1. Our results indicate that AC1 inhibitors represent a promising new class of analgesic agents that treat pain and appear to produce less adverse effects than currently-used opioids.
Cross-platform Bayesian optimization system for autonomous biological assay development
Authors: Elder Sam , Klumpp-Thomas Carleen , Yasgar Adam , Travers Jameson , Frebert Shayne , Wilson Kelli M. , Zakharov Alexey V. , Dahlin Jayme L. , Kreisbeck Christoph , Sheberla Dennis , Sittampalam Gurusingham S. , Godfrey Alexander G. , Simeonov Anton , Michael Sam 
Published: June 2021

AbstractCurrent high-throughput screening assay optimization is often a manual and time-consuming process, even when utilizing design-of-experiment approaches. A cross-platform, Cloud-based Bayesian optimization-based algorithm was developed as part of the NCATS ASPIRE Initiative to accelerate preclinical drug discovery. A cell-free assay for papain enzymatic activity was used as proof-of-concept for biological assay development. Compared to a brute force approach that sequentially tested all 294 assay conditions to find the global optimum, the Bayesian optimization algorithm could find suitable conditions for optimal assay performance by testing only 21 assay conditions on average, with up to 20 conditions being tested simultaneously. The algorithm could achieve a seven-fold reduction in costs for lab supplies and high-throughput experimentation run-time, all while being controlled from a remote site through a secure connection. Based on this proof-of-concept, this technology is expected to be applied to more complex biological assays and automated chemistry reaction screening at NCATS, and should be transferable to other institutions.
Computational and experimental assessment of backbone templates for computational protein design
Authors: Marin Frederikke Isa , Johansson Kristoffer Enøe , O’Shea Charlotte , Lindorff-Larsen Kresten , Winther Jakob Rahr 
Published: June 2021

AbstractComputational protein design has taken big strides over the recent years, however, the tools available are still not at a state where a sequence can be designed to fold into a given protein structure at will and with high probability. We have here applied a recent release of Rosetta Design to redesign a set of structurally very similar proteins belonging to the Thioredoxin fold. We determined design success using a combination of a genetic screening tool to assay folding/stability in E. coli and selecting the best hits from this for further biochemical characterization. We have previously used this set of template proteins for redesign and found that success was highly dependent on template structure, a trait which was also found in this study. Nevertheless, state of the art design software is now able to predict the best template, most likely due to the introduction of the cart_bonded energy term. The template that led to the greatest fraction of successful designs was the same (a Thioredoxin from spinach) as that identified in our previous study. Our previously described redesign of Thioredoxin, which also used the spinach protein as template, however also performed well. In the present study, both these templates yielded proteins with compact folded structures, and enforces the conclusion that any design project must carefully consider different design templates. Fortunately, selecting designs using the cart_bonded energy term appears to correctly identify such templates.
Spatial organization of face part representations within face-selective areas revealed by high-field fMRI
Authors: Zhang Jiedong , Jiang Yong , Song Yunjie , Zhang Peng , He Sheng 
Published: June 2021

AbstractRegions sensitive to specific object categories as well as organized spatial patterns sensitive to different features have been found across the whole ventral temporal cortex (VTC). However, it is unclear that within each object category region, how specific feature representations are organized to support object identification. Would object features, such as object parts, be represented in fine-scale spatial organization within object category-specific regions? Here we used high-field 7T fMRI to examine the spatial organization of neural tuning to different face parts within each face-selective region. Our results show consistent spatial organization across individuals that within right posterior fusiform face area (pFFA) and right occipital face area (OFA), the posterior portion of each region was biased to eyes, while the anterior portion was biased to mouth and chin stimuli. Our results demonstrate that within the occipital and fusiform face processing regions, there exist systematic spatial organizations of neural tuning to different face parts that support further computation combining them.