bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of activation and desensitization of full-length glycine receptor in lipid nanodiscs
Authors: Kumar Arvind , Basak Sandip , Rao Shanlin , Gicheru Yvonne , Mayer Megan L. , Sansom Mark S. P. , Chakrapani Sudha 
Published: July 2020

AbstractGlycinergic synapses play a central role in motor control and pain processing in the central nervous system. Glycine receptors (GlyRs) are key players in mediating fast inhibitory neurotransmission at these synapses. While previous high-resolution structures have provided insights into the molecular architecture of GlyR, several mechanistic questions pertaining to channel function are still unanswered. Here, we present Cryo-EM structures of the full-length GlyR protein complex reconstituted into lipid nanodiscs that are captured in the unliganded (closed), glycine-bound (open and desensitized), and allosteric modulator-bound conformations. A comparison of these states reveals global conformational changes underlying GlyR channel gating and modulation. The functional state assignments were validated by molecular dynamics simulations, and the observed permeation events are in agreement with the anion selectivity and conductance of GlyR. These studies provide the structural basis for gating, ion selectivity, and single-channel conductance properties of GlyR in a lipid environment.
The architecture and stabilisation of flagellotropic tailed bacteriophages
Authors: Hardy Joshua M. , Dunstan Rhys A. , Grinter Rhys , Belousoff Matthew J. , Wang Jiawei , Pickard Derek , Venugopal Hariprasad , Dougan Gordon , Lithgow Trevor , Coulibaly Fasséli 
Published: July 2020

AbstractFlagellotropic bacteriophages engage flagella to reach the bacterial surface as an effective means to increase the capture radius for predation. Structural details of these viruses are of great interest given the substantial drag forces and torques they face when moving down the spinning flagellum. We show that the main capsid and auxiliary proteins form two nested chainmails that ensure the integrity of the bacteriophage head. Core stabilising structures are conserved in herpesviruses suggesting their ancestral origin. The structure of the tail also reveals a robust yet pliable assembly. Hexameric rings of the tail-tube protein are braced by the N-terminus and a β-hairpin loop, and interconnected along the tail by the splayed β-hairpins. By contrast, we show that the β-hairpin has an inhibitory role in the tail-tube precursor, preventing uncontrolled self-assembly. Dyads of acidic residues inside the tail-tube present regularly-spaced motifs well suited to DNA translocation into bacteria through the tail.
Directional translocation resistance of Zika xrRNA
Authors: Suma Antonio , Coronel Lucia , Bussi Giovanni , Micheletti Cristian 
Published: July 2020

AbstractxrRNAs from flaviviruses survive in host cells because of their exceptional dichotomic response to the unfolding action of different enzymes. They can be unwound, and hence copied, by replicases, and yet can resist degradation by exonucleases. How the same stretch of xrRNA can encode such diverse responses is an open question. Here, by using atomistic models and translocation simulations, we uncover an elaborate and directional mechanism for how stress propagates when the two xrRNA ends, $${5}^{\prime}$$

5

′

and $${3}^{\prime}$$

3

′

, are driven through a pore. Pulling the $${3}^{\prime}$$

3

′

end, as done by replicases, elicits a progressive unfolding; pulling the $${5}^{\prime}$$

5

′

end, as done by exonucleases, triggers a counterintuitive molecular tightening. Thus, in what appears to be a remarkable instance of intra-molecular tensegrity, the very pulling of the $${5}^{\prime}$$

5

′

end is what boosts resistance to translocation and consequently to degradation. The uncovered mechanistic principle might be co-opted to design molecular meta-materials.
Coupling of 5S RNP rotation with maturation of functional centers during large ribosomal subunit assembly
Authors: Micic Jelena , Li Yu , Wu Shan , Wilson Daniel , Tutuncuoglu Beril , Gao Ning , Woolford John L. 
Published: July 2020

AbstractThe protein composition and structure of assembling 60S ribosomal subunits undergo numerous changes as pre-ribosomes transition from the nucleolus to the nucleoplasm. This includes stable anchoring of the Rpf2 subcomplex containing 5S rRNA, rpL5, rpL11, Rpf2 and Rrs1, which initially docks onto the flexible domain V of rRNA at earlier stages of assembly. In this work, we tested the function of the C-terminal domain (CTD) of Rpf2 during these anchoring steps, by truncating this extension and assaying effects on middle stages of subunit maturation. The rpf2Δ255-344 mutation affects proper folding of rRNA helices H68-70 during anchoring of the Rpf2 subcomplex. In addition, several assembly factors (AFs) are absent from pre-ribosomes or in altered conformations. Consequently, major remodeling events fail to occur: rotation of the 5S RNP, maturation of the peptidyl transferase center (PTC) and the nascent polypeptide exit tunnel (NPET), and export of assembling subunits to the cytoplasm.
Neuroligin 2 regulates absence seizures and behavioral arrests through GABAergic transmission within the thalamocortical circuitry
Authors: Cao Feng , Liu Jackie J. , Zhou Susan , Cortez Miguel A. , Snead O. Carter , Han Jing , Jia Zhengping 
Published: July 2020

AbstractEpilepsy and autism spectrum disorders (ASD) are two distinct brain disorders but have a high rate of co-occurrence, suggesting shared pathogenic mechanisms. Neuroligins are cell adhesion molecules important in synaptic function and ASD, but their role in epilepsy remains unknown. In this study, we show that Neuroligin 2 (NLG2) knockout mice exhibit abnormal spike and wave discharges (SWDs) and behavioral arrests characteristic of absence seizures. The anti-absence seizure drug ethosuximide blocks SWDs and rescues behavioral arrests and social memory impairment in the knockout mice. Restoring GABAergic transmission either by optogenetic activation of the thalamic reticular nucleus (nRT) presynaptic terminals or postsynaptic NLG2 expression in the thalamic neurons reduces the SWDs and behavioral arrests in the knockout mice. These results indicate that NLG2-mediated GABAergic transmission at the nRT-thalamic circuit represents a common mechanism underlying both epileptic seizures and ASD.
VoPo leverages cellular heterogeneity for predictive modeling of single-cell data
Authors: Stanley Natalie , Stelzer Ina A. , Tsai Amy S. , Fallahzadeh Ramin , Ganio Edward , Becker Martin , Phongpreecha Thanaphong , Nassar Huda , Ghaemi Sajjad , Maric Ivana , Culos Anthony , Chang Alan L. , Xenochristou Maria , Han Xiaoyuan , Espinosa Camilo , Rumer Kristen , Peterson Laura , Verdonk Franck , Gaudilliere Dyani , Tsai Eileen , Feyaerts Dorien , Einhaus Jakob , Ando Kazuo , Wong Ronald J. , Obermoser Gerlinde , Shaw Gary M. , Stevenson David K. , Angst Martin S. , Gaudilliere Brice , Aghaeepour Nima 
Published: July 2020

AbstractHigh-throughput single-cell analysis technologies produce an abundance of data that is critical for profiling the heterogeneity of cellular systems. We introduce VoPo (https://github.com/stanleyn/VoPo), a machine learning algorithm for predictive modeling and comprehensive visualization of the heterogeneity captured in large single-cell datasets. In three mass cytometry datasets, with the largest measuring hundreds of millions of cells over hundreds of samples, VoPo defines phenotypically and functionally homogeneous cell populations. VoPo further outperforms state-of-the-art machine learning algorithms in classification tasks, and identified immune-correlates of clinically-relevant parameters.
Nano-topology optimization for materials design with atom-by-atom control
Authors: Chen Chun-Teh , Chrzan Daryl C. , Gu Grace X. 
Published: July 2020

AbstractAtoms are the building blocks of matter that make up the world. To create new materials to meet some of civilization’s greatest needs, it is crucial to develop a technology to design materials on the atomic and molecular scales. However, there is currently no computational approach capable of designing materials atom-by-atom. In this study, we consider the possibility of direct manipulation of individual atoms to design materials at the nanoscale using a proposed method coined “Nano-Topology Optimization”. Here, we apply the proposed method to design nanostructured materials to maximize elastic properties. Results show that the performance of our optimized designs not only surpasses that of the gyroid and other triply periodic minimal surface structures, but also exceeds the theoretical maximum (Hashin–Shtrikman upper bound). The significance of the proposed method lies in a platform that allows computers to design novel materials atom-by-atom without the need of a predetermined design.
One-step fabrication of carbonaceous adsorbent from corncob for enhancing adsorption capability of methylene blue removal
Authors: Wang Youming , Zhou Yulong , Jiang Guojing , Chen Peirong , Chen Zhen 
Published: July 2020

AbstractA novel and simple method was described for preparation of carbonaceous adsorbent (CA) from corncob under phosphoric acid conditions. The method succeeded to introduce oxygen-containing groups onto the product surface through hydrothermal carbonization (HTC) at low temperature of 160 °C. Adsorption of methylene blue (MB) was studied systematically through the effect of pH, contact time and initial dye concentrations. The MB adsorption kinetics and isotherms experiments showed that Langmuir model and pseudo-second-order model could better describe the adsorption behavior, with a maximum adsorption capacity of MB was 140.25 mg/g. The high adsorption capacity could be ascribed to the presence of surface oxygen-containing functional groups and pore channels. In conclusion, it could be a potential adsorbent in the removal of methylene blue from wastewater.
Serum deprivation initiates adaptation and survival to oxidative stress in prostate cancer cells
Authors: White ElShaddai Z. , Pennant Nakea M. , Carter Jada R. , Hawsawi Ohuod , Odero-Marah Valerie , Hinton Cimona V. 
Published: July 2020

AbstractInadequate nutrient intake leads to oxidative stress disrupting homeostasis, activating signaling, and altering metabolism. Oxidative stress serves as a hallmark in developing prostate lesions, and an aggressive cancer phenotype activating mechanisms allowing cancer cells to adapt and survive. It is unclear how adaptation and survival are facilitated; however, literature across several organisms demonstrates that a reversible cellular growth arrest and the transcription factor, nuclear factor-kappaB (NF-κB), contribute to cancer cell survival and therapeutic resistance under oxidative stress. We examined adaptability and survival to oxidative stress following nutrient deprivation in three prostate cancer models displaying varying degrees of tumorigenicity. We observed that reducing serum (starved) induced reactive oxygen species which provided an early oxidative stress environment and allowed cells to confer adaptability to increased oxidative stress (H2O2). Measurement of cell viability demonstrated a low death profile in stressed cells (starved + H2O2), while cell proliferation was stagnant. Quantitative measurement of apoptosis showed no significant cell death in stressed cells suggesting an adaptive mechanism to tolerate oxidative stress. Stressed cells also presented a quiescent phenotype, correlating with NF-κB nuclear translocation, suggesting a mechanism of tolerance. Our data suggests that nutrient deprivation primes prostate cancer cells for adaptability to oxidative stress and/or a general survival mechanism to anti-tumorigenic agents.
Antibody drug separation using thermoresponsive anionic polymer brush modified beads with optimised electrostatic and hydrophobic interactions
Authors: Nagase Kenichi , Ishii Saki , Ikeda Koji , Yamada Sota , Ichikawa Daiju , Akimoto Aya Mizutani , Hattori Yutaka , Kanazawa Hideko 
Published: July 2020

AbstractAntibody drugs play an important role in biopharmaceuticals, because of the specificity for target biomolecules and reduction of side effects. Thus, separation and analysis techniques for these antibody drugs have increased in importance. In the present study, we develop functional chromatography matrices for antibody drug separation and analysis. Three types of polymers, poly(N-isopropylacrylamide (NIPAAm)-co-2-acrylamido-2-methylpropanesulfonic acid (AMPS)-co-N-phenyl acrylamide (PhAAm)), P(NIPAAm-co-AMPS-co-n-butyl methacrylate (BMA)), and P(NIPAAm-co-AMPS-co-tert-butylacrylamide (tBAAm)), were modified on silica beads through atom transfer radical polymerisation. Rituximab elution profiles were observed using the prepared beads-packed column. Rituximab adsorption at high temperature and elution at low temperature from the column were observed, as a result of the temperature-modulated electrostatic and hydrophobic interactions. Using the column, rituximab purification from contaminants was performed simply by changing the temperature. Additionally, three types of antibody drugs were separated using the column through temperature-modulated hydrophobic and electrostatic interactions. These results demonstrate that the temperature-responsive column can be applied for the separation and analysis of biopharmaceuticals through a simple control of the column temperature.
The molecular basis of thioalcohol production in human body odour
Authors: Rudden Michelle , Herman Reyme , Rose Matthew , Bawdon Daniel , Cox Diana S. , Dodson Eleanor , Holden Matthew T. G. , Wilkinson Anthony J. , James A. Gordon , Thomas Gavin H. 
Published: July 2020

AbstractBody odour is a characteristic trait of Homo sapiens, however its role in human behaviour and evolution is poorly understood. Remarkably, body odour is linked to the presence of a few species of commensal microbes. Herein we discover a bacterial enzyme, limited to odour-forming staphylococci that are able to cleave odourless precursors of thioalcohols, the most pungent components of body odour. We demonstrated using phylogenetics, biochemistry and structural biology that this cysteine-thiol lyase (C-T lyase) is a PLP-dependent enzyme that moved horizontally into a unique monophyletic group of odour-forming staphylococci about 60 million years ago, and has subsequently tailored its enzymatic function to human-derived thioalcohol precursors. Significantly, transfer of this enzyme alone to non-odour producing staphylococci confers odour production, demonstrating that this C-T lyase is both necessary and sufficient for thioalcohol formation. The structure of the C-T lyase compared to that of other related enzymes reveals how the adaptation to thioalcohol precursors has evolved through changes in the binding site to create a constrained hydrophobic pocket that is selective for branched aliphatic thioalcohol ligands. The ancestral acquisition of this enzyme, and the subsequent evolution of the specificity for thioalcohol precursors implies that body odour production in humans is an ancient process.
The ‘Threat of Scream’ paradigm: a tool for studying sustained physiological and subjective anxiety
Authors: Beaurenaut Morgan , Tokarski Elliot , Dezecache Guillaume , Grèzes Julie 
Published: July 2020

AbstractProgress in understanding the emergence of pathological anxiety depends on the availability of paradigms effective in inducing anxiety in a simple, consistent and sustained manner. The Threat-of-Shock paradigm has typically been used to elicit anxiety, but poses ethical issues when testing vulnerable populations. Moreover, it is not clear from past studies whether anxiety can be sustained in experiments of longer durations. Here, we present empirical support for an alternative approach, the ‘Threat-of-Scream’ paradigm, in which shocks are replaced by screams. In two studies, participants were repeatedly exposed to blocks in which they were at risk of hearing aversive screams at any time vs. blocks in which they were safe from screams. Contrary to previous ‘Threat-of-Scream’ studies, we ensured that our screams were neither harmful nor intolerable by presenting them at low intensity. We found higher subjective reports of anxiety, higher skin conductance levels, and a positive correlation between the two measures, in threat compared to safe blocks. These results were reproducible and we found no significant change over time. The unpredictable delivery of low intensity screams could become an essential part of a psychology toolkit, particularly when investigating the impact of anxiety in a diversity of cognitive functions and populations.
Three-dimensional super-resolution fluorescence imaging of DNA
Authors: Yardimci Sevim , Burnham Daniel R. , Terry Samantha Y. A. , Yardimci Hasan 
Published: July 2020

AbstractRecent advances in fluorescence super-resolution microscopy are providing important insights into details of cellular structures. To acquire three dimensional (3D) super-resolution images of DNA, we combined binding activated localization microscopy (BALM) using fluorescent double-stranded DNA intercalators and optical astigmatism. We quantitatively establish the advantage of bis- over mono-intercalators before demonstrating the approach by visualizing single DNA molecules stretched between microspheres at various heights. Finally, the approach is applied to the more complex environment of intact and damaged metaphase chromosomes, unravelling their structural features.
Modulating electrophysiology of motor neural networks via optogenetic stimulation during neurogenesis and synaptogenesis
Authors: Pagan-Diaz Gelson J. , Drnevich Jenny , Ramos-Cruz Karla P. , Sam Richard , Sengupta Parijat , Bashir Rashid 
Published: July 2020

AbstractControl of electrical activity in neural circuits through network training is a grand challenge for biomedicine and engineering applications. Past efforts have not considered evoking long-term changes in firing patterns of in-vitro networks by introducing training regimens with respect to stages of neural development. Here, we used Channelrhodopsin-2 (ChR2) transfected mouse embryonic stem cell (mESC) derived motor neurons to explore short and long-term programming of neural networks by using optical stimulation implemented during neurogenesis and synaptogenesis. Not only did we see a subsequent increase of neurite extensions and synaptophysin clustering, but by using electrophysiological recording with micro electrode arrays (MEA) we also observed changes in signal frequency spectra, increase of network synchrony, coordinated firing of actions potentials, and enhanced evoked response to stimulation during network formation. Our results demonstrate that optogenetic stimulation during neural differentiation can result in permanent changes that extended to the genetic expression of neurons as demonstrated by RNA Sequencing. To our knowledge, this is the first time that a correlation between training regimens during neurogenesis and synaptogenesis and the resulting plastic responses has been shown in-vitro and traced back to changes in gene expression. This work demonstrates new approaches for training of neural circuits whose electrical activity can be modulated and enhanced, which could lead to improvements in neurodegenerative disease research and engineering of in-vitro multi-cellular living systems.
Changes in the vaginal microbiota across a gradient of urbanization
Authors: Vargas-Robles Daniela , Morales Natalia , Rodríguez Iveth , Nieves Tahidid , Godoy-Vitorino Filipa , Alcaraz Luis David , Pérez María-Eglée , Ravel Jacques , Forney Larry J. , Domínguez-Bello María Gloria 
Published: July 2020

AbstractThe vaginal microbiota of healthy women typically has low diversity, which increases after perturbations. Among these, lifestyle associated with certain sexual and antimicrobial practices may be associated with higher diversity. To test this hypothesis, we characterized the vaginal microbiota in the cervicovaginal and introital sites in sexually active Amerindians (N = 82) spanning urbanization, and in urban mestizos (N = 29), in the Venezuelan Amazonas. HPV status was also considered. Sampling was performed in an urban gradient from remote villages to a town, and women were individually classified by the degree of urbanization (low, medium, and high). Amerindian cervicovaginal and introital microbiota diversity were not associated with major changes in urbanization or ethnicity. There was a non-significant trend of increased diversity with urbanization, with a few taxa found overrepresented in urban Amerindians (Brevibacterium linensandPeptoniphilus lacrimalis) or mestizos (Mobiluncus mulierisandPrevotella sp.). Among all women, cervicovaginal and introital samples clustered, respectively, in four and two community state types (CSTs), where most profiles were dominated byLactobacillus iners, Gardnerella vaginalisor were highly diverse profiles. HPV status did not associate with microbial diversity. In conclusion, no association was found between urban level and the vaginal microbiome in Amerindian women, and little difference was found between ethnicities.L. inersand high diversity profiles, associated with vaginal health outcomes, prevail in these populations.
A thrombolytic therapy using diagnostic ultrasound combined with RGDS-targeted microbubbles and urokinase in a rabbit model
Authors: Guan Lina , Wang Chunmei , Yan Xue , Liu Liyun , Li Yanhong , Mu Yuming 
Published: July 2020

AbstractThis study aimed to explore thrombolysis therapy based on ultrasound combined with urokinase and Arg–Gly–Asp sequence (RGDS)-targeted microbubbles by evaluating the histological changes in a thrombotic rabbit model. Forty-two New Zealand rabbits featuring platelet-rich thrombi in the femoral artery were randomized to (n = 6/group): ultrasound alone (US); urokinase alone (UK); ultrasound plus non-targeted microbubbles (US + M); ultrasound plus RGDS-targeted microbubbles (US + R); RGDS-targeted microbubbles plus urokinase (R + UK); ultrasound, non-targeted microbubbles and urokinase (US + M + UK); and ultrasound, RGDS-targeted microbubbles and urokinase (US + R + UK) groups. Diagnostic ultrasound was used transcutaneously over the thrombus for 30 min. We evaluated the thrombolytic effect based on ultrasound thrombi detection, blood flow, and histological observations. Among all study groups, complete recanalization was achieved in the US + R + UK group. Hematoxylin and eosin staining showed that the thrombi were completely dissolved. Scanning electron microscopy examination demonstrated that the fiber network structure of the thrombi was damaged. Transmission electron microscopy showed that the thrombus was decomposed into high electron-dense particles. Histology for von Willebrand factor and tissue factor were both negative in the US + R + UK group. This study revealed that a thrombolytic therapy consisting of diagnostic ultrasound together with RGDS-targeted and urokinase coupled microbubbles.