bluuebunny/crossref_metadata_2025_split huggingface dataset:
Task-dependent switching of feedback controllers
Authors: Česonis Justinas , Franklin David W. 
Published: December 2021

AbstractThe separation of distinct motor memories by contextual cues is a well known and well studied phenomenon of feedforward human motor control. However, there is no clear evidence of such context-induced separation in feedback control. Here we test both experimentally and computationally if context-dependent switching of feedback controllers is possible in the human motor system. Specifically, we probe visuomotor feedback responses of our human participants in two different tasks – stop and hit – and under two different schedules. The first, blocked schedule, is used to measure the behaviour of stop and hit controllers in isolation, showing that it can only be described by two independent controllers with two different sets of control gains. The second, mixed schedule, is then used to compare how such behaviour evolves when participants regularly switch from one task to the other. Our results support our hypothesis that there is contextual switching of feedback controllers, further extending the accumulating evidence of shared features between feedforward and feedback control.
Omicron BA.1 and BA.2 Variants Increase the Interactions of SARS-CoV-2 Spike Glycoprotein with ACE2
Authors: Golcuk Mert , Yildiz Ahmet , Gur Mert 
Published: December 2021

ABSTRACTSARS-CoV-2 infection is initiated by binding of the receptor-binding domain (RBD) of its spike glycoprotein to the peptidase domain (PD) of angiotensin-converting enzyme 2 (ACE2) receptors in host cells. Recently detected Omicron variant of SARS-CoV-2 (B.1.1.529) is heavily mutated on RBD. Currently, the most common Omicron variants are the original BA.1 Omicron strain and the BA.2 variant, which became more prevalent since it first appeared. To investigate how these mutations affect RBD-PD interactions, we performed all-atom molecular dynamics simulations of the BA.1 and BA.2 RBD-PD in the presence of full-length glycans, explicit water and ions. Simulations revealed that RBDs of BA.1 and BA.2 variants exhibit a more dispersed interaction network and make an increased number of salt bridges and hydrophobic interactions with PD compared to wild-type RBD. Although BA.1 and BA.2 differ in two residues at the RBD-ACE2 interface, no major difference in RBD-PD interactions and binding strengths were observed between these variants. Using the conformations sampled in each trajectory, the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) method estimated ~34% and ~51% stronger binding free energies for BA.1 and BA.2 RBD, respectively, than wild-type RBD, which may result in higher binding efficiency of the Omicron variant to infect host cells.
Homeostatic Synaptic Plasticity Rescues Neural Coding Reliability
Authors: Rozenfeld Eyal , Ehmann Nadine , Manoim Julia E. , Kittel Robert J. , Parnas Moshe 
Published: December 2021

AbstractTo survive, animals must recognize reoccurring stimuli. A key requirement for repeated identification of stimuli is reliable representation by the neural code on each encounter. Synaptic transmission underlies neural codes propagation between brain regions. A hallmark of chemical synapses is their plasticity, which enables signal transfer to be modified in an activity-dependent manner. Despite many decades of intense research on synapses, it remains unclear how the plastic features of synaptic transmission can maintain reliable neural coding. By studying the olfactory system of Drosophila melanogaster, we aimed to obtain a deeper mechanistic understanding of how synaptic function shapes neural coding reliability in the live, behaving animal. We show that the properties of the active zone (AZ), the presynaptic site of neurotransmitter release, are critical for generating a reliable neural code. Reducing neurotransmitter release probability specifically at AZs of olfactory sensory neurons disrupted both neural coding and behavioral reliability. Strikingly, these defects were rescued within a day by target-specific synaptic plasticity, whereby a homeostatic increase in the number of AZs compensated the drop in release probability. These findings demonstrate an important role for synaptic plasticity in maintaining neural coding reliability and are of pathophysiological interest by uncovering an elegant mechanism through which the neural circuitry can counterbalance perturbations.
Nucleotide imbalance decouples cell growth from cell proliferation
Authors: Diehl Frances F. , Miettinen Teemu P. , Elbashir Ryan , Nabel Christopher S. , Manalis Scott R. , Lewis Caroline A. , Vander Heiden Matthew G. 
Published: December 2021

AbstractNucleotide metabolism supports RNA synthesis and DNA replication to enable cell growth and division. Nucleotide depletion can accordingly inhibit cell growth and proliferation, but how cells sense and respond to changes in the relative levels of individual nucleotides is unclear. Moreover, the nucleotide requirement for biomass production changes over the course of the cell cycle, and how cells coordinate differential nucleotide demands with cell cycle progression is also not well understood. Here we find that excess levels of individual nucleotides can inhibit proliferation by disrupting the relative levels of nucleotide bases needed for DNA replication. The resulting purine and pyrimidine imbalances are not sensed by canonical growth regulatory pathways, causing aberrant biomass production and excessive cell growth despite inhibited proliferation. Instead, cells rely on replication stress signaling to survive during, and recover from, nucleotide imbalance during S phase. In fact, replication stress signaling is activated during unperturbed S phases and promotes nucleotide availability to support DNA replication. Together, these data reveal that imbalanced nucleotide levels are not detected until S phase, rendering cells reliant on replication stress signaling to cope with this metabolic problem, and disrupting the coordination of cell growth and division.
Frontal plane ankle stiffness increases with axial load independent of muscle activity
Authors: Villamar Zoe , Perreault Eric J. , Ludvig Daniel 
Published: December 2021

ABSTRACTAnkle sprains are the most common musculoskeletal injury, typically resulting from excessive inversion of the ankle. One way to prevent excessive inversion and maintain ankle stability is to generate a stiffness that is sufficient to resist externally imposed rotations. Frontal-plane ankle stiffness increases as participants place more weight on their ankle, but whether this effect is due to muscle activation or axial loading of the ankle is unknown. Identifying whether and to what extent axial loading affects ankle stiffness is important in understanding what role the passive mechanics of the ankle joint play in maintaining its stability. The objective of this study was to determine the effect of passive axial load on frontal-plane ankle stiffness. We had subjects seated in a chair as an axial load was applied to the ankle ranging from 10% to 50% body weight. Small rotational perturbations were applied to the ankle in the frontal plane to estimate stiffness. We found a significant, linear, 3-fold increase in ankle stiffness with axial load from the range of 0% bodyweight to 50% bodyweight. This increase could not be due to muscle activity as we observed no significant axial-load-dependent change in any of the recorded muscle activations. These results demonstrate that axial loading is a significant contributor to maintaining frontal-plane ankle stability, and that disruptions to the mechanism mediating this sensitivity of stiffness to axial loading may result in pathological cases of ankle instability.
TRAP1 and cyclophilin D compete at OSCP subunit to regulate enzymatic activity and permeability transition pore opening by F-ATP synthase
Authors: Cannino Giuseppe , Urbani Andrea , Gaspari Marco , Varano Mariaconcetta , Negro Alessandro , Filippi Antonio , Ciscato Francesco , Masgras Ionica , Gerle Christoph , Tibaldi Elena , Brunati Anna Maria , Lippe Giovanna , Bernardi Paolo , Rasola Andrea 
Published: December 2021

AbstractBinding of the mitochondrial chaperone TRAP1 to client proteins shapes cell bioenergetic and proteostatic adaptations, but the panel of TRAP1 clients is only partially defined. Here we show that TRAP1 interacts with F-ATP synthase, the protein complex that provides most cellular ATP. TRAP1 competes with the peptidyl-prolylcis-transisomerase cyclophilin D (CyPD) for binding to the oligomycin sensitivity-conferring protein (OSCP) subunit of F-ATP synthase, increasing its catalytic activity and counteracting the inhibitory effect of CyPD. Moreover, TRAP1 inhibits opening of the permeability transition pore (PTP) formed by F-ATP synthase and effectively antagonizes the PTP-inducing effect of CyPD, which elicits mitochondrial depolarization and cell death. Consistently, electrophysiological measurements indicate that TRAP1 and CyPD compete in the modulation of channel activity of purified F-ATP synthase, resulting in PTP inhibition and activation, respectively, and outcompeting each other effect on the channel. Moreover, TRAP1 counteracts PTP induction by CyPD, whereas CyPD reverses TRAP1-mediated PTP inhibition. Our data identify TRAP1 as a F-ATP synthase regulator that can influence cell bioenergetics and survival and can be targeted in pathological conditions where these processes are dysregulated, such as cancer.
A convolutional neural network highlights mutations relevant to antimicrobial resistance in Mycobacterium tuberculosis
Authors: Green Anna G. , Yoon Chang H. , Chen Michael L. , Freschi Luca , Gröschel Matthias I. , Kohane Isaac , Beam Andrew , Farhat Maha 
Published: December 2021

AbstractLong diagnostic wait times hinder international efforts to address multi-drug resistance in M. tuberculosis. Pathogen whole genome sequencing, coupled with statistical and machine learning models, offers a promising solution. However, generalizability and clinical adoption have been limited in part by a lack of interpretability and verifiability, especially in deep learning methods. Here, we present a deep convolutional neural network (CNN) that predicts the antibiotic resistance phenotypes of M. tuberculosis isolates. The CNN performs with state-of-the-art levels of predictive accuracy. Evaluation of salient sequence features permits biologically meaningful interpretation and validation of the CNN’s predictions, with promising repercussions for functional variant discovery, clinical applicability, and translation to phenotype prediction in other organisms.
Creation of photocyclic vertebrate rhodopsin by single amino acid substitution
Authors: Sakai Kazumi , Shichida Yoshinori , Imamoto Yasushi , Yamashita Takahiro 
Published: December 2021

AbstractOpsins are universal photoreceptive proteins in animals and can be classified into three types based on their photoreaction properties. Upon light irradiation, vertebrate rhodopsin forms a metastable active state, which cannot revert back to the original dark state via either photoreaction or thermal reaction. By contrast, after photoreception, most opsins form a stable active state which can photo-convert back to the dark state. Moreover, we recently found a novel type of opsins whose activity is regulated by photocycling. However, the molecular mechanism underlying this diversification of opsins remains unknown. In this study, the molecular property of vertebrate rhodopsin successfully converted to the photocyclic and photoreversible properties by a single mutation at position 188. This revealed that the residue at position 188 contributes to the diversification of photoreaction properties of opsins by the regulation of the recovery from the active state to the original dark state.
Neuronal population activity dynamics reveal a low-dimensional signature of operant learning
Authors: Costa Renan M. , Baxter Douglas A. , Byrne John H. 
Published: December 2021

AbstractLearning engages a high-dimensional neuronal population space spanning multiple brain regions. We identified a low-dimensional signature associated with operant conditioning, a ubiquitous form of learning in which animals learn from the consequences of behavior. Using single-neuron resolution voltage imaging, we identified two low-dimensional motor modules in the neuronal population underlying Aplysia feeding. Our findings point to a temporal shift in module recruitment as the primary signature of operant learning.
Control of Leaf Vein Patterning by Regulated Plasmodesma Aperture
Authors: Linh Nguyen Manh , Scarpella Enrico 
Published: December 2021

ABSTRACTTo form tissue networks, animal cells migrate and interact through proteins protruding from their plasma membranes. Plant cells can do neither, yet plants form vein networks. How plants do so is unclear, but veins are thought to form by the coordinated action of the polar transport and signal transduction of the plant hormone auxin. However, plants inhibited in both pathways still form veins. Patterning of vascular cells into veins is instead prevented in mutants lacking the function of theGNOM(GN) regulator of auxin transport and signaling, suggesting the existence of at least one moreGN-dependent vein-patterning pathway. Here we show that pathway depends on the movement of an auxin signal through plasmodesmata (PDs) intercellular channels. PD permeability is high where veins are forming, lowers between veins and nonvascular tissues, but remains high between vein cells. Impaired ability to regulate PD aperture leads to defects in auxin transport and signaling, ultimately leading to vein patterning defects that are enhanced by inhibition of auxin transport or signaling.GNcontrols PD aperture regulation, and simultaneous inhibition of auxin signaling, auxin transport, and regulated PD aperture phenocopies nullgnmutants. Therefore, veins are patterned by the coordinated action of threeGN-dependent pathways: auxin signaling, polar auxin transport, and movement of an auxin signal through PDs. We have identified all the key vein-patterning pathways in plants and an unprecedented mechanism of tissue network formation in multicellular organisms.
Structure-based design of a chemical probe set for the 5-HT5A serotonin receptor
Authors: Kaplan Anat Levit , Strachan Ryan T. , Braz Joao M. , Craik Veronica , Slocum Samuel , Mangano Thomas , Amabo Vanessa , O’Donnell Henry , Lak Parnian , Basbaum Allan I. , Roth Bryan L. , Shoichet Brian 
Published: December 2021

ABSTRACTThe 5-HT5A receptor (5-HT5AR), for which no selective agonists and only a few antagonists exist, remains the least understood serotonin (5-HT) receptor. A single commercial antagonist (SB-699551) has been widely used to investigate central nervous system (CNS) 5-HT5AR function in neurological disorders, including pain. However, because SB-699551 has affinity for many 5-HTRs, lacks inactive property-matched controls, and has assay interference concerns, it has liabilities as a chemical probe. To better illuminate 5-HT5AR function, we developed a probe set through iterative rounds of molecular docking, pharmacological testing, and optimization. Docking over six million lead-like molecules against a 5-HT5AR homology model identified five mid-μM ligand starting points with unique scaffolds. Over multiple rounds of structure-based design and testing, a new quinoline scaffold with high affinity and enhanced selectivity for the 5-HT5AR was developed, leading to UCSF678, a 42 nM arrestin-biased partial agonist at the 5-HT5AR with a much more restricted off-target profile and decreased assay liabilities vs. SB-699551. Site-directed mutagenesis supported the docked pose of UCSF678, which was also consistent with recent published 5-HTR structures. Surprisingly, property-matched analogs of UCSF678 that were either inactive across 5-HTRs or retained affinity for UCSF678’s off-targets revealed that 5-HT5AR engagement is nonessential for alleviating pain in a mouse model, contrary to previous studies using less-selective ligands. Relative to SB-699551, these molecules constitute a well-characterized and more selective probe set with which to study the function of the 5-HT5A receptor.
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Deltamethrin contact exposure mediated toxicity and histopathological aberrations in tissue systems of cockroach speciesPeriplaneta americanaandBlatella germanica
Authors: Dhiman Sunil , Yadav Kavita , Acharya BN , Nagar DP , Ghorpade Rama Rao 
Published: December 2021

AbstractCockroach speciesPeriplaneta americanaandBlatella germanicapotentially survive in locations close to human activity. Besides spoiling food material, cockroaches also transfer pathogens of different diseases among human. Since the insecticides have been used extensively to control cockroaches, information on their insecticide susceptibility and toxicity at cellular level may be crucial. In the study, deltamethrin toxicity as well as the deltamethrin-mediated cytomorphological changes in brain, ovary and midgut of the two important cockroach species has been assessed. Different concentrations [0.00025% (0.0025mg/ml), 0.0025% (0.025mg/ml), 0.025 (0.25mg/ml), 0.25% (2.5mg/ml), 0.5% (5mg/ml), 1% (10mg/ml)] of deltamethrin in acetone were used to expose test species in WHO bottle assay. Knockdown was recorded after 5 min interval while delayed mortality was observed after 24 hr. Brain, ovary and gut were dissected post 1 hr exposure and 24 hr holding (for 0.25%, 0.5% and 1% concentration), and tissues were processed for microscopic analysis. Deltamethrin exposed cockroaches and dissected tissues were used to estimate deltamethrin using HPLC. At 0.00025% (lowest concentration), the percentage knock-down observed was 66.7% forP. americanaand 80%B. germanicarespectively (R2= 0.78; p=0.0001) in 1 hr. KDT50value was found to be 8.7 min (95% CI: 7.3-10.2), while KDT99was 20.7 min (95% CI: 16.0-35.7) inP. americanaat 1% concentration. Whereas, the KDT50and KDT99values forB. germanicawere 7.4 min (95% CI: 5.4-9.1) and 27.4 min (95% CI: 18.2-80.0) at similar concentration. LD50and LD95values (for 60 min standard exposure) were 0.0006 % (95% CI: 0.00-0.001) and 0.034% (95% CI: 0.013-0.49) respectively forP. americana, while these values were 0.0005 (95% CI: 0.00-0.001) and 0.04 (95% CI: 0.01-0.23) forB. germanica. Exposure to 1% deltamethrin induced considerable toxic effect in the epithelial cells in the midgut. HPLC estimated 0.21±0.05 mg (95% CI - 0.18-0.25; CoV 23.9%) deltamethrin inP. americanapost 1% exposure. Even short term exposure of low concentration of synthetic pyrethroid deltamethrin displayed immediate knockdown and delayed mortality in both the test species. Considerable histological damage was observed in both the insects at 1% exposure. In India, resistance to deltamethrin may have been reported among different insects due its extensive use, however the formulations such as insecticide paints, attractant baits etc. developed using deltamethrin as active ingredient could be useful in cockroach control operations.
The war of corals: patterns, drivers, and implications of changing coral competitive performances across reef environments
Authors: Kayal Mohsen , Adjeroud Mehdi 
Published: December 2021

AbstractAmidst global environmental changes, predicting species responses to future environments is a critical challenge for preserving biodiversity and associated human benefits. We explored the original idea that coral competitive performances, the ability of corals to preempt ecological space on the reef through territorial warfare, serve as indicators of species’ ecological niches and environmental windows, and therefore, responses to future environments. Our surveys indicated that coral performances varied with taxonomic-identity, size, and position along environmental gradients, highlighting complex interplays between life-history, warfare-strategy, and niche segregation. Our results forewarn that growing alterations of coastal environments may trigger shifts in coral dominance, with decline of major reef-building taxa like acroporids, and underscore the importance of restraining human impacts for coastal resilience. Our empirical approach untangles the complexity of species’ battle-like interactions and can help identify winners and losers in various communities caught in the interplay between ecological niches, environmental windows, and global changes.
Tubulinopathy mutations in TUBA1A that disrupt neuronal morphogenesis and migration override XMAP215/Stu2 regulation of microtubule dynamics
Authors: Hoff Katelyn J. , Aiken Jayne E. , Gutierrez Mark A. , Franco Santos J. , Moore Jeffrey K. 
Published: December 2021

ABSTRACTHeterozygous, missense mutations in α- or β-tubulin genes are associated with a wide range of human brain malformations, known as tubulinopathies. We seek to understand whether a mutation’s impact at the molecular and cellular levels scale with the severity of brain malformation. Here we focus on two mutations at the valine 409 residue of TUBA1A, V409I and V409A, identified in patients with pachygyria or lissencephaly, respectively. We find that ectopic expression of TUBA1A-V409I/A mutants disrupt neuronal migration in mice and promote excessive neurite branching and delayed retraction in primary neuronal cultures, accompanied by increased microtubule acetylation. To determine the molecular mechanisms, we modeled the V409I/A mutants in budding yeast and found that they promote intrinsically faster microtubule polymerization rates in cells and in reconstitution experiments with purified tubulin. In addition, V409I/A mutants decrease the recruitment of XMAP215/Stu2 to plus ends and ablate tubulin binding to TOG domains. In each assay tested, the TUBA1A-V409I mutant exhibits an intermediate phenotype between wild type and the more severe TUBA1A-V409A, reflecting the severity observed in brain malformations. Together, our data support a model in which the V409I/A mutations may limit tubulin conformational states and thereby disrupt microtubule regulation during neuronal morphogenesis and migration.