bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dysfunction of transfer RNA modifications in inflammatory bowel disease
Authors: Zhang Jilei , Zhang Yongguo , Xia Yinglin , Sun Jun 
Published: May 2022

AbstractBackgrounds and aimsTransfer RNA (tRNA) is the most extensively modified RNA in cells. Queuosine (Q)-modification is a fundamental process for fidelity and efficiency of translation from RNA to proteins. In eukaryotes, tRNA-Q-modification relies on the intestinal microbial product queuine. However, the roles and potential mechanisms of Q-tRNA modifications in IBD are unknown.MethodsWe explored the Q-tRNA modifications and expression of Q tRNA ribosyltransferase catalytic subunit 1 (QTRT1) in patients with IBD by investigating human biopsies and reanalyzing datasets. We used colitis models, organoids, and cultured cells for loss- and gain-of-function studies to investigate the molecular mechanisms of Q-tRNA modifications in intestinal inflammation.ResultsQTRT1 expression was significantly downregulated in ulcerative colitis and Crohn’s disease patients. The four Q-tRNA-related tRNA synthetases (asparaginyl-aspartyl-, histidyl-, and tyrosyl-tRNA synthetase) were decreased in IBD patients. This reduction was further confirmed in DSS-induced colitis and IL10-deficient mice. Reduced QTRT1 was significantly correlated with cell proliferation and intestinal junctions, including downregulated β-catenin and Claudin-5 and upregulated Claudin-2. These alterations were confirmed in vitro by deleting QTRT1 from cells. Queuine treatment significantly enhanced cell proliferation and junction functions in cell lines and human colonoids. Queuine treatment also reduced inflammation in epithelial cells. Moreover, altered QTRT1-related metabolites were found in human IBD.ConclusiontRNA modifications play an unexplored novel role in the pathogenesis of intestinal inflammation by altering epithelial proliferation and junctions. Investigations on tRNA modification will uncover novel molecular mechanisms for potential prevention and therapy for IBD.
A 512-ch dual-mode microchip for simultaneous measurements of electrophysiological and neurochemical activities
Authors: Mulberry Geoffrey , White Kevin A. , Kim Brian N. 
Published: May 2022

AbstractIn the study of the brain, large and high-density microelectrode arrays have been widely used to study the behavior of neurotransmission. CMOS technology has facilitated these devices by enabling the integration of high-performance amplifiers directly on-chip. Usually, these large arrays measure only the voltage spikes resulting from action potentials traveling along firing neuronal cells. However, at synapses, communication between neurons occurs by the release of neurotransmitters, which cannot be measured on typical CMOS electrophysiology devices. Development of electrochemical amplifiers has resulted in the measurement of neurotransmitter exocytosis down to the level of a single vesicle. To effectively monitor the complete picture of neurotransmission, measurement of both action potentials and neurotransmitter activity is needed. Current efforts have not resulted in a device that is capable of the simultaneous measurement of action potential and neurotransmitter release at the same spatiotemporal resolution needed for a comprehensive study of neurotransmission. In this paper, we present a true dual-mode CMOS device that fully integrates 256-ch electrophysiology amplifiers and 256-ch electrochemical amplifiers, along with an on-chip 512 electrode microelectrode array capable of simultaneous measurement from all 512 channels. Electrochemical amplifiers achieve a noise level of 4.51 pARMS with a bandwidth of 10.3 kHz. Electrophysiology amplifiers exhibit 24.9 μVRMS noise in the action potential band and a total usable bandwidth from 0.2 Hz to 10 kHz.
Precision motor timing via scalar input fluctuations
Authors: Pang Rich , Duffy Alison , Bell David , Torok Zsofia , Fairhall Adrienne 
Published: May 2022

Complex motor skills like playing piano require precise timing over long periods, without errors accumulating between subprocesses like the left and right hand movements. While biological models can produce motor-like sequences, how the brain quenches timing errors is not well understood. Motivated by songbirds, where the left and right brain nuclei governing song sequences do not connect but may receive low-dimensional thalamic input, we present a model where timing errors in an autonomous sequence generator are continually corrected by one-dimensional input fluctuations. We show in a spiking neural network model how such input can rapidly correct temporal offsets in a propagating spike pulse, recapitulating the precise timing seen in songbird brains. In a reduced, more general model, we show that such timing correction emerges when the spatial profile of the input over the sequence sufficiently reflects its temporal fluctuations, yielding time-locking attractors that slow advanced sequences and hasten lagging ones, up to the input timescale. Unlike models without fluctuating input, our model predicts anti-correlated durations of adjacent segments of the output sequence, which we verify in recorded zebra finch songs. This work provides a bioplausible picture of how temporal precision could arise in extended motor sequences and generally how low-dimensional input could continuously coordinate time-varying output signals.SignificanceComplex motor skills like playing piano require precision timing over long periods, often among multiple components like left and right muscle groups. Although brain-like network models can produce motor-like outputs, timing regulation is not well understood. We introduce a model, inspired by songbird brains, where imprecise timing in a cortical-like system is corrected by a single thalamic input regulating the sequential propagation, or tempo, of cortical activity. This model illuminates a relation between the input’s spatial structure and temporal variation that lets lagging activity hasten and advanced activity slow, which makes a prediction about output timing that we verify in real birdsong. This work reveals a simple, neuroplausible mechanism that may play a role in precision cortical or motor timing.
Dynamic Structure Of Motor Cortical Neuron Co-Activity Carries Behaviorally Relevant Information
Authors: Sundiang Marina , Hatsopoulos Nicholas G. , MacLean Jason N. 
Published: May 2022

SUMMARYSkillful, voluntary movements are underpinned by computations performed by networks of interconnected neurons in the primary motor cortex (M1). Computations are reflected by patterns of co-activity between neurons. Using spike time correlations, co-activity can be represented as functional networks (FNs). Here, we show that the structure of FNs constructed from instructed-delay reach trials in non-human primates are behaviorally specific: low dimensional embedding and graph alignment scores show that FNs constructed from closer target reach distances are also closer in network space. We next constructed temporal FNs using short intervals across a trial. We find that temporal FNs traverse a low-dimensional subspace in a reach-specific trajectory. Alignment scores show that FNs become separable and correspondingly, decodable shortly after the instruction cue. Finally, we observe that reciprocal connections in FNs transiently decrease following the instruction cue, suggesting the network momentarily switches from a recurrent system to one that is more feedforward.
Heterogeneity in killing efficacy of individual effector CD8+ T cells against Plasmodium liver stages
Authors: Bera Soumen , Amino Rogerio , Cockburn Ian A. , Ganusov Vitaly V. 
Published: May 2022

AbstractVaccination strategies in mice inducing high numbers of memory CD8+ T cells specific to a single epitope are able to provide sterilizing protection against infection with Plasmodium sporozoites. We have recently found that Plasmodium-specific CD8+ T cells cluster around sporozoite-infected hepatocytes but whether such clusters are important in elimination of the parasite remains incompletely understood. Here we used our previously generated data in which we employed intravital microscopy to longitudinally image 32 GFP-expressing Plasmodium yoelii parasites in livers of mice that had received activated Plasmodium-specific CD8+ T cells after sporozoite infection. We found significant heterogeneity in the dynamics of the normalized GFP signal from the parasites (termed “vitality index” or VI) that was weakly correlated with the number of T cells near the parasite. We also found that a simple model assuming mass-action, additive killing by T cells well describes the VI dynamics for most parasites and predicts a highly variable killing efficacy by individual T cells. Given our estimated median per capita kill rate ofk= 0.031/h we predict that a single T cell is typically incapable to kill a parasite within the 48 hour lifespan of the liver stage in mice. Stochastic simulations of T cell clustering and killing of the liver stage also suggested that 1) three or more T cells per infected hepatocyte are required to ensure sterilizing protection; 2) both variability in killing efficacy of individual T cells and resistance to killing by individual parasites may contribute to the observed variability in VI decline, and 3) the stable VI of some clustered parasites cannot be explained by measurement noise. Taken together, our analysis for the first time provides estimates of efficiency at which individual CD8+ T cells eliminate intracellular parasitic infection in vivo.
Chemoproteomics-Enabled Discovery of a Covalent Molecular Glue Degrader Targeting NF-κB
Authors: King Elizabeth A. , Cho Yoojin , Dovala Dustin , McKenna Jeffrey M. , Tallarico John A. , Schirle Markus , Nomura Daniel K. 
Published: May 2022

AbstractTargeted protein degradation using heterobifunctional Proteolysis-Targeting Chimeras (PROTACs) or molecular glues has arisen as a powerful therapeutic modality for degrading disease targets. While PROTAC design is becoming more modular and straightforward, the discovery of novel molecular glue degraders has been more challenging. While several recent studies have showcased phenotypic screening and counter-screening approaches to discover new molecular glue degraders, mechanistically elucidating the ternary complex induced by the small-molecule that led to the initial phenotype—i.e. identifying the degraded target and relevant components of the ubiquitin-proteasome system—has remained cumbersome and laborious. To overcome these obstacles, we have coupled the screening of a covalent ligand library for anti-proliferative effects in leukemia cells with quantitative proteomic and chemoproteomic approaches to rapidly discover both novel covalent molecular glue degraders and their associated ternary complex components and anti-proliferative mechanisms. We have identified a cysteine-reactive covalent ligand EN450 that impairs leukemia cell viability in a NEDDylation and proteasome-dependent manner. Chemoproteomic profiling revealed covalent interaction of EN450 with an allosteric C111 in the E2 ubiquitin ligase UBE2D. Follow-up quantitative proteomic profiling revealed the proteasome-mediated degradation of the oncogenic transcription factor NFKB1 as a putative degradation target. Subsequent validation studies demonstrated that EN450 induced the ternary complex formation between UBE2D and NFKB1 and that both UBE2D and NFKB1 were important for the anti-proliferative mechanisms of EN450. Our study thus puts forth the discovery of a novel molecular glue degrader that uniquely induced the proximity of an E2 ligase with a transcription factor to induce its degradation and anti-proliferative effects in cancer cells. Taken more broadly, our study showcases a rapid and modular approach for discovering novel covalent molecular glue degraders and their respective ternary complex components in an unbiased fashion.
Allosteric Inhibition of PTP1B by a Nonpolar Terpenoid
Authors: Friedman Anika J. , Liechty Evan T. , Kramer Levi , Sarkar Ankur , Fox Jerome M. , Shirts Michael R. 
Published: May 2022

AbstractProtein tyrosine phosphatases (PTPs) are promising drug targets for treating a wide range of diseases such as diabetes, cancer, and neurological disorders, but their conserved active sites have complicated the design of selective therapeutics. This study examines the allosteric inhibition of PTP1B by amorphadiene (AD), a terpenoid hydrocarbon that is an unusually selective inhibitor. Molecular dynamics (MD) simulations carried out in this study suggest that AD can stably sample multiple neighboring sites on the allosterically influential C-terminus of the catalytic domain. Binding to these sites requires a disordered α7 helix, which stabilizes the PTP1B-AD complex and may contribute to the selectivity of AD for PTP1B over TCPTP. Intriguingly, the binding mode of AD differs from that of the most well-studied allosteric inhibitor of PTP1B. Indeed, biophysical measurements and MD simulations indicate that the two molecules can bind simultaneously. Upon binding, both inhibitors destabilize the α7 helix and disrupt hydrogen bonds that facilitate closure of the catalytically essential WPD loop. These findings indicate that AD is a promising scaffold for building allosteric inhibitors of PTP1B and illustrate, more broadly, how unfunctionalized terpenoids can engage in specific interactions with protein surfaces.
Brain-muscle connectivity during gait: corticomuscular coherence as quantification of the cognitive reserve
Authors: Caffi L. , Boccia S. , Longatelli V. , Guanziroli E. , Molteni F. , Pedrocchi A. 
Published: May 2022

AbstractA detailed comprehension of the central and peripheral processes underlying walking is essential to develop effective therapeutic interventions to slow down gait decline with age, and rehabilitation strategies to maximize motor recovery for patients with damages at the central nervous system. The combined use of electromyography (EMG) and electroencephalography (EEG), in the framework of coherence analysis, has recently established for neuromotor integrity/impairment assessment. In this study, we propose corticomuscular (EEG-EMG) and inter/intramuscular (EMG-EMG) coherences as measures of the cognitive reserve, i.e., the process whereby a wider repertoire of cognitive strategies, as well as more flexible and efficient strategies, can moderate the manifestation of brain disease/damage. We recorded EEG signals from the main brain source locations and superficial EMG signals from the main leg muscles involved in gait in 16 healthy young adults (age ≤30 years) and 13 healthy elderly (age ≥65 years) during three different overground walking conditions (i.e., spontaneous walking, walking with cognitive dual-task, and walking with targets drawn on the floor). In all conditions, we calculated corticomuscular and inter/intramuscular coherences. We observed higher corticomuscular and inter/intramuscular coherences during targeted walking compared to spontaneous walking in both groups, even if the increase was greater in young people. Considering dual-task walking compared to spontaneous walking, only corticomuscular coherence in the elderly increased. These results suggest age-related differences in cognitive reserve that reflect different abilities to perform complex cognitive or motor tasks during gait. This study demonstrates the feasibility, repeatability, and effectiveness of the proposed method to investigate brain-to-muscle connectivity during different gait conditions, to study the related changes with age, and to quantify the cognitive reserve.
Spatiotemporal dynamics of membrane surface charge regulates cell polarity and migration
Authors: Banerjee Tatsat , Biswas Debojyoti , Pal Dhiman Sankar , Miao Yuchuan , Iglesias Pablo A. , Devreotes Peter N. 
Published: May 2022

ABSTRACTDuring cell migration and polarization, hundreds of signal transduction and cytoskeletal components self-organize to generate localized protrusions. Although biochemical and genetic analyses have delineated many specific interactions, how the activation and localization of so many different molecules are spatiotemporally orchestrated at the subcellular level has remained unclear. Here we show that the regulation of negative surface charge on the inner leaflet of the plasma membrane plays an integrative role in the molecular interactions. Surface charge, or zeta potential, is transiently lowered at new protrusions and within cortical waves of Ras/PI3K/TORC2/F-actin network activation. Rapid alterations of inner leaflet anionic phospholipids, such as PI(4,5)P2, PI(3,4)P2, phosphatidylserine, and phosphatidic acid, collectively contribute to the surface charge changes. Abruptly reducing the surface charge by recruiting positively charged optogenetic actuators was sufficient to trigger the entire biochemical network, initiate de novo protrusions, and abrogate pre-existing polarity. These effects were blocked by genetic or pharmacological inhibitions of key signaling components such as Akt and PI3K/TORC2. Conversely, increasing the negative surface deactivated the network and locally suppressed chemoattractant-induced protrusions or subverted EGF-induced ERK activation. Computational simulations involving excitable biochemical networks demonstrated that slight changes in feedback loops, induced by recruitment of the actuators, could lead to outsized effects on system activation. We propose that key signaling network components act on, and are in turn acted upon, by surface charge, closing feedback loops which bring about the global-scale molecular self-organization required for spontaneous protrusion formation, cell migration, and polarity establishment.
Comprehensive analysis of the effect of mRNA sequences on translation efficiency and accuracy
Authors: Umemoto S. , Kondo T. , Fujino T. , Hayashi G. , Murakami H. 
Published: May 2022

AbstractMessenger ribonucleic acid (mRNA) sequences influence the translation efficiency and accuracy. To increase our knowledge of how mRNA sequences affect ribosome translation and apply the obtained information to improve the mRNA display method, we conducted a comprehensive analysis of the effect of mRNA sequences on the translation. Translation efficiency depended strongly on the three codons following the start codon. Furthermore, the codons at the ribosomal E- and P-sites strongly influence the misreading of the A-site blank codon by near-cognate transfer RNA. The purine base after the blank codon also induced a higher misread rate than that with a pyrimidine base. Based on these findings, we demonstrated construction of highly diverse monobody and macrocyclic peptide libraries that would be useful in developing functional peptides and proteins in the future.
Spatiotemporal organization of human sensorimotor beta burst activity
Authors: Zich Catharina , Quinn Andrew J , Bonaiuto James J , O’Neill George , Mardell Lydia C , Ward Nick S , Bestmann Sven 
Published: May 2022

AbstractBeta oscillations in human sensorimotor cortex are hallmark signatures of healthy and pathological movement. In single trials, beta oscillations include bursts of intermittent, transient periods of high-power activity. These burst events have been linked to a range of sensory and motor processes, but their precise spatial, spectral, and temporal structure remains unclear. Specifically, a role for beta burst activity in information coding and communication suggests spatiotemporal patterns, or travelling wave activity, along specific anatomical gradients. We here show in human magnetoencephalography recordings that burst activity in sensorimotor cortex occurs in planar spatiotemporal wave-like patterns that dominate along two axes either parallel or perpendicular to the central sulcus. Moreover, we find that the two propagation directions are characterised by distinct anatomical and physiological features. Finally, our results suggest that sensorimotor beta bursts occurring before and after a movement share the same generator but can be distinguished by their anatomical, spectral and spatiotemporal characteristics, indicating distinct functional roles.
Lipopolysaccharide synthesis and traffic in the envelope of the pathogen Brucella abortus
Authors: Servais Caroline , Vassen Victoria , Verhaeghe Audrey , Küster Nina , Carlier Elodie , Phégnon Léa , Mayard Aurélie , De Bolle Xavier 
Published: May 2022

AbstractLipopolysaccharide is essential for most Gram-negative bacteria as it is a main component of the outer membrane. In the pathogen Brucella abortus, smooth lipopolysaccharide containing the O-antigen is required for virulence. Being part of the Rhizobiales, Brucella spp. display unipolar growth and lipopolysaccharide was shown to be incorporated at the active growth sites, i.e. the new pole and the division site. By localizing proteins involved in the lipopolysaccharide transport across the cell envelope, from the inner to the outer membrane, we show that the lipopolysaccharide incorporation sites are determined by the inner membrane complex of the lipopolysaccharide transport system. Moreover, we identify the main O-antigen ligase of Brucella spp involved in smooth lipopolysaccharide synthesis. Altogether, our data highlight a new layer of spatiotemporal organization of the lipopolysaccharide biosynthesis pathway and identify a new class of bifunctional O-antigen ligases.
Oriented evening flight behaviour in the Bogong moth revealed through automated video tracking
Authors: Wallace Jesse R A , Dreyer David , Zeil Jochen , Warrant Eric J 
Published: May 2022

AbstractDuring their period of summer dormancy, Australian Bogong mothsAgrotis infusaundertake seemingly random evening flights, filling the air with densities in the dozens per cubic metre. The purpose of these flights is unknown, but they may serve an important role in Bogong moth navigation, which remarkably enables them to return to the same exact summer sites— generation after generation—after migrating around 1000 km, and with no opportunity to learn their route or destination from prior generations. The recent development of the camera-based insect monitoring method, Camfi, enables quantitative observations of Bogong moth behaviour at an unprecedented scale. To gain a better understanding of the summer evening flights of Bogong moths, we have extended Camfi to facilitate automated video tracking of flying insects, taking the already-high throughput of the method to a new level. We used this new method to record the evening flight behaviour of Bogong moths in two elevational transects below the summit of Mt. Kosciuszko, NSW, on a single night in February 2021, and found that these flights were not random, but were systematically oriented in directions relative to the azimuth of the summit of the mountain. These results stimulate interesting and plausible hypotheses relating to previously unexplained summer evening flight behaviour of Bogong moths, and the mechanisms of their long-distance navigation.