bluuebunny/crossref_metadata_2025_split huggingface dataset:
Online Reference Trajectory Adaptation: A Personalized Control Strategy for Lower Limb Exoskeletons
Authors: Shushtari Mohammad , Nasiri Rezvan , Arami Arash 
Published: June 2021

AbstractThis paper presents a novel method for reference trajectory adaptation in lower limb rehabilitation exoskeletons during walking. Our adaptation rule is extracted from a cost function that penalizes both interaction force and trajectory modification. By adding trajectory modification term into the cost function, we restrict the boundaries of the reference trajectory adaptation according to the patient’s motor capacity. The performance of the proposed adaptation method is studied analytically in terms of convergence and optimality. We also developed a realistic dynamic walking simulator and utilized it in performance analysis of the presented method. The proposed trajectory adaptation technique guarantees convergence to a stable, reliable, and rhythmic reference trajectory with no prior knowledge about the human intended motion. Our simulations demonstrate the convergence of exoskeleton trajectories to those of simulated healthy subjects while the exoskeleton trajectories adapt less to the trajectories of patients with reduced motor capacity (less reliable trajectories). Furthermore, the gait stability and spatiotemporal parameters such as step time symmetry and minimum toe off clearance enhanced by the adaptation in all subjects. The presented mathematical analysis and simulation results show the applicability and effectiveness of the proposed method and its potential to be applied for trajectory adaptation in lower limb rehabilitation exoskeletons.
Power spectrum slope confounds estimation of instantaneous oscillatory frequency
Authors: Samaha Jason , Cohen Michael X 
Published: June 2021

AbstractOscillatory neural dynamics are highly non-stationary and require methods capable of quantifying time-resolved changes in rhythmic activity in order to understand neural function. Recently, a method termed ‘frequency sliding’ was introduced to estimate the instantaneous frequency of oscillatory activity, providing a means of tracking temporal changes in the dominant frequency within a sub-band of field potential recordings. Here, the ability of frequency sliding to recover ground-truth oscillatory frequency in simulated data is tested while the exponent (slope) of the 1/fxcomponent of the signal power spectrum is systematically varied, mimicking real electrophysiological data. The results show that 1) in the presence of 1/factivity, frequency sliding systematically underestimates the true frequency of the signal, 2) the magnitude of underestimation is correlated with the steepness of the slope, suggesting that, if unaccounted for, slope changes could be misinterpreted as frequency changes, 3) the impact of slope on frequency estimates interacts with oscillation amplitude, indicating that changes in oscillation amplitude alone may also influence instantaneous frequency estimates in the presence of strong 1/factivity; and 4) analysis parameters such as filter bandwidth and location also mediate the influence of slope on estimated frequency, indicating that these settings should be considered when interpreting estimates obtained via frequency sliding. The origin of these biases resides in the output of the filtering step of frequency sliding, whose energy is biased towards lower frequencies precisely because of the 1/fstructure of the data. We discuss several strategies to mitigate these biases and provide a proof-of-principle for a 1/f normalization strategy.
Targeting riboswitches with synthetic small RNAs for metabolic engineering
Authors: da Costa Ribeiro Lins Milca Rachel , da Silva Amorim Laura Araujo , Correa Graciely Gomes , Picão Bruno Willian , Mack Matthias , Cerri Marcel Otávio , Pedrolli Danielle Biscaro 
Published: June 2021

AbstractOur growing knowledge of the diversity of non-coding RNAs in natural systems and our deepening knowledge of RNA folding and function have fomented the rational design of RNA regulators. Based on that knowledge, we designed and implemented a small RNA (sRNA) tool to target bacterial riboswitches and activate gene expression. The synthetic sRNA is suitable for regulation of gene expression both in cell-free and in cellular systems. It targets riboswitches to promote the antitermination folding regardless the cognate metabolite concentration. Therefore, it prevents transcription termination increasing gene expression up to 103-fold. We successfully used sRNA arrays for multiplex targeting of riboswitches. Finally, we used the synthetic sRNA to engineer an improved riboflavin producer strain. The easiness to design and construct, and the fact that the riboswitch-targeting sRNA works as a single genome copy, make it an attractive tool for engineering industrial metabolite-producing strains.Graphical Abstract
Genomics analysis ofDrosophila sechelliaresponse toMorinda citrifoliafruit diet
Authors: Drum Z.A. , Lanno S.M. , Gregory S.M. , Shimshak  , Barr W. , Gatesman A. , Schadt M. , Sanford J. , Arkin A. , Assignon B. , Colorado S. , Dalgarno C. , Devanny T. , Ghandour T. , Griffin R. , Hogan M. , Horowitz E. , McGhie E. , Multer J. , O’Halloran H. , Ofori-Darko K. , Pokushalov D. , Richards N. , Sagarin K. , Taylor N. , Thielking A. , Towle P. , Coolon J. D. 
Published: June 2021

AbstractDrosophila sechelliais an island endemic host specialist that has evolved to consume the toxic fruit ofMorinda citrifolia, also known as noni fruit. Recent studies by our group and others have examined genome-wide gene expression responses of fruit flies to individual highly abundant compounds found in noni responsible for the fruit’s unique chemistry and toxicity. In order to relate these reductionist experiments to the gene expression responses to feeding on noni fruit itself, we fed rotten noni fruit to adult femaleD. sechelliaand performed RNA-sequencing. Combining the reductionist and more wholistic approaches, we have identified candidate genes that may contribute to each individual compound and those that play a more general role in response to the fruit as a whole. Using the compound specific and general responses, we used transcription factor prediction analyses to identify the regulatory networks and specific regulators involved in the responses to each compound and the fruit itself. The identified genes and regulators represent the possible genetic mechanisms and biochemical pathways that contribute to toxin resistance and noni specialization inD. sechellia.
Essential role for Ggct in erythrocyte antioxidant defense
Authors: He Zaoke , Sun Xiaoqin , Wang Shixiang , Bai Dongsheng , Zhao Xiangyu , Han Ying , Hao Piliang , Liu Xue-Song 
Published: June 2021

AbstractGGCT encodes γ-glutamyl cyclotransferase enzyme activity, and its expression is up-regulated in various human cancers. γ-glutamyl cyclotransferase enzyme activity was originally purified from human red blood cells (RBCs), however physiological function of GGCT in RBCs is still not clear. Here we reported that Ggct deletion in mouse leads to splenomegaly and progressive anemia phenotypes, due to elevated oxidative damage and shortened life span of Ggct−/− RBCs. Ggct−/− RBCs have increased reactive oxygen species (ROS), and are more sensitive to H2O2 induced damage compared to control RBCs. Glutathione (GSH) and GSH synthesis precursor L-cysteine are decreased in Ggct−/− RBCs. Our study suggests a critical function of Ggct in RBC redox balance and life span maintenance through regulating GSH metabolism.
GABAA and NMDA receptor density alterations and their behavioral correlates in the gestational methylazoxymethanol acetate model for schizophrenia
Authors: Kiemes Amanda , Gomes Felipe V. , Cash Diana , Uliana Daniela L. , Simmons Camilla , Singh Nisha , Vernon Anthony C. , Turkheimer Federico , Davies Cathy , Stone James M. , Grace Anthony A. , Modinos Gemma 
Published: June 2021

AbstractHippocampal hyperactivity driven by GABAergic interneuron deficits and NMDA receptor hypofunction is associated with the hyperdopaminergic state often observed in schizophrenia. Furthermore, previous research in the methylazoxymethanol acetate (MAM) rat model has demonstrated that repeated peripubertal diazepam administration can prevent the emergence of adult hippocampal hyperactivity, dopamine system hyperactivity, and associated psychosis-relevant behaviors. Here, we sought to characterize hippocampal GABAA and NMDA receptors in MAM-treated rats and to elucidate the receptor mechanisms underlying the promising effects of peripubertal diazepam exposure. Quantitative receptor autoradiography was used to measure receptor density in dorsal hippocampus CA1, ventral hippocampus CA1, and in ventral subiculum. Specifically, [3H]-Ro15-4513 was used to quantify the density of α5 GABAA receptors (α5GABAAR), [3H]-flumazenil to quantify α1-3;5GABAAR, and [3H]-MK801 to quantify NMDA receptors. MAM rats exhibited anxiety and schizophrenia-relevant behaviors as measured by elevated plus maze and amphetamine-induced hyperlocomotion (AIH), although diazepam only partially rescued these behaviors. α5GABAAR density was reduced in MAM-treated rats in all hippocampal sub-regions, and negatively correlated with AIH. Ventral hippocampus CA1 α5GABAAR density was positively correlated with anxiety-like behavior. Dorsal hippocampus CA1 NMDA receptor density was increased in MAM-treated rats, and positively correlated with AIH. [3H]-Flumazenil revealed no significant effects. Finally, we found no significant effect of diazepam treatment on receptor densities, potentially related to the only partial rescue of schizophrenia-relevant phenotypes. Overall, our findings provide first evidence of α5GABAAR and NMDA receptor abnormalities in the MAM model, suggesting that more selective pharmacological agents may become a novel therapeutic mechanism in schizophrenia.
Kinetic pathways of water exchange in the first hydration shell of magnesium: Influence of water model and ionic force field
Authors: Falkner Sebastian , Schwierz Nadine 
Published: June 2021

AbstractWater exchange between the first and second hydration shell is essential for the role of Mg2+ in biochemical processes. In order to provide microscopic insights into the exchange mechanism, we resolve the exchange pathways by all-atom molecular dynamics simulations and transition path sampling. Since the exchange kinetics relies on the choice of the water model and the ionic force field, we systematically investigate the influence of seven different polarizable and non-polarizable water and three different Mg2+ models. In all cases, water exchange can occur either via an indirect or direct mechanism (exchanging molecules occupy different/same position on water octahedron). In addition, the results reveal a crossover from an interchange dissociative (Id) to an associative (Ia) reaction mechanism dependent on the range of the Mg2+-water interaction potential of the respective force field. Standard non-polarizable force fields follow the Id mechanism in agreement with experimental results. By contrast, polarizable and long-ranged non-polarizable force fields follow the Ia mechanism. Our results provide a comprehensive view on the influence of the water model and ionic force field on the exchange dynamics and the foundation to assess the choice of the force field in biomolecular simulations.
Impaired succinate oxidation prevents growth and influences drug susceptibility in Mycobacterium tuberculosis
Authors: Adolph Cara , McNeil Matthew B. , Cook Gregory M. 
Published: June 2021

AbstractSuccinate is a major focal point in mycobacterial metabolism and respiration, serving as both an intermediate of the TCA cycle and a direct electron donor for the respiratory chain. Mycobacterium tuberculosis encodes multiple enzymes predicted to be capable of catalyzing the oxidation of succinate to fumarate, including two different succinate dehydrogenases (Sdh1 and Sdh2) and a separate fumarate reductase (Frd) with possible bi-directional behavior. Previous attempts to investigate the essentiality of succinate oxidation in M. tuberculosis have relied on the use of single-gene deletion mutants, raising the possibility that the remaining enzymes could catalyze succinate oxidation in the absence of the other. To address this, we report on the use of mycobacterial CRISPR interference (CRISPRi) to construct single, double, and triple transcriptional knockdowns of sdhA1, sdhA2, and frdA in M. tuberculosis. We show that the simultaneous knockdown of sdhA1 + sdhA2 is required to prevent succinate oxidation and overcome the functional redundancy within these enzymes. Succinate oxidation was demonstrated to be essential for the optimal growth of M. tuberculosis, with the combined knockdown of sdhA1 + sdhA2 significantly impairing the activity of the respiratory chain and preventing growth on a range of carbon sources. Moreover, impaired succinate oxidation was shown to influence the activity of several antitubercular drugs against M. tuberculosis, including potentiating the activity of bioenergetic inhibitors and attenuating the activity of cell wall inhibitors. Together, these data provide fundamental insights into mycobacterial physiology, energy metabolism, and antimicrobial susceptibility.ImportanceNew drugs are urgently required to combat the tuberculosis epidemic that claims 1.5 million lives annually. Inhibitors of mycobacterial energy metabolism have shown significant promise clinically; however, further advancing this nascent target space requires a more fundamental understanding of the respiratory enzymes and pathways used by Mycobacterium tuberculosis. Succinate is a major focal point in mycobacterial metabolism and respiration; yet the essentiality of succinate oxidation, and the consequences of inhibiting this process, are poorly defined. In this study, we demonstrate that impaired succinate oxidation prevents the optimal growth of M. tuberculosis on a range of carbon sources and significantly reduces the activity of the electron transport chain. Moreover, we show that impaired succinate oxidation both positively and negatively influences the activity of a variety of anti-tuberculosis drugs. Combined, these findings provide fundamental insights into mycobacterial physiology and drug susceptibility that will be useful in the continued development of bioenergetic inhibitors.
Pickering stabilization of a dynamic intracellular emulsion
Authors: Folkmann Andrew W. , Putnam Andrea , Lee Chiu Fan , Seydoux Geraldine 
Published: June 2021

AbstractBiomolecular condensates are cellular compartments that form by phase separation in the absence of limiting membranes. Studying the P granules of C. elegans, we find that condensate dynamics are regulated by protein clusters that adsorb to the condensate interface. Using in vitro reconstitution, live observations and theory, we demonstrate that localized assembly of P granules is controlled by MEG-3, an intrinsically disordered protein that forms low dynamic assemblies on P granules. Following classic Pickering emulsion theory, MEG-3 clusters lower surface tension and slow down coarsening. During zygote polarization, MEG-3 recruits DYRK/MBK-2 kinase to accelerate localized growth of the P granule emulsion. By tuning condensate-cytoplasm exchange, interfacial clusters regulate the structural integrity of biomolecular condensates, reminiscent of the role of lipid bilayers in membrane-bound organelles.One Sentence SummaryBiomolecular condensates are stabilized by interfacial nanoscale protein clusters.
A mechanistic density functional theory for ecology across scales
Authors: Trappe Martin-I. , Chisholm Ryan A. 
Published: June 2021

SummaryOur ability to predict the properties of a system typically diminishes as the number of its interacting constituents rises. This poses major challenges for understanding natural ecosystems, and humanity’s effects on them. How do macroecological patterns emerge from the interplay between species and their environment? What is the impact on complex ecological systems of human interventions, such as extermination of large predators, deforestation, and climate change? The resolution of such questions is hampered in part by the lack of a holistic approach that unifies ecology across temporal and spatial scales. Here we use density functional theory, a computational method for many-body problems in physics, to develop a novel computational framework for ecosystem modelling. Our methods accurately fit experimental and synthetic data of interacting multi-species communities across spatial scales and can project to unseen data. Our mechanistic framework provides a promising new avenue for understanding how ecosystems operate and facilitates quantitative assessment of interventions.
Task complexity temporally extends the causal requirement for visual cortex in perception
Authors: Oude Lohuis Matthijs N. , Pie Jean L. , Marchesi Pietro , Montijn Jorrit S. , de Kock Christiaan P.J. , Pennartz Cyriel M. A. , Olcese Umberto 
Published: June 2021

AbstractThe transformation of sensory inputs into behavioral outputs is characterized by an interplay between feedforward and feedback operations in cortical hierarchies. Even in simple sensorimotor transformations, recurrent processing is often expressed in primary cortices in a late phase of the cortical response to sensory stimuli. This late phase is engaged by attention and stimulus complexity, and also encodes sensory-independent factors, including movement and report-related variables. However, despite its pervasiveness, the nature and function of late activity in perceptual decision-making remain unclear. We tested whether the function of late activity depends on the complexity of a sensory change-detection task. Complexity was based on increasing processing requirements for the same sensory stimuli. We found that the temporal window in which V1 is necessary for perceptual decision-making was extended when we increased task complexity, independently of the presented visual stimulus. This window overlapped with the emergence of report-related activity and decreased noise correlations in V1. The onset of these co-occurring activity patterns was time-locked to and preceded reaction time, and predicted the reduction in behavioral performance obtained by optogenetically silencing late V1 activity (>200 ms after stimulus onset), a result confirmed by a second multisensory task with different requirements. Thus, although early visual response components encode all sensory information necessary to solve the task, V1 is not simply relaying information to higher-order areas transforming it into behavioral responses. Rather, task complexity determines the temporal extension of a loop of recurrent activity, which overlaps with report-related activity and determines how perceptual decisions are built.
Known mechanisms cannot account for at least one third of reduced susceptibility in a diverse collection of non-aureusstaphylococci
Authors: Felgate Heather , Crossman Lisa C. , Gray Elizabeth , Clifford Rebecca , Wain John , Langridge Gemma C. 
Published: June 2021

AbstractIntroductionNon-aureusstaphylococci (NAS) are implicated in many healthcare-acquired infections and an understanding of the genetics of antimicrobial resistance in NAS is important in relation to both clinical intervention and the role of NAS as a reservoir of resistance genes.Gap statementThe burden of antimicrobial resistance in NAS, particularly to clinically relevant antimicrobials, is under recognised.MethodologyWe sourced 394 NAS isolates from clinical samples, healthy human volunteers, animals and type cultures and subjected them to agar dilution susceptibility testing against eight antimicrobials. Cefoxitin was used to screen for methicillin resistance inS. aureus, as it stimulates expression ofmecA. We performed whole genome sequencing on 366 isolates and analysed these genotypically for the presence of genetic mechanisms responsible for the phenotypic levels of reduced antimicrobial susceptibility.ResultsWe observed 175 sequenced isolates with a minimum inhibitory concentration (MIC) of at least 4 μg/ml to cefoxitin, of which 50% (87/175) did not harbour a knownmechomologue. Eight clinical NAS isolates displayed high daptomycin MICs (>4 μg/ml), with no known mechanism identified. Differences in MICs against erythromycin were attributable to the presence of different resistance genes (msrAandermC). In total, 49% (193 /394) of isolates displayed reduced susceptibility to three or more of the antimicrobials tested.ConclusionsThe widespread presence of reduced antimicrobial susceptibility in NAS is a concern, with an increased likelihood of (1) harder to treat infections caused directly by NAS, and (2) resistance genes being passed on to other bacteria via horizontal gene transfer, both of which have clinical implications for treatment and management of patients.
Genomic sequencing of Lowe syndrome trios reveal a mechanism for the heterogeneity of neurodevelopmental phenotypes
Authors: Pallikonda Husayn Ahmed , Singh Pramod , Thakur Rajan , Kumari Aastha , Krishnan Harini , Philip Ron George , Vasudevan Anil , Raghu Padinjat 
Published: June 2021

AbstractLowe syndrome is an X-linked recessive monogenic disorder resulting from mutations in theOCRLgene that encodes a phosphatidylinositol 4,5 bisphosphate 5-phosphatase. The disease affects three organs-the kidney, brain and eye and clinically manifests as proximal renal tubule dysfunction, neurodevelopmental delay and congenital cataract. Although Lowe syndrome is a monogenic disorder, there is considerable heterogeneity in clinical presentation; some individuals show primarily renal symptoms with minimal neurodevelopmental impact whereas others show neurodevelopmental defect with minimal renal symptoms. However, the molecular and cellular mechanisms underlying this clinical heterogeneity remain unknown. Here we analyze a Lowe syndrome family in whom affected members show clinical heterogeneity with respect to the neurodevelopmental phenotype despite carrying an identical mutation in theOCRLgene. Genome sequencing and variant analysis in this family identified a large number of damaging variants in each patient. Using novel analytical pipelines and segregation analysis we prioritize variants uniquely present in the patient with the severe neurodevelopmental phenotype compared to those with milder clinical features. The identity of genes carrying such variants underscore the role of additional gene products enriched in the brain or highly expressed during brain development that may be determinants of the neurodevelopmental phenotype in Lowe syndrome. We also identify a heterozygous variant inCEP290, previously implicated in ciliopathies that underscores the potential role ofOCRLin regulating ciliary function that may impact brain development. More generally, our findings demonstrate analytic approaches to identify high-confidence genetic variants that could underpin the phenotypic heterogeneity observed in monogenic disorders.