bluuebunny/crossref_metadata_2025_split huggingface dataset:
Technology-aided assessment of functionally relevant sensorimotor impairments in arm and hand of post-stroke individuals
Authors: Kanzler Christoph M. , Schwarz Anne , Held Jeremia P.O. , Luft Andreas R. , Gassert Roger , Lambercy Olivier 
Published: April 2020

AbstractBackgroundAssessing arm and hand sensorimotor impairments that are functionally relevant is essential to optimize the impact of neurorehabilitation interventions. Technology-aided assessments should provide a sensitive and objective characterization of upper limb impairments, but often provide arm weight support and neglect the importance of the hand, thereby questioning their functional relevance. The Virtual Peg Insertion Test (VPIT) addresses these limitations by quantifying arm movements and grip forces during a goal-directed manipulation task without arm weight support. The aim of this work was to evaluate the potential and robustness of the VPIT metrics to inform on sensorimotor impairments in arm and hand, and especially identify the functional relevance of the detected impairments.MethodsArm and hand sensorimotor impairments were systematically characterized in 30 chronic stroke patients using conventional clinical scales and the VPIT. For the latter, ten previously established kinematic and kinetic core metrics were extracted and compared to conventional clinical scales of impairment and activity limitations. Additionally, the robustness of the VPIT metrics was investigated by analyzing their clinimetric properties (test-retest reliability, measurement error, and learning effects).ResultsTwenty-three of the participants, the ones with mild to moderate sensorimotor impairments and without strong cognitive deficits, were able to successfully complete the VPIT protocol (duration 16.6 min). The VPIT metrics detected impairments in arm and hand in 90.0% of the participants, and were sensitive to increased muscle tone and pathological joint coupling. Most importantly, moderate to high significant correlations between conventional scales of activity limitations and the VPIT metrics were found, thereby indicating their functional relevance when grasping and transporting lightweight objects as well as dexterous finger manipulations. Lastly, the robustness of three out of the ten VPIT core metrics in post-stroke individuals was confirmed.ConclusionsThis work provides evidence that technology-aided assessments requiring goal-directed manipulations without arm weight support can provide an objective, robust, and clinically feasible way to assess functionally relevant sensorimotor impairments in arm and hand in chronic post-stroke individuals with mild to moderate deficits. This allows better identifying impairments with high functional relevance and can contribute to optimizing the functional benefits of neurorehabilitation interventions.Retrospectively registered: clinicaltrials.gov/ct2/show/NCT03135093
Axonal transport of Hrs is activity-dependent and rate limiting for synaptic vesicle protein degradation
Authors: Birdsall Veronica , Zhu Mei , Kirwan Konner , Imoto Yuuta , Watanabe Shigeki , Waites Clarissa L. 
Published: April 2020

AbstractTurnover of synaptic vesicle (SV) proteins is vital for the maintenance of healthy and functional synapses. SV protein turnover is driven by neuronal activity in an ESCRT (endosomal sorting complex required for transport)-dependent manner. Here, we characterize a critical step in this process: axonal transport of ESCRT-0 component Hrs, necessary for sorting proteins into the ESCRT pathway and recruiting downstream ESCRT machinery to catalyze multivesicular body (MVB) formation. We find that neuronal activity stimulates the formation of presynaptic endosomes and MVBs, as well as the motility of Hrs+ vesicles in axons and their delivery to SV pools. Hrs+ vesicles co-transport ESCRT-0 component STAM1 and comprise a subset of Rab5+ vesicles, likely representing pro-degradative early endosomes. Furthermore, we identify kinesin motor protein KIF13A as essential for the activity-dependent transport of Hrs to SV pools and the degradation of SV membrane proteins. Together, these data demonstrate a novel activity- and KIF13A-dependent mechanism for mobilizing axonal transport of ESCRT machinery to facilitate the degradation of SV membrane proteins.
Neuronal hyperexcitability is a DLK-dependent trigger of HSV-1 reactivation that can be induced by IL-1
Authors: Cuddy Sean R. , Schinlever Austin R. , Dochnal Sara , Suzich Jon , Kundu Parijat , Downs Taylor K. , Farah Mina , Desai Bimal , Boutell Chris , Cliffe Anna R. 
Published: April 2020

AbstractHerpes Simplex Virus (HSV) establishes a latent infection in neurons and periodically reactivates to cause disease. The neuronal stimuli that trigger HSV reactivation have not been fully elucidated. Here we demonstrate that HSV reactivation can be induced by neuronal hyperexcitability. Neuronal stimulation-induced reactivation was dependent on voltage-gated ion and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, demonstrating that neuronal activity is required for reactivation. Hyperexcitability-induced reactivation was dependent on the neuronal pathway of DLK/JNK activation and progressed via an initial wave of viral gene expression that was independent of histone demethylase activity and linked to histone phosphorylation. IL-1β induces neuronal hyperexcitability and is released under conditions of stress and fever; both known triggers of clinical HSV reactivation. IL-1β induced histone phosphorylation in sympathetic neurons, and importantly HSV reactivation, which was dependent on DLK and neuronal excitability. Thus, HSV co-opts an innate immune pathway resulting from IL-1 stimulation of neurons to induce reactivation.
Unexpected sounds non-selectively inhibit active visual stimulus representations
Authors: Soh Cheol , Wessel Jan R. 
Published: April 2020

AbstractThe brain’s capacity to process unexpected events is key to cognitive flexibility. The most well-known effect of unexpected events is the interruption of attentional engagement (distraction). We tested whether unexpected events interrupt attentional representations by activating a neural mechanism for inhibitory control. This mechanism is most well-characterized within the motor system. However, recent work showed that it is automatically activated by unexpected events and can explain some of their non-motor effects (e.g., on working memory representations). Here, human participants attended to lateralized flickering visual stimuli, producing steady-state visual evoked potentials (SSVEP) in the scalp-electroencephalogram. After unexpected sounds, the SSVEP was rapidly suppressed. Using a functional localizer (stop-signal) task and independent component analysis, we then identified a fronto-central EEG source whose activity indexes inhibitory motor control. Unexpected sounds in the SSVEP task also activated this source. Using single-trial analyses, we found that sub-components of this source differentially relate to sound-related SSVEP changes: while its N2 component predicted the subsequent suppression of the attended-stimulus SSVEP, the P3 component predicted the suppression of the SSVEP to the unattended stimulus. These results shed new light on the processes underlying fronto-central control signals and have implications for phenomena such as distraction and the attentional blink.
Membrane receptor MerTK is a newly identified transcriptional regulator that associates to chromatin as nanoclusters during human DC differentiation
Authors: Borgman Kyra. J.E. , Flórez-Grau Georgina , Ricci Maria A. , Manzo Carlo , Lakadamyali Melike , Cambi Alessandra , Benítez-Ribas Daniel , Campelo Felix , Garcia-Parajo Maria. F. 
Published: April 2020

AbstractMerTK is a transmembrane receptor tyrosine kinase (RTK) mainly expressed in dendritic cells (DCs) and macrophages where it plays an important role in immunotolerance, but also in activating oncogenic signalling pathways. Albeit MerTK is exploited as clinical target in cancer and auto-immune disorders, the mechanisms that regulate its diverse functions are poorly understood. Here, we identified a remarkably high pool of the full receptor in the nucleus of human DCs. Nuclear translocation was ligand-dependent. Importantly, MerTK nuclear levels correlated to DC differentiation and were spatiotemporally regulated by the transmembrane receptor LRP-1. Using dual-colour super-resolution nanoscopy we discovered that nuclear MerTK forms nanoclusters, whose strength strongly depends on chromatin accessibility during DC differentiation. We finally revealed high transcription capacity of MerTK. Overall, our work indicates that nuclear MerTK acts as a transcription factor regulating DC differentiation, thus implicating for the first time a physiological function for RTK nuclear translocation in immunity.
Taxonomy of neural oscillation events in primate auditory cortex
Authors: Neymotin Samuel A , Tal Idan , Barczak Annamaria , O’Connell Monica N. , McGinnis Tammy , Markowitz Noah , Espinal Elizabeth , Griffith Erica , Anwar Haroon , Dura-Bernal Salvador , Schroeder Charles E , Lytton William W , Jones Stephanie R , Bickel Stephan , Lakatos Peter 
Published: April 2020

AbstractElectrophysiological oscillations in the brain have been shown to occur as multi-cycle events, with onset and offset dependent on behavioral and cognitive state. To provide a baseline for state-related and task-related events, we quantified oscillation features in resting-state recordings. We used two invasively-recorded electrophysiology datasets: one from human, and one from non-human primate auditory system. After removing incidentally occuring event related potentials, we used a wavelet transform based method to quantify oscillation features. We identified about 2 million oscillation events, classified within traditional frequency bands: delta, theta, alpha, beta, low gamma, gamma, high gamma. Oscillation events of 1-44 cycles were present in at least one frequency band in 90% of the time in human and non-human primate recordings. Individual oscillation events were characterized by non-constant frequency and amplitude. This result naturally contrasts with prior studies which assumed such constancy, but is consistent with evidence from event-associated oscillations. We measured oscillation event duration, frequency span, and waveform shape. Oscillations tended to exhibit multiple cycles per event, verifiable by comparing filtered to unfiltered waveforms. In addition to the clearintra-event rhythmicity, there was also evidence ofinter-event rhythmicity within bands, demonstrated by finding that coefficient of variation of interval distributions and Fano Factor measures differed significantly from a Poisson distribution assumption. Overall, our study demonstrates that rhythmic, multi-cycle oscillation events dominate auditory cortical dynamics.
Molecular architecture and domain arrangement of the placental malaria protein VAR2CSA suggests a model for receptor binding
Authors: Bewley Maria C. , Gautam Lovely , Gowda D. Channe , Flanagan John M. 
Published: April 2020

ABSTRACTVAR2CSA is the placental-malaria specific member of the antigenically variantPlasmodium falciparumerythrocyte membrane protein 1 (PfEMP1) family. It is expressed on the surface ofPlasmodium falciparuminfected host red blood cells and binds to specific chondroitin-4-sulfate (CSA) chains of the placental proteoglycan receptor. The functional ~310 kDa ectodomain of VAR2CSA is a multi-domain protein that requires a minimum 12-mer CSA molecule for specific, high affinity receptor binding. However, how these domains interact to create the receptor binding surface is not known, limiting efforts to exploit its potential as an effective vaccine or drug target. Using small angle X-ray scattering and single particle reconstruction from negative stained electron micrographs of the ectodomain and multidomain constructs, we have determined the structural architecture of VAR2CSA. The relative location of the domains creates two distinct pores that can each accommodate the 12-mer of CSA, suggesting a model for receptor binding. This model has important implications for understanding cytoadherence of IRBCs and potentially provides a starting point for developing novel strategies to prevent and/or treat placental malaria.
Thermal Control of T-cell Immunotherapy
Authors: Abedi Mohamad H. , Lee Justin , Piraner Dan I. , Shapiro Mikhail G. 
Published: April 2020

ABSTRACTGenetically engineered T-cells are being developed to perform a variety of therapeutic functions. However, no robust mechanisms exist to externally control the activity of T-cells at specific locations within the body. Such spatiotemporal control could help mitigate potential off-target toxicity due to incomplete molecular specificity in applications such as T-cell immunotherapy against solid tumors. Temperature is a versatile external control signal that can be delivered to target tissuesin vivousing techniques such as focused ultrasound and magnetic hyperthermia. Here, we test the ability of heat shock promoters to mediate thermal actuation of genetic circuits in primary human T-cells in the well-tolerated temperature range of 37–42°C, and introduce genetic architectures enabling the tuning of the amplitude and duration of thermal activation. We demonstrate the use of these circuits to control the expression of chimeric antigen receptors and cytokines, and the killing of target tumor cells. This technology provides a critical tool to direct the activity of T-cells after they are deployed inside the body.
Two spaced training trials induce associative ERK-dependent long-term memory inNeohelice granulata
Authors: Ramos Santiago Ojea , Andina Matías , Romano Arturo , Feld Mariana 
Published: April 2020

ABSTRACTMemory formation depends upon several parametric training conditions. Among them, trial number and inter-trial interval (ITI) are key factors to induce long-term retention. However, it is still unclear how individual training trials contribute to mechanisms underlying memory formation and stabilization. Contextual conditioning inNeohelice granulatahas traditionally elicited associative long-term memory (LTM) after 15 spaced (ITI = 3 min) trials. Here, we show that LTM in crabs can be induced after only two training trials by increasing the ITI to 45 min (2t-LTM) and maintaining the same training duration as in traditional protocols. This new LTM observed was preserved for at least 96 h, exhibited protein synthesis dependence during consolidation and reconsolidation as well as context-specificity. Moreover, we demonstrate that 2t-LTM depends on inter-trial and post-training ERK activation showing a faster phosphorylation after the second trial compared to the first one. In summary, we present a new training protocol in crabs with reduced number of trials that shows associative features similar to traditional spaced training. This novel protocol allows intra-training manipulation and the assessment of individual trial contribution to LTM formation.
Repairing neural damage in aC. eleganschemosensory circuit using genetically engineered synapses
Authors: Rabinowitch Ithai , Upadhyaya Bishal , Pant Aaradhya , Bai Jihong 
Published: April 2020

AbstractNeuronal loss can considerably diminish neural circuit function, impairing normal behavior by disrupting information flow in the circuit. We reasoned that by rerouting the flow of information in the damaged circuit it may be possible to offset these negative outcomes. We examined this possibility using the well-characterized chemosensory circuit of the nematode wormC. elegans. In this circuit, a main sensory neuron class sends parallel outputs to several interneuron classes. We found that the removal of one of these interneuron classes impairs chemotaxis to attractive odors, revealing a prominent path for information flow in the circuit. To alleviate these deficiencies, we sought to reinforce a remaining neural pathway. We used genetically engineered electrical synapses for this purpose, and observed the successful recovery of chemotaxis performance. However, we were surprised to find that the recovery was largely mediated by inadvertently formed left-right lateral electrical connections within individual neuron classes. Our analysis suggests that these additional electrical synapses help restore circuit function by amplifying weakened neuronal signals in the damaged circuit. These results demonstrate the power of genetically engineered synapses to regulate information flow and signal intensity in damaged neural circuits.
Tuning trophoblast invasion in a gelatin hydrogel via soluble cues from the maternal-fetal interface
Authors: Zambuto Samantha G. , Clancy Kathryn B.H. , Harley Brendan A.C. 
Published: April 2020

ABSTRACTTrophoblast cells play multiple critical roles in pregnancy, notably modulating blastocyst attachment to the endometrium as well as invading into and actively remodeling the endometrium to facilitate biotransport needs of the growing embryo. Despite the importance of trophoblast invasion for processes essential at early stages of pregnancy, much remains unknown regarding the balance of signaling molecules that may influence trophoblast invasion into the endometrium. The goal of this study was to use a three-dimensional trophoblast spheroid invasion assays to examine the effect of cues from the maternal-fetal interface on trophoblast invasion. We report use of a methacrylamide-functionalized gelatin (GelMA) hydrogel to support quantitative analysis of trophoblast outgrowth area and cell viability. We show this multidimensional model of trophoblast invasion can resolve quantifiable differences in outgrowth area and viability in the presence of a known invasion promoter, epidermal growth factor, and a known invasion inhibitor, transforming growth factor β1. We then investigate the sensitivity of trophoblast invasion to cortisol, a hormone associated with exogenous stressors. Together, this approach provides a toolset to investigate the coordinated action of physiological and pathophysiological processes on early stages of trophoblast invasion.IMPACT STATEMENTTrophoblast cells from the invading blastocyst play crucial roles in pregnancy, including remodeling endometrial structure to support embryonic biotransport needs; however, much remains unknown regarding the balance of signaling molecules that may influence trophoblast invasion. We show this multidimensional model of invasion can resolve quantifiable differences in outgrowth area and viability in the presence of known invasion promoters and inhibitors and then investigate invasion sensitivity to cortisol, a hormone associated with exogenous stressors. This approach provides a toolset to investigate the coordinated action of molecules from the maternal-fetal interface on trophoblast invasion that may be challenging to study in humans.
Single-cell analysis of human lung epithelia reveals concomitant expression of the SARS-CoV-2 receptor ACE2 with multiple virus receptors and scavengers in alveolar type II cells
Authors: Han Guangchun , Sinjab Ansam , Treekitkarnmongkol Warapen , Brennan Patrick , Hara Kieko , Chang Kyle , Bogatenkova Elena , Sanchez-Espiridion Beatriz , Behrens Carmen , Gao Boning , Girard Luc , Zhang Jianjun , Sepesi Boris , Cascone Tina , Byers Lauren , Gibbons Don L. , Chen Jichao , Moghaddam Seyed Javad , Ostrin Edwin J. , Fujimoto Junya , Shay Jerry , Heymach John V. , Minna John D. , Dubinett Steven , Scheet Paul A. , Wistuba Ignacio I. , Hill Edward , Telesco Shannon , Stevenson Christopher , Spira Avrum E. , Wang Linghua , Kadara Humam 
Published: April 2020

ABSTRACTThe novel coronavirus SARS-CoV-2 was identified as the causative agent of the ongoing pandemic COVID 19. COVID-19-associated deaths are mainly attributed to severe pneumonia and respiratory failure. Recent work demonstrated that SARS-CoV-2 binds to angiotensin converting enzyme 2 (ACE2) in the lung. To better understandACE2abundance and expression patterns in the lung we interrogated our in-house single-cell RNA-sequencing dataset containing 70,085 EPCAM+ lung epithelial cells from paired normal and lung adenocarcinoma tissues. Transcriptomic analysis revealed a diverse repertoire of airway lineages that included alveolar type I and II, bronchioalveolar, club/secretory, quiescent and proliferating basal, ciliated and malignant cells as well as rare populations such as ionocytes. While the fraction of lung epithelial cells expressingACE2was low (1.7% overall), alveolar type II (AT2, 2.2%ACE2+) cells exhibited highest levels ofACE2expression among all cell subsets. Further analysis of the AT2 compartment (n = 27,235 cells) revealed a number of genes co-expressed withACE2that are important for lung pathobiology including those associated with chronic obstructive pulmonary disease (COPD;HHIP), pneumonia and infection (FGGandC4BPA) as well as malarial/bacterial (CD36) and viral (DMBT1) scavenging which, for the most part, were increased in smoker versus light or non-smoker cells. Notably,DMBT1was highly expressed in AT2 cells relative to other lung epithelial subsets and its expression positively correlated withACE2. We describe a population ofACE2-positive AT2 cells that co-express pathogen (including viral) receptors (e.g.DMBT1) with crucial roles in host defense thus comprising plausible phenotypic targets for treatment of COVID-19.
Cryo-EM structure of C9ORF72-SMCR8-WDR41 reveals the role as a GAP for Rab8a and Rab11a
Authors: Tang Dan , Sheng Jingwen , Xu Liangting , Zhan Xiechao , Liu Jiaming , Hui Jiang , Shu Xiaoling , Liu Xiaoyu , Zhang Tizhong , Jiang Lan , Zhou Cuiyan , Li Wenqi , Cheng Wei , Li Zhonghan , Wang Kunjie , Lu Kefeng , Yan Chuangye , Qi Shiqian 
Published: April 2020

AbstractA massive intronic hexanucleotide repeat (GGGGCC) expansion inC9ORF72is a genetic origin of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recently, C9ORF72, together with SMCR8 and WDR41, has been shown to regulate autophagy and function as Rab GEF. However, the precise function of C9ORF72 remains unclear. Here, we report the cryo-EM structure of the human C9ORF72-SMCR8-WDR41 complex at a resolution of 3.2 Å. The structure reveals the dimeric assembly of a heterotrimer of C9ORF72-SMCR8-WDR41. Notably, the C-terminal tail of C9ORF72 and the DENN domain of SMCR8 play critical roles in the dimerization of the two protomers of the C9ORF72-SMCR8-WDR41 complex. In the protomer, C9ORF72 and WDR41 are joined by SMCR8 without direct interaction. WDR41 binds to the DENN domain of SMCR8 by the C-terminal helix. Interestingly, the prominent structural feature of C9ORF72-SMCR8 resembles that of the FLNC-FNIP2 complex, the GTPase activating protein (GAP) of RagC/D. Structural comparison and sequence alignment revealed that Arg147 of SMCR8 is conserved and corresponds to the arginine finger of FLCN, and biochemical analysis indicated that the Arg147 of SMCR8 is critical to the stimulatory effect of the C9ORF72-SMCR8 complex on Rab8a and Rab11a. Our study not only illustrates the basis of C9ORF72-SMCR8-WDR41 complex assembly but also reveals the GAP activity of the C9ORF72-SMCR8 complex.Significance StatementC9ORF72, together with SMCR8 and WDR41, has been shown to form a stable complex that participates in the regulation of membrane trafficking. We report the cryo-EM structure of the C9ORF72-SMCR8-WDR41 complex at atomic resolution. Notably, the stoichiometry of the three subunits in the C9ORF72-SMCR8-WDR41 complex is 2:2:2. Interestingly, the C-termini of C9ORF72 and the DENN domain of SMCR8 mediate the dimerization of the two C9ORF72-SMCR8-WDR41 protomers in the complex. Moreover, WDR41 binds to the DENN domain of SMCR8 by the C-terminal helix without direct contact with C9ORF72. Most importantly, the C9ORF72-SMCR8 complex works as a GAP for Rab8a and Rab11ain vitro,and the Arg147 of SMCR8 is the arginine finger.