Miracle-dz/UniFAR-FTUs huggingface dataset:
Mu oscillations and motor imagery performance: A reflection of success, not ability

Motor imagery, or our ability to imagine movement without actually engaging in the action, has been an increasingly popular tool in rehabilitation settings. Understanding its neural underpinning is crucial for further development of new interventions. Using scalp electroencephalography (EEG), many studies have shown that mu oscillations (8-13 Hz), a variant of the alpha band recorded over the motor cortex electrodes, are involved in both the imagination and performance of movements; however, the exact relationship between mu oscillations and motor imagery is unclear. To further our understanding of the functional significance of mu oscillations and their role in both motor learning and motor performance, our study sought to investigate how suppression in mu oscillations varies during a motor imagery task according to both within subject imagery success and between subject imagery ability. We examined EEG activity while a large sample of participants performed an objective test of motor imagery ability (Test of Ability in Movement Imagery, TAMI). Results demonstrated that mu oscillatory activity significantly decreased during successful imagery trials as compared to unsuccessful ones. However, the extent of reduction in mu oscillations did not correlate with individual imagery ability. These results provide further support for the involvement of mu oscillations in motor behaviours and indicate that suppression in mu oscillations may serve as an important index for determining successful motor imagery performance within an individual. The processes that underlie this success are likely similar to those that underlie successful motor execution, given motor imagery’s proposed functional equivalence to motor imagery.
Exploring the landscape of ectodomain shedding by quantitative protein terminomics

Ectodomain shedding is a proteolytic process that regulates the levels and functions of membrane proteins. Dysregulated shedding is linked to severe diseases, including cancer and Alzheimer’s disease. However, the exact cleavage sites of shedding substrates remain largely unknown. Here, we explore the landscape of ectodomain shedding by generating large-scale, cell-type-specific maps of shedding cleavage sites. By means of N- and C-terminal peptide enrichment and quantitative mass spectrometry, we quantified protein termini in the culture media of 10 human cell lines and identified 411 cleavage sites on the ectodomain of 132 membrane proteins whose proteolytic terminal fragments are downregulated in the presence of a broad-spectrum metalloprotease inhibitor. A major fraction of the presented cleavage sites was identified in a cell-type-specific manner, and mapped onto receptors, cell adhesion molecules, and protein kinases and phosphatases. We confidently identified 86 cleavage sites as metalloprotease substrates by means of knowledge-based scoring.
Basolateral amygdala parvalbumin neurons report aversive prediction error to constrain fear learning

Animals, including humans, use prediction error to guide learning about danger in the environment. The basolateral amygdala (BLA) is obligatory for this learning and BLA excitatory projection neurons are instructed by aversive prediction error to form fear associations. Complex networks of inhibitory interneurons, dominated by parvalbumin (PV) expressing GABAergic neurons, form the intrinsic microcircuitry of the BLA to control projection neuron activity. Whether BLA PV interneurons are also sensitive to prediction error and how they use this error to control fear learning remains unknown. We used PV cell-type specific recording and manipulation approaches in male transgenic PV-Cre rats to address these issues. We show that BLA PV neurons control fear learning about aversive events but not learning about their omission. Furthermore, during fear learning BLA PV neurons express the activity signatures of aversive prediction error: greater activity to unexpected than expected aversive events and greater activity to better rather than poorer predictors of these events. Crucially, we show that BLA PV neurons act to limit fear learning across these variations in prediction error. Together, this demonstrates that prediction error instructs and regulates BLA fear association formation in a cell-type specific manner. Whereas BLA projection neurons use prediction error signals to form and store fear associations, BLA PV interneurons use prediction error signals to constrain fear association formation. Significance Statement The capacity to predict sources of danger in the environment is essential for survival. This capacity is supported by associative learning mechanisms that are triggered when the danger experienced is greater than the danger expected. Here we show that the activity of parvalbumin positive GABAergic interneurons in the rat basolateral amygdala neurons report this difference between the danger expected and the danger experienced and that they use this difference to limit the amount of fear which is learned.
Environmental influences and individual characteristics that affect learner-centered teaching practices

Research-based teaching practices can improve student learning outcomes in a variety of complex educational environments. The implementation of learner-centered teaching practices in STEM can both benefit or be constrained by different factors related to individual instructors and the teaching environment. However, we know little of how the instructional climate varies across institutions and how this climate affects teaching practices. Our study sought to describe the relative importance of environmental influences and individual characteristics on learner- centered teaching practices across institutions. We also assessed departmental climate for 35 US higher education institutions. We found that self-efficacy in teaching and professional development exert a strong influence on faculty teaching practices. While departmental climate did not emerge as a significant predictor of teaching practices, there was consistently low support for teaching, and institution size was negatively correlated with leadership and evaluation of effective teaching. We also found that professional development may prepare instructors to teach learner-centered courses in different collegial teaching climates. Our results suggest that through cultivating self-efficacy and participating in iterative professional development, instructors can implement effective teaching practices across institutional environments.
A second PI(4,5)P2 binding site determines PI(4,5)P2 sensitivity of the tubby domain

Phosphosinositides (PIs) are lipid signaling molecules that operate by recruiting proteins to cellular membranes via PI recognition domains. Such domains are also used widely as fluorescence-coupled biosensors for cellular PIs. For PI(4,5)P2, the dominant PI of the plasma membrane (PM), only two recognition domains have been characterized in detail and used as sensors. One of them, the tubby domain, which is conserved in the tubby-like protein (TULP) family, is essential for targeting proteins into cilia in a process involving reversible membrane association. However, the PI(4,5)P2 binding properties of tubby domains have remained enigmatic. Here we used coarse-grained molecular dynamics (MD) simulations to explore PI(4,5)P2 binding by the prototypic tubby domain (tubbyCT). While the MD simulations showed a comparatively low PI(4,5)P2 affinity of the previously described canonical binding site, they unexpectedly revealed an adjacent second binding site, consisting of a conserved cationic cluster at the protein-membrane interface. Population of this second site dramatically increased membrane association of tubbyCT. Although less specific than the canonical binding pocket, this second site preferred binding of PI(4,5)P2 over PI(4)P and phosphatidyl serine. Mutations in this site impaired PI(4,5)P2-dependent PM localization in living cells and PI(4,5)P2 interaction in silico. Thus, the second binding site essentially contributes to the effective affinity and hence PM association of the tubby domain. The two-ligand binding mode may serve to sharpen the membrane association-dissociation cycle of TULPs that underlies delivery of ciliary cargo.
Prevalence of genetically similar Flavobacterium columnare phages across aquaculture environments reveals a strong potential for pathogen control

Intensive aquaculture conditions expose fish to bacterial infections, leading to significant financial losses, extensive antibiotic use and risk of antibiotic resistance in target bacteria. Flavobacterium columnare causes columnaris disease in aquaculture worldwide. To develop a bacteriophage-based control of columnaris disease, we isolated and characterized 126 F. columnare strains and 63 phages against F. columnare from Finland and Sweden. Bacterial isolates were virulent on rainbow trout (Oncorhynchus mykiss) and fell into four previously described genetic groups A, C, E and G, with genetic groups C and E being the most virulent. Phage host range studied against a collection of 228 bacterial isolates demonstrated modular infection patterns based on host genetic group. Phages infected contemporary and previously isolated bacterial hosts, but bacteria isolated most recently were generally resistant to previously isolated phages. Despite large differences in geographical origin, isolation year or host range of the phages, whole genome sequencing of 56 phages showed high level of genetic similarity to previously isolated F. columnare phages (Ficleduovirus, Myoviridae). Altogether, this phage collection demonstrates a potential to be used in phage therapy. Significance Statement Bacteriophages were discovered already over a century ago, and used widely in treatment of bacterial diseases before the era of antibiotics. Due to harmful effects of antibiotic leakage into environment, aquaculture is a potential target for phage therapy. However, the development of efficient phage therapy approach requires detailed characterization of bacterial pathogen virulence and phage host range. Here, we describe phage-bacterium interactions in the fish pathogen Flavobacterium columnare. We found that genetically similar phages are found from different fish farms, and their infectivity cluster according to genetic group of bacteria. In addition, phages were able to infect bacterial hosts from other farms, which is a preferable trait considering phage therapy approach. However, the most recently isolated phages had broader host range than the previously isolated phages, suggesting a response in the phage community to evolution of resistance in the bacteria. These results show that designing phage therapy for aquaculture (and other) systems needs consideration of both temporal and geographical aspects of the phage-bacterium interaction.
Pioglitazone improves deficits of Fmr1-KO mouse model of Fragile X syndrome by interfering with excessive diacylglycerol signaling

Fragile X syndrome (FXS), the leading cause of familial intellectual disability, is an uncured disease caused by the absence or loss of function of the FMRP protein. FMRP is an RNA binding protein that controls the translation of specific proteins in neurons. A main target of FMRP in neurons is diacylglycerol kinase kappa (DGKk) and the loss of FMRP leads to a loss of DGK activity causing a diacylglycerol excess in the brain. Excessive diacylglycerol signaling could be a significant contributor to the pathomechanism of FXS. Here we tested the contribution of DAG-signaling in Fmr1-KO mouse model of FXS and we show that pioglitazone, a widely prescribed drug for type 2 diabetes, has ability to correct excessive DAG signaling in the brain and rescue behavioral alterations of the Fmr1-KO mouse. This study highlights the role of lipid signaling homeostasis in FXS and provides arguments to support the testing of pioglitazone for treatment of FXS.
Epigenetic clock and DNA methylation studies of roe deer in the wild

DNA methylation-based biomarkers of aging (epigenetic clocks) promise to lead to new insights in the evolutionary biology of ageing. Relatively little is known about how the natural environment affects epigenetic aging effects in wild species. In this study, we took advantage of a unique long-term (>40 years) longitudinal monitoring of individual roe deer (Capreolus capreolus) living in two wild populations (Chizé and Trois Fontaines, France) facing different ecological contexts to investigate the relationship between chronological age and levels of DNA methylation (DNAm). We generated novel DNA methylation data from n=90 blood samples using a custom methylation array (HorvathMammalMethylChip40). We present three DNA methylation-based estimators of age (DNAm or epigenetic age), which were trained in males, females, and both sexes combined. We investigated how sex differences influenced the relationship between DNAm age and chronological age through the use of sex-specific epigenetic clocks. Our results highlight that both populations and sex influence the epigenetic age, with the bias toward a stronger male average age acceleration (i.e. differences between epigenetic age and chronological ages) particularly pronounced in the population facing harsh environmental conditions. Further, we identify the main sites of epigenetic alteration that have distinct aging patterns across the two sexes. These findings open the door to promising avenues of research at the crossroad of evolutionary biology and biogerontology.
Oncogenic Activation of AKT by MAPK6

Mitogen-activated protein kinase 6 (MAPK6) is an atypical MAPK closely related to MAPK4. We recently reported that MAPK4 can promote cancer by activating the Protein Kinase B (PKB/AKT) pathway of cell growth and survival. Here we report that MAPK6 overexpression also activates AKT to induce oncogenic outcomes, including transforming “normal” human epithelial cells into anchorage-independent growth and enhancing cancer cell growth. Knockdown of MAPK6 inhibited cancer cell growth and xenograft growth, supporting the tumor-promoting activities of endogenous MAPK6. Unlike MAPK4, which binds AKT through its kinase domain and phosphorylates AKT at T308, MAPK6 interacts with AKT through its C34 region and the unique C-terminal tail and phosphorylates AKT at S473 independent of mTORC2, the major AKT S473 kinase. MAPK6 overexpression is associated with decreased overall survival and the survival of lung adenocarcinoma, mesothelioma, uveal melanoma, and breast cancer patients. We conclude that MAPK6 can promote cancer by activating AKT and that targeting MAPK6 may be effective in human cancers.
A proof of concept for neutralizing antibody-guided vaccine design against SARS-CoV-2

Mutations and transient conformational movements of receptor binding domain (RBD) that make neutralizing epitopes momentarily unavailable, present immune escape routes to SARS-CoV-2. To mitigate viral escape, we developed a cocktail of neutralizing antibodies (NAbs) targeting epitopes located on different domains of spike (S) protein. Screening of a library of monoclonal antibodies generated from peripheral blood mononuclear cells of COVID-19 convalescent patients yielded potent NAbs, targeting N-terminal domain (NTD) and RBD domain of S, effective at nM concentrations. Remarkably, combination of RBD-targeting NAbs and NTD-binding NAb, FC05, dramatically enhanced the neutralization potency in cell-based assays and animal model. Results of competitive SPR assays and cryo-EM structures of Fabs bound to S unveil determinants of immunogenicity. Combinations of immunogens, identified in NTD and RBD of S, when immunized in rabbits elicited potent protective immune responses against SARS-CoV-2. These results provide a proof-of-concept for neutralization-based immunogen design targeting SARS-CoV-2 NTD and RBD. One sentence summary Immunogens identified in the NTD and RBD of the SARS-CoV-2 spike protein using a cocktail of non-competing NAbs when injected in rabbits elicited a potent protective immune response against SARS-CoV-2.
COMPTEL observations of Ti-44 gamma-ray line emission from Cas A

The Compton Telescope (COMPTEL) telescope aboard the Compton Gamma-Ray Observatory (CGRO) is capable of imaging gamma-ray line sources in the MeV region with a sensitivity of the order 10(exp -5) photons/(sq cm s). During two observations periods in July 1992 and February 1993 the Galactic plane in the region of the young supernova remnant Cas A was observed, showing evidence for line emission at 1.16 MeV from the decay of Ti-44 at a significance level of approximately 4 sigma. This is the first time a supernova remnant has been detected in the gamma-ray line from Ti-44 decay. Adopting a distance of 2.8 kpc to the Cas A remnant, the measured line flux (7.0 +/- 1.7) x 10(exp -5) photons/(sq cm s), can be translated into a Ti-44 mass ejected during the Cas A supernova explosion, between (1.4 +/- 0.4) x 10(exp -4) solar mass and (3.2 +/- 0.8) x 10(exp -4) solar mass, depending on the precise value of the Ti-44 mean life time and on the precise date of the event. Implications of this result for supernova nucleosynthesis models are discussed.
Structural Analysis of Simultaneous Activation and Inhibition of γ-Secretase Activity in Development of Drugs for Alzheimer’s disease

Significance The majority of drugs that target membrane-embedded protease γ-secretase show unusual biphasic activation-inhibition dose-response in cells, model animals, and humans. Semagacestat and avagacestat are two biphasic-drugs that can facilitate cognitive decline in patients with Alzheimer’s disease. Initial mechanistic studies showed that the biphasic-drugs, and pathogenic mutations, can produce the same type of changes in γ-secretase activity. Results DAPT, semagacestat LY-411,575, and avagacestat are four drugs that show different binding constants, and biphasic activation-inhibition dose-response curves, for amyloid-β-40 products in SHSY-5 cells. Multiscale molecular dynamics studies showed that all four drugs bind to the most mobile parts in presenilin structure, at different ends of the 29 Å long active site tunnel. Combined results from structure-activity studies, showed that the biphasic dose-response curves are a result of modulation of γ-secretase activity by concurrent binding of multiple drug molecules at each end of the active site tunnel. The drugs activate γ-secretase by forcing the active site tunnel to open, when the rate-limiting step is the tunnel opening, and formation of the enzyme-substrate complex. The drugs inhibit γ-secretase as uncompetitive inhibitors, by binding next to the substrate to dynamic enzyme structures that regulate processive catalysis. The drugs can modulate the production of different amyloid-β catalytic intermediates, by penetrating into the active site tunnel to different depth with different binding affinity. The drugs and pathogenic mutations affect the same dynamic processes in γ-secretase structure. Conclusions Biphasic-drugs like disease-causing mutations can reduce the catalytic capacity of γ-secretase and facilitate pathogenic changes in amyloid metabolism.
Maturation of the matrix and viral membrane of HIV-1

Structural changes in HIV maturation Nascent HIV particles assemble at the plasma membrane of an infected cell and bud into a membrane-enveloped, immature virion. Assembly and budding are driven by a polyprotein called Gag, which consists of a matrix domain (MA) that is recruited to the plasma membrane, a capsid domain (CA) responsible for self-assembly, and a nucleocapsid domain (NC) that recruits the viral RNA genome. Gag cleavage results in a structural rearrangement that produces the mature virion. Qu et al. imaged mature and immature HIV particles by electron tomography and focused in on the MA domain (see the Perspective by Hikichi and Freed). They found that MA rearranges between two distinct hexameric lattices, and mature MA modulates the viral membrane by binding to a membrane lipid. This finding suggests that MA may play functional roles in the mature virion. Science, abe6821, this issue p. 700; see also abj9075, p. 621 The structure of the HIV-1 matrix domain differs between immature and mature virions, affecting the structure of the viral lipid membrane. Gag, the primary structural protein of HIV-1, is recruited to the plasma membrane for virus assembly by its matrix (MA) domain. Gag is subsequently cleaved into its component domains, causing structural maturation to repurpose the virion for cell entry. We determined the structure and arrangement of MA within immature and mature HIV-1 through cryo–electron tomography. We found that MA rearranges between two different hexameric lattices upon maturation. In mature HIV-1, a lipid extends out of the membrane to bind with a pocket in MA. Our data suggest that proteolytic maturation of HIV-1 not only assembles the viral capsid surrounding the genome but also repurposes the membrane-bound MA lattice for an entry or postentry function and results in the partial removal of up to 2500 lipids from the viral membrane.
Multi-Hops Functional Connectivity Improves Individual Prediction of Fusiform Face Activation via a Graph Neural Network

Brain connectivity plays an important role in determining the brain region’s function. Previous researchers proposed that the brain region’s function is characterized by that region’s input and output connectivity profiles. Following this proposal, numerous studies have investigated the relationship between connectivity and function. However, based on a preliminary analysis, this proposal is deficient in explaining individual differences in the brain region’s function. To overcome this problem, we proposed that a brain region’s function is characterized by that region’s multi-hops connectivity profile. To test this proposal, we used multi-hops functional connectivity to predict the individual face response of the right fusiform face area (rFFA) via a multi-layers graph neural network and showed that the prediction performance is essentially improved. Results also indicated that the 2-layers graph neural network is the best in characterizing rFFA’s face response and revealed a hierarchical network for the face processing of rFFA.
Host-interactor screens of Phytophthora infestans RXLR proteins reveal vesicle trafficking as a major effector-targeted process

Pathogens modulate plant cell structure and function by secreting effectors into host tissues. Effectors typically function by associating with host molecules and modulating their activities. This study aimed to identify the host processes targeted by the RXLR class of host-translocated effectors of the potato blight pathogen Phytophthora infestans. To this end, we performed an in planta protein-protein interaction screen by transiently expressing P. infestans RXLR effectors in Nicotiana benthamiana leaves followed by co-immunoprecipitation (co-IP) and liquid chromatography tandem mass spectrometry (LC-MS/MS). This screen generated an effector-host protein interactome matrix of 59 P. infestans RXLR effectors x 586 N. benthamiana proteins. Classification of the host interactors into putative functional categories revealed over 35 biological processes possibly targeted by P. infestans. We further characterized the PexRD12/31 family of RXLR-WY effectors, which associate and co-localize with components of the vesicle trafficking machinery. One member of this family, PexRD31, increased the number of FYVE positive vesicles in N. benthamiana cells. FYVE positive vesicles also accumulated in leaf cells near P. infestans hyphae, indicating that the pathogen may enhance endosomal trafficking during infection. We anticipate that the interactome dataset we generated will serve as a useful community resource for functional studies of P. infestans effectors and of effector-targeted host processes.