Search

Abstract The conformational dynamics of single-stranded nucleic acids are fundamental for nucleic acid folding and function. However, their elementary chain dynamics have been difficult to resolve experimentally. Here we employ a combination of single-molecule Förster resonance energy transfer, nanosecond fluorescence correlation spectroscopy, and nanophotonic enhancement to determine the conformational ensembles and rapid chain dynamics of short single-stranded nucleic acids in solution. To interpret the experimental results in terms of end-to-end distance dynamics, we utilize the hierarchical chain growth approach, simple polymer models, and refinement with Bayesian inference to generate structural ensembles that closely align with the experimental data. The resulting chain reconfiguration times are exceedingly rapid, in the 10-ns range. Solvent viscosity-dependent measurements indicate that these dynamics of single-stranded nucleic acids exhibit negligible internal friction and are thus dominated by solvent friction. Our results provide a detailed view of the conformational distributions and rapid dynamics of single-stranded nucleic acids.

Abstract The talin-vinculin axis is a key mechanosensing component of cellular focal adhesions. How talin and vinculin respond to forces and regulate one another remains unclear. By combining single-molecule magnetic tweezers experiments, Molecular Dynamics simulations, actin-bundling assays, and adhesion assembly experiments in live cells, we here describe a two-ways allosteric network within vinculin as a regulator of the talin-vinculin interaction. We directly observe a maturation process of vinculin upon talin binding, which reinforces the binding to talin at a rate of 0.03 s−1. This allosteric transition can compete with force-induced dissociation of vinculin from talin only at forces up to 10 pN. Mimicking the allosteric activation by mutation yields a vinculin molecule that bundles actin and localizes to focal adhesions in a force-independent manner. Hence, the allosteric switch confines talin-vinculin interactions and focal adhesion build-up to intermediate force levels. The ‘allosteric vinculin mutant’ is a valuable molecular tool to further dissect the mechanical and biochemical signalling circuits at focal adhesions and elsewhere.

BackgroundCollaborative data sharing between research groups provides an opportunity to explore the basis for the heterogeneity in cognitive training outcomes reported in the schizophrenia literature. The current analyses focused on the contribution of site and participant characteristics to these heterogeneous outcomes.MethodsData from two independent studies, from New York (NY) and Los Angeles (LA), were combined to yield a sample of 132 outpatient adults with schizophrenia/schizoaffective disorder. While similar treatment doses, cognitive exercises and outcome measures were used, sites differed in use of coaching, group discussion and compensation. Between-site differences in participant demographic and baseline clinical characteristics were tested. Regression examined predictors of change in cognition (MCCB) and functional capacity (UPSA) which could explain site differences in treatment effects.ResultsMedium to large treatment effect size differences in MCCB and UPSA favored the NY site over LA. When the studies were combined, the effect of site was significant for both outcomes with a medium effect size difference. After controlling for background characteristics, the effect of site was reduced for both outcomes, but remained significant for cognition. Improvement in UPSA was associated with better baseline MCCB (p

Cryo-electron tomography reveals structural insights into F-actin assembly and dynamic reorganization in the leading edge of spreading cells.

Lamins are the major constituent of the nuclear lamina, a protein meshwork underlying the inner nuclear membrane. Nuclear lamins are type V intermediate filaments that assemble into ~3.5 nm thick filaments. To date, only the conditions for the in vitro assembly of Caenorhabditis elegans lamin (Ce-lamin) are known. Here, we investigated the assembly of Ce-lamin filaments by cryo-electron microscopy and tomography. We show that Ce-lamin is composed of ~3.5 nm protofilaments that further interact in vitro and are often seen as 6–8 nm thick filaments. We show that the assembly of lamin filaments is undisturbed by the removal of flexible domains, that is, the intrinsically unstructured head and tail domains. In contrast, much of the coiled-coil domains are scaffold elements that are essential for filament assembly. Moreover, our results suggest that Ce-lamin helix 1A has a minor scaffolding role but is important to the lateral assembly regulation of lamin protofilaments.

Here, Waltenspühl et al. report the cryo-EM structure of active human oxytocin receptor in complex with oxytocin and with a heterotrimeric G protein, providing insights into this hormone system critically involved in the regulation of social behaviour and reproduction.

BackgroundThe cognitive impairments exhibited by people with ASD, threaten the development of social skills that are essential for establishing and maintaining harmonious social relationships. Cognitive remediation and social skills training are now considered as crucial therapeutic approaches in the management of these disorders. Several programs have already been validated and have shown improvements in social skills or cognitive performance. However, the effects of these training methods seem to be difficult to generalize to other everyday life. The aim of our study is to alleviate cognitive and social deficiencies by using a socio-cognitive framework to adapt the Neuropsychological Educational Approach to Remediation (NEAR) method for adolescents with ASD.Methods/designAdolescents meeting the DSM-5 criteria for ASD, older than 13 years, and following a regular school curriculum will be recruited from clinical population at the Child and Adolescent Psychiatry in Razi University Hospital-Manouba- Tunisia. Our study is an open and non-randomized controlled trial including 30 patients: NEAR group / control group. The NEAR method combines computerized cognitive exercises and bridging groups inspired from cognitive behavioral therapy. NEAR group will be divided into three groups of five patients each. The duration of the sessions will vary according to the capacities of the participants and the exchanges between them (about 60–120 min). In our study, bridging groups will be amended by adding other tasks including planning role plays and scenarios of problematic social situations in autism, taking into account cultural particularities in order to promote social skills. Computerized exercises will be enriched by adding other tasks aiming to improve the recognition and expression of facial emotions by using digital videos and photographs expressing the six basic emotions. The duration of the program will be about 6 months. All selected patients will have an assessment of cognitive function: social cognition, neurocognition and pragmatic skills, social skills, self-esteem and global functioning at baseline, 1 week after the end of the NEAR program and 6 months later.ConclusionThis adaptive program is a promising socio-cognitive intervention that create new perspectives for adolescents with autism spectrum disorder.

AimLow motivation is a core symptom of schizophrenia which significantly impacts successful engagement in and benefit from psychosocial treatments. Therefore, it is important for clinicians to design psychosocial treatments to effectively motivate and engage patients during the treatment. The MUSIC® Model of Academic Motivation Inventory (MMI) is an 18-item instrument with five scales that assess students' motivation during academic tasks. The objective of the current study was to validate the MMI for use with schizophrenia-spectrum patients undergoing cognitive training.MethodsParticipants included 181 people with schizophrenia spectrum disorders enrolled in cognitive training in four countries. A confirmatory factor analysis (CFA) assessed construct validity. Quality of fit was determined using the Comparative Fit Index (CFI), the Standardized Root Mean Square Residual (SRMR), and the Root Mean Square Error of Approximation (RMSEA). Pearson's correlation coefficients assessed construct validity and Cronbach's alphas assessed reliability. Furthermore, we examined factor loadings for each inventory item and assessed predictive validity by analyzing MMI scales with attendance outcomes.ResultsConsistent with the original MMI validation studies used in academic settings, we found CFI values indicated a good fit, as did the SRMR and RMSEA values. The scales were correlated yet distinct. Cronbach's alpha values ranged from good to excellent and factor loadings showed that all items loaded very well onto their intended factors. The MMI had a positive relationship to treatment intensity.ConclusionThe MMI is a valid and reliable tool to use with individuals with schizophrenia spectrum disorders undergoing a cognitive training intervention.

BackgroundMeta-analyses have reported that the effects of cognitive remediation might go beyond improvement in cognition to include unexpected benefits for schizophrenia patients such as negative symptom reduction and improvements in functioning. In addition, some evidence indicated that these potentially beneficial effects are also present in the initial course of schizophrenia, but work in this area is still developing.MethodA RCT compared Cognitive Remediation (CR) to Healthy Behaviors Training (HBT) in 80 patients (78% male) with a mean age of 21.9years and mean education of 12.3years who had a first psychotic episode within two years of study entry. Participants were trained using CR programs or received HBT involving 50 sessions over 6months and then booster sessions over the next 6months. The SANS and BPRS were used to assess symptoms. The UCLA Social Attainment Survey assessed social functioning.ResultsUsing GLMM, improvements over 12months were found favoring CR for SANS Expressive Symptoms (p

Background and Hypothesis With increasing recognition of the importance of cognitive health for recovery in people with psychosis, questions arise as to how to implement cognitive health services in large systems of care. This paper describes the implementation of cognitive health services in OnTrackNY (OTNY), a network of clinics delivering a Coordinated Specialty Care treatment model for early psychosis, with the goal of documenting the processes, challenges, and useful adaptations. Study Design In 2018, OTNY piloted a Cognitive Health Toolkit for implementation across 18 affiliated clinics. The toolkit intended to identify the cognitive health needs of individuals early in the course of psychosis and to integrate cognitive health into the vocabulary of wellness and recovery. Implementation involved creating mechanisms for staff training and support to, in turn, help participants improve how they use cognitive skills in daily life. Study Results The toolkit was disseminated to all 28 OTNY programs throughout New York state by 2023. When simple assessment and decision-making tools were embedded in routine care practices, the majority of participants identified that improving memory, attention, and critical thinking skills would be helpful. Consistently, about 70% of those asked wanted to learn more about how to better their cognitive health. Conclusions Cognitive health services can be implemented in large systems of care that provide a multi-level system of implementation supports. Organizational facilitators of implementation include a training program to educate about cognitive health and the delivery of cognitive health interventions, and embedded quality assurance monitoring and improvement activities. [ABSTRACT FROM AUTHOR]

Intermediate filaments (IFs) comprise a large family of versatile cytoskeletal proteins, divided into six subtypes with tissue-specific expression patterns. IFs have a wide repertoire of cellular functions, including providing structural support to cells, as well as active roles in mechanical support and signaling pathways. Consequently, defects in IFs are associated with more than 100 diseases. In this Cell Science at a Glance article, we discuss the established classes of IFs and their general features, their functions beyond structural support, and recent advances in the field. We also highlight their involvement in disease and potential use as clinical markers of pathological conditions. Finally, we provide our view on current knowledge gaps and the future directions of the IF field. [ABSTRACT FROM AUTHOR]

Nuclear pore complexes (NPCs) create large conduits for cargo transport between the nucleus and cytoplasm across the nuclear envelope (NE).sup.1-3. These multi-megadalton structures are composed of about thirty different nucleoporins that are distributed in three main substructures (the inner, cytoplasmic and nucleoplasmic rings) around the central transport channel.sup.4-6. Here we use cryo-electron tomography on DLD-1 cells that were prepared using cryo-focused-ion-beam milling to generate a structural model for the human NPC in its native environment. We show that--compared with previous human NPC models obtained from purified NEs--the inner ring in our model is substantially wider; the volume of the central channel is increased by 75% and the nucleoplasmic and cytoplasmic rings are reorganized. Moreover, the NPC membrane exhibits asymmetry around the inner-ring complex. Using targeted degradation of Nup96, a scaffold nucleoporin of the cytoplasmic and nucleoplasmic rings, we observe the interdependence of each ring in modulating the central channel and maintaining membrane asymmetry. Our findings highlight the inherent flexibility of the NPC and suggest that the cellular environment has a considerable influence on NPC dimensions and architecture. Structure of human nuclear pore complex in its cellular environment reveals a substantially dilated central channel and shows that its nucleoplasmic and cytoplasmic rings restrict channel dimensions and create membrane asymmetry at the inner ring., Author(s): Anthony P. Schuller [sup.1] , Matthias Wojtynek [sup.2] [sup.3] , David Mankus [sup.4] , Meltem Tatli [sup.2] , Rafael Kronenberg-Tenga [sup.2] , Saroj G. Regmi [sup.5] , Phat V. [...]

ObjectivesVirtual reality and augmented reality have been used in psychosocial rehabilitation for adults with neurodevelopmental disorders in recent years, to provide functional training in a scaffolded and appealing manner. This systematic review attempted to evaluate (1) how virtual reality or augmented reality technology was deployed, when used as an intervention for adults with neurodevelopmental disorders; and (2) how virtual or augmented reality-assisted psychosocial rehabilitation programs impacted on the functional domains of community living, employment and social participation.MethodsThe Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was adopted and a search of publications between June 2012 and June 2022 was carried out. The target groups were adults with schizophrenia/schizoaffective disorders, autism spectrum disorder, intellectual disabilities and attention deficit hyperactivity disorder. Interventions that targeted at least one functional domain were included.ResultsThe database search generated 1,267 records and 38 studies met the inclusion criteria. Three studies utilized augmented reality while the rest utilized virtual reality. The virtual scenarios were displayed in various ways, such as head-mounted displays, computer screens, mobile devices and cave rooms. A few studies also used features such as speech recognition, eye tracking and motion-capture device to provide real-time feedback to participants during rehabilitation. Eleven studies reported interventions that addressed community living, 15 studies addressed vocational skills and nine studies trained participants in social skills or social cognition. Three studies sought to improve quality of life using virtual scenarios to expose participants to various situations. Majority of these studies reported preliminary promising results, with improvement in the functional domains addressed. However, several studies had small sample sizes and many single-arm pretest-posttest studies were assessed to be of serious or critical risk of bias.ConclusionVirtual reality and augmented reality are deployed in various ways to augment psychosocial rehabilitation for adults with neurodevelopmental disorders. Most interventions target skills training or strategy learning in the areas of community living, work and social participation. Preliminary positive findings of their effects on functional performance were reported. Larger and robust studies using ecologically valid outcome measures will be needed to establish their effects on real-world functional outcomes.Systematic review registrationidentifier: CRD42022335443.

ObjectivesThe Augmented Reality Games to Enhance Vocational Ability of Patients (REAP) was an augmented reality vocational training program that provided skills training in the context of a psychiatric rehabilitation program. It was implemented over 10 weeks and consisted of gamified augmented reality café training scenarios and bridging group activities to facilitate transfer of learning to the work context. This pilot study aimed to explore the acceptability and effectiveness of the REAP program when carried out with adults with intellectual and developmental disabilities attending work therapy. Its objectives were: (1) to obtain feedback from participants and trainers on their experiences and acceptability of the REAP program and (2) to measure changes in vocational and cognitive skills of participants in the REAP program.Materials and methodsThis was a pretest–posttest mixed methods study. 15 adults with intellectual and developmental disabilities attending work therapy in a non-profit organization participated in the REAP program and their vocational trainers were involved in assisting in this program. Feasibility Evaluation Checklist (FEC) and the Neurobehavioral Cognitive Status Exam (Cognistat) were administered at baseline, post-training and eight weeks after training. The participants and their trainers also provided user feedback via semi-structured interviews.ResultsMajority of the participants and trainers found the REAP program to be useful and interesting. They also found that the augmented reality games were user-friendly and provided a unique opportunity to acquire new skills. Participants who engaged in this program showed a significant improvement in vocational skills and aspects of cognitive skills, which were maintained eight weeks after training.ConclusionThe gamified augmented reality vocational training was feasible and accepted by both adults with intellectual and developmental disabilities and their trainers. When integrated with bridging sessions to facilitate transfer of learning to existing work therapy, participants on the REAP program showed significant improvements in vocational skills and aspects of cognitive skills. Future experimental studies with larger sample size could provide stronger evidence on its effectiveness in improving vocational outcomes.

The nuclear pore complex (NPC) is the central portal for macromolecular exchange between the nucleus and cytoplasm. In all eukaryotes, NPCs assemble into an intact nuclear envelope (NE) during interphase, but the process of NPC biogenesis remains poorly characterized. Furthermore, little is known about how NPC assembly leads to the fusion of the outer and inner NE, and no factors have been identified that could trigger this event. Here, we characterize the transmembrane protein Brl1 as an NPC assembly factor required for NE fusion in budding yeast. Brl1 preferentially associates with NPC assembly intermediates and its depletion halts NPC biogenesis, leading to NE herniations that contain inner and outer ring nucleoporins but lack the cytoplasmic export platform. Furthermore, we identify an essential amphipathic helix in the luminal domain of Brl1 that mediates interactions with lipid bilayers. Mutations in this amphipathic helix lead to NPC assembly defects, and cryo-electron tomography analyses reveal multilayered herniations of the inner nuclear membrane with NPC-like structures at the neck, indicating a failure in NE fusion. Taken together, our results identify a role for Brl1 in NPC assembly and suggest a function of its amphipathic helix in mediating the fusion of the inner and outer nuclear membranes.

Background. Cognitive impairment in schizophrneia is highly prevalent, the level of impairment range from moderate to severe. It has previously beed stated that cognitive impairment was stable through the course of illness, but newer finding from long-term studies indicate that some patient have improved cognitive function. Cognitive function is marginally reactive to antipsychotic medication, and it is highly predictive of poor social and vocational outcome. Also, it constitute a ‘glass ceiling’ for psychosocial and vocational rehabilitation. Several large batteries have been developed, and internationally, there is an attempt to agree on common measurements of core areas. There is a strong rationale for cognitive remediation, namly that it might improve the ability of patients to function in everyday life and that it has no side effects. Individuals at ultra-high risk (UHR) for psychosis have significant cognitive deficits that can impede functional recovery. Methods. In this randomised, clinical trial 146 individuals at UHR for psychosis were randomly assigned to treatment as usual (TAU) or TAU plus cognitive remediation. The CR targeted neurocognitive and social cognitive remediation. Results. A total of 73 UHR individuals were assigned to TAU and 73 assigned to TAU + cognitive remediation. Cognitive remediation did not result in significant improvement on the primary outcome; the Brief Assessment of Cognition in Schizophrenia composite score at 6-month follow-up (b=-0.125, 95%CI: -0.23 to 0.172, p=0.41). Conclusion. The 20-session treatment protocol was not well received in the UHR group. Possibly situations close to everyday life could be better received and be more motivating

The lives of microbes unfold at the micron scale, and their molecular machineries operate at the nanoscale. Their study at these resolutions is key toward achieving a better understanding of their ecology. We focus on cellulose degradation of the canonical Clostridium thermocellum system to comprehend how microbes build and use their cellulosomal machinery at these nanometer scales. Degradation of cellulose, the most abundant organic polymer on Earth, is instrumental to the global carbon cycle. We reveal that bacterial cells form ‘cellulosome capsules’ driven by catalytic product-dependent dynamics, which can increase the rate of hydrolysis. Biosynthesis of this energetically costly machinery and cell growth are decoupled at the single-cell level, hinting at a division-of-labor strategy through phenotypic heterogeneity. This novel observation highlights intrapopulation interactions as key to understanding rates of fiber degradation.

The interface between the cellular actin network and diverse forms of integrin-mediated cell adhesions displays a unique capacity to serve as accurate chemical and mechanical sensors of the cell’s microenvironment. Focal adhesion-like structures of diverse cell types, podosomes in osteoclasts, and invadopodia of invading cancer cells display distinct morphologies and apparent functions. Yet, all three share a similar composition and mode of coupling between a protrusive structure (the lamellipodium, the core actin bundle of the podosome, and the invadopodia protrusion, respectively), and a nearby adhesion site. Cytoskeletal or external forces, applied to the adhesion sites, trigger a cascade of unfolding and activation of key adhesome components (e.g., talin, vinculin, integrin), which in turn, trigger the assembly of adhesion sites and generation of adhesion-mediated signals that affect cell behavior and fate. The structural and molecular mechanisms underlying the dynamic crosstalk between the actin cytoskeleton and the adhesome network are discussed.

Mechanical strength of in situ assembled nuclear lamin filaments arranged in a 3D meshwork is unclear. Here, using mechanical, structural and simulation tools, the authors report the hierarchical organization of the lamin meshwork that imparts strength and toughness to lamin filaments at par with silk and Kevlar®

Nuclear lamins are type V intermediate filament proteins that polymerize into complex filamentous meshworks at the nuclear periphery and in less structured forms throughout the nucleoplasm. Lamins interact with a wide range of nuclear proteins and are involved in numerous nuclear and cellular functions. Within the nucleus, they play roles in chromatin organization and gene regulation, nuclear shape, size, and mechanics, and the organization and anchorage of nuclear pore complexes. At the whole cell level, they are involved in the organization of the cytoskeleton, cell motility, and mechanotransduction. The expression of different lamin isoforms has been associated with developmental progression, differentiation, and tissue-specific functions. Mutations in lamins and their binding proteins result in over 15 distinct human diseases, referred to as laminopathies. The laminopathies include muscular (e.g., Emery–Dreifuss muscular dystrophy and dilated cardiomyopathy), neurological (e.g., microcephaly), and metabolic (e.g., familial partial lipodystrophy) disorders as well as premature aging diseases (e.g., Hutchinson–Gilford Progeria and Werner syndromes). How lamins contribute to the etiology of laminopathies is still unknown. In this review article, we summarize major recent findings on the structure, organization, and multiple functions of lamins in nuclear and more global cellular processes.