Nuclear blebs are associated with destabilized chromatin packing domains.

Disrupted nuclear shape is associated with multiple pathological processes including premature aging disorders, cancer-relevant chromosomal rearrangements, and DNA damage. Nuclear blebs (i.e., herniations of the nuclear envelope) have been induced by (1) nuclear compression, (2) nuclear migration (e.g., cancer metastasis), (3) actin contraction, (4) lamin mutation or depletion, and (5) heterochromatin enzyme inhibition. Recent work has shown that chromatin transformation is a hallmark of bleb formation, but the transformation of higher-order structures in blebs is not well understood. As higher-order chromatin has been shown to assemble into nanoscopic packing domains, we investigated if (1) packing domain organization is altered within nuclear blebs and (2) if alteration in packing domain structure contributed to bleb formation. Using Dual-Partial Wave Spectroscopic microscopy, we show that chromatin packing domains within blebs are transformed both by B-type lamin depletion and the inhibition of heterochromatin enzymes compared to the nuclear body. Pairing these results with single-molecule localization microscopy of constitutive heterochromatin, we show fragmentation of nanoscopic heterochromatin domains within bleb domains. Overall, these findings indicate that translocation into blebs results in a fragmented higher-order chromatin structure. SUMMARY STATEMENT: Nuclear blebs are linked to various pathologies, including cancer and premature aging disorders. We investigate alterations in higher-order chromatin structure within blebs, revealing fragmentation of nanoscopic heterochromatin domains.

Depletion of lamins B1 and B2 promotes chromatin mobility and induces differential gene expression by a mesoscale-motion-dependent mechanism.

BACKGROUND: B-type lamins are critical nuclear envelope proteins that interact with the three-dimensional genomic architecture. However, identifying the direct roles of B-lamins on dynamic genome organization has been challenging as their joint depletion severely impacts cell viability. To overcome this, we engineered mammalian cells to rapidly and completely degrade endogenous B-type lamins using Auxin-inducible degron technology. RESULTS: Using live-cell Dual Partial Wave Spectroscopic (Dual-PWS) microscopy, Stochastic Optical Reconstruction Microscopy (STORM), in situ Hi-C, CRISPR-Sirius, and fluorescence in situ hybridization (FISH), we demonstrate that lamin B1 and lamin B2 are critical structural components of the nuclear periphery that create a repressive compartment for peripheral-associated genes. Lamin B1 and lamin B2 depletion minimally alters higher-order chromatin folding but disrupts cell morphology, significantly increases chromatin mobility, redistributes both constitutive and facultative heterochromatin, and induces differential gene expression both within and near lamin-associated domain (LAD) boundaries. Critically, we demonstrate that chromatin territories expand as upregulated genes within LADs radially shift inwards. Our results indicate that the mechanism of action of B-type lamins comes from their role in constraining chromatin motion and spatial positioning of gene-specific loci, heterochromatin, and chromatin domains. CONCLUSIONS: Our findings suggest that, while B-type lamin degradation does not significantly change genome topology, it has major implications for three-dimensional chromatin conformation at the single-cell level both at the lamina-associated periphery and the non-LAD-associated nuclear interior with concomitant genome-wide transcriptional changes. This raises intriguing questions about the individual and overlapping roles of lamin B1 and lamin B2 in cellular function and disease.

Detecting schizophrenia with 3D structural brain MRI using deep learning.

Schizophrenia is a chronic neuropsychiatric disorder that causes distinct structural alterations within the brain. We hypothesize that deep learning applied to a structural neuroimaging dataset could detect disease-related alteration and improve classification and diagnostic accuracy. We tested this hypothesis using a single, widely available, and conventional T1-weighted MRI scan, from which we extracted the 3D whole-brain structure using standard post-processing methods. A deep learning model was then developed, optimized, and evaluated on three open datasets with T1-weighted MRI scans of patients with schizophrenia. Our proposed model outperformed the benchmark model, which was also trained with structural MR images using a 3D CNN architecture. Our model is capable of almost perfectly (area under the ROC curve = 0.987) distinguishing schizophrenia patients from healthy controls on unseen structural MRI scans. Regional analysis localized subcortical regions and ventricles as the most predictive brain regions. Subcortical structures serve a pivotal role in cognitive, affective, and social functions in humans, and structural abnormalities of these regions have been associated with schizophrenia. Our finding corroborates that schizophrenia is associated with widespread alterations in subcortical brain structure and the subcortical structural information provides prominent features in diagnostic classification. Together, these results further demonstrate the potential of deep learning to improve schizophrenia diagnosis and identify its structural neuroimaging signatures from a single, standard T1-weighted brain MRI.

Depletion of lamins B1 and B2 alters chromatin mobility and induces differential gene expression by a mesoscale-motion dependent mechanism.

BACKGROUND: B-type lamins are critical nuclear envelope proteins that interact with the 3D genomic architecture. However, identifying the direct roles of B-lamins on dynamic genome organization has been challenging as their joint depletion severely impacts cell viability. To overcome this, we engineered mammalian cells to rapidly and completely degrade endogenous B-type lamins using Auxin-inducible degron (AID) technology. RESULTS: Paired with a suite of novel technologies, live-cell Dual Partial Wave Spectroscopic (Dual-PWS) microscopy, in situ Hi-C, and CRISPR-Sirius, we demonstrate that lamin B1 and lamin B2 depletion transforms chromatin mobility, heterochromatin positioning, gene expression, and loci-positioning with minimal disruption to mesoscale chromatin folding. Using the AID system, we show that the disruption of B-lamins alters gene expression both within and outside lamin associated domains, with distinct mechanistic patterns depending on their localization. Critically, we demonstrate that chromatin dynamics, positioning of constitutive and facultative heterochromatic markers, and chromosome positioning near the nuclear periphery are significantly altered, indicating that the mechanism of action of B-type lamins is derived from their role in maintaining chromatin dynamics and spatial positioning. CONCLUSIONS: Our findings suggest that the mechanistic role of B-type lamins is stabilization of heterochromatin and chromosomal positioning along the nuclear periphery. We conclude that degrading lamin B1 and lamin B2 has several functional consequences related to both structural disease and cancer.

Emprendimiento Social y Trabajo Social Colombiano. Análisis de Caso / Social Entrepreneurship and Colombian Social Work. Case Analysis / Empreendedorismo Social e Serviço Social Colombiano. Análise de Caso

Resumen Introducción: el emprendimiento social realizado por profesionales del trabajo social en Colombia plantea diversos retos en la comunidad académica, evidenciando la emergencia del emprendimiento social como nuevos canales para alcanzar resultados desde el abordaje de las problemáticas. Objetivo: indagar las características de los/las emprendedoras sociales graduadas en el trabajo social en Bogotá. Materiales y métodos: se realiza una investigación cualitativa mediante el análisis de caso de estudio, con la técnica de entrevista semiestructurada, en la cual se tuvieron como categorías principales la relación con la comunidad, relaciones con el Estado, recursos y gestión-organización. Resultados: en cuanto a las relaciones con la comunidad, es fundamental que los emprendedores/as sociales se relacionen directamente con las comunidades y fortalezcan el tejido social. En las relaciones con el Estado, se identifica la importancia de fortalecer la participación y la responsabilidad de este, así como de otros actores. Para la gestión de recursos, las/os trabajadoras/es sociales identifican la importancia del trabajo en equipo u otras habilidades para el desarrollo e implementación del emprendimiento. Por último, en la gestión-organización se rescata la importancia de la debida administración de los recursos económicos y humanos, así como la autosostenibilidad de los emprendimientos sociales. Conclusión: se evidencia la necesidad de formación en procesos de emprendimiento social para el trabajo social en Colombia, ya que, permite un cambio a través de la incidencia social, como ejercicio profesional y alternativa laboral.

Abstract Introduction: the social entrepreneurship developed by social work professionals in Colombia poses several challenges in the academic community, highlighting the emergence of social entrepreneurship as new channels to achieve results from addressing problems. Objective: to ask about the characteristics of social entrepreneurs who graduated in social work in Bogotá. Material and methods: a qualitative research are carried out through a case study analysis, using the semi-structured interview technique, in which the main categories of the relationship with the community, relations with the country, resources and management-organization have been studied classified. Results: in community relations, it is essential that social entrepreneurs interact directly with the communities and strengthen the social fabric. In relations with the country, the importance of strengthening the active participation and responsibility of the country, as well as of other actors, is identified. For resource management, social workers identify the importance of working in teams or other skills for the development and implementation of the company. Finally, in management-organization, the importance of poor management of economic and human resources is highlighted, as well as the self-sustainability of social entrepreneurship. Conclusion: there is a need for training in social entrepreneurship processes for social work in Colombia, which allows a change through social impact, such as professional training and alternative employment.

Resumo Introdução: O empreendedorismo social desenvolvido por profissionais de serviço social na Colômbia apresenta vários desafios na comunidade acadêmica, destacando o surgimento do empreendedorismo como novos canais para obter resultados a partir do tratamento de problemas. Objetivo: conhecer as características dos empreendedores sociais formados em serviço social em Bogotá. Material e métodos: é realizada uma pesquisa qualitativa por meio da análise de um estudo de caso, utilizando a técnica da entrevista semiestruturada, em que foram estudadas as principais categorias da relação com a comunidade, relações com o Estado, recursos e gerenciamento-organização. Resultados: no relacionamento com a comunidade, é fundamental que os empreendedores sociais interajam diretamente com as comunidades e fortaleçam o tecido social. Nas relações com o Estado, identifica-se a importância de fortalecer a participação ativa e a responsabilidade do Estado, bem como de outros atores. Para o gerenciamento de recursos, os assistentes sociais identificam a importância do trabalho em equipe ou outras habilidades para o desenvolvimento e implantação da empresa. Por fim, na gerenciamento-organização, destaca-se a importância da má gestão dos recursos econômicos e humanos, bem como a autossustentabilidade do empreendedorismo social. Conclusão: há necessidade de formação em processos de empreendedorismo social para o serviço social na Colômbia, o que permite uma mudança por meio do impacto social, como a formação profissional e alternativas de emprego.

Monitoring at-home prosthesis control improvements through real-time data logging.

Objective.Validating the ability for advanced prostheses to improve function beyond the laboratory remains a critical step in enabling long-term benefits for prosthetic limb users.Approach.A nine week take-home case study was completed with a single participant with upper limb amputation and osseointegration to better understand how an advanced prosthesis is used during daily activities. The participant was already an expert prosthesis user and used the Modular Prosthetic Limb (MPL) at home during the study. The MPL was controlled using wireless electromyography (EMG) pattern recognition-based movement decoding. Clinical assessments were performed before and after the take-home portion of the study. Data was recorded using an onboard data log in order to measure daily prosthesis usage, sensor data, and EMG data.Main results.The participant's continuous prosthesis usage steadily increased (p= 0.04, max = 5.5 h) over time and over 30% of the total time was spent actively controlling the prosthesis. The duration of prosthesis usage after each pattern recognition training session also increased over time (p= 0.04), resulting in up to 5.4 h of usage before retraining the movement decoding algorithm. Pattern recognition control accuracy improved (1.2% per week,p< 0.001) with a maximum number of ten classes trained at once and the transitions between different degrees of freedom increased as the study progressed, indicating smooth and efficient control of the advanced prosthesis. Variability of decoding accuracy also decreased with prosthesis usage (p< 0.001) and 30% of the time was spent performing a prosthesis movement. During clinical evaluations, Box and Blocks and the Assessment of the Capacity for Myoelectric Control scores increased by 43% and 6.2%, respectively, demonstrating prosthesis functionality and the NASA Task Load Index scores decreased, on average, by 25% across assessments, indicating reduced cognitive workload while using the MPL, over the nine week study.Significance. In this case study, we demonstrate that an onboard system to monitor prosthesis usage enables better understanding of how prostheses are incorporated into daily life. That knowledge can support the long-term goal of completely restoring independence and quality of life to individuals living with upper limb amputation.