Search

Mutations in GBA1 encoding the lysosomal enzyme β-glucocerebrosidase (GCase) are among the most prevalent genetic susceptibility factors for Parkinsons disease (PD), with 10-30% of carriers developing the disease. To identify genetic modifiers contributing to the incomplete penetrance, we examined the effect of 1634 human transcription factors (TFs) on GCase activity in lysates of an engineered human glioblastoma line homozygous for the pathogenic GBA1 L444P variant. Using an arrayed CRISPR activation library, we uncovered 11 TFs as regulators of GCase activity. Among these, activation of MITF and TFEC increased lysosomal GCase activity in live cells, while activation of ONECUT2 and USF2 decreased it. While MITF, TFEC, and USF2 affected GBA1 transcription, ONECUT2 might control GCase trafficking. The effects of MITF, TFEC, and USF2 on lysosomal GCase activity were reproducible in iPSC-derived neurons from PD patients. Our study provides a systematic approach to identifying modulators of GCase activity and deepens our understanding of the mechanisms regulating GCase.

Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous systems limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be repopulated through the transplantation of stem cell-derived neurons or via the induction of endogenous transdifferentiation. The RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium was established to address the challenges associated with the therapeutic repair of the visual pathway in optic neuropathy. In 2022, the RReSTORe Consortium initiated ongoing international collaborative discussions to advance the RGC repopulation field and has identified five critical areas of focus: (1) RGC development and differentiation, (2) Transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) Inner retinal wiring, and (5) Eye-to-brain connectivity. Here, we discuss the most pertinent questions and challenges that exist on the path to clinical translation and suggest experimental directions to propel this work going forward. Using these five subtopic discussion groups (SDGs) as a framework, we suggest multidisciplinary approaches to restore the diseased visual pathway by leveraging groundbreaking insights from developmental neuroscience, stem cell biology, molecular biology, optical imaging, animal models of optic neuropathy, immunology & immunotolerance, neuropathology & neuroprotection, materials science & biomedical engineering, and regenerative neuroscience. While significant hurdles remain, the RReSTORe Consortiums efforts provide a comprehensive roadmap for advancing the RGC repopulation field and hold potential for transformative progress in restoring vision in patients suffering from optic neuropathies.

La pandemia de COVID-19 ha transformado profundamente las estrategias educativas empleadas en diversos cursos universitarios. En particular, los cursos de Agronegocios no han sido ajenos a estos cambios. El objetivo del estudio fue explorar la percepción del estudiantado de Agronomía respecto a cómo las adaptaciones pedagógicas requeridas durante la pandemia, incluida la transición entre modalidades presenciales y virtuales, afectaron su motivación y capacidad de adaptación a las nuevas tecnologías. Se llevó a cabo un estudio con 84 estudiantes de grado de la carrera de Agronomía de la Universidad de Costa Rica, Sede Rodrigo Facio, durante el mes de junio de 2022. Las personas participantes completaron un cuestionario estructurado con 30 ítems, en el que se evaluaron aspectos como el perfil demográfico, la conectividad a Internet, la disponibilidad de equipamiento informático, la aceptación de tecnologías virtuales, la percepción sobre la calidad de los contenidos impartidos, y la motivación personal del estudiantado. Los datos recopilados fueron analizados utilizando modelos de ecuaciones estructurales para examinar las relaciones causales entre las variables de interés. Se observó que la motivación personal tuvo un efecto significativo (β=0.23) en la percepción del estudiantado sobre la enseñanza de Agronegocios durante la pandemia. Este estudio subraya la importancia que el estudiantado de Agronomía le otorga a la calidad de la enseñanza por parte del profesorado y a la realización de actividades prácticas como impulsoras clave de su motivación en el aprendizaje de los contenidos de Agronegocios.

Background: Traditional healing practices are prevalent in rural and mountainous areas of India where Western medicine is not accessible. WHO guidelines recommend integration of traditional and Western medicine to meet rural primary care needs. We explored three dimensions of rural patients' decision-making and satisfaction with their medical care: pregnancy-related concerns, pediatric care for children under five, and acute injuries. Methods: We conducted a qualitative study using a phenomenological approach in India's Spiti Valley between August and October 2023. Sixteen individuals, age 18 years and older, participated in one-on-one interviews. The interviews were transcribed from Hindi into English, reviewed for accuracy by a native speaker, and imported into Dedoose software. Data were analyzed using inductive coding. Findings: Multiparous women aged 35–44 were concerned about pregnancy complications, leading them to choose Western medicine despite access and cost barriers. Pediatric illness requiring urgent care at night was a concern for women with children under five. Those in the injuries group reported having to travel for care beyond basic first aid. Overall, concerns were about limited access to some services locally, as well as costs of travel, medical procedures, and medications when services were obtained beyond the local area. Interpretation: All participants considered their traditional healer their first point of contact for medical care. A number of Western medical services were not available locally. These findings suggest a need to strengthen access to and integration of Western and traditional medical care in rural settings in India.

The United Nations (UN)’s call for a decade of “ecosystem restoration” was prompted by the need to address the extensive impact of anthropogenic activities on natural ecosystems. Marine ecosystem restoration is increasingly necessary due to increasing habitat degredation in deep waters (>200 m depth). At these depths, which are far beyond those accessible by divers, only established and emerging robotic platforms such as remotely operated vehicles (ROVs), autonomous underwater vehicles (AUVs), landers, and crawlers can operate through manipulators and multiparametric sensor arrays (e.g., optoacoustic imaging, omics, and environmental probes). The use of advanced technologies for deep-sea ecosystem restoration can provide: ① high-resolution three-dimensional (3D) imaging and acoustic mapping of substrates and key taxa, ② physical manipulation of substrates and key taxa, ③ real-time supervision of remote operations and long-term ecological monitoring, and ④ the potential to work autonomously. Here, we describe how robotic platforms with in situ manipulation capabilities and payloads of innovative sensors could autonomously conduct active restoration and monitoring across large spatial scales. We expect that these devices will be particularly useful in deep-sea habitats, such as ① reef-building cold-water corals, ② soft-bottom bamboo corals, and ③ soft-bottom fishery resources that have already been damaged by offshore industries (i.e., fishing and oil/gas).

Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions. To address these issues, we assembled a group of multidisciplinary experts to discuss our current understanding of microglial states as a dynamic concept and the importance of addressing microglial function. Here, we provide a conceptual framework and recommendations on the use of microglial nomenclature for researchers, reviewers, and editors, which will serve as the foundations for a future white paper.

BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.