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Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. To better understand common genetic variation associated with brain diseases, we defined noncoding regulatory regions for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer’s disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting disease-risk variants in cell-type–specific enhancers to promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia, but not in neurons or astrocytes. These findings revise and expand the list of genes likely to be influenced by noncoding variants in AD and suggest the probable cell types in which they function.

Background In Germany, the regional Associations of Statutory Health Insurance are responsible for providing an out-of-hours on-call service for family medicine. With a shortage of resident doctors in rural areas, maintaining this service becomes more challenging. This raises the question whether the combination of a physician-run telemedical support with a primary response service led by paramedics is feasible, and in which way the telemedical support affects decision-making on scene. Methods We implemented Germany’s first Standard Operating Procedure (SOP)-based on-call service for paramedics on site with telemedical backup. Between March and June 2018, differentiated SOPs and a special medical backpack were established. Participating paramedics and telemedicine doctors were trained in SOPs and the use of telemedical software. Descriptive statistics were used to analyse data collected during the study period from July 2018 until December 2021. Results Overall, 17% of all cases required telemedical support, primarily for diagnostic confirmation of musculoskeletal disorders, unclear symptom constellations, and diseases of the cardiac circulatory system. In 56% of all telemedicine-assisted cases paramedics on scene altered their originally planned course of action following telemedical support. Conclusion This study demonstrates that telemedical assistance is a feasible alternative to the long-established doctor-run on-call system which is currently implemented throughout Germany. In the majority of cases, the telemedical input had a significant impact on the decision-making process of the responsible paramedic on scene. Limitations arise through limited information on some variables driving that decision-making process. Furthermore, the number of telemedical personnel required to facilitate the provision of telemedical assistance across an entire national healthcare system remains unclear. Trial registration German register for clinical trials DRKS00024037, registered March 18th 2022 (BfArM - Deutsches Register Klinischer Studien (DRKS).

Autism spectrum disorder (ASD) is thought to emerge during early cortical development. However, the exact developmental stages and associated molecular networks that prime disease propensity are elusive. To profile early neurodevelopmental alterations in ASD with macrocephaly, we monitored subject-derived induced pluripotent stem cells (iPSCs) throughout the recapitulation of cortical development. Our analysis revealed ASD-associated changes in the maturational sequence of early neuron development, involving temporal dysregulation of specific gene networks and morphological growth acceleration. The observed changes tracked back to a pathologically primed stage in neural stem cells (NSCs), reflected by altered chromatin accessibility. Concerted over-representation of network factors in control NSCs was sufficient to trigger ASD-like features, and circumventing the NSC stage by direct conversion of ASD iPSCs into induced neurons abolished ASD-associated phenotypes. Our findings identify heterochronic dynamics of a gene network that, while established earlier in development, contributes to subsequent neurodevelopmental aberrations in ASD.

A neuronal model of bipolar disorder based on induced pluripotent stem cell (iPSC) technology finds hyperactive action-potential firing and differential responsiveness to lithium in iPSC-derived neurons from patients with bipolar disorder. Efficacy of lithium in bipolar disorder Lithium is widely used as a mood stabilizer in bipolar disorder, but not all patients respond favourably. In this paper, Fred Gage and colleagues generated hippocampal dentate gyrus-like neurons from induced pluripotent stem cells (iPSCs) obtained from lithium-responsive and lithium-non-responsive patients with bipolar disorder in order to assess differences in cellular phenotypes. They found mitochondrial abnormalities and hyperexcitability in young iPSC-derived neurons from bipolar disorder patients. Hyperexcitability was reversed by lithium treatment only in neurons derived from lithium-responsive individuals. This suggests that hyperexcitability may be an early endophenotype of bipolar disorder and that iPSC models may be useful for the development of new therapies. Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide 1 . Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity 2 . Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models 3 , such as reduced glial cell number in the prefrontal cortex of patients 4 , upregulated activities of the protein kinase A and C pathways 5 , 6 , 7 and changes in neurotransmission 8 , 9 , 10 , 11 . However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca 2+ imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.

Activity-induced remodeling of neuronal circuits is critical for memory formation. This process relies in part on transcription, but neither the rate of activity nor baseline transcription is equal across neuronal cell types. In this study, we isolated mouse hippocampal populations with different activity levels and used single nucleus RNA-seq to compare their transcriptional responses to activation. One hour after novel environment exposure, sparsely active dentate granule (DG) neurons had a much stronger transcriptional response compared to more highly active CA1 pyramidal cells and vasoactive intestinal polypeptide (VIP) interneurons. Activity continued to impact transcription in DG neurons up to 5 h, with increased heterogeneity. By re-exposing the mice to the same environment, we identified a unique transcriptional signature that selects DG neurons for reactivation upon re-exposure to the same environment. These results link transcriptional heterogeneity to functional heterogeneity and identify a transcriptional correlate of memory encoding in individual DG neurons. Single nuclei RNA-seq has been used to characterize transcriptional signature of environment-related activity in cells of the dentate gyrus. Here the authors use this approach to show that whether a neuron will be reactivated in response to re-exposure to a previous environment can be predicted by its transcriptional signature.

This paper presents a lidar‐only state estimation and tracking framework, along with a roadside sensing unit for integration with existing urban infrastructure. Urban deployments demand scalable, real‐time tracking solutions, yet traditional remote sensing remains costly and computationally intensive, especially under perceptually degraded conditions. Our sensor node couples a single lidar with an edge computing unit and runs a computationally efficient, GPU‐free observer that simultaneously estimates object state, class, dimensions, and existence probability. The pipeline performs (i) state updates via an extended Kalman filter, (ii) dimension estimation using a 1D grid map/Bayesian update, (iii) class updates via a lookup table driven by the most probable object footprint, and (iv) existence estimation from track age and bounding box consistency. Experiments in dynamic urban‐like scenes with an instrumented passenger vehicle and additional road users demonstrate real‐time performance. Quantitative tracking accuracy is reported for the vehicle, while detection and classification performance are evaluated across all 48 annotated tracks. The complete end‐to‐end pipeline finishes within 100 ms for 99.88% of messages, with an excellent detection rate. Robustness is further confirmed under simulated wind‐induced sensor vibration. These results indicate that reliable, real‐time roadside tracking is feasible on CPU‐only edge hardware, enabling scalable, privacy‐friendly deployments within existing city infrastructure. The framework integrates with existing poles, traffic lights, and buildings, reducing deployment costs and simplifying large‐scale urban rollouts and maintenance efforts.

Prostate cancer contains nerve cells that are linked to disease progression, but their source was unknown. A mouse study reveals that cells from the brain invade prostate tumours and give rise to this nerve-cell population. The source found of newly formed nerve cells in prostate cancer.

In this study the authors have imaged the growth of adult-born dentate granule cell dendrites in vivo longitudinally over several weeks. They have found that branch addition is dependent on behavioral experience and molecular cues and that pruning acts homeostatically to promote a similar dendritic structure for all granule cells. We longitudinally imaged the developing dendrites of adult-born mouse dentate granule cells (DGCs) in vivo and found that they underwent over-branching and pruning. Exposure to an enriched environment and constraint of dendritic growth by disrupting Wnt signaling led to increased branch addition and accelerated growth, which were, however, counteracted by earlier and more extensive pruning. Our results indicate that pruning is regulated in a homeostatic fashion to oppose excessive branching and promote a similar dendrite structure in DGCs.

Direct conversion of human somatic fibroblasts into induced neurons (iNs) allows for the generation of functional neurons while bypassing any stem cell intermediary stages. Although iN technology has an enormous potential for modeling age-related diseases, as well as therapeutic approaches, the technology faces limitations due to variable conversion efficiencies and a lack of thorough understanding of the signaling pathways directing iN conversion. Here, we introduce a new all-in-one inducible lentiviral system that simplifies fibroblast transgenesis for the two pioneer transcription factors, Ngn2 and Ascl1, and markedly improves iN yields. Further, our timeline RNA-Seq data across the course of conversion has identified signaling pathways that become transcriptionally enriched during iN conversion. Small molecular modulators were identified for four signaling pathways that reliably increase the yield of iNs. Taken together, these advances provide an improved toolkit for iN technology and new insight into the mechanisms influencing direct iN conversion.