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The acquisition of a specific cellular identity is usually paralleled by a restriction of cellular plasticity. Whether and how these two processes are coordinated is poorly understood. Transcription factors called terminal selectors activate identity-specific effector genes during neuronal differentiation to define the structural and functional properties of a neuron. To study restriction of plasticity, we ectopically expressed C. elegans CHE-1, a terminal selector of ASE sensory neuron identity. In undifferentiated cells, ectopic expression of CHE-1 results in activation of ASE neuron type-specific effector genes. Once cells differentiate, their plasticity is restricted and ectopic expression of CHE-1 no longer results in activation of ASE effector genes. In striking contrast, removal of the respective terminal selectors of other sensory, inter-, or motor neuron types now enables ectopically expressed CHE-1 to activate its ASE-specific effector genes, indicating that terminal selectors not only activate effector gene batteries but also control the restriction of cellular plasticity. Terminal selectors mediate this restriction at least partially by organizing chromatin. The chromatin structure of a CHE-1 target locus is less compact in neurons that lack their resident terminal selector and genetic epistasis studies with H3K9 methyltransferases suggest that this chromatin modification acts downstream of a terminal selector to restrict plasticity. Taken together, terminal selectors activate identity-specific genes and make non-identity-defining genes less accessible, thereby serving as a checkpoint to coordinate identity specification with restriction of cellular plasticity.

Objectives. To examine gun violence with respect to hospital visits for treatment of intentional assault gunshot wounds (IGWs). Methods. IGW-coded visits among residents of Cook County, Illinois, were matched to census zip code tabulation areas (ZCTAs) to map changes in IGW visit frequencies between 2018 and 2020. Patient characteristics were compared across years, and Poisson regression models for the likelihood of an inpatient admission or in-hospital death were estimated. Results. Over the study period, Cook County residents made 7122 IGW-coded hospital visits to 89 Illinois hospitals, resulting in $342 million in charges and 24 894 hospital days. The number of visits almost doubled between 2018 and 2020, from 1553 to 3031; 6 ZCTAs had increases of more than 60 visits. Approximately one third of patients with a visit were admitted, and 6.5% died. Conclusions. Hospital statistics do not include the full toll of nonfatal gun injuries or the costs of related community-level trauma. The health care system remains crucial in implementing epidemiological approaches to violence prevention. Addressing the national spike in shootings will require large investments in community economic development and a professional public safety workforce. (Am J Public Health. 2022;112(5):795–802. https://doi.org/10.2105/AJPH.2022.306747 )

Neurons born in the embryo can undergo a protracted period of maturation lasting well into postnatal life. How gene expression changes are regulated during maturation and whether they can be recapitulated in cultured neurons remains poorly understood. Here, we show that mouse motor neurons exhibit pervasive changes in gene expression and accessibility of associated regulatory regions from embryonic till juvenile age. While motifs of selector transcription factors, ISL1 and LHX3, are enriched in nascent regulatory regions, motifs of NFI factors, activity-dependent factors, and hormone receptors become more prominent in maturation-dependent enhancers. Notably, stem cell-derived motor neurons recapitulate ~40% of the maturation expression program in vitro, with neural activity playing only a modest role as a late-stage modulator. Thus, the genetic maturation program consists of a core hardwired subprogram that is correctly executed in vitro and an extrinsically-controlled subprogram that is dependent on the in vivo context of the maturing organism. Patel et al. show that gene expression and regulation in motor neurons is dynamic until juvenile age. A core subprogram (~40% of genes) is faithfully recapitulated in cultured motor neurons, with neuronal activity playing only a modulatory role.

Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by cell-type-specific tau lesions in neurons and glia. Prior work uncovered transcriptome changes in human PSP brains, although their cell-specificity is unknown. Further, systematic data integration and experimental validation platforms to prioritize brain transcriptional perturbations as therapeutic targets in PSP are currently lacking. In this study, we combine bulk tissue ( n  = 408) and single nucleus RNAseq ( n  = 34) data from PSP and control brains with transcriptome data from a mouse tauopathy and experimental validations in Drosophila tau models for systematic discovery of high-confidence expression changes in PSP with therapeutic potential. We discover, replicate, and annotate thousands of differentially expressed genes in PSP, many of which reside in glia-enriched co-expression modules and cells. We prioritize DDR2, STOM , and KANK2 as promising therapeutic targets in PSP with striking cross-species validations. We share our findings and data via our interactive application tool PSP RNAseq Atlas ( https://rtools.mayo.edu/PSP_RNAseq_Atlas/ ). Our findings reveal robust glial transcriptome changes in PSP, provide a cross-species systems biology approach, and a tool for therapeutic target discoveries in PSP with potential application in other neurodegenerative diseases. Progressive supranuclear palsy is a devastating neurological disorder without treatment. Here, the authors leveraged omics data and model organisms to nominate, prioritize, and validate high-confidence candidate genes as therapeutic targets.

Objective We characterized the evolution of neurologic symptoms and self‐perceived recovery of non‐hospitalized COVID‐19 “long haulers” 6–9 months after their initial Neuro‐COVID‐19 clinic evaluation. Methods In this follow‐up study on the first 100 patients, 50 SARS‐CoV‐2 laboratory‐positive (SARS‐CoV‐2+), and 50 laboratory‐negative (SARS‐CoV‐2−), evaluated at our Neuro‐COVID‐19 clinic between May and November 2020, patients completed phone questionnaires on their neurologic symptoms, subjective impression of recovery and quality of life. Results Of 52 patients who completed the study (27 SARS‐CoV‐2+, 25 SARS‐CoV‐2−) a median 14.8 (range 11–18) months after symptom onset, mean age was 42.8 years, 73% were female, and 77% were vaccinated for SARS‐CoV‐2. Overall, there was no significant change in the frequency of most neurologic symptoms between first and follow‐up evaluations, including “brain fog” (81 vs. 71%), numbness/tingling (69 vs. 65%), headache (67 vs. 54%), dizziness (50 vs. 54%), blurred vision (34 vs. 44%), tinnitus (33 vs. 42%), and fatigue (87 vs. 81%). However, dysgeusia and anosmia decreased overall (63 vs. 27%, 58 vs. 21%, both p < 0.001). Conversely, heart rate and blood pressure variation (35 vs. 56%, p = 0.01) and gastrointestinal symptoms (27 vs. 48%, p = 0.04) increased at follow‐up. Patients reported improvements in their recovery, cognitive function, and fatigue, but quality of life measures remained lower than the US normative population (p < 0.001). SARS‐CoV‐2 vaccination did not have a positive or detrimental impact on cognitive function or fatigue. Interpretation Non‐hospitalized COVID‐19 “long haulers” continue to experience neurologic symptoms, fatigue, and compromised quality of life 14.8 months after initial infection.

Selective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable in Alzheimer’s disease (AD), however the degree of involvement of the different brain regions differs among patients. We classified corticolimbic patterns of neurofibrillary tangles in postmortem tissue to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. We identified hippocampal gene expression changes associated with hippocampal vulnerability and used machine learning to identify genes that were associated with AD neuropathology, including SERPINA5 , RYBP , SLC38A2 , FEM1B , and PYDC1 . Further histologic and biochemical analyses suggested SERPINA5 expression is associated with tau expression in the brain. Our study highlights the importance of embracing heterogeneity of the human brain in disease to identify disease-relevant gene expression. Alzheimer’s disease (AD) is typically associated with hippocampal and cortical pathology, although hippocampal sparing and limbic predominant forms exist. The authors use transcriptomic analysis and neuropathology to identify genes associated with selective hippocampal vulnerability in AD.

To uncover molecular changes underlying blood-brain-barrier dysfunction in Alzheimer’s disease, we performed single nucleus RNA sequencing in 24 Alzheimer’s disease and control brains and focused on vascular and astrocyte clusters as main cell types of blood-brain-barrier gliovascular-unit. The majority of the vascular transcriptional changes were in pericytes. Of the vascular molecular targets predicted to interact with astrocytic ligands, SMAD3 , upregulated in Alzheimer’s disease pericytes, has the highest number of ligands including VEGFA , downregulated in Alzheimer’s disease astrocytes. We validated these findings with external datasets comprising 4,730 pericyte and 150,664 astrocyte nuclei. Blood SMAD3 levels are associated with Alzheimer’s disease-related neuroimaging outcomes. We determined inverse relationships between pericytic SMAD3 and astrocytic VEGFA in human iPSC and zebrafish models. Here, we detect vast transcriptome changes in Alzheimer’s disease at the gliovascular-unit, prioritize perturbed pericytic SMAD3 -astrocytic VEGFA interactions, and validate these in cross-species models to provide a molecular mechanism of blood-brain-barrier disintegrity in Alzheimer’s disease. Systematic studies are needed to discover molecular determinants of blood brain barrier dysfunction in Alzheimer’s disease. This study identifies perturbed pericytic SMAD3-astrocytic VEGFA interactions as a potential driver of this dysfunction.

In this study, the authors show that chromatin of Hox genes is arranged in discrete domains. Patterning signals trigger recruitment of transcription factors to these domains, leading to rapid clearance of repressive histone methylation. This provides further insight into the transcriptional mechanisms underlying the establishment of epigenetically inherited rostrocaudal neuronal identity. Hox genes controlling motor neuron subtype identity are expressed in rostrocaudal patterns that are spatially and temporally collinear with their chromosomal organization. Here we demonstrate that Hox chromatin is subdivided into discrete domains that are controlled by rostrocaudal patterning signals that trigger rapid, domain-wide clearance of repressive histone H3 Lys27 trimethylation (H3K27me3) polycomb modifications. Treatment of differentiating mouse neural progenitors with retinoic acid leads to activation and binding of retinoic acid receptors (RARs) to the Hox1 – Hox5 chromatin domains, which is followed by a rapid domain-wide removal of H3K27me3 and acquisition of cervical spinal identity. Wnt and fibroblast growth factor (FGF) signals induce expression of the Cdx2 transcription factor that binds and clears H3K27me3 from the Hox1 – Hox9 chromatin domains, leading to specification of brachial or thoracic spinal identity. We propose that rapid clearance of repressive modifications in response to transient patterning signals encodes global rostrocaudal neural identity and that maintenance of these chromatin domains ensures the transmission of positional identity to postmitotic motor neurons later in development.

Large-scale brain bulk-RNAseq studies identified molecular pathways implicated in Alzheimer’s disease (AD), however these findings can be confounded by cellular composition changes in bulk-tissue. To identify cell intrinsic gene expression alterations of individual cell types, we designed a bioinformatics pipeline and analyzed three AD and control bulk-RNAseq datasets of temporal and dorsolateral prefrontal cortex from 685 brain samples. We detected cell-proportion changes in AD brains that are robustly replicable across the three independently assessed cohorts. We applied three different algorithms including our in-house algorithm to identify cell intrinsic differentially expressed genes in individual cell types (CI-DEGs). We assessed the performance of all algorithms by comparison to single nucleus RNAseq data. We identified consensus CI-DEGs that are common to multiple brain regions. Despite significant overlap between consensus CI-DEGs and bulk-DEGs, many CI-DEGs were absent from bulk-DEGs. Consensus CI-DEGs and their enriched GO terms include genes and pathways previously implicated in AD or neurodegeneration, as well as novel ones. We demonstrated that the detection of CI-DEGs through computational deconvolution methods is promising and highlight remaining challenges. These findings provide novel insights into cell-intrinsic transcriptional changes of individual cell types in AD and may refine discovery and modeling of molecular targets that drive this complex disease.

We present a novel approach to providing greater insight into the characteristics of an unlabelled dataset, increasing the efficiency with which labelled datasets can be created. We leverage dimension-reduction techniques in combination with autoencoders to create an efficient feature representation for image tiles derived from remote sensing satellite imagery. The proposed methodology consists of two main stages. Firstly, an autoencoder network is utilised to reduce the high-dimensional image tile data into a compact and expressive latentfeature representation. Subsequently, features are further reduced to a two-dimensional embedding space using the manifold learning algorithm Uniform Manifold Approximation and Projection (UMAP) and t-distributed Stochastic Neighbour Embedding (t-SNE). This step enables the visualization of the image tile clusters in a 2D plot, providing an intuitive and interactive representation that can be used to aid rapid and geographically distributed image labelling. To facilitate the labelling process, our approach allows users to interact with the 2D visualization and label clusters based on their domain knowledge. In cases where certain classes are not effectively separated, users can re-apply dimension reduction to interactively refine subsets of clusters and achieve better class separation, enabling a comprehensively labelled dataset. We evaluate the proposed approach on real-world remote sensing satellite image datasets and demonstrate its effectiveness in achieving accurate and efficient image tile clustering and labelling. Users actively participate in the labelling process through our interactive approach, leading to enhanced relevance of the labelled data, by allowing domain experts to contribute their expertise and enrich the dataset for improved downstream analysis and applications.