Cell-type-specific 3D epigenomes in the developing human cortex.

Lineage-specific epigenomic changes during human corticogenesis have been difficult to study owing to challenges with sample availability and tissue heterogeneity. For example, previous studies using single-cell RNA sequencing identified at least 9 major cell types and up to 26 distinct subtypes in the dorsal cortex alone1,2. Here we characterize cell-type-specific cis-regulatory chromatin interactions, open chromatin peaks, and transcriptomes for radial glia, intermediate progenitor cells, excitatory neurons, and interneurons isolated from mid-gestational samples of the human cortex. We show that chromatin interactions underlie several aspects of gene regulation, with transposable elements and disease-associated variants enriched at distal interacting regions in a cell-type-specific manner. In addition, promoters with increased levels of chromatin interactivity-termed super-interactive promoters-are enriched for lineage-specific genes, suggesting that interactions at these loci contribute to the fine-tuning of transcription. Finally, we develop CRISPRview, a technique that integrates immunostaining, CRISPR interference, RNAscope, and image analysis to validate cell-type-specific cis-regulatory elements in heterogeneous populations of primary cells. Our findings provide insights into cell-type-specific gene expression patterns in the developing human cortex and advance our understanding of gene regulation and lineage specification during this crucial developmental window.

Sensory experience remodels genome architecture in neural circuit to drive motor learning.

Neuronal-activity-dependent transcription couples sensory experience to adaptive responses of the brain including learning and memory. Mechanisms of activity-dependent gene expression including alterations of the epigenome have been characterized1-8. However, the fundamental question of whether sensory experience remodels chromatin architecture in the adult brain in vivo to induce neural code transformations and learning and memory remains to be addressed. Here we use in vivo calcium imaging, optogenetics and pharmacological approaches to show that granule neuron activation in the anterior dorsal cerebellar vermis has a crucial role in a delay tactile startle learning paradigm in mice. Of note, using large-scale transcriptome and chromatin profiling, we show that activation of the motor-learning-linked granule neuron circuit reorganizes neuronal chromatin including through long-distance enhancer-promoter and transcriptionally active compartment interactions to orchestrate distinct granule neuron gene expression modules. Conditional CRISPR knockout of the chromatin architecture regulator cohesin in anterior dorsal cerebellar vermis granule neurons in adult mice disrupts enhancer-promoter interactions, activity-dependent transcription and motor learning. These findings define how sensory experience patterns chromatin architecture and neural circuit coding in the brain to drive motor learning.

Publisher Correction: Sensory experience remodels genome architecture in neural circuit to drive motor learning.

In this Letter, '≥' should be '≤' in the sentence: "Intra-chromosomal reads were further split into short-range reads (≥1 kb) and long-range reads (>1 kb)". This error has been corrected online.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Transcriptional network orchestrating regional patterning of cortical progenitors.

We uncovered a transcription factor (TF) network that regulates cortical regional patterning in radial glial stem cells. Screening the expression of hundreds of TFs in the developing mouse cortex identified 38 TFs that are expressed in gradients in the ventricular zone (VZ). We tested whether their cortical expression was altered in mutant mice with known patterning defects (Emx2, Nr2f1, and Pax6), which enabled us to define a cortical regionalization TF network (CRTFN). To identify genomic programming underlying this network, we performed TF ChIP-seq and chromatin-looping conformation to identify enhancer-gene interactions. To map enhancers involved in regional patterning of cortical progenitors, we performed assays for epigenomic marks and DNA accessibility in VZ cells purified from wild-type and patterning mutant mice. This integrated approach has identified a CRTFN and VZ enhancers involved in cortical regional patterning in the mouse.

Allele frequency dynamics in a pedigreed natural population.

A central goal of population genetics is to understand how genetic drift, natural selection, and gene flow shape allele frequencies through time. However, the actual processes underlying these changes-variation in individual survival, reproductive success, and movement-are often difficult to quantify. Fully understanding these processes requires the population pedigree, the set of relationships among all individuals in the population through time. Here, we use extensive pedigree and genomic information from a long-studied natural population of Florida Scrub-Jays (Aphelocoma coerulescens) to directly characterize the relative roles of different evolutionary processes in shaping patterns of genetic variation through time. We performed gene dropping simulations to estimate individual genetic contributions to the population and model drift on the known pedigree. We found that observed allele frequency changes are generally well predicted by accounting for the different genetic contributions of founders. Our results show that the genetic contribution of recent immigrants is substantial, with some large allele frequency shifts that otherwise may have been attributed to selection actually due to gene flow. We identified a few SNPs under directional short-term selection after appropriately accounting for gene flow. Using models that account for changes in population size, we partitioned the proportion of variance in allele frequency change through time. Observed allele frequency changes are primarily due to variation in survival and reproductive success, with gene flow making a smaller contribution. This study provides one of the most complete descriptions of short-term evolutionary change in allele frequencies in a natural population to date.

VENOUS THROMBOEMBOLISM IN THE EMERGENCY DEPARTMENT - SINGLE-CENTER EXPERIENCE.

Given the importance of early recognition of acute venous thromboembolism (VTE) and the nonspecificity of its symptoms and signs, it is essential to follow the guidelines for diagnostic and therapeutic decisions. Ultrasound examination of the entire lower extremity is currently the standard diagnostic method for symptomatic patients with a clinical probability of deep vein thrombosis (DVT) according to the Wells scoring system. The aim of this study is to show the demographic structure and analyze the number of patients in the emergency department with suspected venous thrombosis. In the past 10 years, 2,022 patients with DVT and 686 with pulmonary emboli have been diagnosed. Despite adherence to the diagnostic protocol, nearly two-thirds of patients require early ultrasound diagnosis. One-fifth of patients had thrombosis of the superficial venous system of the leg or arm. Thrombus was present in the veins of the lower leg in 37% of patients with DVT. The presence of thrombi above the knee, involving the deep femoropopliteal venous system, was found in as much as one-third of patients. These findings and current guidelines suggest that there is a paradigm shift toward more frequent use of DOAC in patients with DVT. However, greater educational efforts may be needed for many physicians to become comfortable with the use of DOAC in the outpatient management of patient populations at low risk for pulmonary embolism.

Resilience and Quality of Life of Patients with Breast Cancer.

INTRODUCTION: Breast cancer is the most common malignancy in women. Modern research attempts to investigate the relationship between psychoemotional parameters and the length of survival of breast cancer patients. Understanding the factors which affect a higher level of resilience can have important clinical implications and can represent a guiding principle for designing psychological interventions that would accelerate recovery and improve the quality of life of cancer patients. To explore the relationship between resilience and quality of life of women with breast cancer. METHODS: The study was conducted at the Clinic of Oncology of the University Clinical Hospital Mostar, which included 60 subjects. Objective realization was achieved through using the socio-demographic questionnaire purposely made for this research, the quality of life questionnaire WHQOL-BREF and the psychological resilience questionnaire CD-RISC-25. RESULTS: Subjects treated with radiotherapy achieved statistically significantly higher scores on subscales of the quality of life: mental health, social relations, and the environment. No statistically significant correlations were found between the level of resilience and results in the domains of quality of life. CONCLUSION: There is not a statistically significant association between resilience levels and quality of life in patients with breast cancer.

Computational modelling predicts substantial carbon assimilation gains for C3 plants with a single-celled C4 biochemical pump.

Achieving global food security for the estimated 9 billion people by 2050 is a major scientific challenge. Crop productivity is fundamentally restricted by the rate of fixation of atmospheric carbon. The dedicated enzyme, RubisCO, has a low turnover and poor specificity for CO2. This limitation of C3 photosynthesis (the basic carbon-assimilation pathway present in all plants) is alleviated in some lineages by use of carbon-concentrating-mechanisms, such as the C4 cycle-a biochemical pump that concentrates CO2 near RubisCO increasing assimilation efficacy. Most crops use only C3 photosynthesis, so one promising research strategy to boost their productivity focuses on introducing a C4 cycle. The simplest proposal is to use the cycle to concentrate CO2 inside individual chloroplasts. The photosynthetic efficiency would then depend on the leakage of CO2 out of a chloroplast. We examine this proposal with a 3D spatial model of carbon and oxygen diffusion and C4 photosynthetic biochemistry inside a typical C3-plant mesophyll cell geometry. We find that the cost-efficiency of C4 photosynthesis depends on the gas permeability of the chloroplast envelope, the C4 pathway having higher quantum efficiency than C3 for permeabilities below 300 µm/s. However, at higher permeabilities the C4 pathway still provides a substantial boost to carbon assimilation with only a moderate decrease in efficiency. The gains would be capped by the ability of chloroplasts to harvest light, but even under realistic light regimes a 100% boost to carbon assimilation is possible. This could be achieved in conjunction with lower investment in chloroplasts if their cell surface coverage is also reduced. Incorporation of this C4 cycle into C3 crops could thus promote higher growth rates and better drought resistance in dry, high-sunlight climates.

MAPS: Model-based analysis of long-range chromatin interactions from PLAC-seq and HiChIP experiments.

Hi-C and chromatin immunoprecipitation (ChIP) have been combined to identify long-range chromatin interactions genome-wide at reduced cost and enhanced resolution, but extracting information from the resulting datasets has been challenging. Here we describe a computational method, MAPS, Model-based Analysis of PLAC-seq and HiChIP, to process the data from such experiments and identify long-range chromatin interactions. MAPS adopts a zero-truncated Poisson regression framework to explicitly remove systematic biases in the PLAC-seq and HiChIP datasets, and then uses the normalized chromatin contact frequencies to identify significant chromatin interactions anchored at genomic regions bound by the protein of interest. MAPS shows superior performance over existing software tools in the analysis of chromatin interactions from multiple PLAC-seq and HiChIP datasets centered on different transcriptional factors and histone marks. MAPS is freely available at https://github.com/ijuric/MAPS.

The Positive Effects of Running on Mental Health.

Working as a team with patients who are also recreational runners and managing a running school in the City of Mostar had made us thinking on how recreational running affects the mental health in individuals. Previous literature is pretty old dated, so we found this even more interesting. We have wondered why there is no more recent literature on this subject. So, while working on this mini review and discussing on this subjects we came up with an idea on a research about self esteem and life quality of individuals pre and post running school experience. Previous studies show that consistent running results in a number of positive psychological changes among diverse populations. In a study of Kenneth E.C. ordinary nonprofessional runners were surveyed about the psychological aspects of running. Many of the respondents had started running to improve their health, and almost all noted mental and emotional benefits including relief of tension, improved self-image, and better mood. Considering therapeutic effects of running Greist et al. define running as not expensive, and unlike sorne other treatments, it has beneficiai physical side effects. Their results compare favorably with those of patients in psychotherapy and have persisted for at !east one year in follow-up. Taking in mind all of the previously published research it can be concluded that running can be a therapeutic tool for a sereies of negative psychological conditions, such ass depression, anxieta, tension, mood changes, low self esteem etc. Although, these research are a few decades old there is still no recipe or dosage for running, especially in the area of physical ilness prevention. There is much to research and to be discovered in this field.

The Strength of Selection against Neanderthal Introgression.

Hybridization between humans and Neanderthals has resulted in a low level of Neanderthal ancestry scattered across the genomes of many modern-day humans. After hybridization, on average, selection appears to have removed Neanderthal alleles from the human population. Quantifying the strength and causes of this selection against Neanderthal ancestry is key to understanding our relationship to Neanderthals and, more broadly, how populations remain distinct after secondary contact. Here, we develop a novel method for estimating the genome-wide average strength of selection and the density of selected sites using estimates of Neanderthal allele frequency along the genomes of modern-day humans. We confirm that East Asians had somewhat higher initial levels of Neanderthal ancestry than Europeans even after accounting for selection. We find that the bulk of purifying selection against Neanderthal ancestry is best understood as acting on many weakly deleterious alleles. We propose that the majority of these alleles were effectively neutral-and segregating at high frequency-in Neanderthals, but became selected against after entering human populations of much larger effective size. While individually of small effect, these alleles potentially imposed a heavy genetic load on the early-generation human-Neanderthal hybrids. This work suggests that differences in effective population size may play a far more important role in shaping levels of introgression than previously thought.

Size matters for single-cell C4 photosynthesis in Bienertia.

Bienertia cycloptera belongs to a diverse set of plants, recently discovered to perform C4 photosynthesis within individual mesophyll cells. How these plants accomplish high photosynthetic efficiency without adopting Kranz anatomy remains unanswered. By modelling the processes of diffusion, capture, and release of carbon dioxide and oxygen inside a typical Bienertia mesophyll cell geometry, we show that a spatial separation as low as 10 µm between the primary and the secondary carboxylases, can, on its own, provide enough diffusive resistance to sustain a viable C4 pathway at 20 °C, with a CO2 leakage <35%. This critical separation corresponds to a cell diameter of 50 µm, consistent with the observed range where Bienertia's mesophyll cells start to develop their characteristic mature anatomy. Our results are robust to significant alterations in model assumptions and environmental conditions, their applicability extending even to aquatic plants.

LRIG1 engages ligand VISTA and impairs tumor-specific CD8+ T cell responses.

Immune checkpoint blockade is a promising approach to activate antitumor immunity and improve the survival of patients with cancer. V-domain immunoglobulin suppressor of T cell activation (VISTA) is an immune checkpoint target; however, the downstream signaling mechanisms are elusive. Here, we identify leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) as a VISTA binding partner, which acts as an inhibitory receptor by engaging VISTA and suppressing T cell receptor signaling pathways. Mice with T cell-specific LRIG1 deletion developed superior antitumor responses because of expansion of tumor-specific cytotoxic T lymphocytes (CTLs) with increased effector function and survival. Sustained tumor control was associated with a reduction of quiescent CTLs (TCF1+ CD62Lhi PD-1low) and a reciprocal increase in progenitor and memory-like CTLs (TCF1+ PD-1+). In patients with melanoma, elevated LRIG1 expression on tumor-infiltrating CD8+ CTLs correlated with resistance to immunotherapies. These results delineate the role of LRIG1 as an inhibitory immune checkpoint receptor and propose a rationale for targeting the VISTA/LRIG1 axis for cancer immunotherapy.

VISTA promotes the metabolism and differentiation of myeloid-derived suppressor cells by STAT3 and polyamine-dependent mechanisms.

Myeloid-derived suppressor cells (MDSCs) impair antitumor immune responses. Identifying regulatory circuits during MDSC development may bring new opportunities for therapeutic interventions. We report that the V-domain suppressor of T cell activation (VISTA) functions as a key enabler of MDSC differentiation. VISTA deficiency reduced STAT3 activation and STAT3-dependent production of polyamines, which causally impaired mitochondrial respiration and MDSC expansion. In both mixed bone marrow (BM) chimera mice and myeloid-specific VISTA conditional knockout mice, VISTA deficiency significantly reduced tumor-associated MDSCs but expanded monocyte-derived dendritic cells (DCs) and enhanced T cell-mediated tumor control. Correlated expression of VISTA and arginase-1 (ARG1), a key enzyme supporting polyamine biosynthesis, was observed in multiple human cancer types. In human endometrial cancer, co-expression of VISTA and ARG1 on tumor-associated myeloid cells is associated with poor survival. Taken together, these findings unveil the VISTA/polyamine axis as a central regulator of MDSC differentiation and warrant therapeutically targeting this axis for cancer immunotherapy.

Tradeoffs, competition, and coexistence in eastern deciduous forest ant communities.

Ecologists have long sought to explain the coexistence of multiple potentially competing species in local assemblages. This is especially challenging in species-rich assemblages in which interspecific competition is intense, as it often is in ant assemblages. As a result, a suite of mechanisms has been proposed to explain coexistence among potentially competing ant species: the dominance-discovery tradeoff, the dominance-thermal tolerance tradeoff, spatial segregation, temperature-based niche partitioning, and temporal niche partitioning. Through a series of observations and experiments, we examined a deciduous forest ant assemblage in eastern North America for the signature of each of these coexistence mechanisms. We failed to detect evidence for any of the commonly suggested mechanisms of coexistence, with one notable exception: ant species appear to temporally partition foraging times such that behaviourally dominant species foraged more intensely at night, while foraging by subdominant species peaked during the day. Our work, though focused on a single assemblage, indicates that many of the commonly cited mechanisms of coexistence may not be general to all ant assemblages. However, temporal segregation may play a role in promoting coexistence among ant species in at least some ecosystems, as it does in many other organisms.

The Impact of the Initial Clinical Presentation of Bladder Cancer on Histopathological and Morphological Tumor Characteristics.

This study investigated the impact of the initial clinical presentation of bladder cancer on tumor characteristics. A cross-sectional, retrospective study was performed, and it involved 515 patients who underwent transurethral bladder cancer resection at the University Hospital Center Split between April 2019 and April 2023, excluding recurrent cases. The association between symptomatic versus asymptomatic presentation and bladder cancer characteristics was analyzed. A subgroup analysis compared tumor characteristics between patients with gross and microscopic hematuria. Multiple regression analyses revealed a significant association between symptomatic presentation and the detection of high-grade bladder cancer (OR 3.43, 95% CI 2.22-5.29, p < 0.001), concomitant CIS (OR 3.41, 95% CI 1.31-8.88, p = 0.012), T2 stage bladder cancer (OR 5.79, 95% CI 2.45-13.71, p < 0.001), a higher number of tumors (IRR 1.24, 95% CI 1.07-1.45, p = 0.005), and larger tumor size (B 1.68, 95% CI 1.19-2.18, p < 0.001). In the subgroup analysis, gross hematuria was associated with the detection of high-grade bladder cancer (OR 2.07, 95% CI 1.12-3.84, p = 0.020), T2 stage bladder cancer (OR 6.03, 95% CI 1.42-25.49, p = 0.015), and larger tumor size (B 1.8, 95% CI 0.99-2.6, p < 0.001). The identified associations between symptomatic presentation and unfavorable bladder cancer characteristics, likely attributed to early detection in asymptomatic cases, underscore the importance of additional research in the development of bladder cancer screening strategies.

Combinatorial transcription factor binding encodes cis-regulatory wiring of forebrain GABAergic neurogenesis.

Transcription factors (TFs) bind combinatorially to genomic cis-regulatory elements (cREs), orchestrating transcription programs. While studies of chromatin state and chromosomal interactions have revealed dynamic neurodevelopmental cRE landscapes, parallel understanding of the underlying TF binding lags. To elucidate the combinatorial TF-cRE interactions driving mouse basal ganglia development, we integrated ChIP-seq for twelve TFs, H3K4me3-associated enhancer-promoter interactions, chromatin and transcriptional state, and transgenic enhancer assays. We identified TF-cREs modules with distinct chromatin features and enhancer activity that have complementary roles driving GABAergic neurogenesis and suppressing other developmental fates. While the majority of distal cREs were bound by one or two TFs, a small proportion were extensively bound, and these enhancers also exhibited exceptional evolutionary conservation, motif density, and complex chromosomal interactions. Our results provide new insights into how modules of combinatorial TF-cRE interactions activate and repress developmental expression programs and demonstrate the value of TF binding data in modeling gene regulatory wiring.

God's punishment or bad strategy: anti-epidemic measures in the lower Neretva basin at the time of cholera in 1886.

The epidemic of cholera that took place in the Neretva basin in 1886 was part of the fifth pandemic wave that was spreading throughout Europe. Based on the death records, vital statistics and the newspaper articles from that period, in this paper we present the emergence and the course this epidemic. In the context of analysis and experience of the epidemic of cholera in the lower Neretva basin, the newspaper articles have been recognized as a sensitive register of the changes of behavioural patterns, the way of speaking, the mechanisms of reacting and adjusting to the spreading epidemic, but also the resistance to it. It is based on this material that we can make conclusions about the relationship between the individual and the collective in the time of danger, as well as about the particularities of historical events that have been left out in other sources. Two potential paths for cholera to enter the area of the lower Neretva basin have been identified: one from the sea and the other from land, via the neighbouring country of Bosnia and Herzegovina. Quarantine measures had been taken in order to prevent the onslaught of the epidemic, a sanitary cordon was organized, disinfection of the land was carried out and a cholera hospital organized in Metkovic. However, despite the undertaken measures, an inefficiency of the government organs was obvious, because their actions mainly applied to formal fulfilment of anti-epidemic measures and they quite easily handed over individual initiatives to physicians. The analysis of strategies concerning the application of anti-epidemic measures in the past can be useful for learning more about the multilayered nature of social mechanisms in the time of epidemics, which makes it convincing and valuable even in the present day.

Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity.

Defects in pathways governing genomic fidelity have been linked to improved response to immune checkpoint blockade therapy (ICB). Pathogenic POLE/POLD1 mutations can cause hypermutation, yet how diverse mutations in POLE/POLD1 influence antitumor immunity following ICB is unclear. Here, we comprehensively determined the effect of POLE/POLD1 mutations in ICB and elucidated the mechanistic impact of these mutations on tumor immunity. Murine syngeneic tumors harboring Pole/Pold1 functional mutations displayed enhanced antitumor immunity and were sensitive to ICB. Patients with POLE/POLD1 mutated tumors harboring telltale mutational signatures respond better to ICB than patients harboring wild-type or signature-negative tumors. A mutant POLE/D1 function-associated signature-based model outperformed several traditional approaches for identifying POLE/POLD1 mutated patients that benefit from ICB. Strikingly, the spectrum of mutational signatures correlates with the biochemical features of neoantigens. Alterations that cause POLE/POLD1 function-associated signatures generate T cell receptor (TCR)-contact residues with increased hydrophobicity, potentially facilitating T cell recognition. Altogether, the functional landscapes of POLE/POLD1 mutations shape immunotherapy efficacy.

Papillary thyroid carcinoma in a hyper-functional thyroid nodule.

The authors reported the case of 69 years old woman presented with subclinical hyperthyroidism. 99m-Tc pertechnetate scan showed the abnormal focus of hot uptake in the left lobe, suggestive of a hyperfunctioning toxic thyroid nodule. Surgical treatment was advised because of the size of the nodule as a more applicable solution. Histological findings showed papillary thyroid carcinoma.