Regional variations in HIV diagnosis in Japan before and during the COVID-19 pandemic.

Background: The number of people undergoing voluntary HIV testing has abruptly decreased since 2020. The geographical heterogeneity of HIV infection and the impact of COVID-19 on the diagnosis of HIV at regional level are important to understand. This study aimed to estimate the HIV incidence by geographical region and understand how the COVID-19 pandemic influenced diagnosis of HIV. Methods: We used an extended back-calculation method to reconstruct the epidemiological dynamics of HIV/AIDS by geographical region. We used eight regions: Tokyo, the capital of Japan, Hokkaido plus Tohoku, Kanto plus Koshinetsu (excluding Tokyo), Hokuriku, Tokai, Kinki, Chugoku plus Shikoku, and Kyushu plus Okinawa. Four different epidemiological measurements were evaluated: (i) estimated HIV incidence, (ii) estimated rate of diagnosis, (iii) number of undiagnosed HIV infections, and (iv) proportion of HIV infections that had been diagnosed. Results: The incidence of HIV/AIDS during the COVID-19 pandemic from 2020 to 2022 increased in all regions except Kanto/Koshinetsu (51.3 cases/year), Tokyo (183.9 cases/year), Hokuriku (1.0 cases/year), and Tokai (43.1 cases/year). The proportion of HIV infections that had been diagnosed only exceeded 90% in Tokyo (91.7%, 95% confidence interval (CI): 90.6, 93.3), Kanto/Koshinetsu (91.0%, 95% CI: 87.3, 97.8), and Kinki (92.5%, 95% CI: 90.4, 95.9). The proportion of infections that had been diagnosed was estimated at 83.3% (95% CI: 75.1, 98.7) in Chugoku/Shikoku and 80.5% (95% CI: 73.9, 91.0) in Kyusyu/Okinawa. Conclusions: In urban regions with major metropolitan cities, including Tokyo, Kinki, and Kanto/Koshinetsu, the number of undiagnosed HIV infections is substantial. However, the proportion of undiagnosed infections was estimated to be smaller than in other regions. The diagnosed proportion was the lowest in Kyusyu/Okinawa (80.5%), followed by Chugoku/Shikoku and Hokkaido/Tohoku. The level of diagnosis in those regional prefectures may have been more influenced and damaged by the COVID-19 pandemic than in urban settings.

Perspectives on label-free microscopy of heterogeneous and dynamic biological systems.

Significance: Advancements in label-free microscopy could provide real-time, non-invasive imaging with unique sources of contrast and automated standardized analysis to characterize heterogeneous and dynamic biological processes. These tools would overcome challenges with widely used methods that are destructive (e.g., histology, flow cytometry) or lack cellular resolution (e.g., plate-based assays, whole animal bioluminescence imaging). Aim: This perspective aims to (1) justify the need for label-free microscopy to track heterogeneous cellular functions over time and space within unperturbed systems and (2) recommend improvements regarding instrumentation, image analysis, and image interpretation to address these needs. Approach: Three key research areas (cancer research, autoimmune disease, and tissue and cell engineering) are considered to support the need for label-free microscopy to characterize heterogeneity and dynamics within biological systems. Based on the strengths (e.g., multiple sources of molecular contrast, non-invasive monitoring) and weaknesses (e.g., imaging depth, image interpretation) of several label-free microscopy modalities, improvements for future imaging systems are recommended. Conclusion: Improvements in instrumentation including strategies that increase resolution and imaging speed, standardization and centralization of image analysis tools, and robust data validation and interpretation will expand the applications of label-free microscopy to study heterogeneous and dynamic biological systems.

Longitudinal course of inflammatory-cognitive subgroups across first treatment severe mental illness and healthy controls.

BACKGROUND: While inflammation is associated with cognitive impairment in severe mental illnesses (SMI), there is substantial heterogeneity and evidence of transdiagnostic subgroups across schizophrenia (SZ) and bipolar (BD) spectrum disorders. There is however, limited knowledge about the longitudinal course of this relationship. METHODS: Systemic inflammation (C-Reactive Protein, CRP) and cognition (nine cognitive domains) was measured from baseline to 1 year follow-up in first treatment SZ and BD (n = 221), and healthy controls (HC, n = 220). Linear mixed models were used to evaluate longitudinal changes separately in CRP and cognitive domains specific to diagnostic status (SZ, BD, HC). Hierarchical clustering was applied on the entire sample to investigate the longitudinal course of transdiagnostic inflammatory-cognitive subgroups. RESULTS: There were no case-control differences or change in CRP from baseline to follow-up. We confirm previous observations of case-control differences in cognition at both time-points and domain specific stability/improvement over time regardless of diagnostic status. We identified transdiagnostic inflammatory-cognitive subgroups at baseline with differing demographics and clinical severity. Despite improvement in cognition, symptoms and functioning, the higher inflammation - lower cognition subgroup (75% SZ; 48% BD; 38% HC) had sustained inflammation and lower cognition, more symptoms, and lower functioning (SMI only) at follow-up. This was in comparison to a lower inflammation - higher cognition subgroup (25% SZ, 52% BD, 62% HC), where SMI participants showed cognitive functioning at HC level with a positive clinical course. CONCLUSIONS: Our findings support heterogenous and transdiagnostic inflammatory-cognitive subgroups that are stable over time, and may benefit from targeted interventions.

Topographic heterogeneity triggers complementary cascades that enhance ecosystem multifunctionality.

Topographic heterogeneity sets the stage for community assembly, but its effects on ecosystem functioning remain poorly understood. Here, we test the hypothesis that topographic heterogeneity underpins multiple cascading species interactions and functional pathways that indirectly control multifunctionality. To do so, we combined experimental manipulation of a form of topographic heterogeneity on rocky shores (holes of various sizes) with a comprehensive assessment of naturally assembled communities and multifunctionality. Structural equation modeling indicated that heterogeneity: (1) enhanced biodiversity by supporting filter feeder richness; (2) triggered a facilitation cascade via reef-forming (polychaete) and biomass-dominant (macroalga) foundation species, which in turn broadly supported functionally diverse epibiotic and understory assemblages; and (3) inhibited a key consumer (limpet). The model supported that these mechanisms exerted complementary positive effects on individual functions (e.g., water filtration, ecosystem metabolism, nutrient uptake) and, in turn, collectively enhanced multifunctionality. Topographic heterogeneity may therefore serve as a cornerstone physical attribute by initiating multiple cascades that propagate through ecological communities via foundation species, ultimately manifesting disproportionate effects on ecosystem multifunctionality.

Spindle oscillations emerge at the critical state of electrically coupled networks in the thalamic reticular nucleus.

Spindle oscillation is a waxing-and-waning neural oscillation observed in the brain, initiated at the thalamic reticular nucleus (TRN) and typically occurring at 7-15 Hz. Experiments have shown that in the adult brain, electrical synapses, rather than chemical synapses, dominate between TRN neurons, suggesting that the traditional view of spindle generation via chemical synapses may need reconsideration. Based on known experimental data, we develop a computational model of the TRN network, where heterogeneous neurons are connected by electrical synapses. The model shows that the interplay between synchronizing electrical synapses and desynchronizing heterogeneity leads to multiple synchronized clusters with slightly different oscillation frequencies whose summed-up activity produces spindle oscillation as seen in local field potentials. Our results suggest that during spindle oscillation, the network operates at the critical state, which is known for facilitating efficient information processing. This study provides insights into the underlying mechanism of spindle oscillation and its functional significance.

Lipid Droplets Big and Small: Basic Mechanisms That Make Them All.

Lipid droplets (LDs) are dynamic storage organelles with central roles in lipid and energy metabolism. They consist of a core of neutral lipids, such as triacylglycerol, which is surrounded by a monolayer of phospholipids and specialized surface proteins. The surface composition determines many of the LD properties, such as size, subcellular distribution, and interaction with partner organelles. Considering the diverse energetic and metabolic demands of various cell types, it is not surprising that LDs are highly heterogeneous within and between cell types. Despite their diversity, all LDs share a common biogenesis mechanism. However, adipocytes have evolved specific adaptations of these basic mechanisms, enabling the regulation of lipid and energy metabolism at both the cellular and organismal levels. Here, we discuss recent advances in the understanding of both the general mechanisms of LD biogenesis and the adipocyte-specific adaptations controlling these fascinating organelles.

Frontoparietal atrophy trajectories in cognitively unimpaired elderly individuals using longitudinal Bayesian clustering.

INTRODUCTION: Frontal and/or parietal atrophy has been reported during aging. To disentangle the heterogeneity previously observed, this study aimed to uncover different clusters of grey matter profiles and trajectories within cognitively unimpaired individuals. METHODS: Structural magnetic resonance imaging (MRI) data of 307 Aß-negative cognitively unimpaired individuals were modelled between ages 60-85 from three cohorts worldwide. We applied unsupervised clustering using a novel longitudinal Bayesian approach and characterized the clusters' cerebrovascular and cognitive profiles. RESULTS: Four clusters were identified with different grey matter profiles and atrophy trajectories. Differences were mainly observed in frontal and parietal brain regions. These distinct frontoparietal grey matter profiles and longitudinal trajectories were differently associated with cerebrovascular burden and cognitive decline. DISCUSSION: Our findings suggest a conciliation of the frontal and parietal theories of aging, uncovering coexisting frontoparietal GM patterns. This could have important future implications for better stratification and identification of at-risk individuals.

Standard chemotherapy impacts on in vitro cellular heterogeneity in spheroids enriched with cancer stem cells (CSCs) derived from triple-negative breast cancer cell line.

Triple-negative breast cancer is a heterogeneous disease with high recurrence and mortality, linked to cancer stem cells (CSCs). Our study characterized distinct cell subpopulations and signaling pathways to explore chemoresistance. We observed cellular heterogeneity among and within the cells regarding phenotyping and drug response. In untreated BT-549 cells, we noted plasticity properties in both CD44+/CD24+/CD146+ hybrid cells and CD44-/CD24+/CD146+ epithelial cells, enabling phenotypic conversion into CD44+/CD24-/CD146- epithelial-mesenchymal transition (EMT)-like like breast CSCs (BCSCs). Additionally, non-BCSCs may give rise to ALDH+ epithelial-like BCSCs. Enriched BCSCs demonstrated the potential to differentiation into CD44-/CD24-/CD146- cells and exhibited self-renewal capabilities. Similar phenotypic plasticity was not observed in untreated Hs 578T and HMT-3522 S1 cells. BT-549 cells were more resistant to paclitaxel/PTX than to doxorubicin/DOX, a phenomenon potentially linked to the presence of CD24+ cells prior to treatment. Under the CSCs-enriched spheroids model, BT-549 demonstrated extreme resistance to DOX, likely due to the enrichment of BCSCs CD44+/CD24-/CD146- and the tumor cells CD44-/CD24-/CD146-. Additionally, DOX treatment induced the enrichment of plastic and chemoresistant cells, further exacerbating resistance mechanisms. BT-549 exhibited high heterogeneity, leading to significant alterations in cell subpopulations under BCSCs enrichment, demonstrating increased phenotypic plasticity during EMT. This phenomenon appears to play a major role in DOX resistance, as indicated by the presence of the refractory cells CD44+/CD24-/CD146- BCSCs EMT-like, CD44-/CD24-/CD146- tumor cells, and elevated STAT3 expression. Gene expression data from BT-549 CSCs-enriched spheroids suggests that ferroptosis may be occurring via autophagic regulation triggered by RAB7A, highlighting this gene as a potential therapeutic target.

The prognostic value of [18F]FDG PET/CT texture analysis prior to transplantation for unresectable colorectal liver metastases.

INTRODUCTION: To determine whether heterogeneity in colorectal liver metastases (CRLM) 18F fluorodeoxyglucose [18F]FDG distribution is predictive of disease-free survival (DFS) and overall survival (OS) following liver transplantation (LT) for unresectable CRLM. METHODS: The preoperative [18F]FDG positron emission tomography/computed tomography examinations of all patients in the secondary cancer 1 and 2 studies were retrospectively assessed. Maximum standardized uptake value (SUVmax), metabolic tumour volume (MTV), and six texture heterogeneity parameters (joint entropyGLCM, dissimilarityGLCM, grey level varianceSZM, size zone varianceSZM, and zone percentageSZM, and morphological feature convex deficiency) were obtained. DFS and OS for patients over and under the median value for each of these parameters were compared by using the Kaplan Meier method and log rank test. RESULTS: Twenty-eight out of 40 patients who underwent LT for unresectable CRLM had liver metastases with uptake above liver background and were eligible for inclusion. Low MTV (p < 0.001) and dissimilarityGLCM (p = 0.016) were correlated to longer DFS. Low MTV (p < 0.001) and low values of the texture parameters dissimilarityGLCM (p = 0.038), joint entropyGLCM (p = 0.015) and zone percentageSZM (p = 0.037) were significantly correlated to longer OS. SUVmax was not correlated to DFS and OS. CONCLUSION: Although some texture parameters were able to significantly predict DFS and OS, MTV seems to be superior to predict both DFS and OS following LT for unresectable CRLM.

Pan-cancer characterization of cellular senescence reveals its inter-tumor heterogeneity associated with the tumor microenvironment and prognosis.

Cellular senescence (CS) is characterized by the irreversible cell cycle arrest and plays a key role in aging and diseases, such as cancer. Recent years have witnessed the burgeoning exploration of the intricate relationship between CS and cancer, with CS recognized as either a suppressing or promoting factor and officially acknowledged as one of the 14 cancer hallmarks. However, a comprehensive characterization remains absent from elucidating the divergences of this relationship across different cancer types and its involvement in the multi-facets of tumor development. Here we systematically assessed the cellular senescence of over 10,000 tumor samples from 33 cancer types, starting by defining a set of cancer-associated CS signatures and deriving a quantitative metric representing the CS status, called CS score. We then investigated the CS heterogeneity and its intricate relationship with the prognosis, immune infiltration, and therapeutic responses across different cancers. As a result, cellular senescence demonstrated two distinct prognostic groups: the protective group with eleven cancers, such as LIHC, and the risky group with four cancers, including STAD. Subsequent in-depth investigations between these two groups unveiled the potential molecular and cellular mechanisms underlying the distinct effects of cellular senescence, involving the divergent activation of specific pathways and variances in immune cell infiltrations. These results were further supported by the disparate associations of CS status with the responses to immuno- and chemo-therapies observed between the two groups. Overall, our study offers a deeper understanding of inter-tumor heterogeneity of cellular senescence associated with the tumor microenvironment and cancer prognosis.

Understanding variability: the role of meta-analysis of variance.

Meta-analyses traditionally compare the difference in means between groups for one or more outcomes of interest. However, they do not compare the spread of data (variability), which could mean that important effects and/or subgroups are missed. To address this, methods to compare variability meta-analytically have recently been developed, making it timely to review them and consider their strengths, weaknesses, and implementation. Using published data from trials in major depression, we demonstrate how the spread of data can impact both overall effect size and the frequency of extreme observations within studies, with potentially important implications for conclusions of meta-analyses, such as the clinical significance of findings. We then describe two methods for assessing group differences in variability meta-analytically: the variance ratio (VR) and coefficient of variation ratio (CVR). We consider the reporting and interpretation of these measures and how they differ from the assessment of heterogeneity between studies. We propose general benchmarks as a guideline for interpreting VR and CVR effects as small, medium, or large. Finally, we discuss some important limitations and practical considerations of VR and CVR and consider the value of integrating variability measures into meta-analyses.

DrugReSC: targeting disease-critical cell subpopulations with single-cell transcriptomic data for drug repurposing in cancer.

The field of computational drug repurposing aims to uncover novel therapeutic applications for existing drugs through high-throughput data analysis. However, there is a scarcity of drug repurposing methods leveraging the cellular-level information provided by single-cell RNA sequencing data. To address this need, we propose DrugReSC, an innovative approach to drug repurposing utilizing single-cell RNA sequencing data, intending to target specific cell subpopulations critical to disease pathology. DrugReSC constructs a drug-by-cell matrix representing the transcriptional relationships between individual cells and drugs and utilizes permutation-based methods to assess drug contributions to cellular phenotypic changes. We demonstrate DrugReSC's superior performance compared to existing drug repurposing methods based on bulk or single-cell RNA sequencing data across multiple cancer case studies. In summary, DrugReSC offers a novel perspective on the utilization of single-cell sequencing data in drug repurposing methods, contributing to the advancement of precision medicine for cancer.

The Asymmetric Spillover Effects of Retirement on Disability: Evidence From China.

Background and Objectives: Recent research has explored the spillover effects of retirement on spousal well-being, yet limited attention has been given to the short-term impact on spousal disability. This study explored the asymmetric spillover impact of retirement on spouses' disability severity among a national cohort of urban residents in China. Research Design and Methods: Utilizing 4 waves of data (2011-2018) from the China Health and Retirement Longitudinal Survey, we employ a nonparametric regression discontinuity design to estimate the short-term effect of retirement on spousal disability severity. Disability is assessed based on their ability to perform activities of daily living (ADLs) and instrumental activities of daily living (IADLs). Furthermore, we conduct heterogeneity analysis stratified by factors such as the husband's retirement status, health conditions, lifestyle behaviors, and the wife's educational level. Additionally, we explore potential mechanisms including changes in health behaviors, emotions, and disease diagnoses. Results: Our findings indicate that wives' retirement has a significant favorable short-term effect on husbands' ADL scores, with a magnitude of -0.644 points (-9.78% relative to baseline). A significant beneficial effect of wives' retirement on the prevalence of husbands' difficulty in dressing, bathing, and eating was observed with substantial magnitudes of 0.075, 0.201, and 0.051 points, respectively. Various heterogeneity analyses and sensitivity tests confirmed the robustness of our results. The positive spillover effect of wives' retirement likely results from reduced negative emotions in husbands. In contrast, husbands' retirement does not affect the prevalence of ADL/IADL disability in their wives. Discussion and Implications: Underscoring the gender asymmetry in the effects of spousal retirement on disability, this study emphasizes the need for tailored policies considering men's and women's distinct disability experiences.

The influence of fetal bovine serum concentration on stemness and neuronal differentiation markers in stem cells from human exfoliated deciduous teeth.

Dental Stem Cells (DSCs) from discarded teeth are a non-invasive and ethically favorable source with the potential for neurogenesis due to their ectodermal origin. Stem cells from human exfoliated deciduous teeth (SHED) are particularly promising due to their high differentiation potential and relative immaturity compared to other Mesenchymal Stromal Cells (MSCs). Markers like CD56 and CD271 are critical in identifying MSC subpopulations for therapeutic applications because of their roles in neurodevelopment and maintaining stemness. This study investigates how fetal bovine serum (FBS) concentrations affect the expression of CD56 and CD271 in SHED, influencing their stemness and neuronal differentiation potential. SHEDs were isolated from various donors, cultured, and characterized for MSC traits using markers such as CD14, CD19, CD29, CD34, CD45, CD73, CD90, CD105, CD56, and CD271. Culturing SHED in different FBS conditions (standard 15 %, reduced 1 % and 5 %, and FBS-free) showed that lower FBS concentrations increase CD271 and CD56 expression while maintaining the standard MSC immunophenotype. Importantly, the enhanced expression of these markers can be induced even after SHEDs have been expanded in standard FBS concentrations. These findings suggest that FBS concentration can optimize SHED culture conditions, enhancing their suitability for regenerative medicine and tissue engineering applications.

Mimicking and analyzing the tumor microenvironment.

The tumor microenvironment (TME) is increasingly appreciated to play a decisive role in cancer development and response to therapy in all solid tumors. Hypoxia, acidosis, high interstitial pressure, nutrient-poor conditions, and high cellular heterogeneity of the TME arise from interactions between cancer cells and their environment. These properties, in turn, play key roles in the aggressiveness and therapy resistance of the disease, through complex reciprocal interactions between the cancer cell genotype and phenotype, and the physicochemical and cellular environment. Understanding this complexity requires the combination of sophisticated cancer models and high-resolution analysis tools. Models must allow both control and analysis of cellular and acellular TME properties, and analyses must be able to capture the complexity at high depth and spatial resolution. Here, we review the advantages and limitations of key models and methods in order to guide further TME research and outline future challenges.

Density of Limnoperna fortunei larval stages in a cascade of subtropical reservoirs: spatiotemporal variation and environmental influences.

The golden mussel (Limnoperna fortunei) is an invasive bivalve that has established itself in several South American river systems, impacting ecosystem functioning. Reservoir cascades provide their larvae with the means of rapid dispersal, but the relationship between environmental variables and larval stage structure remains unclear. In this study, the density of three L. fortunei larval stages and quantitative detection using DNA are analyzed in a cascade of five reservoirs in the upper Uruguay River Basin and associated with spatiotemporal variation in environmental parameters. The analysis of L. fortunei eDNA presence and absence in freshwater systems appears to be a valuable mapping tool; however, no significant link was found between the eDNA magnitude and the overall larval density. The increase in larval density was related to the fluctuation of environmental parameters over a year, with the highest average larval densities observed in the CN and ITA reservoirs, though no significant difference was observed between the five reservoirs, where D-shaped larvae predominated. During winter, larval density decreased significantly, however, other variables also contribute to species activity and development in the upper Uruguay River Basin reservoirs and may be considered limiting factors. The relationships between environmental parameters were evaluated using a multivariate model. The interaction between reservoir area and precipitation, water temperature, electrical conductivity, and dissolved oxygen had a significant effect on larval density but showed specific influences on each larval stage. Any increase in density was regulated by dissolved oxygen and electrical conductivity content at all larval stages. Furthermore, total phosphorus affected the density of F1 and F3 larvae. The interaction between reservoir area and precipitation, nitrate content, phosphate concentrations, and water temperature had the most influence on the density of F2 and F3 larval stages; the F1 stage was mainly affected by calcium concentrations. The isolated effect of precipitation also contributed to the density of F2 and F3 larvae. Our findings shed light on the interaction between different phases of golden mussel larvae and the main nutrients found in reservoirs, which may be a determining factor in the rise in density of the non-native species in these systems.

Recent progress and applications of single-cell sequencing technology in breast cancer.

Single-cell RNA sequencing (scRNA-seq) technology enables the precise analysis of individual cell transcripts with high sensitivity and throughput. When integrated with multiomics technologies, scRNA-seq significantly enhances the understanding of cellular diversity, particularly within the tumor microenvironment. Similarly, single-cell DNA sequencing has emerged as a powerful tool in cancer research, offering unparalleled insights into the genetic heterogeneity and evolution of tumors. In the context of breast cancer, this technology holds substantial promise for decoding the intricate genomic landscape that drives disease progression, treatment resistance, and metastasis. By unraveling the complexities of tumor biology at a granular level, single-cell DNA sequencing provides a pathway to advancing our comprehension of breast cancer and improving patient outcomes through personalized therapeutic interventions. As single-cell sequencing technology continues to evolve and integrate into clinical practice, its application is poised to revolutionize the diagnosis, prognosis, and treatment strategies for breast cancer. This review explores the potential of single-cell sequencing technology to deepen our understanding of breast cancer, highlighting key approaches, recent advancements, and the role of the tumor microenvironment in disease plasticity. Additionally, the review discusses the impact of single-cell sequencing in paving the way for the development of personalized therapies.

Host heterogeneity in humoral bactericidal activity can be complement independent.

Background: Humoral bactericidal activity was first recognized nearly a century ago. However, the extent of inter-individual heterogeneity and the mechanisms underlying such heterogeneity beyond antibody or complement systems have not been well studied. Methods: The plasma bactericidal activity of five healthy volunteers were tested against 30 strains of Gram-negative uropathogens, Klebsiella pneumoniae and Escherichia coli, associated with bloodstream infections. IgG and IgM titers specific to K. pneumoniae strains KP13883 and KPB1 were measured by ELISA, and complement inhibitor was used to measure the contribution of complement-induced killing. Furthermore, MALDI-TOF mass spectrometry was conducted to determine the metabolomic components of plasma with bactericidal properties in 25 healthy individuals using Bayesian inference of Pearson correlation between peak intensity and colony counts of surviving bacteria. Results: Plasma bactericidal activity varied widely between individuals against various bacterial strains. While individual plasma with higher IgM titers specific to K. pneumoniae strain KP13883 showed more efficient killing of the strain, both IgM and IgG titers for K. pneumoniae strain KPB1 did not correlate well with the killing activity. Complement inhibition assays elucidated that the complement-mediated killing was not responsible for the inter-individual heterogeneity in either isolate. Subsequently, using MALDI-TOF mass spectrometry on plasmas of 25 healthy individuals, we identified several small molecules including gangliosides, pediocins, or saponins as candidates that showed negative correlation between peak intensities and colony forming units of the test bacteria. Conclusion: This is the first study to demonstrate the inter-individual heterogeneity of constitutive innate humoral bactericidal function quantitatively and that the heterogeneity can be independent of antibody or the complement system.

A small population of stress-responsive neurons in the hypothalamus-habenula circuit mediates development of depression-like behavior in mice.

Accumulating evidence has shown that various brain functions are associated with experience-activated neuronal ensembles. However, whether such neuronal ensembles are engaged in the pathogenesis of stress-induced depression remains elusive. Utilizing activity-dependent viral strategies in mice, we identified a small population of stress-responsive neurons, primarily located in the middle part of the lateral hypothalamus (mLH) and the medial part of the lateral habenula (LHbM). These neurons serve as "starter cells" to transmit stress-related information and mediate the development of depression-like behaviors during chronic stress. Starter cells in the mLH and LHbM form dominant connections, which are selectively potentiated by chronic stress. Silencing these connections during chronic stress prevents the development of depression-like behaviors, whereas activating these connections directly elicits depression-like behaviors without stress experience. Collectively, our findings dissect a core functional unit within the LH-LHb circuit that mediates the development of depression-like behaviors in mice.

Emphasizing the Social in Social Emotion Regulation: A Call for Integration and Expansion.

The Future of Affective Science Special Issues illuminate where the field of Affective Science is headed in coming years, highlighting exciting new directions for research. Many of the articles in the issues emphasized the importance of studying emotion regulation, and specifically, social emotion regulation. This commentary draws on these articles to argue that future research needs to more concretely focus on the social aspects of social emotion regulation, which have been underexplored in affective science. Specifically, we discuss the importance of focusing on social goals, strategies and tactics, and outcomes relevant to social emotion regulation interactions, more closely considering these processes for all individuals involved. To do so, we draw on research from neighboring subdisciplines of psychology that have focused on the social aspects of interactions. Moreover, we underscore the need to better integrate components of the process model of social emotion regulation and approach empirical inquiry more holistically, in turn illuminating how piecemeal investigations of these processes might lead to an incomplete or incorrect understanding of social emotion regulation. We hope this commentary supplements the research in the special issues, further highlighting ways to advance the field.