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Affiliative social connections facilitate well-being and survival in numerous species. Engaging in social interactions requires positive or negative motivational drive, elicited through coordinated activity across neural circuits. However, the identity, interconnectivity, and functional encoding of social information within these circuits remains poorly understood. Here, we focus on downstream projections of dorsal raphe nucleus (DRN) dopamine neurons (DRN DAT ) in mice, which we previously implicated in social motivation alongside an aversive affective state. We show that three prominent DRN DAT projections – to the bed nucleus of the stria terminalis (BNST), central amygdala (CeA), and posterior basolateral amygdala (BLP) – play separable roles in behavior, despite substantial collateralization. Photoactivation of the DRN DAT -CeA projection promoted social behavior and photostimulation of the DRN DAT -BNST projection promoted exploratory behavior, while the DRN DAT -BLP projection supported place avoidance, suggesting a negative affective state. Downstream regions showed diverse receptor expression, poising DRN DAT neurons to act through dopamine, neuropeptide, and glutamate transmission. Furthermore, we show ex vivo that the effect of DRN DAT photostimulation on downstream neuron excitability depended on region and baseline cell properties, resulting in excitatory responses in BNST cells and diverse responses in CeA and BLP. Finally, in vivo microendoscopic cellular-resolution recordings in the CeA with DRN DAT photostimulation revealed a correlation between social behavior and neurons excited by social stimuli, suggesting that increased dopamine tone may recruit different CeA neurons to social ensembles. Collectively, these circuit features may facilitate a coordinated, but flexible, response in the presence of social stimuli that can be flexibly guided based on the internal social homeostatic need state of the individual.

Affiliative social connections facilitate well-being and survival in numerous species. Engaging in social interactions requires positive or negative motivational drive, elicited through coordinated activity across neural circuits. However, the identity, interconnectivity, and functional encoding of social information within these circuits remains poorly understood. Here, we focus on downstream projections of dorsal raphe nucleus (DRN) dopamine neurons (DRN DAT ) in mice, which we previously implicated in social motivation alongside an aversive affective state. We show that three prominent DRN DAT projections – to the bed nucleus of the stria terminalis (BNST), central amygdala (CeA), and posterior basolateral amygdala (BLP) – play separable roles in behavior, despite substantial collateralization. Photoactivation of the DRN DAT -CeA projection promoted social behavior and photostimulation of the DRN DAT -BNST projection promoted exploratory behavior, while the DRN DAT -BLP projection supported place avoidance, suggesting a negative affective state. Downstream regions showed diverse receptor expression, poising DRN DAT neurons to act through dopamine, neuropeptide, and glutamate transmission. Furthermore, we show ex vivo that the effect of DRN DAT photostimulation on downstream neuron excitability depended on region and baseline cell properties, resulting in excitatory responses in BNST cells and diverse responses in CeA and BLP. Finally, in vivo microendoscopic cellular-resolution recordings in the CeA with DRN DAT photostimulation revealed a correlation between social behavior and neurons excited by social stimuli, suggesting that increased dopamine tone may recruit different CeA neurons to social ensembles. Collectively, these circuit features may facilitate a coordinated, but flexible, response in the presence of social stimuli that can be flexibly guided based on the internal social homeostatic need state of the individual.

The \"Pain Overlap Theory\" (1) proposes that the experience of social pain overlaps with and amplifies the experience of physical pain by sharing parts of the same underlying processing systems (2-6). In humans, the insular cortex has been implicated in this overlap of physical and social pain, but a mechanistic link has not been made (2,4,5,7-9). To determine whether social pain can subsequently impact responses to nociceptive stimuli via convergent electrical signals (spikes) or convergent chemical signals (neuromodulators), we designed a novel Social Exclusion paradigm termed the Fear of Missing Out (FOMO) Task which facilitates a mechanistic investigation in mice. We found that socially-excluded mice display more severe responses to physical pain, disrupted valence encoding, and impaired neural representations of nociceptive stimuli. We performed a systematic biosensor panel and found that endocannabinoid and oxytocin signaling in the insular cortex have opposing responses during trials where mice were attending or not attending to the Social Exclusion events respectively, demonstrating distinct neuromodulatory substrates that underpin different states of Social Exclusion. We also found that intra-insular blockade of oxytocin signaling increased the response to physical pain following Social Exclusion. Together these findings suggest Social Exclusion effectively alters physical pain perception using neuromodulatory signaling in the insular cortex.

At the ICEA International Convention in Phoenix, I spoke on VBAC (Vaginal Birth After Cesarean): Information for the Community. I knew all the people in my session were convinced of the benefits of VBAC. My guess is that 99.9% of International Journal of Childbirth Education readers are convinced of the benefits of VBAC. This is a worldwide concern, but since I live in the US, I will use it as an example. The tax burden is increased every time a repeat cesarean section (without an attempted VBAC) is performed on a Medicaid woman. Every time a privately insured woman has a repeat cesarean without an attempted VBAC, our health insurance premiums increase. Consider also the woman who has surgery to birth her baby and experiences those increased rates of complication that extend her maternity leave or whose experiences affect her productivity at work. From this perspective, VBAC is suddenly relative to everybody she works with, from executives above her to those who work under her.

Alzheimer′s Disease (AD) is characterized by progressive cognitive decline associated with amyloid-beta (Aβ) plaques, neurofibrillary tangles, inflammation, synaptic loss, and profuse neuronal death. Accumulating evidence demonstrates that cerebrovascular impairment precedes the emergence of neuropathological hallmarks, implicating vascular dysfunction as an early contributor to AD onset and progression. We investigated a non-viral strategy to generate pro-vasculogenic fibroblasts by transiently overexpressing Etv2, Foxc2, and Fli1 (EFF) as a potential cell-based therapy for neurovascular deficits in AD. To assess therapeutic potential, EFF-primed fibroblasts were injected into a mouse model of AD (3xTg-AD) and wild-type controls via the intracerebroventricular (ICV) route, followed by cognitive assessments and subsequent brain tissue analyses. Our findings demonstrate that EFF-primed fibroblasts acquire vasculogenic properties, enhance cerebral blood flow (CBF), and alleviate spatial memory deficits in 3xTg-AD mice. Moreover, transplanted EFF-primed fibroblasts exhibited long-term survival, integrated into the brain vasculature, and promoted cortical vascular remodeling in the AD brain. Notably, ICV deployment of these cells is also correlated with reduced cortical Aβ load, suggesting potential therapeutic benefits in reducing AD pathology. Transcriptomic analysis identified the activation of genes involved in fatty acid oxidation, such as Pparα, known for its anti-amyloidogenic and anti-inflammatory effects. Collectively, these findings highlight non-viral, reprogramming-based vasculogenic cell therapy as a promising strategy for AD, capable of alleviating cognitive decline and addressing AD pathology across cellular and tissue scalesCompeting Interest StatementThe authors have declared no competing interest.

Affiliative social connections facilitate well-being and survival in numerous species. Engaging in social interactions requires positive or negative motivational drive, elicited through coordinated activity across neural circuits. However, the identity, interconnectivity, and functional encoding of social information within these circuits remains poorly understood. Here, we focus on downstream projections of dorsal raphe nucleus (DRN) dopamine neurons (DRNDAT), which we previously implicated in social motivation alongside an aversive affective state. We show that three prominent DRNDATprojections – to the bed nucleus of the stria terminalis (BNST), central amygdala (CeA), and posterior basolateral amygdala (BLP) – play separable roles in behavior, despite substantial collateralization. Photoactivation of the DRNDAT-CeA projection promoted social behavior and photostimulation of the DRNDAT-BNST projection promoted exploratory behavior, while the DRNDAT-BLP projection supported place avoidance, suggesting a negative affective state. Downstream regions showed diverse receptor expression, poising DRNDAT neurons to act through dopamine, neuropeptide, and glutamate transmission. Furthermore, we show ex vivo that the effect of DRNDAT photostimulation on downstream neuron excitability depended on region and baseline cell properties, resulting in excitatory responses in BNST cells and diverse responses in CeA and BLP. Finally, in vivo microendoscopic cellular-resolution recordings in the CeA with DRNDAT photostimulation revealed a correlation between social behavior and neurons excited by social stimuli– suggesting that increased dopamine tone may recruit different CeA neurons to social ensembles. Collectively, these circuit features may facilitate a coordinated, but flexible, response in the presence of social stimuli that can be flexibly guided based on the internal social homeostatic need state of the individual.Competing Interest StatementThe authors have declared no competing interest.

Economic and social progress requires a diverse ecosystem of firms that play complementary roles. Making It Big: Why Developing Countries Need More Large Firms constitutes one of the most up-to-date assessments of how large firms are created in low- and middle-income countries and their role in development. It argues that large firms advance a range of development objectives in ways that other firms do not: large firms are more likely to innovate, export, and offer training and are more likely to adopt international standards of quality, among other contributions. Their particularities are closely associated with productivity advantages and translate into improved outcomes not only for their owners but also for their workers and for smaller enterprises in their value chains. The challenge for economic development, however, is that production does not reach economic scale in low- and middle-income countries. Why are large firms scarcer in developing countries? Drawing on a rare set of data from public and private sources, as well as proprietary data from the International Finance Corporation and case studies, this book shows that large firms are often born large—or with the attributes of largeness. In other words, what is distinct about them is often in place from day one of their operations. To fill the \"missing top\" of the firm-size distribution with additional large firms, governments should support the creation of such firms by opening markets to greater competition. In low-income countries, this objective can be achieved through simple policy reorientation, such as breaking oligopolies, removing unnecessary restrictions to international trade and investment, and establishing strong rules to prevent the abuse of market power. Governments should also strive to ensure that private actors have the skills, technology, intelligence, infrastructure, and finance they need to create large ventures. Additionally, they should actively work to spread the benefits from production at scale across the largest possible number of market participants. This book seeks to bring frontier thinking and evidence on the role and origins of large firms to a wide range of readers, including academics, development practitioners and policy makers.

Malaria in pregnancy is associated with adverse birth outcomes. However, the underlying mechanisms remain poorly understood. Tight regulation of angiogenic, metabolic, and inflammatory pathways are essential for healthy pregnancies. We hypothesized that malaria disrupts these pathways leading to preterm birth (PTB). We conducted a secondary analysis of a randomized trial of malaria prevention in pregnancy conducted in Malawi from July 21, 2011, to March 18, 2013. We longitudinally assessed circulating mediators of angiogenic, metabolic, and inflammatory pathways during pregnancy in a cohort of HIV-negative women (n = 1,628), with a median age of 21 years [18, 25], and 562 (35%) were primigravid. Pregnancies were ultrasound dated, and samples were analyzed at 13 to 23 weeks (Visit 1), 28 to 33 weeks (Visit 2), and/or 34 to 36 weeks (Visit 3). Malaria prevalence was high; 70% (n = 1,138) had PCR-positive Plasmodium falciparum infection at least once over the course of pregnancy and/or positive placental histology. The risk of delivering preterm in the entire cohort was 20% (n = 304/1506). Women with malaria before 24 weeks gestation had a higher risk of PTB (24% versus 18%, p = 0.005; adjusted relative risk [aRR] 1.30, 95% confidence interval [CI] 1.04-1.63, p = 0.021); and those who were malaria positive only before week 24 had an even greater risk of PTB (28% versus 17%, p = 0.02; with an aRR of 1.67, 95% CI 1.20-2.30, p = 0.002). Using linear mixed-effects modeling, malaria before 24 weeks gestation was associated with altered kinetics of inflammatory (C-Reactive Protein [CRP], Chitinase 3-like protein-1 [CHI3L1], Interleukin 18 Binding Protein [IL-18BP], soluble Tumor Necrosis Factor receptor II [sTNFRII], soluble Intercellular Adhesion Molecule-1 [sICAM-1]), angiogenic (soluble Endoglin [sEng]), and metabolic mediators (Leptin, Angiopoietin-like 3 [Angptl3]) over the course of pregnancy (χ2 > 13.0, p ≤ 0.001 for each). Limitations include being underpowered to assess the impact on nonviable births, being unable to assess women who had not received any antimalarials, and, because of the exposure to antimalarials in the second trimester, there were limited numbers of malaria infections late in pregnancy. Current interventions for the prevention of malaria in pregnancy are initiated at the first antenatal visit, usually in the second trimester. In this study, we found that many women are already malaria-infected by their first visit. Malaria infection before 24 weeks gestation was associated with dysregulation of essential regulators of angiogenesis, metabolism, and inflammation and an increased risk of PTB. Preventing malaria earlier in pregnancy may reduce placental dysfunction and thereby improve birth outcomes in malaria-endemic settings.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which causes coronavirus disease 2019 (COVID-19), is spread primarily through exposure to respiratory droplets from close contact with an infected person. To inform prevention measures, we conducted a case-control study among Colorado adults to assess the risk of SARS-CoV-2 infection from community exposures. Cases were symptomatic Colorado adults (aged ≥18 years) with a positive SARS-CoV-2 test by reverse transcription-polymerase chain reaction (RT-PCR) reported to Colorado's COVID-19 surveillance system. From March 16 to December 23, 2021, cases were randomly selected from surveillance data ≤12 days after their specimen collection date. Cases were matched on age, zip code (urban areas) or region (rural/frontier areas), and specimen collection date with controls randomly selected among persons with a reported negative SARS-CoV-2 test result. Data on close contact and community exposures were obtained from surveillance and a survey administered online. The most common exposure locations among all cases and controls were place of employment, social events, or gatherings and the most frequently reported exposure relationship was co-worker or friend. Cases were more likely than controls to work outside the home (adjusted odds ratio (aOR) 1.18, 95% confidence interval (CI): 1.09-1.28) in industries and occupations related to accommodation and food services, retail sales, and construction. Cases were also more likely than controls to report contact with a non-household member with confirmed or suspected COVID-19 (aOR 1.16, 95% CI: 1.06-1.27). Understanding the settings and activities associated with a higher risk of SARS-CoV-2 infection is essential for informing prevention measures aimed at reducing the transmission of SARS-CoV-2 and other respiratory diseases. These findings emphasize the risk of community exposure to infected persons and the need for workplace precautions in preventing ongoing transmission.

Mouse models of human diseases are invaluable tools for studying pathogenic mechanisms and testing interventions and therapeutics. For disorders such as Alzheimer’s disease in which numerous models are being generated, a challenging first step is to identify the most appropriate model and age to effectively evaluate new therapeutic approaches. Here we conducted a detailed phenotypic characterization of the 5xFAD model on a congenic C57BL/6 J strain background, across its lifespan – including a seldomly analyzed 18-month old time point to provide temporally correlated phenotyping of this model and a template for characterization of new models of LOAD as they are generated. This comprehensive analysis included quantification of plaque burden, Aβ biochemical levels, and neuropathology, neurophysiological measurements and behavioral and cognitive assessments, and evaluation of microglia, astrocytes, and neurons. Analysis of transcriptional changes was conducted using bulk-tissue generated RNA-seq data from microdissected cortices and hippocampi as a function of aging, which can be explored at the MODEL-AD Explorer and AD Knowledge Portal. This deep-phenotyping pipeline identified novel aspects of age-related pathology in the 5xFAD model. Measurement(s) Protein Expression • gene expression • electrophysiology data • protein measurement • behavior Technology Type(s) immunofluorescence microscopy assay • RNA sequencing • electrophysiology assay • Electrochemiluminescence Immunoassay • animal activity monitoring system Factor Type(s) genotype • age • sex Sample Characteristic - Organism Mus musculus Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.15176109