Network state transitions during cortical development.

Mammalian cortical networks are active before synaptogenesis begins in earnest, before neuronal migration is complete, and well before an animal opens its eyes and begins to actively explore its surroundings. This early activity undergoes several transformations during development. The most important of these is a transition from episodic synchronous network events, which are necessary for patterning the neocortex into functionally related modules, to desynchronized activity that is computationally more powerful and efficient. Network desynchronization is perhaps the most dramatic and abrupt developmental event in an otherwise slow and gradual process of brain maturation. In this Review, we summarize what is known about the phenomenology of developmental synchronous activity in the rodent neocortex and speculate on the mechanisms that drive its eventual desynchronization. We argue that desynchronization of network activity is a fundamental step through which the cortex transitions from passive, bottom-up detection of sensory stimuli to active sensory processing with top-down modulation.

TGF-ß1 Drives Integrin-Dependent Pericyte Migration and Microvascular Destabilization in Fibrotic Disease.

Interactions between endothelial cells (ECs) and mural pericytes (PCs) are critical in maintaining the stability and function of the microvascular wall. Abnormal interactions between these two cell types are a hallmark of progressive fibrotic diseases such as systemic sclerosis (also known as scleroderma). However, the role of PCs in signaling microvascular dysfunction remains underexplored. We hypothesized that integrin-matrix interactions contribute to PC migration from the vascular wall and conversion into interstitial myofibroblasts. Herein, pro-inflammatory tumor necrosis factor α (TNFα) or a fibrotic growth factor [transforming growth factor ß1 (TGF-ß1)] were used to evaluate human PC inflammatory and fibrotic phenotypes by assessing their migration, matrix deposition, integrin expression, and subsequent effects on endothelial dysfunction. Both TNFα and TGF-ß1 treatment altered integrin expression and matrix protein deposition, but only fibrotic TGF-ß1 drove PC migration in an integrin-dependent manner. In addition, integrin-dependent PC migration was correlated to changes in EC angiopoietin-2 levels, a marker of vascular instability. Finally, there was evidence of changes in vascular stability corresponding to disease state in human systemic sclerosis skin. This work shows that TNFα and TGF-ß1 induce changes in PC integrin expression and matrix deposition that facilitate migration and reduce vascular stability, providing evidence that microvascular destabilization can be an early indicator of tissue fibrosis.

Mainstreaming in parallel with ovarian cancer tumor testing to improve genetic testing uptake.

OBJECTIVES: Although genetic testing (GT) is universally recommended for patients with epithelial ovarian cancer (EOC), rates are low (34%). In 1/2019, we implemented mainstreaming-GT in parallel with tumor testing via MSK-IMPACT within oncology clinics. We sought to determine GT rates pre/post-mainstreaming and patient characteristics associated with GT. METHODS: Patients with newly diagnosed EOC seen at our institution from 7/1/2015-3/31/2022 were included. Clinical data were abstracted including social determinants of health (SDOH) variables, race/ethnicity, marital status, insurance, language, comorbidities, employment, and Yost index, a measure of socioeconomic status. GT rates were calculated overall and pre-/post-mainstreaming (1/2019). Logistic regression models were fit to identify variables associated with GT. RESULTS: Of 1742 patients with EOC, 1591 (91%) underwent GT. Rates of GT increased from 87% to 95% after mainstreaming (p < 0.001). Among 151 patients not undergoing GT, major reasons were lack of provider recommendation (n = 76, 50%) and logistical issues (n = 38, 25%) with few declining (n = 14, 9%) or having medical complications preventing GT (n = 7, 4.6%). High-grade serous histology, advanced stage (III/IV), and having a spouse/partner were associated with increased GT uptake (p < 0.01). Among SDOH variables, there were no differences by insurance, Yost score, language, comorbidities, employment, or race/ethnicity. In multivariable models, likelihood of GT increased with mainstreaming, even after adjustment for histology, stage, and marital status (OR 3.77; 95% CI: 2.56-5.66). CONCLUSIONS: Mainstreaming increased the likelihood of GT in patients with EOC. We found lower testing rates in patients without partners/spouses, non-high-grade serous histology, and early-stage disease, representing potential areas for future interventions.

Does Self-Reported BMI Modify the Association Between Stroke and Depressive Symptoms?

BACKGROUND: Depressive symptoms are common in stroke survivors. While obesity has been associated with stroke and depression, its influence on the association between stroke and depressive symptoms is unknown. METHODS: Cross-sectional data from 2015 to 2016 Canadian Community Health Survey was used. History of stroke was self-reported and our outcome of interest was depressive symptoms in the prior 2 weeks, measured using the 9-item Patient Health Questionnaire. Self-reported body mass index (BMI) was modeled as cubic spline terms to allow for nonlinear associations. We used multivariable logistic regression to evaluate the association between stroke and depressive symptoms and added an interaction term to evaluate the modifying effect of BMI. RESULTS: Of the 47,521 participants, 694 (1.0%) had a stroke and 3314 (6.5%) had depressive symptoms. Those with stroke had a higher odds of depressive symptoms than those without (aOR = 3.13, 95% CI 2.48, 3.93). BMI did not modify the stroke-depressive symptoms association (P interaction = 0.242) despite the observed variation in stroke-depressive symptoms association across BMI categories,: normal BMI [18.5-25 kg/m2] (aOR† = 3.91, 95% CI 2.45, 6.11), overweight [25-30 kg/m2] (aOR† = 2.63, 95% CI 1.58, 4.20), and obese [>30 kg/m2] (aOR† = 2.76, 95% CI 1.92, 3.94). Similar results were found when depressive symptoms were modeled as a continuous measure. CONCLUSION: The association between stroke and depressive symptoms is not modified by BMI, needing additional work to understand the role of obesity on depression after stroke.

Adult genital psoriasis: An updated review for clinicians.

Genital psoriasis is a chronic inflammatory skin condition that has been reported in up to 63% of patients with psoriasis on other parts of their skin. It has a profound impact on quality of life and sexual function which is often overlooked by current severity scores. Despite its prevalence and disease burden, genital psoriasis remains largely under-reported and under-treated. Historically, this was due to the impracticality and limited efficacy data of standard psoriasis treatments when applied to genital skin. However, there have been recent advancements with several new agents currently being developed and evaluated for genital psoriasis. This clinical review aims to provide an overview of the current evidence regarding the clinical features of genital psoriasis, available management options and tools for assessing patients' quality of life. Key takeaways from this review emphasise the recognition of genital psoriasis as a chronic and debilitating condition, unique in its impact on patients' quality of life, necessitating sensitive and attentive approaches to address their needs.

The Utilitarian Virtual Self - Using Embodied Personalized Avatars to Investigate Moral Decision-Making in Semi-Autonomous Vehicle Dilemmas.

Embodied personalized avatars are a promising new tool to investigate moral decision-making by transposing the user into the "middle of the action" in moral dilemmas. Here, we tested whether avatar personalization and motor control could impact moral decision-making, physiological reactions and reaction times, as well as embodiment, presence and avatar perception. Seventeen participants, who had their personalized avatars created in a previous study, took part in a range of incongruent (i.e., harmful action led to better overall outcomes) and congruent (i.e., harmful action led to trivial outcomes) moral dilemmas as the drivers of a semi-autonomous car. They embodied four different avatars (counterbalanced - personalized motor control, personalized no motor control, generic motor control, generic no motor control). Overall, participants took a utilitarian approach by performing harmful actions only to maximize outcomes. We found increased physiological arousal (SCRs and heart rate) for personalized avatars compared to generic avatars, and increased SCRs in motor control conditions compared to no motor control. Participants had slower reaction times when they had motor control over their avatars, possibly hinting at more elaborate decision-making processes. Presence was also higher in motor control compared to no motor control conditions. Embodiment ratings were higher for personalized avatars, and generally, personalization and motor control were perceptually positive features. These findings highlight the utility of personalized avatars and open up a range of future research possibilities that could benefit from the affordances of this technology and simulate, more closely than ever, real-life action.

Adults with depressive symptoms have lower odds of dietary supplement use.

OBJECTIVE: In this study, we aim to evaluate dietary supplement and complementary and alternative medicine (CAM) use in individuals with depressive symptoms. Furthermore, we conducted a comparative analysis of the usage of these agents among individuals with depressive symptoms, differentiating between those who were using antidepressants and those who were not. Additionally, we compared individuals with depressive symptoms who were not using antidepressants with participants who did not have depressive symptoms as well as individuals with depressive symptoms who were using antidepressants with individuals without depressive symptoms. METHOD: The National Health and Nutrition Examination Survey 2007-2018 data was collected. Depressive symptoms were assessed using patient health questionnaire-9. Dietary supplement and antidepressants use was evaluated using Dietary Supplement Use and Prescription Medications Questionnaires. RESULTS: 31,445 participants, with 2870 (8.05%) having depressive symptoms were included. Participants with depressive symptoms had significantly lower odds of dietary supplement use compared with those without depressive symptoms (aOR = 0.827, 95% CI: 0.700,0.977, p = 0.026). Participants with depressive symptoms who were using antidepressants had significantly higher odds of dietary supplement (aOR = 1.290, 95% CI: 1.038,1.604, p = 0.022) compared with participants with depressive symptoms who were not using antidepressants. Furthermore, Participants with depressive symptoms who weren't using antidepressants had significantly lower odds of dietary supplement use (aOR = 0.762, 95% CI: 0.632,0.918, p = 0.005) compared with participants without depressive symptoms. In individuals with treated depressive symptoms compared to those without depressive symptoms, CAM use was significantly lower (aOR = 0.763, 95% CI = 0.598,0.973, p = 0.030). CONCLUSION: Individuals with depressive symptoms have lower odds of dietary supplement use. Further studies are needed to replicate these findings and examine the underlying mechanisms for this association.

The NKCC1 Inhibitor Bumetanide Restores Cortical Feedforward Inhibition and Lessens Sensory Hypersensitivity in Early Postnatal Fragile X Mice.

BACKGROUND: Exaggerated responses to sensory stimuli, a hallmark of fragile X syndrome, contribute to anxiety and learning challenges. Sensory hypersensitivity is recapitulated in the Fmr1 knockout (KO) mouse model of fragile X syndrome. Recent studies in Fmr1 KO mice have demonstrated differences in the activity of cortical interneurons and a delayed switch in the polarity of GABA (gamma-aminobutyric acid) signaling during development. Previously, we reported that blocking the chloride transporter NKCC1 with the diuretic bumetanide could rescue synaptic circuit phenotypes in the primary somatosensory cortex (S1) of Fmr1 KO mice. However, it remains unknown whether bumetanide can rescue earlier circuit phenotypes or sensory hypersensitivity in Fmr1 KO mice. METHODS: We used acute and chronic systemic administration of bumetanide in Fmr1 KO mice and performed in vivo 2-photon calcium imaging to record neuronal activity, while tracking mouse behavior with high-resolution videos. RESULTS: We demonstrated that layer 2/3 pyramidal neurons in the S1 of Fmr1 KO mice showed a higher frequency of synchronous events on postnatal day 6 than wild-type controls. This was reversed by acute administration of bumetanide. Furthermore, chronic bumetanide treatment (postnatal days 5-14) restored S1 circuit differences in Fmr1 KO mice, including reduced neuronal adaptation to repetitive whisker stimulation, and ameliorated tactile defensiveness. Bumetanide treatment also rectified the reduced feedforward inhibition of layer 2/3 neurons in the S1 and boosted the circuit participation of parvalbumin interneurons. CONCLUSIONS: This further supports the notion that synaptic, circuit, and sensory behavioral phenotypes in Fmr1 KO can be mitigated by inhibitors of NKCC1, such as the Food and Drug Administration-approved diuretic bumetanide.

Decreased odds of depressive symptoms and suicidal ideation with higher education, depending on sex and employment status.

BACKGROUND: Higher education is associated with reduced depressive symptoms and requires investment without guaranteed employment. It remains unclear how sex and employment status together contribute to the association between mental health and educational attainment. This study investigated the role of sex and employment status together in the associations of 1) depressive symptoms and 2) suicidal ideation with education. METHODS: Using 2005-2018 National Health and Nutrition Examination Survey data, cross-sectional analyses were conducted on individuals ≥20 years who completed the depression questionnaire and reported their employment status and highest level of education. Survey-weighted multivariable logistic regression models were used to explore how depressive symptoms and suicidal ideation are associated with educational attainment in an analysis stratified by sex and employment status. To account for multiple testing, a significance level of a < 0.01 was used. RESULTS: Participants (n = 23,669) had a weighted mean age of 43.25 (SD = 13.97) years and 47% were female. Employed females (aOR = 0.47, 95% CI 0.32, 0.69), unemployed females (aOR = 0.47, 95% CI 0.29, 0.75), and unemployed males (aOR = 0.31, 95% CI 0.17, 0.56) with college education had reduced odds of depressive symptoms compared to those with high school education. Employed females with college education also had reduced suicidal ideation odds compared to those with high school education (aOR = 0.41, 95% CI 0.22, 0.76). CONCLUSIONS: Females demonstrated significant associations between depressive symptoms and education, regardless of employment status, whereas males demonstrated an association only if unemployed. Employed females, in particular, demonstrated a significant association between suicidal ideation and education. These findings may inform future research investigating the underlying mechanisms and etiology of these sex-employment status differences in the association between mental health and education.

The association between depressive symptoms and high-sensitivity C-reactive protein: Is body mass index a moderator?

Objective: Depression and obesity are highly comorbid conditions with shared biological mechanisms. It remains unclear how depressive symptoms and body mass index (BMI) interact in relation to inflammation. This cross-sectional study investigated the independent associations of depressive symptoms and BMI with high sensitivity C-reactive protein (hs-CRP), as well as the moderating role of BMI on the depressive symptoms-hs-CRP association. Methods: Participants (n = 8827) from the 2015-2018 National Health and Nutrition Examination Surveys were aged ≥20 with a BMI ≥18.5 kg/m2, completed the Depression Screener, and had hs-CRP data. Multivariable linear regression was used to analyze hs-CRP in relation to depressive symptoms and BMI. An interaction term was included to examine whether the depressive symptoms-hs-CRP relationship differs depending on BMI. Results: There was a slight, albeit non-significant, increase in hs-CRP levels with each one-point increase in depressive symptoms (aCoef.Estm. = 0.01, 95% CI = -0.05, 0.06, p = 0.754). Participants with overweight (aCoef.Estm. = 1.07, 95% CI = 0.61, 1.53, p < 0.001) or obese (aCoef.Estm. = 3.51, 95% CI = 3.04, 3.98, p < 0.001) BMIs had higher mean hs-CRP levels than those with a healthy BMI. There were no significant interactions between depressive symptoms and overweight (aCoef.Estm. = 0.04, 95% CI = -0.04, 0.13, p = 0.278) or obese (aCoef.Estm. = 0.11, 95% CI = -0.01, 0.22, p = 0.066) BMI indicating a lack of difference in the depressive symptoms-hs-CRP association across participants in the healthy versus overweight and obese ranges. Conclusions: This study suggests that BMI might not act as a moderator in the association between depressive symptoms and hs-CRP. Results should be replicated in larger samples. Further research is warranted to understand underlying mechanisms.

Depressive symptoms among adults is associated with decreased food security.

OBJECTIVE: We aim to evaluate the association of depressive symptoms, depressive symptoms severity and symptom cluster scores (i.e., cognitive-affective and somatic) with food security (FS). We will also evaluate the interaction effect of sex, income and ethnicity on these associations. METHODS: Data from the 2005-2018 National Health and Nutrition Examination Survey cycles were used in this study. Participants included survey respondents 20+ years who had completed Depression and Food Security questionnaires. Multivariable logistic regression was used to estimate the associations between depressive symptoms and FS. RESULTS: A total of 34,128 participants, including 3,021 (7.73%) with depressive symptoms, were included in this study. In both unadjusted and adjusted models, participants with depressive symptoms had lower odds of FS (aOR = 0.347, 95% CI: 0.307,0.391, p<0.001). Moreover, in both unadjusted and adjusted models, for each 1-point increase in cognitive-affective (aOR = 0.850, 95% CI = 0.836,0.864, p <0.001) and somatic symptoms (aOR = 0.847, 95% CI = 0.831,0.863, p <0.001), odds of high FS decreased correspondingly. Our study found no significant interaction effects of sex on depressive symptoms-FS association. Statistically significant interactions of ethnicity and poverty-to-income ratio on depressive symptoms-FS association were observed, revealing higher odds of FS among Non-Hispanic Black and Mexican American groups, and lower odds of FS in Non-Hispanic White and high-income subgroups. CONCLUSION: Our study demonstrated an association between depressive symptoms and decreased FS. Further research is required to deepen our understanding of the underlying mechanisms and to develop focused interventions.

The Association Between Depressive Symptoms and the Weekly Duration of Physical Activity Subset by Intensity and Domain: Population-Based, Cross-Sectional Analysis of the National Health and Nutrition Examination Survey From 2007 to 2018.

BACKGROUND: Prior literature suggests a dose-response relationship between physical activity (PA) and depressive symptoms. The intensity and domain of PA are suggested to be critical to its protective effect against depression; however, existing literature has shown mixed results. OBJECTIVE: The purpose of this population-based study is to examine the associations between depressive symptoms and weekly duration of (1) total PA and (2) PA subset by intensity, domain, or both. METHODS: A cross-sectional analysis of National Health and Nutrition Examination Survey data from 2007 to 2018 was conducted using multivariable logistic and linear regression models and survey weights. Participants (N=29,730) were 20 years and older and completed the Physical Activity Questionnaire and Depression Screener. The primary outcome was the presence of depressive symptoms, and the secondary outcomes were cognitive-affective and somatic symptoms of depression. RESULTS: Participants (N=29,730) had a weighted mean age of 47.62 (SD 16.99) years, and 15,133 (51.34%) were female. On average, participants without depressive symptoms engaged in 10.87 hours of total PA per week, whereas participants with depressive symptoms engaged in 8.82 hours (P<.001). No significant associations were seen between the weekly duration of total PA and depressive symptom odds, somatic, or cognitive-affective symptoms (all P>.05). Participants with an increased weekly duration of recreational PA had decreases in depressive symptom odds (adjusted odds ratio [aOR] 0.965, 95% CI 0.944-0.986) and in somatic (adjusted coefficient [aß]=-0.016, 95% CI -0.022 to -0.009) and cognitive-affective (aß=-0.015, 95% CI -0.023 to -0.007) symptoms. When recreational PA was subset by intensity, participants with an increased weekly duration of vigorous-intensity recreational PA had decreases in depressive symptom odds (aOR 0.926, 95% CI 0.883-0.972) and in somatic (aß=-0.021, 95% CI -0.032 to -0.010) and cognitive-affective (aß=-0.022, 95% CI -0.035 to -0.009) symptoms. However, significant associations were not seen for the weekly duration of work-related, moderate- or vigorous-intensity PAs (all P>.05). CONCLUSIONS: Findings suggest that recreational, not work-related PA is associated with reduced symptoms of depression. Future studies should explore the impact of the different types and contexts of PA on depressive symptomatology.

Compact RNA sensors for increasingly complex functions of multiple inputs.

Designing single molecules that compute general functions of input molecular partners represents a major unsolved challenge in molecular design. Here, we demonstrate that high-throughput, iterative experimental testing of diverse RNA designs crowdsourced from Eterna yields sensors of increasingly complex functions of input oligonucleotide concentrations. After designing single-input RNA sensors with activation ratios beyond our detection limits, we created logic gates, including challenging XOR and XNOR gates, and sensors that respond to the ratio of two inputs. Finally, we describe the OpenTB challenge, which elicited 85-nucleotide sensors that compute a score for diagnosing active tuberculosis, based on the ratio of products of three gene segments. Building on OpenTB design strategies, we created an algorithm Nucleologic that produces similarly compact sensors for the three-gene score based on RNA and DNA. These results open new avenues for diverse applications of compact, single molecule sensors previously limited by design complexity.

Early immune factors associated with the development of post-acute sequelae of SARS-CoV-2 infection in hospitalized and non-hospitalized individuals.

Background: Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to post-acute sequelae of SARS-CoV-2 (PASC) that can persist for weeks to years following initial viral infection. Clinical manifestations of PASC are heterogeneous and often involve multiple organs. While many hypotheses have been made on the mechanisms of PASC and its associated symptoms, the acute biological drivers of PASC are still unknown. Methods: We enrolled 494 patients with COVID-19 at their initial presentation to a hospital or clinic and followed them longitudinally to determine their development of PASC. From 341 patients, we conducted multi-omic profiling on peripheral blood samples collected shortly after study enrollment to investigate early immune signatures associated with the development of PASC. Results: During the first week of COVID-19, we observed a large number of differences in the immune profile of individuals who were hospitalized for COVID-19 compared to those individuals with COVID-19 who were not hospitalized. Differences between individuals who did or did not later develop PASC were, in comparison, more limited, but included significant differences in autoantibodies and in epigenetic and transcriptional signatures in double-negative 1 B cells, in particular. Conclusions: We found that early immune indicators of incident PASC were nuanced, with significant molecular signals manifesting predominantly in double-negative B cells, compared with the robust differences associated with hospitalization during acute COVID-19. The emerging acute differences in B cell phenotypes, especially in double-negative 1 B cells, in PASC patients highlight a potentially important role of these cells in the development of PASC.

Ongoing genome doubling promotes evolvability and immune dysregulation in ovarian cancer.

Whole-genome doubling (WGD) is a critical driver of tumor development and is linked to drug resistance and metastasis in solid malignancies. Here, we demonstrate that WGD is an ongoing mutational process in tumor evolution. Using single-cell whole-genome sequencing, we measured and modeled how WGD events are distributed across cellular populations within tumors and associated WGD dynamics with properties of genome diversification and phenotypic consequences of innate immunity. We studied WGD evolution in 65 high-grade serous ovarian cancer (HGSOC) tissue samples from 40 patients, yielding 29,481 tumor cell genomes. We found near-ubiquitous evidence of WGD as an ongoing mutational process promoting cell-cell diversity, high rates of chromosomal missegregation, and consequent micronucleation. Using a novel mutation-based WGD timing method, doubleTime , we delineated specific modes by which WGD can drive tumor evolution: (i) unitary evolutionary origin followed by significant diversification, (ii) independent WGD events on a pre-existing background of copy number diversity, and (iii) evolutionarily late clonal expansions of WGD populations. Additionally, through integrated single-cell RNA sequencing and high-resolution immunofluorescence microscopy, we found that inflammatory signaling and cGAS-STING pathway activation result from ongoing chromosomal instability and are restricted to tumors that remain predominantly diploid. This contrasted with predominantly WGD tumors, which exhibited significant quiescent and immunosuppressive phenotypic states. Together, these findings establish WGD as an evolutionarily 'active' mutational process that promotes evolvability and dysregulated immunity in late stage ovarian cancer.