Light Affects Mood and Learning through Distinct Retina-Brain Pathways.

Light exerts a range of powerful biological effects beyond image vision, including mood and learning regulation. While the source of photic information affecting mood and cognitive functions is well established, viz. intrinsically photosensitive retinal ganglion cells (ipRGCs), the central mediators are unknown. Here, we reveal that the direct effects of light on learning and mood utilize distinct ipRGC output streams. ipRGCs that project to the suprachiasmatic nucleus (SCN) mediate the effects of light on learning, independently of the SCN's pacemaker function. Mood regulation by light, on the other hand, requires an SCN-independent pathway linking ipRGCs to a previously unrecognized thalamic region, termed perihabenular nucleus (PHb). The PHb is integrated in a distinctive circuitry with mood-regulating centers and is both necessary and sufficient for driving the effects of light on affective behavior. Together, these results provide new insights into the neural basis required for light to influence mood and learning.

Electron Transport Chain Remodeling by GSK3 during Oogenesis Connects Nutrient State to Reproduction.

Reproduction is heavily influenced by nutrition and metabolic state. Many common reproductive disorders in humans are associated with diabetes and metabolic syndrome. We characterized the metabolic mechanisms that support oogenesis and found that mitochondria in mature Drosophila oocytes enter a low-activity state of respiratory quiescence by remodeling the electron transport chain (ETC). This shift in mitochondrial function leads to extensive glycogen accumulation late in oogenesis and is required for the developmental competence of the oocyte. Decreased insulin signaling initiates ETC remodeling and mitochondrial respiratory quiescence through glycogen synthase kinase 3 (GSK3). Intriguingly, we observed similar ETC remodeling and glycogen uptake in maturing Xenopus oocytes, suggesting that these processes are evolutionarily conserved aspects of oocyte development. Our studies reveal an important link between metabolism and oocyte maturation.

Income variability and incident cardiovascular disease in diabetes: a population-based cohort study.

BACKGROUND AND AIMS: Longitudinal change in income is crucial in explaining cardiovascular health inequalities. However, there is limited evidence for cardiovascular disease (CVD) risk associated with income dynamics over time among individuals with type 2 diabetes (T2D). METHODS: Using a nationally representative sample from the Korean National Health Insurance Service database, 1 528 108 adults aged 30-64 with T2D and no history of CVD were included from 2009 to 2012 (mean follow-up of 7.3 years). Using monthly health insurance premium information, income levels were assessed annually for the baseline year and the four preceding years. Income variability was defined as the intraindividual standard deviation of the percent change in income over 5 years. The primary outcome was a composite event of incident fatal and nonfatal CVD (myocardial infarction, heart failure, and stroke) using insurance claims. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated after adjusting for potential confounders. RESULTS: High-income variability was associated with increased CVD risk (HRhighest vs. lowest quartile 1.25, 95% CI 1.22-1.27; Ptrend < .001). Individuals who experienced an income decline (4 years ago vs. baseline) had increased CVD risk, which was particularly notable when the income decreased to the lowest level (i.e. Medical Aid beneficiaries), regardless of their initial income status. Sustained low income (i.e. lowest income quartile) over 5 years was associated with increased CVD risk (HRn = 5 years vs. n = 0 years 1.38, 95% CI 1.35-1.41; Ptrend < .0001), whereas sustained high income (i.e. highest income quartile) was associated with decreased CVD risk (HRn = 5 years vs. n = 0 years 0.71, 95% CI 0.70-0.72; Ptrend < .0001). Sensitivity analyses, exploring potential mediators, such as lifestyle-related factors and obesity, supported the main results. CONCLUSIONS: Higher income variability, income declines, and sustained low income were associated with increased CVD risk. Our findings highlight the need to better understand the mechanisms by which income dynamics impact CVD risk among individuals with T2D.

An exploratory study of a multi-species probiotic formulation and markers of health in a real-world oncological cohort in the time of covid.

INTRODUCTION: The efficacy of cancer treatments has links to the intestinal microbiome. Mucositis is a dose-limiting intestinal pro-inflammatory side effect of cancer treatments, that increases the risk of diarrhoea, mucositis, and in severe cases, febrile neutropenia. METHODS: The effect of cancer treatments on Quality of Life (QoL) was assessed using the FACT C questionnaire that included patient wellbeing and gut adverse symptoms (e.g. diarrhoea). Participants rated faecal samples via the Bristol Stool Chart. In addition, bacterial DNA was extracted from faecal samples, sequenced, and taxonomically examined. The incidence / severity of neutropenia was assessed with white blood cell and neutrophil counts. Circulating SCFAs and plasma lipopolysaccharide (LPS) endotoxin levels were recorded and correlated to intestinal mucositis. RESULTS: Improvement in bowel function, with reduction in constipation and or diarrhoea or absence of significant disturbance to bowel function was recorded in 85% of the participants. One participant developed febrile neutropenia and two developed bowel toxicity during the study, that was unrelated to the test formulation. No significant changes in microbiota alpha- and beta-diversity at the phylum and species levels respectively from baseline to end of study treatment was observed. None of the participants had raised plasma-endotoxin levels from baseline to the first and subsequent treatment cycles for their cancers. Probiotics in this cohort were deemed safe and tolerable. Significant improvement in emotional QoL scores (p = 0.015) was reported with increased number of chemotherapy cycles. In a related observational study of exceptional responders to chemotherapy, participants were found to have had a high intake of fruits, vegetables, and fibre possibly indicative of a more balanced intestinal microbiota. CONCLUSION: A multi-strain probiotic formulation was safe and tolerated in this chronically ill cohort that were undergoing oncological treatment. The probiotic formulation alleviated diarrhoea, constipation and maintained stool consistency/frequency during the multiple treatments with chemotherapy and radiotherapy. Intestinal dysbiosis that is characterised by decreased microbial diversity and increased pro-inflammatory species was not observed. Probiotic supplementation may have helped reduce dysbiosis during cancer treatments. These improvements may have been critical with the observation that emotional wellbeing was significantly improved from baseline. Hence albeit that the study had limitations, the probiotic intervention provided adjunctive treatment support to the patients. What is of scientifically plausible interest is that probiotics have a long association historically with human hosts and as such ratify their inclusion offering a significant adjunctive therapeutic potential. Future studies warrant larger sample sizes, control groups and should limit recruitment to a largely homogenous group of patients.

Evaluation of the Little Rock Green Schoolyard initiative: a quasi-experimental study protocol.

BACKGROUND: Evidence suggests that access to green schoolyards may facilitate vigorous play and lead to increased physical activity, which could lead to improved academic outcomes and reduce excess childhood weight gain. Greener schoolyards can also provide additional outdoor amenities that help the community at large. The Little Rock Green Schoolyard Initiative, a program aiming to promote outdoor learning and play in two of the city's community schools, provides a natural experiment to evaluate the role of such interventions. This article presents the protocols and study plans that will be used to evaluate this community-led initiative on several outcomes including physical activity, sleep quality, use of schoolgrounds, and perceptions of the school environment. Administrative datasets will be used to assess exposure to green schoolyard improvements on academic achievement, attendance, and disciplinary referrals during elementary school. METHODS: Data will be gathered in two community schools where the green schoolyard improvements are taking place and in two demographically-matched comparison schools located elsewhere within the Little Rock School District. Data will be collected before, during, and after the green schoolyard improvements go into effect. Physical activity and sleep quality will be measured using actigraphy. Physical activity will also be assessed through direct playground observations during recess and outside of school hours. During the final year of the study, administrative data will be assembled and evaluated using difference-in-differences estimation and synthetic controls, two causal inference methods from the program evaluation literature. DISCUSSION: The study is designed to provide new insights into the design, implementation, and evaluation of playgrounds among schoolchildren, especially those who are at risk of developing severe obesity during their elementary school years. The research herein will develop empirical data, elucidate potential mechanisms, and practical experience for future study, policymaking, and health services.

The association between food insecurity and mental health during the COVID-19 pandemic.

OBJECTIVE: To explore the association between food insecurity and mental health outcomes among low-income Americans during the COVID-19 pandemic. METHODS: We conducted a survey of 2714 low-income respondents nationwide from June 29, 2020 to July 21, 2020. A proportional odds logit model was employed to estimate the associations between food insecurity and anxiety and between food insecurity and depression. RESULTS: Food insecurity is associated with a 257% higher risk of anxiety and a 253% higher risk of depression. Losing a job during the pandemic is associated with a 32% increase in risk for anxiety and a 27% increase in risk for depression. CONCLUSIONS: Food insecurity caused by the pandemic was associated with increased risk of mental illness. The relative risk of mental illness from being food insecure is almost three-fold that of losing a job during the pandemic. Public health measures should focus on getting direct subsidies of food purchases to poor families, especially families with children. They should also reduce the stigma and shame that is associated with accepting charitable foods.

Interaction of gut microbiota with dysregulation of bile acids in the pathogenesis of nonalcoholic fatty liver disease and potential therapeutic implications of probiotics.

The intestinal microbiota is now recognised to play key roles in health due to its involvement in many aspects of human physiology. Disturbance in gut microbiota (dysbiosis) is thus associated with many diseases including nonalcoholic fatty liver disease (NAFLD) which includes nonalcoholic fatty liver and nonalcoholic steatohepatitis. The mechanisms for the effect of dysbiosis in NAFLD pathogenesis are not completely elucidated. Many explanations have been proposed to trigger dysbiosis, leading to NAFLD including inflammation, ethanol produced by the gut bacteria and lipotoxicity. Recently the roles of bile acids and nuclear receptors are highly regarded. It is well known that gut microbes produce enzymes that convert primary bile acids into secondary bile acids in the intestines. Several studies have demonstrated that disturbance of the intestinal microbiota leads to decreased synthesis of secondary bile acids, which in turn decreases activation of nuclear receptors such as farnesoid X receptor (FXR), pregnane X receptor, Takeda G-protein-coupled bile acid protein 5 and vitamin D receptor. These receptors are important in energy regulation and their dysregulation can cause NAFLD. Therefore, stimulation of nuclear receptors especially FXR has been extensively explored for the amelioration of NAFLD. However, paradoxical effects of nuclear receptor activation are a major problem for the clinical application of nuclear receptor stimuli. We further posit that microbiome restoration could be an alternative approach for the treatment of NAFLD. Several gut bacteria are now known to be involved in bile acid metabolism. It will be necessary to identify which one/ones is/are feasible. Careful selection of commensal bacteria for probiotics may lead to an effective therapy for NAFLD.

Zinc deficits, mucositis, and mucosal macrophage perturbation: is there a relationship?

PURPOSE OF REVIEW: Mucositis is a common and therapy-limiting adverse effect of cancer treatments including radiotherapy, chemotherapy, and immunotherapy. The optimal zinc formulation, dosage, and timing of administration warrant further research as does the efficacious prevention of febrile mucositis that predisposes to febrile neutropenia. RECENT FINDINGS: Metaanalyses concluded that zinc sulfate failed to significantly reduce the incidence or severity of chemotherapy-induced oral mucositis, whereas polaprezinc was associated with a significant reduction. Three new trials were published in 2018. The first trial found that zinc sulfate reduced the incidence and severity of chemotherapy-induced oral mucositis. The second reported that polaprezinc reduced oral mucositis in pediatric patients receiving high-dose chemotherapy for hematopoietic stem cell transplantation. The third trial demonstrated efficacy for a zinc lozenge for postoperative sore throat induced by an endotracheal intubation. SUMMARY: Zinc deficits, dietary or induced by cancer, are common in patients with cancer. Febrile mucositis may better describe the condition linking mucositis with febrile neutropenia. Febrile mucositis disrupts treatment and may be life-threatening. A paradigm shift is needed for a more comprehensive understanding of febrile mucositis. Zinc effects on the thymic immunological network and T lymphocytes during chemoradiotherapy regimens also warrant further investigation.

Perna canaliculus and the Intestinal Microbiome.

Natural medicines are often an attractive option for patients diagnosed with chronic conditions. Three main classes of bioactives that have been reported from marine mussel extracts include proteins, lipids and carbohydrates. Commercially, the most relevant species of marine mollusks belong to two genera, Perna and Mytilus. Specifically, the Perna canaliculus species has been repeatedly demonstrated to harbor anti-inflammatory compounds such as omega-3 polyunsaturated fatty acids (ω-3 PUFAs) that can ameliorate pro-inflammatory conditions, or proteins that can promote thrombin inhibitory activity. Recent clinical studies have posited that extracts from green-lipped mussels may lead to prebiotic activity in the intestinal microbiome that in turn has been reported to improve symptoms of osteoarthritis of the knee. Prebiotics have been reported to favorably interact with the intestinal microbiome through the proliferation of beneficial bacteria in the gut, suppressing exogenous and endogenous intestinal infections and promoting homeostasis by balancing local pro- and anti-inflammatory actions. Bioactive compounds from Perna canaliculus are functional foods and, in this regard, may positively interact with the intestinal microbiome and provide novel therapeutic solutions for intra-intestinal and extra-intestinal inflammatory conditions.

Transgender Surgery in Denmark From 1994 to 2015: 20-Year Follow-Up Study.

INTRODUCTION: Gender dysphoria is a mismatch between a person's biological sex and gender identity. The best treatment is believed to be hormonal therapy and gender-confirming surgery that will transition the individual toward the desired gender. Treatment in Denmark is covered by public health care, and gender-confirming surgery in Denmark is centralized at a single-center with few specialized plastic surgeons conducting top surgery (mastectomy or breast augmentation) and bottom surgery (vaginoplasty or phalloplasty and metoidioplasty). AIMS: To report the first nationwide single-center review on transsexual patients in Denmark undergoing gender-confirming surgery performed by a single surgical team and to assess whether age at time of gender-confirming surgery decreased during a 20-year period. METHODS: Electronic patient databases were used to identify patients diagnosed with gender identity disorders from January 1994 through March 2015. Patients were excluded from the study if they were pseudohermaphrodites or if their gender was not reported. MAIN OUTCOME MEASURES: Gender distribution, age trends, and surgeries performed for Danish patients who underwent gender-confirming surgery. RESULTS: One hundred fifty-eight patients referred for gender-confirming surgery were included. Fifty-five cases (35%) were male-to-female (MtF) and 103 (65%) were female-to-male (FtM). In total, 126 gender-confirming surgeries were performed. For FtM cases, top surgery (mastectomy) was conducted in 62 patients and bottom surgery (phalloplasty and metoidioplasty) was conducted in 17 patients. For MtF cases, 45 underwent bottom surgery (vaginoplasty), 2 of whom received breast augmentation. The FtM:MtF ratio of the referred patients was 1.9:1. The median age at the time of surgery decreased from 40 to 27 years during the 20-year period. CONCLUSION: Gender-confirming surgery was performed on 65 FtM and 40 MtF cases at our hospital, and 21 transsexuals underwent surgery abroad. Mastectomy was performed in 62 FtM and bottom surgery in 17 FtM cases. Vaginoplasty was performed in 45 MtF and breast augmentation in 2 MtF cases. There was a significant decrease in age at the time of gender-confirming surgery during the course of the study period.

Persistent disparities in obesity risk among public schoolchildren from childhood through adolescence.

INTRODUCTION: Arkansas is among the poorest states and has high rates of childhood obesity. In 2003, it became the first state to systematically screen public schoolchildren for unhealthy weight status. This study aims to examine the socioeconomic disparities in Body Mass Index (BMI) growth and the risk of the onset of obesity from childhood through adolescence. METHODS: This study analyzed (in 2015) the data for a large cohort of Arkansas public schoolchildren for whom BMIs were measured from school years 2003/2004 through 2009/2010. A linear growth curve model was used to assess how child-level sociodemographics and neighborhood characteristics were associated with growth in BMI z-scores. Cox regression was subsequently used to investigate how these factors were associated with the onset of obesity. Because children might be classified as obese in multiple years, sensitivity analysis was conducted using recurrent event Cox regression. RESULTS: Survival analysis indicated that the risk of onset of obesity rose sharply between ages of 5 and 10 and then again after age 15. The socioeconomic disparities in obesity risk persisted from kindergarten through adolescence. While better access to full service restaurants was associated with lower risk of the onset of obesity (Hazard Ratio (HR)=0.98, 95% CI=0.97-0.99), proximity to fast food restaurants was related to increased risk of the onset of obesity (HR=1.01, 95% CI=1.00-1.01). CONCLUSIONS: This analysis stresses the need for policies to narrow the socioeconomic gradient and identifies important time periods for preventative interventions in childhood obesity.

Where the children play: Gender gaps in recess physical activity by age and playground area.

Objective: Recess contributes meaningfully to physical activity (PA), but recess time has declined. The study's purpose was to report PA by age, gender, and playground feature to inform potential playground configurations more conducive to PA during recess. Methods: Using the System for Observing Play and Leisure Activity in the Youth, kindergarten through 5th grade recesses were observed on at least four days at four schools in Little Rock, Arkansas, United States during May 2023. Target playground features were ball courts, grass, pavement, play structures, and swings. To provide inferential analysis, a comparison of conditional means across playground features, age, and gender was conducted using linear regression with robust standard errors clustered by school. Results: 3,356 playground scans (intercoder correlation = 0.93) were collected and aggregated by school, day, gender, age (grade), and target feature for a sample size of 292 observations. The gender gap was widest among 4-5th graders, 79 % (95 % CI: 72, 86) for males and 64 % (95 % CI: 58, 70) for females. Among females, PA was highest on swings [82 % (95 % CI: 77, 86)] and lowest on paved areas [56 % (95 % CI: 43, 69)]. Among males, it was highest on both swings [81 % (95 % CI: 75, 86)] and ball courts [83 % (95 % CI: 77, 89)] and lowest on grassy areas [64 % (95 % CI: 60, 67)]. Conclusion: Swings, courts, and play structures were associated with a higher proportion of children being engaged in PA. Research is needed to identify whether physical improvements to facilitate access to these features increase PA.

Light affects the prefrontal cortex via intrinsically photosensitive retinal ganglion cells.

The ventromedial prefrontal cortex (vmPFC) is a part of the limbic system engaged in the regulation of social, emotional, and cognitive states, which are characteristically impaired in disorders of the brain such as schizophrenia and depression. Here, we show that intrinsically photosensitive retinal ganglion cells (ipRGCs) modulate, through light, the integrity, activity, and function of the vmPFC. This regulatory role, which is independent of circadian and mood alterations, is mediated by an ipRGC-thalamic-corticolimbic pathway. Lack of ipRGC signaling in mice causes dendritic degeneration, dysregulation of genes involved in synaptic plasticity, and depressed neuronal activity in the vmPFC. These alterations primarily undermine the ability of the vmPFC to regulate emotions. Our discovery provides a potential light-dependent mechanism for certain PFC-centric disorders in humans.

Neurexin 3 is required for the specific S-cone to S-cone bipolar cell synapse in the mammalian retina.

Specific wiring is essential for sensory systems to precisely relay information to higher brain regions. The retina, an approachable part of the brain, is an ideal model for studying neural circuits due to its well-organized structure. In the retina, S-cone photoreceptors sense and relay short-wavelength (e.g., blue) light signals for encoding color information and other environmental cues. S-cones usually account for less than 10% of cones and are precisely connected to S-cone bipolar cells (SCBCs). This connection is ancient and highly conserved across species, indicating essential functions. How this wiring specificity is formed and maintained, however, is not understood. To unveil the molecular mechanisms underlying this highly specific connection, we sequenced the transcriptomes of thirteen-lined ground squirrel (TLGS) photoreceptors. We chose TLGS for their cone-rich retina and the absence of cones that co-express multiple opsin proteins, as compared to mice. We used a targeted SMART-seq approach to obtain high-resolution transcriptomes from S- and M-cone photoreceptors and identified a cell-adhesion molecule, Nrxn3, as a potential candidate mediating the S-cone to SCBC connection. Given the limitations of genetic manipulation in TLGS, we utilized mouse models to study the function of Nrxn3 in S-cones. In 'true' S-cones (S-opsin+/M-opsin-) that lack Nrxn3 expression, the number of connections with SCBCs was drastically reduced, indicating a critical role of Nrxn3 for this synapse. While neurexins are well known for their diverse roles in regulating various synapses, this study is the first to document its crucial role in mediating or maintaining a specific synapse in the central nervous system. In addition, the differentially expressed genes identified here provide a valuable resource for further investigating cone subtype-specific functions.

WITHDRAWN: Light affects the prefrontal cortex via intrinsically photosensitive retinal ganglion cells.

This manuscript has been withdrawn by bioRxiv following a formal request by the NIH Intramural Research Integrity Office owing to lack of author consent.

Evaluation of Delivering Breakfast After the Bell and Academic Performance Among Third-Grade Children: An Application of the Synthetic Control Method.

BACKGROUND: Breakfast after the bell (BAB), an alternative way to deliver breakfast after the school day begins, has been shown to increase participation in the School Breakfast Program. However, BAB occupies time that could otherwise be used for instruction and may affect academic performance. This study examined whether BAB affects math and literacy scores in third grade, an age not adequately studied in earlier literature. METHODS: Using data on Arkansas students, we compared schools adopting BAB to corresponding "synthetic" control schools by minimizing preadoption differences in observables that can influence test scores. RESULTS: We found little evidence of positive or negative effects on test scores. We also found little evidence of meaningful program effects over subsamples of schools by district enrollment size and BAB delivery method. Schools that adopted grab-and-go delivery and schools in districts with small enrollments, less than 600 students, showed statistically negative effects on math after BAB adoption. However, these effects were transitory and no longer present by the time the first fully exposed cohort reached third grade. CONCLUSIONS: BAB can be incorporated into the school day without adversely impacting academic achievement, especially if adopting schools seek input from educators and nutrition personnel already experienced with BAB.

Food insecurity during the COVID-19 pandemic: evidence from a survey of low-income Americans.

The COVID-19 pandemic significantly increased food insecurity despite emergency legislation that put more resources into food assistance programs, increased unemployment benefits, and provided stimulus payments. We conducted a survey in the US on food insecurity among low-income Americans during the early months of the pandemic. While we cannot estimate causal effects, we are able to show important associations between food insecurity and nutritional and economic assistance that highlight the need to ensure that those newly at risk for food insecurity are able to connect to resources. For example, our results indicate that those who lost jobs due to the pandemic reported the highest level of food insecurity and also the lowest engagement with food assistance programs. The SNAP expansion appears to be important only among groups with higher levels of income stability including non-minority households and those not experiencing a job loss. Thus, the SNAP expansion may not have had a meaningful impact on those most at risk for food insecurity. Finally, our data highlight the importance of school meal programs during normal times. Those who took advantage of school meals before the outbreak are more likely to have experienced food insecurity during the pandemic-related school closures.

Diversity of satellite glia in sympathetic and sensory ganglia.

Satellite glia are the major glial type found in sympathetic and sensory ganglia in the peripheral nervous system, and specifically, contact neuronal cell bodies. Sympathetic and sensory neurons differ in morphological, molecular, and electrophysiological properties. However, the molecular diversity of the associated satellite glial cells remains unclear. Here, using single-cell RNA sequencing analysis, we identify five different populations of satellite glia from sympathetic and sensory ganglia. We define three shared populations of satellite glia enriched in immune-response genes, immediate-early genes, and ion channels/ECM-interactors, respectively. Sensory- and sympathetic-specific satellite glia are differentially enriched for modulators of lipid synthesis and metabolism. Sensory glia are also specifically enriched for genes involved in glutamate turnover. Furthermore, satellite glia and Schwann cells can be distinguished by unique transcriptional signatures. This study reveals the remarkable heterogeneity of satellite glia in the peripheral nervous system.