Nuclease-independent functions of RAG1 direct distinct DNA damage responses in B cells.

Developing B cells generate DNA double-stranded breaks (DSBs) to assemble immunoglobulin receptor (Ig) genes necessary for the expression of a mature B cell receptor. These physiologic DSBs are made by the RAG endonuclease, which is comprised of the RAG1 and RAG2 proteins. In pre-B cells, RAG-mediated DSBs activate the ATM kinase to coordinate canonical and non-canonical DNA damage responses (DDR) that trigger DSB repair and B cell developmental signals, respectively. Whether this broad cellular response is distinctive to RAG DSBs is poorly understood. To delineate the factors that direct DDR signaling in B cells, we express a tetracycline-inducible Cas9 nuclease in Rag1-deficient pre-B cells. Both RAG- and Cas9-mediated DSBs at Ig genes activate canonical DDR. In contrast, RAG DSBs, but not Cas9 DSBs, induce the non-canonical DDR-dependent developmental program. This unique response to RAG DSBs is, in part, regulated by non-core regions of RAG1. Thus, B cells trigger distinct cellular responses to RAG DSBs through unique properties of the RAG endonuclease that promotes activation of B cell developmental programs.

cIAP1/2 Antagonism Induces Antigen-Specific T Cell-Dependent Immunity.

Checkpoint blockade immunotherapy has failed in pancreatic cancer and other poorly responsive tumor types in part due to inadequate T cell priming. Naive T cells can receive costimulation not only via CD28 but also through TNF superfamily receptors that signal via NF-κB. Antagonists of the ubiquitin ligases cellular inhibitor of apoptosis protein (cIAP)1/2, also called second mitochondria-derived activator of caspases (SMAC) mimetics, induce degradation of cIAP1/2 proteins, allowing for the accumulation of NIK and constitutive, ligand-independent activation of alternate NF-κB signaling that mimics costimulation in T cells. In tumor cells, cIAP1/2 antagonists can increase TNF production and TNF-mediated apoptosis; however, pancreatic cancer cells are resistant to cytokine-mediated apoptosis, even in the presence of cIAP1/2 antagonism. Dendritic cell activation is enhanced by cIAP1/2 antagonism in vitro, and intratumoral dendritic cells show higher expression of MHC class II in tumors from cIAP1/2 antagonism-treated mice. In this study, we use in vivo mouse models of syngeneic pancreatic cancer that generate endogenous T cell responses ranging from moderate to poor. Across multiple models, cIAP1/2 antagonism has pleiotropic beneficial effects on antitumor immunity, including direct effects on tumor-specific T cells leading to overall increased activation, increased control of tumor growth in vivo, synergy with multiple immunotherapy modalities, and immunologic memory. In contrast to checkpoint blockade, cIAP1/2 antagonism does not increase intratumoral T cell frequencies. Furthermore, we confirm our previous findings that even poorly immunogenic tumors with a paucity of T cells can experience T cell-dependent antitumor immunity, and we provide transcriptional clues into how these rare T cells coordinate downstream immune responses.

De novo design of potent and selective mimics of IL-2 and IL-15.

We describe a de novo computational approach for designing proteins that recapitulate the binding sites of natural cytokines, but are otherwise unrelated in topology or amino acid sequence. We use this strategy to design mimics of the central immune cytokine interleukin-2 (IL-2) that bind to the IL-2 receptor ßγc heterodimer (IL-2Rßγc) but have no binding site for IL-2Rα (also called CD25) or IL-15Rα (also known as CD215). The designs are hyper-stable, bind human and mouse IL-2Rßγc with higher affinity than the natural cytokines, and elicit downstream cell signalling independently of IL-2Rα and IL-15Rα. Crystal structures of the optimized design neoleukin-2/15 (Neo-2/15), both alone and in complex with IL-2Rßγc, are very similar to the designed model. Neo-2/15 has superior therapeutic activity to IL-2 in mouse models of melanoma and colon cancer, with reduced toxicity and undetectable immunogenicity. Our strategy for building hyper-stable de novo mimetics could be applied generally to signalling proteins, enabling the creation of superior therapeutic candidates.

Transnuclear mice reveal Peyer's patch iNKT cells that regulate B-cell class switching to IgG1.

Tissue-resident iNKT cells maintain tissue homeostasis and peripheral surveillance against pathogens; however, studying these cells is challenging due to their low abundance and poor recovery from tissues. We here show that iNKT transnuclear mice, generated by somatic cell nuclear transfer, have increased tissue resident iNKT cells. We examined expression of PLZF, T-bet, and RORγt, as well as cytokine/chemokine profiles, and found that both monoclonal and polyclonal iNKT cells differentiated into functional subsets that faithfully replicated those seen in wild-type mice. We detected iNKT cells from tissues in which they are rare, including adipose, lung, skin-draining lymph nodes, and a previously undescribed population in Peyer's patches (PP). PP-NKT cells produce the majority of the IL-4 in Peyer's patches and provide indirect help for B-cell class switching to IgG1 in both transnuclear and wild-type mice. Oral vaccination with α-galactosylceramide shows enhanced fecal IgG1 titers in iNKT cell-sufficient mice. Transcriptional profiling reveals a unique signature of PP-NKT cells, characterized by tissue residency. We thus define PP-NKT as potentially important for surveillance for mucosal pathogens.

A developmental perspective on sleep consistency: Preschool age through emerging adulthood.

OBJECTIVE/BACKGROUND: Beyond sleep duration, the regularity of sleep patterns (e.g., sleep consistency), including variability in sleep timing (e.g., bedtime, wake time) and duration, is a critical marker of sleep health. Sleep consistency is captured using a variety of methods within the literature (e.g., sleep intraindividual variability, social jetlag), but most of the research focuses on adolescents. METHODS: Drawing on a developmental perspective, this narrative review highlights how normative changes at the individual (e.g., biological, cognitive, and social) and contextual (e.g., home, school, sociocultural) levels may contribute to inconsistent sleep patterns across development. RESULTS AND CONCLUSIONS: This review emphasizes how inconsistent sleep may increase across pivotal transitions throughout development (e.g., elimination of naps, puberty, summertime, entering college). Finally, recommendations for measuring sleep consistency and areas to address in future research are discussed.

Later sleep timing predicts accelerated summer weight gain among elementary school children: a prospective observational study.

OBJECTIVES AND BACKGROUND: Social demands of the school-year and summer environment may affect children's sleep patterns and circadian rhythms during these periods. The current study examined differences in children's sleep and circadian-related behaviors during the school-year and summer and explored the association between sleep and circadian parameters and change in body mass index (BMI) during these time periods. METHODS: This was a prospective observational study with 119 children ages 5 to 8 years with three sequential BMI assessments: early school-year (fall), late school-year (spring), and beginning of the following school-year in Houston, Texas, USA. Sleep midpoint, sleep duration, variability of sleep midpoint, physical activity, and light exposure were estimated using wrist-worn accelerometry during the school-year (fall) and summer. To examine the effect of sleep parameters, physical activity level, and light exposure on change in BMI, growth curve modeling was conducted controlling for age, race, sex, and chronotype. RESULTS: Children's sleep midpoint shifted later by an average of 1.5 h during summer compared to the school-year. After controlling for covariates, later sleep midpoints predicted larger increases in BMI during summer, (γ = .0004, p = .03), but not during the school-year. Sleep duration, sleep midpoint variability, physical activity levels, and sedentary behavior were not associated with change in BMI during the school-year or summer. Females tended to increase their BMI at a faster rate during summer compared to males, γ = .06, p = .049. Greater amounts of outdoor light exposure (γ = -.01, p = .02) predicted smaller increases in school-year BMI. CONCLUSIONS: Obesity prevention interventions may need to target different behaviors depending on whether children are in or out of school. Promotion of outdoor time during the school-year and earlier sleep times during the summer may be effective obesity prevention strategies during these respective times.

Potential circadian and circannual rhythm contributions to the obesity epidemic in elementary school age children.

Children gain weight at an accelerated rate during summer, contributing to increases in the prevalence of overweight and obesity in elementary-school children (i.e., approximately 5 to 11 years old in the US). Int J Behav Nutr Phys Act 14:100, 2017 explained these changes with the "Structured Days Hypothesis" suggesting that environmental changes in structure between the school year and the summer months result in behavioral changes that ultimately lead to accelerated weight gain. The present article explores an alternative explanation, the circadian clock, including the effects of circannual changes and social demands (i.e., social timing resulting from societal demands such as school or work schedules), and implications for seasonal patterns of weight gain. We provide a model for understanding the role circadian and circannual rhythms may play in the development of child obesity, a framework for examining the intersection of behavioral and biological causes of obesity, and encouragement for future research into bio-behavioral causes of obesity in children.

Eveningness Is Associated With Greater Depressive Symptoms in Type 2 Diabetes Patients: A Study in Two Different Ethnic Cohorts.

BACKGROUND: Eveningness is associated with greater depressive symptoms in the general population. Depression and type 2 diabetes (T2D) commonly coexist. We aimed to explore the association between morningness-eveningness and depressive symptoms in T2D patients in the United States and in Thailand. PARTICIPANTS: T2D patients (n = 182) from an endocrinology clinic in Chicago, Illinois, and six hospitals in Thailand (n = 251) were enrolled. METHODS: Diabetes history was collected. Depressive symptoms were assessed by the Center for Epidemiologic Studies Depression scale (CES-D). The Chicago cohort completed the Morningness-Eveningness Questionnaire (MEQ) and the Thai cohort completed the Composite Scale of Morningness (CSM). Sleep quality was assessed using the Pittsburg Sleep Quality Index (PSQI). RESULTS: The mean (SD) CES-D score was 13.7 (9.1) in Chicago and 11.9 (6.4) in Thailand. In Chicago participants, after adjusting for age, sex, ethnicity, hemoglobin A1c, insulin use, and PSQI score, greater eveningness (lower MEQ scores) was associated with higher CESD scores (B = -0.117, p = 0.048). In Thai participants, after adjusting for age, sex, and PSQI score, eveningness (lower CSM score) was associated with higher CES-D score (B = -0.147, p = 0.016). In both cohorts, however, eveningness was not independently associated with the likelihood of being in the at-risk range for clinical depression (CES-D ≥ 16). CONCLUSIONS: Eveningness is independently associated with greater depressive symptoms in T2D in two different ethnic cohorts. The results support the association between individual differences in circadian rhythms and psychological functioning in T2D.

Free-running circadian period in adolescents and adults.

Sleep timing shifts later during adolescence (second decade). This trend reverses at ~20 years and continues to shift earlier into adulthood. The current analysis examined the hypothesis that a longer free-running circadian period during late adolescence (14-17 years) compared with adulthood (30-45 years) accounts for sleep timing differences. Sex and ancestry were also examined because previous reports find that women and those with African-American ancestry have shorter free-running periods. Circadian period was measured using an ultradian dark-light protocol (2 hr dark/sleep, 2 hr dim room light [~20 lux]/wake) over 3.4 days. Dim light melatonin onsets were measured before and after the ultradian protocol, from which the circadian period was derived. In contrast to our hypothesis, we found that free-running circadian period was similar in adolescents and adults. African-American adults had shorter free-running circadian periods compared with adults of other ancestries. This ancestry difference was not seen in the adolescent group. Finally, we observed a non-significant trend for shorter free-running circadian periods in females compared with males. These data suggest that age-related changes in circadian period after late adolescence do not account for sleep timing differences. These data provide further support for ancestry-related differences in period, particularly in adults. Whether the large difference in circadian period between African-American and other ancestries emerges later in development should be explored.

An update on adolescent sleep: New evidence informing the perfect storm model.

The maturation of sleep regulatory systems during adolescence in combination with psychosocial and societal pressures culminate in a "Perfect Storm" of short and ill-timed sleep and the associated consequences for many youngsters. This model, first described by Carskadon in 2011, guides our current thinking of adolescent sleep behavior. Since the original description, the field has moved forward with remarkable pace, and this review aims to summarize recent progress and describe how this new work informs our understanding of sleep regulation and sleep behavior during this developmental time frame.

Sex and ancestry determine the free-running circadian period.

The endogenous, free-running circadian period (τ) determines the phase relationship that an organism assumes when entrained to the 24-h day. We found a shorter circadian period in African Americans compared to non-Hispanic European Americans (24.07 versus 24.33 h). We speculate that a short circadian period, closer to 24 h, was advantageous to humans living around the equator, but when humans migrated North out of Africa, where the photoperiod changes with seasons, natural selection favoured people with longer circadian periods. Recently, in evolutionary terms, immigrants came from Europe and Africa to America ('the New World'). The Europeans were descendents of people who had lived in Europe for thousands of years with changing photoperiods (and presumably longer periods), whereas Africans had ancestors who had always lived around the equator (with shorter periods). It may have been advantageous to have a longer circadian period while living in Europe early in the evolution of humans. In our modern world, however, it is better to have a shorter period, because it helps make our circadian rhythms earlier, which is adaptive in our early-bird-dominated society. European American women had a shorter circadian period than men (24.24 versus 24.41), but there was no sex difference in African Americans (24.07 for both men and women). We speculate that selection pressures in Europe made men develop a slightly longer period than women to help them track dawn which could be useful for hunters, but less important for women as gatherers.

Night-shift work is associated with poorer glycaemic control in patients with type 2 diabetes.

The circadian system plays a role in regulating metabolism. Night-shift work, a form of circadian misalignment, is associated with increased type 2 diabetes risk. This study aimed to determine if night-shift workers with type 2 diabetes experience poorer glycaemic control than non-shift workers. Patients with type 2 diabetes (104 unemployed, 85 day workers and 60 night-shift workers) participated. Sleep duration, sleep quality, morningness-eveningness preference, depressive symptoms and dietary intake were assessed using standardized questionnaires. Haemoglobin A1c levels were measured. Night-shift workers had significantly higher haemoglobin A1c levels compared with others, while there were no differences between day workers and unemployed participants (median 7.86% versus 7.24% versus 7.09%, respectively). Additionally, night-shift workers were younger, had a higher body mass index, and consumed more daily calories than others. Among night-shift workers, there were no significant differences in haemoglobin A1c levels between those performing rotating versus non-rotating shifts (P = 0.856), or those with clockwise versus counterclockwise shift rotation (P = 0.833). After adjusting for age, body mass index, insulin use, sleep duration, morningness-eveningness preference and percentage of daily intake from carbohydrates, night-shift work, compared with day work, was associated with significantly higher haemoglobin A1c (B = 0.059, P = 0.044), while there were no differences between unemployed participants and day workers (B = 0.016, P = 0.572). In summary, night-shift work is associated with poorer glycaemic control in patients with type 2 diabetes.

Night eating in patients with type 2 diabetes. Associations with glycemic control, eating patterns, sleep, and mood.

Night eating is a complex behavior associated with disruptions in eating, sleep, and mood regulation. While night eating has been associated with alterations in neuroendocrine functioning, night eating and Night Eating Syndrome (NES) are not well understood in patients with prevalent metabolic conditions, such as diabetes. In this study, 194 adults with Type 2 diabetes completed questionnaires assessing night eating symptoms as well as eating, sleep, and depressive symptoms. Glycemic control data, as measured by hemoglobin A1c (HbA1c), were gathered from patient medical charts. Results indicated that 7% of participants met criteria for NES. Increased symptoms of night eating were associated with poorer glycemic control and disruptions in eating, sleep, and mood, including significantly increased likelihood of having HbA1c levels >7% and endorsing clinical levels of depressive symptoms. Increasing understanding of the relationship between night eating and metabolic and psychosocial functioning in patients with diabetes may provide new avenues for treatment of these patients.

Severe atopic dermatitis, sleep disturbance, and low light exposure.

STUDY OBJECTIVES: Atopic dermatitis (AD) is a chronic inflammatory skin disorder in children. AD worsens at night, particularly in severe disease. Low light exposure contributes to inflammation, poor sleep, and misalignment between circadian (24-hour) rhythms (biological clocks) and social clocks (weekday vs. weekend sleep timing), but has not been evaluated in AD. Our objective was to perform a cross-sectional study to determine whether there is an association between AD severity, recorded light exposure (RLE), and sleep measures in participants with AD and healthy controls. METHODS: Secondary data analysis from two prospective observational studies of 74 participants ages 5-17 years old with severe AD compared to others (healthy controls and mild/moderate AD). Participants wore actigraphy watches for at least 1 weekday and one weekend. Rest/activity and RLE (lux) were obtained from the watches and were analyzed to estimate duration and quality of sleep/light exposure. RESULTS: Participants (n = 74) were on average 10.9 ±â€…3.6 years old, with 45% female, 17% no AD, 27% mild, 32% moderate, and 24% severe AD. On weekends, severe AD participants versus others fell asleep at a similar time (23:52 ±â€…1:08 vs. 23:40 ±â€…1:29 mean clock-time hours ±â€…SD; p = 0.23), had similar sleep-onset latency (8.2 ±â€…8.7 vs. 12.7 ±â€…16.9 minutes; p = 0.28), but woke later (09:12 ±â€…1:04 vs. 08:13 ±â€…1:14 minutes; p < 0.01) resulting in a later sleep-midpoint (04:32 ±â€…0:53 vs. 03:49 ±â€…1:08 minutes; p = 0.02). Severe AD participants had lower levels of daytime RLE than others (mean-over-all-days: 1948.4 ±â€…2130.0 vs. 10341.3 ±â€…13453.8 lux; p = 0.01) and throughout seasons, weekdays, or weekend, yet had similar nighttime RLE. CONCLUSION: Severe AD is characterized by low RLE and sleep disturbance. Low RLE could potentially induce circadian misalignment, contributing to inflammation and worse disease in severe AD. Low RLE can also reflect altered lifestyle and behavior due to atopic disease impacts. Prospective studies are needed to test causality and the potential of bright light as an adjuvant therapy for severe AD.

A descriptive study of sleep patterns and knowledge among department of juvenile services staff.

Study Objectives: Little is known about sleep health among staff in the US juvenile justice system. Poor sleep health is associated with negative mental and physical health, which may impact daily interactions and treatment of detained youth. The current study explored sleep-wake patterns and sleep health knowledge of Department of Juvenile Services (DJS) staff in Maryland (MD). Methods: DJS Staff (N = 218) were invited to complete a survey that queried staff on their own sleep-wake patterns, job role and schedule, and knowledge of youth sleep needs. Descriptive analyses and multivariate analyses of variance (MANCOVA) were conducted to summarize workers' sleep-wake patterns and examine differences by staff position and schedule. Results: Fifty-one percent of staff served as RAs who directly supervise the youth. Just over half (55%) worked in detention and 45% in treatment facilities. Staff reported sleeping 7.24 hours (SD = 4.10) on workdays and 8.59 hours (SD = 2.69) on non-workdays. RA staff working night/rotating versus day shifts reported the most sleep irregularity with larger weekend oversleep times. A little more than half of the staff (53.9%) were knowledgeable regarding youth sleep health with differences by position type. Conclusions: Findings show that DJS staff are meeting recommended sleep duration guidelines but are still experiencing sleep schedule and time in bed irregularity. Knowledge variability of youth sleep health across staff may necessitate focused educational programming. Overall, this study may inform future development and prioritization of sleep and circadian health interventions and educational campaigns for staff who work with detained juveniles. This paper is part of the Sleep and Circadian Health in the Justice System Collection.

Associations between fears related to safety during sleep and self-reported sleep in men and women living in a low-socioeconomic status setting.

South Africans living in low socioeconomic areas have self-reported unusually long sleep durations (approximately 9-10 h). One hypothesis is that these long durations may be a compensatory response to poor sleep quality as a result of stressful environments. This study aimed to investigate whether fear of not being safe during sleep is associated with markers of sleep quality or duration in men and women. South Africans (n = 411, 25-50 y, 57% women) of African-origin living in an urban township, characterised by high crime and poverty rates, participated in this study. Participants are part of a larger longitudinal cohort study: Modelling the Epidemiologic Transition Study (METS)-Microbiome. Customised questions were used to assess the presence or absence of fears related to feeling safe during sleep, and the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index were used to assess daytime sleepiness, sleep quality and insomnia symptom severity respectively. Adjusted logistic regression models indicated that participants who reported fears related to safety during sleep were more likely to report poor sleep quality (PSQI > 5) compared to participants not reporting such fears and that this relationship was stronger among men than women. This is one of the first studies outside American or European populations to suggest that poor quality sleep is associated with fear of personal safety in low-SES South African adults.

Extending weeknight sleep of delayed adolescents using weekend morning bright light and evening time management.

STUDY OBJECTIVES: Shift sleep onset earlier and extend school-night sleep duration of adolescents. METHODS: Forty-six adolescents (14.5-17.9 years; 24 females) with habitual short sleep (≤7 h) and late bedtimes (≥23:00) on school nights slept as usual for 2 weeks (baseline). Then, there were three weekends and two sets of five weekdays in between. Circadian phase (Dim Light Melatonin Onset, DLMO) was measured in the laboratory on the first and third weekend. On weekdays, the "Intervention" group gradually advanced school-night bedtime (1 h earlier than baseline during week 1; 2 h earlier than baseline during week 2). Individualized evening time management plans ("Sleep RouTeen") were developed to facilitate earlier bedtimes. On the second weekend, Intervention participants received bright light (~6000 lux; 2.5 h) on both mornings. A control group completed the first and third weekend but not the second. They slept as usual and had no evening time management plan. Weekday sleep onset time and duration were derived from actigraphy. RESULTS: Dim light melatonin onset (DLMO) advanced more in the Intervention (0.6 ±â€…0.8 h) compared to the Control (-0.1 ±â€…0.8 h) group. By week 2, the Intervention group fell asleep 1.5 ±â€…0.7 h earlier and sleep duration increased by 1.2 ±â€…0.7 h; sleep did not systematically change in the Control group. CONCLUSIONS: This multi-pronged circadian-based intervention effectively increased school-night sleep duration for adolescents reporting chronic sleep restriction. Adolescents with early circadian phases may only need a time management plan, whereas those with later phases probably need both time management and morning bright light. CLINICAL TRIALS: Teen School-Night Sleep Extension: An Intervention Targeting the Circadian System (#NCT04087603): https://clinicaltrials.gov/ct2/show/NCT04087603.

Sleep and circadian health in juvenile justice systems: A descriptive analysis.

OBJECTIVE: Few studies have explored sleep health and environmental influences on sleep and circadian health within juvenile justice facilities. The current study aims to describe sleep and circadian health of adolescents living in detention and treatment facilities. METHODS: Youth (N = 62) were recruited from 11 Department of Juvenile Services facilities. They completed a novel Youth Sleep and Daytime Behavior Questionnaire, daily sleep diary for seven consecutive mornings, and a brief poststudy interview. Healthcare staff completed a Youth Health Background survey for each participating youth. Facilities' 24-hour schedules were also obtained. RESULTS: Descriptive analyses were performed to capture the youths' sleep-wake experience while residing in Department of Juvenile Services facilities. Youth are obtaining the recommended total sleep time (M=8.9 hours, SD=1.2 hours) of 8-10 hours per night. However, they are taking twice as long to fall asleep (M=47 minutes SD=59 minutes) compared to the recommended sleep onset latency of 10-20 minutes. Youths' perceptions reveal potential reasons for long sleep onset latencies, including early facility sleep-wake schedules (78%) and overhead lights (60%) remaining on throughout the night. Furthermore, 37% of youth received facility-ordered behavioral sleep assessments, 36% were taking exogenous melatonin, and the majority of youth were prescribed at least one psychotropic medication. CONCLUSIONS: Findings suggest sleep-wake schedules and light exposure may be associated with an increase in symptoms of insomnia and/or circadian dysregulation. Based on the findings, facility-wide interventions are needed to improve the youths' sleep health.

Human puberty: salivary melatonin profiles in constant conditions.

This analysis examined the relative contributions of sex, age, body mass index (BMI), and puberty (Tanner) stage on salivary melatonin amplitude. Sixty-nine children and adolescents (30 females; 9.6-17.8 years) were examined for Tanner stage. Serial salivary melatonin samples were collected in controlled conditions, from which these melatonin amplitude measures were derived: area under the curve (AUC) and maximum value (MAX). AUC declined with advancing Tanner stage. This melatonin decline was similar between boys and girls, but girls secreted more melatonin compared to boys. Tanner stage and sex explained AUC variability, but age and BMI did not; similar results emerged for MAX. These results indicate that puberty stage may either mediate the decline of melatonin, or the decrease in melatonin amplitude may be an indicator of pubertal progression. These findings also indicate that the melatonin decline during puberty is not entirely accounted for by body mass or by age.

Seasonality of Children's Height and Weight and Their Contribution to Accelerated Summer Weight Gain.

Background: While children have been shown to have increased BMI during the summer compared to the school year, it is not known if this may be due to seasonal variations in height or weight separately. Methods: Trained nurses measured heights (cm) and weights (kg) in a cohort of Kindergarteners (n = 7648) twice per year from the beginning of kindergarten through 5th grade. Variation in height and weight by season (school year vs. summer) was examined using separate mixed-effects models. Season, sex, and BMI trajectory group were tested as fixed effects. Random effects included repeated measurements of time, students nested within a school, intercept, and slope for growth over time. Similar models using BMIz as the outcome examined the interaction of height or weight with season. Results: The rate of height gain was greater during the school year (∼Sept to April) compared to summer (∼April to Sept) (ß = -0.05, SE = 0.013, p < 0.0001). The rate of weight gain did not differ seasonally. Height gain was more strongly associated with increased BMIz during summer compared to the school year (ß =.02, SE = 0.005, p <0 .0001), mainly among children who remained healthy weight throughout elementary school (ß = 0.014, SE = 0.003, p < 0.0001) and those who transitioned to a healthier weight status (ß = 0.026, SE = 0.008, p = 0.004). We found a similar seasonal effect for the association between weight with BMIz among children who maintained a healthy weight status (ß = 0.014, SE = 0.014, p < 0.0001). Conclusion: This study indicates seasonality in children's height gain, gaining height at a faster rate during the school year compared to the summer, while weight gain remained relatively more consistent throughout the year. Seasonality in height and weight gain had the greatest impact on BMIz among children with a healthy weight status. Future research with more frequent measurements is needed to better understand the seasonal regulation of children's growth and weight gain.