Effects of personal cancer history and genomic risk information on mothers' psychological adaptation to inherited breast/ovarian cancer syndrome.

This study aimed to understand long-term coping responses of mothers (N = 287) receiving genetic counseling and testing (GCT) for hereditary breast/ovarian cancer (HBOC) syndrome. Psychological characteristics, including cancer-specific distress (Impact of Events Scale-Revised, α = .85) and coping (Brief COPE, α = .93) were assessed via structured personal communication, along with epidemiologic items assessing personal and family history of cancer. Genetic risk was determined by BRCA1/2 carriage. A principal component analysis was conducted on the coping measure to reduce its summary score to active coping (α = .91) with nine approach-oriented strategies responsive to stress. A multivariable regression model examined the main and interacting effects of clinical and psychological characteristics on maternal coping. Personal cancer history (F = 4.99, df = 1, p = .026), BRCA test result (F = 22.20, df = 1, p < .001), and cancer-specific distress (F = 17.80, df = 1, p < .001) were associated with greater engagement in active coping strategies. When controlling for cancer-specific distress, the interaction between personal cancer history and genetic test results was significant, such that women previously unaffected by cancer who received positive BRCA results reported the greatest levels of active coping (F = 7.92, p < .001). These findings indicate that previous cancer history, genetic risk, and psychological distress independently and jointly impact how women adapt to the threat of cancer over time.

Differential inflammatory profiles in carriers of reciprocal 22q11.2 copy number variants.

BACKGROUND: Genetic copy number variants (CNVs; i.e., a deletion or duplication) at the 22q11.2 locus confer increased risk of neuropsychiatric disorders and immune dysfunction. Inflammatory profiles of 22q11.2 CNV carriers can shed light on gene-immune relationships that may be related to neuropsychiatric symptoms. However, little is known about inflammation and its relationship to clinical phenotypes in 22q11.2 CNV carriers. Here, we investigate differences in peripheral inflammatory markers in 22q11.2 CNV carriers and explore their relationship with psychosis risk symptoms and sleep disturbance. METHODS: Blood samples and clinical assessments were collected from 22q11.2 deletion (22qDel) carriers (n=45), 22q11.2 duplication (22qDup) carriers (n=29), and typically developing (TD) control participants (n=92). Blood plasma levels of pro-inflammatory cytokines, including interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), and anti-inflammatory cytokine interleukin-10 (IL-10) were measured using a MesoScale Discovery multiplex immunoassay. Plasma levels of C-reactive protein (CRP) were measured using Enzyme-linked Immunosorbent Assay (ELISA). Linear mixed effects models controlling for age, sex, and body mass index were used to: a) examine group differences in inflammatory markers between 22qDel, 22qDup, and TD controls, b) test differences in inflammatory markers between 22qDel carriers with psychosis risk symptoms (22qDelPS+) and those without (22qDelPS-), and c) conduct an exploratory analysis testing the effect of sleep disturbance on inflammation in 22qDel and 22qDup carriers. A false discovery rate correction was used to correct for multiple comparisons. RESULTS: 22qDup carriers exhibited significantly elevated levels of IL-8 relative to TD controls (q<0.001) and marginally elevated IL-8 levels relative to 22qDel carriers (q=0.08). There were no other significant differences in inflammatory markers between the three groups (q>0.13). 22qDelPS+ exhibited increased levels of IL-8 relative to both 22qDelPS- (q=0.02) and TD controls (p=0.002). There were no relationships between sleep and inflammatory markers that survived FDR correction (q>0.14). CONCLUSION: Our results suggest that CNVs at the 22q11.2 locus may have differential effects on inflammatory processes related to IL-8, a key mediator of inflammation produced by macrophages and microglia. Further, these IL-8-mediated inflammatory processes may be related to psychosis risk symptoms in 22qDel carriers. Additional research is required to understand the mechanisms contributing to these differential levels of IL-8 between 22q11.2 CNV carriers and IL-8's association with psychosis risk.

A dyadic longitudinal analysis of parent-adolescent inflammation trends and the role of shared socioeconomic characteristics on family inflammation.

The objective of the present study was to evaluate the interdependency of parent-adolescent inflammation trends across time and to examine whether shared family socioeconomic characteristics explained between-family differences in parents' and adolescents' risk for inflammation. A total of N = 348 families, consisting of one parent and one adolescent child, were followed every two years in a three-wave longitudinal study. Sociodemographic questionnaires were used to determine parental educational attainment and family income-to-needs ratio (INR). At each time point, parents and adolescents collected dried blood spot (DBS) samples that were assayed for circulating CRP and log-transformed prior to analysis by longitudinal dyadic models. Models revealed significant differences in parents' and adolescents' inflammation trends over time (bint = - 0.13, p < 0.001). While parental CRP levels remained relatively stable across the study period, adolescent CRP increased by approximately 38% between study waves. Parents' average CRP levels were positively correlated with adolescents' average CRP (r = 0.32, p < 0.001), but parental change in CRP over time was not significantly related to change in adolescents' CRP over time. Family dyads with higher parental educational attainment had lower average CRP (b = -0.08, p = 0.01), but parental education did not predict change in dyads' inflammation over time. Study findings suggest that shared family socioeconomic characteristics contribute to baseline similarities in parents' and adolescents' inflammation and potentially point to adolescence as a period of inflammatory change where youth may diverge from parental inflammation trends.

Associations between emotion reactivity to daily interpersonal stress and acute social-evaluative stress during late adolescence.

Emotion reactivity refers to the intensity of changes in positive and negative emotion following a stimulus, typically studied with respect to daily stressors (e.g., arguments, demands) or laboratory stressors, including the Trier Social Stress Test (TSST). Yet, it is unclear whether emotion reactivity to daily and to laboratory stressors are related. The present study examined whether greater emotion reactivity to daily stressors (i.e., arguments, demands) is associated with greater reactivity to the TSST. Late adolescents (N = 82; Mage = 18.35, SD = 0.51, range 17-19; 56.1% female; 65.9% Latine, 34.2% European American) reported whether they experienced arguments and demands with friends, family, and individuals at school and their negative and positive emotion nightly for 15 days. They also completed the TSST, a validated paradigm for eliciting social-evaluative threat, and reported their emotion at baseline and immediately post-TSST. Multilevel models examined whether daily and laboratory emotion reactivity were related by testing whether the daily associations between arguments and demands with emotion differed by emotion reactivity to the TSST. Individuals with greater positive emotion reactivity (i.e., greater reductions in positive emotion) and greater negative emotion reactivity to the TSST showed greater positive emotion reactivity to daily demands. Emotion reactivity to the TSST was not significantly related to emotion reactivity to arguments. Findings provide preliminary evidence that emotion reactivity to the TSST relates to some aspects of daily emotion reactivity, with relations differing depending on type of daily stressor and valence of emotion. Results contextualise the implications of emotion reactivity to the TSST for daily stress processes.

Resting respiratory sinus arrhythmia is related to emotion reactivity to social-evaluative stress.

BACKGROUND: Higher resting parasympathetic nervous system activity, as indexed by respiratory sinus arrhythmia (RSA), has been considered a marker of emotion regulatory capacity and is consistently related to better mental health. However, it remains unclear how resting RSA relates to emotion reactivity to acute social-evaluative stress, a potent predictor of depression and other negative outcomes. METHOD: A sample of 89 participants (Mage = 18.36, SD = 0.51; 58.43 % female) provided measures of RSA at rest and then completed the Trier Social Stress Test, a standardized laboratory-based social-evaluative stress task that involves public speaking and mental arithmetic while being evaluated by two confederate judges. Participants reported a variety of emotions (e.g., negative emotion, positive emotion) at baseline and immediately after the stress task. RESULTS: Participants with higher resting RSA showed greater increases in negative emotion, guilt, depressive emotion, and anger, as well as greater decreases in positive emotion after the task. LIMITATION: Data were limited to a relatively small sample of late adolescents, who may be particularly responsive to social-evaluative stress compared to adults. CONCLUSIONS: Findings suggest that higher resting RSA may enhance emotion responses to social-evaluative stress in adolescents, potentially due to active engagement and responding to rather than passively viewing stimuli. Higher resting RSA may promote flexible emotion responses to the social environment, which may account for associations between higher RSA and better mental health.

Low subjective social status is associated with daily selection of fewer healthy foods and more high-fat/high sugar foods.

Socioeconomic status has been related to poorer eating behaviors, potentially due to feeling of lower status relative to peers. Despite experimental evidence that temporarily feeling of lower status can contribute to greater caloric intake, it remains unclear how feeling of lower social status relate to eating behavior in daily life. This study aimed to test whether lower subjective social status (SSS)-the feeling of having relatively lower social status-in American society and relative to college peers were related to daily food selection. A sample of 131 young adults (Mage = 20.3, SD = 0.8; 60% female; 46% Latinos; 34% European American; 15% Asian American; 5% of other ethnicities) reported their SSS in society and in college and completed 15 daily reports regarding the number of daily servings they had of fruits, vegetables, fried foods, fast foods, desserts, and sugary drinks. Multilevel models with days nested within individuals were used to test whether low SSS in society or college related to daily food intake. Next, we examined whether associations were driven by young adults' perceived stress and daily stressors. Analyses controlled for age, gender, ethnicity, family and personal income, and parents' education to test the unique associations between subjective status and food intake. Whereas SSS in society was not related to food intake, young adults with lower SSS in their college consumed fewer daily servings of healthy foods and more daily servings of high-fat/high-sugar foods. Although lower college SSS was related to greater perceived stress, perceived stress and daily stressors were consistently unrelated to daily food intake. Findings suggested that lower SSS in local environments (e.g., college) may impact young adults' daily food choices through processes beyond heightened stress.

Socioeconomic disadvantage, chronic stress, and proinflammatory phenotype: an integrative data analysis across the lifecourse.

Socioeconomic disadvantage confers risk for many chronic illnesses, and theories have highlighted chronic psychological stress and alterations to inflammatory processes as key pathways. Specifically, disadvantage can heighten chronic stress, which may promote a proinflammatory phenotype characterized by immune cells mounting exaggerated cytokine responses to challenge and being less sensitive to inhibitory signals. Importantly, lifecourse perspectives emphasize that such immune alterations should be more potent earlier in life during a sensitive period when bodily tissues are highly plastic to environmental inputs. However, examining these propositions is resource intensive, as they require cell-culturing approaches to model functional inflammatory activities, a wide age range, and longitudinal data. Here, we integrated data from five independent studies to create a diverse sample of 1,607 individuals (960 with longitudinal data; 8 to 64 years old; 359 Asian, 205 Black, and 151 Latino/a). Leveraging the resulting lifecourse data, rich interview assessments of disadvantage and stress, and ex vivo assessments of inflammation, we examined two questions: (1) Does chronic stress account for the link between disadvantage and proinflammatory phenotype? (2) Is there a developmental period during which inflammatory responses are more sensitive to disadvantage and chronic stress? Disadvantage was associated with higher chronic stress, which was linked with a proinflammatory phenotype cross-sectionally, longitudinally, and in terms of prospective change across 1.5 to 2 years. Consistent with the sensitive period hypothesis, the magnitude of these indirect associations was strongest in earlier decades and declined across the lifecourse. These findings highlight the importance of taking a lifecourse perspective in examining health disparities.

The Relationship Between Family Socioeconomic Status and Adolescent Sleep and Diurnal Cortisol.

OBJECTIVE: This study aimed to investigate the associations between indices of family socioeconomic status and sleep during adolescence and to examine whether measures of hypothalamic-pituitary-adrenal (HPA) axis functioning mediate the observed associations. METHODS: A total of 350 ethnically diverse adolescents (57% female; mean [standard deviation] age wave 1 = 16.4 [0.7] years) completed a three-wave longitudinal study in which sleep and cortisol data were collected at 2-year time intervals. Sleep duration, latency, and variability were assessed via actigraphy during a period of 8 days per study wave. Salivary cortisol was collected across 3 days per study wave to assess cortisol diurnal slope, area under the curve, and the cortisol awakening response. Adolescents' caregivers reported their education levels, family income, and economic hardship. RESULTS: A greater family income-to-needs ratio was associated with longer adolescent sleep duration ( b = 2.90, p = .023), whereas greater parental education was associated with shorter sleep duration ( b = -3.70, p = .030), less sleep latency ( b = -0.74, p = .016), and less variability across days ( b = -2.06, p = .010). Diurnal cortisol slope statistically mediated the association of parental education with sleep duration ( b = -0.48, 95% confidence interval = -1.099 to -0.042), but not the association of income-to-needs ratio with sleep duration. CONCLUSIONS: Findings suggest that parental education and family resources may have unique impacts upon sleep and HPA axis functioning during the period of adolescence. Future research is needed to examine family and behavioral factors that may underlie socioeconomic status associations with adolescent sleep and HPA axis functioning.

Orgo-Seq integrates single-cell and bulk transcriptomic data to identify cell type specific-driver genes associated with autism spectrum disorder.

Cerebral organoids can be used to gain insights into cell type specific processes perturbed by genetic variants associated with neuropsychiatric disorders. However, robust and scalable phenotyping of organoids remains challenging. Here, we perform RNA sequencing on 71 samples comprising 1,420 cerebral organoids from 25 donors, and describe a framework (Orgo-Seq) to integrate bulk RNA and single-cell RNA sequence data. We apply Orgo-Seq to 16p11.2 deletions and 15q11-13 duplications, two loci associated with autism spectrum disorder, to identify immature neurons and intermediate progenitor cells as critical cell types for 16p11.2 deletions. We further applied Orgo-Seq to identify cell type-specific driver genes. Our work presents a quantitative phenotyping framework to integrate multi-transcriptomic datasets for the identification of cell types and cell type-specific co-expressed driver genes associated with neuropsychiatric disorders.

The US3 Kinase of Herpes Simplex Virus Phosphorylates the RNA Sensor RIG-I To Suppress Innate Immunity.

Recent studies have demonstrated that the signaling activity of the cytosolic pathogen sensor retinoic acid-inducible gene-I (RIG-I) is modulated by a variety of posttranslational modifications (PTMs) to fine-tune the antiviral type I interferon (IFN) response. Whereas K63-linked ubiquitination of the RIG-I caspase activation and recruitment domains (CARDs) catalyzed by TRIM25 or other E3 ligases activates RIG-I, phosphorylation of RIG-I at S8 and T170 represses RIG-I signal transduction by preventing the TRIM25-RIG-I interaction and subsequent RIG-I ubiquitination. While strategies to suppress RIG-I signaling by interfering with its K63-polyubiquitin-dependent activation have been identified for several viruses, evasion mechanisms that directly promote RIG-I phosphorylation to escape antiviral immunity are unknown. Here, we show that the serine/threonine (Ser/Thr) kinase US3 of herpes simplex virus 1 (HSV-1) binds to RIG-I and phosphorylates RIG-I specifically at S8. US3-mediated phosphorylation suppressed TRIM25-mediated RIG-I ubiquitination, RIG-I-MAVS binding, and type I IFN induction. We constructed a mutant HSV-1 encoding a catalytically-inactive US3 protein (K220A) and found that, in contrast to the parental virus, the US3 mutant HSV-1 was unable to phosphorylate RIG-I at S8 and elicited higher levels of type I IFNs, IFN-stimulated genes (ISGs), and proinflammatory cytokines in a RIG-I-dependent manner. Finally, we show that this RIG-I evasion mechanism is conserved among the alphaherpesvirus US3 kinase family. Collectively, our study reveals a novel immune evasion mechanism of herpesviruses in which their US3 kinases phosphorylate the sensor RIG-I to keep it in the signaling-repressed state. IMPORTANCE Herpes simplex virus 1 (HSV-1) establishes lifelong latency in the majority of the human population worldwide. HSV-1 occasionally reactivates to produce infectious virus and to facilitate dissemination. While often remaining subclinical, both primary infection and reactivation occasionally cause debilitating eye diseases, which can lead to blindness, as well as life-threatening encephalitis and newborn infections. To identify new therapeutic targets for HSV-1-induced diseases, it is important to understand the HSV-1-host interactions that may influence infection outcome and disease. Our work uncovered direct phosphorylation of the pathogen sensor RIG-I by alphaherpesvirus-encoded kinases as a novel viral immune escape strategy and also underscores the importance of RNA sensors in surveilling DNA virus infection.

Psychological Stress During Childhood and Adolescence and Its Association With Inflammation Across the Lifespan: A Critical Review and Meta-Analysis.

Psychological stress during childhood and adolescence increases risk of health problems across the lifecourse, and inflammation is implicated as an underlying mechanism. To evaluate the viability of this hypothesis, we used meta-analysis to quantify the association between childhood/adolescent stress and inflammation over the lifecourse. Furthermore, we addressed three unresolved conceptual questions: (a) Does the strength of this association change over the lifecourse? (b) Are different types of childhood/adolescent stressors differentially associated with inflammation? (c) And which components of the inflammatory response are involved? A systematic search identified 187 articles reporting 922 associations. Meta-analyses were conducted using a three-level multilevel approach and controlled for study quality, conversion confidence, and whether effect sizes were unadjusted or adjusted (n = 662, 72%). Results indicated a small but reliable overall adjusted association ( r ^ = .04 ) . The magnitude of the association strengthened across the lifecourse-effect sizes were smallest in studies that measured inflammation in childhood r ^ = .02 and became progressively larger in studies of adolescence r ^ = .04 and adulthood r ^ = .05 , suggesting the impact of early stress strengthens with time. By contrast, effect sizes did not vary by adversity type (socioeconomic disadvantage, maltreatment, other interpersonal stressors, and cumulative exposure across stressors), or component of inflammation (circulating biomarkers of low-grade inflammation vs. cytokine responses to microbial stimuli). Implications and future directions are discussed.

The Small t Antigen of JC Virus Antagonizes RIG-I-Mediated Innate Immunity by Inhibiting TRIM25's RNA Binding Ability.

JC polyomavirus (JCV), a DNA virus that leads to persistent infection in humans, is the causative agent of progressive multifocal leukoencephalopathy, a lethal brain disease that affects immunocompromised individuals. Almost nothing is currently known about how JCV infection is controlled by the innate immune response and, further, whether JCV has evolved mechanisms to antagonize antiviral immunity. Here, we show that the innate immune sensors retinoic acid-inducible gene I (RIG-I) and cGMP-AMP synthase (cGAS) control JCV replication in human astrocytes. We further identify that the small t antigen (tAg) of JCV functions as an interferon (IFN) antagonist by suppressing RIG-I-mediated signal transduction. JCV tAg interacts with the E3 ubiquitin ligase TRIM25, thereby preventing its ability to bind RNA and to induce the K63-linked ubiquitination of RIG-I, which is known to facilitate RIG-I-mediated cytokine responses. Antagonism of RIG-I K63-linked ubiquitination and antiviral signaling is also conserved in the tAg of the related polyomavirus BK virus (BKV). These findings highlight how JCV and BKV manipulate a key innate surveillance pathway, which may stimulate research into designing novel therapies.IMPORTANCE The innate immune response is the first line of defense against viral pathogens, and in turn, many viruses have evolved strategies to evade detection by the host's innate immune surveillance machinery. Investigation of the interplay between viruses and the innate immune response provides valuable insight into potential therapeutic targets against viral infectious diseases. JC polyomavirus (JCV) is associated with a lifelong, persistent infection that can cause a rare neurodegenerative disease, called progressive multifocal leukoencephalopathy, in individuals that are immunosuppressed. The molecular mechanisms of JCV infection and persistence are not well understood, and very little is currently known about the relevance of innate immunity for the control of JCV replication. Here, we define the intracellular innate immune sensors responsible for controlling JCV infection and also demonstrate a novel mechanism by which a JCV-encoded protein acts as an antagonist of the type I interferon-mediated innate immune response.

ISG15-dependent activation of the sensor MDA5 is antagonized by the SARS-CoV-2 papain-like protease to evade host innate immunity.

Activation of the RIG-I-like receptors, retinoic-acid inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), establishes an antiviral state by upregulating interferon (IFN)-stimulated genes (ISGs). Among these is ISG15, the mechanistic roles of which in innate immunity still remain enigmatic. In the present study, we report that ISG15 conjugation is essential for antiviral IFN responses mediated by the viral RNA sensor MDA5. ISGylation of the caspase activation and recruitment domains of MDA5 promotes its oligomerization and thereby triggers activation of innate immunity against a range of viruses, including coronaviruses, flaviviruses and picornaviruses. The ISG15-dependent activation of MDA5 is antagonized through direct de-ISGylation mediated by the papain-like protease of SARS-CoV-2, a recently emerged coronavirus that has caused the COVID-19 pandemic. Our work demonstrates a crucial role for ISG15 in the MDA5-mediated antiviral response, and also identifies a key immune evasion mechanism of SARS-CoV-2, which may be targeted for the development of new antivirals and vaccines to combat COVID-19.

Sleep disturbance and the long-term impact of early adversity.

Sleep disturbance may be a central, yet underappreciated mechanism by which early adversity has a long-term impact upon mental and physical health. The fundamental regulatory processes shaped by early adversity - neural, neuroendocrine, and immune - are also central to sleep. Sleep problems, in turn, lead to a similar constellation of chronic health problems that have been linked to early adversity. We bring together work from the fields of early adversity and sleep in order to suggest a model by which sleep disturbance plays a critical role in the far-reaching impacts of early adversity on health. Future research should employ more longitudinal designs and pay particular attention to the impact of developmental periods such as adolescence and midlife when maturational and environmental factors conspire to create a unique time of sleep disturbance. We also suggesting that intervening to minimize sleep disturbance may be a promising means by which to test the model, as well as potentially blunt the long-term impact of early adversity on health.

Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses.

Nucleic acids are used in many therapeutic modalities, including gene therapy, but their ability to trigger host immune responses in vivo can lead to decreased safety and efficacy. In the case of adeno-associated viral (AAV) vectors, studies have shown that the genome of the vector activates Toll-like receptor 9 (TLR9), a pattern recognition receptor that senses foreign DNA. Here, we engineered AAV vectors to be intrinsically less immunogenic by incorporating short DNA oligonucleotides that antagonize TLR9 activation directly into the vector genome. The engineered vectors elicited markedly reduced innate immune and T cell responses and enhanced gene expression in clinically relevant mouse and pig models across different tissues, including liver, muscle, and retina. Subretinal administration of higher-dose AAV in pigs resulted in photoreceptor pathology with microglia and T cell infiltration. These adverse findings were avoided in the contralateral eyes of the same animals that were injected with the engineered vectors. However, intravitreal injection of higher-dose AAV in macaques, a more immunogenic route of administration, showed that the engineered vector delayed but did not prevent clinical uveitis, suggesting that other immune factors in addition to TLR9 may contribute to intraocular inflammation in this model. Our results demonstrate that linking specific immunomodulatory noncoding sequences to much longer therapeutic nucleic acids can "cloak" the vector from inducing unwanted immune responses in multiple, but not all, models. This "coupled immunomodulation" strategy may widen the therapeutic window for AAV therapies as well as other DNA-based gene transfer methods.

Race, socioeconomic status, and low-grade inflammatory biomarkers across the lifecourse: A pooled analysis of seven studies.

Cardiovascular diseases are patterned by race and socioeconomic status, and chronic low-grade inflammation is proposed as a key underlying mechanism. Theories for how racial and socioeconomic disadvantages foster inflammation emphasize a lifecourse approach: social disadvantages enable chronic or repeated exposure to stressors, unhealthy behaviors, and environmental risks that accumulate across the lifecourse to increase low-grade inflammation. However, single samples rarely include multiple racial and socioeconomic groups that each span a wide age range, precluding examination of this proposition. To address this issue, the current study combined seven studies that measured C-reactive protein and interleukin-6, producing a pooled sample of 1650 individuals aged 11-60 years. We examined (a) whether race and socioeconomic disparities in inflammatory biomarkers vary across the lifecourse, (b) whether adiposity operates as a pathway leading to these disparities, and (c) whether any indirect pathways through adiposity also vary across the lifecourse. Relative to White individuals, Black individuals exhibited higher, whereas Asian individuals exhibited lower, levels of inflammatory biomarkers, and adiposity accounted for these racial differences. Similarly, lower socioeconomic status was associated with higher inflammatory biomarkers via elevated adiposity. Importantly, both racial and socioeconomic disparities, as well as their pathways via adiposity, widened across the lifecourse. This pattern suggests that the impact of social disadvantages compound with age, leading to progressively larger disparities in low-grade inflammation. More broadly, these findings highlight the importance of considering age when examining health disparities and formulating conceptual models that specify how and why disparities may vary across the lifecourse.

ISG15-dependent Activation of the RNA Sensor MDA5 and its Antagonism by the SARS-CoV-2 papain-like protease.

Activation of the RIG-I-like receptors, RIG-I and MDA5, establishes an antiviral state by upregulating interferon (IFN)-stimulated genes (ISGs). Among these is ISG15 whose mechanistic roles in innate immunity still remain enigmatic. Here we report that ISGylation is essential for antiviral IFN responses mediated by the viral RNA sensor MDA5. ISG15 conjugation to the caspase activation and recruitment domains of MDA5 promotes the formation of higher-order assemblies of MDA5 and thereby triggers activation of innate immunity against a range of viruses including coronaviruses, flaviviruses and picornaviruses. The ISG15-dependent activation of MDA5 is antagonized through direct de-ISGylation mediated by the papain-like protease (PLpro) of SARS-CoV-2, a recently emerged coronavirus that causes the COVID-19 pandemic. Our work demonstrates a crucial role for ISG15 in the MDA5-mediated antiviral response, and also identifies a novel immune evasion mechanism of SARS-CoV-2, which may be targeted for the development of new antivirals and vaccines to combat COVID-19.

Sleep and Inflammation During Adolescents' Transition to Young Adulthood.

PURPOSE: This study investigated the extent to which multiple sleep dimensions are associated with inflammation during adolescents' transition to young adulthood, a developmental period when sleep difficulties and systemic inflammation levels are on the rise. Additionally, the moderating roles of socioeconomic status (SES) and ethnicity were explored. METHODS: A total of 350 Asian American, Latino, and European American youth participated at two-year intervals in wave 1 (n = 316, Mage = 16.40), wave 2 (n = 248 including 34 new participants to refresh the sample, Mage = 18.31), and wave 3 (n = 180, Mage = 20.29). Sleep duration (weekday and weekend) and variability in duration (nightly and weekday/weekend) were obtained from eight nights of wrist actigraphy. Subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index. Levels of C-reactive protein (CRP), a biomarker of systemic inflammation, were assayed from dried blood spots obtained from finger pricks. RESULTS: Multilevel models demonstrated that greater weekday/weekend sleep variability and worse sleep quality were associated with higher CRP; shorter weekend duration was associated with higher CRP only at younger ages. Shorter weekday duration was associated with higher CRP only among high-SES youth, whereas greater nightly variability was associated with higher CRP only among European American youth. CONCLUSIONS: Aspects of poor sleep may contribute to the rise of CRP during adolescents' transition to young adulthood, especially in earlier years. In addition, some sleep-CRP associations may vary as a function of youth's SES and ethnicity.

Early life stress, subjective social status, and health during late adolescence.

Objective: Both lower subjective social status (SSS)-or viewing oneself as having lower status relative to others-and greater early life stress consistently relate to poorer health in adolescence. Early life stress can also negatively influence one's social relationships and may thereby shape social status. The present studies investigated how early life stress relates to the development of SSS and how SSS relates to health across the transition to college.Design: In Study 1, 91 older adolescents (Mage = 18.37) reported early life stress, society SSS, and school SSS, and they reported their society SSS and school SSS again 2 years later. In Study 2, 94 first-year college students (Mage = 18.20) reported early life stress and society SSS at study entry and reported their dorm SSS, university SSS, and mental health monthly throughout the year.Results: Greater early life stress was related to lower society SSS, but not school SSS, in both studies. In Study 2, dorm and university SSS and early life stress were uniquely related to mental health, although associations weakened over time.Conclusion: Early life stress may predispose people to have low society SSS, and both low school SSS and high early life stress may increase risk for poorer health during transition periods.

Good Relationships With Parents During Childhood as Buffers of the Association Between Childhood Disadvantage and Adult Susceptibility to the Common Cold.

OBJECTIVE: Children reared by parents of low socioeconomic status (SES) go on to have elevated rates of physical health problems and premature mortality. However, many children reared in low-SES families remain healthy throughout the life-span. Here, secondary analyses of archival data tested the hypothesis that a positive relationship with parents during childhood acts as a buffer of the increased risk of adult susceptibility to infectious illness associated with low childhood SES. METHODS: One hundred seventy-six healthy adults reported their childhood SES and the quality of their relationships with their parents during childhood. Relationship quality was defined as parental care, love and support, lack of conflict with parents, and family cohesiveness. Afterward, participants were exposed to a respiratory virus and monitored in quarantine for 5 days for the development of a "common cold" as indicated by infection and objective markers of illness. RESULTS: The increased risk of developing a cold associated with being reared in a low SES household was attenuated by a positive relationship with parents during childhood (b(SE) = 0.08 (0.03), p = .010). This buffering of disease risk held up across the four components of relationship quality (p values < .05). The association was independent of adult SES, demographics, prechallenge immunity to the virus, current levels of neuroticism and stress, parental divorce during childhood, and number of siblings (p values < .05). CONCLUSIONS: Individuals with positive relationships with their parents during childhood are buffered from the increased risk of adult susceptibility to an infectious disease associated with low childhood SES.