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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.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.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.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.

Dislocation of the polyethylene insert is a rare complication of total knee arthroplasty (TKA), which has only been described in a handful of case reports. Here, we describe a report of a 55-year-old woman presenting 13 months after the primary TKA with signs of neurovascular compromise. A magnetic resonance image showed posterior extrusion of her polyethylene insert causing a mass effect on the gastrocnemius muscle and the popliteal neurovascular bundle. A multidisciplinary team including a joint reconstruction surgeon, vascular surgeon, and nerve specialist performed a revision TKA with peroneal nerve decompression. The polyethylene insert was noted to be dislocated, rotated 90 degrees, and incarcerated in the posterior knee.

Rhodopsin is essential for phototransduction, and many rhodopsin mutations cause heritable retinal degenerations. The P23H rhodopsin variant generates a misfolded rhodopsin protein that photoreceptors quickly target for degradation by mechanisms that are incompletely understood. To gain insight into how P23H rhodopsin is removed from rods, we used mass spectrometry to identify protein interaction partners of P23H rhodopsin immunopurified from RhoP23H/P23H mice and compared them with protein interaction partners of wild-type rhodopsin from Rho+/+ mice. We identified 286 proteins associated with P23H rhodopsin and 276 proteins associated with wild-type rhodopsin. 113 proteins were shared between wild-type and mutant rhodopsin protein interactomes. In the P23H rhodopsin protein interactome, we saw loss of phototransduction, retinal cycle, and rhodopsin protein trafficking proteins but gain of ubiquitin-related proteins when compared with the wild-type rhodopsin protein interactome. In the P23H rhodopsin protein interactome, we saw enrichment of gene ontology terms related to ER-associated protein degradation, ER stress, and translation. Protein–protein interaction network analysis revealed that translational and ribosomal quality control proteins were significant regulators in the P23H rhodopsin protein interactome. The protein partners identified in our study may provide new insights into how photoreceptors recognize and clear mutant rhodopsin, offering possible novel targets involved in retinal degeneration pathogenesis.

Background Social media has been more widely used by urology residency programs since the COVID-19 pandemic. There are no studies on the relationship between Doximity residency ranking and social media usage in urology. Objectives In this study, we aim to investigate the relationship between social media usage and the academic prestige of urology residency programs. Methods Residency reputation data was acquired from the Doximity Residency Navigator website. Twitter and Instagram activity in 2019 and 2021 was analyzed by collecting data on the total number of posts and followers. Data on residency virtual recruitment was obtained from Twitter and UroResidency website. Results By the end of 2021, 122/139 (87.8%) urology residency programs had a Twitter account and 61/139 (43.9%) had an Instagram account. A significant linear regression was found between Doximity ranking and the number of Twitter followers (p0.001), Twitter posts (p=0.005), and Instagram followers (p=0.026). Virtual recruitment events were held by 107/139 (77%) programs in 2021. There was a significant linear regression between Doximity rankings and the number of virtual events (p0.006). Conclusions Social media use by urology residency programs has increased since the COVID-19 pandemic. A program's higher Doximity ranking was correlated with the presence of Twitter and Instagram accounts as well as the number of Twitter followers, Twitter posts, and Instagram followers. There was a significant relationship between Doximity rankings and the number of hosted virtual events. Programs should consider increasing social media visibility to potentially improve their Doximity rankings.

Due to immense phenotypic plasticity and adaptability, Aspergillus niger is a cosmopolitan fungus that thrives in versatile environments, including the International Space Station (ISS). This is the first report of genomic, proteomic, and metabolomic alterations observed in A. niger strain JSC-093350089 grown in a controlled experiment aboard the ISS. Whole-genome sequencing (WGS) revealed that ISS conditions, including microgravity and enhanced irradiation, triggered non-synonymous point mutations in specific regions, chromosomes VIII and XII of the JSC-093350089 genome when compared to the ground-grown control. Proteome analysis showed altered abundance of proteins involved in carbohydrate metabolism, stress response, and cellular amino acid and protein catabolic processes following growth aboard the ISS. Metabolome analysis further confirmed that space conditions altered molecular suite of ISS-grown A. niger JSC-093350089. After regrowing both strains on Earth, production of antioxidant—Pyranonigrin A was significantly induced in the ISS-flown, but not the ground control strain. In summary, the microgravity and enhanced irradiation triggered unique molecular responses in the A. niger JSC-093350089 suggesting adaptive responses.

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.

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.

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.

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.

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.A sample of 89 participants (MParticipants 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.Data were limited to a relatively small sample of late adolescents, who may be particularly responsive to social-evaluative stress compared to adults.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.

Search engines generate lists of the most relevant websites using a keyword or phrase query and are integral in guiding consumer preferences. Digital information is important in the field of medicine, influencing what patients learn about their conditions and who they choose as providers. When two types of healthcare providers, such as podiatry and foot and ankle orthopaedic surgeons (FAOSs), share an overlapping consumer market, whichever group has a larger digital footprint receives increased digital engagement.The Google search engine was used to query nine common foot and ankle-associated terms using a "search term + zip code" format for 150 zip codes divided into urban, suburban, and rural population densities. The first 10 results of each search were classified into one of five categories. Site content was classified as podiatry-oriented, other MD/DO-oriented, or FAOS-oriented. Separately, a ratio between podiatrists and FAOSs was calculated for each population density group. Data were then normalized using this ratio and reanalyzed with the Wilcoxon signed-rank test with significance at P0.05.Of 13,500 total search results, 4,992 (36.9%) were podiatry-oriented, 2,109 (15.6%) were other MD/DO-oriented, and 436 (3.2%) were FAOS-oriented. All geographic areas featured a higher number of podiatry than FAOS-oriented sites. FAOSs have more results per provider in urban areas (P0.001), although podiatrists had more in suburban and rural areas (P0.001, P0.001). Podiatrists have greater digital engagement in descriptive search terms. "Ankle replacement" has greater FAOS engagement in all three geographic areas.Foot and ankle-related Internet search terms results are overwhelmingly composed of podiatry-oriented sites. Per provider, regional differences are demonstrated, with FAOS having more sites in urban areas only. FAOS scope-of-practice terms such as "ankle replacement" still retain greater engagement by FAOSs. Search engine optimization and saturation strategies should be considered.Level 3 (observational study).

Social media has grown significantly and its application in health care has been dramatically accentuated by the COVID-19 pandemic. It is often considered as a "new dimension" of health care, particularly in its ability to provide health information. In 2017, the top social media sites utilized by pediatric orthopaedic surgeons included Facebook, LinkedIn, and Twitter. In our study, we analyze the current social media usage, trends in Instagram and TikTok content, and the perceptions on social media usage among pediatric orthopaedic surgeons.The Pediatric Orthopaedic Society of North America (POSNA) membership directory was searched for the presence of social media. A review of all Instagram and TikTok posts made by the POSNA members were reviewed. A survey regarding the perception of social media networks and content was distributed to all POSNA members.A total of 1231 POSNA members actively practicing in the United States were included in our study. In all, 327 (26.6%) had a LinkedIn profile, 34 (2.8%) had a professional Facebook profile, 15 (1.2%) had a public Instagram account, 0 (0%) had TikTok, and 72 (5.8%) had a professional Twitter account. Fifteen POSNA members with public Instagram accounts had 10,878 followers. A total of 907 Instagram posts were made, 134 (14.8%) of which were education and 462 (50.9%) of which were personal or political. The perception of various social media networks such as Instagram (3.02), Facebook (3.16), and LinkedIn (3.51) were positive on a 5-point Likert scale, while perceptions of TikTok (2.36) and Twitter (2.99) were negative. Educational posts on Instagram (3.19) and Facebook (3.37) were positive.We provide an update to the utilization of social media by pediatric orthopaedists. Use of Instagram and TikTok accounts remain rare. Educational posts, when hosted on an appropriate social media platform, are perceived positively among pediatric orthopaedists.Level IV.

Background/Introduction Patients with COVID-19 are at increased risk for mortality during hospitalization. Better definition of the incidence, predictors, and outcomes of cardiac arrest during hospitalization for COVID-19 may support early identification and intervention. Purpose To estimate the incidence of in-hospital cardiac arrest in patients with COVID-19, describe the temporal trends in incidence of and survival after cardiac arrest, summarise characteristics of those who experienced a cardiac arrest, and compare the characteristics of survivors versus non-survivors of cardiac arrest. Methods We conducted a retrospective cohort study of patients admitted for COVID-19 to a tertiary medical center comprising three hospitals between March and November 2020. Data entry is ongoing for more than 2000 patients admitted through 2021. Clinical variables extracted via review of electronic medical records included age, sex, race/ethnicity, body mass index, history of cardiovascular disease (ie., coronary artery disease, congestive heart failure, atrial fibrillation, or cerebrovascular event), other comorbidities included in the Charlson comorbidity index, date of admission, duration of hospitalization, all cardiac arrest events during hospitalization, presenting rhythm during first cardiac arrest, and death. Data were described using summary statistics. Multivariable logistic regression was used to evaluate associations. Results Among 1666 patients, 107 (6.4%) experienced at least one in-hospital cardiac arrest event during hospitalization for COVID-19, of which 25 (23%) survived to hospital discharge. From March to October 2020, there was a decrease in estimated cardiac arrest incidence in-hospital from 8.2% to 3%, whereas estimated survival to hospital discharge after an arrest remained similar at approximately 20% (Figure). Compared to those who did not, patients who experienced in-hospital cardiac arrest were older and more likely to have existing cardiovascular disease, as well as other comorbidities. Similar factors were associated with lower chance of survival after cardiac arrest (Table). Patients with pulseless ventricular tachycardia/fibrillation (VT/VF) as presenting rhythm in cardiac arrest had better survival to hospital discharge compared to those with other rhythms (OR 3.3, p=0.02). Younger age (per 10 years, OR=0.7, p=0.03) and fewer comorbidities (per one fewer comorbidity, OR=1.5, p=0.05) were associated with better survival after cardiac arrest in multivariable logistic regression. Conclusion There was a decline in estimated incidence of cardiac arrest during hospitalization for COVID-19 since beginning of pandemic, with survival to hospital discharge after cardiac arrest estimated to be stable at around 20%. Younger age and fewer comorbidities especially cardiovascular disease were associated with better survival after an in-hospital cardiac arrest. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Rush University Medical Center Figure 1Table 1

The emerging field of microcrystal electron diffraction (MicroED) is of great interest to industrial researchers working in the drug discovery and drug development space. The promise of being able to routinely solve high-resolution crystal structures without the need to grow large crystals is very appealing. Despite MicroED’s exciting potential, adoption across the pharmaceutical industry has been slow, primarily owing to a lack of access to specialized equipment and expertise. Here we present our experience building a small molecule MicroED service pipeline for members of the pharmaceutical industry. In the past year, we have examined more than fifty small molecule samples submitted by our clients, the majority of which have yielded data suitable for structure solution. We also detail our experience determining small molecule MicroED structures of pharmaceutical interest and offer some insights into the typical experimental outcomes. This experience has led us to conclude that small molecule MicroED adoption will continue to grow within the pharmaceutical industry where it is able to rapidly provide structures inaccessible by other methods.

Background: The aim of the study was to describe the innervation of flexor hallucis longus (FHL) and obtain its surgical coordinates to facilitate selective neurotomy. Materials and methods: Fifteen embalmed lower limbs of adults were studied. Anatomical dissections to isolate the innervating branches of FHL were performed. Distance between the supplying nerve of FHL, including both its origin and termination, and the medial malleolus were obtained, providing anatomical coordinates beneficial for surgery. Results: In all cases, FHL was innervated by only one branch, which originated from the tibial nerve. Mean distance between the medial malleolus and the nervous branch origin was 21.39 ± 3.05 cm. Mean distance between the medial malleolus and the nervous branch termination was 12.7 ± 1.59 cm. Length of the nervous branch innervating FHL was proportional to the length of the leg, measuring 8.69 ± 2.45 cm. All nerves were located 15–17.4 cm above the medial malleolus. Conclusions: This anatomical study traced valuable surgical coordinates useful for performing selective peripheral neurotomy on the nerve branch innervating the FHL.

Sleep disturbance is a symptom of and a well-known risk factor for depression. Further, atypical functioning of the HPA axis has been linked to the pathogenesis of depression. The purpose of this study was to examine the role of adolescent HPA axis functioning in the link between adolescent sleep problems and later depressive symptoms. Methods: A sample of 157 17–18 year old adolescents (61.8% female) completed the Pittsburgh Sleep Quality Inventory (PSQI) and provided salivary cortisol samples throughout the day for three consecutive days. Two years later, adolescents reported their depressive symptoms via the Center for Epidemiological Studies Depression Scale (CES-D). Results: Individuals (age 17–18) with greater sleep disturbance reported greater depressive symptoms two years later (age 19–20). This association occurred through the indirect effect of sleep disturbance on the cortisol awakening response (CAR) (indirect effect = 0.14, 95%CI [.02 -.39]). Conclusions: One pathway through which sleep problems may lead to depressive symptoms is by up-regulating components of the body’s physiological stress response system that can be measured through the cortisol awakening response. Behavioral interventions that target sleep disturbance in adolescents may mitigate this neurobiological pathway to depression during this high-risk developmental phase.

BACKGROUND: Rates of depression increase and peak during late adolescence and alterations in immune processes are thought to be both a risk factor and outcome of depression. However, few studies have examined depression-immune dynamics among adolescents. Using a functional genomics approach, the current study examined whether depressive symptoms were associated with activation of a gene expression profile, characterized by upregulated expression of pro-inflammatory-related genes and downregulated expression of antiviral-related genes in a sample of older adolescents (M(age) = 18.37, SD = .51). METHOD: Participants (n = 87) reported on their depressive symptoms during the past week using the CES-D, and provided blood samples for genome-wide transcriptional profiling of mRNA. RESULTS: Adolescents with clinically-significant levels of depressive symptoms (CES-D ≥ 16) exhibited upregulated expression of inflammation-related genes and downregulated expression of antiviral-related genes compared to their peers with lower levels of depressive symptoms (CES-D < 16). Bioinformatic analyses suggested that this pattern of differential gene expression was mediated by greater activity of the pro-inflammatory transcription factor, nuclear factor-kappa B (NF-κB), and reduced activity of glucocorticoid receptors (GRs) and interferon response factors (IRFs). Additional analyses implicated monocytes, B cells, and dendritic cells as primary cellular sources of the observed gene expression patterns associated with depressive symptoms. CONCLUSION: Results are consistent with past work demonstrating links between depression and altered immunity. They provide a molecular basis for these associations and suggest that the underlying molecular signature may emerge as early as late adolescence when rates of depression tend to increase.

Subjective social status (SSS) reflects one's perception of one's standing within society. SSS has been linked with health outcomes, over and above socioeconomic status, and is thought to influence health in part by shaping stress responsivity. To test this, the present study examined the links between SSS and psychological, hypothalamic-pituitary-adrenal (HPA) axis, and cardiovascular responsivity in a sample of 87 ethnically diverse late adolescents (Mage = 18.39 years). Participants rated their family's SSS while either in high school (n = 50) or 1 year afterward (n = 37). Participants completed the Trier Social Stress Task (TSST) and reported their fear during baseline and after task completion, provided six saliva samples throughout the task, and had their heart rate monitored continuously throughout the task. Multilevel models, with time points nested within participants, were conducted to assess reactivity and recovery for each outcome. Results indicated that lower SSS was associated with greater fear reactivity and faster rates of HPA axis reactivity and recovery to baseline. Regarding cardiovascular responses, no differences were observed with respect to heart rate. Lower SSS predicted increased respiratory sinus arrhythmia during the stress task only among participants who rated their SSS while in high school; no association was observed for those who rated SSS after high school. Results suggest that perceptions of one's family's standing in society can shape responses to stress and potentially broader health.HighlightsSubjective social status (SSS) was linked with differences in stress responsivity. Specifically, lower SSS was associated with greater increases in fear following an acute stressor and faster rates of cortisol reactivity and recovery. Adolescents with lower SSS in high school showed less cardiovascular reactivity and recovery with respect to respiratory sinus arrhythmia, a marker of parasympathetic nervous system activity.

The creep mechanisms of Sn and Sn-1.8Ag along specific orientations are investigated by the constant-strain-rate nanoindentation method. Due to the anisotropy of Sn, the mechanical behaviors could be very different along different crystal orientations. For microelectronic applications, Ag is often added to Sn to increase its strength. Data from creep test show that Ag addition increases the stress exponent by 3, which indicates that the rupture time could be extended by Ag addition. Moreover, the creep rate of Sn (100) grain is lower than that of Sn (001) grain in a low stress regime, namely, that [100] in Sn would have better creep resistance for usual applications. After indentation, transmission electron images of Sn samples show that the slip systems are $$ (1\bar{1}0) $$ $$ [11\bar{1}] $$ in (100) grain and (101) $$ [1\bar{1}\bar{1}] $$ in (001) grain. Lastly, Sn-1.8Ag has better performance along [100] in creep resistance due to greater hindrance of Ag atoms on dislocation motion and its critical threshold stress.

Objective: African Americans and Latinos make up the two largest minority groups in the United States, and compared with Whites, these ethnic minority groups face disproportionate risk for certain physical health problems. However, factors that may protect these groups against early risk for poor health are not entirely understood. Familism, which emphasizes family interdependence and commitment, and is more prevalent among Latino and African American families, may be one such factor. The current study examined whether values and behaviors related to familism were differentially associated with inflammatory processes among White, African American, and Latino youth. Method: Participants were 257 youth who completed measures of familism values and behaviors and whose parents reported on their ethnicity. Participants also provided blood samples for the assessment of proinflammatory cytokine responses to bacterial challenge and of sensitivity to anti-inflammatory features of cortisol and interleukin (IL)-10. Results: Significant familism values and behaviors by ethnicity interactions were observed. For Latino and African American youth but not for White youth, more familism values were associated with greater sensitivity to IL-10. Additionally, for African American youth, more familism behaviors were associated with decreased cytokine responses to bacterial challenge and greater sensitivity to cortisol and IL-10. By contrast, familism behaviors were associated with lower sensitivity to cortisol in White youth and were not associated with any inflammatory outcomes in Latino youth. Conclusion: This pattern of findings suggests that for African American youth and to some extent for Latino youth, familism values and behaviors may be protective against the elevated risk for poor health they face. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

OBJECTIVE Cardiovascular disease (CVD) is one of the most prevalent chronic conditions and leading causes of death. Although CVD clinically manifests in adulthood, underlying processes of CVD begin in the earlier decades of life. Inflammation has been shown to play a key role, but relatively little is understood about how inflammation changes over time among young individuals. Additionally, how psychosocial factors like stress may influence changes in inflammation earlier in the lifespan is not entirely clear. Thus, the current three-wave longitudinal study examined the developmental trajectory of CRP, a marker of systemic inflammation, over a 4-year period from mid-adolescence into young adulthood. Between- and within-person differences in stress in relation to changes in CRP were also examined. METHOD A sample of 350 individuals was recruited during mid-adolescence and participated in 1 to 3 assessments, 2 years apart. At each assessment, participants provided dried blood spots for the assessment of CRP and reported on recent major life events, perceived stress, and daily interpersonal stress. RESULTS Multilevel modeling indicated that CRP increased with age, and within-person increases in perceived stress, but not life events or daily stress, were associated with higher CRP. Between-person differences in average levels of stress from mid-adolescence into young adulthood were not associated with changes in CRP. CONCLUSION These findings suggest that the link between stress and systemic inflammation between mid-adolescence and young adulthood may be most affected by contemporaneous experiences of perceived stress. There was little evidence to suggest that CRP trajectories varied by between-person differences in overall average levels of perceived stress, life events, and daily stress. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

TRIM25 is a multi-domain, RING-type E3 ubiquitin ligase of the tripartite motif family that has important roles in multiple RNA-dependent processes. In particular, TRIM25 functions as an effector of RIG-I and ZAP, which are innate immune sensors that recognize viral RNA and induce ubiquitin-dependent anti-viral response mechanisms. TRIM25 is reported to also bind RNA, but the molecular details of this interaction or its relevance to anti-viral defense have not been elucidated. Here, we characterize the RNA-binding activity of TRIM25 and find that the protein binds both single-stranded and double-stranded RNA. Multiple regions of TRIM25 contribute to this functionality, including the C-terminal SPRY domain and a lysine-rich motif in the linker segment connecting the SPRY and coiled-coil domains. RNA binding modulates TRIM25's ubiquitination activity in vitro, its localization in cells, and its anti-viral activity. Taken together with other studies, our results indicate that RNA binding by TRIM25 has at least three important functional consequences: by enhancing ubiquitination activity, either through allosteric effects or through clustering of multiple TRIM25 molecules; by modulating the multi-domain structure of the TRIM25 dimer, and thereby structural coupling of the SPRY and RBCC elements during the ubiquitination reaction; and by facilitating subcellular localization of the E3 ligase during virus infection.

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), 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.

Black fungi are a group of melanotic microfungi characterized by remarkable polyextremotolerance. Due to a broad ecological plasticity and adaptations at the cellular level, it is predicted that they may survive in a variety of extreme environments, including harsh niches on Earth and Mars, and in outer space. However, the molecular mechanisms aiding survival, especially in space, are yet to be fully elucidated. Based on these premises, the rock-inhabiting black fungus Knufia chersonesos (Wt) and its non-melanized mutant (Mut) were exposed to simulated microgravity—one of the prevalent features characterizing space conditions—by growing the cultures in high-aspect-ratio vessels (HARVs). Qualitative and quantitative proteomic analyses were performed on the mycelia and supernatant of culture medium (secretome) to assess alterations in cell physiology in response to low-shear simulated microgravity (LSSMG) and to ultimately evaluate the role of cell-wall melanization in stress survival. Differential expression was observed for proteins involved in carbohydrate and lipid metabolic processes, transport, and ribosome biogenesis and translation via ribosomal translational machinery. However, no evidence of significant activation of stress components or starvation response was detected, except for the scytalone dehydratase, enzyme involved in the synthesis of dihydroxynaphthalene (DNH) melanin, which was found to be upregulated in the secretome of the wild type and downregulated in the mutant. Differences in protein modulation were observed between K. chersonesos Wt and Mut, with several proteins being downregulated under LSSMG in the Mut when compared to the Wt. Lastly, no major morphological alterations were observed following exposure to LSSMG. Similarly, the strains’ survivability was not negatively affected. This study is the first to characterize the response to simulated microgravity in black fungi, which might have implications on future astrobiological missions.

Li–Fraumeni syndrome is an inherited, autosomal dominant disease. It is categorized as a rare disease caused by mutations of the TP53 gene, which causes increased susceptibility of the patients and their children to many types of cancer. Choroid plexus tumor is rare, which occurs in 0.3 cases per 1,000,000 people, of which 40% turn out to be carcinomas. We present a 12-year-old boy with a history of worsening headaches of more than one month, gait disturbance, projectile vomiting, and right hemiparesis. An intraventricular tumor was identified in the occipital of the left lateral ventricle, which turned out to be a TP53-mutant choroidal plexus carcinoma.

Insight into lipids’ roles in Alzheimer’s disease (AD) pathophysiology is limited because brain membrane lipids have not been characterized in cognitively healthy (CH) individuals. Since age is a significant risk factor of AD, we hypothesize that aging renders the amyloid precursor protein (APP) more susceptible to abnormal processing because of deteriorating membrane lipids. To reflect brain membranes, we studied their lipid components in cerebrospinal fluid (CSF) and brain-derived CSF nanoparticle membranes. Based on CSF Aβ42/Tau levels established biomarkers of AD, we define a subset of CH participants with normal Aβ42/Tau (CH-NAT) and another group with abnormal or pathological Aβ42/Tau (CH-PAT). We report that glycerophospholipids are differentially metabolized in the CSF supernatant fluid and nanoparticle membrane fractions from CH-NAT, CH-PAT, and AD participants. Phosphatidylcholine molecular species from the supernatant fraction of CH-PAT were higher than in the CH-NAT and AD participants. Sphingomyelin levels in the supernatant fraction were lower in the CH-PAT and AD than in the CH-NAT group. The decrease in sphingomyelin corresponded with an increase in ceramide and dihydroceramide and an increase in the ceramide to sphingomyelin ratio in AD. In contrast to the supernatant fraction, sphingomyelin is higher in the nanoparticle fraction from the CH-PAT group, accompanied by lower ceramide and dihydroceramide and a decrease in the ratio of ceramide to sphingomyelin in CH-PAT compared with CH-NAT. On investigating the mechanism for the lipid changes in AD, we observed that phospholipase A2 (PLA2) activity was higher in the AD group than the CH groups. Paradoxically, acid and neutral sphingomyelinase (SMase) activities were lower in AD compared to the CH groups. Considering external influences on lipids, the clinical groups did not differ in their fasting blood lipids or dietary lipids, consistent with the CSF lipid changes originating from brain pathophysiology. The lipid accumulation in a prodromal AD biomarker positive stage identifies perturbation of lipid metabolism and disturbances in APP/Amyloid beta (Aβ) as early events in AD pathophysiology. Our results identify increased lipid turnover in CH participants with AD biomarkers, switching to a predominantly lipolytic state in dementia. This knowledge may be useful for targeting and testing new AD treatments.

Black fungi are a group of melanotic microfungi characterized by remarkable polyextremotolerance. Due to a broad ecological plasticity and adaptations at the cellular level, it is predicted that they may survive in a variety of extreme environments, including harsh niches on Earth and Mars, and in outer space. However, the molecular mechanisms aiding survival, especially in space, are yet to be fully elucidated. Based on these premises, the rock-inhabiting black fungus Knufia chersonesos (Wt) and its non-melanized mutant (Mut) were exposed to simulated microgravity—one of the prevalent features characterizing space conditions—by growing the cultures in high-aspect-ratio vessels (HARVs). Qualitative and quantitative proteomic analyses were performed on the mycelia and supernatant of culture medium (secretome) to assess alterations in cell physiology in response to low-shear simulated microgravity (LSSMG) and to ultimately evaluate the role of cell-wall melanization in stress survival. Differential expression was observed for proteins involved in carbohydrate and lipid metabolic processes, transport, and ribosome biogenesis and translation via ribosomal translational machinery. However, no evidence of significant activation of stress components or starvation response was detected, except for the scytalone dehydratase, enzyme involved in the synthesis of dihydroxynaphthalene (DNH) melanin, which was found to be upregulated in the secretome of the wild type and downregulated in the mutant. Differences in protein modulation were observed between K. chersonesos Wt and Mut, with several proteins being downregulated under LSSMG in the Mut when compared to the Wt. Lastly, no major morphological alterations were observed following exposure to LSSMG. Similarly, the strains’ survivability was not negatively affected. This study is the first to characterize the response to simulated microgravity in black fungi, which might have implications on future astrobiological missions.