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The solubilization of lipid membranes by Tween-20 is crucial for a number of biotechnological applications, but the mechanistic details remain elusive. Evidence from ensemble assays supports a solubilization model that encompasses surfactant association with the membrane and the release of mixed micelles to solution, but whether this process also involves intermediate transitions between regimes is unanswered. In search of mechanistic origins, increasing focus is placed on identifying Tween-20 interactions with controllable membrane mimetics. Here, we employed ultrasensitive biosensing approaches, including single-vesicle spectroscopy based on fluorescence and energy transfer from membrane-encapsulated molecules, to interrogate interactions between Tween-20 and submicrometer-sized vesicles below the optical diffraction limit. We discovered that Tween-20, even at concentrations below the critical micellar concentration, triggers stepwise and phase-dependent structural remodeling events, including permeabilization and swelling, in both freely diffusing and surface-tethered vesicles, highlighting the substantial impact the surfactant has on vesicle conformation and stability prior to lysis.

Background and Objectives Diversity in aging has received increased attention in recent years in the field of gerontology. However, older lesbian, gay, and bisexual (LGB) people have largely been missing from these conversations. In this study, I examine older LGB people’s subjective views on the aging process, focusing specifically on visions of late life. Research Design and Methods Life story interviews were conducted with 60 LGB individuals over the age of 55 who reside in the Southeastern and Midwestern portions of the United States. Inductive coding (e.g., line-by-line, focused) and analyses were conducted. Results Four major themes emerged from the data: (1) financial distress linked to past events of homophobic discrimination, (2) anxieties regarding staying in paid care settings, (3) desires to age in place or “in community” with other lesbian, gay, bisexual, transgender, and queer people, and (4) a prioritization of quality of life over longevity via plans to pursue assisted suicide. Discussion and Implications The findings of this study suggest that views of aging and visions of late life are tied to social group membership, highlighting the need for gerontologists to further consider cumulative inequality processes. The study also offers evidence of queer aging, wherein queer culture, history, and experience produce distinct meanings of aging.

TP53 is the most commonly mutated gene in cancer, and gain-of-function mutations have wide-ranging effects. Efforts to reactivate wild-type p53 function and inhibit mutant functions have been complicated by the variety of TP53 mutations. Identified from a screen, the NSC59984 compound has been shown to restore activity to mutant p53 in colorectal cancer cells. Here, we investigated its effects on esophageal adenocarcinoma cells with specific p53 hot-spot mutations. NSC59984 treatment of cells reactivated p53 transcriptional regulation, inducing mitochondrial intrinsic apoptosis. Analysis of its effects on cellular metabolism demonstrated increased utilization of the pentose phosphate pathway and inhibition of glycolysis at the fructose-1,6-bisphosphate to fructose 6-phosphate junction. Furthermore, treatment of cells with NSC59984 increased reactive oxygen species production and decreased glutathione levels; these effects were enhanced by the addition of buthionine sulfoximine and inhibited by N-acetyl cysteine. We found that the effects of NSC59984 were substantially greater in cells harboring the p53 R248W mutation. Overall, these findings demonstrate p53-dependent effects of NSC59984 on cellular metabolism, with increased activity in cells harboring the p53 R248W mutation. This research highlights the importance of defining the mutational status of a particular cancer to create a patient-centric strategy for the treatment of p53-driven cancers.

Long-term opioid therapy (LTOT) is associated with increased risk for depression. It is not known if the frequency of opioid use during LTOT is associated with new onset depression. We used Optum's de-identified Integrated Claims-Clinical dataset (2010-2018) to create a cohort of 5,146 patients, 18 - 80 years of age with an encounter or claims in the year before new LTOT. New LTOT was defined by > 90 day opioid use after remaining 6-months opioid free. Opioid use frequency during the first 90 days of LTOT was categorized into occasional use (< 50% days covered), intermittent use (50% to < 80% days covered), frequent use (80% to < 90% days covered) and daily use (≥ 90% days covered). Propensity scores and inverse probability of exposure weighting controlled for confounding in models estimating risk for new onset depression. Patients were on average, 54.5 (SD±13.6) years of age, 55.7% were female, 72.5% were white and 9.5% were African-American. After controlling for confounding, daily users (HR=1.40; 95%CI:1.14-1.73) and frequent users (HR=1.34; 95%CI:1.05-1.71) were significantly more likely to develop new onset depression compared to occasional users. This association remained after accounting for the contribution of post-index pain diagnoses and opioid use disorder. In LTOT, risk for new depression episodes is up to 40% greater in near daily users compared to occasional users. Patients could reduce depression risk by avoiding opioid use on as many low pain days as possible. Repeated screening for depression during LTOT is warranted.

CD47 is a marker of self and a signaling receptor for thrombospondin-1 that is also a component of extracellular vesicles (EVs) released by various cell types. Previous studies identified CD47-dependent functional effects of T cell EVs on target cells, mediated by delivery of their RNA contents, and enrichment of specific subsets of coding and noncoding RNAs in CD47+ EVs. Mass spectrometry was employed here to identify potential mechanisms by which CD47 regulates the trafficking of specific RNAs to EVs. Specific interactions of CD47 and its cytoplasmic adapter ubiquilin-1 with components of the exportin-1/Ran nuclear export complex were identified and confirmed by coimmunoprecipitation. Exportin-1 is known to regulate nuclear to cytoplasmic trafficking of 5’-7-methylguanosine (m7G)-modified microRNAs and mRNAs that interact with its cargo protein EIF4E. Interaction with CD47 was inhibited following alkylation of exportin-1 at Cys528 by its covalent inhibitor leptomycin B. Leptomycin B increased levels of m7G-modified RNAs, and their association with exportin-1 in EVs released from wild type but not CD47-deficient cells. In addition to perturbing nuclear to cytoplasmic transport, transcriptomic analyses of EVs released by wild type and CD47-deficient Jurkat T cells revealed a global CD47-dependent enrichment of m7G-modified microRNAs and mRNAs in EVs released by CD47-deficient cells. Correspondingly, decreasing CD47 expression in wild type cells or treatment with thrombospondin-1 enhanced levels of specific m7G-modified RNAs released in EVs, and re-expressing CD47 in CD47-deficient T cells decreased their levels. Therefore, CD47 signaling limits the trafficking of m7G-modified RNAs to EVs through physical interactions with the exportin-1/Ran transport complex.

Mood and anxiety disorders are the most burdensome mental health disorders related to work functioning. This study conducted an in-depth analysis on how mood and anxiety disorders impact work funct...

Cryomicroscopy is commonly hampered by frost accumulation, reducing the visual clarity of the specimen. Pulling a vacuum or purging with nitrogen gas can greatly reduce the sample chamber's humidity, but at cryogenic temperatures, even minute concentrations of water vapor can still result in frost deposition. Here, a hygroscopic ice frame was created around the specimen to suppress frost growth during cryomicroscopy. Specifically, fluorescently tagged rat brain vessels were frozen on a silicon nitride window with an ice frame, and the luminescence of the fluorescent tag was improved by a factor of 6 compared to a similar specimen in only a nitrogen purge environment. These findings suggest that the simple implementation of a hygroscopic ice frame surrounding the specimen can substantially improve the visual clarity for cryomicroscopy, beyond that of a vacuum or nitrogen purge system. Center of BioMolecular Structure (CBMS); National Institutes of Health, the National Institute of General Medical Sciences (NIGMS), through a Center Core P30 Grant [P30GM133893]; DOE Office of Biological and Environmental Research (DOE-BER) [KP1607011]; DOE-BER Published version This work was supported by the Center of BioMolecular Structure (CBMS). CBMS is primarily supported by the National Institutes of Health, the National Institute of General Medical Sciences (NIGMS), through a Center Core P30 Grant (P30GM133893), and by the DOE Office of Biological and Environmental Research (DOE-BER) (KP1607011). The BioImaging Core within the CMBS was supported entirely by the DOE-BER.

OBJECTIVE: Suicide rates continue to rise, necessitating identification of novel risk factors to prevent suicide. Obesity and suicide mortality have been examined, but no studies have examined associations between weight change, suicide mortality, and depression among adults in the U.S. METHODS: People who died by suicide from 2000-2015 with a recorded height and weight in the first and second 6 months preceding their death (“index date”; n = 387) were extracted from a larger sample from the Mental Health Research Network; each was matched with five people in the control group by age, sex, index year, and healthcare site (n = 1,935). Data were analyzed in 2020. RESULTS: People who died by suicide were predominantly male (71%), Caucasian (69%), depressed (55%), middle aged (M = 57 years), with chronic health issues (57%), [Control: 66% Caucasian; M age = 56 years; 43% chronic health issues, 14% depressed]. T-test analyses showed BMI change within a year before the index date differed between those who died by suicide (M = −0.72±2.42 kg/m(2)) and the control group, (M = 0.06±4.99 kg/m(2)) p < 0.001, d = .17. A 1-unit decrease in BMI was associated with 9% increased risk of suicide after adjusting for demographics, mental disorders, and Charlson score (aOR = 0.91, 95% CI = 0.87-0.95, p < 0. 001). BMI change and suicide were associated for those without depression (p < 0.001). CONCLUSIONS: Weight loss in the year before suicide was associated with increased suicide mortality after accounting for physical and mental health indicators.

Natural killer (NK) cells play key roles in immune surveillance against tumors and viral infection. NK cells distinguish abnormal cells from healthy cells by cell–cell interaction with cell surface proteins and then attack target cells via multiple mechanisms. In addition, extracellular vesicles (EVs) derived from NK cells (NK-EVs), including exosomes, possess cytotoxic capacity against tumor cells, but their characteristics and regulation by cytokines remain unknown. Here, we report that EVs derived from human NK-92 cells stimulated with IL-15 + IL-21 show enhanced cytotoxic capacity against tumor cells. Major cytolytic granules, granzyme B and granzyme H, are enriched by IL-15 + IL-21 stimulation in NK-EVs; however, knockout experiments reveal those cytolytic granules are independent of enhanced cytotoxic capacity. To find out the key molecules, mass spectrometry analyses were performed with different cytokine conditions, no cytokine, IL-15, IL-21, or IL-15 + IL-21. We then found that CD226 (DNAM-1) on NK-EVs is enriched by IL-15 + IL-21 stimulation and that blocking antibodies against CD226 reduced the cytolytic activity of NK-EVs. We also show NK-EVs are taken up by target cells via macropinocytosis. Collectively, our findings elucidate the novel properties of NK-EVs and the mechanism of their incorporation into target cells.

The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated coronavirus disease (COVID-19) has led to a pandemic of unprecedented scale. An intriguing feature of the infection is the minimal disease in most children, a demographic at higher risk for other respiratory viral diseases. To investigate age-dependent effects of SARS-CoV-2 pathogenesis, we inoculated two rhesus macaque monkey dam–infant pairs with SARS-CoV-2 and conducted virological and transcriptomic analyses of the respiratory tract and evaluated systemic cytokine and Ab responses. Viral RNA levels in all sampled mucosal secretions were comparable across dam–infant pairs in the respiratory tract. Despite comparable viral loads, adult macaques showed higher IL-6 in serum at day 1 postinfection whereas CXCL10 was induced in all animals. Both groups mounted neutralizing Ab responses, with infants showing a more rapid induction at day 7. Transcriptome analysis of tracheal airway cells isolated at day 14 postinfection revealed significant upregulation of multiple IFN-stimulated genes in infants compared with adults. In contrast, a profibrotic transcriptomic signature with genes associated with cilia structure and function, extracellular matrix composition and metabolism, coagulation, angiogenesis, and hypoxia was induced in adults compared with infants. Our study in rhesus macaque monkey dam–infant pairs suggests age-dependent differential airway responses to SARS-CoV-2 infection and describes a model that can be used to investigate SARS-CoV-2 pathogenesis between infants and adults.

Preterm birth is often associated with chorioamnionitis and increased risk of neurodevelopmental disorders. Preterm birth also leads to cerebellar underdevelopment but the mechanisms of disrupted cerebellar development in preterm infants are little understood. Here, we leveraged single-nuclei RNA-sequencing of the cerebellum in a rhesus macaque model of chorioamnionitis and preterm birth, to show that chorioamnionitis leads to Purkinje cell loss and disrupted maturation of granule cells and oligodendrocytes in the fetal cerebellum at late gestation. Purkinje cell loss is accompanied by decreased sonic hedgehog signaling from Purkinje cells to granule cells, which show an accelerated maturation. Chorioamnionitis also accelerated pre-oligodendrocyte maturation into myelinating oligodendrocytes, confirmed by increased expression of myelin basic protein in the cerebellum of chorioamnionitis-exposed fetuses. These findings are consistent with reported histopathological findings in individuals with autism and suggest a novel mechanism through which perinatal inflammation contributes to neurodevelopmental disorders.

The vein pattern in insect wings allows this lightweight structure to carry multiple biological functions. An investigation of the angular distribution of the vein struts in dragonfly wings revealed that the golden angle or golden ratio dominates the venation patterns in two closely related ways. First, the golden angle dominates the intervein angles in regions where thin veins and membranes demand strength reinforcement. Second, a golden ratio partition method has been developed to explain a set of preferred intervein angles in distorted polygon-shaped venation cells throughout the venation pattern in dragonfly wings. These observations provide new evidence that the wing structure is spatially optimized, by the golden rule in nature, for supporting biomechanical functions of dragonfly wings.

The purpose of this study was to estimate the prevalence of hazardous drinking in the four years after bariatric surgery and investigate whether there are differences between those undergoing Roux-en-Y gastric bypass and sleeve gastrectomy. Participants (N = 564) who underwent bariatric surgery between 2014 and 2017 completed a survey regarding post-surgical alcohol use. The rate of alcohol use following bariatric surgery was significantly higher among those between 1- and 4-years post-surgery compared to those less than 1-year post-surgery. Of those who were consuming alcohol at the time of participation, 16.1% had scores indicative of hazardous drinking. The rate of hazardous drinking among those 3-4 years post-surgery was greater than those less than 1-year post-surgery with 33.3% of patients engaging in hazardous drinking at 3-4 years post-surgery. Patients undergoing sleeve gastrectomy had similar rates of hazardous drinking as RYGB (16.3% vs. 15.7%). Thus, findings showed that rates of hazardous drinking were higher among those further removed from bariatric surgery and patients undergoing sleeve gastrectomy appeared to have similar rates of hazardous drinking as those who underwent RYGB. Results suggest a need for monitoring of alcohol use for all patients pursuing bariatric surgery, regardless of surgery type.

Acceptance of illness is related to better mental health among patients with chronic illness; however, this construct has not been evaluated as part of routine transplantation evaluations. The purpose of this study was to create a brief measure of acceptance of illness for patients pursuing organ transplantation and examine how acceptance is related to distress. Retrospective medical record reviews were conducted for 290 patients who completed a routine psychosocial evaluation prior to transplant listing which included the Illness Acceptance Scale (IAS). Internal consistency for the IAS was excellent (Cronbach's alpha = .92). Illness acceptance was negatively correlated with depression, anxiety, and catastrophizing and was not related to health literacy or health numeracy. The IAS is a reliable and valid measure for patients who are pursuing thoracic transplant or left ventricular assist device. Clinicians may want to screen transplant candidates for illness acceptance and refer those with lower levels to psychological interventions.

Background Existing research demonstrates that parity is associated with risk for obesity. The majority of those who undergo bariatric surgery are women, yet little is known about whether having children before bariatric surgery is associated with pre- and postsurgical weight outcomes. Objectives We aim to evaluate presurgical body mass index (BMI) and postsurgical weight loss among a racially diverse sample of women with and without children. Setting Metropolitan hospital system. Methods Women (n = 246) who underwent bariatric surgery were included in this study. Participants self-reported their number of children. Presurgical BMI and postsurgical weight outcomes at 1 year, including change in BMI (ΔBMI), percentage excess weight loss (%EWL), and percentage total weight loss (%TWL) were calculated from measured height and weight. Results Those with children had a lower presurgical BMI (P = .01) and had a smaller ΔBMI (P = .01) at 1 year after surgery than those without children, although %EWL and %TWL at 1 year did not differ by child status or number of children. After controlling for age, race, and surgery type, the number of children a woman had was related to smaller ΔBMI at 1 year post surgery (P = .01). Conclusions Although women with children had lower reductions in BMI than those without children, both women with and without children achieved successful postsurgical weight loss. Providers should assess for number of children and be cautious not to deter women with children from having bariatric surgery.

Post-traumatic stress disorder (PTSD) is associated with neural processing deficits affecting early automatic and later conscious processing. Event-related Potentials (ERPs) are high resolution indices of automatic and conscious processing, but there are no meta-analyses that have examined automatic and conscious ERPs in PTSD across multiple paradigms. This systematic review examined 69 studies across affective and non-affective auditory and visual paradigms. Individuals with PTSD were compared to trauma-exposed and non-trauma controls on ERPs reflecting automatic (N1, P1, N2, P2) and conscious (P3, LPP) processing. Trauma exposure was associated with increased automatic ERP amplitudes to irrelevant auditory information. PTSD further showed increased automatic and conscious allocation of resources to affective information, reduced automatic attending and classification as well as reduced attention processing and working memory updating of non-affective information. Therefore, trauma exposure is associated with enhanced early processing of incoming stimuli, and PTSD with enhanced processing of affective stimuli and impaired processing of non-affective stimuli. This review highlights the need for longitudinal ERP studies in PTSD, adopting standardized procedures and methodological designs.

Objective Although evidence-based psychological interventions improve chronic pain, many patients do not engage in behavioral health services. Offering a brief intervention in a medical setting may provide benefits to patients with chronic pain. The purpose of this study was to examine preliminary outcomes of a brief psychological intervention for chronic pain delivered in primary care. Design Pilot randomized controlled trial. Setting Primary care clinic. Subjects Sixty participants with chronic pain were randomized to a 5-session psychological intervention or treatment-as-usual control group. Methods Participants completed pre- and post-intervention measures assessing pain severity, pain interference, pain catastrophizing, depression, and anxiety. Results Most participants (76.7%) randomized to the intervention completed all sessions. Compared to the control group, those in the intervention had decreases in pain severity (P = .048), pain catastrophizing (P = .04), and depression (P = .01) from pre- to post-intervention. Within the intervention group, there was a significant improvement in pain interference scores (P = 0.02). Within the intervention group, effect sizes were medium to large for changes in pain severity, pain interference, pain catastrophizing, and depression scores. There were no significant changes in anxiety scores. Conclusion Results suggest that delivery of a brief psychological intervention for chronic pain in primary care appears to offer improvements in pain severity, pain interference, pain catastrophizing, and depression. Findings suggest that shorter-term psychological interventions may offer similar benefits as longer-term ones. Furthermore, offering a brief intervention in primary care may increase access and engagement in behavioral pain management services. Future research should examine this through a fully-powered trial with longer-term outcomes.

The 2020 SARS-CoV-2 pandemic created a unique opportunity for Public Health/General Preventive Medicine (PH/GPM) and Occupational and Environmental Medicine (OM) residents to contribute to pandemic public health response activities. We surveyed all 18 Health Resources and Services Administration (HRSA)-funded PH/GPM and OM residency program directors to evaluate program and resident involvement in pandemic response activities from January 1 through June 30, 2020. Of 116 residents, 110 (95%) participated at some level in the response activities including screening/testing, contact tracing, surveillance, data analysis, incident command, provider support, reopening, direct patient care, education, and risk communication. Residents' response activities were in multiple settings, such as state, local, and federal health agencies; hospital systems; long-term care facilities; academic centers; local businesses and labor unions; Federally Qualified Health Centers; homeless shelters; and clinics. Residents' participation was facilitated by their training in public health, epidemiology, the care of patients and populations, and emergency preparedness. Programs should continue to promote these experiences and key roles that PH/GPM and OM residents can play, as this leadership is a necessity for the successful navigation of future major public health events. As the pandemic continues, evaluation of residents' experiences will help guide longer-term changes to program curriculum and partnerships. Many trainees' contributions and expertise met both educational and service goals and therefore should be integrated into ongoing pandemic response work in PH/GPM and OM programs.

Findings regarding longer term symptoms of depression and the impact of depression on outcomes such as weight loss and patient satisfaction, are mixed or lacking.This study sought to understand the relationship between depression, weight loss, and patient satisfaction in the two years after bariatric surgery.This study used data from a multi-institutional, statewide quality improvement collaborative of 45 different bariatric surgery sites.Participants included patients (N = 1991) who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) between 2015-2018. Participants self-reported symptoms of depression (Patient Health Questionnaire-8 [PHQ-8]), satisfaction with surgery, and weight presurgery and 1 year and 2 years postsurgery.Compared to presurgery, fewer patients' PHQ-8 scores indicated clinically significant depression (PHQ-8≥10) at 1 year (P.001; 14.3% versus 5.1%) and 2 years postsurgery (P.0001; 8.7%). There was a significant increase in the prevalence of clinical depression from the first to second year postsurgery (P.0001; 5.1% versus 8.7%). Higher PHQ-8 at baseline was related to less weight loss (%Total Weight Loss [%TWL] and %Excess Weight Loss [%EWL]) at 1 year postsurgery (P.001), with a trend toward statistical significance at 2 years (P = .06). Postoperative depression was related to lower %TWL and %EWL, and less reduction in body mass index (BMI) at 1 year (P.001) and 2 years (P.0001). Baseline and postoperative depression were associated with lower patient satisfaction at both postoperative time points.This study suggests improvements in depression up to 2 years postbariatric surgery, although it appears that the prevalence of depression increases after the first year. Depression, both pre- and postbariatric surgery, may impact weight loss and patient satisfaction.

Nonhuman primate models have an essential role in understanding progressive respiratory disease pathogenesis. Immune and physiologic parameters in the nonhuman primate closely reflect the complexity of human systems and provide an exceptional translational impact for the investigation of the mucosal immune changes in response to environmental exposures. This potential warrants the development of novel models that will clarify the interaction of respiratory disease and the inhalable environment and the potential of novel therapies to alleviate the untoward results of these interactions. Nonhuman primate models of asthma can be spontaneous, induced, or experimentally manipulated by various exposures. Here we describe a model of exacerbation of airway hyperreactivity induced by exposure to an air pollutant, ozone, in a cohort of young adult asthmatic rhesus macaques.

Depression is common during pregnancy, can elevate risk for excessive or inadequate gestational weight gain (GWG), and is associated with both underutilisation and overutilisation of prenatal care. Whether GWG is associated with adequacy of prenatal care among women with and without depression in the United States is unknown. This study evaluated whether adequacy of prenatal care differed by depression status and GWG.Data from the Pregnancy Risk Assessment Monitoring System from 1,379,870 women who were pregnant with a singleton and delivered at 37-42 weeks gestation during 2016 to 2018 were included. Depression was self-reported. The Kotelchuck index was used to evaluate adequacy of prenatal care. Maternal weight gain was compared to GWG guidelines.Approximately 13.1% of the sample experienced depression during pregnancy. Although those with depression had increased odds of both inadequate and above adequate levels of prenatal care, this association was no longer significant after accounting for demographics, medical comorbidities, and socioeconomic factors. Individuals with inadequate levels of prenatal care with a normal pre-pregnancy body mass index gained less weight during pregnancy.The association between depression and prenatal care utilisation seems driven by demographic, medical comorbidity, and socioeconomic variables. Weight outcomes were associated with inadequate prenatal care utilisation.

Patients undergoing bariatric surgery are at risk for devloping an alcohol use disorder (AUD). The purpose of this study was to investigate pre-surgical psychosocial risk factors for post-surgical alcohol consumption and hazardous drinking. Participants (N = 567) who underwent bariatric surgery between 2014 and 2017 reported their post-surgical alcohol use. Information was collected from the pre-surgical evaluation including history of alcohol use, psychiatric symptoms, and maladaptive eating behaviors (i.e., binge eating, purging, and emotional eating). Younger age and pre-surgical alcohol use predicted post-surgical alcohol use and hazardous drinking. In addition, higher levels of depressive symptoms and maladaptive eating patterns predicted post-surgical binge drinking. Clinicians conducting pre-surgical psychosocial evaluations should be aware of the multiple risk factors related to post-surgical problematic alcohol use. Future research should evaluate whether preventive interventions for high-risk patients decrease risk for post-surgical alcohol misuse.

The Arctic sea-ice-scape is rapidly transforming. Increasing light penetration will initiate earlier seasonal primary production. This earlier growing season may be accompanied by an increase in ice algae and phytoplankton biomass, augmenting the emission of dimethylsulfide and capture of carbon dioxide. Secondary production may also increase on the shelves, although the loss of sea ice exacerbates the demise of sea-ice fauna, endemic fish and megafauna. Sea-ice loss may also deliver more methane to the atmosphere, but warmer ice may release fewer halogens, resulting in fewer ozone depletion events. The net changes in carbon drawdown are still highly uncertain. Despite large uncertainties in these assessments, we expect disruptive changes that warrant intensified long-term observations and modelling efforts., info:eu-repo/semantics/published

Cellular quiescence and cell cycle reentry regulate vital biological processes such as cellular development and tissue homeostasis and are controlled by precise regulation of gene expression. The roles of long noncoding RNAs (lncRNAs) during these processes remain to be elucidated. By performing genome-wide transcriptome analyses, we identify differential expression of several hundreds of lncRNAs, including a significant number of the less-characterized class of microRNA-host-gene (MIRHG) lncRNAs or lnc-MIRHGs, during cellular quiescence and cell cycle reentry in human diploid fibroblasts. We observe that MIR222HG lncRNA displays serum-stimulated RNA processing due to enhanced splicing of the host nascent pri-MIR222HG transcript. The pre-mRNA splicing factor SRSF1 negatively regulates the microprocessor-catalyzed cleavage of pri-miR-222, thereby increasing the cellular pool of the mature MIR222HG. Association of SRSF1 to pri-MIR222HG, including to a mini-exon, which partially overlaps with the primary miR-222 precursor, promotes serum-stimulated splicing over microRNA processing of MIR222HG. Further, we observe that the increased levels of spliced MIR222HG in serum-stimulated cells promote the cell cycle reentry post quiescence in a microRNA-independent manner. MIR222HG interacts with DNM3OS, another lncRNA whose expression is elevated upon serum-stimulation, and promotes cell cycle reentry. The double-stranded RNA binding protein ILF3/2 complex facilitates MIR222HG:DNM3OS RNP complex assembly, thereby promoting DNM3OS RNA stability. Our study identifies a novel mechanism whereby competition between the splicing and microprocessor machinery modulates the serum-induced RNA processing of MIR222HG, which dictates cell cycle reentry.

The presence of bronchus-associated lymphoid tissue (BALT) and its size in humans largely depends upon age. It is detected in 35% of children less than 2 years of age, but absent in the healthy adult lung. Environmental gases or allergens may have an effect on the number of BALT. Lungs of rhesus macaque monkeys were screened by histology for the presence, size, and location of BALT after exposure to filtered air for 2, 6, 12, or 36 months or 12 and 36 months to ozone or 2, 12, or 36 months of house dust mite or a combination of ozone and house dust mite for 12 months. In the lungs of monkeys housed in filtered air for 2 months, no BALT was identified. After 6, 12, or 36 months, the number of BALT showed a significantly increased correlation with age in monkeys housed in filtered air. After 2 months of episodic house dust mite (HDM) exposure, no BALT was found. Monkeys exposed to HDM or HDM + ozone did not show a significant increase in BALT compared to monkeys housed in filtered air. However, monkeys exposed to ozone alone did show significant increases in BALT compared to all other groups. In particular, there were frequent accumulations of lymphocytes in the periarterial space of ozone exposed animals. In conclusion, BALT in rhesus monkeys housed under filtered air conditions is age-dependent. BALT significantly increased in monkeys exposed to ozone in comparison with monkeys exposed to HDM.

Most research on women’s sexualities focuses on a single event or developmental period, often failing to document romantic and sexual trajectories over time. Moreover, life course studies of sexuality have not exclusively examined single women, including major life events that may alter their sexual attitudes and behaviors. Using life story interview data with 60 single, heterosexual women between the ages of 18 and 91, I document five common pathways through romantic and sexual life, including opting out of marital relationships, the development of sexual subjectivity, sexual exploration and maintaining independence, sex positivity and increases in sexual communication, and a maintenance of sexual conservatism. The findings also reveal the role of domestic violence, sexual abuse, relationship dissolution, sexually transmitted illnesses, and menopause in altering sexual attitudes and behaviors. This study has several implications for life course studies of intimate relationships and sexuality.

Black patients typically lose less weight than White patients following bariatric surgery; however, the reasons for this racial disparity are unclear. The purpose of the current study was to evaluate whether there are differences in psychiatric symptoms and problematic eating behaviors between White and Black patients pursuing bariatric surgery as this may aid in understanding postsurgical weight loss disparities and inform psychosocial assessment of bariatric candidates. A retrospective chart review was conducted of participants (N = 284) who completed a psychological evaluation prior to surgery. Information collected included history of binge eating and purging as well as data from measures administered (i.e., the Hospital Anxiety and Depression Scale, the Emotional Eating Scale, and the Yale Food Addiction Scale 2.0). White patients reported higher levels of eating in response to anger/frustration (p = .03) and eating in response to depression (p = .01) than Black patients. White patients also reported more symptoms of food addiction, a difference that was trending toward significance (p = .05). No significant differences were found on measures of anxiety or depression. White patients appear to have higher levels of presurgical problematic eating as compared with Black patients pursuing bariatric surgery; thus, these measurements of problematic eating may not explain the racial disparity in outcomes. However, future research should determine whether measures are valid among diverse populations and identify additional factors that may contribute to racial disparities in bariatric outcomes.

Need to track the progress of a tribal treaty? Examine correspondence between territorial officials and Washington? Research accounts of battles and troop movements? Review records of agricultural and industrial production? Examine shipping records? Explore firsthand accounts of frontier life via letters and financial documents? Trace family histories using passenger lists? View petitions for statehood? All this and more can be done using Territorial Papers of the United States, 1764-1953. Documents come from National Archives and Records Administration and the official records of the Departments of State and the Interior. This is an excellent source for primary documents regarding this period of history, though it should be noted these documents largely come from a white, male, governmental, non-native perspective, as might be expected for the time period. Strong in advanced search options, it could use some improvement in the finer points (see under Searching and Critical Evaluation).

Objective: The objective of this retrospective review was to examine the impact that adding photobiomodulation therapy (PBMt) to rehabilitation therapy had on the pathology of degenerative myelopathy (DM) in canine patients. Background: Canine DM is a progressive, fatal neurodegenerative disease for which there exists a dearth of effective treatments, limiting clinicians to pursue symptom palliation. Methods: Clinical records of dogs referred for presumed DM to a specialty rehabilitation facility were screened for patients meeting study criteria. Qualifying patients were divided into two groups: Protocol A (PTCL-A) and Protocol B (PTCL-B) group, based on the PBMt protocol used. Data related to demographics, diagnostics, rehabilitation protocols, and progression of clinical signs were collected. Data were analyzed to determine differences in outcomes between the two treated groups and historical data expectations, as given by a previously published study. Results: The times between symptom onset and euthanasia of dogs in the PTCL-B group: 38.2 ± 14.67 months (mean ± SD), were significantly longer than those of dogs in the PTCL-A group: 11.09 ± 2.68 months. Similarly, the times between symptom onset and nonambulatory paresis (NAP) or paralysis of dogs in the PTCL-B group: 31.76 ± 12.53 months, were significantly longer than those of dogs in the PTCL-A group: 8.79 ± 1.60 months. Further, Kaplan–Meier survival analysis showed that the times from symptom onset to NAP of dogs in the PTCL-B group were significantly longer than those of dogs in the PTCL-A group (Mantel-Cox Log Rank statistic = 20.434, p

The purpose of this study was to examine the associations among race and socioeconomic factors (receiving social security disability, insurance type, and income) with undergoing bariatric surgery and weight loss outcomes in a racially diverse, urban cohort of bariatric surgery candidates (N = 314). Patients with private insurance and who identified as Caucasian were more likely to undergo bariatric surgery. Income significantly predicted percentage of excess weight loss 1 year after surgery, although this was no longer significant when accounting for race. Race and socioeconomic factors should be considered during psychosocial evaluations to support patients at risk of surgical attrition and poorer weight loss outcomes. Future research should explore policy solutions to improve access, while qualitative work may help with understanding racial disparities in bariatric surgery.

Background and purpose 5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), acting via the OXE receptor, is unique among 5-lipoxygenase products in its ability to directly induce human eosinophil migration, suggesting its involvement in eosinophilic diseases. To address this hypothesis, we synthesized selective indole-based OXE receptor antagonists. Because rodents lack an OXE receptor orthologue, we sought to determine whether these antagonists could attenuate allergen-induced skin eosinophilia in sensitized monkeys. Experimental approach In a pilot study, cynomolgus monkeys with environmentally acquired sensitivity to Ascaris suum were treated orally with the "first-generation" OXE antagonist 230 prior to intradermal injection of 5-oxo-ETE or Ascaris extract. Eosinophils were evaluated in punch biopsy samples taken 6 or 24 hr later. We subsequently treated captive-bred rhesus monkeys sensitized to house dust mite (HDM) allergen with a more recently developed OXE antagonist, S-Y048, and evaluated its effects on dermal eosinophilia induced by either 5-oxo-ETE or HDM. Key results In a pilot experiment, both 5-oxo-ETE and Ascaris extract induced dermal eosinophilia in cynomolgus monkeys, which appeared to be reduced by 230. Subsequently, we found that the related OXE antagonist S-Y048 is a highly potent inhibitor of 5-oxo-ETE-induced activation of rhesus monkey eosinophils in vitro and has a half-life in plasma of about 6 hr after oral administration. S-Y048 significantly inhibited eosinophil infiltration into the skin in response to both intradermally administered 5-oxo-ETE and HDM. Conclusions and implications 5-Oxo-ETE may play an important role in allergen-induced eosinophilia. Blocking its effects with S-Y048 may provide a novel therapeutic approach for eosinophilic diseases.

Cutaneous malignant melanoma is an aggressive cancer of melanocytes with a strong propensity to metastasize. We posit that melanoma cells acquire metastatic capability by adopting an embryonic-like phenotype, and that a lineage approach would uncover metastatic melanoma biology. Using a genetically engineered mouse model to generate a rich melanoblast transcriptome dataset, we identify melanoblast-specific genes whose expression contribute to metastatic competence and derive a 43-gene signature that predicts patient survival. We identify a melanoblast gene, KDELR3, whose loss impairs experimental metastasis. In contrast, KDELR1 deficiency enhances metastasis, providing the first example of different disease etiologies within the KDELR-family of retrograde transporters. We show that KDELR3 regulates the metastasis suppressor, KAI1, and report an interaction with the E3 ubiquitin-protein ligase gp78, a regulator of KAI1 degradation. Our work demonstrates that the melanoblast transcriptome can be mined to uncover targetable pathways for melanoma therapy., Metastatic cells can mimic many of the phenotypic behaviors of embryonic cells. Here, the authors generate a melanoblast-specific transcriptome using a genetically engineered mouse model and identify KDELR3 as a pro-metastasis gene in melanoma.

Vibrio cholerae biofilm formation/maintenance is controlled by myriad factors; chief among these are the regulator VpsR and cyclic di-guanosine monophosphate (c-di-GMP). VpsR has strong sequence similarity to enhancer binding proteins (EBPs) that activate RNA polymerase containing sigma factor σ54. However, we have previously shown that transcription from promoters within the biofilm biogenesis/maintenance pathways uses VpsR, c-di-GMP and RNA polymerase containing the primary sigma factor (σ70). Previous work suggested that phosphorylation of VpsR at a highly conserved aspartate, which is phosphorylated in other EBPs, might also contribute to activation. Using the biofilm biogenesis promoter PvpsL, we show that in the presence of c-di-GMP, either wild type or the phospho-mimic VpsR D59E activates PvpsL transcription, while the phospho-defective D59A variant does not. Furthermore, when c-di-GMP levels are low, acetyl phosphate (Ac∼P) is required for significant VpsR activity in vivo and in vitro. Although these findings argue that VpsR phosphorylation is needed for activation, we show that VpsR is not phosphorylated or acetylated by Ac∼P and either sodium phosphate or potassium phosphate, which are not phosphate donors, fully substitutes for Ac∼P. We conclude that VpsR is an unusual regulator that senses phosphate directly, rather than through phosphorylation, to aid in the decision to form/maintain biofilm.

Prior to the COVID-19 pandemic, growing mental health needs were well documented, particularly those of diverse patient populations. The current study aims to better understand racial and psychosocial factors associated with patient utilization of integrated psychological services via telehealth during the COVID-19 pandemic within a diverse primary care clinic.Retrospective chart reviews were completed for patients seen by an integrated psychology team within a general internal medicine clinic at a large urban health system during the year 2020. Demographics were extracted from the medical record. Multivariate logistic regression analyses were conducted to examine demographic predictors for (1) telehealth video visits vs. audio only telehealth visits and (2) in-person vs. telehealth visits (both video and audio).Older patients, Black patients, and those with Medicare and Medicaid were more likely to complete audio only telehealth visits vs. video visits. There were no significant demographic predictors when comparing in-person vs. telehealth (both video and audio).Some underserved and vulnerable patient populations are more likely to utilize audio-only integrated psychological visits to video visits. The utilization of audio visits over video for certain demographics speaks to the need to better understand how this type of care may benefit psychological services in the future and continued advocacy to extend audio mental health visits beyond the public health emergency to address patient populations with significant mental health needs.

The global spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its associated coronavirus disease (COVID-19) has led to a pandemic of unprecedented scale. An intriguing feature of the infection is the minimal disease in most children, a demographic at higher risk for respiratory viral diseases. To elucidate age-dependent effects of SARS-CoV-2 pathogenesis, we inoculated two rhesus macaque monkey dam-infant pairs with SARS-CoV-2 and conducted virological and transcriptomic analysis of the respiratory tract and evaluated systemic cytokine and antibody responses. Viral RNA levels in all sampled mucosal secretions were comparable across dam-infant pairs in the respiratory tract. Despite comparable viral loads, adult macaques showed higher IL-6 in serum while CXCL10 was induced in all animals. Both groups mounted neutralizing antibody (nAb) responses, with infants showing a more rapid induction at day 7. Transcriptome analysis of tracheal tissue isolated at day 14 post-infection revealed significant upregulation of multiple interferon-stimulated genes in infants compared to adults. In contrast, a profibrotic transcriptomic signature with genes associated with cilia structure and function, extracellular matrix (ECM) composition and metabolism, coagulation, angiogenesis, and hypoxia was induced in adults compared to infants. Our observations suggest age-dependent differential airway responses to SARS-CoV-2 infection that could explain the distinction in pathogenesis between infants and adults.