Growth differentiation factor 15 (GDF15), a distant member of the transforming growth factor (TGF)-β family, is a secreted protein that circulates as a 25-kDa dimer. In humans, elevated GDF15 ...correlates with weight loss, and the administration of GDF15 to mice with obesity reduces body weight, at least in part, by decreasing food intake. The mechanisms through which GDF15 reduces body weight remain poorly understood, because the cognate receptor for GDF15 is unknown. Here we show that recombinant GDF15 induces weight loss in mice fed a high-fat diet and in nonhuman primates with spontaneous obesity. Furthermore, we find that GDF15 binds with high affinity to GDNF family receptor α-like (GFRAL), a distant relative of receptors for a distinct class of the TGF-β superfamily ligands. Gfral is expressed in neurons of the area postrema and nucleus of the solitary tract in mice and humans, and genetic deletion of the receptor abrogates the ability of GDF15 to decrease food intake and body weight in mice. In addition, diet-induced obesity and insulin resistance are exacerbated in GFRAL-deficient mice, suggesting a homeostatic role for this receptor in metabolism. Finally, we demonstrate that GDF15-induced cell signaling requires the interaction of GFRAL with the coreceptor RET. Our data identify GFRAL as a new regulator of body weight and as the bona fide receptor mediating the metabolic effects of GDF15, enabling a more comprehensive assessment of GDF15 as a potential pharmacotherapy for the treatment of obesity.
Zika virus (ZIKV) causes microcephaly by killing neural precursor cells (NPCs) and other brain cells. ZIKV also displays therapeutic oncolytic activity against glioblastoma (GBM) stem cells (GSCs). ...Here we demonstrate that ZIKV preferentially infected and killed GSCs and stem-like cells in medulloblastoma and ependymoma in a SOX2-dependent manner. Targeting SOX2 severely attenuated ZIKV infection, in contrast to AXL. As mechanisms of SOX2-mediated ZIKV infection, we identified inverse expression of antiviral interferon response genes (ISGs) and positive correlation with integrin αv (ITGAV). ZIKV infection was disrupted by genetic targeting of ITGAV or its binding partner ITGB5 and by an antibody specific for integrin αvβ5. ZIKV selectively eliminated GSCs from species-matched human mature cerebral organoids and GBM surgical specimens, which was reversed by integrin αvβ5 inhibition. Collectively, our studies identify integrin αvβ5 as a functional cancer stem cell marker essential for GBM maintenance and ZIKV infection, providing potential brain tumor therapy.
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•ZIKV preferentially infects glioblastoma stem cells (GSCs) rather than neural precursor cells•ZIKV kills SOX2+ cells from a diverse array of malignant brain tumors•SOX2 determines susceptibility to ZIKV infection with reduced antiviral responses•Integrin αvβ5 is a GSC marker and promotes Zika virus infection of GSCs
Zika virus causes microcephaly by killing neural precursor cells but also acts as an oncolytic virus against glioblastoma. Zika preferentially targets glioblastoma stem cells through core stem cell transcription factor downregulation of innate immunity and induction of internalization through an integrin heterodimer that marks cancer stem cells.
Human mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as undifferentiated cells and that have the potential to differentiate to ...lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells were isolated from marrow aspirates of volunteer donors. These cells displayed a stable phenotype and remained as a monolayer in vitro. These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages. Individual stem cells were identified that, when expanded to colonies, retained their multilineage potential.
In myotonic dystrophy (dystrophia myotonica, DM), expression of RNAs that contain expanded CUG or CCUG repeats is associated with degeneration and repetitive action potentials (myotonia) in skeletal ...muscle. Using skeletal muscle from a transgenic mouse model of DM, we show that expression of expanded CUG repeats reduces the transmembrane chloride conductance to levels well below those expected to cause myotonia. The expanded CUG repeats trigger aberrant splicing of pre-mRNA for ClC-1, the main chloride channel in muscle, resulting in loss of ClC-1 protein from the surface membrane. We also have identified a similar defect in ClC-1 splicing and expression in two types of human DM. We propose that a transdominant effect of mutant RNA on RNA processing leads to chloride channelopathy and membrane hyperexcitability in DM.
Improving health equity in depression care and suicide screening requires that measures like the Patient Health Questionnaire 9 (PHQ-9) function similarly for diverse racial and ethnic groups. We ...evaluated PHQ-9 differential item functioning (DIF) between racial/ethnic groups in a retrospective cohort study of secondary electronic health record (EHR) data from eight healthcare systems.
The population (n = 755,156) included patients aged 18–64 with mental health and/or substance use disorder (SUD) diagnoses who had a PHQ-9 with no missing item data in the EHR for primary care or mental health visits between 1/1/2009–9/30/2017. We drew two random samples of 1000 from the following racial/ethnic groups originally recorded in EHRs (n = 14,000): Hispanic, and non-Hispanic White, Black, Asian, American Indian/Alaska Native, Native Hawaiian/Other Pacific Islander, multiracial. We assessed DIF using iterative hybrid ordinal logistic regression and item response theory with p < 0.01 and 1000 Monte Carlo simulations, where change in model R2 > 0.01 represented non-negligible (e.g., clinically meaningful) DIF.
All PHQ-9 items displayed statistically significant, but negligible (e.g., clinically unmeaningful) DIF between compared groups. The negligible DIF varied between random samples, although six items showed negligible DIF between the same comparison groups in both random samples.
Our findings may not generalize to disaggregated racial/ethnic groups or persons without mental health and/or SUD diagnoses.
We found the PHQ-9 had clinically unmeaningful cross-cultural DIF for adult patients with mental health and/or SUD diagnoses. Future research could disaggregate race/ethnicity to discern if within-group identification impacts PHQ-9 DIF.
•We studied the cross-cultural differential item functioning (DIF) of the Patient Health Questionnaire 9 (PHQ-9) for adults with mental health and/or substance use disorders (SUD) seen in primary care or behavioral health at eight healthcare systems.•We found that all items in the PHQ-9 displayed statistically significant, but negligible (e.g., clinically unmeaningful) DIF based on broad racial and ethnic groups.•Six items displayed consistent negligible DIF for some racial and ethnic groups between two random samples.•While DIF levels were negligible, they may suggest within-group variations masked by grouping diverse racial and ethnic groups together into monolithic categories.•Future research should examine whether our findings generalize to disaggregated racial and ethnic groups of adults with mental health and/or SUD diagnoses.
Effective delivery of siRNA (small interfering RNA) into the cells requires the translocation of siRNA into the cytosol. One potential delivery strategy uses cell-delivery peptides that facilitate ...this step. In the present paper, we describe the characterization of an amphipathic peptide that mediates the uptake of non-covalently bound siRNA into cells and its subsequent release into the cytosol. Biophysical characterization of peptide and peptide/siRNA mixtures at neutral and lysosomal (acidic) pH suggested the formation of α-helical structure only in endosomes and lysosomes. Surprisingly, even though the peptide enhanced the uptake of siRNA into cells, no direct interaction between siRNA and peptide was observed at neutral pH by isothermal titration calorimetry. Importantly, we show that peptide-mediated siRNA uptake occurred through endocytosis and, by applying novel endosomal-escape assays and cell-fractionation techniques, we demonstrated a pH-dependent alteration in endosome and lysosome integrity and subsequent release of siRNA and other cargo into the cytosol. These results indicate a peptide-mediated siRNA delivery through a pH-dependent and conformation-specific interaction with cellular membranes and not with the cargo.
AbstractBackgroundThe United States has experienced a significant rise in suicide. As decision makers identify how to address this national concern, healthcare systems have been identified as an ...optimal location for prevention. ObjectiveTo compare variation in patterns of healthcare use, by health setting, between individuals who died by suicide and the general population. DesignCase-Control Study. SettingEight healthcare systems across the United States. Participants2674 individuals who died by suicide between 2000 and 2013 along with 267,400 individuals matched on time-period of health plan membership and health system affiliation. MeasurementsHealthcare use in the emergency room, inpatient hospital, primary care, and outpatient specialty setting measured using electronic health record data during the 7-, 30-, 60-, 90-, 180-, and 365-day time periods before suicide and matched index date for controls. ResultsHealthcare use was more common across all healthcare settings for individuals who died by suicide. Nearly 30% of individuals had a healthcare visit in the 7-days before suicide (6.5% emergency, 16.3% outpatient specialty, and 9.5% primary care), over half within 30 days, and >90% within 365 days. Those who died by suicide averaged 16.7 healthcare visits during the year. The relative risk of suicide was greatest for individuals who received care in the inpatient setting (aOR = 6.23). There was both a large relative risk (aOR = 3.08) and absolute utilization rate (43.8%) in the emergency room before suicide. LimitationsParticipant race/ethnicity was not available. The sample did not include uninsured individuals. ConclusionsThis study provides important data about how care utilization differs for those who die by suicide compared to the general population and can inform decision makers on targeting of suicide prevention activities within health systems.
Health-related quality of life (HRQOL) is frequently impaired in pulmonary arterial hypertension. However, little is known about HRQOL in other forms of pulmonary hypertension (PH).
Does HRQOL vary ...across groups of the World Symposium on Pulmonary Hypertension (WSPH) classification system?
This cross-sectional study included patients with PH from the Pulmonary Vascular Disease Phenomics (PVDOMICS) cohort study. HRQOL was assessed by using emPHasis-10 (e-10), the 36-item Medical Outcomes Study Short Form survey (physical component score PCS and mental component score), and the Minnesota Living with Heart Failure Questionnaire. Pearson correlations between HRQOL and demographic, physiologic, and imaging characteristics within each WSPH group were tested. Multivariable linear regressions compared HRQOL across WSPH groups, adjusting for demographic characteristics, disease prevalence, functional class, and hemodynamics. Cox proportional hazards models were used to assess associations between HRQOL and survival across WSPH groups.
Among 691 patients with PH, HRQOL correlated with functional class and 6-min walk distance but not hemodynamics. HRQOL was severely depressed across WSPH groups for all measures except the 36-item Medical Outcomes Study Short Form survey mental component score. Compared with Group 1 participants, Group 2 participants had significantly worse HRQOL (e-10 score, 29 vs 24 P = .001; PCS, 32.9 ± 8 vs 38.4 ± 10 P < .0001; and Minnesota Living with Heart Failure Questionnaire score, 50 vs 38 P = .003). Group 3 participants similarly had a worse e-10 score (31 vs 24; P < .0001) and PCS (33.3 ± 9 vs 38.4 ± 10; P < .0001) compared with Group 1 participants, which persisted in multivariable models (P < .05). HRQOL was associated in adjusted models with survival across Groups 1, 2, and 3.
HRQOL was depressed in PH and particularly in Groups 2 and 3 despite less severe hemodynamics. HRQOL is associated with functional capacity, but the severity of hemodynamic disease poorly estimates the impact of PH on patients’ lives. Further studies are needed to better identify predictors and treatments to improve HRQOL across the spectrum of PH.
PVDOMICS (Pulmonary Vascular Disease Phenomics) is a precision medicine initiative to characterize pulmonary vascular disease (PVD) using deep phenotyping. PVDOMICS tests the hypothesis that ...integration of clinical metrics with omic measures will enhance understanding of PVD and facilitate an updated PVD classification.
The purpose of this study was to describe clinical characteristics and transplant-free survival in the PVDOMICS cohort.
Subjects with World Symposium Pulmonary Hypertension (WSPH) group 1-5 PH, disease comparators with similar underlying diseases and mild or no PH and healthy control subjects enrolled in a cross-sectional study. PH groups, comparators were compared using standard statistical tests including log-rank tests for comparing time to transplant or death.
A total of 1,193 subjects were included. Multiple WSPH groups were identified in 38.9% of PH subjects. Nocturnal desaturation was more frequently observed in groups 1, 3, and 4 PH vs comparators. A total of 50.2% of group 1 PH subjects had ground glass opacities on chest computed tomography. Diffusing capacity for carbon monoxide was significantly lower in groups 1-3 PH than their respective comparators. Right atrial volume index was higher in WSPH groups 1-4 than comparators. A total of 110 participants had a mean pulmonary artery pressure of 21-24 mm Hg. Transplant-free survival was poorest in group 3 PH.
PVDOMICS enrolled subjects across the spectrum of PVD, including mild and mixed etiology PH. Novel findings include low diffusing capacity for carbon monoxide and enlarged right atrial volume index as shared features of groups 1-3 and 1-4 PH, respectively; unexpected, frequent presence of ground glass opacities on computed tomography; and sleep alterations in group 1 PH, and poorest survival in group 3 PH. PVDOMICS will facilitate a new understanding of PVD and refine the current PVD classification. (Pulmonary Vascular Disease Phenomics Program PVDOMICS PVDOMICS; NCT02980887)
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Objective:
The aim of this study was to identify adverse social determinants of health (SDoH)
International Statistical Classification of Diseases, Ninth Revision, Clinical Modification
(ICD-9-CM) ...code prevalence among individuals who died by suicide and to examine associations between documented adverse SDoH and suicide.
Research Design:
A case-control study using linked medical record, insurance claim, and mortality data from 2000 to 2015 obtained from 9 Mental Health Research Network-affiliated health systems. We included 3330 individuals who died by suicide and 333,000 randomly selected controls matched on index year and health system location. All individuals in the study (cases and controls) had at least 10 months of enrollment before the study index date. The index date for the study for each case and their matched controls was the suicide date for that given case.
Results:
Adverse SDoH documentation was low; only 6.6% of cases had ≥1 documented adverse SDoH in the year before suicide. Any documented SDoH and several specific adverse SDoH categories were more frequent among cases than controls. Any documented adverse SDoH was associated with higher suicide odds adjusted odds ratio (aOR)=2.76; 95% CI: 2.38–3.20, as was family alcoholism/drug addiction (aOR=18.23; 95% CI: 8.54–38.92), being an abuse victim/perpetrator (aOR=2.53; 95% CI: 1.99–3.21), other primary support group problems (aOR=1.91; 95% CI: 1.32–2.75), employment/occupational maladjustment problems (aOR=8.83; 95% CI: 5.62–13.87), housing/economic problems (aOR: 6.41; 95% CI: 4.47–9.19), legal problems (aOR=27.30; 95% CI: 12.35–60.33), and other psychosocial problems (aOR=2.58; 95% CI: 1.98–3.36).
Conclusions:
Although documented SDoH prevalence was low, several adverse SDoH were associated with increased suicide odds, supporting calls to increase SDoH documentation in medical records. This will improve understanding of SDoH prevalence and assist in identification and intervention among individuals at high suicide risk.
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