Whole blood transcriptional signatures distinguishing active tuberculosis patients from asymptomatic latently infected individuals exist. Consensus has not been achieved regarding the optimal reduced ...gene sets as diagnostic biomarkers that also achieve discrimination from other diseases. Here we show a blood transcriptional signature of active tuberculosis using RNA-Seq, confirming microarray results, that discriminates active tuberculosis from latently infected and healthy individuals, validating this signature in an independent cohort. Using an advanced modular approach, we utilise the information from the entire transcriptome, which includes overabundance of type I interferon-inducible genes and underabundance of IFNG and TBX21, to develop a signature that discriminates active tuberculosis patients from latently infected individuals or those with acute viral and bacterial infections. We suggest that methods targeting gene selection across multiple discriminant modules can improve the development of diagnostic biomarkers with improved performance. Finally, utilising the modular approach, we demonstrate dynamic heterogeneity in a longitudinal study of recent tuberculosis contacts.
The use of tough hydrogels as biomaterials is limited as a consequence of time-consuming fabrication techniques, toxic starting materials, and large strain hysteresis under deformation. Herein, we ...report the simultaneous application of nucleophilic thiol-yne and inverse electron-demand Diels–Alder additions to independently create two interpenetrating networks in a simple one-step procedure. The resultant hydrogels display compressive stresses of 14–15 MPa at 98% compression without fracture or hysteresis upon repeated load. The hydrogel networks can be spatially and temporally postfunctionalized via radical thiylation and/or inverse electron-demand Diels–Alder addition to residual functional groups within the network. Furthermore, gelation occurs rapidly under physiological conditions, enabling encapsulation of human cells.
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IJS, KILJ, NUK, PNG, UL, UM
3.
Integrating Physical Activity in Primary Care Practice AuYoung, Mona, PhD, MS, MPH; Linke, Sarah E., PhD, MPH; Pagoto, Sherry, PhD ...
The American journal of medicine,
10/2016, Volume:
129, Issue:
10
Journal Article
Peer reviewed
Open access
Abstract Based on a collaborative symposium in 2014 hosted by the Society of Behavioral Medicine (SBM) and the American College of Sports Medicine (ACSM), this paper presents a model for physical ...activity counseling for primary care physicians (PCPs). Most United States adults do not meet national recommendations for physical activity levels. Socioecological factors drive differences in physical activity levels by geography, gender, age, and racial/ethnic group. The recent Patient Protection and Affordable Care Act (ACA) incentivizes PCPs to offer patients physical activity counseling. However, PCPs have reported socioecological barriers to physical activity counseling and also patient barriers to physical activity, spanning from the individual to the environmental (e.g., lack of safe spaces for physical activity), policy (e.g., reimbursement policies), and organizational (e.g., electronic medical record protocols, worksite norms/policies) levels. The aims of this paper are to: (1) discuss barriers to PCP counseling for physical activity; (2) provide evidence-based strategies and techniques to help PCPs address these counseling barriers; and (3) suggest practical steps for PCPs to counsel patients on physical activityusing strategies and supports from policy, the primary care team, and other support networks.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Tail-anchored (TA) proteins are a distinct class of membrane proteins that are sorted post-translationally to various organelles and function in a number of important cellular processes, ...including redox reactions, vesicular trafficking and protein translocation. While the molecular targeting signals and pathways responsible for sorting TA proteins to their correct intracellular destinations in yeasts and mammals have begun to be characterized, relatively little is known about TA protein biogenesis in plant cells, especially for those sorted to the plastid outer envelope. Methodology/Principal Findings: Here we investigated the biogenesis of three plastid TA proteins, including the 33-kDa and 34-kDa GTPases of the translocon at the outer envelope of chloroplasts (Toc33 and Toc34) and a novel 9-kDa protein of unknown function that we define here as an outer envelope TA protein (OEP9). Using a combination of in vivo and in vitro assays we show that OEP9 utilizes a different sorting pathway than that used by Toc33 and Toc34. For instance, while all three TA proteins interact with the cytosolic OEP chaperone/receptor, AKR2A, the plastid targeting information within OEP9 is distinct from that within Toc33 and Toc34. Toc33 and Toc34 also appear to differ from OEP9 in that their insertion is dependent on themselves and the unique lipid composition of the plastid outer envelope. By contrast, the insertion of OEP9 into the plastid outer envelope occurs in a proteinaceous-dependent, but Toc33/34-independent manner and membrane lipids appear to serve primarily to facilitate normal thermodynamic integration of this TA protein. Conclusions/Significance: Collectively, the results provide evidence in support of at least two sorting pathways for plastid TA outer envelope proteins and shed light on not only the complex diversity of pathways involved in the targeting and insertion of proteins into plastids, but also the molecular mechanisms that underlie the delivery of TA proteins to their proper intracellular locations in general.
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Perfluoroalkyl substances (PFASs) are widespread and persistent environmental pollutants. Previous studies, primarily among non-pregnant individuals, suggest positive associations between PFAS levels ...and certain blood lipids. If there is a causal link between PFAS concentrations and elevated lipids during pregnancy, this may suggest a mechanism by which PFAS exposure leads to certain adverse pregnancy outcomes, including preeclampsia.
This cross-sectional analysis included 891 pregnant women enrolled in the Norwegian Mother and Child (MoBa) Cohort Study in 2003–2004. Non-fasting plasma samples were obtained at mid-pregnancy and analyzed for nineteen PFASs. Total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured in plasma. Linear regression was used to quantify associations between each PFAS exposure and each lipid outcome. A multiple PFAS model was also fitted.
Seven PFASs were quantifiable in >50% of samples. Perfluorooctane sulfonate (PFOS) concentration was associated with total cholesterol, which increased 4.2mg/dL per inter-quartile shift (95% CI=0.8, 7.7) in adjusted models. Five of the seven PFASs studied were positively associated with HDL cholesterol, and all seven had elevated HDL associated with the highest quartile of exposure. Perfluoroundecanoic acid showed the strongest association with HDL: HDL increased 3.7mg/dL per inter-quartile shift (95% CI=2.5, 4.9).
Plasma concentrations of PFASs were positively associated with HDL cholesterol, and PFOS was positively associated with total cholesterol in this sample of pregnant Norwegian women. While elevated HDL is not an adverse outcome per se, elevated total cholesterol associated with PFASs during pregnancy could be of concern if causal.
•We examined associations between perfluoroalkyl substances and lipids in pregnancy.•Plasma PFOS was positively associated with total cholesterol among pregnant women.•Seven perfluoroalkyl substances were positively associated with HDL cholesterol.•Multiple pollutant models reduced all associations with HDL except PFUnDA.•Cholesterol findings may suggest a possible mechanism linking PFOS to preeclampsia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Neighborhood disadvantage has been linked to poor sleep. However, the extant research has primarily focused on self-reported assessments of sleep and neighborhood characteristics. The current study ...examines the association between objective and perceived neighborhood characteristics and actigraphy-assessed sleep duration, efficiency, and wakefulness after sleep onset (WASO) in an urban sample of African American adults.
We examined data from predominantly African American adults (n = 788, mean age 55 years; 77% female) living in two low-income neighborhoods. Perceived neighborhood characteristics included safety, social cohesion, and satisfaction with one's neighborhood as a place to live. Objective neighborhood conditions included walkability, disorder, street lighting, and crime levels. Sleep duration, efficiency, and WASO were measured via 7 days of wrist-worn actigraphy. Analyses estimated each of the sleep outcomes as a function of perceived and objective neighborhood characteristics. Individual-level sociodemographics, body mass index, and psychological distress were included as covariates.
Greater perceived safety was associated with higher sleep efficiency and shorter WASO. Greater neighborhood disorder and street lighting were associated with poorer sleep efficiency and longer WASO and greater likelihood of short sleep duration (<7 versus 7-9 hr as referent). Higher levels of crime were associated with poorer sleep efficiency and longer WASO, but these associations were only evident in one of the neighborhoods.
Both how residents perceive their neighborhood and their exposure to objectively measured neighborhood disorder, lighting, and crime have implications for sleep continuity. These findings suggest that neighborhood conditions may contribute to disparities in sleep health.
Bortezomib therapy has proven successful for the treatment of relapsed/refractory, relapsed, and newly diagnosed multiple myeloma (MM); however, dose-limiting toxicities and the development of ...resistance limit its long-term utility. Here, we show that P5091 is an inhibitor of deubiquitylating enzyme USP7, which induces apoptosis in MM cells resistant to conventional and bortezomib therapies. Biochemical and genetic studies show that blockade of HDM2 and p21 abrogates P5091-induced cytotoxicity. In animal tumor model studies, P5091 is well tolerated, inhibits tumor growth, and prolongs survival. Combining P5091 with lenalidomide, HDAC inhibitor SAHA, or dexamethasone triggers synergistic anti-MM activity. Our preclinical study therefore supports clinical evaluation of USP7 inhibitor, alone or in combination, as a potential MM therapy.
► P5091 is a potent and selective inhibitor of deubiquitylating enzyme USP7 ► P5091 triggers in vitro and in vivo antimyeloma activity ► P5091 activates HDM2/p53/p21 signaling axis ► Synergistic anti-MM activity of P5091 with SAHA, lenalidomide, or dexamethasone
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Expert Working Groups explicitly describe how they were able—or not—to rule out these sources of error with reasonable confidence, as seen in recent evaluations of night shift work,4 opium ...consumption5 and aniline.6 Many approaches to evaluating the direction and magnitude of biases in observational epidemiology have been described in the scientific literature—some new,7 and some existing for decades.8 To make these methodological developments more easily accessible to those conducting cancer hazard identification, the Monographs programme and the National Cancer Institute’s Division of Cancer Epidemiology and Genetics convened a scientific workshop of global experts in cancer epidemiology and in statistical and epidemiological methodology. ...attendees outlined approaches that researchers could adopt to assess the impacts of each source of bias in their own studies. The workshop materials will result in the publication of a new volume in the IARC Scientific Publications series Statistical Methods in Cancer Research, which includes the landmark publications on cohort and case–control studies authored by Breslow and Day.9 10 The new Scientific Publication, expected in early 2024, will summarise methods for bias assessment to support cancer hazard identification, illustrate these methods with examples and discuss how these methods could also be incorporated into future published studies to better inform cancer hazard and risk assessments. Funding This work was supported by the International Agency for Research on Cancer (IARC) and by the National Cancer Institute’s Intramural Research Program, Division of Cancer Epidemiology and Genetics.
We analyzed population-based surveillance data from the Toronto Invasive Bacterial Diseases Network to describe carbapenemase-producing Enterobacteriaceae (CPE) infections during 2007–2015 in ...south-central Ontario, Canada. We reviewed patients’ medical records and travel histories, analyzed microbiologic and clinical characteristics of CPE infections, and calculated incidence. Among 291 cases identified, New Delhi metallo-β-lactamase was the predominant carbapenemase (51%). The proportion of CPE-positive patients with prior admission to a hospital in Canada who had not received healthcare abroad or traveled to high-risk areas was 13% for patients with oxacillinase-48, 24% for patients with New Delhi metallo-β-lactamase, 55% for patients with Klebsiella pneumoniae carbapenemase, and 67% for patients with Verona integron-encoded metallo-β-lactamase. Incidence of CPE infection increased, reaching 0.33 cases/100,000 population in 2015. For a substantial proportion of patients, no healthcare abroad or high-risk travel could be established, suggesting CPE acquisition in Canada. Policy and practice changes are needed to mitigate nosocomial CPE transmission in hospitals in Canada.
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•There is increased interest in food insecurity rates on college campuses.•College food insecurity rates vary widely in the published literature.•No food insecurity measure has been validated for use ...with college students.•Consistent and comparable measurement is critical for efficient policy design.
A growing body of research among college students has estimated remarkably high levels of food insecurity when compared to food insecurity estimates from the general population over the past decade, with recent literature reviews reporting average prevalence rates of 33–51% compared to 9.8% among U.S. adults. Given these high rates of food insecurity, policymakers at the state- and federal-levels are considering legislation to better understand and ultimately alleviate food insecurity in the college student population. Further, the National Postsecondary Student Aid Study will soon collect national surveillance data on college student food insecurity. However, emerging research suggests that existing food insecurity measurement tools may not perform as expected when used with college students. Indeed, there is no food insecurity measure that has been validated for use with college students. The purpose of this commentary is to discuss the current state of food insecurity measurement among college students and set a course for more meaningful measurement in the college-student population that produces consistent and comparable estimates of food insecurity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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