Multiple prebiotic metals mediate translation.

Today, Mg2+ is an essential cofactor with diverse structural and functional roles in life's oldest macromolecular machine, the translation system. We tested whether ancient Earth conditions (low O2, high Fe2+, and high Mn2+) can revert the ribosome to a functional ancestral state. First, SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) was used to compare the effect of Mg2+, Fe2+, and Mn2+ on the tertiary structure of rRNA. Then, we used in vitro translation reactions to test whether Fe2+ or Mn2+ could mediate protein production, and quantified ribosomal metal content. We found that (i) Mg2+, Fe2+, and Mn2+ had strikingly similar effects on rRNA folding; (ii) Fe2+ and Mn2+ can replace Mg2+ as the dominant divalent cation during translation of mRNA to functional protein; and (iii) Fe and Mn associate extensively with the ribosome. Given that the translation system originated and matured when Fe2+ and Mn2+ were abundant, these findings suggest that Fe2+ and Mn2+ played a role in early ribosomal evolution

On ‘Organized Crime’ in the illicit antiquities trade: moving beyond the definitional debate

The extent to which ‘organized crime’ is involved in illicit antiquities trafficking is unknown and frequently debated. This paper explores the significance and scale of the illicit antiquities trade as a unique transnational criminal phenomenon that is often said to be perpetrated by and exhibit traits of so-called ‘organized crime.’ The definitional debate behind the term ‘organized crime’ is considered as a potential problem impeding our understanding of its existence or extent in illicit antiquities trafficking, and a basic progression-based model is then suggested as a new tool to move beyond the definitional debate for future research that may help to elucidate the actors, processes and criminal dynamics taking place within the illicit antiquities trade from source to market. The paper concludes that researchers should focus not on the question of whether organized criminals- particularly in a traditionally conceived, mafia-type stereotypical sense- are involved in the illicit antiquities trade, but instead on the structure and progression of antiquities trafficking itself that embody both organized and criminal dynamics

A Rare Case of Double Belly Soleus Muscle

The rare anatomical anomaly of a double belly soleus muscle has been associated with some clinical and non-clinical correlations in patients. With symptomatic patients, usually not presenting until 20–30 years old, pain is exacerbated by long walks, running, and standing for long periods of time. This presentation could mimic the properties of a soft tissue tumor, thus misleading physicians. The discovery of the double belly soleus muscle is noticed while in surgery, biopsy, computed tomography scan, or magnetic resonance imaging machine. We herewith present a rare case of double belly soleus on the left and right posterior lower leg region of a 58-year-old female cadaver. This article will help bring awareness to the signs and symptoms of this rare anatomical anomaly

Social Cognitive Outcomes are Associated With Improvements in Mobility Performance Following Lifestyle Intervention in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy

Objective To compare the effects of an exercise and dietary intervention with those of standard-of-care management upon change in lift and carry performance and mobility-related self-efficacy beliefs and explore associations in prostate cancer patients undergoing androgen deprivation therapy. Methods 32 prostate cancer patients (M age = 66.2 years; SD = 7.8) undergoing androgen deprivation therapy were randomly assigned to a 3-month exercise and dietary lifestyle intervention (n = 16) or standard-of-care management (n = 16). Outcome assessments were obtained at baseline, 2- and 3-month follow-up. Results The lifestyle intervention resulted in significantly greater improvements in lift and carry performance (p = 0.01) at 2 Months (d = 1.01; p \u3c 0.01) and 3 Months (d = 0.95; p \u3c 0.01) and superior improvements in mobility-related self-efficacy at 2 Months (d = 0.38) and 3 Months (d = 0.58) relative to standard-of-care. Mobility-related self-efficacy (r = -.66; p = 0.006) and satisfaction with function (r = -.63; p = 0.01) were significantly correlated with lift and carry performance at 3 Months. Conclusions The exercise and dietary lifestyle intervention yielded superior improvements in lift and carry performance and mobility-related self-efficacy relative to standard-of-care and key social cognitive outcomes were associated with more favorable mobility performance

Effects of a group-mediated cognitive behavioral lifestyle intervention on select social cognitive outcomes in prostate cancer patients undergoing androgen deprivation therapy

Objective. To compare the effects of a group-mediated cognitive behavioral (GMCB) exercise and dietary (EX+D) intervention with those of standard-of-care (SC) treatment on select social cognitive outcomes in prostate cancer (PCa) patients undergoing androgen deprivation therapy (ADT). Methods. In the single-blind, 2-arm, randomized controlled Individualized Diet and Exercise Adherence–Pilot (IDEA-P) trial, 32 PCa patients (mean age = 66.2 years; SD = 7.8) undergoing ADT were randomly assigned to a 12-week EX+D intervention (n = 16) or SC treatment (n = 16). The exercise component of the personalized EX+D intervention integrated a combination of supervised resistance and aerobic exercise performed twice per week. The dietary component involved counseling and education to modify dietary intake and composition. Blinded assessments of social cognitive outcomes were obtained at baseline and 2-month and 3-month follow-up. Results. Intent-to-treat analysis of covariance demonstrated that the EX+D intervention resulted in significantly greater improvements in scheduling (P \u3c .05), coping (P \u3c .01), and exercise self-efficacy (P \u3c .05), and satisfaction with function (P \u3c .01) at 3 months relative to SC. Results of partial correlation analysis also demonstrated that select social cognitive outcomes were significantly correlated with primary trial outcomes of mobility performance and exercise participation (P \u3c .05) at 3-month follow-up. Conclusions: The GMCB lifestyle intervention yielded more favorable improvements in relevant social cognitive outcomes relative to SC among PCa patients undergoing ADT. Additionally, more favorable social cognitive outcomes were associated with superior mobility performance and exercise participation following the independent maintenance phase of the EX+D intervention

Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants

This is the final version of the article. Available from the publisher via the DOI in this record.Variation in human lifespan is 20 to 30% heritable in twins but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father's and/or mother's data, excluding early deaths). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested. In GWAS, a nicotine receptor locus(CHRNA3, previously associated with increased smoking and lung cancer) was associated with fathers' survival. Less common variants requiring further confirmation were also identified. Offspring of longer lived parents had more protective alleles for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer's disease. In candidate analyses, variants in the TOMM40/APOE locus were associated with longevity, but FOXO variants were not. Associations between extreme longevity (mother >=98 years, fathers >=95 years, n=1,339) and disease alleles were similar, with an additional association with HDL cholesterol (p=5.7x10-3). These results support a multiple protective factors model influencing lifespan and longevity (top 1% survival) in humans, with prominent roles for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.This work was generously funded by an award to DM, TF, AM, LH and CB by the Medical Research Council MR/M023095/1. This research has been conducted using the UK Biobank Resource, under application 1417. The authors wish to thank the UK Biobank participants and coordinators for this unique dataset. S.E.J. is funded by the Medical Research Council (grant: MR/M005070/1). J.T. is funded by a Diabetes Research and Wellness Foundation Fellowship. R.B. is funded by the Wellcome Trust and Royal Society grant: 104150/Z/14/Z. M.A.T., M.N.W. and A.M. are supported by the Wellcome Trust Institutional Strategic Support Award (WT097835MF). R.M.F. is a Sir Henry Dale Fellow (Wellcome Trust and Royal Society grant: 104150/Z/14/Z). A.R.W. H.Y., and T.M.F. are supported by the European Research Council grant: 323195:GLUCOSEGENES-FP7-IDEAS-ERC. The funders had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript. The Framingham Heart Study is supported by Contract No. N01-HC-25195 and HHSN268201500001I and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). The phenotypegenotype association analyses were supported by National Institute of Aging R01AG29451. This work has made use of the resources provided by the University of Exeter Science Strategy and resulting Systems Biology initiative. Primarily these include high-performance computing facilities managed by Konrad Paszkiewicz of the College of Environmental and Life Sciences and Pete Leggett of the University of Exeter Academics services unit

Interaction between the microbiome and TP53 in human lung cancer.

BACKGROUND: Lung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier integrity and increases susceptibility to infections. Herein, we hypothesize that somatic mutations together with cigarette smoke generate a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from 33 controls and 143 cancer cases, we conduct 16S ribosomal RNA (rRNA) bacterial gene sequencing, with RNA-sequencing data from lung cancer cases in The Cancer Genome Atlas serving as the validation cohort. RESULTS: Overall, we demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue. In squamous cell carcinoma specifically, a separate group of taxa are identified, in which Acidovorax is enriched in smokers. Acidovorax temporans is identified within tumor sections by fluorescent in situ hybridization and confirmed by two separate 16S rRNA strategies. Further, these taxa, including Acidovorax, exhibit higher abundance among the subset of squamous cell carcinoma cases with TP53 mutations, an association not seen in adenocarcinomas. CONCLUSIONS: The results of this comprehensive study show both microbiome-gene and microbiome-exposure interactions in squamous cell carcinoma lung cancer tissue. Specifically, tumors harboring TP53 mutations, which can impair epithelial function, have a unique bacterial consortium that is higher in relative abundance in smoking-associated tumors of this type. Given the significant need for clinical diagnostic tools in lung cancer, this study may provide novel biomarkers for early detection

White Matter Hyperintensities in Vascular Contributions to Cognitive Impairment and Dementia (VCID): Knowledge Gaps and Opportunities

White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer\u27s disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia

Mast Cell Diseases in Practice and Research:Issues and Perspectives Raised by Patients and Their Recommendations to the Scientific Community and Beyond

Background: Since 2010, patients and physicians have collaborated to understand unmet needs of patients with mast cell diseases, incorporating mastocytosis and mast cell activation disorders, which include mast cell activation syndromes. Objective: This Open Innovation in Science project aims to expand understanding of the needs of patients affected by mast cell diseases, and encourage global communication among patient advocacy groups, physicians, researchers, industry, and government. A major aim is to support the scientific community's efforts to improve diagnosis, management, therapy, and patients’ quality of life by addressing unmet needs. Methods: In collaboration with mast cell disease specialists, 13 patient advocacy groups from 12 countries and regions developed lists of top patient needs. A core team of leaders from patient advocacy groups collected and analyzed the data and proposed possible actions to address patient needs. Results: Findings identified similarities and differences among participating countries in unmet needs between patients with mastocytosis and those with mast cell activation syndromes. Issues emphasized struggles relating to the nature and rarity of mast cell diseases, their impact on quality of life, the diagnostic process, access to appropriate care, more effective treatment, and the need for research. Conclusions: Solutions vary across countries because situations differ, in particular regarding the existence of and access to centers of excellence and reference centers. Multifaceted mast cell activation syndrome barriers necessitate innovative approaches to improve access to appropriate care. The outcomes of this project should greatly support scientists and clinicians in their efforts to improve diagnosis, management, and treatment of patients with mastocytosis and mast cell activation disorders

A Stochastic Model of Latently Infected Cell Reactivation and Viral Blip Generation in Treated HIV Patients

Motivated by viral persistence in HIV+ patients on long-term anti-retroviral treatment (ART), we present a stochastic model of HIV viral dynamics in the blood stream. We consider the hypothesis that the residual viremia in patients on ART can be explained principally by the activation of cells latently infected by HIV before the initiation of ART and that viral blips (clinically-observed short periods of detectable viral load) represent large deviations from the mean. We model the system as a continuous-time, multi-type branching process. Deriving equations for the probability generating function we use a novel numerical approach to extract the probability distributions for latent reservoir sizes and viral loads. We find that latent reservoir extinction-time distributions underscore the importance of considering reservoir dynamics beyond simply the half-life. We calculate blip amplitudes and frequencies by computing complete viral load probability distributions, and study the duration of viral blips via direct numerical simulation. We find that our model qualitatively reproduces short small-amplitude blips detected in clinical studies of treated HIV infection. Stochastic models of this type provide insight into treatment-outcome variability that cannot be found from deterministic models