GIT2 Acts as a Potential Keystone Protein in Functional Hypothalamic Networks Associated with Age-Related Phenotypic Changes in Rats

The aging process affects every tissue in the body and represents one of the most complicated and highly integrated inevitable physiological entities. The maintenance of good health during the aging process likely relies upon the coherent regulation of hormonal and neuronal communication between the central nervous system and the periphery. Evidence has demonstrated that the optimal regulation of energy usage in both these systems facilitates healthy aging. However, the proteomic effects of aging in regions of the brain vital for integrating energy balance and neuronal activity are not well understood. The hypothalamus is one of the main structures in the body responsible for sustaining an efficient interaction between energy balance and neurological activity. Therefore, a greater understanding of the effects of aging in the hypothalamus may reveal important aspects of overall organismal aging and may potentially reveal the most crucial protein factors supporting this vital signaling integration. In this study, we examined alterations in protein expression in the hypothalami of young, middle-aged, and old rats. Using novel combinatorial bioinformatics analyses, we were able to gain a better understanding of the proteomic and phenotypic changes that occur during the aging process and have potentially identified the G protein-coupled receptor/cytoskeletal-associated protein GIT2 as a vital integrator and modulator of the normal aging process

Relating Differently to Intrusive Images: The Impact of Mindfulness Based Cognitive Therapy (MBCT) on Intrusive Images in Patients With Severe Health Anxiety (Hypochondriasis).

Recurrent distressing intrusive images are a common experience in hypochondriasis. The aim of the current study was to assess the impact of Mindfulness-Based Cognitive Therapy (MBCT) for hypochondriasis on the occurrence and nature of distressing intrusive imagery in hypochondriasis. A semi-structured interview was used to assess intrusive imagery, and an adapted version of the Southampton Mindfulness Questionnaire (SMQ) was used to assess participants’ relationship with their intrusive images. A consecutive series of participants (N = 20) who were receiving MBCT for hypochondriasis as part of an ongoing research program were assessed prior to participating in an 8-week MBCT intervention, immediately following the intervention, and at three month follow-up. As compared to the baseline assessment, the frequency of intrusive images, the distress associated with them, and the intrusiveness of the images were all significantly reduced at the post-MBCT assessment. Participants’ adapted SMQ scores were significantly increased following the MBCT intervention, suggesting that participants’ relationship with their intrusive images had changed in that they had developed a more ‘mindful’ and compassionate response to the images when they did occur. Effect sizes from pre- to post-intervention were medium to large (Cohen’s d = 0.75 - 1.50). All treatment gains were maintained at 3 month follow-up. Results suggest that MBCT may be an effective intervention for addressing intrusive imagery in hypochondriasis

A Qualitative Analysis of Experiential Challenges Associated with Meditation Practice

Although empirical interest in meditation has flourished in recent years, few studies have addressed possible downsides of meditation practice, particularly in community populations. In-depth interviews were conducted with 30 male meditators in London, UK, recruited using principles of maximum variation sampling, and analysed using a modified constant comparison approach. Having originally set out simply to inquire about the impact of various meditation practices (including but not limited to mindfulness) on men’s wellbeing, we uncovered psychological challenges associated with its practice. While meditation was generally reported to be conducive to wellbeing, substantial difficulties accounted for approximately one quarter of the interview data. Our paper focuses specifically on these issues in order to alert health professionals to potential challenges associated with meditation. Four main problems of increasing severity were uncovered: Meditation was a difficult skill to learn and practise; participants encountered troubling thoughts and feelings which were hard to manage; meditation reportedly exacerbated mental health issues, such as depression and anxiety; and in a few cases, meditation was associated with psychotic episodes. Our paper raises important issues around safeguarding those who practise meditation, both within therapeutic settings and in the community

Novel Use of Surveillance Data to Detect HIV-Infected Persons with Sustained High Viral Load and Durable Virologic Suppression in New York City

Background: Monitoring of the uptake and efficacy of ART in a population often relies on cross-sectional data, providing limited information that could be used to design specific targeted intervention programs. Using repeated measures of viral load (VL) surveillance data, we aimed to estimate and characterize the proportion of persons living with HIV/AIDS (PLWHA) in New York City (NYC) with sustained high VL (SHVL) and durably suppressed VL (DSVL). Methods/Principal Findings: Retrospective cohort study of all persons reported to the NYC HIV Surveillance Registry who were alive and $12 years old by the end of 2005 and who had$2 VL tests in 2006 and 2007. SHVL and DSVL were defined as PLWHA with 2 consecutive VLs $100,000 copies/mL and PLWHA with all VLs #400 copies/mL, respectively. Logistic regression models using generalized estimating equations were used to model the association between SHVL and covariates. There were 56,836 PLWHA, of whom 7 % had SHVL and 38 % had DSVL. Compared to those without SHVL, persons with SHVL were more likely to be younger, black and have injection drug use (IDU) risk. PLWHA with SHVL were more likely to die by 2007 and be younger by nearly ten years, on average. Conclusions/Significance: Nearly 60 % of PLWHA in 2005 had multiple VLs, of whom almost 40 % had DSVL, suggesting successful ART uptake. A small proportion had SHVL, representing groups known to have suboptimal engagement in care. This group should be targeted for additional outreach to reduce morbidity and secondary transmission. Measures based o

On the typology and the worship status of sacred trees with a special reference to the Middle East

This article contains the reasons for the establishment of sacred trees in Israel based on a field study. It includes 97 interviews with Muslim and Druze informants. While Muslims (Arabs and Bedouins) consider sacred trees especially as an abode of righteous figures' (Wellis') souls or as having a connection to their graves, the Druze relate sacred trees especially to the events or deeds in the lives of prophets and religious leaders. A literary review shows the existence of 24 known reasons for the establishment of sacred trees worldwide, 11 of which are known in Israel one of these is reported here for the first time. We found different trends in monotheistic and polytheistic religions concerning their current worship of sacred trees

The supernatural characters and powers of sacred trees in the Holy Land

This article surveys the beliefs concerning the supernatural characteristics and powers of sacred trees in Israel; it is based on a field study as well as a survey of the literature and includes 118 interviews with Muslims and Druze. Both the Muslims and Druze in this study attribute supernatural dimensions to sacred trees which are directly related to ancient, deep-rooted pagan traditions. The Muslims attribute similar divine powers to sacred trees as they do to the graves of their saints; the graves and the trees are both considered to be the abode of the soul of a saint which is the source of their miraculous powers. Any violation of a sacred tree would be strictly punished while leaving the opportunity for atonement and forgiveness. The Druze, who believe in the transmigration of souls, have similar traditions concerning sacred trees but with a different religious background. In polytheistic religions the sacred grove/forest is a centre of the community's official worship; any violation of the trees is regarded as a threat to the well being of the community. Punishments may thus be collective. In the monotheistic world (including Christianity, Islam and Druze) the pagan worship of trees was converted into the worship/adoration of saints/prophets; it is not a part of the official religion but rather a personal act and the punishments are exerted only on the violating individual

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca