Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

The effect of calcium and vitamin D supplementation on bone health of male Jockeys

Objectives: Engagement in high volumes of physical activity coupled with energy restriction during periods of musculoskeletal development may compromise bone health. Jockeys limit caloric intakes on a weekly basis often from their mid-to-late teens. The aim of this study was to establish whether calcium and vitamin Dsupplementation would improve bone turnover markers (BTM) and non-weight bearing bone properties of young male jockeys. Design: A six-month randomised, double-blinded, placebo-controlled trial with two groups of apprentice male jockeys was conducted. Methods: Participants (age 20.18 ± 3.23 years) were supplemented with 800 mg of calcium and 400 IU of vitamin D (n = 8) or a placebo (n = 9) daily. Bone properties were assessed at the ultra-distal (4%) and proximal (66%) radius using pQCT at baseline and six months. Vitamin D, P1NP and CTX were assessed. Results: ANCOVA results for blood-borne markers indicated higher vitamin D levels (18.1%, p = 0.014, partial η2 = 0.38) and lower CTX (ng·L−1) (−24.8%, p = 0.011, partial η2 = 0.40) in the supplemented group with no differences observed in P1NP. Analysis of bone variables indicated no between group differences in either trabecular or cortical bone properties at the 4% and 66% sites post-intervention. Conclusions: This trial is the first to examine the efficacy of calcium and vitamin D supplementation in improving non-weight bearing bone properties in a young male athletic population. Results indicate positive alterations to bone metabolism; however, longer duration or higher dosage appears to be required to detect changes in bone material properties at the radius. Further examination of such interventions in weight-restricted athletes is warranted

Exercise performance over the menstrual cycle in temperate and hot, humid conditions

Purpose: This study investigated the effects of the menstrual cycle on prolonged exercise performance both in temperate (20°C, 45% relative humidity) and hot, humid (32°C, 60% relative humidity) conditions. Methods: For each environmental condition, 12 recreationally active females were tested during the early follicular (day 3–6) and midluteal (day 19–25) phases, verified by measurement of estradiol and progesterone. For all four tests, thermoregulatory, cardiorespiratory, and perceptual responses were measured during 60 min of exercise at 60% of maximal oxygen consumption followed by an incremental test to exhaustion. Results: No differences in exercise performance between menstrual cycle phases were found during temperate conditions (n = 8) despite a higher resting and submaximal exercise core temperature (Tc) in the luteal phase. In hot, humid conditions (n = 8), however, prolonged exercise performance, as exercise time to fatigue, was significantly reduced during the luteal phase. This finding was not only accompanied by higher resting and submaximal exercise Tc but also a higher rate of increase in Tc during the luteal phase. Furthermore, submaximal exercise HR, minute ventilation, and RPE measures were higher during the luteal phase in hot, humid conditions. No significant differences were found over the menstrual cycle in heat loss responses (partitional calorimetry, sweat rate, upper arm sweat composition) and Tc at exhaustion. Conclusion: In temperate conditions, no changes in prolonged exercise performance were found over the menstrual cycle, whereas in hot, humid conditions, performance was decreased during the luteal phase. The combination of both exercise and heat stress with the elevated luteal phase Tc at the onset of exercise resulted in physiological and perceptual changes and a greater thermosensitivity, which may explain the decrease in performance

Consuming ethics: articulating the subjects and spaces of ethical consumption

Geography’s debates about how to maintain a sense of morally responsible action often emphasise the problematic nature of caring at a distance, and take for granted particular kinds of moral selfhood in which responsibility is bound into notions of human agency that emphasise knowledge and recognition.Taking commodity consumption as a field in which the ethics, morality, and politics of responsibility has been problematised, we argue that existing research on consumption fails to register the full complexity of the practices, motivations and mechanisms through which the working-up of moral selves is undertaken in relation to consumption practices. Rather than assuming that ethical decision-making works through the rational calculation of obligations, we conceptualise the emergence of ethical consumption as ways in which everyday practical moral dispositions are re-articulated by policies, campaigns and practices that enlist ordinary people into broader projects of social change. Ethical consumption, then, involves both a governing of consumption and a governing of the consuming self. Using the example of Traidcraft, we present a detailed examination of one particular context in which self-consciously ethical consumption is mediated, suggesting that ethical consumption can be understood as opening up ethical and political considerations in new combinations. We therefore argue for the importance of the growth of ethical consumption as a new terrain of political action, while also emphasising the grounds upon which ethical consumption can be opened up to normative critique