Genome and clonal hematopoiesis stability contrasts with immune, cfDNA, mitochondrial, and telomere length changes during short duration spaceflight

BACKGROUND: The Inspiration4 (I4) mission, the first all-civilian orbital flight mission, investigated the physiological effects of short-duration spaceflight through a multi-omic approach. Despite advances, there remains much to learn about human adaptation to spaceflight\u27s unique challenges, including microgravity, immune system perturbations, and radiation exposure. METHODS: To provide a detailed genetics analysis of the mission, we collected dried blood spots pre-, during, and post-flight for DNA extraction. Telomere length was measured by quantitative PCR, while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations. A robust bioinformatic pipeline was used for data analysis, including variant calling to assess mutational burden. RESULT: Telomere elongation occurred during spaceflight and shortened after return to Earth. Cell-free DNA analysis revealed increased immune cell signatures post-flight. No significant clonal hematopoiesis of indeterminate potential (CHIP) or whole-genome instability was observed. The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight. CONCLUSION: Our findings provide valuable insights into the physiological consequences of short-duration spaceflight, with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to Earth. CHIP sequencing data will serve as a reference point for studying the early development of CHIP in astronauts, an understudied phenomenon as previous studies have focused on career astronauts. This study will serve as a reference point for future commercial and non-commercial spaceflight, low Earth orbit (LEO) missions, and deep-space exploration

MAPPING SEA CLIFFS ON DOMINICA USING PHOTO MOSAICS

Mapping on islands covered by rain forest presents challenges due to the extremely limited exposure of bedrock. In general, exposures are limited to road cuts, quarries, and sea cliffs. While the first two are easily accessible, the last one provides the most reliable series of exposures for most islands, and generally forms the largest exposures. However, these outcrops are frequently difficult to impossible to reach from land, due to a lack of roads and/or strong surf right to the bases of the cliffs. Therefore, in July 2007, we chartered a boat to circumnavigate the island of Dominica in the Lesser Antilles to map and photograph the sea cliffs all around the island. The results provide modifications to the published geological map of the island and hitherto unknown details on the geology of the Miocene, Pliocene, and Pleistocene-to-Recent volcanic centers. For example, an area previously mapped as part of the oldest sequence on the island (Miocene), has been identified as a megabreccia that is part of the Pleistocene sequence of the Grande Soufriere Hills volcanic center, and is now identified as much more extensive than was known from exposures accessible from land. Detailed stratigraphic sections of selected sequences will be presented to illustrate the effectiveness of this technique

Synthetic DNA immunotherapy in biochemically relapsed prostate cancer

Background: INO-5150 (PSA and PSMA) +/- INO-9012 (IL-12), a synthetic DNA immunotherapy, was assessed for safety, immunogenicity and efficacy in biochemically recurrent prostate cancer patients (pts). Methods: Phase I, open-label, multi-center study in the US included pts with rising PSA after surgery and/or RT, PSA doubling time (PSADT) \u3e3 months (mos), testosterone \u3e150 ng/dL and no concurrent ADT. Safety, immunogenicity and efficacy (PSA kinetics, PFS) were evaluated in 4 treatment arms of 15 pts each. Arms A: 2mg INO-5150, B: 8.5 mg INO-5150, C: 2mg INO-5150 + 1mg INO-9012 and D: 8.5mg INO-5150 + 1mg INO-9012. Pts received 4 IM doses of vaccine followed by electroporation on day 0, wks 3, 12 and 24 and were followed for 72 wks. Results: 50/61 (82%) pts completed all visits and treatments were well tolerated with no safety concerns. Median PFS for overall population [N = 61, baseline (D0) PSADT range (mos) 1.5-217.1, median 9.8] and for a subset of pts with D0 PSADT ≤12mos (N = 36) has not yet been reached (FU 3-19 mos). 86% of pts with D0 PSADT ≤12 mos were progression free through 19mos FU. 27 out of 36 (75%) pts with D0 PSADT≤ 12 mos had disease stabilization at wks 27 evidenced by significant improvement in log2PSA change over time (slope) and PSADT from D0 (Slope=0.19 declined to 0.1, PSADT=5.3 improved to 10.1 mos, p = \u3c0.0001). This effect was maintained at wk 72 (Slope=0.09, PSADT=10.6, p = \u3c0.0001). Immunogenicity was observed in 77% (47/61) of pts by multiple immunologic assessments. Patient immunogenicity to INO-5150 as determined by CD38 and Perforin + CD8 T cell immune reactivity correlated with attenuated % PSA rise compared to pts without reactivity (p = 0.05, n = 50). Conclusions: INO-5150 +/- INO-9012 was safe, well tolerated and immunogenic. Clinical efficacy was observed in the patients with D0 PSADT≤ 12 mos as evidenced by a significant dampening of log2PSA change over time and increased PSADT up to 72 weeks FU. Additional genomic analyses are ongoing to further elucidate the correlation of immunologic efficacy and clinical benefit. (NCT02514213)

Lesiones faciales en niños y adolescentes víctimas de agresiones

Child maltreatment may occur as the intentional use of power, effective or attempted, against children under 18 years old, that results or may result in actual or potential harm. It affects a vulnerable population, causing physical and/or emotional consequences persisting throughout their lives. This study aimed to characterize episodes of child maltreatment, with focus on facial injuries, in a Brazilian city (Teresina, PI). This is a retrospective study with a quantitative approach, carried out in the database at the Institute of Forensic MedicineinTeresina, between the years 2017 and 2019. All reports of bodily injury of children from 0 to 18 years were collected and statistically analyzed (SPSS 22.0). During the period analysis, 811 reports of bodily injury were identified. There was a predominance of female victims aged between 12 and 18 years old, the involvement of men with some family relationship with the victim was highly associated. Facial injuries represented 35.8% of the whole sample and 98.6% of those found in the head and neck region (41,6% of the total). The orbital (29.0%) was the most affected site, followed by the frontal (25.9%), malar (23.4%), labial (17.6%) and cheek area (11.4%). There is a high prevalence of injuries to the head and neck region, this factemphasizes the importance of a trained professional, especially a dental surgeon, in the analysis and interpretation of these injuries during forensic examination.info:eu-repo/semantics/publishedVersio

Glucose-lactate metabolic cooperation in cancer: insights from a spatial mathematical model and implications for targeted therapy

A recent study has hypothesised a glucose–lactate metabolic symbiosis between adjacent hypoxic and oxygenated regions of a developing tumour, and proposed a treatment strategy to target this symbiosis. However, in vivo experimental support remains inconclusive. Here we develop a minimal spatial mathematical model of glucose–lactate metabolism to examine, in principle, whether metabolic symbiosis is plausible in human tumours, and to assess the potential impact of inhibiting it. We find that symbiosis is a robust feature of our model system—although on the length scale at which oxygen supply is diffusion-limited, its occurrence requires very high cellular metabolic activity—and that necrosis in the tumour core is reduced in the presence of symbiosis. Upon simulating therapeutic inhibition of lactate uptake, we predict that targeted treatment increases the extent of tissue oxygenation without increasing core necrosis. The oxygenation effect is correlated strongly with the extent of wild-type hypoxia and only weakly with wild-type symbiotic behaviour, and therefore may be promising for radiosensitisation of hypoxic, lactate-consuming tumours even if they do not exhibit a spatially well-defined symbiosis. Finally, we conduct in vitro experiments on the U87 glioblastoma cell line to facilitate preliminary speculation as to where highly malignant tumours might fall in our parameter space, and find that these experiments suggest a weakly symbiotic regime for U87 cells, thus raising the new question of what relationship might exist between symbiosis and tumour malignancy

Health professionals’ responses to women’s disclosure of domestic violence

This is the author's PDF version of an article published in Journal of Interpersonal Violence© 2014. The definitive version is available at http:dx.doi.org/10.1177/0886260514552449This study explored women’s experiences of their responses from health professionals following disclosure of domestic violence within a health setting. The existence of health based policies guiding professionals in the provision of appropriate support following disclosure of domestic violence is only effective if health professionals understand the dynamics of violent relationships. This paper focuses on the findings from the interviews conducted with fifteen women living in the UK who disclosed their experiences of domestic violence when accessing healthcare. Following thematic analysis, themes emerged that rotated around their disclosure and the responses they received from health professionals. The first two themes revealed the repudiation of, or recognition of and failure to act upon, domestic violence. A description of how the health professional’s behaviour became analogous with that of the perpetrator is discussed. The final theme illuminated women’s’ receipt of appropriate and sensitive support, leading to a positive trajectory away from a violent relationship. The findings suggest that the implicit understanding of the dynamics of violent relationships and the behaviours of the perpetrator of domestic violence are essential components of health care provision to avoid inadvertent inappropriate interactions with women

Active learning across disciplines : opportunities to develop employability skills and leadership potential in undergraduate students. A student and staff perspective

Working effectively within multidisciplinary teams is an important employability skill common in postgraduate working life, but opportunities to develop this are limited in many undergraduate taught programmes. The projects reported here offered twelve level 5 undergraduate students from a range of science disciplines the opportunity to work with each other and staff on a specific research question. This paper explores the experience of cross-disciplinary research from both the student and staff research partners’ perspectives. In particular the employability skills gained from such partnership working, the potential for developing and demonstrating leadership skills, and the benefits and disadvantages are discussed

Design and Fabrication of Oxygen/RP-2 Multi-Element Oxidizer-Rich Staged Combustion Thrust Chamber Injectors

As part of the Combustion Stability Tool Development project funded by the Air Force Space and Missile Systems Center, the NASA Marshall Space Flight Center was contracted to assemble and hot-fire test a multi-element integrated test article demonstrating combustion characteristics of an oxygen/hydrocarbon propellant oxidizer-rich staged-combustion engine thrust chamber. Such a test article simulates flow through the main injectors of oxygen/kerosene oxidizer-rich staged combustion engines such as the Russian RD-180 or NK-33 engines, or future U.S.-built engine systems such as the Aerojet-Rocketdyne AR-1 engine or the Hydrocarbon Boost program demonstration engine. On the current project, several configurations of new main injectors were considered for the thrust chamber assembly of the integrated test article. All the injector elements were of the gas-centered swirl coaxial type, similar to those used on the Russian oxidizer-rich staged-combustion rocket engines. In such elements, oxidizer-rich combustion products from the preburner/turbine exhaust flow through a straight tube, and fuel exiting from the combustion chamber and nozzle regenerative cooling circuits is injected near the exit of the oxidizer tube through tangentially oriented orifices that impart a swirl motion such that the fuel flows along the wall of the oxidizer tube in a thin film. In some elements there is an orifice at the inlet to the oxidizer tube, and in some elements there is a sleeve or "shield" inside the oxidizer tube where the fuel enters. In the current project, several variations of element geometries were created, including element size (i.e., number of elements or pattern density), the distance from the exit of the sleeve to the injector face, the width of the gap between the oxidizer tube inner wall and the outer wall of the sleeve, and excluding the sleeve entirely. This paper discusses the design rationale for each of these element variations, including hydraulic, structural, thermal, combustion performance, and combustion stability considerations. This paper also discusses the fabrication and assembly of the injector components, including the injector body/interpropellant plate, the additive manufactured GRCop-84 faceplate, and the pieces that make up the injector elements including the oxidizer tube, an inlet to the oxidizer tube, and a facenut that includes the fuel tangential inlets and forms the initial recessed volume where oxidizer and fuel first interact. Hot-fire test results of these main injector designs in an integrated test article that includes an oxidizer-rich preburner are described in companion papers at this JANNAF meeting

Radiative corrections to low energy neutrino reactions

We show that the radiative corrections to charged current (CC) nuclear reactions with an electron(positron) in the final state are described by a universal function. The consistency of our treatment of the radiative corrections with the procedure used to extract the value of the axial coupling constant $g_A$ is discussed. To illustrate we apply our results to (anti)neutrino deuterium disintegration and to $pp$ fusion in the sun. The limit of vanishing electron mass is considered, and a simple formula valid for E_{obs}\gsim 1 MeV is obtained. The size of the nuclear structure-dependent effects is also discussed. Finally, we consider CC transitions with an electron(positron) in the initial state and discuss some applications to electron capture reactions.Comment: 23 pages, 5 figure

MAP4K4 impairs energy metabolism in endothelial cells and promotes insulin resistance in obesity

The blood vasculature responds to insulin, influencing hemodynamic changes in the periphery, which promotes tissue nutrient and oxygen delivery and thus metabolic function. The lymphatic vasculature regulates fluid and lipid homeostasis, and impaired lymphatic function can contribute to atherosclerosis and obesity. Recent studies have suggested a role for endothelial cell (EC) Mitogen activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and lymphangiogenesis as well as atherosclerosis. Here, we show that inducible EC Map4k4 deletion in adult mice ameliorates metabolic dysfunction in obesity despite the development of chylous ascites and a concomitant striking increase in adipose tissue lymphocyte content. Despite these defects, animals lacking endothelial Map4k4 were protected from skeletal muscle microvascular rarefaction in obesity, and primary ECs lacking Map4k4 displayed reduced senescence and increased metabolic capacity. Thus, endothelial Map4k4 has complex and opposing functions in the blood and lymphatic endothelium post-development. Whereas blood endothelial Map4k4 promotes vascular dysfunction and impairs glucose homeostasis in adult animals, lymphatic endothelial Map4k4 is required to maintain lymphatic vascular integrity and regulate immune cell trafficking in obesity