Peritoneal perfusion with oxygenated perfluorocarbon augments systemic oxygenation.

BACKGROUND: Despite maximal ventilatory support, many patients die from hypoxia in the setting of potentially reversible pulmonary failure. There remains a pressing need for additional pulmonary supportive care measures, especially techniques that do not require systemic anticoagulation. The objective of our experiments was to determine whether systemic oxygenation could be increased in a large animal, with induced hypoxia, by perfusing the abdominal cavity with oxygenated perfluorocarbons. METHODS: Fifteen pigs with a mean (+/- SD) weight of 45 +/- 5 kg were intubated and rendered hypoxic by ventilating them with a blend of nitrogen and oxygen to achieve subatmospheric concentrations of inspired oxygen ranging from 18 to 10%, resulting in baseline mean Pao(2) range of 65.9 +/- 9.7 to 26.6 +/- 2.8 mm Hg, respectively. Peritoneal perfusion was performed in eight animals with oxygenated perfluorocarbon and in seven control animals with oxygenated saline solution. RESULTS: The average increase in Pao(2) with oxygenated perfluorocarbon perfusion, compared to oxygenated saline solution perfusion, ranged from 8.1 to 18.2 mm Hg. A common treatment effect was estimated across all fraction of inspired oxygen (Fio(2)) values, representing the average mean difference in oxygen uptake between oxygenated perfluorocarbon and saline solution, irrespective of the level of Fio(2). This average was 12.8 mm Hg (95% confidence interval, 7.4 to 18.2; p \u3c 0.001). The most clinically relevant results occurred at an Fio(2) of 14%, resulting in a baseline mean Pao(2) of 39.4 +/- 5.0 mm Hg with oxygenated saline solution perfusion, and a mean Pao(2) of 55.3 +/- 7.6 mm Hg with oxygenated perfluorocarbon perfusion. This corresponded to an increase in arterial oxygen saturation from 73 to 89%. CONCLUSION: These results of our principle experiments demonstrate that the peritoneal cavity can be used for gas exchange and, in our model, yielded clinically relevant increases in systemic arterial oxygen levels. This technique may have the potential for the supportive care of patients dying from hypoxia in the setting of reversible lung injury

Water Throughout the Green Energy Transition: Hydrosocial Dimensions of Coal, Natural Gas, and Lithium

Energy transitions are reshaping hydrosocial relations. How they will be reshaped, however, depends on location and water\u27s material relationship to other resources and industrial activities embedded within energy transitions. To highlight this, we focus on three different resources—coal, natural gas, and lithium—to signal how the water–energy nexus will be reworked in a transition away from fossil fuels. We examine the water–coal nexus as an example of a resource relationship that is transitioning out, or that is being moved away from in the green energy transition. Natural gas represents the “bridge fuel” used through the transition. Lithium illustrates a resource inside the green transition, as it is a fundamental material for green technologies in the transition to a low-carbon future. Coal, natural gas, and lithium each have their own material impacts to water resources that stem from their industrial lifecycle and different implications for communities shaped by coal, natural gas, and lithium activities. To explore this, we review each of these resources\u27 connection to water, their legal and regulatory dimensions, and their impact on communities and water justice. We argue that the energy transition is also a hydrosocial transition that will create uneven water-related benefits and burdens. To maximize sustainability and equity, efforts to decarbonize energy systems must examine the localized, place-based hydrosocial relations that differentially affect communities

Traumatic brain injury: future assessment tools and treatment prospects

Traumatic brain injury (TBI) is widespread and leads to death and disability in millions of individuals around the world each year. Overall incidence and prevalence of TBI are likely to increase in absolute terms in the future. Tackling the problem of treating TBI successfully will require improvements in the understanding of normal cerebral anatomy, physiology, and function throughout the lifespan, as well as the pathological and recuperative responses that result from trauma. New treatment approaches and combinations will need to be targeted to the heterogeneous needs of TBI populations. This article explores and evaluates the research evidence in areas that will likely lead to a reduction in TBI-related morbidity and improved outcomes. These include emerging assessment instruments and techniques in areas of structural/chemical and functional neuroimaging and neuropsychology, advances in the realms of cell-based therapies and genetics, promising cognitive rehabilitation techniques including cognitive remediation and the use of electronic technologies including assistive devices and virtual reality, and the emerging field of complementary and alternative medicine

Inhibition of BACH1 (FANCJ) helicase by backbone discontinuity is overcome by increased motor ATPase or length of loading strand

The BRCA1 associated C-terminal helicase (BACH1) associated with breast cancer has been implicated in double strand break (DSB) repair. More recently, BACH1 (FANCJ) has been genetically linked to the chromosomal instability disorder Fanconi Anemia (FA). Understanding the roles of BACH1 in cellular DNA metabolism and how BACH1 dysfunction leads to tumorigenesis requires a comprehensive investigation of its catalytic mechanism and molecular functions in DNA repair. In this study, we have determined that BACH1 helicase contacts with both the translocating and the non-translocating strands of the duplex are critical for its ability to track along the sugar phosphate backbone and unwind dsDNA. An increased motor ATPase of a BACH1 helicase domain variant (M299I) enabled the helicase to unwind the backbone-modified DNA substrate in a more proficient manner. Alternatively, increasing the length of the 5′ tail of the DNA substrate allowed BACH1 to overcome the backbone discontinuity, suggesting that BACH1 loading mechanism is critical for its ability to unwind damaged DNA molecules

A genetic ensemble approach for gene-gene interaction identification

<p>Abstract</p> <p>Background</p> <p>It has now become clear that gene-gene interactions and gene-environment interactions are ubiquitous and fundamental mechanisms for the development of complex diseases. Though a considerable effort has been put into developing statistical models and algorithmic strategies for identifying such interactions, the accurate identification of those genetic interactions has been proven to be very challenging.</p> <p>Methods</p> <p>In this paper, we propose a new approach for identifying such gene-gene and gene-environment interactions underlying complex diseases. This is a hybrid algorithm and it combines genetic algorithm (GA) and an ensemble of classifiers (called genetic ensemble). Using this approach, the original problem of SNP interaction identification is converted into a data mining problem of combinatorial feature selection. By collecting various single nucleotide polymorphisms (SNP) subsets as well as environmental factors generated in multiple GA runs, patterns of gene-gene and gene-environment interactions can be extracted using a simple combinatorial ranking method. Also considered in this study is the idea of combining identification results obtained from multiple algorithms. A novel formula based on pairwise <it>double fault </it>is designed to quantify the degree of complementarity.</p> <p>Conclusions</p> <p>Our simulation study demonstrates that the proposed genetic ensemble algorithm has comparable identification power to Multifactor Dimensionality Reduction (MDR) and is slightly better than Polymorphism Interaction Analysis (PIA), which are the two most popular methods for gene-gene interaction identification. More importantly, the identification results generated by using our genetic ensemble algorithm are highly complementary to those obtained by PIA and MDR. Experimental results from our simulation studies and real world data application also confirm the effectiveness of the proposed genetic ensemble algorithm, as well as the potential benefits of combining identification results from different algorithms.</p

Mosaic: A Satellite Constellation to Enable Groundbreaking Mars Climate System Science and Prepare for Human Exploration

The Martian climate system has been revealed to rival the complexity of Earth\u27s. Over the last 20 yr, a fragmented and incomplete picture has emerged of its structure and variability; we remain largely ignorant of many of the physical processes driving matter and energy flow between and within Mars\u27 diverse climate domains. Mars Orbiters for Surface, Atmosphere, and Ionosphere Connections (MOSAIC) is a constellation of ten platforms focused on understanding these climate connections, with orbits and instruments tailored to observe the Martian climate system from three complementary perspectives. First, low-circular near-polar Sun-synchronous orbits (a large mothership and three smallsats spaced in local time) enable vertical profiling of wind, aerosols, water, and temperature, as well as mapping of surface and subsurface ice. Second, elliptical orbits sampling all of Mars\u27 plasma regions enable multipoint measurements necessary to understand mass/energy transport and ion-driven escape, also enabling, with the polar orbiters, dense radio occultation coverage. Last, longitudinally spaced areostationary orbits enable synoptic views of the lower atmosphere necessary to understand global and mesoscale dynamics, global views of the hydrogen and oxygen exospheres, and upstream measurements of space weather conditions. MOSAIC will characterize climate system variability diurnally and seasonally, on meso-, regional, and global scales, targeting the shallow subsurface all the way out to the solar wind, making many first-of-their-kind measurements. Importantly, these measurements will also prepare for human exploration and habitation of Mars by providing water resource prospecting, operational forecasting of dust and radiation hazards, and ionospheric communication/positioning disruptions

A Deep Catalogue of Protein-Coding Variation in 983,578 Individuals

Rare coding variants that substantially affect function provide insights into the biology of a gene1-3. However, ascertaining the frequency of such variants requires large sample sizes4-8. Here we present a catalogue of human protein-coding variation, derived from exome sequencing of 983,578 individuals across diverse populations. In total, 23% of the Regeneron Genetics Center Million Exome (RGC-ME) data come from individuals of African, East Asian, Indigenous American, Middle Eastern and South Asian ancestry. The catalogue includes more than 10.4 million missense and 1.1 million predicted loss-of-function (pLOF) variants. We identify individuals with rare biallelic pLOF variants in 4,848 genes, 1,751 of which have not been previously reported. From precise quantitative estimates of selection against heterozygous loss of function (LOF), we identify 3,988 LOF-intolerant genes, including 86 that were previously assessed as tolerant and 1,153 that lack established disease annotation. We also define regions of missense depletion at high resolution. Notably, 1,482 genes have regions that are depleted of missense variants despite being tolerant of pLOF variants. Finally, we estimate that 3% of individuals have a clinically actionable genetic variant, and that 11,773 variants reported in ClinVar with unknown significance are likely to be deleterious cryptic splice sites. To facilitate variant interpretation and genetics-informed precision medicine, we make this resource of coding variation from the RGC-ME dataset publicly accessible through a variant allele frequency browser