Abstract X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in ...SH2D1A . In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant clinical phenotype. Among 25 symptomatic patients diagnosed with XIAP deficiency, we identified 17 patients who initially presented with manifestations other than HLH. These included Crohn-like bowel disease (n = 6), severe infectious mononucleosis (n = 4), isolated splenomegaly (n = 3), uveitis (n = 1), periodic fever (n = 1), fistulating skin abscesses (n = 1) and severe Giardia enteritis (n = 1). Subsequent manifestations included celiac-like disease, antibody deficiency, splenomegaly and partial HLH. Screening by flow cytometry identified 14 of 17 patients in our cohort. However, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients. XIAP deficiency must be considered in a wide range of clinical presentations.
Electrochemical CO2 reduction is a promising process to store intermittent renewable energy in the form of chemical bonds and to meet the demand for hydrocarbon chemicals without relying on fossil ...fuels. Researchers in the field have used gas diffusion electrodes (GDEs) to supply CO2 to the catalyst layer from the gas phase. This approach allows us to bypass mass transfer limitations imposed by the limited solubility and diffusion of CO2 in the liquid phase at a laboratory scale. However, at a larger scale, pressure differences across the porous gas diffusion layer can occur. This can lead to flooding and electrolyte breakthrough, which can decrease performance. The aim of this study is to understand the effects of the GDE structure on flooding behavior and CO2 reduction performance. We approach the problem by preparing GDEs from commercial substrates with a range of structural parameters (carbon fiber structure, thickness, and cracks). We then determined the liquid breakthrough pressure and measured the Faradaic efficiency for CO at an industrially relevant current density. We found that there is a trade-off between flooding resistance and mass transfer capabilities that limits the maximum GDE height of a flow-by electrolyzer. This trade-off depends strongly on the thickness and the structure of the carbon fiber substrate. We propose a design strategy for a hierarchically structured GDE, which might offer a pathway to an industrial scale by avoiding the trade-off between flooding resistance and CO2 reduction performance.
Malaria vector control relies on toxicity of insecticides used in long lasting insecticide treated nets and indoor residual spraying. This is despite evidence that sub-lethal insecticides reduce ...human-vector contact and malaria transmission. The impact of sub-lethal insecticides on host seeking and blood feeding of mosquitoes was measured. Taxis boxes distinguished between repellency and attraction inhibition of mosquitoes by measuring response of mosquitoes towards or away from Transfluthrin coils and humans. Protective effective distance of coils and long-term effects on blood feeding were measured in the semi-field tunnel and in a Peet Grady chamber. Laboratory reared pyrethroid susceptible Anopheles gambiae sensu stricto mosquitoes were used. In the taxis boxes, a higher proportion of mosquitoes (67%-82%) were activated and flew towards the human in the presence of Transfluthrin coils. Coils did not hinder attraction of mosquitoes to the human. In the semi-field Tunnel, coils placed 0.3 m from the human reduced feeding by 86% (95% CI 0.66; 0.95) when used as a "bubble" compared to 65% (95% CI 0.51; 0.76) when used as a "point source". Mosquitoes exposed to coils inside a Peet Grady chamber were delayed from feeding normally for 12 hours but there was no effect on free flying and caged mosquitoes exposed in the semi-field tunnel. These findings indicate that airborne pyrethroids minimize human-vector contact through reduced and delayed blood feeding. This information is useful for the development of target product profiles of spatial repellent products that can be used to complement mainstream malaria vector control tools.
Imidacloprid is a neonicotinoid pesticide heavily used by the agricultural industry and shown to have negative impacts on honey bees above certain concentrations. We evaluated the effects of ...different imidacloprid concentrations in sugar syrup using cage and field studies, and across different environments. Honey bee colonies fed sublethal concentrations of imidicloprid (0, 5, 20 and 100 ppb) over 6 weeks in field trials at a desert site (Arizona), a site near intensive agriculture (Arkansas) and a site with little nearby agriculture but abundant natural forage (Mississippi) were monitored with respect to colony metrics, such as adult bee and brood population sizes, as well as pesticide residues. Hive weight and internal hive temperature were monitored continuously over two trials in Arizona. Colonies fed 100 ppb imidacloprid in Arizona had significantly lower adult bee populations, brood surface areas and average frame weights, and reduced temperature control, compared to colonies in one or more of the other treatment groups, and consumption rates of those colonies were lower compared to other colonies in Arizona and Arkansas, although no differences in capped brood or average frame weight were observed among treatments in Arkansas. At the Mississippi site, also rich in alternative forage, colonies fed 5 ppb imidacloprid had less capped brood than control colonies, but contamination of control colonies was detected. In contrast, significantly higher daily hive weight variability among colonies fed 5 ppb imidacloprid in Arizona suggested greater foraging activity during a nectar flow post treatment, than any other treatment group. Imidacloprid concentrations in stored honey corresponded well with the respective syrup concentrations fed to the colonies and remained stable within the hive for at least 7 months after the end of treatment.
Electronic devices contain important resources, including precious and critical raw materials. For an efficient management of these resources, it is important to know where the devices are located, ...how long they are used and when and how they are disposed of. In this article, we explore the past and current quantities of electronic devices in the in-use stock and storage stock in Switzerland and quantify the flows between the use, storage and disposal phase with dynamic material flow analysis (MFA). Devices included are mobile phones, desktop and laptop computers, monitors, cathode ray tube and flat panel display televisions, DVD players, and headphones. The system for the dynamic MFA was developed as a cascade model dividing the use phase in first, second and further use, with each of these steps consisting of an in-use stock and a storage stock for devices. Using a customized software tool, we apply Monte Carlo simulation to systematically consider data uncertainty. The results highlight the importance of the storage stock, which accounts for 25% (in terms of mass) or 40% (in terms of pieces) of the total stock of electronic devices in 2014. Reuse and storage significantly influence the total lifetime of devices and lead to wide and positively skewed lifetime distributions.
Abstract
The mutation patterns at Cas9 targeted sites contain unique information regarding the nuclease activity and repair mechanisms in mammalian cells. However, analytical framework for extracting ...such information are lacking. Here, we present a novel computational platform called Rational InDel Meta-Analysis (RIMA) that enables an in-depth comprehensive analysis of Cas9-induced genetic alterations, especially InDels mutations. RIMA can be used to quantitate the contribution of classical microhomology-mediated end joining (c-MMEJ) pathway in the formation of mutations at Cas9 target sites. We used RIMA to compare mutational signatures at 15 independent Cas9 target sites in human A549 wildtype and A549-POLQ knockout cells to elucidate the role of DNA polymerase θ in c-MMEJ. Moreover, the single nucleotide insertions at the Cas9 target sites represent duplications of preceding nucleotides, suggesting that the flexibility of the Cas9 nuclease domains results in both blunt- and staggered-end cuts. Thymine at the fourth nucleotide before protospacer adjacent motif (PAM) results in a two-fold higher occurrence of single nucleotide InDels compared to guanine at the same position. This study provides a novel approach for the characterization of the Cas9 nucleases with improved accuracy in predicting genome editing outcomes and a potential strategy for homology-independent targeted genomic integration.
High-quality Ga2O3 thin films in the orthorhombic κ-phase are grown by pulsed-laser deposition using a tin containing target on c-sapphire, MgO(111), SrTiO3(111), and yttria-stabilized ZrO2(111) ...substrates. The structural quality of the layers is studied based on the growth parameters employing X-ray diffraction 2θ-ω scans, rocking curves, ϕ scans, and reciprocal space maps. Our layers exhibit superior crystalline properties in comparison to thin films deposited in the monoclinic β-phase at nominally identical growth parameters. Furthermore, the surface morphology is significantly improved and the root-mean-squared roughness of the layers was as low as ≈0.5 nm, on par with homoepitaxial β-Ga2O3 thin films in the literature. The orthorhombic structure of the thin films was evidenced, and the epitaxial relationships were determined for each kind of the substrate. A tin-enriched surface layer on our thin films measured by depth-resolved photoelectron spectroscopy suggests surfactant-mediated epitaxy as a possible growth mechanism. Thin films in the κ-phase are a promising alternative for β-Ga2O3 layers in electronic and optoelectronic device applications.
Non-alcoholic fatty liver disease (NAFLD) and its more severe form non-alcoholic steatohepatitis (NASH) are a major public health concern with high and increasing global prevalence, and a significant ...disease burden owing to its progression to more severe forms of liver disease and the associated risk of cardiovascular disease. Treatment options, however, remain scarce, and a better understanding of the pathological and physiological processes involved could enable the development of new therapeutic strategies. One process implicated in the pathology of NAFLD and NASH is cellular oxygen sensing, coordinated largely by the hypoxia-inducible factor (HIF) family of transcription factors. Activation of HIFs has been demonstrated in patients and mouse models of NAFLD and NASH and studies of activation and inhibition of HIFs using pharmacological and genetic tools point toward important roles for these transcription factors in modulating central aspects of the disease. HIFs appear to act in several cell types in the liver to worsen steatosis, inflammation, and fibrosis, but may nevertheless improve insulin sensitivity. Moreover, in liver and other tissues, HIF activation alters mitochondrial respiratory function and metabolism, having an impact on energetic and redox homeostasis. This article aims to provide an overview of current understanding of the roles of HIFs in NAFLD, highlighting areas where further research is needed.
The CRISPR-Cas9 system has increased the speed and precision of genetic editing in cells and animals. However, model generation for drug development is still expensive and time-consuming, demanding ...more target flexibility and faster turnaround times with high reproducibility. The generation of a tightly controlled ObLiGaRe doxycycline inducible SpCas9 (ODInCas9) transgene and its use in targeted ObLiGaRe results in functional integration into both human and mouse cells culminating in the generation of the ODInCas9 mouse. Genomic editing can be performed in cells of various tissue origins without any detectable gene editing in the absence of doxycycline. Somatic in vivo editing can model non-small cell lung cancer (NSCLC) adenocarcinomas, enabling treatment studies to validate the efficacy of candidate drugs. The ODInCas9 mouse allows robust and tunable genome editing granting flexibility, speed and uniformity at less cost, leading to high throughput and practical preclinical in vivo therapeutic testing.
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