Genome-wide association studies (GWAS) provide biological insights into disease onset and progression and have potential to produce clinically useful biomarkers. A growing body of GWAS focuses on ...quantitative and transdiagnostic phenotypic targets, such as symptom severity or biological markers, to enhance gene discovery and the translational utility of genetic findings. The current review discusses such phenotypic approaches in GWAS across major psychiatric disorders. We identify themes and recommendations that emerge from the literature to date, including issues of sample size, reliability, convergent validity, sources of phenotypic information, phenotypes based on biological and behavioral markers such as neuroimaging and chronotype, and longitudinal phenotypes. We also discuss insights from multi-trait methods such as genomic structural equation modelling. These provide insight into how hierarchical 'splitting' and 'lumping' approaches can be applied to both diagnostic and dimensional phenotypes to model clinical heterogeneity and comorbidity. Overall, dimensional and transdiagnostic phenotypes have enhanced gene discovery in many psychiatric conditions and promises to yield fruitful GWAS targets in the years to come.
The crystalline nature of cellulose microfibrils is one of the key factors influencing biomass recalcitrance which is a key technical and economic barrier to overcome to make cellulosic biofuels a ...commercial reality. To date, all known fungal enzymes tested have great difficulty degrading highly crystalline cellulosic substrates. We have demonstrated that the CelA cellulase from Caldicellulosiruptor bescii degrades highly crystalline cellulose as well as low crystallinity substrates making it the only known cellulase to function well on highly crystalline cellulose. Unlike the secretomes of cellulolytic fungi, which typically comprise multiple, single catalytic domain enzymes for biomass degradation, some bacterial systems employ an alternative strategy that utilizes multi-catalytic domain cellulases. Additionally, CelA is extremely thermostable and highly active at elevated temperatures, unlike commercial fungal cellulases. Furthermore we have determined that the factors negatively affecting digestion of lignocellulosic materials by C. bescii enzyme cocktails containing CelA appear to be significantly different from the performance barriers affecting fungal cellulases. Here, we explore the activity and degradation mechanism of CelA on a variety of pretreated substrates to better understand how the different bulk components of biomass, such as xylan and lignin, impact its performance.
•3.5 year-long study with simultaneous open- and closed path CH4 flux measurements.•Quantification of systematic, random and gap-filling errors and resulting uncertainty.•Average annual emissions of ...18 g−CH4 m-2 yr-1 agreed within 0.6 g−CH4 m-2 yr-1 between analyzers.•Total flux uncertainty on annual fluxes was estimated to range from 7% to 17%.
Wetlands represent the dominant natural source of methane (CH4) to the atmosphere. Thus, substantial effort has been spent examining the CH4 budgets of global wetlands via continuous ecosystem-scale measurements using the eddy covariance (EC) technique. Robust error characterization for such measurements, however, remains a major challenge. Here, we quantify systematic, random and gap-filling errors and the resulting uncertainty in CH4 fluxes using a 3.5 year time series of simultaneous open- and closed path CH4 flux measurements over a sub-boreal wetland.
After correcting for high- and low frequency flux attenuation, the magnitude of systematic frequency response errors were negligible relative to other uncertainties. Based on three different random flux error estimations, we found that errors of the CH4 flux measurement systems were smaller in magnitude than errors associated with the turbulent transport and flux footprint heterogeneity. Errors on individual half-hourly CH4 fluxes were typically 6%–41%, but not normally distributed (leptokurtic), and thus need to be appropriately characterized when fluxes are compared to chamber-derived or modeled CH4 fluxes.
Integrated annual fluxes were only moderately sensitive to gap-filling, based on an evaluation of 4 different methods. Calculated budgets agreed on average to within 7% (≤1.5 g−CH4 m−2 yr−1). Marginal distribution sampling using open source code was among the best-performing of all the evaluated gap-filling approaches and it is therefore recommended given its transparency and reproducibility.
Overall, estimates of annual CH4 emissions for both EC systems were in excellent agreement (within 0.6 g−CH4 m−2 yr−1) and averaged 18 g−CH4 m−2 yr−1. Total uncertainties on the annual fluxes were larger than the uncertainty of the flux measurement systems and estimated between 7–17%. Identifying trends and differences among sites or site years requires that the observed variability exceeds these uncertainties.
Biological and non-biological variables unrelated to acute myeloid leukemia (AML) preclude standard therapy in many settings, with "real world" patients under-represented in clinical trials and ...prognostic models. Here, using a case-based format, we illustrate the impact that socioeconomic and anthropogeographical constraints can have on optimally managing AML in 4 different healthcare systems. The granular details provided, emphasize the need for the development and targeting of socioeconomic interventions that are commensurate with the changing landscape of AML therapeutics, in order to avoid worsening the disparity in outcomes between patients with biologically similar disease.
Blue light receptors using FAD (BLUFs) facilitate blue light‐induced signal transduction via light‐induced rearrangement of hydrogen bonds between the flavin chromophore and a conserved glutamine ...side chain. Here, we investigated the photochemistry of the BLUF domain Slr1694 from Synechocystis sp. in which the glutamine side chain was removed. Without the glutamine, no red‐shifted signaling state is formed, but light‐induced proton‐coupled electron transfer between protein and flavin takes place similarly as for the wild‐type protein. However, the lifetime of the neutral flavin semiquinone–tyrosyl radical pair is greatly prolonged from < 100 ps to several nanoseconds, which indicates that the formation of radical intermediates drives the hydrogen bond rearrangement in BLUF photoactivation. Moreover, glutamine plays a central role in the molecular organization of the hydrogen bond network in the flavin‐binding pocket, as its removal enhances electron transfer from tyrosine to the excited flavin, and enables competing electron transfer from a nearby tryptophan.
Two different commercial hyperbranched poly(ethyleneimine)s (HBPEI), with molecular weights (MW) of 800 and 25,000 g/mol, and denoted as PEI800 and PEI25000, respectively, as well as the mixtures ...with a Diglycidyl Ether of Bisphenol-A (DGEBA) epoxy resin, have been studied using thermal analysis techniques (DSC, TGA), dielectric relaxation spectroscopy (DRS), and dynamic mechanical analysis (DMA). Only a single glass transition is observed in these mixtures by DSC. DRS of the HBPEIs shows three dipolar relaxations: γ, β, and α. The average activation energy for the γ-relaxation is similar for all HBPEIs and is associated with the motion of the terminal groups. The β-relaxation has the same average activation energy for both PEI800 and PEI25000; this relaxation is attributed to the mobility of the branches. The α-relaxation peak for all the HBPEIs is an asymmetric peak with a shoulder on the high temperature side. This shoulder suggests the existence of ionic charge trapped in the PEI. For the mixtures, the γ- and β-relaxations follow the behaviour of the epoxy resin alone, indicating that the epoxy resin dominates the molecular mobility. The α-relaxation by DRS is observed only as a shoulder, as a consequence of an overlap with conductivity effects, whereas by DMA, it is a clear peak.
This work demonstrates that the application of even moderate pressures during cure can result in a remarkable enhancement of the thermal conductivity of composites of epoxy and boron nitride (BN). ...Two systems have been used: epoxy-thiol and epoxy-diamine composites, filled with BN particles of different sizes and types: 2, 30 and 180 μm platelets and 120 μm agglomerates. Using measurements of density and thermal conductivity, samples cured under pressures of 175 kPa and 2 MPa are compared with the same compositions cured at ambient pressure. The thermal conductivity increases for all samples cured under pressure, but the mechanism responsible depends on the composite system: For epoxy-diamine composites, the increase results principally from a reduction in the void content; for the epoxy-thiol system with BN platelets, the increase results from an improved matrix-particle interface; for the epoxy-thiol system with BN agglomerates, which has a thermal conductivity greater than 10 W/mK at 44.7 vol.% filler content, the agglomerates are deformed to give a significantly increased area of contact. These results indicate that curing under pressure is an effective means of achieving high conductivity in epoxy-BN composites.
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•Oxygen limitation may be more common during immature life stages.•We measured the effects of heat and hypoxia on performance.•Heat tolerance of locusts depended on oxygen supply ...during the first instar but not during later instars.
Although scientists know that overheating kills many organisms, they do not agree on the mechanism. According to one theory, referred to as oxygen- and capacity-limitation of thermal tolerance, overheating occurs when a warming organism’s demand for oxygen exceeds its supply, reducing the organism’s supply of ATP. This model predicts that an organism’s heat tolerance should decrease under hypoxia, yet most terrestrial organisms tolerate the same amount of warming across a wide range of oxygen concentrations. This point is especially true for adult insects, who deliver oxygen through highly efficient respiratory systems. However, oxygen limitation at high temperatures may be more common during immature life stages, which have less developed respiratory systems. To test this hypothesis, we measured the effects of heat and hypoxia on the survival of South American locusts (Schistocerca cancellata) throughout development and during specific instars. We demonstrate that the heat tolerance of locusts depends on oxygen supply during the first instar but not during later instars. This finding provides further support for the idea that oxygen limitation of thermal tolerance depends on respiratory performance, especially during immature life stages.
Histone deacetylase inhibitors (HDACi) show promise as cancer therapeutics; however, the full scope of their utility remains unknown. Here we report findings that strongly rationalize clinical ...evaluation of HDACis in malignant peripheral nerve sheath tumors (MPNST), a class of highly aggressive, therapeutically resistant, and commonly fatal malignancies that occur sporadically or in patients with the inherited neurofibromatosis type-1 (NF1) syndrome. We evaluated the effects of the chemical HDACis PCI-24781, suberoylanilide hydroxamic acid, and MS-275 on a panel of human NF1-associated and sporadic MPNSTs in vitro and in vivo. A subset of MPNSTs was found to be highly sensitive to HDACis, especially to PCI-24781. All cell lines in this group were NF1-associated. Significant proapoptotic effects were noted in vitro and in vivo and were independent of p53 mutational status. In contrast, as a group the sporadic-MPNST cells were markedly resistant to HDACi treatment. HDACis were found to induce productive autophagy in MPNST cells. Genetic and/or pharmacologic autophagy blockade resulted in significant HDACi-induced apoptosis in cells defined as resistant or sensitive, leading to abrogated growth of primary tumors and lung metastases in tumor xenograft assays. Among autophagy-associated genes expressed in response to HDACi, the immunity-related GTPase family, M was validated as a critical target in mediating HDACi-induced autophagy and enhanced apoptosis. Taken together, our findings strongly support the evaluation of HDACi currently in clinical trials as an important new therapeutic strategy to treat MPNST, including in combination with autophagy blocking combination regimens in particular for patients with sporadic MPNST.
Therapies directed to specific molecular targets are still unmet for patients with triple-negative breast cancer (TNBC). Deubiquitinases (DUB) are emerging drug targets. The identification of highly ...active DUBs in TNBC may lead to novel therapies.
Using DUB activity probes, we profiled global DUB activities in 52 breast cancer cell lines and 52 patients' tumor tissues. To validate our findings
, we employed both zebrafish and murine breast cancer xenograft models. Cellular and molecular mechanisms were elucidated using
and
biochemical methods. A specific inhibitor was synthesized, and its biochemical and biological functions were assessed in a range of assays. Finally, we used patient sera samples to investigate clinical correlations.
Two DUB activity profiling approaches identified UCHL1 as being highly active in TNBC cell lines and aggressive tumors. Functionally, UCHL1 promoted metastasis in zebrafish and murine breast cancer xenograft models. Mechanistically, UCHL1 facilitates TGFβ signaling-induced metastasis by protecting TGFβ type I receptor and SMAD2 from ubiquitination. We found that these responses are potently suppressed by the specific UCHL1 inhibitor, 6RK73. Furthermore, UCHL1 levels were significantly increased in sera of patients with TNBC, and highly enriched in sera exosomes as well as TNBC cell-conditioned media. UCHL1-enriched exosomes stimulated breast cancer migration and extravasation, suggesting that UCHL1 may act in a paracrine manner to promote tumor progression.
Our DUB activity profiling identified UCHL1 as a candidate oncoprotein that promotes TGFβ-induced breast cancer metastasis and may provide a potential target for TNBC treatment.
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