Alcohol use disorder (AUD) is a common and chronic disorder with substantial effects on personal and public health. The underlying pathophysiology is poorly understood but strong evidence suggests ...significant roles of both genetic and epigenetic components. Given that alcohol affects many organ systems, we performed a cross-tissue and cross-phenotypic analysis of genome-wide methylomic variation in AUD using samples from 3 discovery, 4 replication, and 2 translational cohorts. We identified a differentially methylated region in the promoter of the proprotein convertase subtilisin/kexin 9 (PCSK9) gene that was associated with disease phenotypes. Biological validation showed that PCSK9 promoter methylation is conserved across tissues and positively correlated with expression. Replication in AUD datasets confirmed PCSK9 hypomethylation and a translational mouse model of AUD showed that alcohol exposure leads to PCSK9 downregulation. PCSK9 is primarily expressed in the liver and regulates low-density lipoprotein cholesterol (LDL-C). Our finding of alcohol-induced epigenetic regulation of PCSK9 represents one of the underlying mechanisms between the well-known effects of alcohol on lipid metabolism and cardiovascular risk, with light alcohol use generally being protective while chronic heavy use has detrimental health outcomes.
Abstract Based on high-resolution measurements from the Magnetospheric Multiscale mission from 2015 May to 2018 June, we statistically investigate the properties of small-scale field-aligned currents ...(SFACs) in the magnetopause boundary layer. A total of 2235 SFACs are successfully identified. The durations of SFACs mainly fall between 0.2 and 0.3 s. Over 90% of SFACs have a width of less than 1 ion inertia length and are primarily distributed from 5 to 25 electron inertia lengths, implying that the SFACs belong to the kinetic-scale current layer. The main carriers of SFACs are electrons, and over 70% of SFACs exhibit net energy dissipation (i.e., J · E ′ > 0) with the majority of energy dissipation taking place in the parallel direction. SFACs are widely distributed spatially, and the occurrence rate of SFACs is higher in the boundary layer closer to the magnetosphere. Additionally, less than half of the total SFACs are identified in well-known structures, including the magnetic reconnection region, flux transfer event, Kelvin–Helmholtz vortex, and exhaust region, and 54% of the SFACs are in the “others” unknown structures. These results improve our comprehension of the current system at the magnetopause and the roles of SFACs in the coupling between the solar wind and magnetosphere.
Hong Kong imposed a partial restriction on application of organotin-based antifouling paints in 1992. Since September 2008, the International Maritime Organization prohibited the use of such ...antifouling systems on all sea-going vessels globally. Therefore, it is anticipated a gradual reduction of organotin contamination in Hong Kong's marine waters. Using the rock shell Reishia clavigera as a biomonitor, we evaluated the organotin contamination along Hong Kong's coastal waters over the past two decades (1990-2015). In 2010 and 2015, adult R. clavigera were examined for imposex status and analysed for tissue concentrations of six organotins. We consistently found 100% imposex incidence in female R. clavigera across all sites. Tissue triphenyltin (TPT) concentrations were high in most samples. A probabilistic risk assessment showed that there were over 69% of chance that local R. clavigera would be at risk due to exposure to phenyltins. Comparing with those of previous surveys (2004-2010), both imposex levels and tissue concentrations of organotins did not decline, while the ecological risks due to exposure to organotins were increasing. We also observed high concentrations of monobutyltin and TPT in seawater and sediment from locations with intense shipping activities and from stormwater or sewage discharge. Overall, organotins are still prevalent in Hong Kong's marine waters showing that the global convention alone may be inadequate in reducing organotin contamination in a busy international port like Hong Kong. Appropriate management actions should be taken to control the use and release of organotins in Hong Kong and South China.
Abstract Activated hepatic stellate cells (HSCs) possess strong immune inhibitory activity. The present study highlighted the protective role of HSCs in islet transplantation. Recipients were ...randomly divided into 4 groups: a diabetic group, an HSC-alone group, an islet-alone transplant group, and a cotransplant group. Graft survival was compared among the 4 groups. Serum transforming growth factor β (TGFβ), tumor necrosis factor α, interleukin-1β, and interferon gamma expression levels were measured. The infiltration of lymphocytes was observed via hematoxylin and eosin staining, and immunohistochemical examinations were performed. Results showed that allogeneic HSCs protect islet allografts better than syngeneic HSCs. There was significant prolonged graft survival and a higher level of TGFβ in the cotransplant group ( P < .01). The infiltration of lymphocytes in the cotransplant group was notably less than in the islet-alone group ( P < .01). The formation of desmin-positive HSC packages was detected in the cotransplant group. In conclusion, allogeneic HSCs can better prolong the survival of islet allografts by stimulating TGFβ expression and forming a biological capsule around the graft.
Our study aimed to investigate the effects of different dietary vitamin D (VD) combinations during the grower (1–32 d of age) and feed restriction (33–52 d of age) phases on growth performance. We ...also evaluated sternal morphology, mineralization, and related genes expression of bone metabolism as well as absorption of calcium and phosphorous in duodenal mucosa and kidney in Pekin ducks. During the grower phase, we used 2 VD regimes (Group A: 3,160 IU/kg VD3; Group B: 400 IU/kg VD3 + 69 μg/kg 25-OH-D3). Each dietary treatment had 50 replicate pens of 10 ducks per pen. During the feed restriction phase, 30 replicate pens selected from Group A and Group B, repetitively, were redivided into 5 different dietary VD regimes to form a 2 × 5 experimental design. Each group consisted of 6 replicates, each with 10 ducks. During the feed restriction phase, we evaluated 5 different dietary VD combinations were as follows: T1: 2,000 IU/kg VD3 ; T2: 5,000 IU/kg VD3; T3: 3,620 IU/kg VD3 + 34.5 μg/kg 25-OH-D3; T4: 2,240 IU/kg VD3 + 69 μg/kg 25-OH-D3; T5: 1,800 IU/kg VD3 + 80 μg/kg 25-OH-D3). Results showed that Group B combinations with T5 had a better growth performance and breast meat deposition (P < 0.1). Regardless of 5 dietary VD regimes during the feed restriction phase, Group B significantly increased (P < 0.05) 52 d sternal depth and tended to increase (P < 0.1) 52 d sternal defatted weight, ash content, and phosphate (P) content of ducks. A significant interactive effect (P < 0.05) was observed on the mRNA abundance of DMP1 and Sost1 as well as RANKL/OPG in sternum and of VDR in duodenal mucosa of ducks at 52 d of age between dietary VD combinations during 2 phases. These results indicated that dietary VD regimes during the grower phase could affect the effectiveness of dietary VD regimes during the feed restriction phases; Dietary VD combinations of both phases could affect the genes expression of bone formation and the absorption as well as reabsorption of calcium and phosphorus in duodenum and kidney.
Mammalian genomes are populated with thousands of transcriptional enhancers that orchestrate cell-type-specific gene expression programs, but how those enhancers are exploited to institute ...alternative, signal-dependent transcriptional responses remains poorly understood. Here we present evidence that cell-lineage-specific factors, such as FoxA1, can simultaneously facilitate and restrict key regulated transcription factors, exemplified by the androgen receptor (AR), to act on structurally and functionally distinct classes of enhancer. Consequently, FoxA1 downregulation, an unfavourable prognostic sign in certain advanced prostate tumours, triggers dramatic reprogramming of the hormonal response by causing a massive switch in AR binding to a distinct cohort of pre-established enhancers. These enhancers are functional, as evidenced by the production of enhancer-templated non-coding RNA (eRNA) based on global nuclear run-on sequencing (GRO-seq) analysis, with a unique class apparently requiring no nucleosome remodelling to induce specific enhancer-promoter looping and gene activation. GRO-seq data also suggest that liganded AR induces both transcription initiation and elongation. Together, these findings reveal a large repository of active enhancers that can be dynamically tuned to elicit alternative gene expression programs, which may underlie many sequential gene expression events in development, cell differentiation and disease progression.
Intrinsic and evasive antiangiogenic drug (AAD) resistance is frequently developed in cancer patients, and molecular mechanisms underlying AAD resistance remain largely unknown. Here we describe ...AAD-triggered, lipid-dependent metabolic reprogramming as an alternative mechanism of AAD resistance. Unexpectedly, tumor angiogenesis in adipose and non-adipose environments is equally sensitive to AAD treatment. AAD-treated tumors in adipose environment show accelerated growth rates in the presence of a minimal number of microvessels. Mechanistically, AAD-induced tumor hypoxia initiates the fatty acid oxidation metabolic reprogramming and increases uptake of free fatty acid (FFA) that stimulates cancer cell proliferation. Inhibition of carnitine palmitoyl transferase 1A (CPT1) significantly compromises the FFA-induced cell proliferation. Genetic and pharmacological loss of CPT1 function sensitizes AAD therapeutic efficacy and enhances its anti-tumor effects. Together, we propose an effective cancer therapy concept by combining drugs that target angiogenesis and lipid metabolism.
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•Tumors grown in adipose tissues tend to be AAD resistant•AAD induces hypoxia and limits glucose supply and induces lipolysis•Tumor cells switch from glycolysis to FAO metabolism upon AAD treatment•Dual targeting angiogenesis and FAO increases anti-tumor activity
Antiangiogenic drug (AAD) resistance is a frequent problem in cancer patients. Iwamoto et al. show that vascularization is not a limiting factor. Instead, AAD triggered a lipid-dependent metabolic reprogramming, resulting in increased free fatty acid and cancer cell proliferation. Inhibition of fatty acid oxidation enhanced the therapeutic efficacy of AAD.
Close white dwarf binaries consisting of a white dwarf and an A-, F-, G-, or K-type main-sequence star, henceforth close WD+AFGK binaries, are ideal systems to understand the nature of type Ia ...supernovae progenitors and to test binary evolution models. In this work we identify 775 WD+AFGK candidates from TGAS (The Tycho-Gaia Astrometric Solution) and Gaia Data Release 2 (DR2), a well-defined sample of stars with available parallaxes, and we measure radial velocities (RVs) for 275 of them with the aim of identifying close binaries. The RVs have been measured from high-resolution spectra obtained at the Xinglong 2.16 m Telescope and the San Pedro Mártir 2.12 m Telescope and/or from available LAMOST DR6 (low-resolution) and RAVE DR5 (medium-resolution) spectra. We identify 23 WD+AFGK systems displaying more than 3 RV variation among 151 systems for which the measured values are obtained from different nights. Our WD+AFGK binary sample contains both AFGK dwarfs and giants, with a giant fraction ∼43%. The close binary fractions we determine for the WD+AFGK dwarf and giant samples are 24% and 15%, respectively. We also determine the stellar parameters (i.e., effective temperature, surface gravity, metallicity, mass, and radius) of the AFGK companions with available high-resolution spectra. The stellar parameter distributions of the AFGK companions that are members of close and wide binary candidates do not show statistically significant differences.
Quantum heat engines are expected to outperform the classical counterparts due to quantum coherences involved. Here we experimentally execute a single-ion quantum heat engine and demonstrate, for the ...first time, the dynamics and the enhanced performance of the heat engine originating from the Liouvillian exceptional points (LEPs). In addition to the topological effects related to LEPs, we focus on thermodynamic effects, which can be understood by the Landau-Zener-Stückelberg process under decoherence. We witness a positive net work from the quantum heat engine if the heat engine cycle dynamically encircles a LEP. Further investigation reveals that a larger net work is done when the system is operated closer to the LEP. We attribute the enhanced performance of the quantum heat engine to the Landau-Zener-Stückelberg process, enabled by the eigenenergy landscape in the vicinity of the LEP, and the exceptional point-induced topological transition. Therefore, our results open new possibilities toward LEP-enabled control of quantum heat engines and of thermodynamic processes in open quantum systems.
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