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Several studies are conducted to determine the different factors that lead to the onset of the autosomal recessive urofacial syndrome (UFS). The results demonstrate that the loss-of-function mutations in Heparanse 2 (HPSE2) is the main cause of the disorder.

Microplastics (MPs) are of environmental concern due to their bioavailability and potential impacts on a wide range of marine biota. In this study, we investigated the ingestion, bioaccumulation and egestion of fluorescent polystyrene (PS) micospheres (10 μm) in both larvae and adults of marine medaka (Oryzias melastigma), with or without food supply. The post-exposure effects of non-fluorescent PS (10 μm) on the survival, growth and reproduction of medaka larvae were also explored. Results showed that the PS microspheres could be ingested by both larvae and adults during the 48 h-exposure. Notably, feeding status was found to significantly affect the ingestion in medaka adults, which was not observed in the larvae. The egestion process of PS was rapid during the first recovery day but there was still certain percent of particles retained in digestive tracts at the end of 7 d recovery for either larvae or adults. After a 14 d pre-exposure with the non-fluorescent PS microspheres, the subsequent survival, growth and reproduction of medaka larvae were all significantly affected at the end of 120 d of experiment without PS. Overall, these results indicate that fishes might ingest or retain more MPs if the environmental abundance of MPs continues to increase while the available food decreases. Medaka fishes in larval stage have no capacity to select natural food sources like the adults. The chronic and "legacy effect" of MPs might also be a problem worthy paid more attention in future research instead of acute and immediate effect studies. • Marine medaka larvae and adults can ingest and egest microplastics (MPs). • Feeding status was found to significantly affect the ingestion in medaka adults. • Larvae had no capacity to select food sources like the adults. • Increased mortality, decreased growth and reproduction were observed after exposure. • The chronic and legacy effect of MPs should be paid more attention in future. [ABSTRACT FROM AUTHOR]

Abstract Worldwide the seafloor has been recognized as a major sink for microplastics. However, currently nothing is known about the sediment microplastic pollution in the North Pacific sector of the Arctic Ocean. Here, we present the first record of microplastic contamination in the surface sediment from the northern Bering and Chukchi Seas. The microplastics were extracted by the density separation method from collected samples. Each particle was identified using the microscopic Fourier transform infrared spectroscopy (μFTIR). The abundances of microplastics in sediments from all sites ranged from not detected (ND) to 68.78 items/kg dry weight (DW) of sediment. The highest level of microplastic contamination in the sediment was detected from the Chukchi Sea. A negative correlation between microplastic abundance and water depth was observed. Polypropylene (PP) accounted for the largest proportion (51.5%) of the identified microplastic particles, followed by polyethylene terephthalate (PET) (35.2%) and rayon (13.3%). Fibers constituted the most common shape of plastic particles. The range of polymer types, physical shapes and spatial distribution characteristics of the microplastics suggest that water masses from the Pacific and local coastal inputs are possible sources for the microplastics found in the study area. In overall, our results highlight the global distribution of these anthropogenic pollutants and the importance of management action to reduce marine debris worldwide. Graphical abstract Image 1 Highlights • This is the first report of MPs in sediments from the Bering-Chukchi Sea shelf. • MPs levels were lower than those found in other regions of the world. • The sediments from the Chukchi Sea possessed the highest MPs abundances. • Fibers constituted the most common type in the Arctic sediments. [ABSTRACT FROM AUTHOR]

Abstract Microplastics are a contaminant of emerging concern which enter the marine environment from a variety of sources. The ingestion and toxic effects of microplastics on marine life, especially for filter feeders, are a cause of concern in view of their ubiquitous nature and their similar size as food sources. To assess the toxic effects of microspheres ingested by brine shrimp larvae, we exposed Artemia parthenogenetica to 10 μm polystyrene microspheres at different concentrations. These concentrations were approximate to the extrapolated marine aquatic environmentally relevant concentrations. The lowest polystyrene concentrations at which ingestion was visualized in A. parthenogenetica were 12 ± 0.57 particles/mL (6.7 ± 0.32 μg/L) and 1.1 ± 0.16 particles/mL (0.61 ± 0.088 μg/L), respectively. There were no significant impacts on the survival, growth or development in A. parthenogenetica occurring over the 14-d exposure across a range of polystyrene nominal concentrations (1–1000 particles/mL or 0.55–550 μg/L). However, abnormal ultrastructures of intestinal epithelial cells were observed upon exposure to polystyrene microspheres, including fewer and disordered microvilli, an increased number of mitochondrion and the appearance of autophagosome. These phenomena could affect nutrition absorption and energy metabolism. Although no major acute or chronic toxicity effects on A. parthenogenetica were observed over 24-h or 14-d exposures, this study provides evidence that the ingestion of polystyrene microplastics at extrapolated environmentally relevant concentrations can be visualized through a microscope to be causing a series of responses in intestinal epithelial cells. Graphical abstract Image 1 Highlights • The lowest polystyrene concentrations at which ingestion could be visualized were at extrapolated environmentally relevant. • No significant impacts of survival, growth and development on A. parthenogenetica occurred. • Morphological analysis on digestive tract epithelial cells showed the occurrence of a series of abnormal ultrastructures. Although no acute or chronic toxicity effects of ingested microplastics on Artemia were observed, they caused a series of responses in intestinal epithelial cells. [ABSTRACT FROM AUTHOR]

The negative effects of metal oxide nanoparticles on aquatic environment and organisms have caused much concern. In this study, the embryotoxicity of zinc oxide nanoparticles (ZnO NP) to marine medaka, Oryzias melastigma , was explored and compared with that of aqueous Zn (ZnSO 4 ·7H 2 O). The Zn 2+ released from ZnO NP in artificial seawater at exposure concentrations was also measured. Results showed that zinc ion release percentage (%) decreased with increasing concentration, which was 44%, 41% and 25% at 0.1, 1 and 10 mg/L of ZnO NP suspension, respectively. After 20 d exposure of medaka embryos to ZnO NP, we observed increased mortality and heart rate, reduced percent total hatching success, delayed hatching of embryos and increased malformation% of newly-hatched larvae in ZnO NP treatment compared to the control group. Furthermore, ZnO NPs have significantly greater effects than the aqueous Zn for mortality and heart rate, indicating that ZnO NPs themselves, in particulate or aggregate form, contribute to the observed toxicity. Edema was the most commonly found malformation in newly-hatched larvae after ZnO NP exposure. Overall, our findings suggest that the embryonic stage of marine medaka is sensitive to ZnO NP exposure. Studies of the toxic mechanism of ZnO NPs should not ignore the impact of NPs since the greater effects of ZnO NPs than of aqueous Zn ions observed in this study cannot be explained by the ZnO NP dissolution. The ion release profile of ZnO NPs in marine environment is related to both NP and seawater characteristics, which should be analyzed on a case-by-case basis. The ZnO NP-related Zn speciation may play an important role in the dissolution and toxicity processes of ZnO NPs in marine environment, and further speciation study may contribute to the interpretation of ZnO NP toxicity. [ABSTRACT FROM AUTHOR]

As the only E2 conjugating enzyme for the SUMO system, Ubc9-mediated SUMOylation has been recognized to regulate diverse biological processes, but its impact on adipocytes relevant to obesity and insulin resistance is yet to be elucidated. We established adipocyte-specific Ubc9 deficient mice to explore the effects of Ubc9 on obesity and metabolic disorders induced by high-fat diet (HFD) in adult mice. The molecular targets of SUMOylation were explored by liquid chromatography-mass spectrometry, and the regulatory mechanism of SUMOylation in T2D was analyzed. Adipocyte-specific depletion of Ubc9 (AdipoQ-Cre-Ubc9 fl/fl , Ubc9 AKO ) protected mice from HFD-induced obesity, insulin resistance, and hepatosteatosis. The Ubc9 AKO mice were featured by the reduced HFD-induced endoplasmic reticulum (ER) stress and inflammatory response. Mechanically, over nutrition rendered adipocytes to undergo a SUMOylation turnover characterized by the change of SUMOylation levels and substrates. ERp44 displayed the highest change in terms of SUMOylation levels of substrates involved in ER-related functions. The lack of ERp44 SUMOylation at lysine 76 (K76) located within the thioredoxin (TRX)-like domain by Ubc9 deficiency enhanced its degradation and suppressed its covalent binding to Ero1α, an oxidase that exists in the ER but lacks ER retention motif, thereby alleviating endoplasmic reticulum stress by promoting Ero1α secretion. Our data suggest that modulation of ERp44 SUMOylation in adipocytes could be a feasible strategy against obesity and insulin resistance in clinical settings. [Display omitted] • Ubc9 expression is upregulated in adipocyte during obese state. • Adipocyte-specific Ubc9 knockout ameliorates HFD-induced obesity and insulin resistance. • Ubc9-mediated ERp44 SUMOylation in K76 site exacerbates adipocyte ER stress and insulin resistance caused by lipotoxicity. • Disruption of ERp44 SUMOylation promotes Ero1α ER secretion, thereby attenuating lipotoxicity-induced ER stress. [ABSTRACT FROM AUTHOR]

In this study, the toxicities of sediment-associated silver added to sediment as commercially available silver nanoparticles (Ag NPs, 20 and 80 nm) and aqueous Ag (AgNO 3 ) to the estuarine polychaete, Nereis (Hediste) diversicolor , were investigated for both individual and subcellular endpoints after 10 d of exposure. Both Ag NP types were characterized in parallel to the toxicity studies and found to be polydispersed and overlapping in size. Burrowing activity decreased (marginally) with increasing Ag concentration and depended on the form of Ag added to sediment. All worms accumulated Ag regardless of the form in which it was added to the sediment, and worm size (expressed as dry weight) was found to significantly affect bioaccumulation such that smaller worms accumulated more Ag per body weight than larger worms. Lysosomal membrane permeability (neutral red retention time, NRRT) and DNA damage (comet assay tail moment and tail DNA intensity %) of Nereis coelomocytes increased in a concentration-dependent manner in all three Ag treatments. Ag NP treatments were more toxic than aqueous Ag for all toxicity endpoints, even though bioaccumulation did not differ significantly among Ag forms. No significant difference in toxicity was observed between the two Ag NP treatments which was attributed to their overlap in particle size. [ABSTRACT FROM AUTHOR]

Abstract: There is increasing concern about the toxicities and potential risks, both still poorly understood, of silver nanoparticles for the aquatic environment after their eventual release via wastewater discharges. In this study, the toxicities of sediment associated nano (<100nm)-, micron (2–3.5μm)- and ionic (AgNO3)-Ag on the sediment-dwelling polychaete, Nereis diversicolor, were compared after 10 days of sediment exposure, using survival, DNA damage (comet assay) and bioaccumulation as endpoints. The nominal concentrations used in all exposure scenarios were 0, 1, 5, 10, 25, and 50μgAg/g dry weight (dw) sediment. Our results showed that Ag was able to cause DNA damage in Nereis coelomocytes, and that this effect was both concentration- and Ag form-related. There was significantly greater genotoxicity (higher tail moment and tail DNA intensities) at 25 and 50μg/gdw in nano- and micron-Ag treatments and at 50μg/gdw in the ionic-Ag treatment compared to the controls (0μg/gdw). The nano-Ag treatment had the greatest genotoxic effect of the three tested Ag forms, and the ionic-Ag treatment was the least genotoxic. N. diversicolor did accumulate sediment-associated Ag from all three forms. Ag body burdens at the highest exposure concentration were 8.56±6.63, 6.92±5.86 and 9.86±4.94μg/gdw for worms in nano-, micron- and ionic-Ag treatments, respectively, but there was no significant difference in Ag bioaccumulation among the three treatments. [Copyright &y& Elsevier]

Abstract: N-n-Butyl haloperidol iodide (F2), a novel compound derived from haloperidol, protects against the damaging effects of ischemia/reperfusion (I/R) injury in vitro and in vivo. We tested whether the myocardial protection of F2 on cardiomyocyte hypoxia/reoxygenation (H/R) injury is mediated by modulating protein kinase C (PKC) activity in primary cultured cardiomyocytes. Primary cultures of ventricular cardiomyocytes underwent 2-h hypoxia and 30-min reoxygenation. Total PKC activity was measured, and the translocation pattern of PKCα, βII, δ and ɛ isoforms was assessed by fractionated western blot analysis. We investigated the association of PKC isoform translocation and H/R-induced injury in the presence and absence of the specific inhibitors and activator. Measurements included cell damage evaluated by creatine kinase (CK) release, and apoptosis measured by annexin V-FITC assay. In primary cultured cardiomyocytes exposed to H/R, PKCα, δ and ɛ were translocated, with no change in PKCβII activity. Total PKC activity, CK release and apoptosis were increased after H/R. Treatment with the conventional PKC inhibitor Gő6976 reduced early growth response-1 (Egr-1) protein expression and attenuated apoptosis. The PKCɛ inhibitor peptide ɛV1–2 increased H/R injury without influencing Egr-1 expression. Pretreatment with F2 inhibited translocation of PKCα, increased translocation of PKCɛ, and relieved the CK release and apoptosis. The protection of F2 was blocked in part by the conventional PKC activator thymeleatoxin (TXA) and ɛV1–2 peptide. F2 significantly alleviated H/R-induced injury, which might be attributed to the combined benefits of inhibiting PKCα and activating PKCɛ. [Copyright &y& Elsevier]

Abstract: For the mechanism of production of γ-ray bursts (GRBs) it is rather generally recognized that the long-term γ-ray burst (LGRB) originates from the deaths of massive stars while the short-term γ-ray burst (SGRB) originates from the merging of close binaries. Therefore the speculation naturally follows that the number of LGRBs is directly proportional to the star formation rate (SFR). However, it is indicated from recent data analyses that this speculation does not fit the observations very well. It is considered that only massive stars with masses greater than a certain critical mass can produce the LGRB, so the initial mass function (IMF) of stars can significantly affect the production rate of LGRBs. In this paper it is considered that the IMF of stars can be used to explain the observed number distribution of the LGRBs with the redshift, and this has led to some good results. [Copyright &y& Elsevier]

We have recently cloned four novel human genes that encode the ancient conserved domain proteins (ACDP). The full-length cDNA sequence of ACDP1 consists of 5898 bp and encodes a predicted protein of 951 amino acids (AA). The transcript for ACDP2 has 4058 bp of cDNA sequence, encoding a protein of 875 AA. ACDP3 contains 3113 bp of cDNA sequence and encodes a putative protein of 707 AA. ACDP4 contains 4765 bp of cDNA sequence and encodes a protein of 775 AA. The ACDP genes belong to a highly conserved new gene family. The conserved region showed 62.8% of nucleotide sequence identity, and 65.5% of AA identity with 92% of AA homologies among ACDP members. The conserved domain is also found in genes from evolutionarily divergent species from bacteria, yeast, Caenorhabditis elegans, and Drosophila melanogaster to mammals. All ACDP genes except ACDP1 have a ubiquitous expression pattern while ACDP1 expression is restricted to the brain and testis. Immunofluorescence staining of premeablized HeLa cells showed that ACDP proteins are predominantly localized in the nucleus. Sequence homology analyses revealed AA property and structural homologies between the ACD domain and cyclin molecules. [Copyright &y& Elsevier]

Aldehyde dehydrogenase 2 (ALDH2), an acetaldehyde dehydrogenase in mitochondria, is primarily responsible for metabolizing alcohol-derived acetaldehyde and other endogenous aldehydes. Inactivating ALDH2 rs671 polymorphism is found in up to 8 % of the global population and 40 % of the East Asian population. Recent studies have shown that rs671 SNP mutation in the human ALDH2 gene is associated with an increased risk of metabolic dysfunction-associated steatotic liver diseases (MASLD), but the mechanism remains unclear. Here, we identify the role of ALDH2 in MASLD. Firstly, ALDH2 activity was lower in MASLD patients and the methionine-choline deficiency (MCD) diet induced MASLD model. Secondly, activation of ALDH2 activity with Alda-1 (ALDH2 agonist) attenuated MCD-diet induced hepatic triglyceride (TG) accumulation and steatosis, whereas the opposite result was observed with cyanamide (CYA, ALDH2 inhibitor). Furthermore, ALDH2 deficiency exacerbated hepatic steatosis, inflammation, and fibrosis in the MCD-diet induced mice. RNA sequencing (RNA-seq) revealed that oxysterol 7-α hydroxylase (Cyp7b1) and the related metabolic pathway significantly changed in the MCD-diet challenged ALDH2−/− mice. In ALDH2−/− mice, the expression of Cyp7b1 was downregulated and FXR/SHP signaling was inhibited, reducing the alternative bile acid (BA) synthetic pathway. In our in vitro experiments, knockdown of ALDH2 exacerbated TG accumulation in hepatocytes, whereas the opposite result was observed with overexpression of ALDH2. Moreover, chenodeoxycholic acid (CDCA) rescued ALDH2 downregulation induced TG accumulation in hepatocytes. Our study reveals that ALDH2 attenuates hepatocyte steatosis by regulating the alternative BA synthesis pathway, and ALDH2 may serve as a potential target for the treatment of MASLD. [Display omitted] • MASLD induces a decrease in hepatic ALDH2 activity. • ALDH2 deficiency down-regulates BA metabolism pathway-related genes in liver and exacerbates hepatic steatosis, inflammation and fibrosis. • ALDH2 attenuates hepatocyte steatosis by upregulating Cyp7b1 related alternative BA synthesis pathway and FXR/SHP signaling. • CDCA can alleviate ALDH2 downregulation induced TG accumulation in hepatocytes. [ABSTRACT FROM AUTHOR]

Nanoplastics (NPs) are emerging pollutants posing risks to marine biota and human health due to their small size and high bioavailability. However, there are still knowledge gaps regarding effects of co-existing pollutants on NPs toxicity to marine organisms at their respective environmentally relevant concentrations. Herein we investigated developmental toxicity and histopathological alterations caused by co-exposure of polystyrene nanoplastics (PS-NPs) and bisphenol A (BPA) to marine medaka, Oryzias melastigma. Embryos at 6 h post-fertilization were exposed to 50-nm PS-NPs (55 μg/L) or BPA (100 μg/L) or co-exposed to a combination of both. Results showed that PS-NPs exhibited decreased embryonic heart rate, larval body length, and embryonic survival as well as larval deformities such as hemorrhaging and craniofacial abnormality. When co-exposed, BPA mitigated all the adverse developmental effects caused by PS-NPs. PS-NPs also led to an increase in histopathological condition index of liver with early inflammatory responses, while co-exposure of BPA with PS-NPs did not. Our data suggest that the toxicity reduction of PS-NPs in the presence of BPA might result from the decreased bioaccumulation of PS-NPs caused by the interaction between BPA and PS-NPs. This study unveiled the impact of BPA on the toxicity of nanoplastics in marine fish during early developmental stages and highlight the need of more research on the long-term effects of complex mixtures in the marine environment by applying omics approaches to better understand the toxicity mechanism. [Display omitted] • PS-NPs showed a declined waterborne concentration in the presence of BPA. • PS-NPs caused mortality, growth inhibition and deformities of developing medaka. • PS-NPs caused liver inflammatory responses with vacuolation, apoptosis and necrosis. • BPA mitigated the developmental toxicity of PS-NPs. • BPA reduced the liver inflammatory responses caused by PS-NPs. [ABSTRACT FROM AUTHOR]

Random amplified polymorphism DNA (RAPD) analysis was applied to germplasm characterization in 33 different selected Laminaria male and female gametophytes. The positional homology of the RAPD analysis using sequence characterized applied region (SCAR) method was successfully conducted. A total of 233 polymorphic loci were obtained from 18 selected primers after screening, of which 27 stable and clear bands were selected to construct a fingerprint map for discrimination of each gametophyte. Seven RAPD markers from five primers were finally determined by a computer program to construct the fingerprint map. Three specific markers closely related with gametophytes were obtained and were converted to gametophytic SCAR markers, the first SCAR marker report on Laminaria germplasm and applicable to cultivars identification. These results demonstrated the feasibility of applying RAPD markers to germplasm characterization in selected Laminaria gametophytes, and can provide a molecular basis for breeding new Laminaria strains. [Copyright &y& Elsevier]

Robust neuroprotective effects have been shown for minocycline. Whether it also protects nonneuronal cells or tissues is unknown. More importantly, the mechanisms of minocylcine protection appear multifaceted and remain to be clarified. Here we show that minocycline can protect kidney epithelial cells in vitro and protect the kidneys from ischemic injury in vivo. We further show that Bcl-2 is a key molecular determinant of minocycline protection. Minocycline protected kidney epithelial cells against apoptosis induced by hypoxia, azide, cisplatin, and staurosporine. The protection occurred at mitochondria, involving the suppression of Bax accumulation, outer membrane damage, and cytochrome c release. Minocycline induced Bcl-2, which accumulated in mitochondria and interacted with death-promoting molecules including Bax, Bak, and Bid. Down-regulation of Bcl-2 by specific antisense oligonucleotides abolished the cytoprotective effects of minocycline. Thus, minocycline can protect neuronal as well as nonneuronal cells and tissues. One mechanism for minocycline protection involves the induction of Bcl-2, an antiapoptotic protein. [ABSTRACT FROM AUTHOR]

• Endogenous carbohydrates levels affect the parthenocarpic fruit set of cucumber. • Exogenous sugars induced parthenocarpic fruit initiation. • Sugars enhance parthenocarpic fruit set through auxin and cytokinin signaling. Parthenocarpy is an important agricultural trait that determines the yield of cucumber. The role of sugars in parthenocarpic fruit formation is unknown. Therefore, we investigated these factors by using one highly parthenocarpic line DDX and one weakly parthenocarpic line ZK. To identify the possible effect of photosynthesis on parthenocarpy, leaf of ZK and DDX were covered for limiting the synthesis of carbohydrates. Leaf covering inhibited parthenocarpic fruit initiation and growth. Sugars (sucrose, fructose and glucose) contents in CPPU-induced, pollinated fruit of ZK and non-pollinated fruit of DDX were higher than those in non-pollinated fruit of ZK. The exogenous application of sugars (especially fructose and sucrose) significantly induced the parthenocarpic fruit set and growth. Transcriptomes of fruits treated with and without exogenously applied sugars showed that genes involved in auxin signaling and cytokinin signaling were more strongly expressed in the treated fruits. Auxin responsive gene IAA14 , and cytokinin responsive genes encoding histidine-containing phosphotransfer protein 4 and two-component response regulator 17 were upregulated in sugar-induced parthenocarpic fruits. These results show that parthenocarpic fruit formation is regulated by the interplay among sugars and the plant hormones auxin and cytokinin. [ABSTRACT FROM AUTHOR]

Microplastics are a ubiquitous contaminant of marine ecosystems that have received considerable global attention. The effects of microplastic ingestion on some marine biota have been evaluated, but the uptake, elimination, and histopathological impacts of microplastics remain under-investigated especially for zooplankton larvae. Here, we show that 10 μm polystyrene microspheres can be ingested and egested by Artemia parthenogenetica larvae, which impact their health. The results indicate that A. parthenogenetica larvae have a varying capacity to consume 10 μm polystyrene microspheres that is dependent on microplastic exposure concentrations, exposure times, and the availability of food. The lowest level of microplastics that was ingested by A. parthenogenetica was 0.15 particles/individual when exposed to 10 particles/mL and 0.05 particles/individual when exposed to 1 particle/mL over 24 h and 14 d, respectively. A. parthenogenetica larvae were able to egest feces with microplastics within 3 h of ingestion. However, ingested microplastics persisted in individuals for up to 14 days. Furthermore, microalgal feeding was significantly reduced by 27.2% in the presence of 102 particles/mL microplastics over 24 h. Histological analyses indicated that a greater abundance of lipid droplets was present among epithelia after 24 h of exposure at a concentration of 10 particles/mL. Moreover, intestinal epithelia were deformed and disorderedly arranged after 14 d of exposure. Overall, these results indicate that marine microplastic pollution could pose a threat to A. parthenogenetica health, especially that of larvae. Consequently, further research is required to evaluate the potential physiological and histopathological effects of microplastics for other marine invertebrate species. Image 1 • Brine shrimp larvae have a large capacity to consume 10 μm polystyrene microspheres. • Brine shrimp larvae egested 97% of microplastics within 3 h of ingestion. • Microplastics persisted in individuals (1.23 particles/individual) for up to 14 days. • Microalgal feeding was significantly reduced in the presence of microplastics. • Several histological changes were observed in intestines of exposed individuals. [ABSTRACT FROM AUTHOR]

• UBC9, the only conjugating enzyme essential for the SUMO system, was found to play a critical role in hematopoietic development in the bone marrow. • Remarkably, Ubc9 deletion in the hematopoietic system caused decreased thymus weight and reduced lymphocyte to myeloid cell ratio. • Importantly, Ubc9 deficiency only selectively impaired the functionality of common lymphoid progenitors during hematopoietic development. Hematopoietic development occurs in the bone marrow, and this process begins with hematopoietic stem cells (HSCs). Ubc9 is a unique E2-conjugating enzyme required for SUMOylation, an evolutionarily conserved post-translational modification system. We herein show that a conditional Ubc9 deletion in the hematopoietic system caused decreased thymus weight and reduced lymphocyte to myeloid cell ratio. Importantly, Ubc9 deletion in the hematopoietic system only selectively impaired the development of common lymphoid progenitors (CLPs) in the bone marrow and perturbed their potential to differentiate into lymphocytes, thereby decreasing the number of T/B cells in the periphery. Ubc9 was found to be required for CLP viability, and therefore, Ubc9 deficiency rendered CLPs to undergo apoptosis and attenuated their proliferation. Thus, Ubc9 plays a critical role in the regulation of CLP function during hematopoietic development in the bone marrow. [ABSTRACT FROM AUTHOR]

Highlights • Autophagy is an evolutionarily conserved cellular process that directs cytoplasmic proteins, organelles and microbes to lysosomes for degradation. • Regulatory T cells are a population of suppressor T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. • Autophagy is active in regulatory T cells and supports their linage stability and survival fitness. • Autophagy might be a promising target to manipulate regulatory T cell function in different disease settings. Abstract Autophagy is an evolutionarily conserved catabolic process that directs cytoplasmic proteins, organelles and microbes to lysosomes for degradation. It not only represents an essential cell-intrinsic mechanism to protect against internal and external stresses but also shapes both innate and adaptive immunity. Regulatory T cells (Tregs) are a developmentally and functionally distinct T cell subpopulation engaged in sustaining immunological self-tolerance and homeostasis. There is compelling evidence that autophagy is actively regulated in Tregs and serves as a central signal-dependent controller for Tregs by restraining excessive apoptotic and metabolic activities. In this review, we discuss how autophagy modulates the stability and functionality of Tregs in different disease settings, and provide a perspective on how manipulation of autophagy enables better control of immune response by targeting the generation of Tregs and the maintenance of their stability. [ABSTRACT FROM AUTHOR]

• Summarized the practice of combined national park protection around the world. • Analyzed spatial patterns of 87 protected areas in the Greater Shangri-La region. • Proposed screening framework for national park agglomerations. • The framework covers ecosystem, landscape, culture, distance, and management. National park agglomerations are a collection of multiple types of regional protected areas, and these agglomerations are of great importance for giving play to the functions of various ecosystem services in protected areas, establishing ecological corridors, and improving the level of regional ecological protection. The Greater Shangri-La region is located at the junction of Sichuan, Yunnan, and Tibet Provinces in China and is in the transition zone of two major biogeographical regions, the Palearctic and Indo-Malay regions, with numerous and rich types of protected areas. This study summarizes the practice of combined national park protection globally, analyzes the spatial pattern of 87 protected areas in the Greater Shangri-La region, proposes a framework for the spatial identification and screening of national park agglomerations based on ecoregions, and establishes the ecosystem, landscape type, cultural heritage, spatial distance, and protection management used as indicators for the screening framework of national park agglomerations. Five national park agglomerations, namely, Three Parallel Rivers, Shaluli Mountain-Daxue Mountain, Southeast Tibetan Plateau, Liangshan Mountain, and Panxi Rift, are present in this area, covering 52 protected areas, with characteristics of spatial agglomeration, diverse types, and natural and cultural heritage-rich features. These results help improve the environmental protection system in the Greater Shangri-La region and better promote the construction of national park agglomerations in other places of the world. [ABSTRACT FROM AUTHOR]

With the continuous development of modern electronic technology, it is of great significance to explore materials with flexibility and stable electromagnetic interference shielding (EMI) properties in extreme environments. In response to this, a highly conductive polyimide-Ti 3 C 2 T x MXene-silver nanoparticles (PI-MXene-AgNPs) composite film was prepared by performing a self-reduction reaction on the surface of poly(amic acid) nanofibers. The polyimide nanofibers are wrapped with Ti 3 C 2 T x nanosheets and AgNPs. The film has excellent EMI shielding performance in X-band (8.2–12.4 GHz). When the mass ratio of MXene/AgNO 3 is 4:1, the PI-MXene-AgNPs films have high absolute EMI shielding effectiveness up to 16785.67 dB cm2 g−1 at a thickness of 30 μ m. The composite film has stable EMI shielding performance even after high (300 °C) temperature, cryogenic (−196 °C), corrosive environment, multiple bending and physical shaking. Furthermore, PI-MXene-AgNPs films exhibit excellent flexibility and superior mechanical properties that can be maintained even after treatment under harsh conditions. In addition, the PI-MXene-AgNPs composite films show good versatility, such as photothermal conversion properties, antibacterial properties. Therefore, this work provides a feasible strategy for the preparation of flexible electronic devices in extreme environments. [Display omitted] [ABSTRACT FROM AUTHOR]

Obesity has emerged as an imminent global public health concern over the past several decades. It has now become evident that obesity is characterized by the persistent and low-grade inflammation in the adipose tissue, and serves as an independent risk factor for many metabolic disorders such as diabetes and cardiovascular disease. Particularly, adipocytes originated from obese mice and humans likely predominate necrosis upon stressful insults, leading to passive release of cellular contents including the high mobility group box 1 (HMGB1) into the extracellular milieu. Extracellular HMGB1 acts as an innate alarmin to stimulate the activation of resident immune cells in the adipose tissue. Upon activation, those resident immune cells actively secrete additional HMGB1, which in turn activates/recruits additional immune cells, and induces adipocyte death. This review summarizes those novel discoveries in terms of HMGB1 in the initiation and maintenance of chronic inflammatory state in adipose tissue in obesity, and discusses its potential application in clinical settings. [ABSTRACT FROM AUTHOR]

Imbalanced nutrient intake causes abnormal energy metabolism, which results in obesity. There is feasible evidence that selenium-rich (Se-rich) foods may alleviate obesity and enhance general public health, but the underlying mechanisms remain elusive. Herein we examined the effect of Se supplementation on white adipose tissue beiging process. The mice were fed with a normal diet or a Se-deficient high-fat diet group (DHFD) until there were significant differences in body weight, intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT). Then, the diet of DHFD group was changed to a high-fat diet (HFD) containing specified amounts of selenomethionine (SeMet) (0, 150, 300, and 600 μg/kg) and continued to feed for 14 weeks. Notably, 150 μg/kg SeMet supplement was highly protected from DHFD-induced obesity, insulin resistance, and lipid deposits in liver and kidney, and featured by the enhanced beiging process in white adipose tissue and increased energy expenditure. Moreover, upon cold challenge, 150 μg/kg SeMet supplement enhanced cold tolerance in mice for inducing adipose beiging to promote energy expenditure, evidenced by the increased expression of uncoupling protein-1 (UCP1) in adipocytes. Similarly, SeMet (10 μM) promoted the differentiation of beige adipocytes from the stromal vascular fraction. Collectively, our data support that optimal supplementation of SeMet could enhance the beiging process to attenuate HFD-induced obesity, thus providing new insights into the relationship between dietary SeMet and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Macrophages function as an essential component of innate immune system, contributing to both the initiation and appropriate resolution of inflammation. The exposure of macrophages to the microbial products, such as lipopolysaccharide (LPS), can strongly shift the balance between tissue homeostasis and inflammation in favor of causing systemic damage, in which macrophage M1 polarization play important roles. Strategies aiming at restoring the balance of macrophage polarization remain to be further explored. Herein, we have demonstrated that poliovirus receptor (PVR), the receptor of TIGIT, was dramatically upregulated on the surface of mouse peritoneal macrophages when exposed to LPS. TIGIT-Fc fusion protein not only inhibited the macrophage activation, but also skewed M1/M2 balance toward an anti-inflammatory profile, especially enhanced the secretion of IL-10. The activation of TIGIT/PVR pathway in macrophages correlated with increased nuclear translocation of c-Maf, which promotes IL-10 transcription. Treatment with fibroblasts stably secreting TIGIT-Fc fusion protein significantly reversed the lethal and sublethal endotoxic shock, which facilitated peritoneal macrophages to switch towards anti-inflammatory M2 cytokine profiles. These findings highlight a novel role of the TIGIT/PVR pathway in macrophage M2 polarization and suggest that TIGIT may have the potential to optimize the treatment of macrophage-involved inflammatory diseases. [ABSTRACT FROM AUTHOR]

The anticancer effects and mechanism of all-trans retinoic acid (ATRA), C-phycocyanin (C-PC) or ATRA+C-PC on the growth of A549 cells were studied in in vitro and in vivo experiments. The effects of C-PC and ATRA on the growth of A549 cells were determined. The expression of CDK-4 and caspase-3, and the cellular apoptosis levels were detected. The tumor model was established by subcutaneous injection of A549 cells to the left axilla of the NU/NU mice. The weights of tumor and the spleen were tested. The viabilities of T-cells and spleen cells, TNF levels, the expression of Bcl-2 protein and Cyclin D1 gene were examined. Results showed both C-PC and ATRA could inhibit the growth of tumor cells in vivo and in vitro . ATRA+C-PC cooperatively showed a higher antitumor activity. The dosage of ATRA was reduced when it was administered with C-PC together, and the toxicity was reduced as well. ATRA+C-PC could decrease CDK-4 but increase caspase-3 protein expression level and induce cell apoptosis. ATRA alone could lower the activities of T lymphocytes and spleen weights, but the combination with C-PC could effectively promote viability of T cells and spleen. C-PC+ATRA could up-regulate TNF, and down-regulate Bcl-2 and Cyclin D1 gene. The combination might inhibit tumor growth by inhibiting the progress of cell cycle, inducing cell apoptosis and enhancing the body immunity. [ABSTRACT FROM AUTHOR]

We conducted a case/control study to assess the impact of two SNPs, rs2241766 and rs1501299 within the ADIPOQ gene, on type 2 diabetes (T2D) susceptibility in a Chinese Han dataset (741 cases and 902 controls). SNP rs2241766 was found significantly associated with T2D risk in the additive model, dominant model and recessive model. A marginal association was detected for SNP rs1501299 in the additive model and recessive model after Bonferroni correction, and haplotype analysis provided additional evidence supporting the association between these two SNPs and T2D risk. A meta-analysis including 29 published datasets along with current dataset was next carried out to further confirm the association. In consistent with our case/control results, rs2241766 showed a significant association with T2D in the dominant model and additive model, and the association between rs1501299 and T2D was also characterized in the homozygote model, dominant model, recessive model, and additive model. Of note, the association became much stronger in East Asians after exclusion of ethnic stratification. Together, our data support that the rs2241766 and rs1501299 polymorphisms within the ADIPOQ gene confer genetic susceptibility for type 2 diabetes, especially in the Chinese Han population. [ABSTRACT FROM AUTHOR]

Highlights: [•] CD59 gene could inhibit the progress of atherosclerosis. [•] The anti-atherosclerotic effects were enhanced with the increase of CD59 gene dose. [•] The molecular mechanism of the inhibitory effects of CD59 gene on occurrence and development of atherosclerosis was revealed. [ABSTRACT FROM AUTHOR]

Abstract: Soluble epoxide hydrolase (sEH) is an enzyme involved in the metabolism of endogenous inflammatory and anti-apoptotic mediators. In the present study, we determined the effects of the inhibition of sEH on glucose homeostasis and islet damage in mice treated with streptozotocin (STZ), a model of chemical-induced diabetes. STZ increased daily water intake and decreased visceral (spleen and pancreas) weight in mice; sEH inhibition in STZ mice decreased water intake, but did not affect visceral weight. Hyperglycemia induced by STZ treatment in mice was attenuated by inhibiting sEH. The beneficial effects of sEH inhibition were accompanied, after 2 and 4 weeks of initial administration, by improving glucose tolerance. In contrast, sEH inhibition did not affect insulin tolerance. Using LC/MS analysis, neither STZ nor STZ plus sEH inhibition affected pancreatic and plasma ratios of epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), an index of EETs levels. Western blot analysis showed that mouse cytochrome P450 (CYP) 2C enzymes are the major epoxygenases in islets. On day 5 after initial STZ treatment, STZ induced islet cell apoptosis, while sEH inhibition in STZ mice significantly reduced islet cell apoptosis. These studies provide pharmacological evidence that inhibiting sEH activity provides significant protection against islet β-cell damage and improves glucose homeostasis in STZ-induced diabetes. [Copyright &y& Elsevier]

Abstract: The effects of three fatty acids on cytotoxic aggregate formation of Ca2+-depleted bovine α-lactalbumin (apo-BLA) have been studied by UV absorbance spectroscopy and transmission electron microscopy. The experimental results demonstrate that two unsaturated fatty acids, oleic acid and linoleic acid, and one saturated fatty acid, stearic acid, induce the intermediate of apo-BLA at pH 4.0–4.5 to form amorphous aggregates in time- and concentration-dependent manners. These aggregates are dissolved under physiological conditions at 37°C and further characterized by fluorescence spectroscopy, circular dichroism and time-of-flight mass spectrometry. Our data here indicate that the structural characteristics of these aggregates are similar to those of HAMLET/BAMLET (human/bovine α-lactalbumin made lethal to tumor cells), a complex of the partially unfolded α-lactalbumin with oleic acid. Cell viability experiments indicate the aggregates of apo-BLA induced by oleic acid and linoleic acid show significant dose-dependent cytotoxicity to human lung tumor cells of A549 but those induced by stearic acid have no toxicity to tumor cells. Furthermore, the cytotoxic aggregates of apo-BLA induced by both unsaturated fatty acids induce apoptosis of human lung cancer cell line A549, suggesting that such cytotoxic aggregates of apo-BLA could be potential antitumor drugs. The present study provides insight into the mechanism of fatty acid-dependent oligomerization and cytotoxicity of α-lactalbumin, and will be helpful in the understanding of the molecular mechanism of HAMLET/BAMLET formation. [Copyright &y& Elsevier]

Abstract: Protective immune responses in shrimp induced by DNA vaccines against white spot syndrome virus (WSSV) with intramuscular injection have been reported in recent reports. In this study, we investigated the utilities of attenuated Salmonella enterica serovar Typhimurium (Salmonella typhimurium) as a bactofection vehicle for the oral delivery of a DNA vaccine plasmid to crayfish (Cambarus clarkii). The DNA vaccine plasmid pcDNA3.1-VP28, encoding viral envelope protein VP28, was transformed to an attenuated S. typhimurium strain SV4089 and the resulting recombinant bacteria named SV/pcDNA3.1-VP28 were used to orally immunize crayfish with coated feed. Successful delivery of the DNA vaccine plasmid was shown by the isolation of recombinant bacteria SV/pcDNA3.1-VP28 from the vaccinated crayfish. The distribution analysis of plasmid pcDNA3.1-VP28 in different tissues revealed the effective release of DNA vaccine plasmid into crayfish. RT-PCR and immunoflurescence results confirmed the expression of protein VP28 in the vaccinated crayfish. Challenge experiments with WSSV at 7, 15, 25 days post-vaccination demonstrated significant protection in immunized crayfish with relative survival rate 83.3%, 66.7% and 56.7%, respectively. Studies on stability and safety of SV/pcDNA3.1-VP28 showed the recombinant bacteria could exist in crayfish at least 7 days but not more than 10 days and without any observable harm to the host. Our study here demonstrates, for the first time, the ability of attenuated Salmonella as a live vector to orally deliver a DNA vaccine against WSSV into the arthropod crayfish and provides a new way to design more practical strategies for the control of WSSV and other invertebrate pathogens. [Copyright &y& Elsevier]

Clofibrate, a peroxisome proliferator-activated receptor-α (PPARα) agonist, increases renal tubular cytochrome P450 4a (Cyp4a) expression thereby increasing 20-hydroxyeicosatetraenoic acid (20-HETE) production. To determine if clofibrate affects blood pressure regulation we studied mice with DOCA-salt induced hypertension in wild-type and PPARα knockout mice. Wild-type mice treated with DOCA-salt had higher mean arterial pressures and higher cumulative sodium balance, but lower renal 20-HETE production than did vehicle-treated mice. Treating DOCA-salt mice with clofibrate attenuated the increase in mean arterial pressure and cumulative sodium balance while increasing 20-HETE production and renal Cyp4a expression. In contrast the PPARα knockout mice treated with clofibrate and DOCA-salt showed no attenuation in the increase of blood pressure, cumulative sodium balance, renal 20-HETE production or Cyp4a protein expression. Expression of the PPARα protein was greater in proximal tubules than in renal microvessels. Our results show that PPARα pathway induces renal tubular 20-HETE production which affects sodium retention and blood pressure regulation in DOCA-salt-treated mice.Kidney International (2008) 74, 1040–1048; doi:10.1038/ki.2008.300; published online 2 July 2008 [ABSTRACT FROM AUTHOR]

Despite recent extensive studies, the molecular mechanism through which DCs induce allograft tolerance largely remains poorly understood. In the current study, we presented strong evidence supporting a role for IDO in DC-mediated allograft tolerance. Pre-treatment of recipient mice with IDO-transduced donor-specific BMDCs induced skin allograft tolerance in an antigen-dependent manner. Our data suggest that IDO-expressing DCs may regulate a delicate balance of cytokines that favors the differentiation of naïve CD4+ T cells into Tregs instead of CD4+ effector T cells. In addition, BMDCs with forced IDO expression also have higher capability to expand natural Tregs. In consistent with the observation of augmented Tregs detected in the recipient mice, the capacity for splenic T cell alloresponse was significantly reduced in recipient mice pre-treated with IDO-transduced BMDCs. Furthermore, the expression of inflammatory cytokines such as IL-2, IFN±γ, IL-6, IL-l 7A and IL-23p 19, in splenic T cells of these recipient mice, was significantly lower as compared to that of recipient mice pre-treated with either GFP-transduced BMDCs or untransduced BMDCs. [ABSTRACT FROM AUTHOR]

Abstract: Nephrotoxicity is a major side effect of cisplatin, a widely used cancer therapy drug. Recent work has suggested a role of p53 in renal cell injury by cisplatin. However, the mechanism of p53 activation by cisplatin is unclear. This study determined the possible involvement of oxidative stress in p53 activation under the pathological condition using in vitro and in vivo models. In cultured renal proximal tubular cells, cisplatin at 20μM induced an early p53 phosphorylation followed by protein accumulation. Cisplatin also induced reactive oxygen species (ROS), among which hydroxyl radicals showed a rapid and drastic accumulation. Dimethylthiourea (DMTU) and N-acetyl-cysteine (NAC) attenuated hydroxyl radical accumulation, and importantly, diminished p53 activation during cisplatin treatment. This was accompanied by the suppression of PUMA-α, a p53-regulated apoptotic gene. Concomitantly, mitochondrial cytochrome c release and apoptosis were ameliorated. Notably, DMTU and NAC, when added post-cisplatin treatment, were also inhibitory to p53 activation and apoptosis. In C57BL/6 mice, cisplatin at 30mg/kg induced p53 phosphorylation and protein accumulation, which was also abrogated by DMTU. DMTU also ameliorated tissue damage, tubular cell apoptosis and cisplatin-induced renal failure. Collectively, this study has suggested a role of oxidative stress, particularly hydroxyl radicals, in cisplatin-induced p53 activation, tubular cell apoptosis and nephrotoxicity. [Copyright &y& Elsevier]

• DUSP regulates T cell activation and its effector function. • The impact of DUSP proteins on Treg development and functionality is dynamic. • DUSP regulates T cell senescence/exhaustion and involves in chronic immune related diseases. • DUSP proteins hold the potential to be promising diagnostic biomarkers and therapeutic targets in various immune related disease settings. The functional state of T cells is diverse and under dynamic control for adapting to the changes of microenvironment. Reversible protein phosphorylation represents an important post-translational modification that not only involves in the immediate early response of T cells, but also affects their functionality in the long run. Perturbation of global phosphorylation profile and/or phosphorylation of specific signaling nodes result in aberrant T cell activity. Dual specific phosphatases (DUSPs), which target MAPKs and beyond, have increasingly been emerged as a versatile regulator in T cell biology. Herein in this mini review, we sought to summarize and discuss the impact of DUSP proteins on the regulation of effector T cell activity, T cell polarization, regulatory T cell development and T cell senescence/exhaustion. Given the distinctive engagement of each DUSP member under various disease settings such as chronic infection, autoimmune disorders, cancer and age-related diseases, DUSP proteins likely hold the promise to become a druggable target other than the existing therapeutics that are predominantly by manipulating protein kinase activity. [ABSTRACT FROM AUTHOR]