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The urban heat island (UHI) effect generated by the development of high-speed urbanization has become one of the major problems affecting the urban ecological environment. As the main body of urbanization in China, China's urban agglomerations are the core areas of urban heat island effect. The purpose of this study is to study the spatial–temporal characteristics and driving factors of surface urban heat island in 19 urban agglomerations in China, with a view to providing theoretical references for the prevention of urban thermal environmental risks. Based on Google Earth Engine (GEE), this paper estimated the surface urban heat island intensity (SUHII) of 19 urban agglomerations in China from 2003 to 2019 using MODIS land surface temperature (LST) data. Correlation analysis and regression analysis were used to explore the correlation between the change of SUHII and driving factors. Finally, the driving factors of SUHII were detected by the geo-detector model. Results showed that (1) the SUHII of 19 urban agglomerations in arid and semi-arid areas of northwestern China is higher than that in humid areas of eastern and southeastern China. (2) The SUHII of 19 urban agglomerations in China generally shows a decreasing trend, and the spatial variation of the change trend is significant. (3) There are positive correlations between SUHII and reference evapotranspiration (ET0), population density (POP), gross domestic product (GDP), nitrogen dioxide (NO2), ozone (O3), and ultraviolet aerosol index (UVAI); negative correlations with normalized difference vegetation index (NDVI), DEM, sulfur dioxide (SO2), carbon monoxide (CO), and formaldehyde (HCHO); the correlations all pass the significance test of P < 0.05 and are statistically significant. (4) The factor detection results showed that NDVI, land cover type (LC), and UVAI were the main driving factors of SUHII. The interaction detection results showed that the interaction between O3 and UVAI had the most significant impact on SUHII. [ABSTRACT FROM AUTHOR]

Welding technology plays a critical role in materials joining, especially in the manufacture and maintenance of space stations, ships, and nuclear equipment that operate under extreme conditions. These conditions present researchers with a wide range of research topics. This paper reviews the current research and application progress of welding technology under extreme conditions, such as microgravity, high temperature, and corrosion. Initially, the characteristics of extreme environments are introduced, and the technical bottlenecks faced by current welding technology in extreme environments are analyzed. The comprehensive performance changes of welded structures in these extreme environments are summarized. Subsequently, the influence of extreme environments, such as underwater and space, on the appearance quality, microstructure, and mechanical properties of welded joints is analyzed. The influence mechanism of environmental factors, such as temperature, gravity, pressure, and corrosion, on the performance of joints was elucidated based on typical welding cases of materials and engineering equipment. The various countermeasures studied to overcome the adverse effects of these extreme environments are compared. Finally, the current challenges in welding technology under extreme conditions are summarized and sorted out. The development and research of extreme welding technology in conjunction with engineering application needs are envisioned. [ABSTRACT FROM AUTHOR]

Anion exchanger 2 (AE2) is an electroneutral Na+-independent Cl-/HCO3- exchanger belongs to the SLC4 transporter family. The widely expressed AE2 participates in a variety of physiological processes, including transepithelial acid-base secretion and osteoclastogenesis. Both the transmembrane domains (TMDs) and the N-terminal cytoplasmic domain (NTD) are involved in regulation of AE2 activity. However, the regulatory mechanism remains unclear. Here, we report a 3.2 Å cryo-EM structure of the AE2 TMDs in complex with PIP2 and a 3.3 Å full-length mutant AE2 structure in the resting state without PIP2. We demonstrate that PIP2 at the TMD dimer interface is involved in the substrate exchange process. Mutation in the PIP2 binding site leads to the displacement of TM7 and further stabilizes the interaction between the TMD and the NTD. Reduced substrate transport activity and conformation similar to AE2 in acidic pH indicating the central contribution of PIP2 to the function of AE2. Anion exchanger 2 (AE2), a widely expressed Cl- /HCO3 - exchanger, participates in the regulation of intracellular pH. Here, the authors present the structures of AE2 and uncover the regulatory mechanism of PIP2. [ABSTRACT FROM AUTHOR]

Objective: Visceral adipose index (VAI) is a novel parameter for the evaluation of visceral obesity. The present study aimed to investigate the association between VAI levels and stress urinary incontinence (SUI) in a nationally representative population. Materials and methods: The National Health and Nutrition Examination Survey (NHANES) women population aged > 20 years were analyzed from 2001 to 2018. SUI was determined by self-reported questions. VAI was calculated using physical examination data and laboratory tests. Survey-weighted logistic regression models were used to analyze the correlation between SUI and VAI. Results: The final analysis included 9709 women. Among them, 4032 (41.53%) were any SUI, 1130 (11.64%) were at least weekly SUI, and 506 (5.21%) were at least daily SUI. In multivariate analysis, the odds ratio (OR) for overall SUI increased slightly after full adjustment (OR 1.06, 95% CI 1.03–1.10, P = 0.001). Similar results were observed in weekly (OR 1.04, 95% CI 1.00–1.08, P = 0.0327) and daily (OR 1.04, 95% CI 1.00–1.09, P = 0.0702) SUI. The analysis of VAI categorized showed an increased OR of any, weekly, and daily SUI in the highest compared to the lowest tertile (OR 1.44, 95% CI 1.26–1.65, P < 0.0001 for trend, OR 1.38, 95% CI 1.07–1.78, P = 0.0153 for trend, OR 1.33, 95% CI 0.94–1.87, P = 0.094 for trend). Conclusion: This study revealed a significant association between SUI and VAI among US adult women. VAI is an easily applicable index for the evaluation of visceral fat dysfunction, which might be useful for the calculation of SUI risk. [ABSTRACT FROM AUTHOR]

BTR1 (SLC4A11) is a NH3 stimulated H+ (OH-) transporter belonging to the SLC4 family. Dysfunction of BTR1 leads to diseases such as congenital hereditary endothelial dystrophy (CHED) and Fuchs endothelial corneal dystrophy (FECD). However, the mechanistic basis of BTR1 activation by alkaline pH, transport activity regulation and pathogenic mutations remains elusive. Here, we present cryo-EM structures of human BTR1 in the outward-facing state in complex with its activating ligands PIP2 and the inward-facing state with the pathogenic R125H mutation. We reveal that PIP2 binds at the interface between the transmembrane domain and the N-terminal cytosolic domain of BTR1. Disruption of either the PIP2 binding site or protonation of PIP2 phosphate groups by acidic pH can transform BTR1 into an inward-facing conformation. Our results provide insights into the mechanisms of how the transport activity and conformation changes of BTR1 are regulated by PIP2 binding and interaction of TMD and NTD. BTR1 is an electrogenic H+ transporter belonging to the bicarbonate transporter family. Here, the authors present structures of BTR1 in different conformations and uncover PIP2 as the activator of BTR1. [ABSTRACT FROM AUTHOR]

The development of efficient contrast agents for tumor-targeted imaging remains a critical challenge in the clinic. Herein, we proposed a tumor-derived extracellular vesicle (EV)-mediated targeting approach to improve in vivo tumor imaging using ternary downconversion nanoparticles (DCNPs) with strong near infrared II (NIR-II) luminescence at 1,525 nm. The EVs were metabolically engineered with azide group, followed by in vivo labeling of DCNPs through copper-free click chemistry. By taking advantage of the homologous targeting property of tumor derived EVs, remarkable improvement in the tumor accumulation (6.5% injection dose (ID)/g) was achieved in the subcutaneous colorectal cancer model when compared to that of individual DCNPs via passive targeting (1.1% ID/g). Importantly, such bioorthogonal labeling significantly increased NIR-II luminescence signals and prolonged the retention at tumor sites. Our work demonstrates the great potential of EVs-mediated bioorthogonal approach for in vivo labeling of NIR-II optical probes, which provides a robust tool for tumor-specific imaging and targeted therapy. [ABSTRACT FROM AUTHOR]

The development of urbanization has changed the original land cover and exacerbated the urban heat island effect, seriously affecting the sustainable development of the ecological environment. Research on urban heat island characteristics and land cover changes in five major urban agglomerations in China to provide a reference for preventing thermal environmental risks and urban agglomeration construction planning. This paper estimates the surface urban heat island intensity (SUHII) of the five major urban agglomerations in China from 2003 to 2019 based on Google Earth Engine (GEE) through the urban–rural dichotomy, analyzes their trends through the Sen + M–K trend analysis method, and combines the detrending rate matrix to analyze the impact of land cover type shift on urban heat island change. Research shows that (1) the land cover types of the five major urban agglomerations in China have changed considerably from 2003 to 2019, and all five major urban agglomerations in China experienced varying degrees of urban expansion. (2) The annual average value of SUHII decreases in Beijing-Tianjin-Hebei, Yangtze River Delta, and middle reaches of the urban agglomerations, while the annual average value of SUHII increases in Chengdu-Chongqing and Pearl River Delta urban agglomerations. (3) The spatial composition of land cover types in the five major urban agglomerations in China is highly spatially correlated with urban heat islands, with urban land and bare land urban heat islands being the most pronounced. (4) The land cover type shift has the most significant heat island impact on Beijing-Tianjin-Hebei, Yangtze River Delta, and Chengdu-Chongqing urban agglomerations. (5) The land cover change (LCC) with an increasing trend in SUHII is mainly bare land converted to arable land, and water bodies, grassland, forest land, and arable land converted to urban land. [ABSTRACT FROM AUTHOR]

RIG-I/DDX58 plays a key role in host innate immunity. However, its therapeutic potential for inflammation-related cancers remains to be explored. Here we identify frameshift germline mutations of RIG-I occurring in patients with colon cancer. Accordingly, Rig-ifs/fs mice bearing a frameshift mutant Rig-i exhibit increased susceptibility to colitis-related colon cancer as well as enhanced inflammatory response to chemical, virus or bacteria. In addition to interruption of Rig-i mRNA translation, the Rig-i mutation changes the secondary structure of Rig-i pre-mRNA and impairs its association with DHX9, consequently inducing a circular RNA generation from Rig-i transcript, thereby, designated as circRIG-I. CircRIG-I is frequently upregulated in colon cancers and its upregulation predicts poor outcome of colon cancer. Mechanistically, circRIG-I interacts with DDX3X, which in turn stimulates MAVS/TRAF5/TBK1 signaling cascade, eventually activating IRF3-mediated type I IFN transcription and aggravating inflammatory damage. Reciprocally, all-trans retinoic acid acts as a DHX9 agonist, ameliorates immunopathology through suppression of circRIG-I biogenesis. Collectively, our results provide insight into mutant RIG-I action and propose a potential strategy for the treatment of colon cancer. By recognizing double-stranded RNA, RIG-I is implicated in anti-viral immune responses, but also in cancer development and intestinal inflammation. Here the authors identify frameshift germline mutations of RIG-I, resulting in the generation of a circular RNA associated with increased susceptibility to colitis-associated colon cancer. [ABSTRACT FROM AUTHOR]

Mechanical clinching is often used as a green technology to join lightweight materials. The conventional clinching process creates a joint with a high protrusion at the bottom, which affects the aesthetics of the joint. It also limits the application of the clinching process to certain functional surfaces. A modified clinching technology, flat clinch-rivet clinching, has been developed to eliminate protrusions. In the study, the effect of blank holder force on the joining quality of the modified clinched joint was investigated experimentally. Different combinations of disc springs were used to produce different blank holder forces to join double-layer AA5052 sheets. Geometry, failure modes, shear strength, and tensile strength were analyzed. The results show that increasing the blank holder force helps to prevent warping of the sheet and bulging of the joint bottom. The shear strength and tensile strength for the modified joint also increase with the growth of the blank holder force. [ABSTRACT FROM AUTHOR]

The folded mitochondria inner membrane-cristae is the structural foundation for oxidative phosphorylation (OXPHOS) and energy production. By mechanically simulating mitochondria morphogenesis, we speculate that efficient sculpting of the cristae is organelle non-autonomous. It has long been inferred that folding requires buckling in living systems. However, the tethering force for cristae formation and regulation has not been identified. Combining electron tomography, proteomics strategies, super resolution live cell imaging and mathematical modeling, we reveal that the mitochondria localized actin motor-myosin 19 (Myo19) is critical for maintaining cristae structure, by associating with the SAM-MICOS super complex. We discover that depletion of Myo19 or disruption of its motor activity leads to altered mitochondria membrane potential and decreased OXPHOS. We propose that Myo19 may act as a mechanical tether for effective ridging of the mitochondria cristae, thus sustaining the energy homeostasis essential for various cellular functions. The structure of the mitochondrial inner membrane, or cristae, is important for functional oxidative phosphorylation and energy production. Here, the authors show that loss of myosin 19 impairs cristae structure as well as energy production, connecting motor activity to membrane potential. [ABSTRACT FROM AUTHOR]

Therapeutic interventions of hepatic ischemia-reperfusion injury to attenuate liver dysfunction or multiple organ failure following liver surgery and transplantation remain limited. Here we present an innovative strategy by integrating a platinum nanoantioxidant and inducible nitric oxide synthase into the zeolitic imidazolate framework-8 based hybrid nanoreactor for effective prevention of ischemia-reperfusion injury. We show that platinum nanoantioxidant can scavenge excessive reactive oxygen species at the injury site and meanwhile generate oxygen for subsequent synthesis of nitric oxide under the catalysis of nitric oxide synthase. We find that such cascade reaction successfully achieves dual protection for the liver through reactive oxygen species clearance and nitric oxide regulation, enabling reduction of oxidative stress, inhibition of macrophage activation and neutrophil recruitment, and ensuring suppression of proinflammatory cytokines. The current work establishes a proof of concept of multifunctional nanotherapeutics against ischemia-reperfusion injury, which may provide a promising intervention solution in clinical use. Pharmacological interventions against hepatic ischemia-reperfusion injury remain limited. Here, the authors provide a nanotherapeutics-based solution combining reactive oxygen species scavenging and nitric oxide modulation. [ABSTRACT FROM AUTHOR]

Predicting compound–protein interactions (CPIs) is of great importance for drug discovery and repositioning, yet still challenging mainly due to the sparse nature of CPI matrixes, resulting in poor generalization performance. Hence, unlike typical CPI prediction models focused on representation learning or model selection, we propose a deep neural network-based strategy, PCM-AAE, that re-explores and augments the pharmacological space of kinase inhibitors by introducing the adversarial auto-encoder model (AAE) to improve the generalization of the prediction model. To complete the data space, we constructed Ensemble of PCM-AAE (EPA), an ensemble model that quickly and accurately yields quantitative predictions of binding affinity between any human kinase and inhibitor. In rigorous internal validation, EPA showed excellent performance, consistently outperforming the model trained with the imbalanced set, especially for targets with relatively fewer training data points. Improved prediction accuracy of EPA for external datasets enhances its generalization ability, making it possible to gracefully handle previously unseen kinases and inhibitors. EPA showed promising potential when directly applied to virtual screening and off-target prediction, exhibiting its practicality in hit prediction. Our strategy is expected to facilitate kinase-centric drug development, as well as to solve more challenging prediction problems with insufficient data points. [ABSTRACT FROM AUTHOR]

PTEN is frequently mutated in human cancers and PTEN mutants promote tumor progression and metastasis. PTEN mutations have been implicated in immune regulation, however, the underlying mechanism is largely unknown. Here, we report that PTENα, the isoform of PTEN, remains active in cancer bearing stop-gained PTEN mutations. Through counteraction of CD8+ T cell-mediated cytotoxicity, PTENα leads to T cell dysfunction and accelerates immune-resistant cancer progression. Clinical analysis further uncovers that PTENα-active mutations suppress host immune responses and result in poor prognosis in cancer as relative to PTENα-inactive mutations. Furthermore, germline deletion of Ptenα in mice increases cell susceptibility to immune attack through augmenting stress granule formation and limiting synthesis of peroxidases, leading to massive oxidative cell death and severe inflammatory damage. We propose that PTENα protects tumor from T cell killing and thus PTENα is a potential target in antitumor immunotherapy. PTENα is an N-terminally extended isoform of PTEN, a gene frequently mutated in human cancers. Here the authors show that PTENα remains active in PTEN-mutant cancers and is associated with tumor immune escape by promoting tumor cell resistance to T cell cytotoxicity. [ABSTRACT FROM AUTHOR]

Background: Oesophageal cancer (EC) ranks high in both morbidity and mortality. A non-invasive and high-sensitivity diagnostic approach is necessary to improve the prognosis of EC patients.Methods: A total of 525 serum samples were subjected to lipidomic analysis. We combined serum lipidomics and machine-learning algorithms to select important metabolite features for the detection of oesophageal squamous cell carcinoma (ESCC), the major subtype of EC in developing countries. A diagnostic model using a panel of selected features was developed and evaluated. Integrative analyses of tissue transcriptome and serum lipidome were conducted to reveal the underlying mechanism of lipid dysregulation.Results: Our optimised diagnostic model with a panel of 12 lipid biomarkers together with age and gender reaches a sensitivity of 90.7%, 91.3% and 90.7% and an area under receiver-operating characteristic curve of 0.958, 0.966 and 0.818 in detecting ESCC for the training cohort, validation cohort and independent validation cohort, respectively. Integrative analysis revealed matched variation trend of genes encoding key enzymes in lipid metabolism.Conclusions: We have identified a panel of 12 lipid biomarkers for diagnostic modelling and potential mechanisms of lipid dysregulation in the serum of ESCC patients. This is a reliable, rapid and non-invasive tumour-diagnostic approach for clinical application. [ABSTRACT FROM AUTHOR]

Shieldin, including SHLD1, SHLD2, SHLD3 and REV7, functions as a bridge linking 53BP1-RIF1 and single-strand DNA to suppress the DNA termini nucleolytic resection during non-homologous end joining (NHEJ). However, the mechanism of shieldin assembly remains unclear. Here we present the crystal structure of the SHLD3-REV7-SHLD2 ternary complex and reveal an unexpected C (closed)-REV7-O (open)-REV7 conformational dimer mediated by SHLD3. We show that SHLD2 interacts with O-REV7 and the N-terminus of SHLD3 by forming β sheet sandwich. Disruption of the REV7 conformational dimer abolishes the assembly of shieldin and impairs NHEJ efficiency. The conserved FXPWFP motif of SHLD3 binds to C-REV7 and blocks its binding to REV1, which excludes shieldin from the REV1/Pol ζ translesion synthesis (TLS) complex. Our study reveals the molecular architecture of shieldin assembly, elucidates the structural basis of the REV7 conformational dimer, and provides mechanistic insight into orchestration between TLS and NHEJ. Shieldin, including SHLD1, SHLD2, SHLD3 and REV7, functions to suppress the DNA termini nucleolytic resection during non-homologous end joining (NHEJ). Here the authors present the crystal structure of the SHLD3-REV7-SHLD2 ternary complex revealing insights into the mechanism of the complex. [ABSTRACT FROM AUTHOR]

This paper mainly investigated the controllable preparation of well-dispersed ZnO nanoparticles by a surfactant-assisted method which selected laminated 6-polyglycerol monostearate (6-PGME) supermicelle as template. Typically, nano-ZnO particles confined in 6-PGME (6-PGME-ZnO) exhibited promising ultraviolet (UV) absorption with a blue-shift in comparison with the conventional bulk ZnO. Notably, the as-prepared 6-PGME-ZnO particles could be easily dispersed in sweet almond, jojoba oil and/or evening primrose oil as sunscreen agent. The physicochemical properties of 6-PGME-ZnO sample were further characterized to elucidate its relationship with adsorption capacity. This work might provide an alternative and green route for the development of ZnO-based nanomaterials, which have remarkable potential application in anti-UV fields. [ABSTRACT FROM AUTHOR]

Neurosteroids are synthesized in the nervous system from cholesterol or steroidal precursors imported from peripheral sources. These compounds are important allosteric modulators of γ-aminobutyric acid A receptors (GABARs), which play a vital role in pain modulation in the lateral thalamus, a main gate where somatosensory information enters the cerebral cortex. Using high-performance liquid chromatography/tandem mass spectrometry, we found increased levels of neurosteroids (pregnenolone, progesterone, deoxycorticosterone, allopregnanolone, and tetrahydrodeoxycorticosterone) in the chronic stage of neuropathic pain (28 days after spared nerve injury) in rats. The expression of the translocator protein TSPO, the upstream steroidogenesis rate-limiting enzyme, increased at the same time. In vivo stereotaxic microinjection of neurosteroids or the TSPO activator AC-5216 into the lateral thalamus (AP −3.0 mm, ML ±3.0 mm, DV 6.0 mm) alleviated the mechanical allodynia in neuropathic pain, while the TSPO inhibitor PK 11195 exacerbated it. The analgesic effects of AC-5216 and neurosteroids were significantly attenuated by the GABAR antagonist bicuculline. These results suggested that elevated neurosteroids in the lateral thalamus play a protective role in the chronic stage of neuropathic pain. [ABSTRACT FROM AUTHOR]

Deregulation of the TH17 subset of helper T cells is closely linked with immunological disorders and inflammatory diseases. However, the mechanism by which TH17 cells are regulated remains elusive. Here we found that the phosphatase DUSP2 (PAC1) negatively regulated the development of TH17 cells. DUSP2 was directly associated with the signal transducer and transcription activator STAT3 and attenuated its activity through dephosphorylation of STAT3 at Tyr705 and Ser727. DUSP2-deficient mice exhibited severe susceptibility to experimental colitis, with enhanced differentiation of TH17 cells and secretion of proinflammatory cytokines. In clinical patients with ulcerative colitis, DUSP2 was downregulated by DNA methylation and was not induced during T cell activation. Our data demonstrate that DUSP2 is a true STAT3 phosphatase that modulates the development of TH17 cells in the autoimmune response and inflammation. [ABSTRACT FROM AUTHOR]

Tumor suppressor PTEN regulates cellular activities and controls genome stability through multiple mechanisms. In this study, we report that PTEN is necessary for the protection of DNA replication forks against replication stress. We show that deletion of PTEN leads to replication fork collapse and chromosomal instability upon fork stalling following nucleotide depletion induced by hydroxyurea. PTEN is physically associated with replication protein A 1 (RPA1) via the RPA1 C-terminal domain. STORM and iPOND reveal that PTEN is localized at replication sites and promotes RPA1 accumulation on replication forks. PTEN recruits the deubiquitinase OTUB1 to mediate RPA1 deubiquitination. RPA1 deletion confers a phenotype like that observed in PTEN knockout cells with stalling of replication forks. Expression of PTEN and RPA1 shows strong correlation in colorectal cancer. Heterozygous disruption of RPA1 promotes tumorigenesis in mice. These results demonstrate that PTEN is essential for DNA replication fork protection. We propose that RPA1 is a target of PTEN function in fork protection and that PTEN maintains genome stability through regulation of DNA replication. [ABSTRACT FROM AUTHOR]

PTEN is one of the most frequently mutated tumour suppressors and reduction in PTEN protein stability also plays a role in tumorigenesis. Although several ubiquitin ligases for PTEN have been identified, the deubiquitylase for de-polyubiquitylation and stabilization of PTEN is less defined. Here, we report OTUD3 as a deubiquitylase of PTEN. OTUD3 interacts with, de-polyubiquitylates and stabilizes PTEN. Depletion of OTUD3 leads to the activation of Akt signalling, induction of cellular transformation and cancer metastasis. OTUD3 transgenic mice exhibit higher levels of the PTEN protein and are less prone to tumorigenesis. Reduction of OTUD3 expression, concomitant with decreased PTEN abundance, correlates with human breast cancer progression. Furthermore, we identified loss-of-function OTUD3 mutations in human cancers, which either abolish OTUD3 catalytic activity or attenuate the interaction with PTEN. These findings demonstrate that OTUD3 is an essential regulator of PTEN and that the OTUD3-PTEN signalling axis plays a critical role in tumour suppression. [ABSTRACT FROM AUTHOR]

The tumor suppressor p53 is essential for several cellular processes that are involved in the response to diverse genotoxic stress, including cell cycle arrest, DNA repair, apoptosis and senescence. Studies of the regulation of p53 have mostly focused on its stability and transactivation; however, new regulatory molecules for p53 have also been frequently identified. Here, we report that human ssDNA binding protein SSB1 (hSSB1), a novel DNA damage-associated protein, can interact with p53 and protect p53 from ubiquitin-mediated degradation. Furthermore, hSSB1 also associates with the acetyltransferase p300 and is required for efficient transcriptional activation of the p53 target gene p21 by affecting the acetylation of p53 at lysine382. Functionally, the hSSB1 knockdown-induced abrogation of the G2/M checkpoint is partially dependent on p53 or p300. Collectively, our results indicate that hSSB1 may regulate DNA damage checkpoints by positively modulating p53 and its downstream target p21. [ABSTRACT FROM AUTHOR]

The date palm ( Phoenix dactylifera L.), famed for its sugar-rich fruits (dates) and cultivated by humans since 4,000 B.C., is an economically important crop in the Middle East, Northern Africa, and increasingly other places where climates are suitable. Despite a long history of human cultivation, the understanding of P. dactylifera genetics and molecular biology are rather limited, hindered by lack of basic data in high quality from genomics and transcriptomics. Here we report a large-scale effort in generating gene models (assembled expressed sequence tags or ESTs and mapped to a genome assembly) for P. dactylifera, using the long-read pyrosequencing platform (Roche/454 GS FLX Titanium) in high coverage. We built fourteen cDNA libraries from different P. dactylifera tissues (cultivar Khalas) and acquired 15,778,993 raw sequencing reads-about one million sequencing reads per library-and the pooled sequences were assembled into 67,651 non-redundant contigs and 301,978 singletons. We annotated 52,725 contigs based on the plant databases and 45 contigs based on functional domains referencing to the Pfam database. From the annotated contigs, we assigned GO (Gene Ontology) terms to 36,086 contigs and KEGG pathways to 7,032 contigs. Our comparative analysis showed that 70.6 % (47,930), 69.4 % (47,089), 68.4 % (46,441), and 69.3 % (47,048) of the P. dactylifera gene models are shared with rice, sorghum, Arabidopsis, and grapevine, respectively. We also assigned our gene models into house-keeping and tissue-specific genes based on their tissue specificity. [ABSTRACT FROM AUTHOR]

Alkylating agents induce genome-wide base damage, which is repaired mainly by N-methylpurine DNA glycosylase (MPG). An elevated expression of MPG in certain types of tumor cells confers higher sensitivity to alkylation agents because MPG-induced apurinic/apyrimidic (AP) sites trigger more strand breaks. However, the determinant of drug sensitivity or insensitivity still remains unclear. Here, we report that the p53 status coordinates with MPG to play a pivotal role in such process. MPG expression is positive in breast, lung and colon cancers (38.7%, 43.4% and 25.3%, respectively) but negative in all adjacent normal tissues. MPG directly binds to the tumor suppressor p53 and represses p53 activity in unstressed cells. The overexpression of MPG reduced, whereas depletion of MPG increased, the expression levels of pro-arrest gene downstream of p53 including p21, 14-3-3σ and Gadd45 but not proapoptotic ones. The N-terminal region of MPG was specifically required for the interaction with the DNA binding domain of p53. Upon DNA alkylation stress, in p53 wild-type tumor cells, p53 dissociated from MPG and induced cell growth arrest. Then, AP sites were repaired efficiently, which led to insensitivity to alkylating agents. By contrast, in p53-mutated cells, the AP sites were repaired with low efficacy. To our knowledge, this is the first direct evidence to show that a DNA repair enzyme functions as a selective regulator of p53, and these findings provide new insights into the functional linkage between MPG and p53 in cancer therapy. [ABSTRACT FROM AUTHOR]

Date palm provides both staple food and gardening for the Middle East and North African countries for thousands of years. Its fruits have diversified significantly, such as nutritional content, size, length, weight color, and ripping process. Dates palm represent an excellent model system for the study of fruit development and diversity of fruit-bearing palm species that produce the most versatile fruit types as compared to other plant families. Using Roche/454 GS FLX instrument, we acquired 7.6 million sequence tags from seven fruiting stages (F1-F7). Over 99% of the raw reads are assembled, and the numbers of isotigs (equivalent to transcription units or unigenes) range from 30,684 to 40,378 during different fruiting stages. We annotated isotigs using BLASTX and BLASTN, and mapped 74% of the isotigs to known functional sequences or genes. Based on gene ontology categorization and pathway analysis, we have identified 10 core cell division genes, 18 ripening related genes, and 7 starch metabolic enzymes, which are involved as nutrition storage and sugar/starch metabolisms. We noticed that many metabolic pathways vary significantly during fruit development, and carbohydrate metabolism (especially sugar synthesis) is particularly prominent during fruit ripening. Transcriptomics study on various fruiting stages of date palm shows complicated metabolic activities during fruit development, ripening, synthesis and accumulation of starch enzymes and other related sugars. Most Genes are highly expressed in early stages of development, while late developmental stages are critical for fruit ripening including most of the metabolism associated ones. [ABSTRACT FROM AUTHOR]

In this study, we describe a method for highly specific enrichment of phosphopeptides with multifunctional chitosan-glycidyl methacrylate (GMA)-iminodiacetic acid (IDA)-Fe (III) nanospheres for direct analysis by matrix-assisted laser desorption-ionization mass spectrometry (MALDI-MS). This is the first time that chitosan has been used to create nanospheres support material for selective enrichment of phosphopeptides by modification with GMA, derivatization with IDA, and loading with Fe (III) ions. Chitosan-GMA-IDA-Fe (III) nanospheres with a diameter of 20 to 100 nm have multifunctional chemical moieties which confer unique properties, good dispersibility in highly acidic binding buffers, as well as good biocompatibility and chemical stability which improves their specific interaction with phosphopeptides using various types of acid binding buffers. The process of enrichment is very simple, quick, efficient, and specific. Its high specificity and efficiency for purification of phosphopeptides is reflected in the very low and substoichiometric amounts of phosphopeptides which can be detected, in quantities as low as 1:3,000 M ratios. Compared with other state-of the-art technologies such as the use of conventional Fe-IMAC and TiO, these chitosan nanosphere techniques show superior specificity and sensitivity. Moreover, the resultant chitosan-GMA-IDA-Fe nanosphere-absorbed phosphopeptides can be either directly analyzed by MALDI-TOF MS analysis or eluted and further analyzed by nano-LC-MS/MS. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

We investigated the effect of HMT (hexamethylenetetraamine) on the anodic growth of TiO2 nanotube arrays. The tube length increases to 4.3 μm with HMT concentration increasing to 0.04 mol·L−1. Adsorption of HMT on the TiO2 surface is shown to markedly decrease the chemical dissolution rate of tube mouth, resulting in longer nanotube length. Furthermore, Pt nanoparticles were successfully deposited on the surface of TiO2 nanotubes by ac electrodeposition method. The TiO2/Pt composites were characterized by field emission scanning electron microscope (FESEM), X-ray photoelectron spectra (XPS), and photoelectrochemistry. An enhancement in photocurrent density has been achieved upon modification of TiO2 nanotubes with Pt nanoparticles. [ABSTRACT FROM AUTHOR]

Triangle sail mussel ( Hyriopsis cumingii) is the most important mussel species commercially exploited for freshwater pearl production in China. However, its genome research is still at the infantry. Genomic resources for this species are largely not available. The objectives of this study was to generate expressed sequence tags from a hemocyte cDNA library, to identify genes involved in defense mechanisms, and to identify polymorphic markers from the expressed sequence tag (EST) resources for genetic analysis. A total of 5,290 ESTs were sequenced, obtaining 481 contigs and 1,165 singletons. BLAST similarity analysis indicated almost half (46.5%) of these ESTs were homologs of known genes while 53.5% were transcripts of unknown identities. Based on sequence similarities, 50 genes were identified as putative genes involved in immune and defense functions such as hemocyte immune process, stress proteins, adhesive proteins, proteases and protease regulators, antimicrobial peptides, lysosomal enzymes, cell apoptosis, and cell cycle proteins. A total of 201 microsatellites were identified from these ESTs, with 31 having sufficient flanking sequences for primer design. Polymerase chain reaction amplification was successful for 18 primer pairs and 14 of them were polymorphic. A total of 987 putative single nucleotide polymorphisms were identified including 204 transitions, 611 transversions, and 172 indels; 12 of them were involved in nine genes of defense mechanisms. These resources provide the material basis for future marker validation and genetic linkage and quantitative trait loci analysis in the freshwater pearl mussel. [ABSTRACT FROM AUTHOR]

p53 has a role in many cellular processes through the transcriptional regulation of target genes. PAC1 (phosphatase of activated cells 1; also known as dual specificity phosphatase 2, DUSP2) is a dual threonine/tyrosine phosphatase that specifically dephosphorylates and inactivates mitogen-activated protein (MAP) kinases. Here we show that during apoptosis, p53 activates transcription of PAC1 by binding to a palindromic site in the PAC1 promoter. PAC1 transcription is induced in response to serum deprivation and oxidative stress, which results in p53-dependent apoptosis, but not in response to ?-irradiation, which causes cell cycle arrest. Reduction of PAC1 transcription using small interfering RNA inhibits p53-mediated apoptosis, whereas overexpression of PAC1 increases susceptibility to apoptosis and suppresses tumour formation. Moreover, activation of p53 significantly inhibits MAP kinase activity. We conclude that, under specific stress conditions, p53 regulates transcription of PAC1 through a new p53-binding site, and that PAC1 is necessary and sufficient for p53-mediated apoptosis. Identification of a palindromic motif as a p53-binding site may reveal a novel mechanism whereby p53 regulates its target genes. [ABSTRACT FROM AUTHOR]

Presents research which showed that the protein p85 participates in the cell death process that is induced in response to oxidative stress without involving the signaling protein phosphatidyl-3-OH kinase (PI(3)K). Effects of reactive oxygen species on cells; Disruption of p85 by homologous recombination; Relation between p85 and the protein p53; Methods; p85 acting as a signal transducer and mediating cell death regulated by p53.

The hallmark of type 2 diabetes, the most common metabolic disorder, is a defect in insulin-stimulated glucose transport in peripheral tissues. Although a role for phosphoinositide-3kinase (PI3K) activity in insulin-stimulated glucose transport and glucose transporter isoform 4 (Glut4) translocation has been suggested in vitro, its role in viva and the molecular link between activation of PI3K and translocation has not yet been elucidated. To determine the role of PI3K in glucose homeostasis, we generated mice with a targeted disruption of the gene encoding the p85α regulatory subunit of PI3K (Pik3r1; refs 3-5). Pik3r1[sup -/-] mice showed increased insulin sensitivity and hypoglycaemia due to increased glucose transport in skeletal muscle and adipocytes. Insulin-stimulated PI3K activity associated with insulin receptor substrates (IRSs) was mediated via full-length p85α in wild-type mice, but via the p50α alternative splicing isoform of the same gene in Pik3r1[sup -/-] mice. This isoform switch was associated with an increase in insulin-induced generation of phosphatidylinositol(3,4,5)triphosphate (Ptdlns(3,4,5)P[sub 3]) in Pik3r1[sup -/-] adipocytes and facilitation of Glut4 translocation from the low-density microsome (LDM) fraction to the plasma membrane (PM). This mechanism seems to be responsible for the phenotype of Pik3r1[sup -/-] mice, namely increased glucose transport and hypoglycaemia. Our work provides the first direct evidence that PI3K and its regulatory subunit have a role in glucose homeostasis in vivo. [ABSTRACT FROM AUTHOR]

Introduction: Schizophrenia (SCH) is one of the most common psychiatric disorders, which involves impairments in motivation and cognition. The pathological mechanisms underlying SCH are still unknown, and no effective therapies can prevent or treat perfectly the cognitive impairments and deficit symptoms caused by SCH.Objectives: We aimed to find the lipid expression change in plasma that underlie SCH onset and antipsychotics treatment.Methods: We performed a data independent acquisition-based untargeted lipidomic approach on a quadrupole-time of flight liquid chromatography coupled to mass spectrometry platform. The plasma lipidomic profiles of SCH patients (n = 20) pre- and post-antipsychotics treatment were acquired as well as healthy controls (n = 29). Grouped or paired t-test were used to analyze the data.Results: Over 1000 features were detected by our lipidomic analysis, of which 445 lipids belonging to 17 lipid species were reliably identified by tandem mass spectrometry. After statistical analysis, 47 lipids belonging to 9 lipid species were found to be dysregulated between naive SCH patients and healthy controls, and 50 lipids belonging to 9 lipid species were found to be dysregulated after antipsychotics treatment. These findings include several new SCH-relevant lipid species such as sphingomyelin, acylcarnitine and ceramide. Four types of lipid expression regulative patterns can be concluded from the above mentioned findings, revealing information about mechanism, side-effect and potential target of antipsychotics.Conclusions: The work presented here have revealed several new lipid species which are significantly dysregulated in SCH disease development or antipsychotics treatment. These lipids provide new evidence for the pathological studies of SCH and new antipsychotics development, or can be considered as potentially candidate biomarkers for further validation. [ABSTRACT FROM AUTHOR]

Cullin-RING E3 ubiquitin ligase (CRL) family members play critical roles in numerous biological processes and diseases including cancer and Alzheimer's disease. Oligomerization of CRLs has been reported to be crucial for the regulation of their activities. However, the structural basis for its regulation and mechanism of its oligomerization are not fully known. Here, we present cryo-EM structures of oligomeric CRL2FEM1B in its unneddylated state, neddylated state in complex with BEX2 as well as neddylated state in complex with FNIP1/FLCN. These structures reveal that asymmetric dimerization of N8-CRL2FEM1B is critical for the ubiquitylation of BEX2 while FNIP1/FLCN is ubiquitylated by monomeric CRL2FEM1B. Our data present an example of the asymmetric homo-dimerization of CRL. Taken together, this study sheds light on the ubiquitylation strategy of oligomeric CRL2FEM1B according to substrates with different scales. Synopsis: The structural basis and biological importance of cullin-RING ubiquitin ligase (CRL) oligomerization remain largely unclear. Here, high-resolution cryo-EM and biochemical data reveal that oligomerization of CRL2FEM1B serves as a structural foundation for accommodating substrates of varying sizes. Cryo-EM structures show oligomeric CRL2FEM1B in its unneddylated state and as neddylated form in complex with different substrates. RBX1 and CUL2 participate in the assembly of CRL2FEM1B oligomers. Asymmetric homo-dimerization allows CRL2FEM1B to ubiquitinate substrates with small scales, such as BEX2. Large substrates such as FNIP1/FLCN complexes are ubiquitinated by monomeric CRL2FEM1B. Asymmetric homo-dimerization allows ubiquitination of substrates with small scales, while large substrates are targeted by monomeric CRL2-FEM1B E3. [ABSTRACT FROM AUTHOR]

PTEN is a critical tumour suppressor that is frequently mutated in human cancer. We have previously identified a CUG initiated PTEN isoform designated PTENα, which functions in mitochondrial bioenergetics. Here we report the identification of another N-terminal extended PTEN isoform, designated PTENβ. PTENβ translation is initiated from an AUU codon upstream of and in-frame with the AUG initiation sequence for canonical PTEN. We show that the Kozak context and a downstream hairpin structure are critical for this alternative initiation. PTENβ localizes predominantly in the nucleolus, and physically associates with and dephosphorylates nucleolin, which is a multifunctional nucleolar phosphoprotein. Disruption of PTENβ alters rDNA transcription and promotes ribosomal biogenesis, and this effect can be reversed by re-introduction of PTENβ. Our data show that PTENβ regulates pre-rRNA synthesis and cellular proliferation. These results demonstrate the complexity of the PTEN protein family and the diversity of its functions. [ABSTRACT FROM AUTHOR]

PTEN is one of the most frequently mutated genes in malignancies and acts as a powerful tumor suppressor. Tumorigenesis is involved in multiple and complex processes including initiation, invasion, and metastasis. The complexity of PTEN function is partially attributed to PTEN family members such as PTENα and PTENβ. Here, we report the identification of PTENε (also named as PTEN5), a novel N‐terminal‐extended PTEN isoform that suppresses tumor invasion and metastasis. We show that the translation of PTENε/PTEN5 is initiated from the CUG816 codon within the 5′UTR region of PTEN mRNA. PTENε/PTEN5 mainly localizes in the cell membrane and physically associates with and dephosphorylates VASP and ACTR2, which govern filopodia formation and cell motility. We found that endogenous depletion of PTENε/PTEN5 promotes filopodia formation and enhances the metastasis capacity of tumor cells. Overall, we identify a new isoform of PTEN with distinct subcellular localization and molecular function compared to the known members of the PTEN family. These findings advance our current understanding of the importance and diversity of PTEN functions. Synopsis: The dual‐specificity phosphatase PTEN has long been appreciated as a pivotal tumor suppressor with complex functions partially attributed to the PTENα and PTENβ family members. This work identifies a novel PTEN isoform designated PTENε (PTEN5), which mainly localizes to the cell membrane and suppresses tumorigenesis by controlling filopodia dynamics. Translation of PTENε is initiated from the CTG816 codon within the 5′UTR of PTEN mRNA.Endogenous expression of PTENε is regulated by eIF2A and a downstream hairpin structure is critical for its alternative initiation.PTENε specifically interacts with cell motility‐related proteins, dephosphorylating VASP at Ser157 or ACTR2 at Thr237/Thr238 sites.Loss of PTENε promotes filopodia formation and tumor metastasis in cell culture and mice, respectively. [ABSTRACT FROM AUTHOR]