Splicing of precursor messenger RNA is accomplished by a dynamic megacomplex known as the spliceosome. Assembly of a functional spliceosome requires a preassembled U4/U6.U5 tri-snRNP complex, which ...comprises the U5 small nuclear ribonucleoprotein (snRNP), the U4 and U6 small nuclear RNA (snRNA) duplex, and a number of protein factors. Here we report the three-dimensional structure of a Saccharomyces cerevisiae U4/U6.U5 tri-snRNP at an overall resolution of 3.8 angstroms by single-particle electron cryomicroscopy. The local resolution for the core regions of the tri-snRNP reaches 3.0 to 3.5 angstroms, allowing construction of a refined atomic model. Our structure contains U5 snRNA, the extensively base-paired U4/U6 snRNA, and 30 proteins including Prp8 and Snu114, which amount to 8495 amino acids and 263 nucleotides with a combined molecular mass of ~1 megadalton. The catalytic nucleotide U80 from U6 snRNA exists in an inactive conformation, stabilized by its base-pairing interactions with U4 snRNA and protected by Prp3. Pre-messenger RNA is bound in the tri-snRNP through base-pairing interactions with U6 snRNA and loop I of U5 snRNA. This structure, together with that of the spliceosome, reveals the molecular choreography of the snRNAs in the activation process of the spliceosomal ribozyme.
This study evaluates the potential use of the regional climate model version 3 (RegCM3) driven by (1) the National Centers for Environmental Prediction (NCEP) Climate Forecast System Reanalysis ...(CFSR) data during 1982–2001 and (2) the NCEP Climate Forecast System Version 2 (CFS2) hindcast data during 2000–2010 in forecasting Western North Pacific (WNP) tropical cyclone (TC) activity. The first experiment is conducted to investigate the ability of the model in generating a good climatology of TC activity in spatial and temporal scales, so the model could be used in the second experiment to test its ability in forecasting TC genesis and landfall. Both experiments extend through the May to October WNP-TC season. Results show that the use of RegCM3 driven by the CFSR achieves a better simulation on the temporal and spatial variation of WNP-TC genesis during 1982–2001, as compared to previous studies using the same model but driven by the ERA40 reanalysis. In addition, diagnoses on the use of RegCM3 driven by the CFS2 point out that the 2000–2010 WNP-TC genesis locations and numbers from the model are very similar to those from the observations. The skill of RegCM3 in the forecasts of landfalling TCs is higher over the Southeast Asian region than over the other sub-regions of East Asia. Potential causes for such regional differences are discussed. Most importantly, statistical analyses show that the use of RegCM3 driven by the CFS2 gives a better forecast skill than the use of CFS2 alone for the prediction of WNP-TCs making landfall in East Asia. This indicates that the use of a dynamical downscaling method for the global forecast data would likely lead to a higher forecast skill of regional TC landfalls in most of the East Asian region.
Metastasis of tumors requires angiogenesis, which is comprised of multiple biological processes that are regulated by angiogenic factors. The fibroblast growth factor (FGF) is a potent angiogenic ...factor and aberrant FGF signaling is a common property of tumors. Yet, how the aberration in cancer cells contributes to angiogenesis in the tumor is not well understood. Most studies of its angiogenic signaling mechanisms have been in endothelial cells. FGF receptor substrate 2α (FRS2α) is an FGF receptor-associated protein required for activation of downstream signaling molecules that include those in the mitogen-activated protein and AKT kinase pathways. Herein, we demonstrated that overactivation and hyperactivity of FRS2α, as well as overexpression of cJUN and HIF1α, were positively correlated with vessel density and progression of human prostate cancer (PCa) toward malignancy. We also demonstrate that FGF upregulated the production of vascular endothelial growth factor A mainly by increasing expression of cJUN and HIF1α. This then promoted recruitment of endothelial cells and vessel formation for the tumor. Tumor angiogenesis in mouse PCa tissues was compromised by tissue-specific ablation of Frs2α in prostate epithelial cells. Depletion of Frs2α expression in human PCa cells and in a preclinical xenograft model, MDA PCa 118b, also significantly suppressed tumor angiogenesis accompanied with decreased tumor growth in the bone. The results underscore the angiogenic role of FRS2α-mediated signaling in tumor epithelial cells in angiogenesis. They provide a rationale for treating PCa with inhibitors of FGF signaling. They also demonstrate the potential of overexpressed FRS2α as a biomarker for PCa diagnosis, prognosis and response to therapies.
Aim To compare the diagnostic performance of breast elastography versus conventional ultrasound in the assessment of breast lesions. Materials and methods The study was approved by the hospital’s ...institutional review board. A prospective study involving 99 consecutive women who gave informed consent were enrolled from September 2007 to March 2008. One hundred and ten breast lesions were evaluated separately by conventional ultrasound, elastography and combined conventional ultrasound with elastography. Ultrasound assessment was based on the BIRADS classification, whereas elastographic assessment was based on strain pattern and the elastographic size ratios. Histological diagnosis was used as the reference standard. The sensitivity, specificity, and accuracy of each technique were compared. Results The mean age of the patients was 46.7 years. Twenty-six lesions were malignant and 84 were benign. Sensitivity, specificity, and accuracy were 88.5, 42.9 and 53.6%, respectively, for conventional ultrasound, 100, 73.8, and 80%, respectively, for elastography, and 88.5, 78.6, and 80.9%, respectively, for combined imaging. The specificity and accuracy of elastography and combined imaging were significantly better than that of conventional ultrasound ( p <0.0001), whereas there was no statistically significant difference in the sensitivity between all three groups. Two-thirds (66.7%) of sonographic false-positive lesions had benign elastogram findings, which might have been spared from biopsy. Conclusion This initial experience with ultrasound breast elastography showed that it was more specific and more accurate than conventional ultrasound. Combining elastography with ultrasound improved specificity and accuracy of ultrasound and can potentially reduce unnecessary breast biopsies.
Mixed lineage leukemia 5 (MLL5) protein is a trithorax family histone 3 lysine 4 (H3K4) methyltransferase that regulates diverse biological processes, including cell cycle progression, hematopoiesis ...and cancer. The mechanisms by which MLL5 protein stability is regulated have remained unclear to date. Here, we showed that MLL5 protein stability is cooperatively regulated by O-GlcNAc transferase (OGT) and ubiquitin-specific protease 7 (USP7). Depletion of OGT in cells led to a decrease in the MLL5 protein level through ubiquitin/proteasome-dependent proteolytic degradation, whereas ectopic expression of OGT protein suppressed MLL5 ubiquitylation. We further identified deubiquitinase USP7 as a novel MLL5-associated protein using mass spectrometry. USP7 stabilized the MLL5 protein through direct binding and deubiquitylation. Loss of USP7 induced degradation of MLL5 protein. Conversely, overexpression of USP7, but not a catalytically inactive USP7 mutant, led to decreased ubiquitylation and increased MLL5 stability. Co-immunoprecipitation and co-immunostaining assays revealed that MLL5, OGT and USP7 interact with each other to form a stable ternary complex that is predominantly located in the nucleus. In addition, upregulation of MLL5 expression was correlated with increased expression of OGT and USP7 in human primary cervical adenocarcinomas. Our results collectively reveal a novel molecular mechanism underlying regulation of MLL5 protein stability and provide new insights into the functional interplay among O-GlcNAc transferase, deubiquitinase and histone methyltransferase.
This study investigated the family well‐being of Hong Kong people through a randomized telephone survey of 2008 adults, using a standardized six‐domain index developed specifically for this ...population. Multiple regression analyses were conducted to examine the heterogeneity of family well‐being according to demographic, family structural, and socioeconomic characteristics. The results showed significant gender and age differences in people's perception of family well‐being. Education, family income, and hiring a domestic helper were also associated with higher family wellbeing index scores, while the impacts of economic activity status, family size, and caring for young children were found to be insignificant. The impact of marital status was somewhat complicated. This article discusses variations observed in the influence of the set of demographic, family structural, and socioeconomic characteristics on overall and domain‐specific family well‐being. Implications for future studies and for social policy formulation and social work practice are suggested.
Objective
The aim of this study was to examine the clinical features, treatment and outcome of systemic lupus erythematosus (SLE) patients in our centre who presented with lupus pneumonitis as the ...initial manifestation.
Methods
We performed a retrospective review of all patients who presented with lupus pneumonitis during the initial SLE manifestation from March 2006 to March 2015.
Results
There were a total of five patients in our study who presented with fever and cough as the main clinical features. All patients had pulmonary infiltrates on chest radiographs. High-resolution computed tomography, which was performed in two patients, showed ground glass opacities with patchy consolidations bilaterally. All patients received high-dose steroids, 80% received intravenous cyclophosphamide and 60% received intravenous immunoglobulin. Two patients died from severe lupus pneumonitis within 2 weeks of admission despite treatment with ventilation, steroids, cyclophosphamide and intravenous immunoglobulin.
Conclusions
Acute lupus pneumonitis is an uncommon presentation of SLE. Mortality in this case series is 40%.
A simple and versatile technique has been developed to prepare TiO2 and TiO2‐based composite (TiO2–CdS and TiO2–Au) nanotube arrays. Scanning electron microscopy (SEM), transmission electron ...microscopy (TEM), energy‐dispersive X‐ray (EDX) analysis, X‐ray diffraction (XRD), thermogravimetric analysis (TGA), UV‐vis spectroscopy, and photoluminescence (PL) spectroscopy are used to characterize their morphology, structure, composition, and properties. The TiO2–CdS nanotubes contained many TiO2 and CdS quantum dots and exhibited a novel PL band in the blue‐wavelength range. The reported strategy will be useful for fabricating nanoparticle–nanoparticle composite nanostructure arrays, which are suitable for applications in catalysis, chemical sensors, nanoelectrodes, and nanodevices.
TiO2 and TiO2‐based composite nanotube arrays have been prepared via the layer‐by‐layer assembly of polyelectrolytes, organic precursors, and nanoparticles on porous anodic alumina membranes. The nanotubes (see Figure) contain a large number of TiO2 nanocrystals, and other semiconductor quantum dots (CdS) or metallic nanoparticles (Au), and represent a new type of composite nanostructure.
Abstract
MyoD is a skeletal muscle-specifically expressed transcription factor and plays a critical role in regulating myogenesis during muscle development and regeneration. However, whether ...myofibers-expressed MyoD exerts its metabolic function in regulating whole body energy homeostasis in vivo remains largely unknown. Here, we report that genetic deletion of
Myod
in male mice enhances the oxidative metabolism of muscle and, intriguingly, renders the male mice resistant to high fat diet-induced obesity. By performing lipidomic analysis in muscle-conditioned medium and serum, we identify 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) as a muscle-released lipid that is responsible for MyoD-orchestrated body energy homeostasis in male
Myod
KO mice. Functionally, the administration of DLPC significantly ameliorates HFD-induced obesity in male mice. Mechanistically, DLPC is found to induce white adipose browning via lipid peroxidation-mediated p38 signaling in male mice. Collectively, our findings not only uncover a novel function of MyoD in controlling systemic energy homeostasis through the muscle-derived lipokine DLPC but also suggest that the DLPC might have clinical potential for treating obesity in humans.
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