Characteristics of the Mantle Flow System Beneath the Indochina Peninsula Revealed by Teleseismic Shear Wave Splitting Analysis

Numerous geoscientific investigations have been conducted on the southeastern Tibetan Plateau and adjacent areas for understanding crustal and mantle deformation associated with the indentation of the Indian Plate into Eurasia. A number of key issues, such as the causes of a sudden change of fast polarization orientations from N-S to almost E-W at approximately 26°N revealed by shear wave splitting (SWS) studies, and the geodynamic implications of the transition still remain enigmatic, partially due to the lack of sufficient SWS measurements on the Indochina Peninsula. Here we employ the SWS technique to systematically illuminate upper mantle anisotropy beneath the Indochina Peninsula with an unprecedented data coverage. The resulting 409 SWS measurements from 29 stations show that upper mantle anisotropy beneath the vast majority of the study area is characterized by dominantly E-W fast orientations which are nearly orthogonal to the strike of most of the major tectonic features in the study area, ruling out significant lithospheric contributions to the observed anisotropy. This observation, when combined with results from seismic tomography, numerical modeling, surface movement, and focal mechanism investigations, suggests that the observed azimuthal anisotropy is mostly the consequence of absolute plate motion or the westward rollback of the oceanic Indian slab. The flow system induced by the rollback or absolute plate motion may experience regional alteration from mantle upwelling along the eastern edge of the slab and through a previously detected slab window, leading to local variations in the observed splitting parameters

Efficient induction of CD25- iTreg by co-immunization requires strongly antigenic epitopes for T cells

Background: We previously showed that co-immunization with a protein antigen and a DNA vaccine coding for the same antigen induces CD40(low) IL-10(high) tolerogenic DCs, which in turn stimulates the expansion of antigenspecific CD4(+)CD25(-)Foxp3(+) regulatory T cells (CD25(-) iTreg). However, it was unclear how to choose the antigen sequence to maximize tolerogenic antigen presentation and, consequently, CD25(-) iTreg induction. Results: In the present study, we demonstrated the requirement of highly antigenic epitopes for CD25(-) iTreg induction. Firstly, we showed that the induction of CD25(-) iTreg by tolerogenic DC can be blocked by anti-MHC-II antibody. Next, both the number and the suppressive activity of CD25(-) iTreg correlated positively with the overt antigenicity of an epitope to activate T cells. Finally, in a mouse model of dermatitis, highly antigenic epitopes derived from a flea allergen not only induced more CD25(-) iTreg, but also more effectively prevented allergenic reaction to the allergen than did weakly antigenic epitopes. Conclusions: Our data thus indicate that efficient induction of CD25- iTreg requires highly antigenic peptide epitopes. This finding suggests that highly antigenic epitopes should be used for efficient induction of CD25- iTreg for clinical applications such as flea allergic dermatitis

A splicing isoform of TEAD4 attenuates the Hippo–YAP signalling to inhibit tumour proliferation

Aberrant splicing is frequently found in cancer, yet the biological consequences of such alterations are mostly undefined. Here we report that the Hippo–YAP signalling, a key pathway that regulates cell proliferation and organ size, is under control of a splicing switch. We show that TEAD4, the transcription factor that mediates Hippo–YAP signalling, undergoes alternative splicing facilitated by the tumour suppressor RBM4, producing a truncated isoform, TEAD4-S, which lacks an N-terminal DNA-binding domain, but maintains YAP interaction domain. TEAD4-S is located in both the nucleus and cytoplasm, acting as a dominant negative isoform to YAP activity. Consistently, TEAD4-S is reduced in cancer cells, and its re-expression suppresses cancer cell proliferation and migration, inhibiting tumour growth in xenograft mouse models. Furthermore, TEAD4-S is reduced in human cancers, and patients with elevated TEAD4-S levels have improved survival. Altogether, these data reveal a splicing switch that serves to fine tune the Hippo–YAP pathway

Engineering a Novel Antibody-Peptide Bispecific Fusion Protein Against MERS-CoV

In recent years, tremendous efforts have been made in the engineering of bispecific or multi-specific antibody-based therapeutics by combining two or more functional antigen-recognizing elements into a single construct. However, to the best of our knowledge there has been no reported cases of effective antiviral antibody-peptide bispecific fusion proteins. We previously developed potent fully human monoclonal antibodies and inhibitory peptides against Middle East Respiratory Syndrome Coronavirus (MERS-CoV), a novel coronavirus that causes severe acute respiratory illness with high mortality. Here, we describe the generation of antibody-peptide bispecific fusion proteins, each of which contains an anti-MERS-CoV single-chain antibody m336 (or normal human IgG1 CH3 domain as a control) linked with, or without, a MERS-CoV fusion inhibitory peptide HR2P. We found that one of these fusion proteins, designated as m336 diabody-pep, exhibited more potent inhibitory activity than the antibody or the peptide alone against pseudotyped MERS-CoV infection and MERS-CoV S protein-mediated cell-cell fusion, suggesting its potential to be developed as an effective bispecific immunotherapeutic for clinical use

MiR-770-5p inhibits cisplatin chemoresistance in human ovarian cancer by targeting ERCC2

In this study, we examined the role of the miRNA miR-770-5p in cisplatin chemotherapy resistance in ovarian cancer (OVC) patients. miR-770-5p expression was reduced in platinum-resistant patients. Using a 6.128-fold in expression as the cutoff value, miR-770-5p expression served as a prognostic biomarker and predicted the response to cisplatin treatment and survival among OVC patients. Overexpression of miR-770-5p in vitro reduced survival in chemoresistant cell lines after cisplatin treatment. ERCC2, a target gene of miR-770-5p that participates in the NER system, was negatively regulated by miR-770-5p. siRNA-mediated silencing of ERCC2 reversed the inhibition of apoptosis resulting from miR-770-5p downreglation in A2780S cells. A comet assay confirmed that this restoration of cisplatin chemosensitivity was due to the inhibition of DNA repair. These findings suggest that endogenous miR-770-5p may function as an anti-oncogene and promote chemosensitivity in OVC, at least in part by downregulating ERCC2. miR-770-5p may therefore be a useful biomarker for predicting chemosensitivity to cisplatin in OVC patients and improve the selection of effective, more personalized, treatment strategies

The 3M Complex Maintains Microtubule and Genome Integrity

CUL7, OBSL1, and CCDC8 genes are mutated in a mutually exclusive manner in 3M and other growth retardation syndromes. The mechanism underlying the function of the three 3M genes in development is not known. We found that OBSL1 and CCDC8 form a complex with CUL7 and regulate the level and centrosomal localization of CUL7, respectively. CUL7 depletion results in altered microtubule dynamics, prometaphase arrest, tetraploidy and mitotic cell death. These defects are recaptured in CUL7 mutated 3M cells and can be rescued by wild-type, but not 3M patients-derived CUL7 mutants. Depletion of either OBSL1 or CCDC8 results in similar defects and sensitizes cells to microtubule damage as loss of CUL7 function. Microtubule damage reduces the level of CCDC8 that is required for the centrosomal localization of CUL7. We propose that CUL7, OBSL1, and CCDC8 proteins form a 3M complex that functions in maintaining microtubule and genome integrity and normal development

SRSF1 modulates PTPMT1 alternative splicing to regulate lung cancer cell radioresistance

Background Radioresistance is the major cause of cancer treatment failure. Additionally, splicing dysregulation plays critical roles in tumorigenesis. However, the involvement of alternative splicing in resistance of cancer cells to radiotherapy remains elusive. We sought to investigate the key role of the splicing factor SRSF1 in the radioresistance in lung cancer. Methods Lung cancer cell lines, xenograft mice models, and RNA-seq were employed to study the detailed mechanisms of SRSF1 in lung cancer radioresistance. Clinical tumor tissues and TCGA dataset were utilized to determine the expression levels of distinct SRSF1-regulated splicing isoforms. KM-plotter was applied to analyze the survival of cancer patients with various levels of SRSF1-regulated splicing isoforms. Findings Splicing factors were screened to identify their roles in radioresistance, and SRSF1 was found to be involved in radioresistance in cancer cells. The level of SRSF1 is elevated in irradiation treated lung cancer cells, whereas knockdown of SRSF1 sensitizes cancer cells to irradiation. Mechanistically, SRSF1 modulates various cancer-related splicing events, particularly the splicing of PTPMT1, a PTEN-like mitochondrial phosphatase. Reduced SRSF1 favors the production of short isoforms of PTPMT1 upon irradiation, which in turn promotes phosphorylation of AMPK, thereby inducing DNA double-strand break to sensitize cancer cells to irradiation. Additionally, the level of the short isoform of PTPMT1 is decreased in cancer samples, which is correlated to cancer patients' survival. Conclusions Our study provides mechanistic analyses of aberrant splicing in radioresistance in lung cancer cells, and establishes SRSF1 as a potential therapeutic target for sensitization of patients to radiotherapy

Association of Polymorphisms in the Atrial Natriuretic Factor Gene with the Risk of Essential Hypertension: A Systematic Review and Meta-Analysis

Background: Studies evaluating the association between the atrial natriuretic peptide (ANP) genetic polymorphism and the risk of essential hypertension (EH) have reported inconsistent results. The aim of this meta-analysis was to provide a more reliable estimation of the possible relationship between the atrial natriuretic peptide genetic polymorphism and the risk of essential hypertension (EH). Methods: Relevant articles were searched to identify all case-control or cohort design studies of the associations between ANP polymorphism and EH. The heterogeneity was checked using the Q test and the inconsistent index (I2). The odds ratio (OR) test and 95% confidence interval (CI) were calculated in a fixed or random effects model to evaluate the strength of association. Begg’s test and Egger’s test were applied to evaluate the publication bias. Results: A total of 25 case-control studies including 5520 cases and 5210 controls exploring the association between ANP polymorphism and EH were available for this meta-analysis. No significant association between the T2238C polymorphism and overall EH risk under the five genetic models was found (C vs. T: OR = 1.1, 95%CI = 0.94–1.2, p = 0.38; TC vs. TT: OR = 1.1, 95%CI = 0.88–1.5, p = 0.32; CC vs. TT: OR = 1.3, 95%CI = 0.90–1.9, p = 0.16; (CC + TC) vs. TT: OR = 1.1, 95%CI = 0.88–1.4, p = 0.35; CC vs. (TT + TC): OR = 1.1, 95%CI = 0.83–1.4, p = 0.55). We also found that the G1837A polymorphism had no significant association with overall EH risk (A vs. G: OR = 1.3, 95%CI = 0.96–1.9, p = 0.090; GA vs. GG: OR = 1.5, 95%CI = 0.83–2.6, p = 0.19; AA vs. GG: OR = 0.87, 95%CI = 0.34–2.3, p = 0.78; (AA + GA) vs. GG: OR = 1.5, 95%CI = 0.86–2.5, p = 0.17; AA vs. (GG + GA): OR = 1.3, 95%CI = 0.85–2.0, p = 0.22). In the analysis of the T1766C polymorphism, after removing the study of Nkeh, the 1766C allele suggested a protective effect in the model of TC vs. TT (OR = 0.64, 95%CI = 0.47–0.86, p = 0.003) and (CC + TC) vs. TT (OR = 0.64, 95%CI = 0.48–0.87, p = 0.004). Conclusions: This meta-analysis suggested that no significant relationships between ANP T2238C, G1837A gene polymorphisms and the risk of essential hypertension exist. Conversely, the ANP T1766C gene polymorphism may be associated with the risk of essential hypertension, and the 1766C allele may be a protective factor against EH. However, due to the number of limited articles on the T1766C polymorphisms, further studies are still needed to accurately prove the association between the T1766C gene polymorphism and the risk of essential hypertension

Comparison of Secular Trends in Cervical Cancer Mortality in China and the United States: An Age-Period-Cohort Analysis

Background: As one of the most common cancers in the female population, cervical cancer has ranked as the second most incident gynecological cancer in recent years, trailing only breast cancer. We aimed to assess and compare the secular trends in cervical cancer mortality in China and the United States and analyze the independent effects of chronological age, time period and birth cohort using age-period-cohort (APC) analysis. Methods: We performed an age-period-cohort analysis using the intrinsic estimator method to estimate the independent effects of age, time period, and birth cohort on cervical cancer mortality. We collected mortality data for China and the United States from the WHO Mortality Database and China Health Statistical Yearbook database. Results: We examined the general trends in cervical mortality rates in China and the United States during the periods 1988–2012 and 1953–2012, respectively. The age-standardized mortality rates (ASMRs) for cervical cancer in urban China, rural China and the U.S. showed a general decreasing trend during the observation period, except for urban China, which experienced a significant increase beginning in 2002. The mortality rates for cervical cancer in the three areas showed a general increasing trend with age, regardless of the period effect. Period effects declined steadily in both rural China (from 0.19 to −0.26) and the U.S. (from −0.20 to −0.43); however, a slight increasing trend was identified (from −0.25 to 0.33) in urban China, which indicated that the risk of mortality increased with time. Cohort effects peaked in the cohort born in 1911–1915 in both rural China and urban China, declined consistently in the cohort born before 1950, and then decreased again in the cohort born after 1976–1980. The cohort effect in the U.S. peaked in the birth cohort born in 1876–1880, then leveled off and slightly decreased in younger generations. Conclusions: Our study showed that in general, cervical cancer mortality rates increased with age and decreased with birth cohort in the U.S., while the risk of mortality was highest in the cohort born during 1946–1975 in urban China. Additionally, the risk of mortality consistently increased with age in women younger than 64 years old in urban and rural China and began to decline in older groups. Although the age and cohort effects were relatively strong, the period effect may be the key factor affecting cervical cancer mortality trends, mainly reflecting the immediate effects of effective treatment and the implementation of screening