bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of nonfounder BRCA1/2 mutations in Ashkenazi Jewish patients presenting for genetic testing at a hereditary breast and ovarian cancer center
Authors: Frey Melissa K. , Kopparam Rohini V. , Ni Zhou Zhen , Fields Jessica C. , Buskwofie Ama , Carlson Ann D. , Caputo Thomas , Holcomb Kevin , Chapman‐Davis Eloise
Published: November 2018

Background

Genetic assessment in Ashkenazi Jewish (AJ) patients often is limited to BRCA1/2 founder mutation testing. With access to time‐efficient and cost‐efficient multigene panel testing, some advocate expanding genetic testing in this population. However, to the best of the authors’ knowledge, rates of nonfounder BRCA1/2 mutations and mutations in cancer‐associated genes other than BRCA1/2 among AJ are not known. In the current study, the authors sought to assess the prevalence of mutations other than BRCA1/2 founder mutations among AJ patients undergoing genetic assessment.

Methods

The authors reviewed the medical records for all AJ patients who underwent genetic assessment at a single institution between June 2013 and December 2016. Mutations were categorized as 1) BRCA1/2 AJ founder mutations (BRCA1 185delAG, BRCA1 5382insC, or BRCA2 6174delT); 2) nonfounder BRCA1/2 mutations; or 3) mutations in non‐BRCA1/2 cancer‐associated genes.

Results

A total of 732 AJ patients underwent genetic assessment. Of these, 371 patients (51%) had a personal history of breast or ovarian cancer, 540 patients (73.8%) had a family history of breast cancer, and 132 patients (18%) had a family history of ovarian cancer. In the study population, 101 patients (13.8%) were found to have a pathogenic mutation, 78 patients (10.7%) had a BRCA1/2 founder mutation, 3 patients (0.4%) had a nonfounder BRCA1/2 mutation, and 20 patients (2.7%) had a mutation in a non‐BRCA1/2 cancer‐associated gene. Non‐BRCA1/2 cancer‐associated genes harboring mutations included RAD51D, TP53, mutS homolog 6 (MSH6), checkpoint kinase 2 (CHEK2), adenomatous polyposis coli (APC), and Fanconi anemia group C protein (FANCC).

Conclusions

Among AJ patients found to have a pathogenic mutation on genetic assessment, approximately 22.8% had a mutation that would be missed with BRCA1/2 AJ founder mutation testing. Comprehensive multigene panel sequencing can provide clinically relevant genetic information for AJ patients and should be considered for genetic assessment in this population.
Trends in liver cancer mortality in the United States: Dual burden among foreign‐ and US‐born persons
Authors: Endeshaw Meheret , Hallowell Benjamin D. , Razzaghi Hilda , Senkomago Virginia , McKenna Matthew T. , Saraiya Mona
Published: November 2018

Background

Since the mid‐1980s, the burden of liver cancer in the United States has doubled, with 31,411 new cases and 24,698 deaths occurring in 2014. Foreign‐born individuals may be more likely to die of liver cancer than individuals in the general US‐born population because of higher rates of hepatitis B infection, a low socioeconomic position, and language barriers that limit the receipt of early cancer detection and effective treatment.

Methods

To determine whether liver cancer mortality rates were higher among foreign‐born individuals versus US‐born individuals in the United States, population‐based cancer mortality data were obtained from the National Center for Health Statistics of the Centers for Disease Control and Prevention. Annual population estimates were obtained from the US Census Bureau’s American Community Survey. Age‐adjusted mortality rates and rate ratios (RRs) for liver cancer stratified by birth place were calculated, and the average annual percent change (AAPC) was used to evaluate trends.

Results

A total of 198,557 deaths from liver and intrahepatic bile duct cancer were recorded during 2005‐2014, and 16% occurred among foreign‐born individuals. Overall, foreign‐born individuals had a 24% higher risk of liver cancer mortality than US‐born individuals (RR, 1.24; 95% confidence interval [CI], 1.22‐1.25). Foreign‐born individuals did not have any significant changes in liver cancer mortality rates overall, but among US‐born individuals, liver cancer mortality rates significantly increased (AAPC, 2.7; 95% CI, 2.1‐3.3).

Conclusions

Efforts that address the major risk factors for liver cancer are needed to help to alleviate the health disparities observed among foreign‐born individuals and reverse the increasing trend observed in the US‐born population.
Risk stratification of salivary gland cytology utilizing the Milan system of classification
Authors: Savant Deepika , Jin Cao , Chau Karen , Hagan Tamla , Chowdhury Maruf , Koppenhafer Joshua , Kercy Mercedes , Laser Alice , Gimenez Cecilia , Das Kasturi
Published: November 2018

Background

The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is based on risk stratification. Our study is a retrospective review of salivary gland fine needle aspiration cytology (FNAC) with the goal of determining the risk of malignancy (ROM) in each of the categories proposed by the MSRSGC.

Methods

FNAC of salivary gland lesions with corresponding surgical resection specimens were retrieved over a 5‐year period. Metastatic tumors were excluded. BothFNAC and corresponding surgical resections were reviewed blindly and classified as per criteria published by the MSRSGC. The ROM for each of the diagnostic categories was determined and compared with the ROM published by the MSRSGC.

Results

The total number of entities and ROM in 199 reviewed cases were as follows: Nondiagnostic 18 (9.2%) (ROM 0%), non‐neoplastic 4(2%) (ROM 0%), atypia of undetermined significance (AUS) 12(6%) (ROM 33%), benign neoplasm 118(59.2%) (ROM 0.8%), salivary gland neoplasm of uncertain malignant potential (SUMP) 22(11%) (ROM 40.9%), suspicious for malignancy 3(1.5%) (ROM 100%), malignant 22(11%) (ROM 100%).

Conclusion

The ROM reported in our study was mostly concordant with ROM published by the MSRSGC. This classification is helpful for the management of categories; nondiagnostic, non‐neoplastic, benign neoplasm, suspicious for malignancy and malignant. The management is not standardized for the category, salivary gland neoplasm of uncertain malignant potential, as clinical information plays an important role in planning surgical procedures at an individual basis. Further studies will need to be performed using this new classification to help define appropriate management and predict ROM more accurately.
Identifying a male clinical cutoff on the Eating Disorder Examination‐Questionnaire (EDE‐Q)
Authors: Schaefer Lauren M. , Smith Kathryn E. , Leonard Rachel , Wetterneck Chad , Smith Brad , Farrell Nicholas , Riemann Bradley C. , Frederick David A. , Schaumberg Katherine , Klump Kelly L. , Anderson Drew A. , Thompson J. Kevin
Published: November 2018

Objective

Evidence suggests that eating disorders (EDs) may be under‐detected in males. Commonly used measures of EDs such as the Eating Disorder Examination‐Questionnaire (EDE‐Q) were initially developed within female samples, raising concern regarding the extent to which these instruments may be appropriate for detecting EDs in males. The current study used receiver operating characteristic curve analysis to (a) examine the accuracy of the EDE‐Q global score in correctly classifying males with and without clinically significant ED pathology, and (b) establish the optimal EDE‐Q global clinical cutoff for males.

Method

Participants were a clinical sample of 245 male ED patients and a control sample of 205 male undergraduates.

Results

Eating Disorder Examination‐Questionnaire global scores demonstrated moderate‐high accuracy in predicting ED status (area under the curve = 0.85, 95% CI: 0.82–0.89). The optimal cutoff of 1.68 yielded a sensitivity of 0.77 and specificity of 0.77.

Discussion

Overall, results provide preliminary support for the discriminant validity of EDE‐Q scores among males. However, concerns remain regarding the measure's ability to comprehensively assess domains of disordered eating most relevant to males. Therefore, careful attention to the possibility for measurement bias and continued evaluation of the scale in males is encouraged.
Monitoring treatment response to tafamidis by serial native T1 and extracellular volume in transthyretin amyloid cardiomyopathy
Authors: Shintani Yasuhiro , Okada Atsushi , Morita Yoshiaki , Hamatani Yasuhiro , Amano Masashi , Takahama Hiroyuki , Amaki Makoto , Hasegawa Takuya , Ohta‐Ogo Keiko , Kanzaki Hideaki , Ishibashi‐Ueda Hatsue , Yasuda Satoshi , Shimazaki Chihiro , Yoshinaga Tsuneaki , Yazaki Masahide , Sekijima Yoshiki , Izumi Chisato
Published: November 2018

Tafamidis meglumine, a transthyretin (TTR) stabilizer, is effective in delaying the progression of neuropathy in TTR amyloidosis with Val30Met mutations. However, its efficacy in TTR amyloid cardiomyopathy is not fully elucidated. Herein, we report a 73‐year‐old Japanese man with a diagnosis of TTR amyloid cardiomyopathy with Val30Met mutation treated with tafamidis. To evaluate treatment response, cardiac magnetic resonance imaging was performed before and after 12 months of tafamidis treatment. Native T1, extracellular volume, and left ventricular mass showed no obvious worsening, and findings of other diagnostic studies also supported the efficacy of tafamidis to delay the progression of amyloid cardiomyopathy. Our case suggests that serial native T1 and extracellular volume may be novel non‐invasive imaging methods to monitor the treatment response to TTR stabilizers in cardiac amyloidosis and also that tafamidis may be effective in suppressing cardiac progression in TTR amyloid cardiomyopathy with Val30Met mutation.
Helicenic Complexes of Lanthanides: Influence of the f‐Element on the Intersystem Crossing Efficiency and Competition between Luminescence and Oxygen Sensitization
Authors: Galland Margaux , Riobé François , Ouyang Jiangkun , Saleh Nidal , Pointillart Fabrice , Dorcet Vincent , Le Guennic Boris , Cador Olivier , Crassous Jeanne , Andraud Chantal , Monnereau Cyrille , Maury Olivier
Published: November 2018

The coordination of a helicene‐functionalized bipyridine to various lanthanide complexes (Ln = Y, Eu, Yb, Gd) led to the formation of an isostructural series. The photophysical study indicated that non‐emissive lanthanides act as heavy atoms strongly enhancing singlet oxygen generation. We also demonstrated that sensitization of the f‐f luminescence is in competition with singlet oxygen generation.
Stereoselective Synthesis of the β‐Amino Acid Moiety of Fijiolide A
Authors: Kurzawa Timon , Kerste Eric , Nikodemiak Paul , Bothe Daniel , Harms Klaus , Koert Ulrich
Published: November 2018

An enantioselective synthesis of the β‐amino acid moiety of fijiolide A is described. Starting from eugenol, two sulfamates could be obtained on gram scale as substrates for an enantioselective C–H amination using Rh2(R/S‐nap)4. Acylation and ring opening of the resulting oxathiazinanes, followed by stepwise oxidation of the corresponding amino alcohol and TES‐protection of the catechol gave rise to Cramer's amino acid fragment from the total synthesis of fijiolide A.
Multiplexed Electrochemical Cancer Diagnostics With Automated Microfluidics
Authors: Mercer Conan , Jones Abby , Rusling James F. , Leech Dónal
Published: November 2018

Microfluidic platforms can lead to miniaturisation, increased throughput and reduced reagent consumption, particularly when the processes are automated. Here, a programmable microcontroller is used for automation of a microfluidic platform configured to electrochemically determine the levels of 8 proteins simultaneously in complex liquid samples. The platform system is composed of a programmable Arduino microcontroller that controls inexpensive valve actuators, pump, magnetic stirrer and electronic display. The programmable microcontroller results in repeatable timing for each step in a complex assay protocol, such as sandwich immunoassays. Application of the platform is demonstrated using a multiplexed electrochemical immunoassay based on capture at the electrode surface of magnetic particles labelled with horseradish peroxidase and detection antibody. The multiplexed assay protocol is completed in less than 30 mins and results in detection of eight proteins associated with prostate cancer. The approach presented can be used to automate and simplify high‐throughput screening campaigns, such as detection of multiple biomarkers in patient samples.
Beyond the traditional simulation design for evaluating type 1 error control: From the “theoretical” null to “empirical” null
Authors: Zhang Ting , Sun Lei
Published: November 2018

When evaluating a newly developed statistical test, an important step is to check its type 1 error (T1E) control using simulations. This is often achieved by the standard simulation design S0 under the so‐called “theoretical” null of no association. In practice, the whole‐genome association analyses scan through a large number of genetic markers (s) for the ones associated with an outcome of interest (), where comes from an alternative while the majority of s are not associated with ; the relationships are under the “empirical” null. This reality can be better represented by two other simulation designs, where design S1.1 simulates from analternative model based on , then evaluates its association with independently generated ; while design S1.2 evaluates the association between permutated and . More than a decade ago, Efron (2004) has noted the important distinction between the “theoretical” and “empirical” null in false discovery rate control. Using scale tests for variance heterogeneity, direct univariate, and multivariate interaction tests as examples, here we show that not all null simulation designs are equal. In examining the accuracy of a likelihood ratio test, while simulation design S0 suggested the method being accurate, designs S1.1 and S1.2 revealed its increased empirical T1E rate if applied in real data setting. The inflation becomes more severe at the tail and does not diminish as sample size increases. This is an important observation that calls for new practices for methods evaluation and T1E control interpretation.
Assessing potential shared genetic aetiology between body mass index and sleep duration in 142,209 individuals
Authors: Garfield Victoria , Fatemifar Ghazaleh , Dale Caroline , Smart Melissa , Bao Yanchun , Llewellyn Clare H. , Steptoe Andrew , Zabaneh Delilah , Kumari Meena
Published: November 2018

Observational studies find an association between increased body mass index (BMI) and short self‐reported sleep duration in adults. However, the underlying biological mechanisms that underpin these associations are unclear. Recent findings from the UK Biobank suggest a weak genetic correlation between BMI and self‐reported sleep duration. However, the potential shared genetic aetiology between these traits has not been examined using a comprehensive approach. To investigate this, we created a polygenic risk score (PRS) of BMI and examined its association with self‐reported sleep duration in a combination of individual participant data and summary‐level data, with a total sample size of 142,209 individuals. Although we observed a nonsignificant genetic correlation between BMI and sleep duration, using LD score regression (rg = −0.067 [SE = 0.039], P = 0.092) we found that a PRS of BMI is associated with a decrease in sleep duration (unstandardized coefficient = −1.75 min [SE = 0.67], P = 6.13 × 10−7), but explained only 0.02% of the variance in sleep duration. Our findings suggest that BMI and self‐reported sleep duration possess a small amount of shared genetic aetiology and other mechanisms must underpin these associations.
Application of artificial neural networks (ANN) for vapor‐liquid‐solid equilibrium prediction for CH4‐CO2 binary mixture
Authors: Ali Abulhassan , Abdulrahman Aymn , Garg Sahil , Maqsood Khuram , Murshid Ghulam
Published: November 2018

The
study of the frosting behavior of CO2 in the binary CH4‐CO2 is very important for energy minimization and for the smooth operation of the cryogenic purification process for natural gas due to its extensive cooling requirements. The present study focuses on the solid region of the phase envelope and the development of a predictive model using the artificial neural network (ANN) technique. It validates the model using available experimental data. The model points out the outlying data points. The ANN prediction method developed in this work can be successfully used for the vapor‐solid (V‐S) and vapor‐liquid‐solid (V‐L‐S) equilibrium of a CH4‐CO2 binary mixture for CO2 concentration of 1 to 54.2% and a temperature range of −50°C to −200°C. The use of the model for the liquid‐solid (L‐S) region in its current form is not recommended because the model was not validated due to lack of experimental data in this region. © 2018 Society of Chemical Industry and John Wiley & Sons, Ltd.
Major, trace element, and SrNd isotopic geochemistry of Cenozoic basalts in Central‐North and East Mongolia: Petrogenesis and tectonic implication
Authors: Togtokh Khasmaral , Miao Laicheng , Zhang Fochin , Baatar Munkhtsengel , Anaad Chimedtseren , Bars Amarjargal
Published: November 2018

This paper presents new major element, trace element, and SrNd isotope data of Cenozoic basalts in volcanic provinces Hovsgol, Taatsiin Gol, and Dariganga‐Abaga in Northern, Central, and Eastern Mongolia, respectively, to explore the petrogenesis of the basalts and their geodynamic setting. Cenozoic volcanic rocks in Mongolia are dominated by basalts, belonging to alkaline and tholeiitic series, and are characterized by ocean island basalts (OIB)‐like major and trace element signature, such as enrichment of light REE relative to heavy REE and enrichment in both large‐ion lithophile elements (LILE) and high‐field‐strength elements (HFSE) with positive NbTa anomalies in primitive mantle‐normalized spider diagram. On the other hand, the Central‐North Mongolian basalts are higher in SiO2 and Al2O3 but lower in MgO, CaO, and TiO2 than East Mongolian basalts and display positive K anomaly, which is in contrast to the negative K anomaly of the latter. Despite the evolved nature of the Central‐North Mongolian basalts, the roles of crustal contamination and fractional crystallization, or assimilation coupled with fractional crystallization (AFC), are insignificant in the genesis of the basalt; instead, both the mantle heterogeneity and melting condition have significant contributions to the compositional variations of the basalts. Importantly, the SrNd isotopic signatures suggest that the mantle sources are characterized by mixing of two isotopic components, a depleted mantle (DM) and an enriched mantle (EM). Although, the EM component is variable, which can be ascribed to metasomatized subcontinent lithosphere (SCLM) and altered recycled oceanic crust (ROC) for the mantle sources of the Central‐North and East Mongolian basalts, respectively. Taking these results together with published age and high‐resolution tomographic data, we propose that all Cenozoic volcanism in Mongolia is related to shallow mantle (asthenosphere) upwelling stemming from the mantle transitional zone (MTZ), but the triggering causes for the mantle upwellings are different. The mantle upwelling related to generation of the Central‐North Mongolian basalts was likely triggered by a far‐field effect of the Indo‐Asian collision, which might have caused the avalanched/subducted materials of the Mongol‐Okhotsk and/or the Central Asian orogenic belt (CAOB) that sink into and stagnated within the MTZ. The mantle upwelling related to the formation of the East Mongolian basalts, which are located at the westernmost of the big mantle wedge constructed by the subducting and stagnant Pacific slab, was induced directly by the westward subduction of the Pacific Plate beneath East Asia.
Tectonic affinity and evolution of the Alxa Block during the Neoproterozoic: Constraints from zircon U‐Pb dating, trace elements, and Hf isotopic composition
Authors: Xiao Wenzhou , Lai Jianqing , Dick Jeffrey M. , Mao Xiancheng , Chen Yan , Ou Quan , Xie Fenquan , Zeng Renyu
Published: November 2018

The Jinchuan deposit, which is located in the Longshoushan uplift (LU) on the southwest margin of the Alxa Block (AB), is the third largest Ni‐Cu deposit in the world. There are igneous rocks in the LU that widely developed in ~830 Ma, which include ore‐bearing ultramafic rock and ore‐poor mafic‐ultramafic rocks. These rocks were produced in an intracontinental extension‐rift environment, which is likely related to the Rodinia supercontinent (RS) breakup. However, contemporary magmatic rocks are absent in the AB, except the ~830 Ma igneous rocks in the LU. In this study, we present two types of metamorphic mafic‐ultramafic rocks at the border of Jinchuan II and IV mineral areas, which is inside the F17 fault zone. One type is a red‐coloured altered rock formed by ultramafic rock oxidation; there are a small number of zircons with multiple ages in the rock, which are considered to be inherited and metamorphic (hydrothermal) zircons. The other type is a chlorite tremolite schist formed by the metamorphism of fault clastics; there are a large number of zircons developed in this rock, which are mostly magmatic zircons with ages between 900 and 800 Ma and a few hydrothermal zircons. Analysis of the trace elements, the 900–800 Ma zircons, have high (Sm/La)N, low Ce/Ce*, and high Th/U values, which fit the characteristics of typical magmatic zircons. There are also high Y, U, HREE, Nb, and Ta values, which indicates that the host rocks were mostly larvikite and dolerite, and high Y, Ce, Yb, Th, Gd, and Er values indicate a within‐plate basaltic origin. All these 900–800 Ma zircons have a εHf (t) in the range of −2 to −7, which is similar to the Jinchuan ore‐bearing ultramafic rock with a partial melting origin of enriched mantle. The absence of detrital zircon age peaks in the Neoproterozoic indicates that the AB has been separated from the North China Craton since the Neoproterozoic to Paleozoic. The detrital zircons in the Yangtze Block (YB) strata with Neoproterozoic ages are slightly younger than those in the AB, with more depleted εHf (t) values, which is similar to the zircons from the Jiangnan Orogen igneous rocks. All this evidence indicates that the AB may have experienced at least 100 Myr of intracontinental extension‐rift environment from 900 to 800 Ma during the Neoproterozoic and participated in the breakup of the RS. However, the location of the AB during the Rodinia may not have been beside the YB.
Tracking the timing and nature of protolith, metamorphism, and partial melting of tourmaline‐bearing migmatites by zircon U–Pb and Hf isotopic compositions in the Yuka terrane, North Qaidam UHP metamorphic belt
Authors: Gao Shunbao , Chen Xin , Xu Rongke , Cai Pengjie , Lu Lihui , Hou Weidong , Guo Xianzheng
Published: November 2018

An integrated study using cathodoluminescence (CL) images, U–Pb geochronology, and Hf isotopic characterization of zircons was performed on migmatites from the Yuka terrane to provide insights into the timing and nature of the protoliths, metamorphism, and partial melting of these rocks. Zircon grains separated from the migmatites have three distinct domains. Residual zircon cores in samples YKT01 and YKT02 exhibit oscillatory zoning, high Th/U ratios (0.10–0.79), steep heavy rare earth element (HREE) patterns, and mean ages of 936 ± 5 Ma and 927 ± 11 Ma, respectively, indicating that they are igneous in origin and record Neoproterozoic magmatism during the Grenvillian Orogeny. CL‐grey cores record an ultrahigh‐pressure (UHP) peak metamorphism age of 435 ± 5 Ma and have low Th/U and176Lu/177Hf ratios, weak negative Eu anomalies, and relatively flat HREE patterns. The CL‐bright rims have steep HREE patterns with lower middle rare earth element (MREE) concentrations but higher HREE concentrations compared with the metamorphic cores and a weighted average age of 422 ± 4 Ma, which records the timing of melt crystallization. The migmatites incorporate garnet relicts coexisting with fluid inclusions and hydrous minerals like peritectic phengite and peritectic large anhedral poikilitic tourmaline in the leucosomes. Peak temperatures are less than 750°C, suggesting that the anatectic melts may be derived from melting of felsic gneiss in the presence of water. The timing of melt crystallization is ca. 13 Ma later than UHP metamorphism, indicating that the partial melting took place during the exhumation stage. The metamorphic zircon cores have higher176Hf/177Hf(t) ratios than the residual magmatic cores, which provides powerful evidence for the generation of the metamorphic zircons through the incorporation of internal high Hf minerals other than zircon in a closed system. Anatectic rims with lower176Hf/177Hf(t) ratios but higher176Lu/177Hf ratios than metamorphic cores suggest that the main formation mechanism is dissolution‐reprecipitation of pre‐existing zircons. In conclusion, the elevated176Hf/177Hf(t), TDM2age and decreasing176Lu/177Hf(t) ratios in the metamorphic and anatectic domains imply that the new zircons in some migmatites and granites may not reflect the Hf isotope compositions of their source rocks, accounting for the variable Hf isotope compositions in S‐type granites.
Detrital zircon U–Pb geochronology of early Cretaceous sedimentary rocks in Dingzi Bay and Taolin area from the Sulu Orogen: Provenances and tectonic implications
Authors: Liu Feifei , Zhou Yaoqi , Zhang Zhenkai , Yue Baojing
Published: November 2018

Early Cretaceous sedimentary rocks in the Sulu Orogen (SO) have been a popular topic in recent years. The provenances of sedimentary rocks can help elucidate the tectonic history of the SO, China. The Dingzi Bay and Taolin areas in the SO have always been poorly known. Thus, we date detrital zircons from four sedimentary rock samples including sandstone, siltstone, and greywacke collected in both areas. Age distributions from Dingzi Bay exhibit three major age populations including Palaeoproterozoic (1900–1800 Ma), Neoproterozoic (800–700 Ma), and Early Cretaceous (136–106 Ma) ages and small age populations including early Mesozoic, Palaeozoic, and Palaeoproterozoic–Archean ages, while age distributions in the Taolin area show the largest age population of Early Cretaceous (132–102 Ma) with minor early Mesozoic, Palaeozoic, and Neoproterozoic populations. The youngest detrital zircon populations yield weighted mean ages of ca. 116 Ma in Dingzi Bay and ca. 120 Ma in the Taolin area as the maximum depositional ages, which correspond to the Early Cretaceous Lower Qingshan Group. Age distributions in both areas indicate that the local SO served as the primary source area, whereas the Yangtze Block might have been a lesser source of detrital zircons. The comparison of geochronological, geochemical, and sedimentary data among Dingzi Bay, Taolin, Laoshan, and Lingshan Island suggests an Early Cretaceous marine basin formed over the SO. Further, considering previous regional tectonic history, we propose a two‐stage (Laiyang and Qingshan stages) evolutionary model for this marine basin. We suggest that transpression between the Laiyang and Qingshan stages due to subduction of the Pacific Plate might have caused rapid uplift of the south‐eastern SO and closing of the marine basin. Correspondingly, this process influenced the input of the source material from the Yangtze Block to the marine basin during the Qingshan stage.
Timing and evolution of Mesozoic volcanism in the central Great Xing'an Range, northeastern China
Authors: Tang Zong‐Yuan , Sun De‐You , Mao An‐Qi , Yang Dong‐Guang , Deng Chang‐Zhou
Published: November 2018

In this paper, we report on LA‐ICP‐MS zircon U–Pb dates of 14 Mesozoic volcanic rocks from the central Great Xing'an Range (CGXR). These data are integrated with the temporal and spatial distribution of local magmatism‐related Mesozoic mineralization, in an effort to develop an understanding of the geodynamic evolution of the region. Periodic magmatic events in the GXR date from ~1,703 through ~145 Ma. Mesozoic volcanism in the CGXR can be subdivided into three episodes: Triassic (250–205 Ma), Early–Middle Jurassic (182–165 Ma), and Late Jurassic–Early Cretaceous (155–115 Ma). A revision of the previously defined volcanic sequence is offered using a combination of our zircon U–Pb ages and published Mesozoic geological and geophysical evidence from northeast China. We propose that (a) Early–Middle Triassic volcanism in the CGXR resulted from subduction of the Paleo‐Asian oceanic plate; (b) Late Triassic volcanism was related to subduction of the Mongol–Okhotsk oceanic plate (especially near the Erguna Block) and subsequent extension after the closure of the Paleo‐Asian Ocean; (c) Early–Middle Jurassic volcanism was mainly controlled by the southward subduction of the Mongol–Okhotsk oceanic plate; (d) Late Jurassic–initial Early Cretaceous magmatism was initiated by closure of the Mongol–Okhotsk Ocean; and (e) late Early Cretaceous volcanism was induced following the final closure of the Mongol–Okhotsk Ocean and rollback of the Paleo‐Pacific oceanic plate.
40Ar/39Ar ages and geological significance of Neoproterozoic–Cambrian mafic rocks in the Aksu–Wushi area, NW Tarim Craton
Authors: Lu Yuanzhi , Zhu Wenbin , Jourdan Fred , Ge Rongfeng , Cui Xiang , Wen Bin
Published: November 2018

Mafic dyke swarms and continental flood basalts record crucial information on mantle dynamics, crustal palaeostress, and supercontinent cycle. However, these mafic rocks are relatively difficult to date using zircon U–Pb methods because autogenous magmatic zircons are rare or absent in the rapidly cooled mafic magmas and most zircons extracted from these rocks are likely captured from their wall rocks. One good example of this dilemma is the Precambrian mafic dykes and layered basites in the Aksu–Wushi area, NW Tarim Craton, from which abundant zircon U–Pb data have yielded age spectra similar to those of the detrital zircons from the associated (meta‐)sedimentary rocks. In this paper, we performed the first40Ar/39Ar dating on separated mineral grains from the mafic dykes (plagioclase and amphibole) and layered basites (plagioclase and pyroxene) in this area. Amphiboles from a mafic dyke cross‐cutting the blueschist‐bearing Aksu Group yielded a40Ar/39Ar plateau age of 744.5 ± 2.8 Ma, whereas pyroxenes from a layered basite within the Sugetbrak Formation yielded a40Ar/39Ar plateau age of 521.0 ± 2.1 Ma. The40Ar/39Ar plateau age of 744.5 ± 2.8 was interpreted as the crystallization age of the studied mafic dykes and provides a minimum constraint for the third phase of deformation of the blueschist terrane. The mini‐plateau age of 521.0 ± 2.1 Ma was interpreted as a minimum crystallization age for basite of the Sugetbrak Formation. We also conducted geochemical analyses on layered basites of the Sugetbrak Formation from the Xiaoenbrak Formation, and the results indicated that these layered basites shared a uniform geochemical characteristic. Combining geochronological and geochemical analyses, we propose that the basites of the Sugetbrak Formation probably recorded a rifting event on the north‐western margin of the Tarim Craton during Early Cambrian.
Trajectories of social support in adults with type 2 diabetes: Associations with depressive symptoms and functional disability
Authors: Levy Melanie , Deschênes Sonya S. , Burns Rachel J. , Elgendy Randa , Schmitz Norbert
Published: November 2018

Objectives

Little is known about temporal trajectories of social support in adults with type 2 diabetes (T2D) and how they are associated with diabetes‐related outcomes. This study identified and explored different trajectories of social support in a community sample of adults with T2D, as well as the extent to which different trajectories were prospectively associated with depressive symptoms and functional disability.

Methods

Data came from five annual waves of the Evaluation of Diabetes Treatment study (N = 1077). Social support, depressive symptoms, and functional disability were assessed via self‐report. Separate analyses were conducted to examine the associations between social support trajectories, depressive symptoms, and functional disability, adjusting for demographic characteristics, diabetes‐related covariates, and baseline depressive symptoms and functional disability.

Results

Latent class growth modeling identified four distinct social support trajectories. Trajectory Groups 1 and 2 comprised participants with persistently low and persistently moderate‐low social support, respectively. Trajectory Groups 3 and 4 included participants with persistently moderate‐high and persistently high social support, respectively. People with persistently low social support reported higher functional disability relative to those with persistently moderate‐high and persistently high social support.

Conclusions

The findings of the present study indicate that temporal patterns of social support are a predictor of future functional disability among adults with T2D.
Medical leadership competencies: A comparative study of physicians in public and private sector hospitals in India
Authors: Gulati Kamal , Madhukar Vikas , Verma Vivek , Singh Angel Rajan , Gupta Shakti Kumar , Sarkar Chitra
Published: November 2018

Purpose

Indian health care system comprising of public and private sectors needs enhancement of medical leadership capacity to face the growing challenges. Hence, this study was designed to evaluate medical leadership competencies of public and private sector doctors.

Findings

A survey questionnaire was developed to assess “self‐assessed proficiency levels” as well as “perceived importance of competency levels,” to which 532 doctors responded—290 (54.5%) from private sector and 242 (45.5%) from public sector hospitals. Statistically significant “leadership competency gap” was observed for all 30 leadership competencies in both sectors, more so in public sector. The 10 most deficient competencies were mainly in the NHS‐MLCF domains of “working with others,” “managing services,” and “setting direction.” The most low‐rated competency among public sector doctors was “knowledge of HR, procurement, financial, and contract management” while “ability to influence key decision makers who determine future government policies” was most deficient among private sector physicians. Further, deficiencies related to “time and stress management” and “conducting need analysis, identifying and prioritizing requirements” were confined to public and private sector doctors, respectively.

Conclusions

This study, first from India, highlights a critical need for medical leadership development programs in both sectors for enhancement of medical leadership capacity in the country.
Availability of health workforce in urban and rural areas in relation to Canadian seniors
Authors: Ariste Ruolz
Published: November 2018

Geographic imbalances in health human resources exist in a health care system when the composition, level, or use of health care providers does not lead to the same optimal health‐system goals in all regions. This can lead to inequitable distribution of health care services, particularly for rural and remote populations. This study aims to determine to what extent the distribution of regulated health professionals and seniors in urban and rural areas of the Canadian jurisdictions is different from one another and from the national average. Data used in this study are for the 2016 calendar year. Information about physicians was obtained from the Canadian Institute for Health Information (CIHI) Scott's Medical Database. The data for nurses (nurse practitioners, registered nurses, and licensed practical nurses) were also sourced from CIHI, Health Workforce Database. Geographic information is based on the postal code of physicians' preferred mailing address, and the residence in the case of nurses and the population. Using the Statistical Area Classification from Statistics Canada, each physician and nurse was assigned to either an urban metropolitan, urban non‐metropolitan, or rural/remote area. Findings indicate that there were twice as many nurses per 1000 seniors in urban Canada than in rural Canada. However, this gap was threefold in the case of physicians. Provinces with the largest and lowest gap and international comparisons are also provided. Three broad strategies are offered for policymakers in order to mitigate this health workforce imbalance and reduce the regional shortage of nurses and physicians.
A functional ex vivo assay to detect PARP1‐EJ repair and radiosensitization by PARP‐inhibitor in prostate cancer
Authors: Köcher Sabrina , Beyer Burkhard , Lange Tobias , Nordquist Lena , Volquardsen Jennifer , Burdak‐Rothkamm Susanne , Schlomm Thorsten , Petersen Cordula , Rothkamm Kai , Mansour Wael Yassin
Published: November 2018

Here, we present a functional assay to detect the repair switch to the alternative PARP1‐dependent end joining (PARP1‐EJ) pathway and the associated susceptibility to PARPi‐mediated radiosensitization in freshly collected tumor samples from prostate cancer (PCa) patients, thereby facilitating the selection of patients who should benefit from combined PARPi plus radiotherapy (RT) treatment. Our optimized ex‐vivo approach sustains tumor slices for up to 15 days under culture conditions that maintain proliferation and oxygenation rates, as measured by EdU incorporation and pimonidazole staining, respectively. We present a robust system to analyze DSB repair using, for the first time in an ex vivo tumor slice setting, two DSB‐markers simultaneously i.e. γH2AX and 53BP1. A computer‐based processing method (i) controls variations in DNA content and slicing on the number of repair foci and (ii) measures the PARPi‐mediated enhancement ratio on DSB foci numbers to ensure inter‐patient‐comparability. We validated this approach using a PC3 xenograft model with its previously described repair switch to PARP1‐EJ. More importantly, we show that approximately 30% of the analyzed tumor tissue samples collected from PCa patients display a switch to PARP1‐EJ, as indicated by the enhanced number of residual γH2AX/53BP1 foci exclusively after PARPi+RT. Furthermore, normal prostatic tissues show no repair switch to PARP1‐EJ, indicating that this repair switch and its associated radiosensitizing effect is tumor‐specific. Collectively, we present here a predictive assay for the switch to PARP1‐EJ that enables individualization of anti‐cancer treatment using a combination of RT and radiosensitizing anticancer agents such as PARPi in PCa.
Active vitamin D regulates macrophage M1/M2 phenotypes via the STAT‐1‐TREM‐1 pathway in diabetic nephropathy
Authors: Zhang Xiaoliang , Zhao Yu , Zhu Xiaodong , Guo Yinfeng , Yang Ying , Jiang Yuteng , Liu Bicheng
Published: November 2018

Aim

Imbalance of M1/M2 macrophages phenotype activation is a key point in diabetic nephropathy (DN). This study aimed to investigate whether active vitamin D (VD) suppresses macrophage transition to the M1 phenotype via inhibiting the high glucose‐induced STAT‐1 phosphorylation to reduce TREM‐1 expression.

Methods

In vivo, pathological changes in kidney tissue were detected and the expression of CD68 TREM‐1, STAT‐1, M1 makers, and M2 makers were acquired in renal tissue of patients with DN and 18w DN rats. In vitro, RAW 264.7 cells were incubated in the presence of high glucose with or without VD. Silencing and overexpression of TREM‐1 and silencing and activate of STAT‐1 were explored to elucidate the underlying mechanism. The expression of TREM‐1 and STAT‐1 and the changes of macrophage phenotype were examined separately by western blot and immunofluorescence staining.

Results

(a) Expression of TREM‐1, p‐STAT‐1, and M1 markers (iNOS and TNF‐α) were increased and positively correlated in kidneys from patients with DN. (b) In DN rats, the enlargement of glomerular surface area, expansion of glomerular mesangial matrix, the expression of CD68, TREM‐1, p‐STAT‐1, and M1 marker (iNOS) were significantly increased in comparison with the normal control group, whereas above changes were markedly decreased in the diabetic group treated with the VD group. (c) In vitro, VD significantly decreased high glucose‐induced CD68, TREM‐1, p‐STAT‐1, and M1 marker (iNOS) expression. However, above‐mentioned effects of VD are abolished when TREM‐1 is overexpressed or STAT‐1 is activated. Reductions in STAT‐1 expression decreased the TREM‐1 expression.

Conclusion

VD can inhibit macrophage transition to the M1 phenotype through the STAT‐1/TREM‐1 pathway.
Intersectin‐Cdc42 interaction is required for orderly meiosis in porcine oocytes
Authors: Li Xiaoyan , Gao Min , He Yongfu , Xiong Bo , Liu Honglin , Gu Ling
Published: November 2018

Intersectins (ITSNs) have been shown to act as adaptor proteins that govern multiple cellular events via regulating Cdc42 activity. However, it remains to be determined whether the ITSN‐Cdc42 pathway is functional in porcine oocytes. To address this question, we used a small molecule, ZCL278, to selectively disrupt the ITSN2‐Cdc42 interaction. In the present study, we find that porcine oocytes exposed to ZCL278 are unable to completely progress through meiosis. Meanwhile, the spindle defects and chromosomal congression failure are frequently detected in these oocytes. In support of this, we observed the accumulated distribution of vesicle‐like ITSN2 signals around the chromosome/spindle region during porcine oocyte maturation. In addition, our results also showed that inhibition of the ITSN‐Cdc42 interaction impairs the actin polymerization in porcine oocytes. In summary, the findings support a model where ITSNs, through the interaction with Cdc42, modulates the assembly of meiotic apparatus and actin polymerization, consequently ensuring the orderly meiotic progression during porcine oocyte maturation.
MicroRNA‐145 induces the senescence of activated hepatic stellate cells through the activation of p53 pathway by ZEB2
Authors: Yang Junfa , Lu Yuchen , Yang Peipei , Chen Qingfeng , Wang Yang , Ding Qi , Xu Tao , Li Xiaofeng , Li Changyao , Huang Cheng , Meng Xiaoming , Li Jun , Zhang Lei , Wang Xiao
Published: November 2018

Activation of quiescent hepatic stellate cells (HSCs) is the major event in liver fibrosis, along with enhancement of cell proliferation and overproduction of extracellular matrix. Recent findings suggest that senescence of activated HSCs might limit the development of liver fibrosis. The p53, a guardian of the genome is associated with liver fibrosis, has been shown to regulate HSCs senescence. In this study, we report that microRNA‐145 (miR‐145) and p53 were downregulated in vivo and in vitro, concomitant with the enhanced expression of zinc finger E‐box binding homeobox 2 (ZEB2). In addition, overexpression of miR‐145 and p53 led to upregulation of the number of senescence‐associated β‐galactosidase‐positive HSCs and the expression of senescence markers p16 and p21, along with the reduced abundance of HSC activation markers α‐smooth muscle actin and type I collagen in activated HSCs. Furthermore, silencing of ZEB2 promoted senescence of activated HSCs. Moreover, we also demonstrated that miR‐145 specifically targeted the 3′‐untranslated regions of ZEB2. In vitro promoter regulation studies show that ZEB2 could bind to the E‐box of the p53 promoter as well as inhibit its promoter activity and thus suppress the expression of p53, which in turn repressed activated HSCs senescence. Taken together, our results describe a novel miR‐145‐ZEB2‐p53 regulatory line might participate in the senescence of activated HSCs and might carry potential therapeutic targets for restraining liver fibrosis.
Expression and regulatory networks of Mycobacterium tuberculosis PE/PPE family antigens
Authors: Li Wu , Deng Wanyan , Xie Jianping
Published: November 2018

PE/PPE family antigens are distributed mainly in pathogenic mycobacteria and serve as potential antituberculosis (TB) vaccine components. Some PE/PPE family antigens can regulate the host innate immune response, interfere with macrophage activation and phagolysosome fusion, and serve as major sources of antigenic variation. PE/PPE antigens have been associated with mycobacteria pathogenesis; pe/ppe genes are mainly found in pathogenic mycobacteria and are differentially expressed between Mtb and Mycobacterium bovis. PE/PPE proteins were essential for the growth of Mtb, and PE/PPE proteins were differentially expressed under a variety of conditions. Multiple mycobacterial‐virulence‐related transcription factors, sigma factors, the global transcriptional regulation factor Lsr2, MprAB, and PhoPR two‐component regulatory systems, and cyclic adenine monophosphate‐dependent regulators, regulate the expression of PE/PPE family antigens. Multiple‐scale integrative analysis revealed the expression and regulatory networks of PE/PPE family antigens underlying the virulence and pathogenesis of Mtb, providing important clues for the discovery of new anti‐TB measures.
Redefining the signaling pathways from pluripotency to pancreas development: In vitro β‐cell differentiation
Authors: Hashemitabar Mahmoud , Heidari Elham
Published: November 2018

Pancreatic β‐cells are destroyed by the immune system, in type 1 diabetes (T1D) and are impaired by glucose insensitivity in type 2 diabetes (T2D). Islet‐cells transplantation is a promising therapeutic approach based on in vitro differentiation of pluripotent stem cells (PSCs) to insulin‐producing cells (IPCs). According to evolutionary stages in β‐cell development, there are several distinct checkpoints; each one has a unique characteristic, including definitive endoderm (DE), primitive gut (PG), posterior foregut (PF), pancreatic epithelium (PE), endocrine precursor (EP), and immature β‐cells up to functional β‐cells. A better understanding of the gene regulatory networks (GRN) and associated transcription factors in each specific developmental stage, guarantees the achievement of the next successful checkpoints and ensures an efficient β‐cell differentiation procedure. The new findings in signaling pathways, related to the development of the pancreas are discussed here, including Wnt, Activin/Nodal, FGF, BMP, retinoic acid (RA), sonic hedgehog (Shh), Notch, and downstream regulators, required for β‐cell commitment. We also summarized different approaches in the IPCs protocol to conceptually define a standardized system, leading to the creation of a reproducible method for β‐cell differentiation. To normalize blood glucose level in diabetic mice, the replacement therapy in the early differentiation stage, such as EP stages was associated with better outcome when compared with the fully differentiated β‐cells’ graft.