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Jie He and colleagues report exome sequencing of 113 tumor-normal pairs of esophageal squamous cell carcinoma. They highlight mutations in genes involved in cell cycle and apoptosis regulation, histone modifier genes and genes encoding members of the Hippo and Notch pathways. Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers 1 . We performed exome sequencing on 113 tumor-normal pairs, yielding a mean of 82 non-silent mutations per tumor, and 8 cell lines. The mutational profile of ESCC closely resembles those of squamous cell carcinomas of other tissues but differs from that of esophageal adenocarcinoma. Genes involved in cell cycle and apoptosis regulation were mutated in 99% of cases by somatic alterations of TP53 (93%), CCND1 (33%), CDKN2A (20%), NFE2L2 (10%) and RB1 (9%). Histone modifier genes were frequently mutated, including KMT2D (also called MLL2 ; 19%), KMT2C ( MLL3 ; 6%), KDM6A (7%), EP300 (10%) and CREBBP (6%). EP300 mutations were associated with poor survival. The Hippo and Notch pathways were dysregulated by mutations in FAT1 , FAT2 , FAT3 or FAT4 (27%) or AJUBA ( JUB ; 7%) and NOTCH1 , NOTCH2 or NOTCH3 (22%) or FBXW7 (5%), respectively. These results define the mutational landscape of ESCC and highlight mutations in epigenetic modulators with prognostic and potentially therapeutic implications.

Background Suicide is the second leading cause of death among 15- to 29-year-olds in China, and 60 % of suicidal patients have a history of depression. Previous brain imaging studies have shown that depression and suicide may be associated with abnormal activity in default mode network (DMN) regions. However, no study has specifically investigated the relationship between DMN functional activity and suicidal behavior in depressed individuals. Therefore, in the present study, we directly investigated features of DMN brain activity in adolescent patients with histories of depression and attempted suicide. Methods A total of 35 sex- and age-matched suicidal depressed patients were compared with 18 non-suicidal depressed patients and 47 healthy controls. We explored functional activity changes in DMN regions that could be associated with suicidal behavior by comparing resting-state functional magnetic resonance imaging (rs-fMRI) signals using independent component analysis (ICA). Scores on six clinical scales that measure depression severity (Hamilton Depression Scale (HDRS) and Beck Depression Inventory (BDI)) and suicidal traits (Barratt Impulsiveness Scale (BIS-11), Suicide Attitude Questionnaire (SAQ), Beck Hopelessness Scale (BHS), and Scale for Suicide Ideation (SSI)) were compared in the three groups. Results Compared with the healthy controls, all of the evaluated depressed patients showed increased functional connectivity in select DMN regions. The suicidal patients showed increased connectivity in the left cerebellum and decreased connectivity in the right posterior cingulate cortex (PCC), whereas the non-suicidal depressed patients showed increased connectivity in the left superior frontal gyrus, left lingual gyrus and right precuneus and decreased connectivity in the left cerebellum. Compared to the non-suicidal patients, the suicidal patients showed increased connectivity in the left cerebellum and the left lingual gyrus and decreased connectivity in the right precuneus. No differences in the scores of any clinical scales were found between the suicidal and non-suicidal depressed patients. Conclusions Collectively, our results highlight the importance of the DMN in the pathophysiology of depression and suggest that suicidal behavior in depressed adolescents may be related to abnormal functional connectivity in the DMN. In particular, abnormal connectivity in the PCC/precuneus and left cerebellum might be a predictor of suicidal behavior in depressed adolescent patients.

Glomerular endothelial cell （GEC） injury plays an important role in the early stage of diabetic nephropathy （DN）. Previous studies show that a PKCβ inhibitor is effective for treating DN. In the current study we further explored the effects and molecular mechanisms of PKCI3 inhibitors on GEC apoptosis in DN in streptozotocin-induced diabetic mice in vivo and high glucoseor PMA-treated human renal glomerular endothelial cells （HRGECs） in vitro. In the diabetic mice, hyperglycemia caused aggravated nephropathy and GEC apoptosis accompanied by significantly increased expression of swiprosin-1, a potentally pro-apoptotic protein. Administration of LY333531 （1 mg.kg-1.d-1 for 8 weeks） significantly attenuated both GEC apoptosis and swiprosin-1 upregulation in the diabetic mice. Similar results were observed in high glucoseor PMA-treated HRGECs in vitro. The pro-apoptotic role of swiprosin-1 was further examined using HRGECs treated with lentivirus mediating RNA interference or over-expression and swiprosin-1-knockout mice. Over-expression of swiprosin-1 in HRGECs resulted in increases in apoptosis and in caspase-9, caspase-3 and Bax expression. In contrast, knockdown of swiprosin-1 attenuated high glucoseor PMA-induced HRGECs apoptosis. Furthermore, over-expression of swiprosin-1 promoted interaction between swiprosin-1 and caspase-9 and increased the formation of apoptosomes. In diabetic swiprosin-1-/- mice, the kidney/body weight, urinary albumin, glomerular hypertrophy, mitochondrial apoptotic-associated proteins and GEC apoptosis were significantly attenuated as compared with those in diabetic swiprosin-1＋/＋ mice. These results demonstrate that swiprosin-1 is up-regulated by PKCβ in the early stage of DN, and that PKCβ facilitates GEC apoptosis through the mitochondrial-dependent pathway.

High-performance composites containing various kinds of nanofibers as reinforcing building blocks have recently received considerable attention, owing to their superior mechanical properties. One of the effective strategies to reinforce these composites involves strengthening interfacial interactions via covalent bonds. However, in contrast to nanosheets, covalent bonds have been rarely used in nanofiber-reinforced composites. Herein, we report the macroscale fabrication of a series of Ag nanowire （NW）-thiolated chitosan （TCS） composite films via spray induced self-assembly. The obtained films were significantly strengthened by Ag-S covalent bonds formed between the Ag NWs and the thiol groups of TCS. The tensile strength of the optimized Ag NW-TCS film was up to 3.9 and 1.5 times higher compared with that of pure TCS and Ag NW-chitosan （CS） films, respectively.

Although arsenic-contaminated groundwater in the Datong Basin has been studied for more than 10 years, little has been known about the complex patterns of solute transport in the aquifer systems. Field monitoring and transient 3D unsaturated groundwater flow modeling studies were car- ried out on the riparian zone of the Sanggan River at the Datong Basin, northern China, to better un- derstand the effects of groundwater flow on As mobilization and transport. The results indicate that ir- rigation is the primary factor in determining the groundwater flow paths. Irrigation can not only in- crease groundwater level and reduce horizontal groundwater velocity and thereby accelerate vertical and horizontal groundwater exchange among sand, silt and clay formations, but also change the HS concentration, redox conditions of the shallow groundwater. Results of net groundwater flux estimation suggest that vertical infiltration is likely the primary control of As transport in the vadose zone, while horizontal water exchange is dominant in controlling As migration within the sand aquifers. Recharge water, including irrigation return water and flushed saltwater, travels downward from the ground surface to the aquifer and then nearly horizontally across the sand aquifer. The maximum value of As enriched in the riparian zone is roughly estimated to be 1 706.2 mg.d-1 for a horizontal water exchange of 8.98 m3.d-1 close to the river and an As concentration of 190 μg.L-1.

Development of efficient and robust electrocatalysts is critical for practical fuel cells. We report one-dimensional bunched platinum-nickel (Pt-Ni) alloy nanocages with a Pt-skin structure for the oxygen reduction reaction that display high mass activity (3.52 amperes per milligram platinum) and specific activity (5.16 milliamperes per square centimeter platinum), or nearly 17 and 14 times higher as compared with a commercial platinum on carbon (Pt/C) catalyst. The catalyst exhibits high stability with negligible activity decay after 50,000 cycles. Both the experimental results and theoretical calculations reveal the existence of fewer strongly bonded platinum-oxygen (Pt-O) sites induced by the strain and ligand effects. Moreover, the fuel cell assembled by this catalyst delivers a current density of 1.5 amperes per square centimeter at 0.6 volts and can operate steadily for at least 180 hours.

To achieve a sensitive and accurate method in body temperature measurement of cattle, this study explores the uses of infrared thermography (IRT), an anemometer, and a humiture meter as a multiple sensors architecture. The influence of environmental factors on IRT, such as wind speed, ambient temperature, and humidity, was considered. The proposed signal processes removed the IRT frames affected by air flow, and also eliminated the IRT frames affected by random body movement of cattle using the frame difference method. In addition, the proposed calibration method reduced the impact of ambient temperature and humidity on IRT results, thereby increasing the accuracy of IRT temperature. The difference of mean value and standard deviation value between recorded rectal reference temperature and IRT temperature were 0.04 °C and 0.10 °C, respectively, and the proposed system substantially improved the measurement consistency of the IRT temperature and reference on cattle body temperature. Moreover, with a relatively small IRT image sensor, the combination of multiple sensors architecture and proper data processing still achieved good temperature accuracy. The result of the root-mean-square error (RMSE) was 0.74 °C, which is quite close to the accurate result of the IRT measurement.

Osteoblast apoptosis plays an important role in age-related bone loss and osteoporosis. Our previous study revealed that advanced oxidation protein products (AOPPs) could induce nicotinamide adenine dinucleotide phosphate oxidase (NOX)-derived reactive oxygen species (ROS) production, cause mitochondrial membrane potential (ΔΨm) depolarization, trigger the mitochondria-dependent intrinsic apoptosis pathway, and lead to osteoblast apoptosis and ultimately osteopenia and bone microstructural destruction. In this study, we found that AOPPs also induced mitochondrial ROS (mtROS) generation in osteoblastic MC3T3-E1 cells, which was closely related to NOX-derived ROS, and aggravated the oxidative stress condition, thereby further promoting apoptosis. Removing excessive ROS and damaged mitochondria is the key factor in reversing AOPP-induced apoptosis. Here, by in vitro studies, we showed that rapamycin further activated PINK1/Parkin-mediated mitophagy in AOPP-stimulated MC3T3-E1 cells and significantly alleviated AOPP-induced cell apoptosis by eliminating ROS and damaged mitochondria. Our in vivo studies revealed that PINK1/Parkin-mediated mitophagy could decrease the plasma AOPP concentration and inhibit AOPP-induced osteoblast apoptosis, thus ameliorating AOPP accumulation-related bone loss, bone microstructural destruction and bone mineral density (BMD) loss. Together, our study indicated that therapeutic strategies aimed at upregulating osteoblast mitophagy and preserving mitochondrial function might have potential for treating age-related osteoporosis.

The Chinese medicine compound, ]isuikang, can promote recovery of neurological function by inhibiting lipid peroxidation, scavenging oxygen free radicals, and effectively improving the local microenvironment after spinal cord injury. However, the mechanism remains unclear. Thus, we established a rat model of acute spinal cord injury using a modified version of Allen＇s method. Jisuikang （50, 25, and 12.5 g/kg/d） and prednis- olone were administered 30 minutes after anesthesia. Basso, Beattie, and Bresnahan locomotor scale scores and the oblique board test showed improved motor function recovery in the prednisone group and moderate-dose Jisuikang group compared with the other groups at 3-7 days post-injury. The rats in the moderate-dose Jisuikang group recovered best at 14 days post-injury. Hematoxylin-eosin staining and transmis- sion electron microscopy showed that the survival rate of neurons in treatment groups increased after 3-7 days of administration. Further, the structure of neurons and glial cells was more distinct, especially in prednisolone and moderate-dose Jisuikang groups. Western blot assay and immunohistochemistry showed that expression of brain-derived neurotrophic factor （BDNF） in injured segments was maintained at a high level after 7-14 days of treatment. In contrast, expression of nerve growth factor （NGF） was down-regulated at 7 days after spinal cord injury. Re- al-time fluorescence quantitative polymerase chain reaction showed that expression of BDNF and NGF mRNA was induced in injured segments by prednisolone and Jisuikang. At 3-7 days after injury, the effect of prednisolone was greater, while 14 days after injury, the effect of moder- ate-dose Jisuikang was greater. These results confirm that Jisuikang can upregulate BDNF and NGF expression for a prolonged period after spinal cord injury and promote repair of acute spinal cord injury, with its effect being similar to prednisolone.

The aim of this study was to determine the impact of glycyrrhizin, an inhibitor of high mobility group box 1, on glucose metabolic disorders and ovarian dysfunction in mice with polycystic ovary syndrome. We generated a polycystic ovary syndrome mouse model by using dehydroepiandrosterone plus high-fat diet. Glycyrrhizin (100 mg/kg) was intraperitoneally injected into the polycystic ovary syndrome mice and the effects on body weight, glucose tolerance, insulin sensitivity, estrous cycle, hormone profiles, ovarian pathology, glucolipid metabolism, and some molecular mechanisms were investigated. Increased number of cystic follicles, hormonal disorders, impaired glucose tolerance, and decreased insulin sensitivity in the polycystic ovary syndrome mice were reverted by glycyrrhizin. The increased high mobility group box 1 levels in the serum and ovarian tissues of the polycystic ovary syndrome mice were also reduced by glycyrrhizin. Furthermore, increased expressions of toll-like receptor 9, myeloid differentiation factor 88, and nuclear factor kappa B as well as reduced expressions of insulin receptor, phosphorylated protein kinase B, and glucose transporter type 4 were restored by glycyrrhizin in the polycystic ovary syndrome mice. Glycyrrhizin could suppress the polycystic ovary syndrome-induced upregulation of high mobility group box 1, several inflammatory marker genes, and the toll-like receptor 9/myeloid differentiation factor 88/nuclear factor kappa B pathways, while inhibiting the insulin receptor/phosphorylated protein kinase B/glucose transporter type 4 pathways. Hence, glycyrrhizin is a promising therapeutic agent against polycystic ovary syndrome. Summary Sentence Glycyrrhizin could improve inflammation, glucose metabolic disorders, and ovarian dysfunction in polycystic ovary syndrome mice by inhibiting the expression of high mobility group box 1.