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| 1 | Association of assisted reproductive technology, germline de novo mutations and congenital heart defects in a prospective birth cohort study显示文摘Emerging evidence suggests that children conceived through assisted reproductive technology(ART)have a higher risk of congenital heart defects(CHDs)even when there is no family history.De novo mutation(DNM)is a well-known cause of sporadic congenital diseases;however,whether ART procedures increase the number of germline DNM(gDNM)has not yet been well studied.Here,we performed whole-genome sequencing of 1137 individuals from 160 families conceived through ART and 205 families conceived spontaneously.Children conceived via ART carried 4.59 more gDNMs than children conceived spontaneously,including 332 paternal and 1.26 maternal DNMs,after correcting for parental age at conception,cigarette smoking,alcohol drinking,and exercise behaviors.Paternal DNMs in offspring conceived via ART are characterized by C>T substitutions at CpG sites,which potentially affect protein-coding genes and are significantly associated with the increased risk of CHD.In addition,the accumulation of non-coding functional mutations was independently associated with CHD and 87.9% of the mutations were originated from the father.Among ART offspring,infertility of the father was associated with elevated paternal DNMs;usage of both recombinant and urinary follicle-stimulating hormone and high-dosage human chorionic gonadotropin trigger was associated with an increase of maternal DNMs.In sum,the increased gDNMs in offspring conceived by ART were primarily originated from fathers,indicating that ART itself may not be a major reason for the accumulation of gDNMs.Our findings emphasize the importance of evaluating the germline status of the fathers in families with the use of ART. | Cheng Wang Hong Lv Xiufeng Ling Hong Li Feiyang Diao Juncheng Dai Jiangbo Du Ting Chen Qi Xi Yang Zhao Kun Zhou Bo Xu Xiumei Han Xiaoyu Liu Meijuan Peng Congcong Chen Shiyao Tao Lei Huang Cong Liu Mingyang Wen Yangqian Jiang Tao Jiang Chuncheng Lu Wei Wu Di Wu Minjian Chen Yuan Lin Xuejiang Guo Ran Huo Jiayin Liu Hongxia Ma Guangfu Jin Yankai Xia Jiahao Sha Hongbing Shen Zhibin Hu | 2021 | Cell Research2021，31，8： | 2 |
| 2 | Time-dependent dilatancy for brittle rocks显示文摘This paper presents a theoretical study on time-dependent dilatancy behaviors for brittle rocks. The theory employs a well-accepted postulation that macroscopically observed dilatancy originates from the expansion of microcracks. The mechanism and dynamic process that microcracks initiate from local stress concentration and grow due to localized tensile stress are analyzed. Then, by generalizing the results from the analysis of single cracks, a parameter and associated equations for its evolution are developed to describe the behaviors of the microcracks. In this circumstance, the relationship between microcracking and dilatancy can be established, and the theoretical equations for characterizing the process of rock dilatancy behaviors are derived. Triaxial compression and creep tests are conducted to validate the developed theory. With properly chosen model parameters, the theory yields a satisfactory accuracy in comparison with the experimental results. | Jie Li Mingyang Wang Kaiwen Xia Ning Zhang Houxu Huang | 2017 | Journal of Rock Mechanics and Geotechnical Engineering2017，9，6： | 1 |
| 3 | Flexible triboelectric nanogenerator toward ultrahigh-frequency vibration sensing显示文摘Flexible high-frequency vibration sensors are highly desirable in various real-world applications such as structural health monitoring,environmental monitoring,and the internet of things.However,developing a facile and effective method to fabricate vibration sensors simultaneously featuring high vibration frequency response-ability and flexibility remains a grand challenge.Herein,we report a flexible ultrahigh-frequency triboelectric vibration sensor(UTVS)prepared by a layer-particle-layer structure.Owing to the flexibility of the materials(i.e.,polyethylene terephthalate membrane)and the ultrahigh-frequency vibration response-ability of internal microparticles,the flexible UTVS exhibits an enhanced working frequency range of 3–170 kHz,which is much broader than previously reported triboelectric vibration sensors.Moreover,the UTVS can work not only in a flat state but also in a bent state due to its flexibility and the unique layer-particle-layer structural design.The UTVS shows nanometer-level vibration response-ability,omnidirectional response,stability in the temperature range of 10–70°C,good frequency resolution of 0.01 kHz,and excellent performance in burst vibration detection(e.g.,pencil lead break events and impact events from falling steel balls).With a collection of compelling features,the device is successfully demonstrated in vibration monitoring of curved structures(e.g.,real-time water pipeline leak monitoring).Such a flexible ultrahigh-frequency triboelectric vibration sensor holds great potential in a wide range of practical applications,such as communication,health care,and infrastructure monitoring. | Zhiwei Lin Chenchen Sun Gaoqiang Zhang Endong Fan Zhihao Zhou Ziying Shen Jun Yang Mingyang Liu Yushu Xia Shaobo Si Jin Yang | 2022 | Nano Research2022，15，8： | 0 |
| 4 | On the density of Birkhoff sums for Anosov diffeomorphisms显示文摘Let f : M → M be an Anosov diffeomorphism on a nilmanifold. We consider Birkhoff sums for a Holder continuous observation along periodic orbits. We show that if there are two Birkhoff sums distributed at both sides of zero, then the set of Birkhoff sums of all the periodic points is dense in R. | Shaobo Gan Yi Shi Mingyang Xia | 2022 | Science China Mathematics2022，65，2： | 0 |
| 5 | Antitumor and off-target effects of cholesterol-conjugated let-7a mimics in an orthotopic hepatocellular carcinoma xenograft nude mouse model显示文摘Objective: To explore the antitumor and potential off-target effects of systemically delivered cholesterol-conjugatedlet-7a mimics(Chol-let-7a) and control mimics(Chol-miRCtrl) on hepatocellular carcinomain vivo.Methods: The antitumor effects of two intravenous dosing regimens ofChol-let-7a on heptocellular carcinoma growth were compared using an orthotopic xenograft mouse model. Off-targets were analyzed with histopathological and ultrapathological features of heparenal tissue and cells in theChol-let-7a-, Chol-miRCtrl-, and saline-treated (blank) xenograft mice and normal control mice. Then,let-7a abundance in orthotopic tumors, corresponding paracancerous hepatic tissue, and normal liver tissue from healthy nude mice was examined by reverse transcription-polymerase chain reaction. The distribution ofChol-let-7a andChol-miRCtrl in vivo was examined by whole-animal imaging and frozen-sections observation. The experiments were approved by the Institutional Research Board of Peking Union Medical College Hospital.Results: Continuous treatment withChol-let-7a resulted in tumors that were 35.86% and 40.02% the size of those in theChol-miRCtrl and blank xenograft group (P < 0.01 andP < 0.01, respectively), while intermittent dosing withChol-let-7a resulted in tumors that were 65.42% and 56.66% the size of those in theChol-miRCtrl and the blank control group, respectively (P < 0.05 andP < 0.05). In addition, some histopathological and ultrapathological features were only observed after treatment with the two cholesterol-conjugated molecules, however mild with intermittent dosingChol-let-7a treatment, such as diffuse sinusoidal dilation and edema, primarily around the centrolobular vein in heptic tissues;mild hypercellularity with dilated capillary lumens in the renal tissue;and some organelle abnormalities found in heptic and renal cells. Furthermore, whole-animal imaging showed thatChol-let-7a andChol-miRCtrl were predominantly distributed in the liver, kidney, and bladder regions after injection, and that the concentration ofChol-let-7a andChol-miRCtrl in the kidney and the bladder decreased much slowly in the xenograft animals, especially in theChol-miRCtrl group. Finally, RT-PCR analysis showed thatlet-7a levels were significantly increased in Chol-let-7a-treated xenografts compared withChol-miRCtrl group (P=0.003) and blank xenograft group (P=0.001);however, the level was only equivalent to 50.6% and 40.7% of that in paracancerous hepatic tissue and hepatic tissue in normal mice, respectively.Conclusions: Chol-let-7a, administered either continuously or intermittently, showed effective antitumor efficacy.Chol-let-7a had some off-target effects, such as mild acute hepatitis-like inflammation and non-specific drug-induced kidney injury. The intermittent dosing regimen resulted in less damage than the continuous regimen, while maintaining relatively satisfactory antitumor efficacy, which could be useful for the investigation and possible clinical use of miRNA treatment regimens in the future. | Jian Guan Mingyang Liu Xin Li Liangrui Zhou Xueyu Dong Wei Dai Yu Xia Tao Yang Shaojuan Guo Xingqi Li Yehua Han Yufeng Luo | 2022 | Journal of Bio-X Research2022，5，4： | 0 |
| 6 | A PD-L1-targeting chimeric switch receptor enhances efficacy of CAR-T cell for pleural and peritoneal metastasis显示文摘Pleural and peritoneal metastasis accompanied by malignant pleural effusion(MPE)or malignant ascites(MA)is frequent in patients with advanced solid tumors that originate from the lung,breast,gastrointestinal tract and ovary.Regional delivery of CAR-T cells represents a new strategy to control tumor dissemination in serous cavities.However,malignant effusions constitute an immune-suppressive environment that potentially induces CAR-T cell dysfunction.Here,we demonstrated that the anti-tumor cytotoxicity of conventional 2nd-generation CAR-T cells was significantly inhibited by both the cellular and non-cellular components of MPE/MA,which was primarily attributed to impaired CAR-T cell proliferation and cytokine production in MPE/MA environment.Interestingly,we found that PD-L1 was widely expressed on freshly-isolated MPE/MA cells.Based on this feature,a novel PD-L1-targeting chimeric switch receptor(PD-L1.BB CSR)was designed,which can bind to PD-L1,switching the inhibitory signal into an additional 4-1BB signal.When co-expressed with a 2nd-generation CAR,PD-L1.BB CSR-modified CAR-T cells displayed superior fitness and enhanced functions in both culture medium and MPE/MA environment,causing rapid and durable eradication of pleural and peritoneal metastatic tumors in xenograft models.Further investigations revealed elevated expressions of T-cell activation,proliferation,and cytotoxicity-related genes,and we confirmed that PD-L1 scFv and 4-1BB intracellular domain,the two important components of PD-L1.BB CSR,were both necessary for the functional improvements of CAR-T cells.Overall,our study shed light on the clinical application of PD-L1.BB CSR-modified dual-targeting CAR-T cells.Based on this study,a phase I clinical trial was initiated in patients with pleural or peritoneal metastasis(NCT04684459). | Qizhi Ma Xia He Benxia Zhang Fuchun Guo Xuejin Ou Qiyu Yang Pei Shu Yue Chen Kai Li Ge Gao Yajuan Zhu Diyuan Qin Jie Tang Xiaoyu Li Meng Jing Jian Zhao Zeming Mo Ning Liu Yao Zeng Kexun Zhou Mingyang Feng Weiting Liao Wanting Lei Qiu Li Dan Li Yongsheng Wang | 2022 | Signal Transduction and Targeted Therapy2022，7，12： | 0 |
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