The proliferation and differentiation of adult stem cells must be tightly controlled in order to maintain resident tissue homeostasis. Dysfunction of stem cells is implicated in many human diseases, including cancer. ...The proliferation and differentiation of adult stem cells must be tightly controlled in order to maintain resident tissue homeostasis. Dysfunction of stem cells is implicated in many human diseases, including cancer. However, the regulation of stem cell proliferation and differentiation is not fully understood. Here we show that the sterile-like 20 kinase, Tao, controls tissue homeostasis by regulating the Hippo pathway in the Drosophila adult midgut. Depletion of Tao in the progenitors leads to rapid intestinal stem cell （ISC） proliferation and midgut homeostasis loss. Meanwhile, we find that the Janus kinase （JAK）/signal transducer and activator of transcription （STAT） signaling activity and cytokine production are significantly increased, resulting in stimulated ISC proliferation. Furthermore, expression of the Hippo pathway downstream targets, Diapl and bantam, is dramatically increased in Tao knockdown intestines. Consistently, we show that the Yorkie （Yki） acts downstream of Tao to regulate ISC proliferation. Together, our results provide insights into our understanding of the mechanisms of stem cell proliferation and tissue homeostasis control.展开更多
Considering that the particular geometric shape of a quasi-rectangular shield,the grout flowing law and its motion process are more complicated than those of a conventional circular shield.To interpret the grouting me...Considering that the particular geometric shape of a quasi-rectangular shield,the grout flowing law and its motion process are more complicated than those of a conventional circular shield.To interpret the grouting mechanical ehaviour in the special-shape shield tail void,the filling and diffusion mechanism of synchronous grouting was analysed.The grout flowing is separated into two independent motion processes,which contains a circumferential filling and a longitudinal diffusion.The theoretical model of the grout pressure spatial distribution was derived based on the principle of fluid mechanics.Then,the pressure distributions in the two directions were obtained using a case study and compared with the field measured data to verify the validation of the model.Although the overall spatial pattern of grout pressure distribution on the tunnel profile show a change trend dominated by the self-weight effect mostly,its local fluctuation characteristics is very abnormal relative to that of a circular shield tunnel.Moreover,the important factors in the model were analysed,including the grout material parameters,the grouting construction parameters,and some geometry parameters.The results show that the pressure loss along this way is positively correlated with the grout flow velocity and is sensitive to the shear yield stress of the grout.The pressure loss along the circumferential direction is the most sensitive to the thickness of the ring cake,and the value range suitable for the model should be 0.02-0.03 m.The pressure loss along the longitudinal diffusion direction is the most sensitive to the size of the tail void.The research results can provide a theoretical basis for the control of special-shape shield construction.展开更多
PAD4 is a promising epigenetic drug target for various cancers and immune diseases. In this work, we applied a Cu-catalyzed C–H arylation reaction of N-heteroarene to the synthesis of complex non-covalent PAD4 inhibi...PAD4 is a promising epigenetic drug target for various cancers and immune diseases. In this work, we applied a Cu-catalyzed C–H arylation reaction of N-heteroarene to the synthesis of complex non-covalent PAD4 inhibitors bearing a bi-heteroaryl pharmacophore. This strategy allowed us to access various analogs of C_2-aryl substituted benzimidazoles from a common benzimidazole core and easily accessible aryl iodides. Preliminary SAR studies revealed the indole motif of GSK-484 is critical to its activity. Replacing the N-cyclopropylmethyl group to N-benzyl group on the indole ring of GSK-484 resulted in more than5-fold increase in cell killing efficacy against 4T1 cell line.展开更多
基金supported by the grants from the National Natural Science Foundation of China (Nos. 31271582 and 31030049)Wenzhou Medical University (No. XNK07005)+2 种基金Research Foundation for Advanced Talents of Wenzhou Medical College (No. QTJ08012)the National Basic Research Program of China (Nos. 2011CB943901, 2011 CB943902 and 2011CB943802)Strategic Priority Research Program of the Chinese Academy of Sciences (No.XDA01010101)
文摘The proliferation and differentiation of adult stem cells must be tightly controlled in order to maintain resident tissue homeostasis. Dysfunction of stem cells is implicated in many human diseases, including cancer. However, the regulation of stem cell proliferation and differentiation is not fully understood. Here we show that the sterile-like 20 kinase, Tao, controls tissue homeostasis by regulating the Hippo pathway in the Drosophila adult midgut. Depletion of Tao in the progenitors leads to rapid intestinal stem cell （ISC） proliferation and midgut homeostasis loss. Meanwhile, we find that the Janus kinase （JAK）/signal transducer and activator of transcription （STAT） signaling activity and cytokine production are significantly increased, resulting in stimulated ISC proliferation. Furthermore, expression of the Hippo pathway downstream targets, Diapl and bantam, is dramatically increased in Tao knockdown intestines. Consistently, we show that the Yorkie （Yki） acts downstream of Tao to regulate ISC proliferation. Together, our results provide insights into our understanding of the mechanisms of stem cell proliferation and tissue homeostasis control.
基金sponsored by the Shanghai Rising-Star Program of China(Grant No.18QB1403800)supported by the Fundamental Research Funds for the Central Universities(Grant No.21D111320).
文摘Considering that the particular geometric shape of a quasi-rectangular shield,the grout flowing law and its motion process are more complicated than those of a conventional circular shield.To interpret the grouting mechanical ehaviour in the special-shape shield tail void,the filling and diffusion mechanism of synchronous grouting was analysed.The grout flowing is separated into two independent motion processes,which contains a circumferential filling and a longitudinal diffusion.The theoretical model of the grout pressure spatial distribution was derived based on the principle of fluid mechanics.Then,the pressure distributions in the two directions were obtained using a case study and compared with the field measured data to verify the validation of the model.Although the overall spatial pattern of grout pressure distribution on the tunnel profile show a change trend dominated by the self-weight effect mostly,its local fluctuation characteristics is very abnormal relative to that of a circular shield tunnel.Moreover,the important factors in the model were analysed,including the grout material parameters,the grouting construction parameters,and some geometry parameters.The results show that the pressure loss along this way is positively correlated with the grout flow velocity and is sensitive to the shear yield stress of the grout.The pressure loss along the circumferential direction is the most sensitive to the thickness of the ring cake,and the value range suitable for the model should be 0.02-0.03 m.The pressure loss along the longitudinal diffusion direction is the most sensitive to the size of the tail void.The research results can provide a theoretical basis for the control of special-shape shield construction.
基金supported by the National Natural Science Foundation of China(21502098,21672105,21725204,91753124)Natural Science Foundation of Tianjin(17JCYBJC19700,18JCZDJC32800)+1 种基金Qingdao National Laboratory for Marine Science and Technologythe State Key Laboratory of Elemento-Organic Chemistry at Nankai University
文摘PAD4 is a promising epigenetic drug target for various cancers and immune diseases. In this work, we applied a Cu-catalyzed C–H arylation reaction of N-heteroarene to the synthesis of complex non-covalent PAD4 inhibitors bearing a bi-heteroaryl pharmacophore. This strategy allowed us to access various analogs of C_2-aryl substituted benzimidazoles from a common benzimidazole core and easily accessible aryl iodides. Preliminary SAR studies revealed the indole motif of GSK-484 is critical to its activity. Replacing the N-cyclopropylmethyl group to N-benzyl group on the indole ring of GSK-484 resulted in more than5-fold increase in cell killing efficacy against 4T1 cell line.
