The first long-term rainfall monitoring experiment using the commercial microwave links(CMLs)network in East China is introduced.The network,located in Jiangyin,Jiangsu Province,consists of 49 links with frequencies r...The first long-term rainfall monitoring experiment using the commercial microwave links(CMLs)network in East China is introduced.The network,located in Jiangyin,Jiangsu Province,consists of 49 links with frequencies ranging from 15 GHz to 26 GHz and lengths from 1.14 km to 4.78 km.An OTT PARSIVEL disdrometer is deployed to refine the local rain-induced attenuation relationship,and the CML observations are compared simultaneously with five rain gauges.The inversion parameters of the CML are optimized by minimizing the error of the accumulated rainfall of historical rainfall events.The inversion results show that the daily accumulated rainfall retrieved by the CMLs agrees well with the rain gauge measurements.As an opportunistic approach to monitor near-surface rainfall with high spatiotemporal representativeness and accuracy,the CML network can be used to monitor and forecast urban flood disasters,especially in regions where the widepread deployment of conventional meteorological instruments is impractical.展开更多
Background:Mushrooms are a good source of many nutrients which are potentially beneficial for chronic diseases.We speculated that due to its abundant nutrients edible mushrooms might have a beneficial effect on the pr...Background:Mushrooms are a good source of many nutrients which are potentially beneficial for chronic diseases.We speculated that due to its abundant nutrients edible mushrooms might have a beneficial effect on the prevention of subclinical thyroid dysfunction(SCTD).Therefore,we designed a large-scale cohort study to examine whether mushrooms consumption is a protective factor for SCTD in adults.Methods:This prospective cohort study investigated 6631 participants(mean age:(45.0±10.2)years;55.1%men).Edible mushrooms consumption was measured at baseline using a validated food frequency questionnaire.SCTD was defined as abnormal serum thyroid-stimulating hormone levels and normal free thyroxine.Cox proportional hazards regression models were used to examine the association of edible mushrooms consumption with incident SCTD.Results:During follow-up period,a total of 262 new cases of SCTD were identified,the incidence rate of subclinical hypothyroidism was 8.9/1000 person-years and subclinical hyperthyroidism was 7.2/1000 person-years.After adjusting potential confounding factors,the multivariable hazard ratios(95%confidence intervals)for subclinical hypothyroidism were 1.00(reference)for almost never,0.53(0.29,0.97)for 1-3 times/week and 0.30(0.10,0.87)for≥4 times/week(P for trend=0.02).It also showed edible mushrooms consumption was inversely associated with subclinical hypothyroidism in obese individuals but not non-obese individuals,the final hazard ratios(95%confidence intervals)were 0.14(0.03,0.73)(P for trend<0.01).Conclusions:This population-based prospective cohort study has firstly demonstrated that higher edible mushrooms consumption was significantly associated with lower incidence of subclinical hypothyroidism among general adult population,especially in obese individuals.展开更多
Electrochemical measurements were conducted to study the electrochemical behavior of gold (Au) and its commonly associated minerals in alkaline thiourea solutions. The results indicated that without addition of any ...Electrochemical measurements were conducted to study the electrochemical behavior of gold (Au) and its commonly associated minerals in alkaline thiourea solutions. The results indicated that without addition of any stabilizer, selective dissolution of Au from stibnite and pyrite was only possible at relatively low thiourea concentrations. As Na2SiO3 was added, pyrite started to become active and an oxida- tion peak appeared; the oxidation peaks of axsenopyrite and chalcocite appeared earlier thaxl that of Au. The chalcocite peak shifted in the positive direction and the peak current increased. Stibnite did not show an oxidation peak and its current was nearly zero. Adding Na2SiO3 favored the selective dissolution of Au when its minerals were associated with chalcocite and stibinte. At pH 12, the Au anode dissolution peak current increased with stabilizer concentration. At 0.38 and 0.42 V and for Na2SiO3 concentration below 0.09 M, the current density continuously increased with Na2SiO3 concentration. The Na2SiO3 concentration had to be adequate to stabilize thiourea. When the potential was higher than 0.42 V, the surface of the Au electrode started to passivate. With an additional increase in potential, the presence of Na2SiO3 could not stop the inevitable decomposition of thiourea.展开更多
The Chinese water pine Glyptostrobus pensilis is the sole surviving species of the genus Glyptostrobus. It is endemic to southern China, central Vietnam, and eastern Laos, and today it is nearly extinct in the wild. F...The Chinese water pine Glyptostrobus pensilis is the sole surviving species of the genus Glyptostrobus. It is endemic to southern China, central Vietnam, and eastern Laos, and today it is nearly extinct in the wild. Forest community characteristics and population structure of G. pensilis in China have remained un-known up to now. We investigated six swamp forest stands and analyzed their forest community characteristics (i.e. vertical stratification, species composition, and diversity) and population structure, including the frequency distribution of DBH (diameter at breast height) and age-classes as found in Fujian Province, southeastern China. The vertical stratifications of all the forest stands were rather simple. The remaining wild specimens ranged from roughly 15 to some 357 years for an average of ca. 85 years, with only a few individuals less than 20 years old. Compared with the stands and populations of G. pensilis in Vietnam, the taxonomic compositions of the stands in the two regions were different, except for the dominant species-G. pensilis. The Shannon-Wiener index showed the overstory of each stand had much lower diversity (0.26 on average) in Fujian Province than that (1.97 on average) in Vietnam, whereas the diversity indices were about the same (around 2.41) for the understories in the two regions. Furthermore, we discovered 18 G. pensilis seedlings at the study sites in Fujian Province. This discovery demonstrates that G. pensilis regeneration is extremely poor and its populations are declining, although these populations are rela-tively healthier than those in Vietnam.展开更多
Numerous researches have focused on the physical behavior of an elastic material in the vicinity of a single hole under the assumption that the interaction effects arising from the introduction of multiple holes remai...Numerous researches have focused on the physical behavior of an elastic material in the vicinity of a single hole under the assumption that the interaction effects arising from the introduction of multiple holes remain negligible if the holes are placed sufficiently far from each other.In an effort to understand hole interaction effects on heat conduction and thermal stress,we consider the case when two circular holes are embedded in an infinite elastic material and use complex variable methods together with numerical analysis to obtain solutions describing temperature and elastic fields in the vicinity of the two circular holes.The results indicate that the interaction effects on temperature distribution and stress strongly depend on the relative size of the two holes and the distance placed between them but not on the actual size of the holes.展开更多
Colorectal cancer(CRC)is the second leading cause of cancer mortality worldwide.At initial diagnosis,approximately 20%of patients are diagnosed with metastatic CRC(mCRC).Although the APC-Asef interaction is a well-est...Colorectal cancer(CRC)is the second leading cause of cancer mortality worldwide.At initial diagnosis,approximately 20%of patients are diagnosed with metastatic CRC(mCRC).Although the APC-Asef interaction is a well-established target for mCRC therapy,the discovery and development of effective and safe drugs for mCRC patients remains an urgent and challenging endeavor.In this study,we identified a novel structural scaffold based on MAI inhibitors,the first-in-class APC-Asef inhibitors we reported previously.ONIOM model-driven optimizations of the N-terminal cap and experimental evaluations of inhibitory activity were performed,and 24-fold greater potency was obtained with the best inhibitor compared to the parental compound.In addition,the cocrystal structure validated that the two-layerπ-πstacking interactions were essential for inhibitor stabilization in the bound state.Furthermore,in vitro and in vivo studies have demonstrated that novel inhibitors suppressed lung metastasis in CRC by disrupting the APC-Asef interaction.These results provide an intrinsic structural basis to further explore drug-like molecules for APC-Asef-mediated CRC therapy.展开更多
We conducted a prospective study to assess the non-inferiority of adjuvant chemotherapy alone versus adjuvant concurrent chemoradiotherapy (CCRT) as an alternative strategy for patients with early-stage (FIGO 2009 sta...We conducted a prospective study to assess the non-inferiority of adjuvant chemotherapy alone versus adjuvant concurrent chemoradiotherapy (CCRT) as an alternative strategy for patients with early-stage (FIGO 2009 stage IB–IIA) cervical cancer having risk factors after surgery. The condition was assessed in terms of prognosis, adverse effects, and quality of life. This randomized trial involved nine centers across China. Eligible patients were randomized to receive adjuvant chemotherapy or CCRT after surgery. The primary end-point was progression-free survival (PFS). From December 2012 to December 2014, 337 patients were subjected to randomization. Final analysis included 329 patients, including 165 in the adjuvant chemotherapy group and 164 in the adjuvant CCRT group. The median follow-up was 72.1 months. The three-year PFS rates were both 91.9%, and the five-year OS was 90.6% versus 90.0% in adjuvant chemotherapy and CCRT groups, respectively. No significant differences were observed in the PFS or OS between groups. The adjusted HR for PFS was 0.854 (95% confidence interval 0.415–1.757;P = 0.667) favoring adjuvant chemotherapy, excluding the predefined non-inferiority boundary of 1.9. The chemotherapy group showed a tendency toward good quality of life. In comparison with post-operative adjuvant CCRT, adjuvant chemotherapy treatment showed non-inferior efficacy in patients with early-stage cervical cancer having pathological risk factors. Adjuvant chemotherapy alone is a favorable alternative post-operative treatment.展开更多
The effects of La on the catalytic performance,SO_(2)and H2O resistance of Cu-Ce/TNU-9 catalyst were studied in the selective catalytic reduction of NO_(x)via ammonia(NH_(3)-SCR).The results show that the La doped Ce-...The effects of La on the catalytic performance,SO_(2)and H2O resistance of Cu-Ce/TNU-9 catalyst were studied in the selective catalytic reduction of NO_(x)via ammonia(NH_(3)-SCR).The results show that the La doped Ce-Cu/TNU-9(CCL/T9)catalyst exhibits better SCR performance than Ce-Cu/TNU-9(CC/T9)and Cu/TNU-9(C/T9)in the wide temperature window(200-450℃)due to La benefiting from enhancing Cu^(+)+Ce^(4+)?Cu^(2+)-+Ce^(3+)to facilitate the electron transfer,which further accelerates the oxidation of NO into NO_(2)that leads to the"Fast SCR".The La can also enhance the surface acidic,redox property and is beneficial to the formation of oxygen vacancy.Meanwhile,the larger co ntent of Ce^(3+) can produce oxygen vacancy,resulting in rising SCR activity.The CCL/T9 has outstanding water and SO_(2) resistance,which may be due to the adso rbed S on the surface of these catalysts mainly existing in the form of a small amount of sulfate and sulfite,the decomposition of ammonium bisulphite under high temperature and the hydrophobicity of TNU-9 zeolite.展开更多
Dear Editor,Ion gradients are characteristic features of a living cell that do not represent thermodynamic equilibrium.These unequilibrium status are maintained by various ion pumps such as Na-K-ATPase,which are known...Dear Editor,Ion gradients are characteristic features of a living cell that do not represent thermodynamic equilibrium.These unequilibrium status are maintained by various ion pumps such as Na-K-ATPase,which are known as the P-type ATPases.Working mechanism of Na-K-ATPase is described as Post-Albers cycle1(Fig.1a).However,the reaction scheme is non-Michaelis-Menten kinetics assembled from transient-state results,which can hardly be used to rebuild the real reaction cycle.展开更多
Poly(ADP-ribose)polymerase(PARP)inhibitors are one of the most exciting classes of targeted therapy agents for cancers with homologous recombination(HR)deficiency.However,many patients without apparent HR defects also...Poly(ADP-ribose)polymerase(PARP)inhibitors are one of the most exciting classes of targeted therapy agents for cancers with homologous recombination(HR)deficiency.However,many patients without apparent HR defects also respond well to PARP inhibitors/cisplatin.The biomarker responsible for this mechanism remains unclear.Here,we identified a set of ribosomal genes that predict response to PARP inhibitors/cisplatin in HR-proficient patients.PARP inhibitor/cisplatin selectively eliminates cells with high expression of the eight genes in the identified panel via DNA damage(ATM)signaling-induced pro-apoptotic ribosomal stress,which along with ATM signaling-induced pro-survival HR repair constitutes a new model to balance the cell fate in response to DNA damage.Therefore,the combined examination of the gene panel along with HR status would allow for more precise predictions of clinical response to PARP inhibitor/cisplatin.The gene panel as an independent biomarker was validated by multiple published clinical datasets,as well as by an ovarian cancer organoids library we established.More importantly,its predictive value was further verified in a cohort of PARP inhibitor-treated ovarian cancer patients with both RNA-seq and WGS data.Furthermore,we identified several marketed drugs capable of upregulating the expression of the genes in the panel without causing HR deficiency in PARP inhibitor/cisplatin-resistant cell lines.These drugs enhance PARP inhibitor/cisplatin sensitivity in both intrinsically resistant organoids and cell lines with acquired resistance.Together,our study identifies a marker gene panel for HR-proficient patients and reveals a broader application of PARP inhibitor/cisplatin in cancer therapy.展开更多
Vulvar cancer is the fourth most common gynecological malignancy,with a global incidence of an estimated 45,240 new cases and 17,427 deaths in 2022.1 The 5-year survival rate for vulvar cancer is about 70%based on dat...Vulvar cancer is the fourth most common gynecological malignancy,with a global incidence of an estimated 45,240 new cases and 17,427 deaths in 2022.1 The 5-year survival rate for vulvar cancer is about 70%based on data from the SEER database.2 More than 90%of vulvar cancer was vulvar squamous cell carcinoma(SCC),which included keratinizing,non-keratinizing,basaloid,warty,and verrucous carcinoma.展开更多
Dear Editor,Platelets are circulating anucleate cytoplasmic fragments of megakaryocytes and characterized by their functions in wound healing and vascular integrity maintenance.Increasing evidence highlights the exten...Dear Editor,Platelets are circulating anucleate cytoplasmic fragments of megakaryocytes and characterized by their functions in wound healing and vascular integrity maintenance.Increasing evidence highlights the extensive reciprocal signaling interactions between platelets and tumor cells(Haemmerle et al.,2018).Tumor cells activate and aggregate platelets to sustain proliferation(Cho et al.,2012),resist apoptosis,and promote metastasis(Haemmerle et al.,2017).展开更多
Although opioids still remain the most powerful pain-killers,the chronic use of opioid analgesics is largely limited by their numerous side-effects,including opioid dependence.However,the mechanism underlying this dep...Although opioids still remain the most powerful pain-killers,the chronic use of opioid analgesics is largely limited by their numerous side-effects,including opioid dependence.However,the mechanism underlying this dependence is largely unknown.In this study,we used the withdrawal symptoms precipitated by naloxone to characterize opioid dependence in mice.We determined the functional role of mu-opioid receptors(MORs)expressed in different subpopulations of neurons in the development of morphine withdrawal.We found that conditional deletion of MORs from glutamatergic neurons expressing vesicular glutamate transporter 2(Vglut2^+)largely eliminated the naloxone-precipitated withdrawal symptoms.In contrast,conditional deletion of MORs expressed in GABAergic neurons had a limited effect on morphine withdrawal.Consistently,mice with MORs deleted from Vglut2^+glutamatergic neurons also showed no morphine-induced locomotor hyperactivity.Furthermore,morphine withdrawal and morphine-induced hyperactivity were not significantly affected by conditional knockout of MORs from dorsal spinal neurons.Taken together,our data indicate that the development of morphine withdrawal is largely mediated by MORs expressed in Vglut2^+glutamatergic neurons.展开更多
SIRT6 belongs to the conserved NAD^(+)-dependent deacetylase superfamily and mediates multiple biological and pathological processes.Targeting SIRT6 by allosteric modulators represents a novel direction for therapeuti...SIRT6 belongs to the conserved NAD^(+)-dependent deacetylase superfamily and mediates multiple biological and pathological processes.Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics,which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases.Here,developing a reversed allosteric strategy Allo Reverse,we identified a cryptic allosteric site,Pocket Z,which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD^(+).Based on Pocket Z,we discovered an SIRT6 allosteric inhibitor named JYQ-42.JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation,with an IC50 of 2.33μmol/L.JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production.JYQ-42,to our knowledge,is the most potent and selective allosteric SIRT6 inhibitor.This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.展开更多
NF-κB signaling regulates diverse processes such as cell death,inflammation,immunity,and cancer.The activity of NF-κB is controlled by methionine 1-linked linear polyubiquitin,which is assembled by the linear ubiqui...NF-κB signaling regulates diverse processes such as cell death,inflammation,immunity,and cancer.The activity of NF-κB is controlled by methionine 1-linked linear polyubiquitin,which is assembled by the linear ubiquitin chain assembly complex(LUBAC)and the ubiquitin-conjugating enzyme UBE2L3.Recent studies found that the deubiquitinase OTULIN breaks the linear ubiquitin chain,thus inhibiting NF-κB signaling.Despite the essential role of OTULIN in NF-κB signaling has been established,the regulatory mechanism for OTULIN is not well elucidated.To discover the potential regulators of OTULIN,we analyzed the OTULIN protein complex by proteomics and revealed several OTULIN-binding proteins,including LUBAC and tripartite motif-containing protein 32(TRIM32).TRIM32 is known to activate NF-κB signaling,but the mechanism is not dear.Genetic complement experiments found that TRIM32 is upstream of OTULIN and TRIM32-mediated NF-κB activation is dependent on OTULIN.Mutagenesis of the E3 ligase domain showed that the E3 ligase activity is essential for TRIM32-mediated NF-κB activation.Further experiments found that TRIM32 conjugates polyubiquitin onto OTULIN and the polyubiquitin blocks the interaction between HOIP and OTULIN,thereby activating NF-κB signaling.Taken together,we report a novel regulatory mechanism by which TRIM32-mediated non-proteolytic ubiquitination of OTULIN impedes the access of OTULIN to the LUBAC and promotes NF-κB activation.展开更多
基金This research was funded by the China Postdoctoral Science Foundation(2021M701650)the Excellent Youth Scholars of the Natural Science Foundation of Hunan Province of China(2021JJ20046)+1 种基金the Open Grants of the State Key Laboratory of Severe Weather(Grant 2021LASW-A01)the National Natural Science Foundation of China(Grant No.42222505).
文摘The first long-term rainfall monitoring experiment using the commercial microwave links(CMLs)network in East China is introduced.The network,located in Jiangyin,Jiangsu Province,consists of 49 links with frequencies ranging from 15 GHz to 26 GHz and lengths from 1.14 km to 4.78 km.An OTT PARSIVEL disdrometer is deployed to refine the local rain-induced attenuation relationship,and the CML observations are compared simultaneously with five rain gauges.The inversion parameters of the CML are optimized by minimizing the error of the accumulated rainfall of historical rainfall events.The inversion results show that the daily accumulated rainfall retrieved by the CMLs agrees well with the rain gauge measurements.As an opportunistic approach to monitor near-surface rainfall with high spatiotemporal representativeness and accuracy,the CML network can be used to monitor and forecast urban flood disasters,especially in regions where the widepread deployment of conventional meteorological instruments is impractical.
基金supported by grants from the National Natural Science Foundation of China (81941024)Tianjin Major Public Health Science and Technology Project (21ZXGWSY00090)+2 种基金National Health Commission of China (SPSYYC 2020015)Food Science and Technology Foundation of Chinese Institute of FoodScience and Technology (2019-12)2014 and 2016 Chinese NutritionSociety (CNS) Nutrition Research Foundation -DSM Research Fund(2016-046, 2014-071 and 2016-023), China
文摘Background:Mushrooms are a good source of many nutrients which are potentially beneficial for chronic diseases.We speculated that due to its abundant nutrients edible mushrooms might have a beneficial effect on the prevention of subclinical thyroid dysfunction(SCTD).Therefore,we designed a large-scale cohort study to examine whether mushrooms consumption is a protective factor for SCTD in adults.Methods:This prospective cohort study investigated 6631 participants(mean age:(45.0±10.2)years;55.1%men).Edible mushrooms consumption was measured at baseline using a validated food frequency questionnaire.SCTD was defined as abnormal serum thyroid-stimulating hormone levels and normal free thyroxine.Cox proportional hazards regression models were used to examine the association of edible mushrooms consumption with incident SCTD.Results:During follow-up period,a total of 262 new cases of SCTD were identified,the incidence rate of subclinical hypothyroidism was 8.9/1000 person-years and subclinical hyperthyroidism was 7.2/1000 person-years.After adjusting potential confounding factors,the multivariable hazard ratios(95%confidence intervals)for subclinical hypothyroidism were 1.00(reference)for almost never,0.53(0.29,0.97)for 1-3 times/week and 0.30(0.10,0.87)for≥4 times/week(P for trend=0.02).It also showed edible mushrooms consumption was inversely associated with subclinical hypothyroidism in obese individuals but not non-obese individuals,the final hazard ratios(95%confidence intervals)were 0.14(0.03,0.73)(P for trend<0.01).Conclusions:This population-based prospective cohort study has firstly demonstrated that higher edible mushrooms consumption was significantly associated with lower incidence of subclinical hypothyroidism among general adult population,especially in obese individuals.
基金financial support from the National Natural Science Foundation of China(No.51504031)the innovation fund of the General Research Institute for Nonferrous Metals(No.53319)
文摘Electrochemical measurements were conducted to study the electrochemical behavior of gold (Au) and its commonly associated minerals in alkaline thiourea solutions. The results indicated that without addition of any stabilizer, selective dissolution of Au from stibnite and pyrite was only possible at relatively low thiourea concentrations. As Na2SiO3 was added, pyrite started to become active and an oxida- tion peak appeared; the oxidation peaks of axsenopyrite and chalcocite appeared earlier thaxl that of Au. The chalcocite peak shifted in the positive direction and the peak current increased. Stibnite did not show an oxidation peak and its current was nearly zero. Adding Na2SiO3 favored the selective dissolution of Au when its minerals were associated with chalcocite and stibinte. At pH 12, the Au anode dissolution peak current increased with stabilizer concentration. At 0.38 and 0.42 V and for Na2SiO3 concentration below 0.09 M, the current density continuously increased with Na2SiO3 concentration. The Na2SiO3 concentration had to be adequate to stabilize thiourea. When the potential was higher than 0.42 V, the surface of the Au electrode started to passivate. With an additional increase in potential, the presence of Na2SiO3 could not stop the inevitable decomposition of thiourea.
基金funding by the National Natural Science Foundation of China (31760152 and 31500355)the Key National Research and Development Plan Program of China (2016YFC050310203)+1 种基金the Natural Science Foundation Project of CQ CSTC, China (cstc2016jcyj A0379)the National Program on Space Science and Technology, Vietnam Academy of Science and Technology, Vietnam (project VT-UD.09/18-20)
文摘The Chinese water pine Glyptostrobus pensilis is the sole surviving species of the genus Glyptostrobus. It is endemic to southern China, central Vietnam, and eastern Laos, and today it is nearly extinct in the wild. Forest community characteristics and population structure of G. pensilis in China have remained un-known up to now. We investigated six swamp forest stands and analyzed their forest community characteristics (i.e. vertical stratification, species composition, and diversity) and population structure, including the frequency distribution of DBH (diameter at breast height) and age-classes as found in Fujian Province, southeastern China. The vertical stratifications of all the forest stands were rather simple. The remaining wild specimens ranged from roughly 15 to some 357 years for an average of ca. 85 years, with only a few individuals less than 20 years old. Compared with the stands and populations of G. pensilis in Vietnam, the taxonomic compositions of the stands in the two regions were different, except for the dominant species-G. pensilis. The Shannon-Wiener index showed the overstory of each stand had much lower diversity (0.26 on average) in Fujian Province than that (1.97 on average) in Vietnam, whereas the diversity indices were about the same (around 2.41) for the understories in the two regions. Furthermore, we discovered 18 G. pensilis seedlings at the study sites in Fujian Province. This discovery demonstrates that G. pensilis regeneration is extremely poor and its populations are declining, although these populations are rela-tively healthier than those in Vietnam.
基金the National Natural Science Foundation of China(No.11902116)the China Postdoctoral Science Foundation(No.2020M671313)the Natural Sciences and Engineering Research Council of Canada(No.RGPIN 155112)。
文摘Numerous researches have focused on the physical behavior of an elastic material in the vicinity of a single hole under the assumption that the interaction effects arising from the introduction of multiple holes remain negligible if the holes are placed sufficiently far from each other.In an effort to understand hole interaction effects on heat conduction and thermal stress,we consider the case when two circular holes are embedded in an infinite elastic material and use complex variable methods together with numerical analysis to obtain solutions describing temperature and elastic fields in the vicinity of the two circular holes.The results indicate that the interaction effects on temperature distribution and stress strongly depend on the relative size of the two holes and the distance placed between them but not on the actual size of the holes.
基金funded by the National Key R&D Program of China(2023YFF1205103 to Jian Zhang)the Key Research and Construction Programs of Ningxia Hui Autonomous Region(2022BEG01002 to Jian Zhang,China)+3 种基金the Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study(SN-ZJU-SIAS-007 to Jian Zhang,China)the National Natural Science Foundation of China(22237005 and 81925034 to Jian Zhang)the open fund of state key laboratory of Pharmaceutical Biotechnology,Nanjing University(KF-202201 to Jian Zhang,China)the open fund of Basic Science Research Center Base(Pharmaceutical Science Y202203 to Xiuyan Yang,China).
文摘Colorectal cancer(CRC)is the second leading cause of cancer mortality worldwide.At initial diagnosis,approximately 20%of patients are diagnosed with metastatic CRC(mCRC).Although the APC-Asef interaction is a well-established target for mCRC therapy,the discovery and development of effective and safe drugs for mCRC patients remains an urgent and challenging endeavor.In this study,we identified a novel structural scaffold based on MAI inhibitors,the first-in-class APC-Asef inhibitors we reported previously.ONIOM model-driven optimizations of the N-terminal cap and experimental evaluations of inhibitory activity were performed,and 24-fold greater potency was obtained with the best inhibitor compared to the parental compound.In addition,the cocrystal structure validated that the two-layerπ-πstacking interactions were essential for inhibitor stabilization in the bound state.Furthermore,in vitro and in vivo studies have demonstrated that novel inhibitors suppressed lung metastasis in CRC by disrupting the APC-Asef interaction.These results provide an intrinsic structural basis to further explore drug-like molecules for APC-Asef-mediated CRC therapy.
基金National Natural Science Foundation of China (Nos. 81630060, 81230038, 81372805, and 81472444)National Key Research & Development Program of China (No. 2016YFC0902900)Bristol-Myers Squibb CA139-702 and the National Science-technology Supporting Plan Projects (No.2015BAI13B05).
文摘We conducted a prospective study to assess the non-inferiority of adjuvant chemotherapy alone versus adjuvant concurrent chemoradiotherapy (CCRT) as an alternative strategy for patients with early-stage (FIGO 2009 stage IB–IIA) cervical cancer having risk factors after surgery. The condition was assessed in terms of prognosis, adverse effects, and quality of life. This randomized trial involved nine centers across China. Eligible patients were randomized to receive adjuvant chemotherapy or CCRT after surgery. The primary end-point was progression-free survival (PFS). From December 2012 to December 2014, 337 patients were subjected to randomization. Final analysis included 329 patients, including 165 in the adjuvant chemotherapy group and 164 in the adjuvant CCRT group. The median follow-up was 72.1 months. The three-year PFS rates were both 91.9%, and the five-year OS was 90.6% versus 90.0% in adjuvant chemotherapy and CCRT groups, respectively. No significant differences were observed in the PFS or OS between groups. The adjusted HR for PFS was 0.854 (95% confidence interval 0.415–1.757;P = 0.667) favoring adjuvant chemotherapy, excluding the predefined non-inferiority boundary of 1.9. The chemotherapy group showed a tendency toward good quality of life. In comparison with post-operative adjuvant CCRT, adjuvant chemotherapy treatment showed non-inferior efficacy in patients with early-stage cervical cancer having pathological risk factors. Adjuvant chemotherapy alone is a favorable alternative post-operative treatment.
基金supported by the National Natural Science Foundation of China(51708309)the Fundamental Research Funds in Heilongjiang Provincial Universities(145109115)。
文摘The effects of La on the catalytic performance,SO_(2)and H2O resistance of Cu-Ce/TNU-9 catalyst were studied in the selective catalytic reduction of NO_(x)via ammonia(NH_(3)-SCR).The results show that the La doped Ce-Cu/TNU-9(CCL/T9)catalyst exhibits better SCR performance than Ce-Cu/TNU-9(CC/T9)and Cu/TNU-9(C/T9)in the wide temperature window(200-450℃)due to La benefiting from enhancing Cu^(+)+Ce^(4+)?Cu^(2+)-+Ce^(3+)to facilitate the electron transfer,which further accelerates the oxidation of NO into NO_(2)that leads to the"Fast SCR".The La can also enhance the surface acidic,redox property and is beneficial to the formation of oxygen vacancy.Meanwhile,the larger co ntent of Ce^(3+) can produce oxygen vacancy,resulting in rising SCR activity.The CCL/T9 has outstanding water and SO_(2) resistance,which may be due to the adso rbed S on the surface of these catalysts mainly existing in the form of a small amount of sulfate and sulfite,the decomposition of ammonium bisulphite under high temperature and the hydrophobicity of TNU-9 zeolite.
基金supported by National Natural Science Foundation of China (81970418,82272116)Shanghai Municipal Science and Technology Major Project (No.2018SHZDZX01)+3 种基金ZJLabScience and Technology Commission of Shanghai Municipality (Grant No.18JC1410403)MOE Frontiers Center for Brain ScienceShanghai Municipal Health Commission Key Research Centre (2022ZZ01006).
文摘Dear Editor,Ion gradients are characteristic features of a living cell that do not represent thermodynamic equilibrium.These unequilibrium status are maintained by various ion pumps such as Na-K-ATPase,which are known as the P-type ATPases.Working mechanism of Na-K-ATPase is described as Post-Albers cycle1(Fig.1a).However,the reaction scheme is non-Michaelis-Menten kinetics assembled from transient-state results,which can hardly be used to rebuild the real reaction cycle.
基金supported by funds from the National Key Technology Research and Development Program of China(2022YFC2704200,2022YFC2704205)key research and development program of Zhejiang province(2019C03010)+1 种基金the National Natural Science Foundation of China(82072889,81772787)key project of CScO pilot oncology research funding(Y-2019AZZD-0359).
文摘Poly(ADP-ribose)polymerase(PARP)inhibitors are one of the most exciting classes of targeted therapy agents for cancers with homologous recombination(HR)deficiency.However,many patients without apparent HR defects also respond well to PARP inhibitors/cisplatin.The biomarker responsible for this mechanism remains unclear.Here,we identified a set of ribosomal genes that predict response to PARP inhibitors/cisplatin in HR-proficient patients.PARP inhibitor/cisplatin selectively eliminates cells with high expression of the eight genes in the identified panel via DNA damage(ATM)signaling-induced pro-apoptotic ribosomal stress,which along with ATM signaling-induced pro-survival HR repair constitutes a new model to balance the cell fate in response to DNA damage.Therefore,the combined examination of the gene panel along with HR status would allow for more precise predictions of clinical response to PARP inhibitor/cisplatin.The gene panel as an independent biomarker was validated by multiple published clinical datasets,as well as by an ovarian cancer organoids library we established.More importantly,its predictive value was further verified in a cohort of PARP inhibitor-treated ovarian cancer patients with both RNA-seq and WGS data.Furthermore,we identified several marketed drugs capable of upregulating the expression of the genes in the panel without causing HR deficiency in PARP inhibitor/cisplatin-resistant cell lines.These drugs enhance PARP inhibitor/cisplatin sensitivity in both intrinsically resistant organoids and cell lines with acquired resistance.Together,our study identifies a marker gene panel for HR-proficient patients and reveals a broader application of PARP inhibitor/cisplatin in cancer therapy.
基金supported by the Tai-Shan Scholar Program of Shandong Province (Code:ts20070743)Beijing Hospitals Authority's Ascent Plan (Code:DFL20221201).
文摘Vulvar cancer is the fourth most common gynecological malignancy,with a global incidence of an estimated 45,240 new cases and 17,427 deaths in 2022.1 The 5-year survival rate for vulvar cancer is about 70%based on data from the SEER database.2 More than 90%of vulvar cancer was vulvar squamous cell carcinoma(SCC),which included keratinizing,non-keratinizing,basaloid,warty,and verrucous carcinoma.
基金supported by the National Science and Technology Major Sub-Project (2018ZX10301402-002)National Natural Science Foundation of China (81772787,82072889,31822030,and 31771458)+2 种基金Technical Innovation Special Project of Hubei Province (2018ACA138)Fundamental Research Funds for the Central Universities (2019kfyXMBZ024)Wuhan Municipal Health Commission (WX18Q16).
文摘Dear Editor,Platelets are circulating anucleate cytoplasmic fragments of megakaryocytes and characterized by their functions in wound healing and vascular integrity maintenance.Increasing evidence highlights the extensive reciprocal signaling interactions between platelets and tumor cells(Haemmerle et al.,2018).Tumor cells activate and aggregate platelets to sustain proliferation(Cho et al.,2012),resist apoptosis,and promote metastasis(Haemmerle et al.,2017).
基金This work was supported by the National Basic Research Program of China(2017YFA0103303)Strategic Priority Research Program of the Chinese Academy of Sciences(XDB32010100,XDB02050400,XDB02050005,XDA16020601)+2 种基金National Basic Research Program of China(2017YFA0102601,2019YFA0110100)National Natural Science Foundation of China(NSFC)(91732301,31671072,31771140,81891001,91432111,81527901,31400977,31625013)Grants of Beijing Brain Initiative of Beijing Municipal Science&Technology Commission(Z181100001518004).
基金the National Natural Science Foundation of China(21708025,81925034,91753117,and 81773793)the Open Fund of State Key Laboratory of Oncogenes and Related Genes,Shanghai Jiao Tong University School of Medicine+3 种基金the Innovation Program of Shanghai Municipal Education Commission(2019-01-07-00-01-E00036)the Shanghai Science and Technology Innovation Foundation(19431901600)the China Postdoctoral Science Foundation(2016M601618 and 2017T100303)the National Science and Technology Major Project of China(2018ZX09711001-005-022)。
基金We thank Yan-Jing Zhu for technical support.This work was supported by the National Natural Science Foundation of China(31825013 and 61890952)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB32010200).
文摘Although opioids still remain the most powerful pain-killers,the chronic use of opioid analgesics is largely limited by their numerous side-effects,including opioid dependence.However,the mechanism underlying this dependence is largely unknown.In this study,we used the withdrawal symptoms precipitated by naloxone to characterize opioid dependence in mice.We determined the functional role of mu-opioid receptors(MORs)expressed in different subpopulations of neurons in the development of morphine withdrawal.We found that conditional deletion of MORs from glutamatergic neurons expressing vesicular glutamate transporter 2(Vglut2^+)largely eliminated the naloxone-precipitated withdrawal symptoms.In contrast,conditional deletion of MORs expressed in GABAergic neurons had a limited effect on morphine withdrawal.Consistently,mice with MORs deleted from Vglut2^+glutamatergic neurons also showed no morphine-induced locomotor hyperactivity.Furthermore,morphine withdrawal and morphine-induced hyperactivity were not significantly affected by conditional knockout of MORs from dorsal spinal neurons.Taken together,our data indicate that the development of morphine withdrawal is largely mediated by MORs expressed in Vglut2^+glutamatergic neurons.
基金supported by the National Natural Science Foundation of China(81925034,81903458,22077082,82003605,81901423)the Innovation Program of Shanghai Municipal Education Commission(2019-01-07-00-01-E00036,China)+3 种基金Shanghai Science and Technology Innovation Fundation(19431901600,China)the Shanghai Health and Family Planning System Excellent Subject Leader and Excellent Young Medical Talents Training Program(2018BR12,China)Special Financial Grant of Postdoctoral Research Foundation of China(2019M660090)。
文摘SIRT6 belongs to the conserved NAD^(+)-dependent deacetylase superfamily and mediates multiple biological and pathological processes.Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics,which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases.Here,developing a reversed allosteric strategy Allo Reverse,we identified a cryptic allosteric site,Pocket Z,which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD^(+).Based on Pocket Z,we discovered an SIRT6 allosteric inhibitor named JYQ-42.JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation,with an IC50 of 2.33μmol/L.JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production.JYQ-42,to our knowledge,is the most potent and selective allosteric SIRT6 inhibitor.This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.
基金supported by the National Institutes of Health(R15AI126360,R21AI137750,R01AI141399,and P20GM103648 to S.L.R01AI121288 to M.E.D.)+1 种基金the Research Advisory Committee Fund(to L.W.)the Oklahoma Center for the Advancement of Science and Technology(HR17-045 to S.L.).
文摘NF-κB signaling regulates diverse processes such as cell death,inflammation,immunity,and cancer.The activity of NF-κB is controlled by methionine 1-linked linear polyubiquitin,which is assembled by the linear ubiquitin chain assembly complex(LUBAC)and the ubiquitin-conjugating enzyme UBE2L3.Recent studies found that the deubiquitinase OTULIN breaks the linear ubiquitin chain,thus inhibiting NF-κB signaling.Despite the essential role of OTULIN in NF-κB signaling has been established,the regulatory mechanism for OTULIN is not well elucidated.To discover the potential regulators of OTULIN,we analyzed the OTULIN protein complex by proteomics and revealed several OTULIN-binding proteins,including LUBAC and tripartite motif-containing protein 32(TRIM32).TRIM32 is known to activate NF-κB signaling,but the mechanism is not dear.Genetic complement experiments found that TRIM32 is upstream of OTULIN and TRIM32-mediated NF-κB activation is dependent on OTULIN.Mutagenesis of the E3 ligase domain showed that the E3 ligase activity is essential for TRIM32-mediated NF-κB activation.Further experiments found that TRIM32 conjugates polyubiquitin onto OTULIN and the polyubiquitin blocks the interaction between HOIP and OTULIN,thereby activating NF-κB signaling.Taken together,we report a novel regulatory mechanism by which TRIM32-mediated non-proteolytic ubiquitination of OTULIN impedes the access of OTULIN to the LUBAC and promotes NF-κB activation.