BACKGROUND Donor-specific antibodies(DSAs)against human leukocyte antigen(HLA)-DQ are increasingly recognized as major contributors to antibody-mediated rejection(AMR)and graft failure in kidney transplantation.Howeve...BACKGROUND Donor-specific antibodies(DSAs)against human leukocyte antigen(HLA)-DQ are increasingly recognized as major contributors to antibody-mediated rejection(AMR)and graft failure in kidney transplantation.However,their clinical impact remains understudied in Morocco.AIM To evaluate the presence and implications of anti-HLA-DQ DSAs in Moroccan kidney transplant recipients.METHODS We retrospectively analyzed the immunological profiles and clinical outcomes of kidney transplant recipients screened for anti-HLA antibodies between 2015 and 2020,who developed anti-HLA-DQ DSAs either before or after transplantation.Anti-HLA antibodies were identified using Luminex®single antigen bead technology,and clinical follow-up included graft function assessment,biopsy interpretation,and evaluation of immunosuppression.RESULTS In the pre-transplant group(n=6 with confirmed donor typing),patients with low to moderate median fluorescence intensity(MFI)anti-HLA-DQ DSAs(MFI 561-1581)underwent successful transplantation and maintained stable graft function under optimized immunosuppression.In contrast,in the post-transplant group(n=6 with confirmed donor typing),the emergence of de novo anti-HLA-DQ DSAs was consistently associated with AMR,with MFI values reaching up to 19473,with biopsy-proven AMR in 5 of 6 cases and suspicion of AMR in 1 case.Two representative cases are detailed to illustrate the clinical impact of DQ DSAs:one patient developed high-level anti-DQB1*02 de novo DSA(MFI 12029)with persistent AMR after 5 years,while another developed anti-DQA1*05:01 de novo DSA after an early AMR episode but maintained stable graft function after 5 years(creatinine 1.48 mg/dL).CONCLUSION Our findings underscore the clinical significance of anti-HLA-DQ DSAs in Moroccan kidney transplant recipients.While preformed DSAs with low immunogenicity may permit successful transplantation,de novo DSAs strongly correlate with AMR.Proactive monitoring,including routine DSA screening and HLA-DQ typing,could improve graft outcomes by enabling early intervention and better donor selection.展开更多
Background Quantitative flow ratio(QFR) holds significant value in guiding drug-coated balloon(DCB) treatment and enhancing outcomes. However, the predictive capability of post-angioplasty QFR for long-term clinical e...Background Quantitative flow ratio(QFR) holds significant value in guiding drug-coated balloon(DCB) treatment and enhancing outcomes. However, the predictive capability of post-angioplasty QFR for long-term clinical events in patients with de novo lesions who receive DCB treatment remains uncertain. The aim of this study was to explore the potential significance of post-angioplasty QFR measurements in predicting clinical outcomes in patients underwent DCB treatment for de novo lesions.Methods Patients who underwent DCB-only intervention for de novo lesions were enrolled. QFR was conducted after DCB treatment. The patients were then categorized based on post-angioplasty QFR. The primary endpoint was major adverse cardiac events(MACE), encompassing all-cause death, cardiovascular death, nonfatal myocardial infarction, stroke, and target vessel revascularization.Results A total of 553 patients with 561 lesions were included. The median follow-up period was 505 days, during which 66(11.8%) MACEs occurred. Based on post-procedural QFR grouping, there were 259 cases in the high QFR group(QFR > 0.93) and302 cases in the low QFR group(QFR ≤ 0.93). Kaplan-Meier analysis revealed a significantly higher cumulative incidence of MACE in the low QFR group(log-rank P = 0.004). The multivariate Cox proportional hazards model demonstrated a significant inverse correlation between QFR and the occurrence of MACEs(HR = 0.522, 95%CI: 0.289-0.942, P = 0.031). Landmark analysis indicated that high QFR had a significant reducing effect on the cumulative incidence of MACEs within 1 year(log-rank P = 0.016)and 1-5 years(log-rank P = 0.026).Conclusions In patients who underwent DCB-only treatment for de novo lesions, higher post-procedural QFR values(> 0.93)were identified as an independent protective factor against adverse prognosis.展开更多
Liver transplantation(LT)is the definitive treatment for end-stage liver disease,acute liver failure,and liver cancer.Although advancements in surgical techniques,postoperative care,and immunosuppressive therapies hav...Liver transplantation(LT)is the definitive treatment for end-stage liver disease,acute liver failure,and liver cancer.Although advancements in surgical techniques,postoperative care,and immunosuppressive therapies have significantly improved outcomes,the long-term use of immunosuppression has increased the risk of complications,including infections,cardiovascular disease,and cancer.Among these,de novo malignancies(DNMs)are a major concern,accounting for 20%-25%of deaths in LT recipients surviving beyond the early post-transplant period.Non-melanoma skin cancers,particularly squamous cell carcinoma are the most prevalent DNMs.Other significant malignancies include Kaposi's sarcoma,post-transplant lymphoproliferative disorders,and various solid organ cancers,including head and neck cancers.Compared to the general population,LT patients face a twofold increase in solid organ malignancies and a 30-fold increase in lymphoproliferative disorders.Risk factors for DNM include chronic immunosuppression,alcohol or tobacco use,viral infections,and underlying liver disease.Emerging evidence emphasizes the importance of tailored cancer screening and prevention strategies,including regular dermatological examinations,targeted screenings for high-risk cancers,and patient education on lifestyle modifications.Early detection through enhanced surveillance protocols has been shown to improve outcomes.Management of DNMs involves a combination of standard oncological therapies and adjustments to immunosuppressive regimens,with promising results from the use of mTOR inhibitors in select patients.The review highlights the critical need for ongoing research to refine risk stratification,optimize screening protocols,and improve treatment approaches to mitigate the burden of DNMs in LT recipients.By implementing personalized preventive and therapeutic strategies,we can enhance long-term outcomes and quality of life for this vulnerable population.展开更多
Dental implants have restored masticatory function to over 100000000 individuals,yet almost 1000000 implants fail each year due to peri-implantitis,a disease triggered by peri-implant microbial dysbiosis.Our ability t...Dental implants have restored masticatory function to over 100000000 individuals,yet almost 1000000 implants fail each year due to peri-implantitis,a disease triggered by peri-implant microbial dysbiosis.Our ability to prevent and treat peri-implantitis is hampered by a paucity of knowledge of how these biomes are acquired and the factors that engender normobiosis.Therefore,we combined a 3-month interventional study of 15 systemically and periodontally healthy adults with whole genome sequencing,finescale enumeration and graph theoretics to interrogate colonization dynamics in the pristine peri-implant sulcus.We discovered that colonization trajectories of implants differ substantially from adjoining teeth in acquisition of new members and development of functional synergies.Source-tracking algorithms revealed that this niche is initially seeded by bacteria trapped within the coverscrew chamber during implant placement.These pioneer species stably colonize the microbiome and exert a sustained influence on the ecosystem by serving as anchors of influential hubs and by providing functions that enable cell replication and biofilm maturation.Unlike the periodontal microbiome,recruitment of new members to the peri-implant community occurs on nepotistic principles.Maturation is accompanied by a progressive increase in anaerobiosis,however,the predominant functionalities are oxygen-dependent over the 12-weeks.The peri-implant community is easily perturbed following crown placement,but demonstrates remarkable resilience;returning to pre-perturbation states within three weeks.This study highlights important differences in the development of the periodontal and peri-implant ecosystems,and signposts the importance of placing implants in periodontally healthy individuals or following the successful resolution of periodontal disease.展开更多
It has recently become evident that the de novo emergence of genes is widespread and documented for a variety of organisms.De novo genes frequently emerge in proximity to existing genes,forming gene overlaps.Here,we p...It has recently become evident that the de novo emergence of genes is widespread and documented for a variety of organisms.De novo genes frequently emerge in proximity to existing genes,forming gene overlaps.Here,we present an analysis of the evolutionary history of a putative de novo gene,lawc,which overlaps with the conserved Trf2 gene,which encodes a general transcription factor in Drosophila melanogaster.We demonstrate that lawc emerged approximately 68 million years ago in the 5'-untranslated region(UTR)of Trf2 and displays an extensive spatiotemporal expression pattern.One of the most remarkable features of the lawc evolutionary history is that its emergence was facilitated by the engagement of Drosophilidae-specific short,highly conserved regions located in Trf2 introns.This represents a unique example of putative de novo gene birth involving conserved DNA regions localized in introns of conserved genes.The observed lawc expression pattern may be due to the overlap of lawc with the 5'-UTR of Trf2.This study not only enriches our understanding of gene evolution but also highlights the complex interplay between genetic conservation and innovation.展开更多
Tomato is one of the most essential vegetable crops worldwide,with the highest annual production rate of all agricultural staples(Kimura and Sinha,2008).Long-term domestication of tomatoes has led to the selection of ...Tomato is one of the most essential vegetable crops worldwide,with the highest annual production rate of all agricultural staples(Kimura and Sinha,2008).Long-term domestication of tomatoes has led to the selection of favorable agronomic traits that often come at the expense of stress resistance.To identify potential genetic targets for improved stress tolerance,whole-genome sequencing(WGS)has been applied to wild and cultivated accessions.展开更多
Insulin plays a crucial role in the metabolic priming and proliferation of neural stem cells(NSCs).However,insulin resistance(IR)is associated with impaired NSC proliferation and cognitive dysfunction,which are the ha...Insulin plays a crucial role in the metabolic priming and proliferation of neural stem cells(NSCs).However,insulin resistance(IR)is associated with impaired NSC proliferation and cognitive dysfunction,which are the hallmarks of psychiatric disorders(PDs).In addition to insulin,de novo lipogenesis(DNL)also plays an essential role in NSC proliferation and function as it supplies fatty acids for membrane phospholipid synthesis and cell signaling.However,enhanced DNL is associated with lipid/fatty acid accumulation,IR,and impaired NSC proliferation.Intriguingly,data from lipidomic studies suggest that DNL could be enhanced before the onset of classical symptoms in patients with PDs.Further,evidence suggests that patients with PDs may develop IR during childhood or before adolescence;therefore,DNL could be enhanced preceding the development of IR.Regarding treatment,while most antidepressants and antipsychotic drugs have been shown to further deteriorate IR and stimulate DNL,various adjunctive drugs/therapies,including chemical,physical,and stem cell therapy,which have shown promising success in treating PDs,reduce DNL while enhancing insulin sensitivity,NSC proliferation,and cognitive function in laboratory animals.Preliminary clinical outcomes and future prospects of these adjunctive drugs/therapies,especially stem cell therapy in treating PDs including schizophrenia and depression,are discussed.展开更多
Autism spectrum disorder(ASD)is a neurodevelopmental disorder where de novo mutations play a significant role.Although coding mutations in ASD have been extensively characterized,the impact of non-coding de novo mutat...Autism spectrum disorder(ASD)is a neurodevelopmental disorder where de novo mutations play a significant role.Although coding mutations in ASD have been extensively characterized,the impact of non-coding de novo mutations(ncDNMs)remains less understood.Here,we integrate cortex cell-specific cis-regulatory element annotations,a deep learning-based variant prediction model,and massively parallel reporter assays to systematically evaluate the functional impact of 227,878 ncDNMs from Simons Simplex Collection(SSC)and Autism Speaks MSSNG resource(MSSNG)cohorts.Our analysis identifies 238 ncDNMs with confirmed functional regulatory effects,including 137 down-regulated regulatory mutations(DrMuts)and 101 up-regulated regulatory mutations(UrMuts).Subsequent association analyses reveal that only DrMuts regulating loss-of-function(LoF)intolerant genes rather than other ncDNMs are significantly associated with the risk of ASD(Odds ratio=4.34;P=0.001).A total of 42 potential ASD-risk DrMuts across 41 candidate ASD-susceptibility genes are identified,including 12 recognized and 29 unreported genes.Interestingly,these noncoding disruptive mutations tend to be observed in genes extremely intolerant to LoF mutations.Our study introduces an optimized approach for elucidating the functional roles of ncDNMs,thereby expanding the spectrum of pathogenic variants and deepening our understanding of the complex molecular mechanisms underlying ASD.展开更多
Orthotopic liver transplantation(OLT) is an established life-saving procedure for alcoholic cirrhotic(AC) patients, but the incidence of de novo tumors ranges between 2.6% and 15.7% and is significantly increased in c...Orthotopic liver transplantation(OLT) is an established life-saving procedure for alcoholic cirrhotic(AC) patients, but the incidence of de novo tumors ranges between 2.6% and 15.7% and is significantly increased in comparison with patients who undergo OLT for other etiologies. Tobacco, a known carcinogen, has been reported to be between 52% and 83.3% in AC patients before OLT. Other risk factors that contribute to the development of malignancies are dose-dependent immunosuppression, advanced age, viral infections, sun exposure, and premalignant lesions(inflammatory bowel disease, Barrett's esophagus). A significantly more frequent incidence of upper aerodigestive(UAD) tract, lung, skin, and kidney-bladder tumors has been found in OLT recipients for AC in comparison with other etiologies. Liver transplant recipients who develop de novo non-skin tumors have a decreased long-term survival rate compared with controls. This significantly lower survival rate is more evident in AC recipients who develop UAD tract or lung tumors after OLT mainly because the diagnosis is usually performed at an advanced stage. All transplant candidates, especially AC patients, should be encouraged to cease smoking and alcohol consumption in the pre- and postOLT periods, use skin protection, avoid sun exposure and over-immunosuppression, and have a yearly otopharyngolaryngeal exploration and chest computed tomography scan in order to prevent or reduce the incidence of de novo malignancies. Although still under investigation, substitution of calcineurin inhibitors for sirolimus or everolimus may reduce the incidence of de novo tumors after OLT.展开更多
序列拼接是生物信息学的基础问题.全面总结了面向下一代测序技术的de novo DNA序列拼接工具,介绍下一代测序平台产生的数据特点以及de novo序列拼接算法所面临的挑战;给出序列拼接算法的形式化定义,总结目前最常用的拼接策略以及根据相...序列拼接是生物信息学的基础问题.全面总结了面向下一代测序技术的de novo DNA序列拼接工具,介绍下一代测序平台产生的数据特点以及de novo序列拼接算法所面临的挑战;给出序列拼接算法的形式化定义,总结目前最常用的拼接策略以及根据相应策略开发的拼接工具的特点和实现细节;对评估拼接性能的主要参数进行描述,并通过不同物种、不同规模的真实基因组序列数据对多个具有代表性的拼接工具进行测试,比较它们的拼接性能以验证相应的工具特点.为研究人员提供工具选择指导或改善拼接工具性能提供帮助;最后总结并阐述序列拼接工具存在的问题和发展趋势.展开更多
基金Supported by the National Science and Technology Research Center(Morocco)“PhD-Associate Scholarship-PASS”Program,No.88UH2C2023.
文摘BACKGROUND Donor-specific antibodies(DSAs)against human leukocyte antigen(HLA)-DQ are increasingly recognized as major contributors to antibody-mediated rejection(AMR)and graft failure in kidney transplantation.However,their clinical impact remains understudied in Morocco.AIM To evaluate the presence and implications of anti-HLA-DQ DSAs in Moroccan kidney transplant recipients.METHODS We retrospectively analyzed the immunological profiles and clinical outcomes of kidney transplant recipients screened for anti-HLA antibodies between 2015 and 2020,who developed anti-HLA-DQ DSAs either before or after transplantation.Anti-HLA antibodies were identified using Luminex®single antigen bead technology,and clinical follow-up included graft function assessment,biopsy interpretation,and evaluation of immunosuppression.RESULTS In the pre-transplant group(n=6 with confirmed donor typing),patients with low to moderate median fluorescence intensity(MFI)anti-HLA-DQ DSAs(MFI 561-1581)underwent successful transplantation and maintained stable graft function under optimized immunosuppression.In contrast,in the post-transplant group(n=6 with confirmed donor typing),the emergence of de novo anti-HLA-DQ DSAs was consistently associated with AMR,with MFI values reaching up to 19473,with biopsy-proven AMR in 5 of 6 cases and suspicion of AMR in 1 case.Two representative cases are detailed to illustrate the clinical impact of DQ DSAs:one patient developed high-level anti-DQB1*02 de novo DSA(MFI 12029)with persistent AMR after 5 years,while another developed anti-DQA1*05:01 de novo DSA after an early AMR episode but maintained stable graft function after 5 years(creatinine 1.48 mg/dL).CONCLUSION Our findings underscore the clinical significance of anti-HLA-DQ DSAs in Moroccan kidney transplant recipients.While preformed DSAs with low immunogenicity may permit successful transplantation,de novo DSAs strongly correlate with AMR.Proactive monitoring,including routine DSA screening and HLA-DQ typing,could improve graft outcomes by enabling early intervention and better donor selection.
基金supported by grants from the National Natural Science Foundation of China (82070408)the Traditional Chinese Medicine Science and Technology Project of Zhejiang Province (2023ZL496)。
文摘Background Quantitative flow ratio(QFR) holds significant value in guiding drug-coated balloon(DCB) treatment and enhancing outcomes. However, the predictive capability of post-angioplasty QFR for long-term clinical events in patients with de novo lesions who receive DCB treatment remains uncertain. The aim of this study was to explore the potential significance of post-angioplasty QFR measurements in predicting clinical outcomes in patients underwent DCB treatment for de novo lesions.Methods Patients who underwent DCB-only intervention for de novo lesions were enrolled. QFR was conducted after DCB treatment. The patients were then categorized based on post-angioplasty QFR. The primary endpoint was major adverse cardiac events(MACE), encompassing all-cause death, cardiovascular death, nonfatal myocardial infarction, stroke, and target vessel revascularization.Results A total of 553 patients with 561 lesions were included. The median follow-up period was 505 days, during which 66(11.8%) MACEs occurred. Based on post-procedural QFR grouping, there were 259 cases in the high QFR group(QFR > 0.93) and302 cases in the low QFR group(QFR ≤ 0.93). Kaplan-Meier analysis revealed a significantly higher cumulative incidence of MACE in the low QFR group(log-rank P = 0.004). The multivariate Cox proportional hazards model demonstrated a significant inverse correlation between QFR and the occurrence of MACEs(HR = 0.522, 95%CI: 0.289-0.942, P = 0.031). Landmark analysis indicated that high QFR had a significant reducing effect on the cumulative incidence of MACEs within 1 year(log-rank P = 0.016)and 1-5 years(log-rank P = 0.026).Conclusions In patients who underwent DCB-only treatment for de novo lesions, higher post-procedural QFR values(> 0.93)were identified as an independent protective factor against adverse prognosis.
文摘Liver transplantation(LT)is the definitive treatment for end-stage liver disease,acute liver failure,and liver cancer.Although advancements in surgical techniques,postoperative care,and immunosuppressive therapies have significantly improved outcomes,the long-term use of immunosuppression has increased the risk of complications,including infections,cardiovascular disease,and cancer.Among these,de novo malignancies(DNMs)are a major concern,accounting for 20%-25%of deaths in LT recipients surviving beyond the early post-transplant period.Non-melanoma skin cancers,particularly squamous cell carcinoma are the most prevalent DNMs.Other significant malignancies include Kaposi's sarcoma,post-transplant lymphoproliferative disorders,and various solid organ cancers,including head and neck cancers.Compared to the general population,LT patients face a twofold increase in solid organ malignancies and a 30-fold increase in lymphoproliferative disorders.Risk factors for DNM include chronic immunosuppression,alcohol or tobacco use,viral infections,and underlying liver disease.Emerging evidence emphasizes the importance of tailored cancer screening and prevention strategies,including regular dermatological examinations,targeted screenings for high-risk cancers,and patient education on lifestyle modifications.Early detection through enhanced surveillance protocols has been shown to improve outcomes.Management of DNMs involves a combination of standard oncological therapies and adjustments to immunosuppressive regimens,with promising results from the use of mTOR inhibitors in select patients.The review highlights the critical need for ongoing research to refine risk stratification,optimize screening protocols,and improve treatment approaches to mitigate the burden of DNMs in LT recipients.By implementing personalized preventive and therapeutic strategies,we can enhance long-term outcomes and quality of life for this vulnerable population.
基金supported by National Institutes of Health R03DE027492 to Shareef Dabdoubsupported by National Institutes of Health,project number 7R01DE027857-06supported by National Institutes of Health R56DE033913 awarded to Purnima Kumar.
文摘Dental implants have restored masticatory function to over 100000000 individuals,yet almost 1000000 implants fail each year due to peri-implantitis,a disease triggered by peri-implant microbial dysbiosis.Our ability to prevent and treat peri-implantitis is hampered by a paucity of knowledge of how these biomes are acquired and the factors that engender normobiosis.Therefore,we combined a 3-month interventional study of 15 systemically and periodontally healthy adults with whole genome sequencing,finescale enumeration and graph theoretics to interrogate colonization dynamics in the pristine peri-implant sulcus.We discovered that colonization trajectories of implants differ substantially from adjoining teeth in acquisition of new members and development of functional synergies.Source-tracking algorithms revealed that this niche is initially seeded by bacteria trapped within the coverscrew chamber during implant placement.These pioneer species stably colonize the microbiome and exert a sustained influence on the ecosystem by serving as anchors of influential hubs and by providing functions that enable cell replication and biofilm maturation.Unlike the periodontal microbiome,recruitment of new members to the peri-implant community occurs on nepotistic principles.Maturation is accompanied by a progressive increase in anaerobiosis,however,the predominant functionalities are oxygen-dependent over the 12-weeks.The peri-implant community is easily perturbed following crown placement,but demonstrates remarkable resilience;returning to pre-perturbation states within three weeks.This study highlights important differences in the development of the periodontal and peri-implant ecosystems,and signposts the importance of placing implants in periodontally healthy individuals or following the successful resolution of periodontal disease.
基金funded by a grant from the Russian Science Foundation № 24-24-00354
文摘It has recently become evident that the de novo emergence of genes is widespread and documented for a variety of organisms.De novo genes frequently emerge in proximity to existing genes,forming gene overlaps.Here,we present an analysis of the evolutionary history of a putative de novo gene,lawc,which overlaps with the conserved Trf2 gene,which encodes a general transcription factor in Drosophila melanogaster.We demonstrate that lawc emerged approximately 68 million years ago in the 5'-untranslated region(UTR)of Trf2 and displays an extensive spatiotemporal expression pattern.One of the most remarkable features of the lawc evolutionary history is that its emergence was facilitated by the engagement of Drosophilidae-specific short,highly conserved regions located in Trf2 introns.This represents a unique example of putative de novo gene birth involving conserved DNA regions localized in introns of conserved genes.The observed lawc expression pattern may be due to the overlap of lawc with the 5'-UTR of Trf2.This study not only enriches our understanding of gene evolution but also highlights the complex interplay between genetic conservation and innovation.
基金supported by grants from the Shanghai Agriculture Applied Technology Development Program(2021-02-08-00-12-F00792)Projects of International Cooperation and Exchanges NSFC(3201101910).
文摘Tomato is one of the most essential vegetable crops worldwide,with the highest annual production rate of all agricultural staples(Kimura and Sinha,2008).Long-term domestication of tomatoes has led to the selection of favorable agronomic traits that often come at the expense of stress resistance.To identify potential genetic targets for improved stress tolerance,whole-genome sequencing(WGS)has been applied to wild and cultivated accessions.
文摘Insulin plays a crucial role in the metabolic priming and proliferation of neural stem cells(NSCs).However,insulin resistance(IR)is associated with impaired NSC proliferation and cognitive dysfunction,which are the hallmarks of psychiatric disorders(PDs).In addition to insulin,de novo lipogenesis(DNL)also plays an essential role in NSC proliferation and function as it supplies fatty acids for membrane phospholipid synthesis and cell signaling.However,enhanced DNL is associated with lipid/fatty acid accumulation,IR,and impaired NSC proliferation.Intriguingly,data from lipidomic studies suggest that DNL could be enhanced before the onset of classical symptoms in patients with PDs.Further,evidence suggests that patients with PDs may develop IR during childhood or before adolescence;therefore,DNL could be enhanced preceding the development of IR.Regarding treatment,while most antidepressants and antipsychotic drugs have been shown to further deteriorate IR and stimulate DNL,various adjunctive drugs/therapies,including chemical,physical,and stem cell therapy,which have shown promising success in treating PDs,reduce DNL while enhancing insulin sensitivity,NSC proliferation,and cognitive function in laboratory animals.Preliminary clinical outcomes and future prospects of these adjunctive drugs/therapies,especially stem cell therapy in treating PDs including schizophrenia and depression,are discussed.
基金supported by the National Natural Science of China(82322032 and 82221005)the Outstanding Youth Foundation of Jiangsu Province(BK20220050)+4 种基金the National Key Research&Development(R&D)Program of China(2024YFC2706800 and 2021YFC2700600)the Major Project of Changzhou Medical Center(CZKY1040101)the Major Project of Taizhou Clinical Medical College(TZKY20240003)the Major Program of Gusu School(GSKY20210102)the China Postdoctoral Science Foundation(2024M760296).
文摘Autism spectrum disorder(ASD)is a neurodevelopmental disorder where de novo mutations play a significant role.Although coding mutations in ASD have been extensively characterized,the impact of non-coding de novo mutations(ncDNMs)remains less understood.Here,we integrate cortex cell-specific cis-regulatory element annotations,a deep learning-based variant prediction model,and massively parallel reporter assays to systematically evaluate the functional impact of 227,878 ncDNMs from Simons Simplex Collection(SSC)and Autism Speaks MSSNG resource(MSSNG)cohorts.Our analysis identifies 238 ncDNMs with confirmed functional regulatory effects,including 137 down-regulated regulatory mutations(DrMuts)and 101 up-regulated regulatory mutations(UrMuts).Subsequent association analyses reveal that only DrMuts regulating loss-of-function(LoF)intolerant genes rather than other ncDNMs are significantly associated with the risk of ASD(Odds ratio=4.34;P=0.001).A total of 42 potential ASD-risk DrMuts across 41 candidate ASD-susceptibility genes are identified,including 12 recognized and 29 unreported genes.Interestingly,these noncoding disruptive mutations tend to be observed in genes extremely intolerant to LoF mutations.Our study introduces an optimized approach for elucidating the functional roles of ncDNMs,thereby expanding the spectrum of pathogenic variants and deepening our understanding of the complex molecular mechanisms underlying ASD.
文摘Orthotopic liver transplantation(OLT) is an established life-saving procedure for alcoholic cirrhotic(AC) patients, but the incidence of de novo tumors ranges between 2.6% and 15.7% and is significantly increased in comparison with patients who undergo OLT for other etiologies. Tobacco, a known carcinogen, has been reported to be between 52% and 83.3% in AC patients before OLT. Other risk factors that contribute to the development of malignancies are dose-dependent immunosuppression, advanced age, viral infections, sun exposure, and premalignant lesions(inflammatory bowel disease, Barrett's esophagus). A significantly more frequent incidence of upper aerodigestive(UAD) tract, lung, skin, and kidney-bladder tumors has been found in OLT recipients for AC in comparison with other etiologies. Liver transplant recipients who develop de novo non-skin tumors have a decreased long-term survival rate compared with controls. This significantly lower survival rate is more evident in AC recipients who develop UAD tract or lung tumors after OLT mainly because the diagnosis is usually performed at an advanced stage. All transplant candidates, especially AC patients, should be encouraged to cease smoking and alcohol consumption in the pre- and postOLT periods, use skin protection, avoid sun exposure and over-immunosuppression, and have a yearly otopharyngolaryngeal exploration and chest computed tomography scan in order to prevent or reduce the incidence of de novo malignancies. Although still under investigation, substitution of calcineurin inhibitors for sirolimus or everolimus may reduce the incidence of de novo tumors after OLT.
文摘序列拼接是生物信息学的基础问题.全面总结了面向下一代测序技术的de novo DNA序列拼接工具,介绍下一代测序平台产生的数据特点以及de novo序列拼接算法所面临的挑战;给出序列拼接算法的形式化定义,总结目前最常用的拼接策略以及根据相应策略开发的拼接工具的特点和实现细节;对评估拼接性能的主要参数进行描述,并通过不同物种、不同规模的真实基因组序列数据对多个具有代表性的拼接工具进行测试,比较它们的拼接性能以验证相应的工具特点.为研究人员提供工具选择指导或改善拼接工具性能提供帮助;最后总结并阐述序列拼接工具存在的问题和发展趋势.
