Autism spectrum disorder (ASD) is a neurodevelopmental disorder with considerable clinical and genetic heterogeneity.In this study,we identified all classes of genomic variants from whole-genome sequencing (WGS) datas...Autism spectrum disorder (ASD) is a neurodevelopmental disorder with considerable clinical and genetic heterogeneity.In this study,we identified all classes of genomic variants from whole-genome sequencing (WGS) dataset of 32 Chinese trios with ASD,including de novo mutations,inherited variants,copy number variants (CNVs) and genomic structural variants.A higher mutation rate (Poisson test,P<2.2×10^(-16)) in exonic (1.37×10^(-8)) and 3'-UTR regions (1.42×10^(-8)) was revealed in comparison with that of whole genome (1.05×10^(-8)).Using an integrated model,we identified 87 potentially risk genes (P<0.01) from 4832 genes harboring various rare deleterious variants,including CHD8 and NRXN2,implying that the disorders may be in favor to multiple-hit.In particular,frequent rare inherited mutations of several microcephaly-associated genes (ASPM,WDR62,and ZNF335)were found in ASD.In chromosomal structure analyses,we found four de novo CNVs and one de novo chromosomal rearrangement event,including a de novo duplication of UBE3A-containing region at 15q11.2-q13.1,which causes Angelman syndrome and microcephaly,and a disrupted TNR due to de novo chromosomal translocation t (1;5) (q25.1;q33.2).Taken together,our results suggest that abnormalities of centrosomal function and chromatin remodeling of the microcephaly-associated genes may be implicated in pathogenesis of ASD.Adoption of WGS as a new yet efficient technique to illustrate the full genetic spectrum in complex disorders,such as ASD,could provide novel insights into pathogenesis,diagnosis and treatment.展开更多
Sizing treatment is a suitable technique to modify the fiber-matrix interfaces without damage of inherent performance of fibers.In this work,sizing agents based on Janus particles(JPs)were utilized to enhance the inte...Sizing treatment is a suitable technique to modify the fiber-matrix interfaces without damage of inherent performance of fibers.In this work,sizing agents based on Janus particles(JPs)were utilized to enhance the interface of basalt fiber(BF)/poly(vinyl chloride)(PVC)composites.polystyrene/poly(butyl acrylate)(PS/PBA)@silica JPs were synthesized by seed emulsion polymerization and three different sizing agents were prepared for BF sizing treatment.JPs with organic soft sphere and inorganic hard hemisphere enhanced the interfaces through their amphiphilicity,chemical bonding and mechanical interlock.The mechanical properties of composite with JPs sizing treated BFs performed better when there was one JPs layer modified on the interface.According to the intermitting bonding and gradient modulus theory,JPs patterned interfaces are ideal transition layers between high modulus BF and low modulus PVC.展开更多
Ammonia(NH_(3))is considered as a potential alternative carbon free fuel to reduce greenhouse gas emission to meet the increasingly stringent emission requirements.Co-burning NH_(3) and H_(2) is an effective way to ov...Ammonia(NH_(3))is considered as a potential alternative carbon free fuel to reduce greenhouse gas emission to meet the increasingly stringent emission requirements.Co-burning NH_(3) and H_(2) is an effective way to overcome ammonia’s relative low burning velocity.In this work,3D Reynolds Averaged Navier-Stokes(RANS)numerical simulations are conducted on a premixed NH_(3)/H_(2) swirling flame with reduced chemical kinetic mechanism.The effects of(A)overall equivalence ratio Φ and(B)hydrogen blended molar fraction XH2 on combustion and emission characteristics are examined.The present results show that when 100%NH_(3)-0%H_(2)-air are burnt,the NO emission and unburned NH3 of at the swirling combustor outlet has the opposite varying trends.With the increase of Φ,NO emission is found to be decreased,while the unburnt ammonia emission is increased.NH_(2)→HNO,NH→HNO and HNO→NO sub-paths are found to play a critical role in NO formation.Normalized reaction rate of all these three sub-paths is shown to be decreased with increased Φ.Hydrogen addition is shown to significantly increase the laminar burning velocity of the mixed fuel.However,adding H_(2) does not affect the critical equivalence ratio corresponding to the maximum burning velocity.The emission trend of NO and unburnt NH_(3) with increased Φ is unchanged by blending H_(2).NO emission with increased X_(H2) is increased slightly less at a larger Φ than that at a smaller Φ.In addition,reaction rates of NH_(2)→HNO and HNO→NO sub-paths are decreased with increased X_(H2),when Φ is larger.Under all tested cases,blending H_(2) with NH_(3) reduces the unburned NH_(3) emission,especially for rich combustion conditions.In summary,the present work provides research finding on supporting applying ammonia with hydrogen blended in low-emission gas turbine engines.展开更多
The goal of this study was to identify MSX1 gene variants in multiple Chinese families with nonsyndromic oligodontia and analyse the functional influence of these variants.Whole-exome sequencing(WES)and Sanger sequenc...The goal of this study was to identify MSX1 gene variants in multiple Chinese families with nonsyndromic oligodontia and analyse the functional influence of these variants.Whole-exome sequencing(WES)and Sanger sequencing were performed to identify the causal gene variants in five families with nonsyndromic oligodontia,and a series of bioinformatics databases were used for variant confirmation and functional prediction.Phenotypic characterization of the members of these families was described,and an in vitro analysis was performed for functional evaluation.Five novel MSX1 heterozygous variants were identified:three missense variants[c.662A>C(p.Q221P),c.670C>T(p.R224C),and c.809C>T(p.S270L)],one nonsense variant[c.364G>T(p.G122*)],and one frameshift variant[c.277delG(p.A93Rfs*67)].Preliminary in vitro studies demonstrated that the subcellular localization of MSX1 was abnormal with the p.Q221P,p.R224C,p.G122*,and p.A93Rfs*67 variants compared to the wild type.Three variants(p.Q221P,p.G122*,and p.A93Rfs*67)were classified as pathogenic or likely pathogenic,while p.S270L and p.R224C were of uncertain significance in the current data.Moreover,we summarized and analysed the MSX1-related tooth agenesis positions and found that the type and variant locus were not related to the severity of tooth loss.Our results expand the variant spectrum of nonsyndromic oligodontia and provide valuable information for genetic counselling.展开更多
Unusually severe weather is occurring more frequently due to global climate change. Heat waves, rainstorms, snowstorms, and droughts are becoming increasingly common all over the world, threatening human lives and pro...Unusually severe weather is occurring more frequently due to global climate change. Heat waves, rainstorms, snowstorms, and droughts are becoming increasingly common all over the world, threatening human lives and property. Both temperature and precipitation are representative variables usually used to directly reflect and forecast the influences of climate change. In this study, daily data （from 1953 to 1995） and monthly data （from 1950 to 2010） of temperature and precipitation in five regions of the Amur River were examined. The significance of changes in temperature and precipitation was tested using the Mann-Kendall test method. The amplitudes were computed using the linear least-squares regression model, and the extreme temperature and precipitation were analyzed using hydrological statistical methods. The results show the following： the mean annual temperature increased significantly from 1950 to 2010 in the five regions, mainly due to the warming in spring and winter; the annual precipitation changed significantly from 1950 to 2010 only in the lower mainstream of the Amur River; the frequency of extremely low temperature events decreased from 1953 to 1995 in the mainstream of the Amur River; the frequency of high temperature events increased from 1953 to 1995 in the mainstream of the Amur River; and the frequency of extreme precipitation events did not change significantly from 1953 to 1995 in the mainstream of the Amur River. This study provides a valuable theoretical basis for settling disputes between China and Russia on sustainable development and utilization of water resources of the Amur River.展开更多
BACKGROUND Dermatofibrosarcoma protuberans(DFSP)is a rare low-grade malignant soft tissue tumor characterized by rosette-like infiltrative growth.Postoperative recurrence of this tumor is very common.AIM To evaluate t...BACKGROUND Dermatofibrosarcoma protuberans(DFSP)is a rare low-grade malignant soft tissue tumor characterized by rosette-like infiltrative growth.Postoperative recurrence of this tumor is very common.AIM To evaluate the risk factors related to recurrence after wide local excision(WLE)of DFSP and to guide clinical diagnosis and treatment.METHODS The medical records of 44 DFSP patients confirmed by pathology at our hospital from 2012 to 2019 were retrospectively reviewed.The relationship between clinical features,tumor characteristics,treatment,and recurrence risk were analyzed,and the possible risk factors for postoperative tumor recurrence were evaluated.RESULTS There were 44 patients in total,including 21 males and 23 females.The median progression free survival was 36 mo(range,1-240 mo).Twenty patients were treated for the first time,while 24 had previous treatment experience.Forty-two cases were followed for 25.76±22.0 mo,among whom four(9.52%)experienced recurrence after WLE(rate was 9.52%).The recurrence rate in the recurrent group was higher than that in the patients with primary tumor(19.05%vs 0%,P=0.028).Eighteen cases had a history of misdiagnosis(rate was 40.91%).The recurrence rate among patients with previous experience of misdiagnosis was significantly higher than in patients without(68%vs 36.84%,P=0.04).The tumor diameter in patients with a history of treatment was larger than in patients treated for the first time(4.75±0.70 cm vs 2.25±0.36 cm,P=0.004).CONCLUSION To sum up,the clinical manifestations of DFSP are not specific and are easily misdiagnosed,thus commonly causing the recurrence of DFSP.After incomplete resection,the tumor may rapidly grow.Previous recurrence history may be a risk factor for postoperative recurrence,and tumor location may have an indirect effect on postoperative recurrence;however,we found no significant correlation between sex,age,course of the disease,or tumor size and postoperative recurrence.展开更多
Particle swarm optimizer(PSO),a new evolutionary computation algorithm,exhibits good performance for optimization problems,although PSO can not guarantee convergence of a global minimum,even a local minimum.However,th...Particle swarm optimizer(PSO),a new evolutionary computation algorithm,exhibits good performance for optimization problems,although PSO can not guarantee convergence of a global minimum,even a local minimum.However,there are some adjustable parameters and restrictive conditions which can affect performance of the algorithm.In this paper,the algorithm are analyzed as a time-varying dynamic system,and the sufficient conditions for asymptotic stability of acceleration factors,increment of acceleration factors and inertia weight are deduced.The value of the inertia weight is enhanced to(-1,1).Based on the deduced principle of acceleration factors,a new adaptive PSO algorithm-harmonious PSO(HPSO)is proposed.Furthermore it is proved that HPSO is a global search algorithm.In the experiments,HPSO are used to the model identification of a linear motor driving servo system.An Akaike information criteria based fitness function is designed and the algorithms can not only estimate the parameters,but also determine the order of the model simultaneously.The results demonstrate the effectiveness of HPSO.展开更多
Background Formolase(FLS)is a computationally designed enzyme that catalyzes the carboligation of two or three C1 formaldehyde molecules into C2 glycolaldehyde or C3 dihydroxyacetone(DHA).FLS lays the foundation for s...Background Formolase(FLS)is a computationally designed enzyme that catalyzes the carboligation of two or three C1 formaldehyde molecules into C2 glycolaldehyde or C3 dihydroxyacetone(DHA).FLS lays the foundation for several artificial carbon fixation and valorization pathways,such as the artificial starch anabolic pathway.However,the application of FLS is limited by its low catalytic activity and product promiscuity.Findings FLS,designed and engineered based on benzoylformate decarboxylase from Pseudomonas putida,was selected as a candidate for modification.To evaluate its catalytic activity,25 residues located within an 8Ådistance from the active center were screened using single-point saturation mutagenesis.A screening approach based on the color reaction of the DHA product was applied to identify the desired FLS variants.After screening approximately 5,000 variants(approximately 200 transformants per site),several amino acid sites that were not identified by directed evolution were found to improve DHA formation.The serine-to-phenylalanine substitution at position 236 improved the activity towards DHA formation by 7.6-fold.Molecular dynamics simulations suggested that the mutation increased local hydrophobicity at the active site,predisposing the cofactor-C2 intermediate to nucleophilic attack by the third formaldehyde molecule for subsequent DHA generation.Conclusions This study provides improved FLS variants and valuable information into the influence of residues adjacent to the active center affecting catalytic efficiency,which can guide the rational engineering or directed evolution of FLS to optimize its performance in artificial carbon fixation and valorization.展开更多
In this work, we propose and examine an ammonia-hydrogen fueled micro-combustor with a single-channel inlet and double-channel outlet (SIDO). The combustion characteristics and nitrogen oxide emission of ammonia/hydro...In this work, we propose and examine an ammonia-hydrogen fueled micro-combustor with a single-channel inlet and double-channel outlet (SIDO). The combustion characteristics and nitrogen oxide emission of ammonia/hydrogen-oxygen premixed combustion are explored. Comparison is then made between the conventional and the proposed SIDO combustors. It is found that our proposed new design could lead to an increase of the outer wall temperature and reduced nitrogen oxide emission. The performances of different hydrogen blended ratios (Φ_(b)), inlet velocities (V_(in)), and equivalence ratios (Φ) are evaluated. It is found that increasing Φ_(b) reduces the maximum flame temperature and the pressure loss, enabling the flame to move upstream. When Φ_(b) is set to 25 %, the convective heat transfer performance reaches its optimal level. The wall temperature and its uniformity can be improved by increasing V_(in). However, it is accompanied by increased NO emissions at the outlet. Increasing Φ can significantly reduce nitrogen oxide emission, and such a reduction effect is much more remarkable at a lower Φ_(b). Examining the exergy efficiency is shown to be greatly improved by increasing Φ_(b). Increasing Φ could reduce the combustion efficiency of hydrogen in the mixed fuel and have almost no effect on ammonia. This study demonstrates the feasibility of improving thermal performance and reducing emissions by varying its structure for thermophotovoltaic applications.展开更多
Artificial conversion of CO_(2)into foods and chemicals offers a sustainable way to tackle population-relatedand environmental issues.Thermochemical and electrochemical methods for reducing CO_(2)to low-carbonmolecule...Artificial conversion of CO_(2)into foods and chemicals offers a sustainable way to tackle population-relatedand environmental issues.Thermochemical and electrochemical methods for reducing CO_(2)to low-carbonmolecules have made significant progress;however,it remains challenging to generate long-chain,structurally diverse carbohydrates,which are the most abundant substances in nature.Here,we report thesuccessful design and realization of in vitro sucrose synthesis from C1 and C3 molecules through a thermodynamically favorable pathway with short reaction steps and low energy input.By engineering thephosphatase and sucrose synthase to improve their catalytic efficiency by 3-to 71-fold,and by optimizing the reaction system through an iterative scanning strategy,we achieved a high conversion yield of86%and a specific synthetic rate of 5.7 g L^(−1)h^(−1).Additionally,we demonstrated the cell-free starch synthesis without the need for dextrin primers,achieving a superior C1-to-starch synthesis rate compared topreviously developed multienzyme systems.Building upon this platform,we further extended methanolconversion to a variety of sugars,especially for cellooligosaccharides with a degree of polymerization ofCn≥18.Together,our system provides a promising,plant-independent route for de novo synthesis ofstructure-diversified oligosaccharides and polysaccharides.展开更多
Purpose:Familial exudative vitreoretinopathy(FEVR)is a genetically heterogeneous retinal vascular disorder,with nearly half of the cases attributed to mutations in genes involved in the Norrin/β-catenin signaling pat...Purpose:Familial exudative vitreoretinopathy(FEVR)is a genetically heterogeneous retinal vascular disorder,with nearly half of the cases attributed to mutations in genes involved in the Norrin/β-catenin signaling pathway.This study aimed to identify and functionally characterize novel FZD4 variants in patients with FEVR.Methods:Genetic sequencing of FZD4 was performed in a cohort of FEVR families,leading to the identification of five novel variants:c.434G>A,c.610T>G,c.844T>C,c.277C>T,and c.1155delC.Bioinformatic predictions,comprehensive clinical evaluations,and dual-luciferase reporter assays were conducted to assess the functional impact and pathogenicity of these variants.Results:All five FZD4 variants were found to significantly reduceβ-catenin signaling activity compared to wild-type FZD4.Among them,two variants previously classified as variants of uncertain significance(VUS)demon-strated functional impairment and clinical segregation consistent with pathogenicity,supporting their reclassi-fication as disease-causing mutations.Conclusions:These findings expand the known mutational spectrum of FZD4 in FEVR and highlight the critical role of functional validation in the interpretation of novel and uncertain variants.Incorporating experimental assays can improve diagnostic accuracy and inform clinical genetic counseling.展开更多
Background:In the Yunnan province of China,18 counties in six prefectures border Myanmar.Due to its particular combination of geographic features,climate conditions,and cultural landscape,the area provides a suitable ...Background:In the Yunnan province of China,18 counties in six prefectures border Myanmar.Due to its particular combination of geographic features,climate conditions,and cultural landscape,the area provides a suitable environment for the spread of insect-borne diseases such as malaria.In five identified Myanmar Special Regions along the China-Myanmar border,economic development is lagging,people live in extreme poverty,and the healthcare system is fragile.Coupled with political and other reasons,this precludes malaria control work to be effectively carried out in Myanmar,resulting in a heavy burden of the disease.Frequent population movements and favorable conditions for malaria transmission on the border fuel difficulties in controlling and eliminating the spread of the disease in the area.Case presentation:To reduce the prevalence of malaria in the China-Myanmar border area and improve healthcare services for local residents in this particular environment,Health Poverty Action(HPA)has provided malaria aid in the area since the beginning of 2006,as a sub-recipient of the China Global Fund Malaria Programs.In this case study,we examined HPA’s activities as part of its malaria control programs in the area,analyzed and summarized the effectiveness and impact of the cross-border healthcare model as implemented by non-governmental organizations,and put forward suggestions for cross-border health aid models and for the prevention of malaria transmission in the Greater Mekong Subregion.Conclusions:HPA had carried out a great quantity of successful malaria control activities in border areas between China and Myanmar,strengthened the partnership and established the collaboration,coordination and cooperation channels among stakeholders.HPA has laid good groundwork and developed its valuable model that could be highlighted and referenced.展开更多
Methanol is a promising one-carbon feedstock for biomanufacturing,which can be sustainably produced from carbon dioxide and natural gas.However,the efficiency of methanol bioconversion is limited by the poor catalytic...Methanol is a promising one-carbon feedstock for biomanufacturing,which can be sustainably produced from carbon dioxide and natural gas.However,the efficiency of methanol bioconversion is limited by the poor catalytic properties of nicotinamide adenine dinucleotide(NAD^(+))-dependent methanol dehydrogenase(Mdh)that oxidizes methanol to formaldehyde.Herein,the neutrophilic and mesophilic NAD^(+)-dependent Mdh from Bacillus stearothermophilus DSM 2334(Mdh_(Bs))was subjected to directed evolution for enhancing the catalytic activity.The combination of formaldehyde biosensor and Nash assay allowed high-throughput and accurate measurement of formaldehyde and facilitated efficient selection of desired variants.Mdh_(Bs)variants with up to 6.5-fold higher K_(cat)/K_(M)value for methanol were screened from random mutation libraries.The T153 residue that is spatially proximal to the substrate binding pocket has significant influence on enzyme activity.The beneficial T153P mutation changes the interaction network of this residue and breaks theα-helix important for substrate binding into two shortα-helices.Reconstructing the interaction network of T153 with surrounding residues may represent a promising strategy to further improve Mdh_(Bs),and this study provides an efficient strategy for directed evolution of Mdh.展开更多
Background:For many countries where malaria is endemic,the burden of malaria is high in border regions.In ethnic minority areas along the Myanmar-China border,residents have poor access to medical care for diagnosis a...Background:For many countries where malaria is endemic,the burden of malaria is high in border regions.In ethnic minority areas along the Myanmar-China border,residents have poor access to medical care for diagnosis and treatment,and there have been many malaria outbreaks in such areas.Since 2007,with the support of the Global Fund to Fight AIDS,Tuberculosis and Malaria(GFATM),a malaria control project was introduced to reduce the malaria burden in several ethnic minority regions.Methods:A malaria control network was established during the period from 2007 to 2014.Multiple malaria interventions,including diagnosis,treatment,distribution of LLINs and health education,were conducted to improve the accessibility and quality of malaria control services for local residents.Annual cross-sectional surveys were conducted to evaluate intervention coverage and indicators of malaria transmission.Results:In ethnic minority regions where a malaria control network was established,both the annual malaria incidence(19.1 per thousand per year,in 2009;8.7,in 2014)and malaria prevalence(13.6%in 2008;0.43%in 2014)decreased dramatically during the past 5–6 years.A total of 851393 febrile patients were detected,202598 malaria cases(including confirmed cases and suspected cases)were treated,and 759574 LLINs were delivered to populations at risk.Of households in 2012,73.9%had at least one ITNs/LLINs(vs.28.3%,in 2008),and 50.7%of children less than 5 years and 50.3%of pregnant women slept under LLINs the night prior to their visit.Additionally,malaria knowledge was improved in 68.4%of residents.Conclusion:There has been great success in improving malaria control in these regions from 2007 to 2014.Malaria burdens have decreased,especially in KOK and WA.The continued maintenance of sustainable malaria control networks in these regions may be a long-term process,due to regional conflicts and the lack of funds,technology,and health workers.Furthermore,information and scientific support from the international community should be offered to these ethnic minority regions to uphold recent achievements.展开更多
The rhesus macaque(Macaca mulatta)is a crucial experimental animal that shares many genetic,brain organizational,and behavioral characteristics with humans.A macaque brain atlas is fundamental to biomedical and evolut...The rhesus macaque(Macaca mulatta)is a crucial experimental animal that shares many genetic,brain organizational,and behavioral characteristics with humans.A macaque brain atlas is fundamental to biomedical and evolutionary research.However,even though connectivity is vital for understanding brain functions,a connectivity-based whole-brain atlas of the macaque has not previously been made.In this study,we created a new whole-brain map,the Macaque Brainnetome Atlas(MacBNA),based on the anatomical connectivity profiles provided by high angular and spatial resolution ex vivo diffusion MRI data.The new atlas consists of 248 cortical and 56 subcortical regions as well as their structural and functional connections.The parcellation and the diffusion-based tractography were evaluated with invasive neuronal-tracing and Nissl-stained images.As a demonstrative application,the structural connectivity divergence between macaque and human brains was mapped using the Brainnetome atlases of those two species to uncover the genetic underpinnings of the evolutionary changes in brain structure.The resulting resource includes:(1)the thoroughly delineated Macaque Brainnetome Atlas(MacBNA),(2)regional connectivity profiles,(3)the postmortem high-resolution macaque diffusion and T2-weighted MRI dataset(Brainnetome-8),and(4)multi-contrast MRI,neuronal-tracing,and histological images collected from a single macaque.MacBNA can serve as a common reference frame for mapping multifaceted features across modalities and spatial scales and for integrative investigation and characterization of brain organization and function.Therefore,it will enrich the collaborative resource platform for nonhuman primates and facilitate translational and comparative neuroscience research.展开更多
Although DNA methylation is known to play an important role in the silencing of transposable elements （TEs） and introduced transgenes, the mechanisms that generate DNA methylation-independent transcrip- tional silen...Although DNA methylation is known to play an important role in the silencing of transposable elements （TEs） and introduced transgenes, the mechanisms that generate DNA methylation-independent transcrip- tional silencing are poorly understood. Previous studies suggest that RNA-directed DNA methylation （RdDM） is required for the silencing of the RD29A-LUC transgene in the Arabidopsis rosl mutant back- ground with defective DNA demethylase. Loss of function of ARGONAUTE 4 （AGO4） gene, which encodes a core RdDM component, partially released the silencing of RD29A-LUC in the rosl/ago4 double mutant plants. A forward genetic screen was performed to identify the mutants with elevated RD29A-LUC trans- gene expression in the rosl/ago4 mutant background. We identified a mutation in the homologous gene of PRP31, which encodes a conserved pre-mRNA splicing factor that regulates the formation of the U4/ U6.U5 snRNP complex in fungi and animals. We previously demonstrated that the splicing factors ZOP1 and STA1 contribute to transcriptional gene silencing. Here, we reveal that Arabidopsis PRP31 associates with ZOP1, STA1, and several other splicing-related proteins, suggesting that these splicing factors are both physically and functionally connected. We show that Arabidopsis PRP31 participates in transcrip- tional gene silencing. Moreover, we report that PRP31, STA1, and ZOP1 are required for development and stress response. Under cold stress, PRP31 is not only necessary for pre-mRNA splicing but also for regulation of cold-responsive gene expression. Our results suggest that the splicing machinery has multiple functions including pre-mRNA splicing, gene regulation, transcriptional gene silencing, and stress response.展开更多
基金supported by the grants from the Major State Basic Research Development Program of China(2012CB517902 and 2012CB517904)National Key Technology Research and Development Program of China(2012BAI03B00)+3 种基金Special Research Program of National Health and Family Planning Commission of China(201302002)International S&T Cooperation Program of China(2011DFA30670)National Natural Science Foundation of China(31571357/31771404)supported in part by research funding from AstraZeneca Innovation Center China and Wenzhou Medical University
文摘Autism spectrum disorder (ASD) is a neurodevelopmental disorder with considerable clinical and genetic heterogeneity.In this study,we identified all classes of genomic variants from whole-genome sequencing (WGS) dataset of 32 Chinese trios with ASD,including de novo mutations,inherited variants,copy number variants (CNVs) and genomic structural variants.A higher mutation rate (Poisson test,P<2.2×10^(-16)) in exonic (1.37×10^(-8)) and 3'-UTR regions (1.42×10^(-8)) was revealed in comparison with that of whole genome (1.05×10^(-8)).Using an integrated model,we identified 87 potentially risk genes (P<0.01) from 4832 genes harboring various rare deleterious variants,including CHD8 and NRXN2,implying that the disorders may be in favor to multiple-hit.In particular,frequent rare inherited mutations of several microcephaly-associated genes (ASPM,WDR62,and ZNF335)were found in ASD.In chromosomal structure analyses,we found four de novo CNVs and one de novo chromosomal rearrangement event,including a de novo duplication of UBE3A-containing region at 15q11.2-q13.1,which causes Angelman syndrome and microcephaly,and a disrupted TNR due to de novo chromosomal translocation t (1;5) (q25.1;q33.2).Taken together,our results suggest that abnormalities of centrosomal function and chromatin remodeling of the microcephaly-associated genes may be implicated in pathogenesis of ASD.Adoption of WGS as a new yet efficient technique to illustrate the full genetic spectrum in complex disorders,such as ASD,could provide novel insights into pathogenesis,diagnosis and treatment.
基金supported by the National Natural Science Foundation of China(Nos.U22A20252 and 52173076)the Beijing Natural Science Foundation(Nos.Z240030 and L248023)the Liaoning Province Key Research and Development Project(No.2024JH2/102400046)。
文摘Sizing treatment is a suitable technique to modify the fiber-matrix interfaces without damage of inherent performance of fibers.In this work,sizing agents based on Janus particles(JPs)were utilized to enhance the interface of basalt fiber(BF)/poly(vinyl chloride)(PVC)composites.polystyrene/poly(butyl acrylate)(PS/PBA)@silica JPs were synthesized by seed emulsion polymerization and three different sizing agents were prepared for BF sizing treatment.JPs with organic soft sphere and inorganic hard hemisphere enhanced the interfaces through their amphiphilicity,chemical bonding and mechanical interlock.The mechanical properties of composite with JPs sizing treated BFs performed better when there was one JPs layer modified on the interface.According to the intermitting bonding and gradient modulus theory,JPs patterned interfaces are ideal transition layers between high modulus BF and low modulus PVC.
基金financially supported by the University of Canterbury,New Zealand(No.452STUPDZ)the National Research Foundation,Prime Minister’s Office,Singapore(No.NRF2016NRF-NSFC001-102)the National Natural Science Foundation of China(No.11661141020)。
文摘Ammonia(NH_(3))is considered as a potential alternative carbon free fuel to reduce greenhouse gas emission to meet the increasingly stringent emission requirements.Co-burning NH_(3) and H_(2) is an effective way to overcome ammonia’s relative low burning velocity.In this work,3D Reynolds Averaged Navier-Stokes(RANS)numerical simulations are conducted on a premixed NH_(3)/H_(2) swirling flame with reduced chemical kinetic mechanism.The effects of(A)overall equivalence ratio Φ and(B)hydrogen blended molar fraction XH2 on combustion and emission characteristics are examined.The present results show that when 100%NH_(3)-0%H_(2)-air are burnt,the NO emission and unburned NH3 of at the swirling combustor outlet has the opposite varying trends.With the increase of Φ,NO emission is found to be decreased,while the unburnt ammonia emission is increased.NH_(2)→HNO,NH→HNO and HNO→NO sub-paths are found to play a critical role in NO formation.Normalized reaction rate of all these three sub-paths is shown to be decreased with increased Φ.Hydrogen addition is shown to significantly increase the laminar burning velocity of the mixed fuel.However,adding H_(2) does not affect the critical equivalence ratio corresponding to the maximum burning velocity.The emission trend of NO and unburnt NH_(3) with increased Φ is unchanged by blending H_(2).NO emission with increased X_(H2) is increased slightly less at a larger Φ than that at a smaller Φ.In addition,reaction rates of NH_(2)→HNO and HNO→NO sub-paths are decreased with increased X_(H2),when Φ is larger.Under all tested cases,blending H_(2) with NH_(3) reduces the unburned NH_(3) emission,especially for rich combustion conditions.In summary,the present work provides research finding on supporting applying ammonia with hydrogen blended in low-emission gas turbine engines.
基金supported by the National Natural Science Foundation of China(81970902,81771054,and 81600846).
文摘The goal of this study was to identify MSX1 gene variants in multiple Chinese families with nonsyndromic oligodontia and analyse the functional influence of these variants.Whole-exome sequencing(WES)and Sanger sequencing were performed to identify the causal gene variants in five families with nonsyndromic oligodontia,and a series of bioinformatics databases were used for variant confirmation and functional prediction.Phenotypic characterization of the members of these families was described,and an in vitro analysis was performed for functional evaluation.Five novel MSX1 heterozygous variants were identified:three missense variants[c.662A>C(p.Q221P),c.670C>T(p.R224C),and c.809C>T(p.S270L)],one nonsense variant[c.364G>T(p.G122*)],and one frameshift variant[c.277delG(p.A93Rfs*67)].Preliminary in vitro studies demonstrated that the subcellular localization of MSX1 was abnormal with the p.Q221P,p.R224C,p.G122*,and p.A93Rfs*67 variants compared to the wild type.Three variants(p.Q221P,p.G122*,and p.A93Rfs*67)were classified as pathogenic or likely pathogenic,while p.S270L and p.R224C were of uncertain significance in the current data.Moreover,we summarized and analysed the MSX1-related tooth agenesis positions and found that the type and variant locus were not related to the severity of tooth loss.Our results expand the variant spectrum of nonsyndromic oligodontia and provide valuable information for genetic counselling.
基金supported by the Innovative Project of Scientific Research for Postgraduates in Ordinary Universities in Jiangsu Province (Grant No. CX09B_161Z)the Cultivation Project for Excellent Doctoral Dissertations in Hohai University+1 种基金the Fundamental Research Funds for the Central Universities (Grant No.2010B18714)Special Funds for Scientific Research on Public Causes of the Ministry of Water Resources of China (Grant No. 201001052)
文摘Unusually severe weather is occurring more frequently due to global climate change. Heat waves, rainstorms, snowstorms, and droughts are becoming increasingly common all over the world, threatening human lives and property. Both temperature and precipitation are representative variables usually used to directly reflect and forecast the influences of climate change. In this study, daily data （from 1953 to 1995） and monthly data （from 1950 to 2010） of temperature and precipitation in five regions of the Amur River were examined. The significance of changes in temperature and precipitation was tested using the Mann-Kendall test method. The amplitudes were computed using the linear least-squares regression model, and the extreme temperature and precipitation were analyzed using hydrological statistical methods. The results show the following： the mean annual temperature increased significantly from 1950 to 2010 in the five regions, mainly due to the warming in spring and winter; the annual precipitation changed significantly from 1950 to 2010 only in the lower mainstream of the Amur River; the frequency of extremely low temperature events decreased from 1953 to 1995 in the mainstream of the Amur River; the frequency of high temperature events increased from 1953 to 1995 in the mainstream of the Amur River; and the frequency of extreme precipitation events did not change significantly from 1953 to 1995 in the mainstream of the Amur River. This study provides a valuable theoretical basis for settling disputes between China and Russia on sustainable development and utilization of water resources of the Amur River.
文摘BACKGROUND Dermatofibrosarcoma protuberans(DFSP)is a rare low-grade malignant soft tissue tumor characterized by rosette-like infiltrative growth.Postoperative recurrence of this tumor is very common.AIM To evaluate the risk factors related to recurrence after wide local excision(WLE)of DFSP and to guide clinical diagnosis and treatment.METHODS The medical records of 44 DFSP patients confirmed by pathology at our hospital from 2012 to 2019 were retrospectively reviewed.The relationship between clinical features,tumor characteristics,treatment,and recurrence risk were analyzed,and the possible risk factors for postoperative tumor recurrence were evaluated.RESULTS There were 44 patients in total,including 21 males and 23 females.The median progression free survival was 36 mo(range,1-240 mo).Twenty patients were treated for the first time,while 24 had previous treatment experience.Forty-two cases were followed for 25.76±22.0 mo,among whom four(9.52%)experienced recurrence after WLE(rate was 9.52%).The recurrence rate in the recurrent group was higher than that in the patients with primary tumor(19.05%vs 0%,P=0.028).Eighteen cases had a history of misdiagnosis(rate was 40.91%).The recurrence rate among patients with previous experience of misdiagnosis was significantly higher than in patients without(68%vs 36.84%,P=0.04).The tumor diameter in patients with a history of treatment was larger than in patients treated for the first time(4.75±0.70 cm vs 2.25±0.36 cm,P=0.004).CONCLUSION To sum up,the clinical manifestations of DFSP are not specific and are easily misdiagnosed,thus commonly causing the recurrence of DFSP.After incomplete resection,the tumor may rapidly grow.Previous recurrence history may be a risk factor for postoperative recurrence,and tumor location may have an indirect effect on postoperative recurrence;however,we found no significant correlation between sex,age,course of the disease,or tumor size and postoperative recurrence.
基金This work was supported by the Teaching and Research Award Program for Outstanding Young Teacher in Higher Education Institute of Ministry ofEducation of China(NO.20010248).
文摘Particle swarm optimizer(PSO),a new evolutionary computation algorithm,exhibits good performance for optimization problems,although PSO can not guarantee convergence of a global minimum,even a local minimum.However,there are some adjustable parameters and restrictive conditions which can affect performance of the algorithm.In this paper,the algorithm are analyzed as a time-varying dynamic system,and the sufficient conditions for asymptotic stability of acceleration factors,increment of acceleration factors and inertia weight are deduced.The value of the inertia weight is enhanced to(-1,1).Based on the deduced principle of acceleration factors,a new adaptive PSO algorithm-harmonious PSO(HPSO)is proposed.Furthermore it is proved that HPSO is a global search algorithm.In the experiments,HPSO are used to the model identification of a linear motor driving servo system.An Akaike information criteria based fitness function is designed and the algorithms can not only estimate the parameters,but also determine the order of the model simultaneously.The results demonstrate the effectiveness of HPSO.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDC0110201)the National Natural Science Foundation of China(32222004 and 32070083)+3 种基金the Major Program and Innovation Fund of Haihe Laboratory of Synthetic Biology(22HHSWSS00003 and 22HHSWSS00017)the CAS Project for Young Scientists in Basic Research(YSBR-072)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2021177)the Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project(TSBICIP-KJGG-008).
文摘Background Formolase(FLS)is a computationally designed enzyme that catalyzes the carboligation of two or three C1 formaldehyde molecules into C2 glycolaldehyde or C3 dihydroxyacetone(DHA).FLS lays the foundation for several artificial carbon fixation and valorization pathways,such as the artificial starch anabolic pathway.However,the application of FLS is limited by its low catalytic activity and product promiscuity.Findings FLS,designed and engineered based on benzoylformate decarboxylase from Pseudomonas putida,was selected as a candidate for modification.To evaluate its catalytic activity,25 residues located within an 8Ådistance from the active center were screened using single-point saturation mutagenesis.A screening approach based on the color reaction of the DHA product was applied to identify the desired FLS variants.After screening approximately 5,000 variants(approximately 200 transformants per site),several amino acid sites that were not identified by directed evolution were found to improve DHA formation.The serine-to-phenylalanine substitution at position 236 improved the activity towards DHA formation by 7.6-fold.Molecular dynamics simulations suggested that the mutation increased local hydrophobicity at the active site,predisposing the cofactor-C2 intermediate to nucleophilic attack by the third formaldehyde molecule for subsequent DHA generation.Conclusions This study provides improved FLS variants and valuable information into the influence of residues adjacent to the active center affecting catalytic efficiency,which can guide the rational engineering or directed evolution of FLS to optimize its performance in artificial carbon fixation and valorization.
基金support provided by the University of Canterbury,New Zealand(grant no.CPS20-03-002,grant no.452DISDZ)National Research Foundation Singapore(grant no.NRF2016 NRF-NSFC001-102)+1 种基金Hui Rong would like to thank College of Engineering,University of Canterbury and China Scholarship Council(grant no.202208250030)for providing his PhD studentship and scholarshipDS would like to thank for the financial support by the Science Center for Gas Turbine Project(P2022-C-II-003-001).
文摘In this work, we propose and examine an ammonia-hydrogen fueled micro-combustor with a single-channel inlet and double-channel outlet (SIDO). The combustion characteristics and nitrogen oxide emission of ammonia/hydrogen-oxygen premixed combustion are explored. Comparison is then made between the conventional and the proposed SIDO combustors. It is found that our proposed new design could lead to an increase of the outer wall temperature and reduced nitrogen oxide emission. The performances of different hydrogen blended ratios (Φ_(b)), inlet velocities (V_(in)), and equivalence ratios (Φ) are evaluated. It is found that increasing Φ_(b) reduces the maximum flame temperature and the pressure loss, enabling the flame to move upstream. When Φ_(b) is set to 25 %, the convective heat transfer performance reaches its optimal level. The wall temperature and its uniformity can be improved by increasing V_(in). However, it is accompanied by increased NO emissions at the outlet. Increasing Φ can significantly reduce nitrogen oxide emission, and such a reduction effect is much more remarkable at a lower Φ_(b). Examining the exergy efficiency is shown to be greatly improved by increasing Φ_(b). Increasing Φ could reduce the combustion efficiency of hydrogen in the mixed fuel and have almost no effect on ammonia. This study demonstrates the feasibility of improving thermal performance and reducing emissions by varying its structure for thermophotovoltaic applications.
基金supported by the Strategic Priority ResearchProgram of the Chinese Academy of Sciences(XDC0120203)the National Natural Science Foundation of China(32271545)+1 种基金Major Program of Haihe Laboratory of Synthetic Biology(22HHSWSS00016 and 22HHSWSS00003)Youth Promotion Association of Chinese Academy of Sciences(2021176),and TianjinYoung Scientific and Technological Talents(QN20230219).
文摘Artificial conversion of CO_(2)into foods and chemicals offers a sustainable way to tackle population-relatedand environmental issues.Thermochemical and electrochemical methods for reducing CO_(2)to low-carbonmolecules have made significant progress;however,it remains challenging to generate long-chain,structurally diverse carbohydrates,which are the most abundant substances in nature.Here,we report thesuccessful design and realization of in vitro sucrose synthesis from C1 and C3 molecules through a thermodynamically favorable pathway with short reaction steps and low energy input.By engineering thephosphatase and sucrose synthase to improve their catalytic efficiency by 3-to 71-fold,and by optimizing the reaction system through an iterative scanning strategy,we achieved a high conversion yield of86%and a specific synthetic rate of 5.7 g L^(−1)h^(−1).Additionally,we demonstrated the cell-free starch synthesis without the need for dextrin primers,achieving a superior C1-to-starch synthesis rate compared topreviously developed multienzyme systems.Building upon this platform,we further extended methanolconversion to a variety of sugars,especially for cellooligosaccharides with a degree of polymerization ofCn≥18.Together,our system provides a promising,plant-independent route for de novo synthesis ofstructure-diversified oligosaccharides and polysaccharides.
基金supported by the National Natural Science Foundation of China(82271092).
文摘Purpose:Familial exudative vitreoretinopathy(FEVR)is a genetically heterogeneous retinal vascular disorder,with nearly half of the cases attributed to mutations in genes involved in the Norrin/β-catenin signaling pathway.This study aimed to identify and functionally characterize novel FZD4 variants in patients with FEVR.Methods:Genetic sequencing of FZD4 was performed in a cohort of FEVR families,leading to the identification of five novel variants:c.434G>A,c.610T>G,c.844T>C,c.277C>T,and c.1155delC.Bioinformatic predictions,comprehensive clinical evaluations,and dual-luciferase reporter assays were conducted to assess the functional impact and pathogenicity of these variants.Results:All five FZD4 variants were found to significantly reduceβ-catenin signaling activity compared to wild-type FZD4.Among them,two variants previously classified as variants of uncertain significance(VUS)demon-strated functional impairment and clinical segregation consistent with pathogenicity,supporting their reclassi-fication as disease-causing mutations.Conclusions:These findings expand the known mutational spectrum of FZD4 in FEVR and highlight the critical role of functional validation in the interpretation of novel and uncertain variants.Incorporating experimental assays can improve diagnostic accuracy and inform clinical genetic counseling.
基金supported by the National Natural Science Foundation of China(32271545 and 31972030)Major Program of Haihe Laboratory of Synthetic Biology(22HHSWSS00016 and 22HHSWSS00003)+2 种基金Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project(TSBICIP-KJGG-008-03 and TSBICIP-PTJJ-007-10)Youth Promotion Association of Chinese Academy of Sciences(CAS)(2021176)CAS Project for Young Scientists in Basic Research(YSBR-072)。
基金The case study was funded by China UK Global Health Support Programme(GHSP-OP202)-Centre of Excellence in Health Development Aid in China:Capacity Building and Information Dissemination.
文摘Background:In the Yunnan province of China,18 counties in six prefectures border Myanmar.Due to its particular combination of geographic features,climate conditions,and cultural landscape,the area provides a suitable environment for the spread of insect-borne diseases such as malaria.In five identified Myanmar Special Regions along the China-Myanmar border,economic development is lagging,people live in extreme poverty,and the healthcare system is fragile.Coupled with political and other reasons,this precludes malaria control work to be effectively carried out in Myanmar,resulting in a heavy burden of the disease.Frequent population movements and favorable conditions for malaria transmission on the border fuel difficulties in controlling and eliminating the spread of the disease in the area.Case presentation:To reduce the prevalence of malaria in the China-Myanmar border area and improve healthcare services for local residents in this particular environment,Health Poverty Action(HPA)has provided malaria aid in the area since the beginning of 2006,as a sub-recipient of the China Global Fund Malaria Programs.In this case study,we examined HPA’s activities as part of its malaria control programs in the area,analyzed and summarized the effectiveness and impact of the cross-border healthcare model as implemented by non-governmental organizations,and put forward suggestions for cross-border health aid models and for the prevention of malaria transmission in the Greater Mekong Subregion.Conclusions:HPA had carried out a great quantity of successful malaria control activities in border areas between China and Myanmar,strengthened the partnership and established the collaboration,coordination and cooperation channels among stakeholders.HPA has laid good groundwork and developed its valuable model that could be highlighted and referenced.
基金the National Key Research and Development Program of China(2018YFA0901500)the National Natural Science Foundation of China(32070083 and 32222004)+2 种基金the Youth Innovation Promotion Association of Chinese Academy of Sciences(2021177)the Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project(TSBICIP-KJGG-008)the Innovation Fund of Haihe Laboratory of Synthetic Biology.
文摘Methanol is a promising one-carbon feedstock for biomanufacturing,which can be sustainably produced from carbon dioxide and natural gas.However,the efficiency of methanol bioconversion is limited by the poor catalytic properties of nicotinamide adenine dinucleotide(NAD^(+))-dependent methanol dehydrogenase(Mdh)that oxidizes methanol to formaldehyde.Herein,the neutrophilic and mesophilic NAD^(+)-dependent Mdh from Bacillus stearothermophilus DSM 2334(Mdh_(Bs))was subjected to directed evolution for enhancing the catalytic activity.The combination of formaldehyde biosensor and Nash assay allowed high-throughput and accurate measurement of formaldehyde and facilitated efficient selection of desired variants.Mdh_(Bs)variants with up to 6.5-fold higher K_(cat)/K_(M)value for methanol were screened from random mutation libraries.The T153 residue that is spatially proximal to the substrate binding pocket has significant influence on enzyme activity.The beneficial T153P mutation changes the interaction network of this residue and breaks theα-helix important for substrate binding into two shortα-helices.Reconstructing the interaction network of T153 with surrounding residues may represent a promising strategy to further improve Mdh_(Bs),and this study provides an efficient strategy for directed evolution of Mdh.
基金This work was supported by the Global Fund to Fight AIDS,Tuberculosis and Malaria(No.CHN-607-G09-M,No.CHN-011-G15-M)the China-UK Global Health Support Programme funded by UK DFID(No.GHSP-CS-OP2-02).
文摘Background:For many countries where malaria is endemic,the burden of malaria is high in border regions.In ethnic minority areas along the Myanmar-China border,residents have poor access to medical care for diagnosis and treatment,and there have been many malaria outbreaks in such areas.Since 2007,with the support of the Global Fund to Fight AIDS,Tuberculosis and Malaria(GFATM),a malaria control project was introduced to reduce the malaria burden in several ethnic minority regions.Methods:A malaria control network was established during the period from 2007 to 2014.Multiple malaria interventions,including diagnosis,treatment,distribution of LLINs and health education,were conducted to improve the accessibility and quality of malaria control services for local residents.Annual cross-sectional surveys were conducted to evaluate intervention coverage and indicators of malaria transmission.Results:In ethnic minority regions where a malaria control network was established,both the annual malaria incidence(19.1 per thousand per year,in 2009;8.7,in 2014)and malaria prevalence(13.6%in 2008;0.43%in 2014)decreased dramatically during the past 5–6 years.A total of 851393 febrile patients were detected,202598 malaria cases(including confirmed cases and suspected cases)were treated,and 759574 LLINs were delivered to populations at risk.Of households in 2012,73.9%had at least one ITNs/LLINs(vs.28.3%,in 2008),and 50.7%of children less than 5 years and 50.3%of pregnant women slept under LLINs the night prior to their visit.Additionally,malaria knowledge was improved in 68.4%of residents.Conclusion:There has been great success in improving malaria control in these regions from 2007 to 2014.Malaria burdens have decreased,especially in KOK and WA.The continued maintenance of sustainable malaria control networks in these regions may be a long-term process,due to regional conflicts and the lack of funds,technology,and health workers.Furthermore,information and scientific support from the international community should be offered to these ethnic minority regions to uphold recent achievements.
基金partially supported by the Science and Technology Innovation 2030-Brain Science and Brain-Inspired Intelligence Project(2021ZD0200200)the National Natural Science Foundation of China(62327805,82151307,82072099,82202253)。
文摘The rhesus macaque(Macaca mulatta)is a crucial experimental animal that shares many genetic,brain organizational,and behavioral characteristics with humans.A macaque brain atlas is fundamental to biomedical and evolutionary research.However,even though connectivity is vital for understanding brain functions,a connectivity-based whole-brain atlas of the macaque has not previously been made.In this study,we created a new whole-brain map,the Macaque Brainnetome Atlas(MacBNA),based on the anatomical connectivity profiles provided by high angular and spatial resolution ex vivo diffusion MRI data.The new atlas consists of 248 cortical and 56 subcortical regions as well as their structural and functional connections.The parcellation and the diffusion-based tractography were evaluated with invasive neuronal-tracing and Nissl-stained images.As a demonstrative application,the structural connectivity divergence between macaque and human brains was mapped using the Brainnetome atlases of those two species to uncover the genetic underpinnings of the evolutionary changes in brain structure.The resulting resource includes:(1)the thoroughly delineated Macaque Brainnetome Atlas(MacBNA),(2)regional connectivity profiles,(3)the postmortem high-resolution macaque diffusion and T2-weighted MRI dataset(Brainnetome-8),and(4)multi-contrast MRI,neuronal-tracing,and histological images collected from a single macaque.MacBNA can serve as a common reference frame for mapping multifaceted features across modalities and spatial scales and for integrative investigation and characterization of brain organization and function.Therefore,it will enrich the collaborative resource platform for nonhuman primates and facilitate translational and comparative neuroscience research.
文摘Although DNA methylation is known to play an important role in the silencing of transposable elements （TEs） and introduced transgenes, the mechanisms that generate DNA methylation-independent transcrip- tional silencing are poorly understood. Previous studies suggest that RNA-directed DNA methylation （RdDM） is required for the silencing of the RD29A-LUC transgene in the Arabidopsis rosl mutant back- ground with defective DNA demethylase. Loss of function of ARGONAUTE 4 （AGO4） gene, which encodes a core RdDM component, partially released the silencing of RD29A-LUC in the rosl/ago4 double mutant plants. A forward genetic screen was performed to identify the mutants with elevated RD29A-LUC trans- gene expression in the rosl/ago4 mutant background. We identified a mutation in the homologous gene of PRP31, which encodes a conserved pre-mRNA splicing factor that regulates the formation of the U4/ U6.U5 snRNP complex in fungi and animals. We previously demonstrated that the splicing factors ZOP1 and STA1 contribute to transcriptional gene silencing. Here, we reveal that Arabidopsis PRP31 associates with ZOP1, STA1, and several other splicing-related proteins, suggesting that these splicing factors are both physically and functionally connected. We show that Arabidopsis PRP31 participates in transcrip- tional gene silencing. Moreover, we report that PRP31, STA1, and ZOP1 are required for development and stress response. Under cold stress, PRP31 is not only necessary for pre-mRNA splicing but also for regulation of cold-responsive gene expression. Our results suggest that the splicing machinery has multiple functions including pre-mRNA splicing, gene regulation, transcriptional gene silencing, and stress response.
