Irreversible electroporation is a promising non-thermal ablation method that has been shown to increase overall survival in locally advanced pancreatic cancer in some studies.However,higher quality studies with proper...Irreversible electroporation is a promising non-thermal ablation method that has been shown to increase overall survival in locally advanced pancreatic cancer in some studies.However,higher quality studies with proper controls and randomization are required to establish its superiority when added with neoadjuvant chemotherapy over the current management of choice,which is chemotherapy alone.Further studies are required before establishment of any survival benefit in metastatic pancreatic carcinoma,and such evidence is lacking at present.展开更多
The current study was designed to explore how disruption of specific molecular circuits in the cerebral cortex may cause sensorimotor cortico-striatal community structure deficits in both a mouse model and patients wi...The current study was designed to explore how disruption of specific molecular circuits in the cerebral cortex may cause sensorimotor cortico-striatal community structure deficits in both a mouse model and patients with schizophrenia.We used prepulse inhibition(PPI)and brain structural and diffusion MRI scans in 23 mice with conditional ErbB4 knockout in parvalbumin interneurons and 27 matched controls.Quantitative real-time PCR was used to assess the differential levels of GABA-related transcripts in brain regions.Concurrently,we measured structural and diffusion MRI and the cumulative contribution of risk alleles in the GABA pathway genes in firstepisode treatment-naı¨ve schizophrenic patients(n=117)and in age-and sex-matched healthy controls(n=86).We present the first evidence of gray and white matter impairment of right sensorimotor cortico-striatal networks and reproduced the sensorimotor gating deficit in a mouse model of schizophrenia.Significant correlations between gray matter volumes(GMVs)in the somatosensory cortex and PPI as well as glutamate decarboxylase 1 mRNA expression were found in controls but not in knockout mice.Furthermore,these findings were confirmed in a human sample in which we found significantly decreased gray and white matter in sensorimotor cortico-striatal networks in schizophrenic patients.The psychiatric risk alleles of the GABA pathway also displayed a significant negative correlation with the GMVs of the somatosensory cortex in patients.Our study identified that ErbB4 ablation in parvalbumin interneurons induced GABAergic dysregulation,providing valuable mechanistic insights into the sensorimotor cortico-striatal community structure deficits associated with schizophrenia.展开更多
Apple replant disease(ARD)is a major limitation to the establishment of economically viable orchards on replant sites due to the buildup and long-term survival of pathogen inoculum.Several soilborne necrotrophic fungi...Apple replant disease(ARD)is a major limitation to the establishment of economically viable orchards on replant sites due to the buildup and long-term survival of pathogen inoculum.Several soilborne necrotrophic fungi and oomycetes are primarily responsible for ARD,and symptoms range from serious inhibition of growth to the death of young trees.Chemical fumigation has been the primary method used for control of ARD,and manipulating soil microbial ecology to reduce pathogen density and aggressiveness is being investigated.To date,innate resistance of apple rootstocks as a means to control this disease has not been carefully explored,partly due to the complex etiology and the difficulty in phenotyping the disease resistance.Molecular defense responses of plant roots to soilborne necrotrophic pathogens are largely elusive,although considerable progress has been achieved using foliar disease systems.Plant defense responses to necrotrophic pathogens consist of several interacting modules and operate as a network.Upon pathogen detection by plants,cellular signals such as the oscillation of Ca^(2+)concentration,reactive oxygen species(ROS)burst and protein kinase activity,lead to plant hormone biosynthesis and signaling.Jasmonic acid(JA)and ethylene(ET)are known to be fundamental to the induction and regulation of defense mechanisms toward invading necrotrophic pathogens.Complicated hormone crosstalk modulates the fine-tuning of transcriptional reprogramming and metabolic redirection,resulting in production of antimicrobial metabolites,enzyme inhibitors and cell wall refortification to restrict further pathogenesis.Transcriptome profiling of apple roots in response to inoculation with Pythium ultimum demonstrated that there is a high degree of conservation regarding the molecular framework of defense responses compared with those observed with foliar tissues.It is conceivable that the timing and intensity of genotype-specific defense responses may lead to different outcomes between rootstocks in response to invasion by necrotrophic pathogens.Elucidation of host defense mechanisms is critical in developing molecular tools for genomics-assisted breeding of resistant apple rootstocks.Due to their perennial nature,use of resistant rootstocks as a component for disease management might offer a durable and cost-effective benefit to tree performance than the standard practice of soil fumigation for control of ARD.展开更多
Although seed oil production and composition are genetically controlled, changes of oil level and oil composition across genotypes and environments such as drought and temperature were observed. The mechanisms of how ...Although seed oil production and composition are genetically controlled, changes of oil level and oil composition across genotypes and environments such as drought and temperature were observed. The mechanisms of how genotypes interact with environment, affecting oil production and composition, are still not well understood. The objective of this research was to investigate the effect of drought/water stress and temperature on soybean genotypes. Two soybean genotypes of maturity group (MG) II (PI 597411 B and PI 597408) and two of MG VI (Arksoy and PI 437726) were used. A repeated greenhouse experiment to study the effect of water stress and a repeated growth chamber experiment to study the effect of temperature were conducted. The results showed that both water stress and high temperature altered seed oil composition by increasing oleic acid and decreasing linoleic and linolenic acid concentrations. Severe water stress (soil water potential between -150 to -200 kPa) or high temperature (40/33℃, day/night) resulted in higher palmitic acid and lower stearic acid. Genotypes differed in their responses to water stress or temperature. Analyses of seed carbohydrates (glucose, fructose, sucrose, raffinose, and stachyose) showed a significant decline of glucose, fructose, and sucrose and a significant increase of stachyose concentration by water stress and high temperature. Analyses of natural abundance of δ15N and δ13C isotopes showed changes in sources of nitrogen and carbon fixation, possibly affecting nitrogen and carbon metabolism pathways. The research demonstrated that both water stress and high temperature altered oil production and composition, and this could be partially related to limited availability and movement of carbohydrates from leaves to seed. Further research to investigate the enzymes controlling fatty acids conversion and nitrogen and carbon metabolism is needed.展开更多
Oral cancer(OC)is one of the most recurrent cancers in the head and neck squamous cancer(SCCHN)category.Recently,the genome-wide association studies(GWAS)have gained growing interest in the scientific community.GWAS h...Oral cancer(OC)is one of the most recurrent cancers in the head and neck squamous cancer(SCCHN)category.Recently,the genome-wide association studies(GWAS)have gained growing interest in the scientific community.GWAS have identified several pathways involved in the interactions among general risk factors and genomic variants affecting SCCHN.This systematic overview aims to critically evaluate the latest data reported within the scientific literature.The aim was to investigate the impact of genetic aspects on SCCHN onset and prognosis,involving other clinical and systemic co-factors.PubMed,Google Scholar,and Cancer Genetics Web databases have been systematically investigated for original articles published in the last two years,reporting studies on the main queries addressed in this work.This review also comparatively describes the impact of environmental and pathological co-factors in different types of cancers,clarifying and updating the role of genetic factors in SCCHN onset and development.The main outcomes reported may be helpful to drive clinicians towards their clinical evaluations for the most appropriate therapeutic approach in SCCHN.展开更多
Sexual reproduction in diploid organisms requires the production of haploid gametes via the process of meiosis, in which a single round of DNA replication is followed by two consecutive cell divisions （or two nuclear...Sexual reproduction in diploid organisms requires the production of haploid gametes via the process of meiosis, in which a single round of DNA replication is followed by two consecutive cell divisions （or two nuclear divisions and one cytokinesis）. In the majority of known cases the proper segregation of the parental genome into gametes is accom- panied and facilitated by meiotic crossover formation, which contributes to physical association between homologous chromosomes and results in the generation of new combina- tions of alleles in the progeny. This is necessarily a complex and highly regulated process with multiple steps in a tight sequence, including exit from mitosis, DNA double strand break （DSB） formation, homology search, recombinational repair of DSBs and regulation of cohesion between homolo- gous chromosomes. The process of meiosis is astonishingly effective, even in mammals and flowering plants with extremely large genomes, in which this entails the manipula- tion of approximately twelve metres or even more of the replicated diploid DNA, on the order of 10^10 base pairs, with close to base pair accuracy. In plants, meiosis does not pro- duce gametes directly, but progenitors of haploid multicellular structures called gametophytes, which contain haploid cells that differentiate into gametes.展开更多
Since Type 1 diabetes(T1DM)occurs whenβ-cells mass is reduced to less than 20%of the normal level due to autoimmune destruction of cells resulting in the inability to secrete insulin,preservation or replenishment of ...Since Type 1 diabetes(T1DM)occurs whenβ-cells mass is reduced to less than 20%of the normal level due to autoimmune destruction of cells resulting in the inability to secrete insulin,preservation or replenishment of the functionalβ-cells mass has become a major therapeutic focus for this diabetic type treatment.Thus,this 4-week work plan was designed to determine which mesenchymal stem cells(MSCs)type is more appropriate to alleviate pancreatic hazards resulting from diabetes induction;via tracking a comparative study between MSCs derived from adipose tissue(AD-MSCs)and from bone marrow(BM-MSCs)in management of T1DM considering their immunomodulatory,anti-apoptotic and antioxidative roles.Rats were divided randomly into 4 groups;control,STZdiabetic(D),D+AD-MSCs,and D+BM-MSCs groups.Both stem cells types in this study were allogenic.Herein,both oxidative stress and antioxidant markers were evaluated using colorimetric analysis,while inflammatory,immune and apoptotic markers were assessed through flow cytometric analysis.Results showed that diabetic rats treated with either AD-MSCs or BM-MSCs exhibited marked pancreatic antioxidant and anti-inflammatory activities that were able to initiate pancreatic immunomodulation and reducingβ-cells apoptotic death,thus,help to restore their normal insulin secretion and hypoglycemic abilities.However,AD-MSCs injection was shown to be superior as a pancreatic regenerative tool in overcoming diabetes;owing to their marked antioxidant,anti-inflammatory,immunomodulatory,and anti-apoptotic characteristics over BM-MSCs treatment.展开更多
Genes encoding early signaling events in pathogen defense often are identified only by their phenotype. Such genes involved in barley-powdery mildew interactions include Mla, specifying race-specific resistance; Rarl ...Genes encoding early signaling events in pathogen defense often are identified only by their phenotype. Such genes involved in barley-powdery mildew interactions include Mla, specifying race-specific resistance; Rarl （Required for Mla12-specified resistance1）, and Roml （Restoration of Mla-specified resistancel）. The HSP90-SGT1-RAR1 complex appears to function as chaperone in MLA-specified resistance, however, much remains to be discovered regarding the precise signaling underlying plant immunity. Genetic analyses of fast-neutron mutants derived from CI 16151 （Mla6） uncovered a novel locus, designated Rar3 （R_equired for Mla6-specified resitance3）. Rar3 segregates independent of Mla6 and Rarl, and rar3 mutants are susceptible to Blumeria graminis f. sp. hordei （Bgh） isolate 5874 （A VRar）, whereas, wild-type progenitor plants are resistant. Comparative expression analyses of the rar3 mutant vs. its wild-type progenitor were conducted via Barleyl GeneChip and GAIIx paired-end RNA-Seq. Whereas Rarl affects transcription of relatively few genes; Rar3 appears to influence thousands, notably in genes controlling ATP binding, catalytic activity, transcription, and phosphorylation; possibly membrane bound or in the nucleus, eQTL analysis of a segregating doubled haploid population identified over two-thousand genes as being regulated by Mla （q value/FDR=0.00001）, a subset of which are significant in Rar3 interactions. The intersection of datasets derived from mla-loss-of-function mutants, Mla-associated eQTL, and rar3-mediated transcriptome reprogramming are narrowing the focus on essential genes required for Mla-specified immunity.展开更多
Background: Cystinosis is a multisystemic autosomal recessive deficiency of the lysosomal membrane transporter protein (cystinosin) caused by mutations in CTNS gene. Objective: This study summarizes the Portuguese exp...Background: Cystinosis is a multisystemic autosomal recessive deficiency of the lysosomal membrane transporter protein (cystinosin) caused by mutations in CTNS gene. Objective: This study summarizes the Portuguese experience in the diagnosis and management of patients with this rare disease over the past few years and reports recurrent mutations in the CTNS gene. Methods: Unrelated patients from different pediatric and adult hospitals all over Portugal with non-nephrotic proteinuria, hypercalciuria, hypokalemia impaired proximal reabsorption of amino acids, glycosuria and hypophosphatemia, suggestive of a Fanconi syndrome and ocular problems, were studied. Intra-leukocyte cystine levels were determined and molecular analysis was performed, to determine the presence or absence of the 57-kb deletion in CTNS, followed by direct sequencing of the coding exons of CTNS. Results: From 1998 to 2017, twenty-one cystinotic patients were biochemically diagnosed. From the remaining seventeen (four deceased), eleven were studied for CTNS gene. Five out of eleven patients were homozygous for the 57-kb deletion (10/22;45.5%), and other five were compound heterozygous for this variant (15/22;68.2%). The other mutations found were p.Q128X (c.721 C>T;2/22), p.S139F (c.755 C>T;4/22) and c.18-21delGACT (p.T7FfsX7;1/22). All of these seventeen cystinotic patients are in treatment. Approximately 84% are adults, 16% are young children, and 54.5% are kidney transplant recipient. Conclusions: The authors would like to emphasize the importance of first screening for the 57-kb deletion since it is very common in our population. This genetic study is the first in our country and it could be the basis for future genetic counseling in Portuguese population.展开更多
The retrospective study by Lew et al(2022)examined the rising hospitalization rates for chronic pancreatitis(CP)and its association with pancreatic ductal adenocarcinoma(PDAC),revealing significant ethno-racial dispar...The retrospective study by Lew et al(2022)examined the rising hospitalization rates for chronic pancreatitis(CP)and its association with pancreatic ductal adenocarcinoma(PDAC),revealing significant ethno-racial disparities and risk factors.Overweight black men aged 40-59 years and white men over 40 years with higher incomes showed an elevated risk of PDAC among CP patients.The study,which included 14.2 million admissions from 2016-2017,found that 2.6%of adult patients were diagnosed with CP,with white males being the majority.Multivariate regression analysis identified men,black individuals,those aged 40-59 years,and individuals with a body mass index(BMI)between 25 and 29.9 as having an increased risk for CP.Moreover,0.78%of CP patients also had PDAC,with older age and BMI being significant risk factors for developing PDAC in CP patients.The study also highlighted disparities in healthcare access and utilization among different socioeconomic and ethno-racial groups,which may impact the risk and outcomes of CP and PDAC.展开更多
We focus specifically on the rare occurrence of cardiac thrombi in Li-Fraumeni syndrome(LFS).LFS is a hereditary risk to a diverse range of specific,uncommon,malignancies.Children and young adults have a heightened su...We focus specifically on the rare occurrence of cardiac thrombi in Li-Fraumeni syndrome(LFS).LFS is a hereditary risk to a diverse range of specific,uncommon,malignancies.Children and young adults have a heightened susceptibility to many malignancies,particularly soft-tissue and bone tumors,breast malignancies,central nervous system malignancies,adrenocortical carcinoma,and blood cancers.Additionally,LFS patients may experience other cancer types such as gastrointestinal,lung,kidney,thyroid,and skin cancers,along with those affecting gonadal organs(ovaries,testicles,and prostate).An accurate diagnosis of LFS is crucial to enable affected families to access appropriate genetic counseling and undergo surveillance for early cancer detection.展开更多
Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack ...Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers.Previous studies have indicated the association between treatment response and genetic and epigenetic factors,but no effective biomarkers have been identified.Hence,further research is imperative to enhance precision medicine in SCZ treatment.Methods:Participants with SCZ were recruited from two randomized trials.The discovery cohort was recruited from the CAPOC trial(n=2307)involved 6 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,Quetiapine,Aripiprazole,Ziprasidone,and Haloperidol/Perphenazine(subsequently equally assigned to one or the other)groups.The external validation cohort was recruited from the CAPEC trial(n=1379),which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,and Aripiprazole groups.Additionally,healthy controls(n=275)from the local community were utilized as a genetic/epigenetic reference.The genetic and epigenetic(DNA methylation)risks of SCZ were assessed using the polygenic risk score(PRS)and polymethylation score,respectively.The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis,methylation quantitative trait loci,colocalization,and promoteranchored chromatin interaction.Machine learning was used to develop a prediction model for treatment response,which was evaluated for accuracy and clinical benefit using the area under curve(AUC)for classification,R^(2) for regression,and decision curve analysis.Results:Six risk genes for SCZ(LINC01795,DDHD2,SBNO1,KCNG2,SEMA7A,and RUFY1)involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response.The developed and externally validated prediction model,which incorporated clinical information,PRS,genetic risk score(GRS),and proxy methylation level(proxyDNAm),demonstrated positive benefits for a wide range of patients receiving different APDs,regardless of sex[discovery cohort:AUC=0.874(95%CI 0.867-0.881),R^(2)=0.478;external validation cohort:AUC=0.851(95%CI 0.841-0.861),R^(2)=0.507].Conclusions:This study presents a promising precision medicine approach to evaluate treatment response,which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ.Trial registration Chinese Clinical Trial Registry(https://www.chictr.org.cn/),18 Aug 2009 retrospectively registered:CAPOC-ChiCTR-RNC-09000521(https://www.chictr.org.cn/showproj.aspx?proj=9014),CAPEC-ChiCTRRNC-09000522(https://www.chictr.org.cn/showproj.aspx?proj=9013).展开更多
Pancreatic cancer(PanCa)is a catastrophic disease,being third lethal in both the genders around the globe.The possible reasons are extreme disease invasiveness,highly fibrotic and desmoplastic stroma,dearth of confirm...Pancreatic cancer(PanCa)is a catastrophic disease,being third lethal in both the genders around the globe.The possible reasons are extreme disease invasiveness,highly fibrotic and desmoplastic stroma,dearth of confirmatory diagnostic approaches and resistance to chemotherapeutics.This inimitable tumor microenvironment(TME)or desmoplasia with excessive extracellular matrix accumulation,create an extremely hypovascular,hypoxic and nutrient-deficient zone inside the tumor.To survive,grow and proliferate in such tough TME,pancreatic tumor and stromal cells transform their metabolism.Transformed glucose,glu-tamine,fat,nucleotide metabolism and inter-metabolite communication between tumor and TME in synergism,impart therapy resistance,and immunosuppression in PanCa.Thus,a finer knowledge of altered metabolism would uncover its metabolic susceptibilities.These unique metabolic targets may help to device novel diagnostic/prognostic markers and therapeutic strategies for better management of PanCa.In this review,we sum up reshaped metabolic pathways in PanCa to formulate detection and remedial strategies of this devastating disease.展开更多
Plasma membrane intrinsic proteins(PIPs),a subclass of aquaporins,play an important role in plant immunity by acting as H2O2 transporters.Their homeostasis is mostly maintained by C-terminal serine phosphorylation.How...Plasma membrane intrinsic proteins(PIPs),a subclass of aquaporins,play an important role in plant immunity by acting as H2O2 transporters.Their homeostasis is mostly maintained by C-terminal serine phosphorylation.However,the kinases that phosphorylate PIPs and manipulate their turnover are largely unknown.Here,we found that Arabidopsis thaliana PIP2;7 positively regulates plant immunity by transporting H_(2)O_(2).Arabidopsis CALCIUM-DEPENDENT PROTEIN KINASE 28(CPK28)directly interacts with and phosphorylates PIP2;7 at Ser273/276 to induce its degradation.During pathogen infection,CPK28 dissociates from PIP2;7 and destabilizes,leading to PIP2;7 accumulation.As a countermeasure,oomycete pathogens produce conserved kinase effectors that stably bind to and mediate the phosphorylation of PIP2;7 to induce its degradation.Our study identifies PIP2;7 as a novel substrate of CPK28 and shows that its protein stability is negatively regulated by CPK28.Such phosphorylation could be mimicked by Phytophthora kinase effectors to promote infection.Accordingly,we developed a strategy to combat oomycete infection using a phosphorylation-resistant PIP2;7S273/276A mutant.The strategy only allows accumulation of PIP2;7^(S273/276A) during infection to limit potential side effects on normal plant growth.展开更多
Some main recent researches that have dissected tumor microenvironment(TME)by imaging mass cytometry(IMC)in different subtypes of primary breast cancer samples were considered.The many phenotypic variants,clusters of ...Some main recent researches that have dissected tumor microenvironment(TME)by imaging mass cytometry(IMC)in different subtypes of primary breast cancer samples were considered.The many phenotypic variants,clusters of epithelial tumor and immune cells,their structural features as well as the main genetic aberrations,sub-clonal heterogeneity and their systematic classification also have been examined.Mutational evolution has been assessed in primary and metastatic breast cancer samples.Overall,based on these findings the current concept of precision medicine is questioned and challenged by alternative therapeutic strategies.In the last two decades,immunotherapy as a powerful and harmless tool to fight cancer has received huge attention.Thus,the tumor immune microenvironment(TIME)composition,its prognostic role for clinical course as well as a novel definition of immunogenicity in breast cancer are proposed.Investigational clinical trials carried out by us and other findings suggest that G0-G1 state induced in endocrine-dependent metastatic breast cancer is more suitable for successful immune manipulation.Residual micro-metastatic disease seems to be another specific condition that can significantly favor the immune response in breast and other solid tumors.展开更多
基金Supported by Department of Biotechnology,Government of India,No.RLS/BT/Re-entry/05/2012.
文摘Irreversible electroporation is a promising non-thermal ablation method that has been shown to increase overall survival in locally advanced pancreatic cancer in some studies.However,higher quality studies with proper controls and randomization are required to establish its superiority when added with neoadjuvant chemotherapy over the current management of choice,which is chemotherapy alone.Further studies are required before establishment of any survival benefit in metastatic pancreatic carcinoma,and such evidence is lacking at present.
基金supported by the National Natural Science Foundation of China(81630030,81130024,and 81528008)the National Natural Science Foundation of China/Research Grants Council of Hong Kong Joint Research Scheme(81461168029)+2 种基金the National Basic Research Development Program of China(2016YFC0904300)the Science and Technology Project of the Health Planning Committee of Sichuan(19PJ090)the National Natural Science Foundation of China for Distinguished Young Scholars(81501159).
文摘The current study was designed to explore how disruption of specific molecular circuits in the cerebral cortex may cause sensorimotor cortico-striatal community structure deficits in both a mouse model and patients with schizophrenia.We used prepulse inhibition(PPI)and brain structural and diffusion MRI scans in 23 mice with conditional ErbB4 knockout in parvalbumin interneurons and 27 matched controls.Quantitative real-time PCR was used to assess the differential levels of GABA-related transcripts in brain regions.Concurrently,we measured structural and diffusion MRI and the cumulative contribution of risk alleles in the GABA pathway genes in firstepisode treatment-naı¨ve schizophrenic patients(n=117)and in age-and sex-matched healthy controls(n=86).We present the first evidence of gray and white matter impairment of right sensorimotor cortico-striatal networks and reproduced the sensorimotor gating deficit in a mouse model of schizophrenia.Significant correlations between gray matter volumes(GMVs)in the somatosensory cortex and PPI as well as glutamate decarboxylase 1 mRNA expression were found in controls but not in knockout mice.Furthermore,these findings were confirmed in a human sample in which we found significantly decreased gray and white matter in sensorimotor cortico-striatal networks in schizophrenic patients.The psychiatric risk alleles of the GABA pathway also displayed a significant negative correlation with the GMVs of the somatosensory cortex in patients.Our study identified that ErbB4 ablation in parvalbumin interneurons induced GABAergic dysregulation,providing valuable mechanistic insights into the sensorimotor cortico-striatal community structure deficits associated with schizophrenia.
文摘Apple replant disease(ARD)is a major limitation to the establishment of economically viable orchards on replant sites due to the buildup and long-term survival of pathogen inoculum.Several soilborne necrotrophic fungi and oomycetes are primarily responsible for ARD,and symptoms range from serious inhibition of growth to the death of young trees.Chemical fumigation has been the primary method used for control of ARD,and manipulating soil microbial ecology to reduce pathogen density and aggressiveness is being investigated.To date,innate resistance of apple rootstocks as a means to control this disease has not been carefully explored,partly due to the complex etiology and the difficulty in phenotyping the disease resistance.Molecular defense responses of plant roots to soilborne necrotrophic pathogens are largely elusive,although considerable progress has been achieved using foliar disease systems.Plant defense responses to necrotrophic pathogens consist of several interacting modules and operate as a network.Upon pathogen detection by plants,cellular signals such as the oscillation of Ca^(2+)concentration,reactive oxygen species(ROS)burst and protein kinase activity,lead to plant hormone biosynthesis and signaling.Jasmonic acid(JA)and ethylene(ET)are known to be fundamental to the induction and regulation of defense mechanisms toward invading necrotrophic pathogens.Complicated hormone crosstalk modulates the fine-tuning of transcriptional reprogramming and metabolic redirection,resulting in production of antimicrobial metabolites,enzyme inhibitors and cell wall refortification to restrict further pathogenesis.Transcriptome profiling of apple roots in response to inoculation with Pythium ultimum demonstrated that there is a high degree of conservation regarding the molecular framework of defense responses compared with those observed with foliar tissues.It is conceivable that the timing and intensity of genotype-specific defense responses may lead to different outcomes between rootstocks in response to invasion by necrotrophic pathogens.Elucidation of host defense mechanisms is critical in developing molecular tools for genomics-assisted breeding of resistant apple rootstocks.Due to their perennial nature,use of resistant rootstocks as a component for disease management might offer a durable and cost-effective benefit to tree performance than the standard practice of soil fumigation for control of ARD.
文摘Although seed oil production and composition are genetically controlled, changes of oil level and oil composition across genotypes and environments such as drought and temperature were observed. The mechanisms of how genotypes interact with environment, affecting oil production and composition, are still not well understood. The objective of this research was to investigate the effect of drought/water stress and temperature on soybean genotypes. Two soybean genotypes of maturity group (MG) II (PI 597411 B and PI 597408) and two of MG VI (Arksoy and PI 437726) were used. A repeated greenhouse experiment to study the effect of water stress and a repeated growth chamber experiment to study the effect of temperature were conducted. The results showed that both water stress and high temperature altered seed oil composition by increasing oleic acid and decreasing linoleic and linolenic acid concentrations. Severe water stress (soil water potential between -150 to -200 kPa) or high temperature (40/33℃, day/night) resulted in higher palmitic acid and lower stearic acid. Genotypes differed in their responses to water stress or temperature. Analyses of seed carbohydrates (glucose, fructose, sucrose, raffinose, and stachyose) showed a significant decline of glucose, fructose, and sucrose and a significant increase of stachyose concentration by water stress and high temperature. Analyses of natural abundance of δ15N and δ13C isotopes showed changes in sources of nitrogen and carbon fixation, possibly affecting nitrogen and carbon metabolism pathways. The research demonstrated that both water stress and high temperature altered oil production and composition, and this could be partially related to limited availability and movement of carbohydrates from leaves to seed. Further research to investigate the enzymes controlling fatty acids conversion and nitrogen and carbon metabolism is needed.
文摘Oral cancer(OC)is one of the most recurrent cancers in the head and neck squamous cancer(SCCHN)category.Recently,the genome-wide association studies(GWAS)have gained growing interest in the scientific community.GWAS have identified several pathways involved in the interactions among general risk factors and genomic variants affecting SCCHN.This systematic overview aims to critically evaluate the latest data reported within the scientific literature.The aim was to investigate the impact of genetic aspects on SCCHN onset and prognosis,involving other clinical and systemic co-factors.PubMed,Google Scholar,and Cancer Genetics Web databases have been systematically investigated for original articles published in the last two years,reporting studies on the main queries addressed in this work.This review also comparatively describes the impact of environmental and pathological co-factors in different types of cancers,clarifying and updating the role of genetic factors in SCCHN onset and development.The main outcomes reported may be helpful to drive clinicians towards their clinical evaluations for the most appropriate therapeutic approach in SCCHN.
文摘Sexual reproduction in diploid organisms requires the production of haploid gametes via the process of meiosis, in which a single round of DNA replication is followed by two consecutive cell divisions （or two nuclear divisions and one cytokinesis）. In the majority of known cases the proper segregation of the parental genome into gametes is accom- panied and facilitated by meiotic crossover formation, which contributes to physical association between homologous chromosomes and results in the generation of new combina- tions of alleles in the progeny. This is necessarily a complex and highly regulated process with multiple steps in a tight sequence, including exit from mitosis, DNA double strand break （DSB） formation, homology search, recombinational repair of DSBs and regulation of cohesion between homolo- gous chromosomes. The process of meiosis is astonishingly effective, even in mammals and flowering plants with extremely large genomes, in which this entails the manipula- tion of approximately twelve metres or even more of the replicated diploid DNA, on the order of 10^10 base pairs, with close to base pair accuracy. In plants, meiosis does not pro- duce gametes directly, but progenitors of haploid multicellular structures called gametophytes, which contain haploid cells that differentiate into gametes.
基金This study was funded by Taif University Researchers Supporting Project No.TURSP-2020/222,Taif University,Taif,Saudi Arabia.
文摘Since Type 1 diabetes(T1DM)occurs whenβ-cells mass is reduced to less than 20%of the normal level due to autoimmune destruction of cells resulting in the inability to secrete insulin,preservation or replenishment of the functionalβ-cells mass has become a major therapeutic focus for this diabetic type treatment.Thus,this 4-week work plan was designed to determine which mesenchymal stem cells(MSCs)type is more appropriate to alleviate pancreatic hazards resulting from diabetes induction;via tracking a comparative study between MSCs derived from adipose tissue(AD-MSCs)and from bone marrow(BM-MSCs)in management of T1DM considering their immunomodulatory,anti-apoptotic and antioxidative roles.Rats were divided randomly into 4 groups;control,STZdiabetic(D),D+AD-MSCs,and D+BM-MSCs groups.Both stem cells types in this study were allogenic.Herein,both oxidative stress and antioxidant markers were evaluated using colorimetric analysis,while inflammatory,immune and apoptotic markers were assessed through flow cytometric analysis.Results showed that diabetic rats treated with either AD-MSCs or BM-MSCs exhibited marked pancreatic antioxidant and anti-inflammatory activities that were able to initiate pancreatic immunomodulation and reducingβ-cells apoptotic death,thus,help to restore their normal insulin secretion and hypoglycemic abilities.However,AD-MSCs injection was shown to be superior as a pancreatic regenerative tool in overcoming diabetes;owing to their marked antioxidant,anti-inflammatory,immunomodulatory,and anti-apoptotic characteristics over BM-MSCs treatment.
基金Research supported in part by USA National Science Foundation-Plant Genome Program grant(0922746)
文摘Genes encoding early signaling events in pathogen defense often are identified only by their phenotype. Such genes involved in barley-powdery mildew interactions include Mla, specifying race-specific resistance; Rarl （Required for Mla12-specified resistance1）, and Roml （Restoration of Mla-specified resistancel）. The HSP90-SGT1-RAR1 complex appears to function as chaperone in MLA-specified resistance, however, much remains to be discovered regarding the precise signaling underlying plant immunity. Genetic analyses of fast-neutron mutants derived from CI 16151 （Mla6） uncovered a novel locus, designated Rar3 （R_equired for Mla6-specified resitance3）. Rar3 segregates independent of Mla6 and Rarl, and rar3 mutants are susceptible to Blumeria graminis f. sp. hordei （Bgh） isolate 5874 （A VRar）, whereas, wild-type progenitor plants are resistant. Comparative expression analyses of the rar3 mutant vs. its wild-type progenitor were conducted via Barleyl GeneChip and GAIIx paired-end RNA-Seq. Whereas Rarl affects transcription of relatively few genes; Rar3 appears to influence thousands, notably in genes controlling ATP binding, catalytic activity, transcription, and phosphorylation; possibly membrane bound or in the nucleus, eQTL analysis of a segregating doubled haploid population identified over two-thousand genes as being regulated by Mla （q value/FDR=0.00001）, a subset of which are significant in Rar3 interactions. The intersection of datasets derived from mla-loss-of-function mutants, Mla-associated eQTL, and rar3-mediated transcriptome reprogramming are narrowing the focus on essential genes required for Mla-specified immunity.
文摘Background: Cystinosis is a multisystemic autosomal recessive deficiency of the lysosomal membrane transporter protein (cystinosin) caused by mutations in CTNS gene. Objective: This study summarizes the Portuguese experience in the diagnosis and management of patients with this rare disease over the past few years and reports recurrent mutations in the CTNS gene. Methods: Unrelated patients from different pediatric and adult hospitals all over Portugal with non-nephrotic proteinuria, hypercalciuria, hypokalemia impaired proximal reabsorption of amino acids, glycosuria and hypophosphatemia, suggestive of a Fanconi syndrome and ocular problems, were studied. Intra-leukocyte cystine levels were determined and molecular analysis was performed, to determine the presence or absence of the 57-kb deletion in CTNS, followed by direct sequencing of the coding exons of CTNS. Results: From 1998 to 2017, twenty-one cystinotic patients were biochemically diagnosed. From the remaining seventeen (four deceased), eleven were studied for CTNS gene. Five out of eleven patients were homozygous for the 57-kb deletion (10/22;45.5%), and other five were compound heterozygous for this variant (15/22;68.2%). The other mutations found were p.Q128X (c.721 C>T;2/22), p.S139F (c.755 C>T;4/22) and c.18-21delGACT (p.T7FfsX7;1/22). All of these seventeen cystinotic patients are in treatment. Approximately 84% are adults, 16% are young children, and 54.5% are kidney transplant recipient. Conclusions: The authors would like to emphasize the importance of first screening for the 57-kb deletion since it is very common in our population. This genetic study is the first in our country and it could be the basis for future genetic counseling in Portuguese population.
文摘The retrospective study by Lew et al(2022)examined the rising hospitalization rates for chronic pancreatitis(CP)and its association with pancreatic ductal adenocarcinoma(PDAC),revealing significant ethno-racial disparities and risk factors.Overweight black men aged 40-59 years and white men over 40 years with higher incomes showed an elevated risk of PDAC among CP patients.The study,which included 14.2 million admissions from 2016-2017,found that 2.6%of adult patients were diagnosed with CP,with white males being the majority.Multivariate regression analysis identified men,black individuals,those aged 40-59 years,and individuals with a body mass index(BMI)between 25 and 29.9 as having an increased risk for CP.Moreover,0.78%of CP patients also had PDAC,with older age and BMI being significant risk factors for developing PDAC in CP patients.The study also highlighted disparities in healthcare access and utilization among different socioeconomic and ethno-racial groups,which may impact the risk and outcomes of CP and PDAC.
文摘We focus specifically on the rare occurrence of cardiac thrombi in Li-Fraumeni syndrome(LFS).LFS is a hereditary risk to a diverse range of specific,uncommon,malignancies.Children and young adults have a heightened susceptibility to many malignancies,particularly soft-tissue and bone tumors,breast malignancies,central nervous system malignancies,adrenocortical carcinoma,and blood cancers.Additionally,LFS patients may experience other cancer types such as gastrointestinal,lung,kidney,thyroid,and skin cancers,along with those affecting gonadal organs(ovaries,testicles,and prostate).An accurate diagnosis of LFS is crucial to enable affected families to access appropriate genetic counseling and undergo surveillance for early cancer detection.
基金supported by the National Natural Science Foundation of China(81825009,82071505,81901358)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2MC&T-B-099,2019-I2M-5–006)+2 种基金the Program of Chinese Institute for Brain Research Beijing(2020-NKX-XM-12)the King’s College London-Peking University Health Science Center Joint Institute for Medical Research(BMU2020KCL001,BMU2019LCKXJ012)the National Key R&D Program of China(2021YFF1201103,2016YFC1307000).
文摘Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers.Previous studies have indicated the association between treatment response and genetic and epigenetic factors,but no effective biomarkers have been identified.Hence,further research is imperative to enhance precision medicine in SCZ treatment.Methods:Participants with SCZ were recruited from two randomized trials.The discovery cohort was recruited from the CAPOC trial(n=2307)involved 6 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,Quetiapine,Aripiprazole,Ziprasidone,and Haloperidol/Perphenazine(subsequently equally assigned to one or the other)groups.The external validation cohort was recruited from the CAPEC trial(n=1379),which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,and Aripiprazole groups.Additionally,healthy controls(n=275)from the local community were utilized as a genetic/epigenetic reference.The genetic and epigenetic(DNA methylation)risks of SCZ were assessed using the polygenic risk score(PRS)and polymethylation score,respectively.The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis,methylation quantitative trait loci,colocalization,and promoteranchored chromatin interaction.Machine learning was used to develop a prediction model for treatment response,which was evaluated for accuracy and clinical benefit using the area under curve(AUC)for classification,R^(2) for regression,and decision curve analysis.Results:Six risk genes for SCZ(LINC01795,DDHD2,SBNO1,KCNG2,SEMA7A,and RUFY1)involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response.The developed and externally validated prediction model,which incorporated clinical information,PRS,genetic risk score(GRS),and proxy methylation level(proxyDNAm),demonstrated positive benefits for a wide range of patients receiving different APDs,regardless of sex[discovery cohort:AUC=0.874(95%CI 0.867-0.881),R^(2)=0.478;external validation cohort:AUC=0.851(95%CI 0.841-0.861),R^(2)=0.507].Conclusions:This study presents a promising precision medicine approach to evaluate treatment response,which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ.Trial registration Chinese Clinical Trial Registry(https://www.chictr.org.cn/),18 Aug 2009 retrospectively registered:CAPOC-ChiCTR-RNC-09000521(https://www.chictr.org.cn/showproj.aspx?proj=9014),CAPEC-ChiCTRRNC-09000522(https://www.chictr.org.cn/showproj.aspx?proj=9013).
基金Supported by the Department of Biotechnology,Government of India,Ramalingaswami Reentry Fellowship,No.RLS/BT/Reentry/05/2012Department of Higher,Education,Science&Technology and Biotechnology,Government of West Bengal,India,No.BT/P/Budget/RD-37/2016.
文摘Pancreatic cancer(PanCa)is a catastrophic disease,being third lethal in both the genders around the globe.The possible reasons are extreme disease invasiveness,highly fibrotic and desmoplastic stroma,dearth of confirmatory diagnostic approaches and resistance to chemotherapeutics.This inimitable tumor microenvironment(TME)or desmoplasia with excessive extracellular matrix accumulation,create an extremely hypovascular,hypoxic and nutrient-deficient zone inside the tumor.To survive,grow and proliferate in such tough TME,pancreatic tumor and stromal cells transform their metabolism.Transformed glucose,glu-tamine,fat,nucleotide metabolism and inter-metabolite communication between tumor and TME in synergism,impart therapy resistance,and immunosuppression in PanCa.Thus,a finer knowledge of altered metabolism would uncover its metabolic susceptibilities.These unique metabolic targets may help to device novel diagnostic/prognostic markers and therapeutic strategies for better management of PanCa.In this review,we sum up reshaped metabolic pathways in PanCa to formulate detection and remedial strategies of this devastating disease.
基金supported by the National Natural Science Foundation of China(32230089,32070139,32372493,32402315,and 32270208)the China Agricultural Research System(CARS-21)+1 种基金the China Postdoctoral Science Foundation(2022M721655)the Postdoctoral Innovation Talent Support Program(BX20220153).
文摘Plasma membrane intrinsic proteins(PIPs),a subclass of aquaporins,play an important role in plant immunity by acting as H2O2 transporters.Their homeostasis is mostly maintained by C-terminal serine phosphorylation.However,the kinases that phosphorylate PIPs and manipulate their turnover are largely unknown.Here,we found that Arabidopsis thaliana PIP2;7 positively regulates plant immunity by transporting H_(2)O_(2).Arabidopsis CALCIUM-DEPENDENT PROTEIN KINASE 28(CPK28)directly interacts with and phosphorylates PIP2;7 at Ser273/276 to induce its degradation.During pathogen infection,CPK28 dissociates from PIP2;7 and destabilizes,leading to PIP2;7 accumulation.As a countermeasure,oomycete pathogens produce conserved kinase effectors that stably bind to and mediate the phosphorylation of PIP2;7 to induce its degradation.Our study identifies PIP2;7 as a novel substrate of CPK28 and shows that its protein stability is negatively regulated by CPK28.Such phosphorylation could be mimicked by Phytophthora kinase effectors to promote infection.Accordingly,we developed a strategy to combat oomycete infection using a phosphorylation-resistant PIP2;7S273/276A mutant.The strategy only allows accumulation of PIP2;7^(S273/276A) during infection to limit potential side effects on normal plant growth.
文摘Some main recent researches that have dissected tumor microenvironment(TME)by imaging mass cytometry(IMC)in different subtypes of primary breast cancer samples were considered.The many phenotypic variants,clusters of epithelial tumor and immune cells,their structural features as well as the main genetic aberrations,sub-clonal heterogeneity and their systematic classification also have been examined.Mutational evolution has been assessed in primary and metastatic breast cancer samples.Overall,based on these findings the current concept of precision medicine is questioned and challenged by alternative therapeutic strategies.In the last two decades,immunotherapy as a powerful and harmless tool to fight cancer has received huge attention.Thus,the tumor immune microenvironment(TIME)composition,its prognostic role for clinical course as well as a novel definition of immunogenicity in breast cancer are proposed.Investigational clinical trials carried out by us and other findings suggest that G0-G1 state induced in endocrine-dependent metastatic breast cancer is more suitable for successful immune manipulation.Residual micro-metastatic disease seems to be another specific condition that can significantly favor the immune response in breast and other solid tumors.
