Marker-assisted selection(MAS)is often employed in crop breeding programs to accelerate and enhance cultivar development,via selection during the juvenile phase and parental selection prior to crossing.Next-generation...Marker-assisted selection(MAS)is often employed in crop breeding programs to accelerate and enhance cultivar development,via selection during the juvenile phase and parental selection prior to crossing.Next-generation sequencing and its derivative technologies have been used for genome-wide molecular marker discovery.To bridge the gap between marker development and MAS implementation,this study developed a novel practical strategy with a semi-automated pipeline that incorporates trait-associated single nucleotide polymorphism marker discovery,low-cost genotyping through amplicon sequencing(AmpSeq)and decision making.The results document the development of a MAS package derived from genotyping-by-sequencing using three traits(flower sex,disease resistance and acylated anthocyanins)in grapevine breeding.The vast majority of sequence reads(⩾99%)were from the targeted regions.Across 380 individuals and up to 31 amplicons sequenced in each lane of MiSeq data,most amplicons(83 to 87%)had<10%missing data,and read depth had a median of 220–244×.Several strengths of the AmpSeq platform that make this approach of broad interest in diverse crop species include accuracy,flexibility,speed,high-throughput,low-cost and easily automated analysis.展开更多
Powdery mildew resistance genes restrict infection attempts at different stages of pathogenesis.Here,a strong and rapid powdery mildew resistance phenotype was discovered from Vitis amurensis‘PI 588631’that rapidly ...Powdery mildew resistance genes restrict infection attempts at different stages of pathogenesis.Here,a strong and rapid powdery mildew resistance phenotype was discovered from Vitis amurensis‘PI 588631’that rapidly stopped over 97%of Erysiphe necator conidia,before or immediately after emergence of a secondary hypha from appressoria.This resistance was effective across multiple years of vineyard evaluation on leaves,stems,rachises,and fruit and against a diverse array of E.necator laboratory isolates.Using core genome rhAmpSeq markers,resistance mapped to a single dominant locus(here named REN12)on chromosome 13 near 22.8–27.0 Mb,irrespective of tissue type,explaining up to 86.9%of the phenotypic variation observed on leaves.Shotgun sequencing of recombinant vines using skim-seq technology enabled the locus to be further resolved to a 780 kb region,from 25.15 to 25.93 Mb.RNASeq analysis indicated the allele-specific expression of four resistance genes(NLRs)from the resistant parent.REN12 is one of the strongest powdery mildew resistance loci in grapevine yet documented,and the rhAmpSeq sequences presented here can be directly used for marker-assisted selection or converted to other genotyping platforms.While no virulent isolates were identified among the genetically diverse isolates and wild populations of E.necator tested here,NLR loci like REN12 are often race-specific.Thus,stacking of multiple resistance genes and minimal use of fungicides should enhance the durability of resistance and could enable a 90%reduction in fungicides in low-rainfall climates where few other pathogens attack the foliage or fruit.展开更多
Brassica oleracea forms a diverse and economically significant crop group.Improvement efforts are often hindered by limited knowledge of diversity contained within available germplasm.Here,we employ genotyping-by-sequ...Brassica oleracea forms a diverse and economically significant crop group.Improvement efforts are often hindered by limited knowledge of diversity contained within available germplasm.Here,we employ genotyping-by-sequencing to investigate a diverse panel of 85 landrace and improved B.oleracea broccoli,cauliflower,and Chinese kale entries.Ultimately,21,680 high-quality SNPs were used to reveal a complex and admixed population structure and clarify phylogenetic relationships among B.oleracea groups.Each broccoli landrace contained,on average,8.4 times as many unique alleles as an improved broccoli and landraces collectively represented 81%of all broccoli-specific alleles.Commercial broccoli hybrids were largely represented by a single subpopulation identified within a complex population structure.Greater allelic diversity in landrace broccoli and 96.1%of SNPs differentiating improved cauliflower from landrace cauliflower were common to the larger pool of broccoli germplasm,supporting a parallel or later development of cauliflower due to introgression events from broccoli.Chinese kale was readily distinguished by principal coordinate analysis.Genotyping was accomplished with and without reliance upon a reference genome producing 141,317 and 20,815 filtered SNPs,respectively,supporting robust SNP discovery methods in neglected or unimproved crop groups that lack a reference genome.This work clarifies the population structure,phylogeny,and domestication footprints of landrace and improved B.oleracea broccoli using many genotyping-by-sequencing markers.Additionally,a large pool of genetic diversity contained in broccoli landraces is described which may enhance future breeding efforts.展开更多
Background In the current context of global warming,thermal manipulation of avian embryos has received increasing attention as a strategy to promote heat tolerance in avian species by simply increasing the egg incubat...Background In the current context of global warming,thermal manipulation of avian embryos has received increasing attention as a strategy to promote heat tolerance in avian species by simply increasing the egg incubation temperature.However,because of their likely epigenetic origin,thermal manipulation effects may last more than one generation with consequences for the poultry industry.In this work,a multigenerational and transgenerational analysis of thermal manipulation during embryogenesis was performed to uncover the long-term effects of such procedure.Results Thermal manipulation repeated during 4 generations had an effect on hatchability,body weight,and weight of eggs laid in Japanese quails,with some effects increasing in importance over generations.Moreover,the effects on body weight and egg weight could be transmitted transgenerationally,suggesting non-genetic inheritance mechanisms.This hypothesis is reinforced by the observed reversion of the effect on growth after five unexposed generations.Interestingly,a beneficial effect of thermal manipulation on heat tolerance was observed a few days after hatching,but this effect was not transgenerational.Conclusions Our multigenerational study showed that thermal conditioning of quail embryos has a beneficial effect on post-hatch heat tolerance hampered by transgenerational but reversible defects on growth.Assuming that no genetic variability underlies these changes,this study provides the first demonstration of epigenetic inheritance of traits induced by environmental temperature modification associated with long-term impacts in an avian species.展开更多
Beta-defensin 20(DEFB20)is widely expressed in the epididymis with gene features involved in epididymal sperm maturation.However,the action mechanism and function of DEFB20 in sperm maturation are still unclear.One of...Beta-defensin 20(DEFB20)is widely expressed in the epididymis with gene features involved in epididymal sperm maturation.However,the action mechanism and function of DEFB20 in sperm maturation are still unclear.One of the important roles of beta-defensin is the ion channel activity.The cation channel sperm-associated protein(CatSper)alpha is an ion channel protein found on the sperm surface.This study aimed to investigate the interaction between DEFB20 and CatSper1–4 protein in relation to the sperm maturation process.Protein sequences were obtained from the National Center for Biotechnology Information(NCBI).Protein modeling and validation were carried out by using the Robetta modeling server and the Ramachandran plot method.Rosetta web server was used for the docking analysis.The results revealed a natural interaction between DEFB20 and CatSper1–4.The interaction occurred at the cation channel(close to the casein kinase II),ion transport protein,and kinase c phosphorylation of the CatSper1–4 active site.The DEFB20 region interacting with CatSper2–4 was the beta-defensin domain,while with CatSper1 was the non-beta-defensin domain.Based on the analysis,DEFB20 may interact with CatSperαsubunits,particularly CatsSper1,to affect ion channel activity during sperm maturation.展开更多
Tuberculosis is thought to have infected one-third of the world’s population and antibiotic resistance is a growing problem in multi-drug-resistant tuberculosis which is caused by Mycobacterium tuberculosis (MTB). It...Tuberculosis is thought to have infected one-third of the world’s population and antibiotic resistance is a growing problem in multi-drug-resistant tuberculosis which is caused by Mycobacterium tuberculosis (MTB). It has been reported that Mycobacterial cell walls are characterized by high DAP (diaminopimelic acid) content—an intermediate of the (S)-lysine biosynthetic pathway. Hence, the Lysine/DAP biosynthetic pathway is a promising target because of its role in cell wall and amino acid biosynthesis. In this study we performed a molecular docking analysis of a novel antibacterial isolated from Streptomyces sps. 201 against dihydrodipicolinate synthase (DHDPS) enzyme of Mycobacterium tuberculosis. The docking studies suggest that the novel molecule binds at active site LYS 171 forming a cleft and at other potential ligand binding site exhibiting all the major interactions such as hydrogen bonding, hydrophobic interaction and electrostatic interaction with (THR55, TYR143, ARG148, LYS171, VAL257 and GLY256) residues.展开更多
Hsp90 is a major protein involved in the stabilization of various proteins in cancer cells.The present investigation focused on the molecular docking simulation studies of flavanols as inhibitors of Hsp90 at the high ...Hsp90 is a major protein involved in the stabilization of various proteins in cancer cells.The present investigation focused on the molecular docking simulation studies of flavanols as inhibitors of Hsp90 at the high affinity adenosine triphosphate（ATP）binding site and analyzed absorption,distribution,metabolism,excretion and toxicity（ADME-toxicity）.The molecular docking analysis revealed that the flavanols showed competitive inhibition with ATP molecule at the active site and enhanced pharmacological parameters.展开更多
The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer(TNBC),primarily by contributing to tumor cell survival and treatment resistance.However,the pre...The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer(TNBC),primarily by contributing to tumor cell survival and treatment resistance.However,the precise mechanisms remain unclear.In a model of local recurrence(LR),circulating tumor cells(CTC)engrafting in the post-resection tumor bed developed a radioresistant phenotype linked to an ENPP1+-gene signature which was also identified in TNBC patients,suggesting ENPP1´s role in genome integrity.Blockade of ENPP1 using a permeable ENPP1 inhibitor(AVA-NP-695)reduced radioresistance,mechanistically attributed to decreased homologous recombination(HR)resulting in persistent DNA damage,as evidenced by enhanced tail moment and sustainedγH2AX formation.This impaired DNA damage repair(DDR)sensitized tumor cells to ionizing radiation(IR).Notably,several DDR inhibitors(i)(including PARPi and ATMi)showed the highest synergy score in a targeted pharmacological screening.In vivo,dual ENPP1/ATM inhibition heightened radiosensitivity,compromised tumor cell survival and enhanced STINGTBK1 signaling by preventing ENPP1-mediated cGAMP hydrolysis.This resulted in robust innate and long-lasting adaptive antitumor immune memory responses,leading to significant tumor regression.Remarkably,combined treatment post-IR reduced spontaneous metastasis and local recurrence,and induced abscopal effects that impacted distant tumor spread in orthotopic tumor models.Thus,these findings position ENPP1 as a critical link between genome integrity and immunosuppression,offering promising translational opportunities for treating local or distant dissemination in TNBC.展开更多
Diversity analysis and taxonomic profiles can be generated from marker-gene sequence data with the help of many available computational tools.The Quantitative Insights into Microbial Ecology Version 2(QIIME2)has been ...Diversity analysis and taxonomic profiles can be generated from marker-gene sequence data with the help of many available computational tools.The Quantitative Insights into Microbial Ecology Version 2(QIIME2)has been widely used for 16S rRNA data analysis.While many articles have demonstrated the use of QIIME2 with suitable datasets,the application to preclinical data has rarely been talked about.The issues involved in the pre-clinical data include the low-quality score and small sample size that should be addressed properly during analysis.In addition,there are few articles that discuss the detailed statistical methods behind those alpha and beta diversity significance tests that researchers are eager to find.Running the program without knowing the logic behind it is extremely risky.In this article,we first provide a guideline for analyzing 16S rRNA data using QIIME2.Then we will talk about issues in pre-clinical data,and how they could impact the outcome.Finally,we provide brief explanations of statistical methods such as group significance tests and sample size calculation.展开更多
Dear Editor,The global burden of cancer is significant.The list of malignancies regarded as obesity-related continues to expand as evidence accumulates[1,2].Fueled by the ongoing obesity epidemic,obesity has emerged a...Dear Editor,The global burden of cancer is significant.The list of malignancies regarded as obesity-related continues to expand as evidence accumulates[1,2].Fueled by the ongoing obesity epidemic,obesity has emerged as one of the most important preventable causes of cancerworldwide[1,3].Given the long latency periods of many obesity-related adult cancers,risk factors with onset during early age and accumulation of risks during one’s life course are likely to be of importance[4].展开更多
近年来，年轻人的卒中发病率一直在上升，而老年人的卒中发病率却在下降。虽然尚不清楚其原因，但青年卒中发病率的增高与肥胖的流行是同时出现的。因此，瑞典哥德堡哥德堡大学的Ohlsson等进行了一项基于人群的研究，对男性儿童期体重...近年来，年轻人的卒中发病率一直在上升，而老年人的卒中发病率却在下降。虽然尚不清楚其原因，但青年卒中发病率的增高与肥胖的流行是同时出现的。因此，瑞典哥德堡哥德堡大学的Ohlsson等进行了一项基于人群的研究，对男性儿童期体重指数（body mass index，BMI）和青春期BMI变化与成年卒中风险之间的联系进行了探讨。展开更多
Dioxin-like molecules have been associated with endocrine disruption and liver disease.To better understand aryl hydrocarbon receptor(AHR)biology,metabolic phenotyping and liver proteomics were performed in mice follo...Dioxin-like molecules have been associated with endocrine disruption and liver disease.To better understand aryl hydrocarbon receptor(AHR)biology,metabolic phenotyping and liver proteomics were performed in mice following ligand-activation or whole-body genetic ablation of this receptor.Male wild type(WT)and Ahr^(-/-) mice(Taconic)were fed a control diet and exposed to 3,3',4,4',5-pentachlorobiphenyl(PCB126)(61 nmol/kg by gavage)or vehicle for two weeks.PCB126 increased expression of canonical AHR targets(Cyp1 a1 and Cyp1 a2)in WT but not Ahr^(-/-).Knockouts had increased adiposity with decreased glucose tolerance;smaller livers with increased steatosis and perilipin-2;and paradoxically decreased blood lipids.PCB126 was associated with increased hepatic triglycerides in Ahr^(-/-).The liver proteome was impacted more so by Ahr^(-/-) genotype than ligandactivation,but top gene ontology(GO)processes were similar.The PCB126-associated liver proteome was Ahr-dependent.Ahr principally regulated liver metabolism(e.g.,lipids,xenobiotics,organic acids)and bioenergetics,but it also impacted liver endocrine response(e.g.,the insulin receptor)and function,including the production of steroids,hepatokines,and pheromone binding proteins.These effects could have been indirectly mediated by interacting transcription factors or microRNAs.The biologic roles of the AHR and its ligands warrant more research in liver metabolic health and disease.展开更多
The overexpression of sialic acids on glycans,called hypersialylation,is a common alteration found in cancer cells.Sialylated glycans can enhance immune evasion by interacting with sialic acid-binding immunoglobulin-l...The overexpression of sialic acids on glycans,called hypersialylation,is a common alteration found in cancer cells.Sialylated glycans can enhance immune evasion by interacting with sialic acid-binding immunoglobulin-like lectin(Siglec)receptors on tumorinfiltrating immune cells.Here,we investigated the effect of sialylated glycans and their interaction with Siglec receptors on myeloid-derived suppressor cells(MDSCs).We found that MDSCs derived from the blood of lung cancer patients and tumor-bearing mice strongly express inhibitory Siglec receptors and are highly sialylated.In murine cancer models of emergency myelopoiesis,Siglec-E knockout in myeloid cells resulted in prolonged survival and increased tumor infiltration of activated T cells.Targeting suppressive myeloid cells by blocking Siglec receptors or desialylation strongly reduced their suppressive potential.We further identified CCL2 as a mediator involved in T-cell suppression upon interaction between sialoglycans and Siglec receptors on MDSCs.Our results demonstrated that sialylated glycans inhibit anticancer immunity by modulating CCL2 expression.展开更多
Serum albumin is a globular protein which is most abundant in human that binds remarkably with wide range of drugs.A reliable prediction of protein and drug binding at the atomic level by optical spectroscopy and mole...Serum albumin is a globular protein which is most abundant in human that binds remarkably with wide range of drugs.A reliable prediction of protein and drug binding at the atomic level by optical spectroscopy and molecular modeling methods provides the basis for the design of new drug compounds.In the current study,A newly synthesized 3-(1-Phenylsulfonyl-2-methylindol-3-ylcarbonyl)propanoic acid(PA)which has a antifungal and anti bacterial effects also plays vital role for the nutrition,micro biome and physiology triangle.It has been reported that 90%of PA quantity is metabolized by the liver and the rest is transported into the peripheral blood,since PA has binding characteristics,understanding pharmacokinetic mechanism of the drug is important.In this regard,the binding of PA-Bovine Serum Albumin(BSA)was investigated by UV-Vis,fluorescence spectroscopy and molecular docking studies.From the experimental and modeling studies it is observed that PA could bind BSA through the hydrophobic force,and hydrogen bonding.The current study reveals that the optical spectroscopy and molecular modeling techniques could be effectively used to study the design of new drug and understanding their pharmacokinetics.展开更多
In this study,antimicrobial investigations for the efficiently synthesized biocompatible Phloroglucinol Succinic acid(PGSA)dendrimer with anionic surfaces were performed using broth dilution method against a Gram-posi...In this study,antimicrobial investigations for the efficiently synthesized biocompatible Phloroglucinol Succinic acid(PGSA)dendrimer with anionic surfaces were performed using broth dilution method against a Gram-positive bacterium(Staphylococcus aureus),a Gram-negative bacterium(Escherichia coli)and a fungal human pathogen(Candida albicans)to determine the minimal inhibitory concentration(MIC)value.Additionally,fluorescence and UV absorbance spectroscopy techniques were used to monitor the release of intracellular materials from the pathogens owing to anionic dendrimers.The exact binding sites of this dendrimer on these pathogens by molecular modelling studies motivated us to report this nanocarrier as a new antimicrobial agent.展开更多
基金The US Department of Agriculture National Institute of Food and Agriculture Specialty Crop Research Initiative provided funding for this project(award no.2011-51181-30635).
文摘Marker-assisted selection(MAS)is often employed in crop breeding programs to accelerate and enhance cultivar development,via selection during the juvenile phase and parental selection prior to crossing.Next-generation sequencing and its derivative technologies have been used for genome-wide molecular marker discovery.To bridge the gap between marker development and MAS implementation,this study developed a novel practical strategy with a semi-automated pipeline that incorporates trait-associated single nucleotide polymorphism marker discovery,low-cost genotyping through amplicon sequencing(AmpSeq)and decision making.The results document the development of a MAS package derived from genotyping-by-sequencing using three traits(flower sex,disease resistance and acylated anthocyanins)in grapevine breeding.The vast majority of sequence reads(⩾99%)were from the targeted regions.Across 380 individuals and up to 31 amplicons sequenced in each lane of MiSeq data,most amplicons(83 to 87%)had<10%missing data,and read depth had a median of 220–244×.Several strengths of the AmpSeq platform that make this approach of broad interest in diverse crop species include accuracy,flexibility,speed,high-throughput,low-cost and easily automated analysis.
文摘Powdery mildew resistance genes restrict infection attempts at different stages of pathogenesis.Here,a strong and rapid powdery mildew resistance phenotype was discovered from Vitis amurensis‘PI 588631’that rapidly stopped over 97%of Erysiphe necator conidia,before or immediately after emergence of a secondary hypha from appressoria.This resistance was effective across multiple years of vineyard evaluation on leaves,stems,rachises,and fruit and against a diverse array of E.necator laboratory isolates.Using core genome rhAmpSeq markers,resistance mapped to a single dominant locus(here named REN12)on chromosome 13 near 22.8–27.0 Mb,irrespective of tissue type,explaining up to 86.9%of the phenotypic variation observed on leaves.Shotgun sequencing of recombinant vines using skim-seq technology enabled the locus to be further resolved to a 780 kb region,from 25.15 to 25.93 Mb.RNASeq analysis indicated the allele-specific expression of four resistance genes(NLRs)from the resistant parent.REN12 is one of the strongest powdery mildew resistance loci in grapevine yet documented,and the rhAmpSeq sequences presented here can be directly used for marker-assisted selection or converted to other genotyping platforms.While no virulent isolates were identified among the genetically diverse isolates and wild populations of E.necator tested here,NLR loci like REN12 are often race-specific.Thus,stacking of multiple resistance genes and minimal use of fungicides should enhance the durability of resistance and could enable a 90%reduction in fungicides in low-rainfall climates where few other pathogens attack the foliage or fruit.
基金This work is supported by Specialty Crop Research Initiative grant no.2016-51181-25402 from the USDA National Institute of Food and Agriculture.
文摘Brassica oleracea forms a diverse and economically significant crop group.Improvement efforts are often hindered by limited knowledge of diversity contained within available germplasm.Here,we employ genotyping-by-sequencing to investigate a diverse panel of 85 landrace and improved B.oleracea broccoli,cauliflower,and Chinese kale entries.Ultimately,21,680 high-quality SNPs were used to reveal a complex and admixed population structure and clarify phylogenetic relationships among B.oleracea groups.Each broccoli landrace contained,on average,8.4 times as many unique alleles as an improved broccoli and landraces collectively represented 81%of all broccoli-specific alleles.Commercial broccoli hybrids were largely represented by a single subpopulation identified within a complex population structure.Greater allelic diversity in landrace broccoli and 96.1%of SNPs differentiating improved cauliflower from landrace cauliflower were common to the larger pool of broccoli germplasm,supporting a parallel or later development of cauliflower due to introgression events from broccoli.Chinese kale was readily distinguished by principal coordinate analysis.Genotyping was accomplished with and without reliance upon a reference genome producing 141,317 and 20,815 filtered SNPs,respectively,supporting robust SNP discovery methods in neglected or unimproved crop groups that lack a reference genome.This work clarifies the population structure,phylogeny,and domestication footprints of landrace and improved B.oleracea broccoli using many genotyping-by-sequencing markers.Additionally,a large pool of genetic diversity contained in broccoli landraces is described which may enhance future breeding efforts.
文摘Background In the current context of global warming,thermal manipulation of avian embryos has received increasing attention as a strategy to promote heat tolerance in avian species by simply increasing the egg incubation temperature.However,because of their likely epigenetic origin,thermal manipulation effects may last more than one generation with consequences for the poultry industry.In this work,a multigenerational and transgenerational analysis of thermal manipulation during embryogenesis was performed to uncover the long-term effects of such procedure.Results Thermal manipulation repeated during 4 generations had an effect on hatchability,body weight,and weight of eggs laid in Japanese quails,with some effects increasing in importance over generations.Moreover,the effects on body weight and egg weight could be transmitted transgenerationally,suggesting non-genetic inheritance mechanisms.This hypothesis is reinforced by the observed reversion of the effect on growth after five unexposed generations.Interestingly,a beneficial effect of thermal manipulation on heat tolerance was observed a few days after hatching,but this effect was not transgenerational.Conclusions Our multigenerational study showed that thermal conditioning of quail embryos has a beneficial effect on post-hatch heat tolerance hampered by transgenerational but reversible defects on growth.Assuming that no genetic variability underlies these changes,this study provides the first demonstration of epigenetic inheritance of traits induced by environmental temperature modification associated with long-term impacts in an avian species.
文摘Beta-defensin 20(DEFB20)is widely expressed in the epididymis with gene features involved in epididymal sperm maturation.However,the action mechanism and function of DEFB20 in sperm maturation are still unclear.One of the important roles of beta-defensin is the ion channel activity.The cation channel sperm-associated protein(CatSper)alpha is an ion channel protein found on the sperm surface.This study aimed to investigate the interaction between DEFB20 and CatSper1–4 protein in relation to the sperm maturation process.Protein sequences were obtained from the National Center for Biotechnology Information(NCBI).Protein modeling and validation were carried out by using the Robetta modeling server and the Ramachandran plot method.Rosetta web server was used for the docking analysis.The results revealed a natural interaction between DEFB20 and CatSper1–4.The interaction occurred at the cation channel(close to the casein kinase II),ion transport protein,and kinase c phosphorylation of the CatSper1–4 active site.The DEFB20 region interacting with CatSper2–4 was the beta-defensin domain,while with CatSper1 was the non-beta-defensin domain.Based on the analysis,DEFB20 may interact with CatSperαsubunits,particularly CatsSper1,to affect ion channel activity during sperm maturation.
文摘Tuberculosis is thought to have infected one-third of the world’s population and antibiotic resistance is a growing problem in multi-drug-resistant tuberculosis which is caused by Mycobacterium tuberculosis (MTB). It has been reported that Mycobacterial cell walls are characterized by high DAP (diaminopimelic acid) content—an intermediate of the (S)-lysine biosynthetic pathway. Hence, the Lysine/DAP biosynthetic pathway is a promising target because of its role in cell wall and amino acid biosynthesis. In this study we performed a molecular docking analysis of a novel antibacterial isolated from Streptomyces sps. 201 against dihydrodipicolinate synthase (DHDPS) enzyme of Mycobacterium tuberculosis. The docking studies suggest that the novel molecule binds at active site LYS 171 forming a cleft and at other potential ligand binding site exhibiting all the major interactions such as hydrogen bonding, hydrophobic interaction and electrostatic interaction with (THR55, TYR143, ARG148, LYS171, VAL257 and GLY256) residues.
文摘Hsp90 is a major protein involved in the stabilization of various proteins in cancer cells.The present investigation focused on the molecular docking simulation studies of flavanols as inhibitors of Hsp90 at the high affinity adenosine triphosphate（ATP）binding site and analyzed absorption,distribution,metabolism,excretion and toxicity（ADME-toxicity）.The molecular docking analysis revealed that the flavanols showed competitive inhibition with ATP molecule at the active site and enhanced pharmacological parameters.
基金supported the Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional“Una manera de hacer Europa”to RMM(PI 19/01884 and PI22/01506)by the Government of Navarra(34/2021)/50%FEDER 2014-2020 and by the Foundation AECC(PRYES211377MART)+7 种基金funded by Cancer Research Thematic Network of the Instituto de Salud Carlos III(RTICC RD12/0036/0066)SAF2015-71606R,RTI2018-094507B-100 financed by MCIN/AEI/10.13039/501100011033/and by FEDER“Una manera de hacer Europa”MICIU PID2021-1226380B-100 and PID2024-156335OB-100supported by FIS(PI22/01253)supported by the Foundation for Applied Medical Research(FIMA)and CIBERONC(CB16/12/00443)funded by the Government of Navarra of the I+D 2022-25,GEMA(GRANATE:Grupo de Radioterapia Avanzada de Navarra,0011-1411-2022-000066 and 0011-1411-2022-000073)supported by a Project PID2023-152755OB-I00 funded by MICIU/AEI/10.13039/501100011033 and by FEDER,EU.K.Vsupported by an Investigator grant from AECC.F.L.and S.V.report research funding from Roche.F.L.and R.M.-M.report consulting fees from Ellipses Life.No potential conflicts of interest were disclosed by the other authors.
文摘The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer(TNBC),primarily by contributing to tumor cell survival and treatment resistance.However,the precise mechanisms remain unclear.In a model of local recurrence(LR),circulating tumor cells(CTC)engrafting in the post-resection tumor bed developed a radioresistant phenotype linked to an ENPP1+-gene signature which was also identified in TNBC patients,suggesting ENPP1´s role in genome integrity.Blockade of ENPP1 using a permeable ENPP1 inhibitor(AVA-NP-695)reduced radioresistance,mechanistically attributed to decreased homologous recombination(HR)resulting in persistent DNA damage,as evidenced by enhanced tail moment and sustainedγH2AX formation.This impaired DNA damage repair(DDR)sensitized tumor cells to ionizing radiation(IR).Notably,several DDR inhibitors(i)(including PARPi and ATMi)showed the highest synergy score in a targeted pharmacological screening.In vivo,dual ENPP1/ATM inhibition heightened radiosensitivity,compromised tumor cell survival and enhanced STINGTBK1 signaling by preventing ENPP1-mediated cGAMP hydrolysis.This resulted in robust innate and long-lasting adaptive antitumor immune memory responses,leading to significant tumor regression.Remarkably,combined treatment post-IR reduced spontaneous metastasis and local recurrence,and induced abscopal effects that impacted distant tumor spread in orthotopic tumor models.Thus,these findings position ENPP1 as a critical link between genome integrity and immunosuppression,offering promising translational opportunities for treating local or distant dissemination in TNBC.
基金S.N.Rai was partly supported with Wendell Cherry Chair in Clinical Trial Research Fund and NIH grants 5P20GM113226(CJM),1P42ES023716(PI:Sanjay Srivastava)and 1P20GM125504(PI:Richard Lamont).C.Qian was supported by the National Institutes of Health grant 5P50AA024337(CJM)and the University of Louisville Fellowship.
文摘Diversity analysis and taxonomic profiles can be generated from marker-gene sequence data with the help of many available computational tools.The Quantitative Insights into Microbial Ecology Version 2(QIIME2)has been widely used for 16S rRNA data analysis.While many articles have demonstrated the use of QIIME2 with suitable datasets,the application to preclinical data has rarely been talked about.The issues involved in the pre-clinical data include the low-quality score and small sample size that should be addressed properly during analysis.In addition,there are few articles that discuss the detailed statistical methods behind those alpha and beta diversity significance tests that researchers are eager to find.Running the program without knowing the logic behind it is extremely risky.In this article,we first provide a guideline for analyzing 16S rRNA data using QIIME2.Then we will talk about issues in pre-clinical data,and how they could impact the outcome.Finally,we provide brief explanations of statistical methods such as group significance tests and sample size calculation.
基金Thisworkwas supported by the Swedish Research Council and by grants from the Swedish state under the agreement between the Swedish Government and the County Councils,the ALF-agreement(grant numbers 883541,723791 and 238261),Swedish Heart-Lung Foundation,the Lundberg Foundation,the Torsten Soderberg Foundation,the Novo Nordisk Foundation and the Knut and Alice Wallenberg Foundation.None of the funders had any role in the design and conduct of the study,collection,management,analysis,and interpretation of the data,or preparation,review,or approval of the manuscript.
文摘Dear Editor,The global burden of cancer is significant.The list of malignancies regarded as obesity-related continues to expand as evidence accumulates[1,2].Fueled by the ongoing obesity epidemic,obesity has emerged as one of the most important preventable causes of cancerworldwide[1,3].Given the long latency periods of many obesity-related adult cancers,risk factors with onset during early age and accumulation of risks during one’s life course are likely to be of importance[4].
文摘近年来，年轻人的卒中发病率一直在上升，而老年人的卒中发病率却在下降。虽然尚不清楚其原因，但青年卒中发病率的增高与肥胖的流行是同时出现的。因此，瑞典哥德堡哥德堡大学的Ohlsson等进行了一项基于人群的研究，对男性儿童期体重指数（body mass index，BMI）和青春期BMI变化与成年卒中风险之间的联系进行了探讨。
基金supported,in part,by the National Institute of Environmental Health Sciences(R35ES028373,R01ES032189,T32ES011564,P42ES023716,P30ES030283,F31ES028982 and R21ES031510,USA)the National Institute of General Medical Sciences(P20GM113226,USA)+1 种基金the National Institute on Alcohol Abuse and Alcoholism(P50AA024337 and 1F32AA027950,USA)the Kentucky Council on Postsecondary Education(PON24151900002934,USA)。
文摘Dioxin-like molecules have been associated with endocrine disruption and liver disease.To better understand aryl hydrocarbon receptor(AHR)biology,metabolic phenotyping and liver proteomics were performed in mice following ligand-activation or whole-body genetic ablation of this receptor.Male wild type(WT)and Ahr^(-/-) mice(Taconic)were fed a control diet and exposed to 3,3',4,4',5-pentachlorobiphenyl(PCB126)(61 nmol/kg by gavage)or vehicle for two weeks.PCB126 increased expression of canonical AHR targets(Cyp1 a1 and Cyp1 a2)in WT but not Ahr^(-/-).Knockouts had increased adiposity with decreased glucose tolerance;smaller livers with increased steatosis and perilipin-2;and paradoxically decreased blood lipids.PCB126 was associated with increased hepatic triglycerides in Ahr^(-/-).The liver proteome was impacted more so by Ahr^(-/-) genotype than ligandactivation,but top gene ontology(GO)processes were similar.The PCB126-associated liver proteome was Ahr-dependent.Ahr principally regulated liver metabolism(e.g.,lipids,xenobiotics,organic acids)and bioenergetics,but it also impacted liver endocrine response(e.g.,the insulin receptor)and function,including the production of steroids,hepatokines,and pheromone binding proteins.These effects could have been indirectly mediated by interacting transcription factors or microRNAs.The biologic roles of the AHR and its ligands warrant more research in liver metabolic health and disease.
基金supported by funding from the Swiss National Science Foundation(SNSF Grant No.310030-215237/1)the Schoenmakers-Müller Foundation,a research grant from Ono Pharmaceuticals,and the Cancer League of Basel(KlbB).Open access funding provided by University of Basel.
文摘The overexpression of sialic acids on glycans,called hypersialylation,is a common alteration found in cancer cells.Sialylated glycans can enhance immune evasion by interacting with sialic acid-binding immunoglobulin-like lectin(Siglec)receptors on tumorinfiltrating immune cells.Here,we investigated the effect of sialylated glycans and their interaction with Siglec receptors on myeloid-derived suppressor cells(MDSCs).We found that MDSCs derived from the blood of lung cancer patients and tumor-bearing mice strongly express inhibitory Siglec receptors and are highly sialylated.In murine cancer models of emergency myelopoiesis,Siglec-E knockout in myeloid cells resulted in prolonged survival and increased tumor infiltration of activated T cells.Targeting suppressive myeloid cells by blocking Siglec receptors or desialylation strongly reduced their suppressive potential.We further identified CCL2 as a mediator involved in T-cell suppression upon interaction between sialoglycans and Siglec receptors on MDSCs.Our results demonstrated that sialylated glycans inhibit anticancer immunity by modulating CCL2 expression.
基金supported by the Board of Research in Nuclear Sciences,Department of Atomic Energy,Government of India,Project no.2009/34/38/BRNS/3206.
文摘Serum albumin is a globular protein which is most abundant in human that binds remarkably with wide range of drugs.A reliable prediction of protein and drug binding at the atomic level by optical spectroscopy and molecular modeling methods provides the basis for the design of new drug compounds.In the current study,A newly synthesized 3-(1-Phenylsulfonyl-2-methylindol-3-ylcarbonyl)propanoic acid(PA)which has a antifungal and anti bacterial effects also plays vital role for the nutrition,micro biome and physiology triangle.It has been reported that 90%of PA quantity is metabolized by the liver and the rest is transported into the peripheral blood,since PA has binding characteristics,understanding pharmacokinetic mechanism of the drug is important.In this regard,the binding of PA-Bovine Serum Albumin(BSA)was investigated by UV-Vis,fluorescence spectroscopy and molecular docking studies.From the experimental and modeling studies it is observed that PA could bind BSA through the hydrophobic force,and hydrogen bonding.The current study reveals that the optical spectroscopy and molecular modeling techniques could be effectively used to study the design of new drug and understanding their pharmacokinetics.
基金funding agency,Board of Research in Nuclear Science(BRNS,Ref.No.2009/38/BRNS/3206),Govt.of India for providing the fellowship.
文摘In this study,antimicrobial investigations for the efficiently synthesized biocompatible Phloroglucinol Succinic acid(PGSA)dendrimer with anionic surfaces were performed using broth dilution method against a Gram-positive bacterium(Staphylococcus aureus),a Gram-negative bacterium(Escherichia coli)and a fungal human pathogen(Candida albicans)to determine the minimal inhibitory concentration(MIC)value.Additionally,fluorescence and UV absorbance spectroscopy techniques were used to monitor the release of intracellular materials from the pathogens owing to anionic dendrimers.The exact binding sites of this dendrimer on these pathogens by molecular modelling studies motivated us to report this nanocarrier as a new antimicrobial agent.
