Radiotherapy is a critical component of cancer care but can cause osteoporosis and pathological insufficiency fractures in surrounding and otherwise healthy bone.Presently,no effective countermeasure exists,and ionizi...Radiotherapy is a critical component of cancer care but can cause osteoporosis and pathological insufficiency fractures in surrounding and otherwise healthy bone.Presently,no effective countermeasure exists,and ionizing radiation-induced bone damage continues to be a substantial source of pain and morbidity.The purpose of this study was to investigate a small molecule aminopropyl carbazole named P7C3 as a novel radioprotective strategy.Our studies revealed that P7C3 repressed ionizing radiation(IR)-induced osteoclastic activity,inhibited adipogenesis,and promoted osteoblastogenesis and mineral deposition in vitro.We also demonstrated that rodents exposed to clinically equivalent hypofractionated levels of IR in vivo develop weakened,osteoporotic bone.However,the administration of P7C3 significantly inhibited osteoclastic activity,lipid formation and bone marrow adiposity and mitigated tissue loss such that bone maintained its area,architecture,and mechanical strength.Our findings revealed significant enhancement of cellular macromolecule metabolic processes,myeloid cell differentiation,and the proteins LRP-4,TAGLN,ILK,and Tollip,with downregulation of GDF-3,SH2B1,and CD200.These proteins are key in favoring osteoblast over adipogenic progenitor differentiation,cell matrix interactions,and shape and motility,facilitating inflammatory resolution,and suppressing osteoclastogenesis,potentially via Wnt/β-catenin signaling.A concern was whether P7C3 afforded similar protection to cancer cells.Preliminarily,and remarkably,at the same protective P7C3 dose,a significant reduction in triple-negative breast cancer and osteosarcoma cell metabolic activity was found in vitro.Together,these results indicate that P7C3 is a previously undiscovered key regulator of adipo-osteogenic progenitor lineage commitment and may serve as a novel multifunctional therapeutic strategy,leaving IR an effective clinical tool while diminishing the risk of adverse post-IR complications.Our data uncover a new approach for the prevention of radiation-induced bone damage,and further work is needed to investigate its ability to selectively drive cancer cell death.展开更多
The spined loach Cobitis taenia, is listed as a protected species under Appendix 3 of the Bern Convention and Annex II of the European Council Directive (92/43/EEC) on the conservation of natural habitats and of wild ...The spined loach Cobitis taenia, is listed as a protected species under Appendix 3 of the Bern Convention and Annex II of the European Council Directive (92/43/EEC) on the conservation of natural habitats and of wild fauna and flora. It is desirable therefore to understand the genetic diversity within European populations. In a molecular genetic analysis of the cytochrome b gene in Cobitis taenia from three sites in the upper reaches of the River Trent catchment, a novel high frequency variant was identified which has not been previously reported in any European or Non-European population.展开更多
Comprehensive identification of conditionally essential genes requires efficient tools for generating high-density transposon libraries that, ideally, can be analysed using next-generation sequencing methods such as T...Comprehensive identification of conditionally essential genes requires efficient tools for generating high-density transposon libraries that, ideally, can be analysed using next-generation sequencing methods such as Transposon Directed Insertion-site Sequencing (TraDIS). The Himar1 (mariner) transposon is ideal for generating near-saturating mutant libraries, especially in AT-rich chromosomes, as the requirement for integration is a TA dinucleotide, and this transposon has been used for mutagenesis of a wide variety of bacteria. However, plasmids for mariner delivery do not necessarily work well in all bacteria. In particular, there are limited tools for functional genomic analysis of Pasteurellaceae species of major veterinary importance, such as swine and cattle pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida, respectively. Here, we developed plasmids, pTsodCPC9 and pTlacPC9 (differing only in the promoter driving expression of the transposase gene), that allow delivery of mariner into both these pathogens, but which should also be applicable to a wider range of bacteria. Using the pTlacPC9 vector, we have generated, for the first time, saturating mariner mutant libraries in both A. pleuropneumoniae and P. multocida that showed a near random distribution of insertions around the respective chromosomes as detected by TraDIS. A preliminary screen of 5000 mutants each identified 8 and 14 genes, respectively, that are required for growth under anaerobic conditions. Future high-throughput screening of the generated libraries will facilitate identification of mutants required for growth under different conditions, including in vivo, highlighting key virulence factors and pathways that can be exploited for development of novel therapeutics and vaccines.展开更多
The revolution of genome sequencing is continuing after the successful secondgeneration sequencing （SGS） technology. The third-generation sequencing （TGS） technology, led by Pacific Biosciences （PacBio）, is prog...The revolution of genome sequencing is continuing after the successful secondgeneration sequencing （SGS） technology. The third-generation sequencing （TGS） technology, led by Pacific Biosciences （PacBio）, is progressing rapidly, moving from a technology once only capable of providing data for small genome analysis, or for performing targeted screening, to one that promises high quality de novo assembly and structural variation detection for human-sized genomes. In 2014, the MinION, the first commercial sequencer using nanopore technology, was released by Oxford Nanopore Technologies （ONT）. MiniON identifies DNA bases by measuring the changes in electrical conductivity generated as DNA strands pass through a biological pore. Its portability, affordability, and speed in data production makes it suitable for real-time applications, the release of the long read sequencer MiniON has thus generated much excitement and interest in the genomics community. While de novo genome assemblies can be cheaply produced from SGS data, assem- bly continuity is often relatively poor, due to the limited ability of short reads to handle long repeats. Assembly quality can be greatly improved by using TGS long reads, since repetitive regions can be easily expanded into using longer sequencing lengths, despite having higher error rates at the base level. The potential of nanopore sequencing has been demonstrated by various studies in genome surveillance at locations where rapid and reliable sequencing is needed, but where resources are limited.展开更多
Artemisia annua is the major natural source of artemisinin,an anti-malarial medicine commonly used worldwide.Here,we present chromosome-level haploid maps for two A.annua strains with different artemisinin contents to...Artemisia annua is the major natural source of artemisinin,an anti-malarial medicine commonly used worldwide.Here,we present chromosome-level haploid maps for two A.annua strains with different artemisinin contents to explore the relationships between genomic organization and artemisinin production.High-fidelity sequencing,optical mapping,and chromatin conformation capture sequencing were used to assemble the heterogeneous and repetitive genome and resolve the haplotypes of A.annua.Approximately 5o,ooo genes were annotated for each haplotype genome,and a triplication event that occurred approximately 58.12million years ago was examined for the first time in this species.A total of 3,903,467-5,193,414 variants(SNPs,indels,and structural variants)were identified in the 1.5-Gb genome during pairwise comparison between haplotypes,consistent with the high heterozygosity of this species.Genomic analyses revealed a correlation between artemisinin concents and the copy number of amorpha-4,11-dienes ynthasegenes.This correlation was further confirmed by resequencing of 36A.annua samples with varied artemisinin contents.Circular consensus sequencing of transcripts facilitated the detection of paralog expression.Collectively,our study provides chromosome-level allele-aware genome assemblies for two A.annua strains and new insights into the biosynthesis of artemisinin and its regulation,which will contribute to conquering malaria worldwide.展开更多
Background:Drug resistance is one of the greatest challenges of malaria control programmes,with the monitoring of parasite resistance to artemisinins or to Artemisinin Combination Therapy(ACT)partner drugs critical to...Background:Drug resistance is one of the greatest challenges of malaria control programmes,with the monitoring of parasite resistance to artemisinins or to Artemisinin Combination Therapy(ACT)partner drugs critical to elimination efforts.Markers of resistance to a wide panel of antimalarials were assessed in natural parasite populations from southwestern Cameroon.Methods:Individuals with asymptomatic parasitaemia or uncomplicated malaria were enrolled through crosssectional surveys from May 2013 to March 2014 along the slope of mount Cameroon.Plasmodium falciparum malaria parasitaemic blood,screened by light microscopy,was depleted of leucocytes using CF11 cellulose columns and the parasite genotype ascertained by sequencing on the Illumina HiSeq platform.Results:A total of 259 participants were enrolled in this study from three different altitudes.While some alleles associated with drug resistance in pfdhfr,pfmdr1 and pfcrt were highly prevalent,less than 3%of all samples carried mutations in the pfkelch13 gene,none of which were amongst those associated with slow artemisinin parasite clearance rates in Southeast Asia.The most prevalent haplotypes were triple mutants PfdhfrI51R59N108I164(99%),pfcrt-C72V73I74E75T76(47.3%),and single mutants PfdhpsS_(436)G_(437)K_(540)A_(581)A_(613)(69%)and Pfmdr1 N_(86)F)(184)D_(1246)(53.2%).Conclusions:The predominance of the Pf pfcrt CVIET and Pf dhfr IRN triple mutant parasites and absence of pfkelch13 resistance alleles suggest that the amodiaquine and pyrimethamine components of AS-AQ and SP may no longer be effective in their role while chloroquine resistance still persists in southwestern Cameroon.展开更多
Dear Editor Salvia miltiorrhiza Bunge （Danshen） is a medicinal plant of the Lamiaceae family, and its dried roots have long been used in traditional Chinese medicine with hydrophilic phenolic acids and tanshinones a...Dear Editor Salvia miltiorrhiza Bunge （Danshen） is a medicinal plant of the Lamiaceae family, and its dried roots have long been used in traditional Chinese medicine with hydrophilic phenolic acids and tanshinones as pharmaceutically active components （Zhang et al., 2014; Xu et al., 2016）. The first step of tanshinone biosynthesis is bicyclization of the general diterpene precursor （E,E,E）-geranylgeranyl diphosphate （GGPP） to copalyl diphosphate （CPP） by CPP synthases （CPSs）, which is followed by a cyclization or rearrangement reaction catalyzed by kaurene synthase-like enzymes （KSL）. The resulting intermediate is usually an olefin, which requires the insertion of oxygen by cytochrome P450 mono-oxygenases （CYPs） for the final production of diterpenoids （Zi et al., 2014）. While the CPS, KSL, and several early acting CYPs （CYP76AH1, CYP76AH3, and CYP76AK1） for tanshinone biosynthesis have been identified in S. miltiorrhiza （Gao et al., 2009; Guo et al., 2013, 2016; Zi and Peters, 2013）, the majority of the overall biosynthetic pathway, as well as the relevant regulatory factors associated with tanshinone production, remains elusive （Figure 1B）.展开更多
The human mutation rate—how often new changes appear in the DNA—is fundamental to understanding many aspects of medical genetics and human evolutionary genetics.But it is low,and has therefore been difficult to meas...The human mutation rate—how often new changes appear in the DNA—is fundamental to understanding many aspects of medical genetics and human evolutionary genetics.But it is low,and has therefore been difficult to measure.In the past,scientists could only estimate it approximately, either by observing how often mutant phenotypes appeared,or by comparison of humans and closely related species,such as chimpanzee, where many mutations could accumulate but the time period was uncertain.Now,a new study supported by the NSFC in China and The Royal Society in the UK reports the first direct measurement of the human mutation rate at the individual letters(nucleotides or bases) of DNA.This was possible because new(next)-generation sequencing technology is much more powerful than the methods available previously.The work was published in the leading journal Current Biology on 15th September 2009.The results were reported in the news by Nature, Science and the BBC,as well as in more than 20 Chinese newspapers and radio stations after the work first appeared online on 27th August.It was also one of the research highlights in Nature on 3rd September,which commented'This direct measurement of the human mutation rate should help researchers to refine evolutionary dating and better understand the source of genetic disease'.From the work,researchers could estimate that everyone has around 200 new mutations in their genome;as the authors said,'we are all mutants'.The ability to reliably measure rates of DNA mutation means we can begin to ask how mutation rates vary between different regions of the genome and perhaps also between different individuals.展开更多
Pluripotency is depicted by a self-renewing state that can competently differentiate to form the three germ layers.Different stages of early murine development can be captured on a petri dish,delineating a spectrum of...Pluripotency is depicted by a self-renewing state that can competently differentiate to form the three germ layers.Different stages of early murine development can be captured on a petri dish,delineating a spectrum of pluripotent states,ranging from embryonic stem cells,embryonic germ cells to epiblast stem cells.Anomalous cell populations displaying signs of pluripotency have also been uncovered,from the isolation of embryonic carcinoma cells to the derivation of induced pluripotent stem cells.Gaining insight into the molecular circuitry within these cell types enlightens us about the significance and contribution of each stage,hence deepening our understanding of vertebrate development.In this review,we aim to describe experimental milestones that led to the understanding of embryonic development and the conception of pluripotency.We also discuss attempts at exploring the realm of pluripotency with the identification of pluripotent stem cells within mouse teratocarcinomas and embryos,and the generation of pluripotent cells through nuclear reprogramming.In conclusion,we illustrate pluripotent cells derived from other organisms,including human derivatives,and describe current paradigms in the comprehension of human pluripotency.展开更多
Laboratory mice have widely been used as tools for basic biological research and models for studying human diseases.With the advances of genetic engineering and conditional knockout(CKO)mice,we now understand hematopo...Laboratory mice have widely been used as tools for basic biological research and models for studying human diseases.With the advances of genetic engineering and conditional knockout(CKO)mice,we now understand hematopoiesis is a dynamic stepwise process starting from hematopoietic stem cells(HSCs)which are responsible for replenishing all blood cells.Transcriptional factors play important role in hematopoiesis.In this review we compile several studies on using genetic modified mice and humanized mice to study function of transcriptional factors in lymphopoiesis,including T lymphocyte and Natural killer(NK)cell development.Finally,we focused on the key transcriptional factor Bcl11b and its function in regulating T cell specification and commitment.展开更多
Nuclear reprogramming is described as a molecular switch,triggered by the conversion of one cell type to another.Several key experiments in the past century have provided insight into the field of nuclear repro-grammi...Nuclear reprogramming is described as a molecular switch,triggered by the conversion of one cell type to another.Several key experiments in the past century have provided insight into the field of nuclear repro-gramming.Previously deemed impossible,this re-search area is now brimming with new findings and developments.In this review,we aim to give a historical perspective on how the notion of nuclear reprogram-ming was established,describing main experiments that were performed,including(1)somatic cell nuclear transfer,(2)exposure to cell extracts and cell fusion,and(3)transcription factor induced lineage switch.Ultimately,we focus on(4)transcription factor induced pluripotency,as initiated by a landmark discovery in 2006,where the process of converting somatic cells to a pluripotent state was narrowed down to four tran-scription factors.The conception that somatic cells possess the capacity to revert to an immature status brings about huge clinical implications including per-sonalized therapy,drug screening and disease model-ing.Although this technology has potential to revolu-tionize the medical field,it is still impeded by technical and biological obstacles.This review describes the effervescent changes in this field,addresses bottle-necks hindering its advancement and in conclusion,applies the latest findings to overcome these issues.展开更多
Africa is the cradle of all human beings, and although it has been the focus of a number of genetic studies, there are many questions that remain unresolved. We have performed one of the largest and most comprehensive...Africa is the cradle of all human beings, and although it has been the focus of a number of genetic studies, there are many questions that remain unresolved. We have performed one of the largest and most comprehensive meta-analyses of mitochondrial DNA （mtDNA） lineages carried out in the African continent to date. We generated high-throughput mtDNA single nucleotide polymorphism （SNP） data （230 SNPs） from 2024 Africans, where more than 500 of them were additionally genotyped for the control region. These data were analyzed together with over 12,700 control region profiles collected from the literature, representing more than 300 population samples from Africa. Insights into the African homeland of humans are discussed. Phylogeographic patterns for the African continent are shown at a high phylogeographic resolution as well as at the population and regional levels. The deepest branch of the mtDNA tree, haplogroup L0, shows the highest sub-haplogroup diversity in Southeast and East Africa, suggesting this region as the homeland for modem humans. Several demographic estimates point to the coast as a facilitator of human migration in Africa, but the data indicate complex patterns, perhaps mirroring the effect of recent continental-scaled demographic events in re-shaping African mtDNA variability.展开更多
基金funded by the Department of Internal Medicine,College of Medicine,University of Central Florida (Award#2508074)supported by the National Aeronautics and Space Administration [grant No.80NSSC21M0309]issued through the NASA Office of STEM Engagement。
文摘Radiotherapy is a critical component of cancer care but can cause osteoporosis and pathological insufficiency fractures in surrounding and otherwise healthy bone.Presently,no effective countermeasure exists,and ionizing radiation-induced bone damage continues to be a substantial source of pain and morbidity.The purpose of this study was to investigate a small molecule aminopropyl carbazole named P7C3 as a novel radioprotective strategy.Our studies revealed that P7C3 repressed ionizing radiation(IR)-induced osteoclastic activity,inhibited adipogenesis,and promoted osteoblastogenesis and mineral deposition in vitro.We also demonstrated that rodents exposed to clinically equivalent hypofractionated levels of IR in vivo develop weakened,osteoporotic bone.However,the administration of P7C3 significantly inhibited osteoclastic activity,lipid formation and bone marrow adiposity and mitigated tissue loss such that bone maintained its area,architecture,and mechanical strength.Our findings revealed significant enhancement of cellular macromolecule metabolic processes,myeloid cell differentiation,and the proteins LRP-4,TAGLN,ILK,and Tollip,with downregulation of GDF-3,SH2B1,and CD200.These proteins are key in favoring osteoblast over adipogenic progenitor differentiation,cell matrix interactions,and shape and motility,facilitating inflammatory resolution,and suppressing osteoclastogenesis,potentially via Wnt/β-catenin signaling.A concern was whether P7C3 afforded similar protection to cancer cells.Preliminarily,and remarkably,at the same protective P7C3 dose,a significant reduction in triple-negative breast cancer and osteosarcoma cell metabolic activity was found in vitro.Together,these results indicate that P7C3 is a previously undiscovered key regulator of adipo-osteogenic progenitor lineage commitment and may serve as a novel multifunctional therapeutic strategy,leaving IR an effective clinical tool while diminishing the risk of adverse post-IR complications.Our data uncover a new approach for the prevention of radiation-induced bone damage,and further work is needed to investigate its ability to selectively drive cancer cell death.
基金supported partly by grants from the Ministry of Science and Technology of China(2005DKA21502)the Joint Foundation of Science and Technology Bureau of Yunnan Province and Kunming Medical University(2007C0024R)
文摘The spined loach Cobitis taenia, is listed as a protected species under Appendix 3 of the Bern Convention and Annex II of the European Council Directive (92/43/EEC) on the conservation of natural habitats and of wild fauna and flora. It is desirable therefore to understand the genetic diversity within European populations. In a molecular genetic analysis of the cytochrome b gene in Cobitis taenia from three sites in the upper reaches of the River Trent catchment, a novel high frequency variant was identified which has not been previously reported in any European or Non-European population.
基金This work was supported by a Longer and Larger(LoLa)grant from the Biotechnology and Biological Sciences Research Council(BBSRC,grant numbers BB/G020744/1,BB/G019177/1,BB/G019274/1 and BB/G018553/1)the UK Department for Environment,Food and Rural Affairs and Zoetis awarded to the Bacterial Respiratory Diseases of Pigs-1 Technology(BRaDP1T)consortium.Funding for LZ was provided by the BBSRC(grant number BB/C508193/1)The funders had no role in study design,data collection and analysis,decision to publish,or preparation of the manuscript.
文摘Comprehensive identification of conditionally essential genes requires efficient tools for generating high-density transposon libraries that, ideally, can be analysed using next-generation sequencing methods such as Transposon Directed Insertion-site Sequencing (TraDIS). The Himar1 (mariner) transposon is ideal for generating near-saturating mutant libraries, especially in AT-rich chromosomes, as the requirement for integration is a TA dinucleotide, and this transposon has been used for mutagenesis of a wide variety of bacteria. However, plasmids for mariner delivery do not necessarily work well in all bacteria. In particular, there are limited tools for functional genomic analysis of Pasteurellaceae species of major veterinary importance, such as swine and cattle pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida, respectively. Here, we developed plasmids, pTsodCPC9 and pTlacPC9 (differing only in the promoter driving expression of the transposase gene), that allow delivery of mariner into both these pathogens, but which should also be applicable to a wider range of bacteria. Using the pTlacPC9 vector, we have generated, for the first time, saturating mariner mutant libraries in both A. pleuropneumoniae and P. multocida that showed a near random distribution of insertions around the respective chromosomes as detected by TraDIS. A preliminary screen of 5000 mutants each identified 8 and 14 genes, respectively, that are required for growth under anaerobic conditions. Future high-throughput screening of the generated libraries will facilitate identification of mutants required for growth under different conditions, including in vivo, highlighting key virulence factors and pathways that can be exploited for development of novel therapeutics and vaccines.
基金supported by the Wellcome Trust,the United Kingdom
文摘The revolution of genome sequencing is continuing after the successful secondgeneration sequencing （SGS） technology. The third-generation sequencing （TGS） technology, led by Pacific Biosciences （PacBio）, is progressing rapidly, moving from a technology once only capable of providing data for small genome analysis, or for performing targeted screening, to one that promises high quality de novo assembly and structural variation detection for human-sized genomes. In 2014, the MinION, the first commercial sequencer using nanopore technology, was released by Oxford Nanopore Technologies （ONT）. MiniON identifies DNA bases by measuring the changes in electrical conductivity generated as DNA strands pass through a biological pore. Its portability, affordability, and speed in data production makes it suitable for real-time applications, the release of the long read sequencer MiniON has thus generated much excitement and interest in the genomics community. While de novo genome assemblies can be cheaply produced from SGS data, assem- bly continuity is often relatively poor, due to the limited ability of short reads to handle long repeats. Assembly quality can be greatly improved by using TGS long reads, since repetitive regions can be easily expanded into using longer sequencing lengths, despite having higher error rates at the base level. The potential of nanopore sequencing has been demonstrated by various studies in genome surveillance at locations where rapid and reliable sequencing is needed, but where resources are limited.
基金This work was supported by the National Key R&D Program of China(2019YFC1711100)the National Natural Science Foundation of China(U1812403-1,81641002)+1 种基金the Fundamental Research Funds forthe Central Public Welfare Research Institutes(ZZ13-YQ-047,ZZ13-YQ-102)the National Major Science and Technology Projects(2017ZX09101002-003-001,2019ZX09201005-006-001,2019ZX09201005-002-002).
文摘Artemisia annua is the major natural source of artemisinin,an anti-malarial medicine commonly used worldwide.Here,we present chromosome-level haploid maps for two A.annua strains with different artemisinin contents to explore the relationships between genomic organization and artemisinin production.High-fidelity sequencing,optical mapping,and chromatin conformation capture sequencing were used to assemble the heterogeneous and repetitive genome and resolve the haplotypes of A.annua.Approximately 5o,ooo genes were annotated for each haplotype genome,and a triplication event that occurred approximately 58.12million years ago was examined for the first time in this species.A total of 3,903,467-5,193,414 variants(SNPs,indels,and structural variants)were identified in the 1.5-Gb genome during pairwise comparison between haplotypes,consistent with the high heterozygosity of this species.Genomic analyses revealed a correlation between artemisinin concents and the copy number of amorpha-4,11-dienes ynthasegenes.This correlation was further confirmed by resequencing of 36A.annua samples with varied artemisinin contents.Circular consensus sequencing of transcripts facilitated the detection of paralog expression.Collectively,our study provides chromosome-level allele-aware genome assemblies for two A.annua strains and new insights into the biosynthesis of artemisinin and its regulation,which will contribute to conquering malaria worldwide.
基金TOA received funding from the UK Medical Research Council—Grant no.G0600718 through the Centre for Genomics and GlobalHealth(http://www.cggh.org)while sequencing was done at the Sanger Institue thanks to the Wellcome Trust Sanger Instutte grant n0.098051 to DK.
文摘Background:Drug resistance is one of the greatest challenges of malaria control programmes,with the monitoring of parasite resistance to artemisinins or to Artemisinin Combination Therapy(ACT)partner drugs critical to elimination efforts.Markers of resistance to a wide panel of antimalarials were assessed in natural parasite populations from southwestern Cameroon.Methods:Individuals with asymptomatic parasitaemia or uncomplicated malaria were enrolled through crosssectional surveys from May 2013 to March 2014 along the slope of mount Cameroon.Plasmodium falciparum malaria parasitaemic blood,screened by light microscopy,was depleted of leucocytes using CF11 cellulose columns and the parasite genotype ascertained by sequencing on the Illumina HiSeq platform.Results:A total of 259 participants were enrolled in this study from three different altitudes.While some alleles associated with drug resistance in pfdhfr,pfmdr1 and pfcrt were highly prevalent,less than 3%of all samples carried mutations in the pfkelch13 gene,none of which were amongst those associated with slow artemisinin parasite clearance rates in Southeast Asia.The most prevalent haplotypes were triple mutants PfdhfrI51R59N108I164(99%),pfcrt-C72V73I74E75T76(47.3%),and single mutants PfdhpsS_(436)G_(437)K_(540)A_(581)A_(613)(69%)and Pfmdr1 N_(86)F)(184)D_(1246)(53.2%).Conclusions:The predominance of the Pf pfcrt CVIET and Pf dhfr IRN triple mutant parasites and absence of pfkelch13 resistance alleles suggest that the amodiaquine and pyrimethamine components of AS-AQ and SP may no longer be effective in their role while chloroquine resistance still persists in southwestern Cameroon.
文摘Dear Editor Salvia miltiorrhiza Bunge （Danshen） is a medicinal plant of the Lamiaceae family, and its dried roots have long been used in traditional Chinese medicine with hydrophilic phenolic acids and tanshinones as pharmaceutically active components （Zhang et al., 2014; Xu et al., 2016）. The first step of tanshinone biosynthesis is bicyclization of the general diterpene precursor （E,E,E）-geranylgeranyl diphosphate （GGPP） to copalyl diphosphate （CPP） by CPP synthases （CPSs）, which is followed by a cyclization or rearrangement reaction catalyzed by kaurene synthase-like enzymes （KSL）. The resulting intermediate is usually an olefin, which requires the insertion of oxygen by cytochrome P450 mono-oxygenases （CYPs） for the final production of diterpenoids （Zi et al., 2014）. While the CPS, KSL, and several early acting CYPs （CYP76AH1, CYP76AH3, and CYP76AK1） for tanshinone biosynthesis have been identified in S. miltiorrhiza （Gao et al., 2009; Guo et al., 2013, 2016; Zi and Peters, 2013）, the majority of the overall biosynthetic pathway, as well as the relevant regulatory factors associated with tanshinone production, remains elusive （Figure 1B）.
文摘The human mutation rate—how often new changes appear in the DNA—is fundamental to understanding many aspects of medical genetics and human evolutionary genetics.But it is low,and has therefore been difficult to measure.In the past,scientists could only estimate it approximately, either by observing how often mutant phenotypes appeared,or by comparison of humans and closely related species,such as chimpanzee, where many mutations could accumulate but the time period was uncertain.Now,a new study supported by the NSFC in China and The Royal Society in the UK reports the first direct measurement of the human mutation rate at the individual letters(nucleotides or bases) of DNA.This was possible because new(next)-generation sequencing technology is much more powerful than the methods available previously.The work was published in the leading journal Current Biology on 15th September 2009.The results were reported in the news by Nature, Science and the BBC,as well as in more than 20 Chinese newspapers and radio stations after the work first appeared online on 27th August.It was also one of the research highlights in Nature on 3rd September,which commented'This direct measurement of the human mutation rate should help researchers to refine evolutionary dating and better understand the source of genetic disease'.From the work,researchers could estimate that everyone has around 200 new mutations in their genome;as the authors said,'we are all mutants'.The ability to reliably measure rates of DNA mutation means we can begin to ask how mutation rates vary between different regions of the genome and perhaps also between different individuals.
文摘Pluripotency is depicted by a self-renewing state that can competently differentiate to form the three germ layers.Different stages of early murine development can be captured on a petri dish,delineating a spectrum of pluripotent states,ranging from embryonic stem cells,embryonic germ cells to epiblast stem cells.Anomalous cell populations displaying signs of pluripotency have also been uncovered,from the isolation of embryonic carcinoma cells to the derivation of induced pluripotent stem cells.Gaining insight into the molecular circuitry within these cell types enlightens us about the significance and contribution of each stage,hence deepening our understanding of vertebrate development.In this review,we aim to describe experimental milestones that led to the understanding of embryonic development and the conception of pluripotency.We also discuss attempts at exploring the realm of pluripotency with the identification of pluripotent stem cells within mouse teratocarcinomas and embryos,and the generation of pluripotent cells through nuclear reprogramming.In conclusion,we illustrate pluripotent cells derived from other organisms,including human derivatives,and describe current paradigms in the comprehension of human pluripotency.
文摘Laboratory mice have widely been used as tools for basic biological research and models for studying human diseases.With the advances of genetic engineering and conditional knockout(CKO)mice,we now understand hematopoiesis is a dynamic stepwise process starting from hematopoietic stem cells(HSCs)which are responsible for replenishing all blood cells.Transcriptional factors play important role in hematopoiesis.In this review we compile several studies on using genetic modified mice and humanized mice to study function of transcriptional factors in lymphopoiesis,including T lymphocyte and Natural killer(NK)cell development.Finally,we focused on the key transcriptional factor Bcl11b and its function in regulating T cell specification and commitment.
文摘Nuclear reprogramming is described as a molecular switch,triggered by the conversion of one cell type to another.Several key experiments in the past century have provided insight into the field of nuclear repro-gramming.Previously deemed impossible,this re-search area is now brimming with new findings and developments.In this review,we aim to give a historical perspective on how the notion of nuclear reprogram-ming was established,describing main experiments that were performed,including(1)somatic cell nuclear transfer,(2)exposure to cell extracts and cell fusion,and(3)transcription factor induced lineage switch.Ultimately,we focus on(4)transcription factor induced pluripotency,as initiated by a landmark discovery in 2006,where the process of converting somatic cells to a pluripotent state was narrowed down to four tran-scription factors.The conception that somatic cells possess the capacity to revert to an immature status brings about huge clinical implications including per-sonalized therapy,drug screening and disease model-ing.Although this technology has potential to revolu-tionize the medical field,it is still impeded by technical and biological obstacles.This review describes the effervescent changes in this field,addresses bottle-necks hindering its advancement and in conclusion,applies the latest findings to overcome these issues.
基金supported by fundings from the People Program (Marie Curie Actions) of the European Union’s Seventh Framework Program FP7/2007-2013/under REA grant agreement (No. 290344)the “Ministerio de Ciencia e Innovación” (No. SAF2011-26983)+3 种基金the Plan Galego IDT (No. EM 2012/045)the Sistema Universitario Gallego e Modalidad REDES (No. 2012-PG226) from the Xunta de Galicia (to A.S.)the Grant Agency of the Czech Republic (No. 13-37998SP505)the grant from “Fundación Barrié” (to M.C.)
文摘Africa is the cradle of all human beings, and although it has been the focus of a number of genetic studies, there are many questions that remain unresolved. We have performed one of the largest and most comprehensive meta-analyses of mitochondrial DNA （mtDNA） lineages carried out in the African continent to date. We generated high-throughput mtDNA single nucleotide polymorphism （SNP） data （230 SNPs） from 2024 Africans, where more than 500 of them were additionally genotyped for the control region. These data were analyzed together with over 12,700 control region profiles collected from the literature, representing more than 300 population samples from Africa. Insights into the African homeland of humans are discussed. Phylogeographic patterns for the African continent are shown at a high phylogeographic resolution as well as at the population and regional levels. The deepest branch of the mtDNA tree, haplogroup L0, shows the highest sub-haplogroup diversity in Southeast and East Africa, suggesting this region as the homeland for modem humans. Several demographic estimates point to the coast as a facilitator of human migration in Africa, but the data indicate complex patterns, perhaps mirroring the effect of recent continental-scaled demographic events in re-shaping African mtDNA variability.
