Genetic and pathogenic characterization of new infectious bronchitis virus strains in the GVI-1 and GI-19 lineages isolated in central China

Avian infectious bronchitis(IB)is a highly contagious infectious disease caused by infectious bronchitis virus(IBV),which is prevalent in many countries worldwide and causes serious harm to the poultry industry.At present,many commercial IBV vaccines have been used for the prevention and control of IB;however,IB outbreaks occur frequently.In this study,two new strains of IBV,SX/2106 and SX/2204,were isolated from two flocks which were immunized with IBV H120 vaccine in central China.Phylogenetic and recombination analysis indicated that SX/2106,which was clustered into the GI-19 lineage,may be derived from recombination events of the GI-19 and GI-7 strains and the LDT3-A vaccine.Genetic analysis showed that SX/2204 belongs to the GVI-1 lineage,which may have originated from the recombination of the GI-13 and GVI-1 strains and the H120 vaccine.The virus cross-neutralization test showed that the antigenicity of SX/2106 and SX/2204 was different from H120.Animal experiments found that both SX/2106 and SX/2204 could replicate effectively in the lungs and kidneys of chickens and cause disease and death,and H120 immunization could not provide effective protection against the two IBV isolates.It is noteworthy that the pathogenicity of SX/2204 has significantly increased compared to the GVI-1 strains isolated previously,with a mortality rate up to 60%.Considering the continuous mutation and recombination of the IBV genome to produce new variant strains,it is important to continuously monitor epidemic strains and develop new vaccines for the prevention and control of IBV epidemics.

Whole Genome Sequencing and Comparisons of Different Chinese Rabies Virus Lineages Including the First Complete Genome of an Arctic-like Strain in China

Objective To learn the rabies genome molecular characteristics and compare the difference of China rabies lineages. Methods The complete genomes of 12 strains from different China rabies lineages were amplified and sequenced, and all the China street strain genomes （total 43）, Arctic and Arctic-like genomes were aligned using ClustalX2, the genome homologies were analyzed using MegAlign software, and the phylogenetic trees were constructed by MEGA 5. Results First Arctic-like rabies genome in China （CO, H1202D） was reported, and we supplemented the rabies genome data of China, ensuring at least one genome was available in each China lineage. The genome size of China V （11908nt） is obviously shorter than other lineages＇ （11923-11925nt） for the difference of N-P non-coding regions. Among different lineages, the genome homologies are almost under 90%. CQH1202D （China IV lineage） has close relationship with strains from South Korea and they share about 95% genome similarities. Conclusion The molecular characteristics of 6 different China rabies lineages were compared and analyzed from genome level, which benefits for continued comprehensive rabies surveillance, rabies prevention and control in China.

Immunological Responses against Different Lineages of Influenza B Antigen in School Children during Two Consecutive Seasons

While Influenza B viruses currently circulating worldwide are of two distinct evolutionary hemagglutinin lineages, current trivalent inactivated influenza virus vaccines (TIV) contain only a single component. Single doses of TIV containing B antigen of B/Florida/4/2006 (Yamagata-like) or B/Brisbane/60/2008 (Victoria-like) were administered during 2008/2009 and 2009/2010 influenza seasons, respectively. The objective of this study was to evaluate the immunological response against different lineages of B antigens in school-aged children. A non-randomized sero-epidemiological study was conducted and the immunogenicity responses based on sero-protection rate and geometric mean titre ratio (GMTR) of hemagglutination inhibition (HI) antibodies were measured before and after immunization as well as post-influenza season. Our results suggested that school-aged children under the age of 9 years receiving TIV vaccination induced and retained higher level of sero-protection rate (66.7% and 69% for the 2008-09 and 2009-10 season, respectively) to the homologous lineage than the heterologous lineage post-vaccination (19.4% and 27.6% for the 2008-09 and 2009-10 season, respectively). The need for the quadrivalent TIV by including both lineages of influenza B viruses is recommended in this study, particularly for children under the age of 9 years.

RNA barcode segments for SARS-CoV-2 identification from HCoVs and SARSr-CoV-2 lineages

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the pathogen responsible for coronavirus disease 2019(COVID-19),continues to evolve,giving rise to more variants and global reinfections.Previous research has demonstrated that barcode segments can effectively and cost-efficiently identify specific species within closely related populations.In this study,we designed and tested RNA barcode segments based on genetic evolutionary relationships to facilitate the efficient and accurate identification of SARS-CoV-2 from extensive virus samples,including human coronaviruses(HCoVs)and SARSr-CoV-2 lineages.Nucleotide sequences sourced from NCBI and GISAID were meticulously selected and curated to construct training sets,encompassing 1733 complete genome sequences of HCoVs and SARSr-CoV-2 lineages.Through genetic-level species testing,we validated the accuracy and reliability of the barcode segments for identifying SARS-CoV-2.Subsequently,75 main and subordinate species-specific barcode segments for SARS-CoV-2,located in ORF1ab,S,E,ORF7a,and N coding sequences,were intercepted and screened based on single-nucleotide polymorphism sites and weighted scores.Post-testing,these segments exhibited high recall rates(nearly 100%),specificity(almost 30%at the nucleotide level),and precision(100%)performance on identification.They were eventually visualized using one and two-dimensional combined barcodes and deposited in an online database(http://virusbarcodedatabase.top/).The successful integration of barcoding technology in SARS-CoV-2 identification provides valuable insights for future studies involving complete genome sequence polymorphism analysis.Moreover,this cost-effective and efficient identification approach also provides valuable reference for future research endeavors related to virus surveillance.

Cell reprogramming therapy for Parkinson’s disease

Parkinson’s disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta.Many studies have been performed based on the supplementation of lost dopaminergic neurons to treat Parkinson’s disease.The initial strategy for cell replacement therapy used human fetal ventral midbrain and human embryonic stem cells to treat Parkinson’s disease,which could substantially alleviate the symptoms of Parkinson’s disease in clinical practice.However,ethical issues and tumor formation were limitations of its clinical application.Induced pluripotent stem cells can be acquired without sacrificing human embryos,which eliminates the huge ethical barriers of human stem cell therapy.Another widely considered neuronal regeneration strategy is to directly reprogram fibroblasts and astrocytes into neurons,without the need for intermediate proliferation states,thus avoiding issues of immune rejection and tumor formation.Both induced pluripotent stem cells and direct reprogramming of lineage cells have shown promising results in the treatment of Parkinson’s disease.However,there are also ethical concerns and the risk of tumor formation that need to be addressed.This review highlights the current application status of cell reprogramming in the treatment of Parkinson’s disease,focusing on the use of induced pluripotent stem cells in cell replacement therapy,including preclinical animal models and progress in clinical research.The review also discusses the advancements in direct reprogramming of lineage cells in the treatment of Parkinson’s disease,as well as the controversy surrounding in vivo reprogramming.These findings suggest that cell reprogramming may hold great promise as a potential strategy for treating Parkinson’s disease.

Cryptic divergences and repeated hybridizations within the endangered “living fossil” dove tree(Davidia involucrata) revealed by whole genome resequencing

The identification and understanding of cryptic intraspecific evolutionary units(lineages) are crucial for planning effective conservation strategies aimed at preserving genetic diversity in endangered species.However, the factors driving the evolution and maintenance of these intraspecific lineages in most endangered species remain poorly understood. In this study, we conducted resequencing of 77 individuals from 22 natural populations of Davidia involucrata, a “living fossil” dove tree endemic to central and southwest China. Our analysis revealed the presence of three distinct local lineages within this endangered species, which emerged approximately 3.09 and 0.32 million years ago. These divergence events align well with the geographic and climatic oscillations that occurred across the distributional range.Additionally, we observed frequent hybridization events between the three lineages, resulting in the formation of hybrid populations in their adjacent as well as disjunct regions. These hybridizations likely arose from climate-driven population expansion and/or long-distance gene flow. Furthermore, we identified numerous environment-correlated gene variants across the total and many other genes that exhibited signals of positive evolution during the maintenance of two major local lineages. Our findings shed light on the highly dynamic evolution underlying the remarkably similar phenotype of this endangered species. Importantly, these results not only provide guidance for the development of conservation plans but also enhance our understanding of evolutionary past for this and other endangered species with similar histories.

Phylotranscriptomic discordance is best explained by incomplete lineage sorting within Allium subgenus Cyathophora and thus hemiplasy accounts for interspecific trait transition

The transition of traits between genetically related lineages is a fascinating topic that provides clues to understanding the drivers of speciation and diversification.Much can be learned about this process from phylogeny-based trait evolution.However,such inference is often plagued by genome-wide gene-tree discordance(GTD),mostly due to incomplete lineage sorting(ILS)and/or introgressive hybridization,especially when the genes underlying the traits appear discordant.Here,by collecting transcriptomes,whole chloroplast genomes(cpDNA),and population genetic datasets,we used the coalescent model to turn GTD into a source of information for ILS and employed hemiplasy to explain specific cases of apparent“phylogenetic discordance”between different morphological traits and probable species phylogeny in the Allium subg.Cyathophora.Both concatenation and coalescence methods consistently showed the same phylogenetic topology for species tree inference based on single-copy genes(SCGs),as supported by the KS distribution.However,GTD was high across the genomes of subg.Cyathophora:~27%e38.9%of the SCG trees were in conflict with the species tree.Plasmid and nuclear incongruence was also present.Our coalescent simulations indicated that such GTD was mainly a product of ILS.Our hemiplasy risk factor calculations supported that random fixation of ancient polymorphisms in different populations during successive speciation events along the subg.Cyathophora phylogeny may have caused the character transition,as well as the anomalous cpDNA tree.Our study exemplifies how phylogenetic noise can be transformed into evolutionary information for understanding character state transitions along species phylogenies.

Ethanol changes Nestin-promoter induced neural stem cells to disturb newborn dendritic spine remodeling in the hippocampus of mice

Adolescent binge drinking leads to long-lasting disorders of the adult central nervous system,particularly aberrant hippocampal neurogenesis.In this study,we applied in vivo fluorescent tracing using NestinCreERT2::Rosa26-tdTomato mice and analyzed the endogenous neurogenesis lineage progression of neural stem cells(NSCs)and dendritic spine formation of newborn neurons in the subgranular zone of the dentate gyrus.We found abnormal orientation of tamoxifen-induced tdTomato+(tdTom^(+))NSCs in adult mice 2 months after treatment with EtOH(5.0 g/kg,i.p.)for 7 consecutive days.EtOH markedly inhibited tdTom^(+)NSCs activation and hippocampal neurogenesis in mouse dentate gyrus from adolescence to adulthood.EtOH(100 mM)also significantly inhibited the proliferation to 39.2%and differentiation of primary NSCs in vitro.Adult mice exposed to EtOH also exhibited marked inhibitions in dendritic spine growth and newborn neuron maturation in the dentate gyrus,which was partially reversed by voluntary running or inhibition of the mammalian target of rapamycinenhancer of zeste homolog 2 pathway.In vivo tracing revealed that EtOH induced abnormal orientation of tdTom+NSCs and spatial misposition defects of newborn neurons,thus causing the disturbance of hippocampal neurogenesis and dendritic spine remodeling in mice.

Two-photon live imaging of direct glia-to-neuron conversion in the mouse cortex

Over the past decade,a growing number of studies have reported transcription factor-based in situ reprogramming that can directly conve rt endogenous glial cells into functional neurons as an alternative approach for n euro regeneration in the adult mammalian central ne rvous system.Howeve r,many questions remain regarding how a terminally differentiated glial cell can transform into a delicate neuron that forms part of the intricate brain circuitry.In addition,concerns have recently been raised around the absence of astrocyte-to-neuron conversion in astrocytic lineage-tra cing mice.In this study,we employed repetitive two-photon imaging to continuously capture the in situ astrocyte-to-neuron conversion process following ecto pic expression of the neural transcription factor NeuroD1 in both prolife rating reactive astrocytes and lineage-tra ced astrocytes in the mouse cortex.Time-lapse imaging over several wee ks revealed the ste p-by-step transition from a typical astrocyte with numero us short,tapered branches to a typical neuro n with a few long neurites and dynamic growth cones that actively explored the local environment.In addition,these lineage-converting cells were able to migrate ra dially or to ngentially to relocate to suitable positions.Furthermore,two-photon Ca2+imaging and patch-clamp recordings confirmed that the newly generated neuro ns exhibited synchronous calcium signals,repetitive action potentials,and spontaneous synaptic responses,suggesting that they had made functional synaptic connections within local neural circuits.In conclusion,we directly visualized the step-by-step lineage conversion process from astrocytes to functional neurons in vivo and unambiguously demonstrated that adult mammalian brains are highly plastic with respect to their potential for neuro regeneration and neural circuit reconstruction.

Identification and virulence test of a new pathogen that causes verticillium striping on rapeseed in northwestern China

Five stems of rapeseed with abundant black microsclerotia were collected from Huangyuan County of Qinghai Province,China,and fungal isolates were obtained from the stems.They were identified based on morphology,molecular features and specific PCR detection.The results showed that the 10 fungal isolates belonged to Verticillium longisporum lineage A1/D3.One of the 10 isolates(HW7-1)was tested for virulence on three species of rapeseed,including B.napus Zhongshuang 9,B.rapa Qingyou 9 and B.juncea Tayou 2 by conidia inoculation of HW7-1 on roots of young seedlings.Control seedlings were inoculated with V.dahliae conidia or water alone.The seedlings of these treatments were transplanted in culture mix and incubated in a growth chamber(20℃).Results suggested that the control seedlings of three cultivars appeared quite healthy,while the seedlings inoculated with HW7-1 turned yellowing leaves,seedling stunting or even death after 22 days post-inoculation.V.longisporum was re-isolated from he yellow leaves,thus fulfilling Koch's postulates.Moreover,compared to the control treatments,inoculation with HW7-1 caused flowering delay and seed yield reduction on Tayou 2 with production of microsclerotia on the stems.To our knowledge,this is the first report of V.longisporum lineage A1/D3 on rapeseed in northwestern China.

The Limbal Niche and Its Role in Maintaining Corneal Regeneration

In recent years, stem cells have been a focal point in research designed to evaluate the efficacy of ophthalmologic therapies, specifically those for corneal conditions. The corneal epithelium is one of the few regions of the body that maintains itself using a residual stem cell population within the adjacent limbus. Stem cell movement has additionally captivated the minds of researchers due to its potential application in different body regions. The cornea is a viable model for varying methods to track stem cell migratory patterns, such as lineage tracing and live imaging from the limbus. These developments have the potential to pave the way for future therapies designed to ensure the continuous regeneration of the corneal epithelium following injury via the limbal stem cell niche. This literature review aims to analyze the various methods of imaging used to understand the limbal stem cell niche and possible future directions that might be useful to consider for the better treatment and prevention of disorders of the cornea and corneal epithelium. .

Direct conversion of mouse astrocytes into neural progenitor cells and specific lineages of neurons

Background:Cell replacement therapy has been envisioned as a promising treatment for neurodegenerative diseases.Due to the ethical concerns of ESCs-derived neural progenitor cells(NPCs)and tumorigenic potential of iPSCs,reprogramming of somatic cells directly into multipotent NPCs has emerged as a preferred approach for cell transplantation.Methods:Mouse astrocytes were reprogrammed into NPCs by the overexpression of transcription factors(TFs)Foxg1,Sox2,and Brn2.The generation of subtypes of neurons was directed by the force expression of cell-type specific TFs Lhx8 or Foxa2/Lmx1a.Results:Astrocyte-derived induced NPCs(AiNPCs)share high similarities,including the expression of NPC-specific genes,DNA methylation patterns,the ability to proliferate and differentiate,with the wild type NPCs.The AiNPCs are committed to the forebrain identity and predominantly differentiated into glutamatergic and GABAergic neuronal subtypes.Interestingly,additional overexpression of TFs Lhx8 and Foxa2/Lmx1a in AiNPCs promoted cholinergic and dopaminergic neuronal differentiation,respectively.Conclusions:Our studies suggest that astrocytes can be converted into AiNPCs and lineage-committed AiNPCs can acquire differentiation potential of other lineages through forced expression of specific TFs.Understanding the impact of the TF sets on the reprogramming and differentiation into specific lineages of neurons will provide valuable strategies for astrocyte-based cell therapy in neurodegenerative diseases.

PANoptosis-like cell death in ischemia/reperfusion injury of retinal neurons

PANoptosis is a newly identified type of regulated cell death that consists of pyroptosis,apoptosis,and nec roptosis,which simultaneously occur during the pathophysiological process of infectious and inflammatory diseases.Although our previous lite rature mining study suggested that PANoptosis might occur in neuronal ischemia/repe rfusion injury,little experimental research has been reported on the existence of PANoptosis.In this study,we used in vivo and in vitro retinal neuronal models of ischemia/repe rfusion injury to investigate whether PAN optosis-like cell death(simultaneous occurrence of pyroptosis,apo ptosis,and necroptosis)exists in retinal neuronal ischemia/repe rfusion injury.Our results showed that ischemia/repe rfusion injury induced changes in morphological features and protein levels that indicate PANoptosis-like cell death in retinal neurons both in vitro and in vivo.Ischemia/repe rfusion inju ry also significantly upregulated caspase-1,caspase-8,and NLRP3 expression,which are important components of the PANoptosome.These results indicate the existence of PANoptosis-like cell death in ischemia/reperfusion injury of retinal neurons and provide preliminary experimental evidence for future study of this new type of regulated cell death.

Evolutionary relationships of mitogenomes in a recently radiated Old World avian family

Environmentally heterogeneous mountains provide opportunities for rapid diversification and speciation.The family Prunellidae(accentors)is a group of birds comprising primarily mountain specialists that have recently radiated across the Palearctic region.This rapid diversification poses challenges to resolving their phylogeny.Herein we sequenced the complete mitogenomes and estimated the phylogeny using all 12(including 28 individuals)currently recognized species of Prunellidae.We reconstructed the mitochondrial genome phylogeny using 13 protein-coding genes of 12 species and 2 Eurasian Tree Sparrows(Passer montanus).Phylogenetic relationships were estimated using a suite of analyses:maximum likelihood,maximum parsimony and the coalescent-based SVDquartets.Divergence times were estimated by implementing a Bayesian relaxed clock model in BEAST2.Based on the BEAST time-calibrated tree,we implemented an ancestral area reconstruction using RASP v.4.3.Our phylogenies based on the maximum likelihood,maximum parsimony and SVDquartets approaches support a clade of large-sized accentors(subgenus Laiscopus)to be sister to all other accentors with small size(subgenus Prunella).In addition,the trees also support the sister relationship of P.immaculata and P.rubeculoides+P.atrogularis with 100%bootstrap support,but the relationships among the remaining eight species in the Prunella clade are poorly resolved.These species cluster in different positions in the three phylogenetic trees and the nodes are often poorly supported.The five nodes separating the seven species diverged simultaneously within less than half million years(i.e.,between 2.71 and 3.15 million years ago),suggesting that the recent radiation is likely responsible for rampant incomplete lineage sorting and gene tree conflicts.Ancestral area reconstruction indicates a central Palearctic region origin for Prunellidae.Our study highlights that whole mitochondrial genome phylogeny can resolve major lineages within Prunellidae but is not sufficient to fully resolve the relationship among the species in the Prunella clade that almost simultaneously diversify during a short time period.Our results emphasize the challenge to reconstruct reliable phylogenetic relationship in a group of recently radiated species.

Myeloid sarcoma as the only manifestation in a rare mixed lineage leukemia-fusion-driven acute myeloid leukemia:A case report

BACKGROUND The mixed lineage leukemia(MLL)-eleven-nineteen lysine-rich leukemia(ELL)fusion gene is a rare occurrence among the various MLL fusion genes.We present the first case in which myeloid sarcoma(MS)was the only manifestation of adult MLL-ELL-positive acute myeloid leukemia(AML).CASE SUMMARY We report a case of a 33-year-old male patient who was admitted in June 2022 with a right occipital area mass measuring approximately 7 cm×8 cm.Blood work was normal.The patient underwent right occipital giant subscalp mass excision and incisional flap grafting.Immunohistochemistry was positive for myeloperoxidase,CD43 and CD45 and negative for CD3,CD20,CD34,and CD56.The bone marrow aspirate showed hypercellularity with 20%myeloblasts.Flow cytometry showed that myeloblasts accounted for 27.21%of the nucleated cells,which expressed CD33,CD38,and CD117.The karyotype was 46,XY,t(11,19)(q23;p13.1),-12,+mar/46,XY.Next-generation sequencing showed a fusion of MLL exon 7 to exon 2 of ELL.A diagnosis of MLL-ELL-positive AML(M2 subtype)with subcutaneous MS was made.CONCLUSION MLL-ELL-positive AML with MS is a rare clinical entity.Additional research is needed to elucidate the molecular mechanisms of the pathogenesis of MS.

Genomic Epidemiology of ST34 Monophasic Salmonella enterica Serovar Typhimurium from Clinical Patients from 2008 to 2017 in Henan,China

Salmonella enterica serovar 4,[5],12:i:-(S.4,[5],12:i:-)is a monophasic variant of Salmonella enterica serovar Typhimurium that has emerged as a global serovar causing public health concern.To date,the epidemiology and genomic characterization of this pathogen in China have not been well described.We investigated the prevalence,antimicrobial resistance(AMR)phenotypes,and population genomics of sequence type 34(ST34)S.4,[5],12:i:-among cases of human salmonellosis in Henan Province,China.A total of 100 ST34 S.4,[5],12:i:-isolates were studied from 2008 to 2017 and found mostly resistant to ampicillin(AMP),streptomycin(STR),sulfonamides(SUL),and tetracycline(TET)(ASSu T).Bayesian phylogenetic analysis demonstrated that isolates identified in China were mostly related to the European lineage and evolved into two major clades with different resistance genes and plasmid profiles.Notably,clade 1 showed a significantly higher rate of mutations in gyr A and plasmid-mediated quinolone resistance genes.The carrying of the resistance-containing region(encoding R-type ASSu T),including bla(conferring resistance to AMP),str AB(STR),sul2(SUL),and tet(B)(TET)inserted into the flj BA operon,was responsible for most of the monophasic variants in clade 2.Inc HI2 plasmids were the dominant multi-drug resistance mobile genetic elements accounting for the transmission of acquired resistance genes in this serovar,and these were more prevalent in clade 1.Our findings highlighted the increasing prevalence of multi-drug resistant S.4,[5],12:i:-in China,along with the differential characteristics of resistance gene acquisition among various lineages.Based on our data,control measures are required to address the spread of this zoonotic pathogen.Further owing to its potential origin in food-producing animals,a"One Health"approach,should be implemented to support surveillance whilst informing interventional strategies.

美国PRRSV 1-4-4 Lineage 1C新型变异株的基因组特征和传入我国的风险分析

猪繁殖与呼吸综合征(Porcine Reproductive and Respiratory Syndrome,PRRS)是严重危害生猪产业的疾病之一,呈全球性流行,其病原猪繁殖与呼吸综合征病毒(Porcine Reproductive and Respiratory Syndrome Virus,PRRSV)具有毒株多样、易变异重组且异源毒株交叉保护不足的特点。2020年10月以来,在美国中西部地区发现一种新型PRRSV 1-4-4 Lineage 1C变异株,其较以往美国流行毒株致病性更强,感染可引起成年母猪死亡,传播更迅速,且现有疫苗对其保护效果不佳。鉴于中美间有大量种猪和猪肉制品贸易,且美国PRRSV毒株曾多次传入我国,该变异株的流行情况、基因组特征、致病性、传入风险以及现有检测方法和防控技术对其有效性等均成为业界关注重点。本文对新型PRRSV 1-4-4 Lineage 1C变异株在美国暴发和流行的情况、分子特征及传入我国的风险进行了总结分析,旨在提高对新型变异株的认识,加强防控技术储备,以保障我国养猪业安全稳定发展。

Treating inflammatory bowel disease by adsorptive leucocytapheresis:A desire to treat without drugs

Ulcerative colitis and Crohn’s disease are the major phenotypes of the idiopathic inflammatory bowel disease(IBD),which afflicts millions of individuals throughout the world with debilitating symptoms,impairing function and quality of life.Current medications are aimed at reducing the symptoms or suppressing exacerbations.However,patients require life-long medications,and this can lead to drug dependency,loss of response together with adverse side effects.Indeed,drug side effects become additional morbidity factor in many patients on long-term medications.Nonetheless,the efficacy of anti-tumour necrosis factors(TNF)-αbiologics has validated the role of inflammatory cytokines notably TNF-αin the exacerbation of IBD.However,inflammatory cytokines are released by patients’own cellular elements including myeloid lineage leucocytes,which in patients with IBD are elevated with activation behaviour and prolonged survival.Accordingly,these leucocytes appear logical targets of therapy and can be depleted by adsorptive granulocyte/monocyte apheresis(GMA)with an Adacolumn.Based on this background,recently GMA has been applied to treat patients with IBD in Japan and in the European Union countries.Efficacy rates have been impressive as well as disappointing.In fact the clinical response to GMA seems to define the patients’disease course,response to medications,duration of active disease,and severity at entry.The best responders have been first episode cases(up to 100%)followed by steroid nave and patients with a short duration of active disease prior to GMA.Patients with deep ulcers together with extensive loss of the mucosal tissue and cases with a long duration of IBD refractory to existing medications are not likely to benefit from GMA.It is clinically interesting that patients who respond to GMA have a good long-term disease course by avoiding drugs including corticosteroids in the early stage of their IBD.Additionally,GMA is very much favoured by patients for its good safety profile.GMA in 21st century reminds us of phlebotomy as a major medical practice at the time of Hippocrates.However,in patients with IBD,there is a scope for removing from the body the sources of proinflammatory cytokines and achieve disease remission.The bottom line is that by introducing GMA at an early stage following the onset of IBD or before patients develop extensive mucosal damage and become refractory to medications,many patients should respond to GMA and avoid pharmacologics.This should fulfill the desire to treat without drugs.

Lineage tracing of direct astrocyte-to-neuron conversion in the mouse cortex

Regenerating functional new neurons in the adult mammalian central nervous system has been proven to be very challenging due to the inability of neurons to divide and repopulate themselves after neuronal loss.Glial cells,on the other hand,can divide and repopulate themselves under injury or diseased conditions.We have previously reported that ectopic expression of NeuroD1 in dividing glial cells can directly convert them into neurons.Here,using astrocytic lineage-tracing reporter mice(Aldh1l1-CreERT2 mice crossing with Ai14 mice),we demonstrate that lineage-traced astrocytes can be successfully converted into NeuNpositive neurons after expressing NeuroD1 through adeno-associated viruses.Retroviral expression of NeuroD1 further confirms that dividing glial cells can be converted into neurons.Importantly,we demonstrate that for in vivo cell conversion study,using a safe level of adeno-associated virus dosage(10^10–10^12 gc/mL,1μL)in the rodent brain is critical to avoid artifacts caused by toxic dosage,such as that used in a recent bioRxiv study(2×10^13 gc/mL,1μL,mouse cortex).For therapeutic purpose under injury or diseased conditions,or for non-human primate studies,adeno-associated virus dosage needs to be optimized through a series of dose-finding experiments.Moreover,for future in vivo gliato-neuron conversion studies,we recommend that the adeno-associated virus results are further verified with retroviruses that mainly express transgenes in dividing glial cells in order to draw solid conclusions.The study was approved by the Laboratory Animal Ethics Committee of Jinan University,China(approval No.IACUC-20180330-06)on March 30,2018.