Environmental hypoxia induces apoptosis in large yellow croaker Larimichthys crocea via both intrinsic and extrinsic pathways

Hypoxia has become an unfavorable factor affecting the sustainable development of the large yellow croaker Larimichthys crocea,an economically important mariculture fish in China.Apoptosis is a consequence of hypoxia on fish.However,the effects of hypoxia stress on apoptosis in L.crocea remain largely unknown.We investigated the effect of environmental hypoxia on apoptosis in L.crocea.Results show that hypoxia induced apoptosis in L.crocea both in vivo and in vitro.The mitochondrial membrane potential was significantly reduced in large yellow croaker fry(LYCF)cells.The expression levels of Bcell lymphoma/leukemia-2(Bcl-2)m RNA and protein were also significantly decreased in the liver and LYCF cells during 96 h and 48 h of hypoxia stress,respectively,whereas the expression level of Bcl-2 associated X(Bax)mRNA,Casp3 mRNA,and activity of caspase-3/7/9 were significantly increased,indicating that hypoxia induced caspase-dependent intrinsic apoptosis in L.crocea.The expression level of the apoptosis-inducing factor(AIF)protein was significantly increased in the liver and LYCF cells.The level of AIF protein was significantly decreased in the cytoplasm but increased in the nuclei of L.crocea,demonstrating that hypoxia induced the AIF-mediated caspase-independent intrinsic apoptosis.In addition,the activity of caspase-8 was significantly increased,indicating that hypoxia stress induced extrinsic apoptosis in L.crocea.Therefore,hypoxia induced apoptosis in L.crocea through both the intrinsic and extrinsic pathways.The present study accumulated basic biological information to help elucidate the mechanism of hypoxia response in marine fish.

Population structure and genome‑wide evolutionary signatures reveal putative climate‑driven habitat change and local adaptation in the large yellow croaker

The large yellow croaker(Larimichthys crocea)is one of the most economically valuable marine fsh in China and is a notable species in ecological studies owing to a serious collapse of wild germplasm in the past few decades.The stock division and species distribution,which have important implications for ecological protection,germplasm recovery,and fshery resource management,have been debated since the 1960s.However,it is still uncertain even how many stocks exist in this species.To address this,we evaluated the fne-scale genetic structure of large yellow croaker populations distributed along the eastern and southern Chinese coastline based on 7.64 million SNP markers.Compared with the widely accepted stock boundaries proposed in the 1960s,our results revealed that a climate-driven habitat change probably occurred between the Naozhou(Nanhai)Stock and the Ming-Yuedong(Mindong)Stock.The boundary between these two stocks might have shifted northwards from the Pearl River Estuary to the northern area of the Taiwan Strait,accompanied by highly asymmetric introgression.In addition,we found divergent landscapes of natural selection between the stocks inhabiting northern and southern areas.The northern population exhibited highly agminated signatures of strong natural selection in genes related to developmental processes,whereas moderate and interspersed selective signatures were detected in many immune-related genes in the southern populations.These fndings establish the stock status and genome-wide evolutionary landscapes of large yellow croaker,providing a basis for conservation,fsheries management and further evolutionary biology studies.

Darbepoetin alfa injection versus epoetin alfa injection for treating anemia of Chinese hemodialysis patients with chronic kidney failure:A randomized,open-label,parallel-group,non-inferiority Phase III trail

Background:Erythropoietin is a glycoprotein that mainly regulates erythropoiesis.In patients with chronic renal failure with anemia,darbepoetin alfa can stimulate erythropoiesis,correct anemia,and maintain hemoglobin levels.This study was designed to demonstrate the efficacy and safety of darbepoetin alfa injections as being not inferior to epoetin alfa injections(Recombinant Human Erythropoietin injection,rHuEPO)when maintaining hemoglobin(Hb)levels within the target range(10.0-12.0 g/dL)for the treatment of renal anemia.Methods:Ninety-five patients were enrolled in this study from April 15,2013 to April 10,2014 at 25 sites.In this study,patients(n=95)aged 18-70 years were randomized into a once per week intravenous darbepoetin alfa group(n=56)and a twice or three times per week intravenous epoetin alfa group(n=39)for 28 weeks,who had anemia with hemoglobin levels between 6 g/dL and 10 g/dL due to chronic kidney disease(CKD)and were undergoing hemodialysis or hemofiltration with ESA-naive(erythropoiesis stimulating agent-naive).The primary efficacy profile was the mean Hb level(the non-inferiority margin was-1.0 g/dL,week 21-28);the secondary efficacy profiles were the Hb increase rate(week 0-4),the target Hb achievement cumulative rate and time,the change trends of the Hb levels,and the target Hb maintenance ratio.Adverse events(AEs)were observed and compared,and the efficacy and safety were analyzed between the two treatment groups.Additionally,the frequencies of dose adjustments between the darbepoetin alfa and epoetin alfa groups were compared during the treatment period.SAS?software version 9.2 was used to perform all statistical analyses.Descriptive statistics were used for all efficacy,safety,and demographic variable analyses,including for the primary efficacy indicators.Results:The mean Hb level was 11.3 g/dL in the darbepoetin alfa group and 10.7 g/dL in the epoetin alfa group,respectively;the difference of the lower limits of the 95%confidence intervals(CI)between the two groups was 0.1 g/dL(>-1.0 g/dL),and non-inferiority was proven;the Hb levels started to increase in the first four weeks at a similar increase rate;no obvious differences were observed between the groups in the target Hb achievement cumulative rates,and the Hb levels as well as the target Hb level maintenance rate changed over time.The incidence of AEs was 62.5%in the darbepoetin alfa group and 76.9%in the epoetin alfa group.All the adverse events observed in the study were those commonly associated with hemodialysis.Conclusion:Darbepoetin alfa intravenously once per week can effectively increase Hb levels and maintain the target Hb levels well,which makes it not inferior to epoetin alfa intravenously twice or three times per week.Darbepoetin alfa shows an efficacy and safety comparable to epoetin alfa for the treatment of renal anemia.

Efficacy and safety of darbepoetin alfa injection replacing epoetin alfa injection for the treatment of renal anemia in Chinese hemodialysis patients:A randomized,open-label,parallel-group,noninferiority phase III trial

Background:This study was to explore the clinical efficacy and safety of darbepoetin alfa injection replacing epoetin alfa injection(recombinant human erythropoietin injection,rHuEPO)for the treatment of anemia associated with chronic kidney failure in Chinese patients undergoing hemodialysis.Method:This study was a multicenter,randomized,open-label,intergroup parallel control phase III noninferiority trial from April 19,2013 to September 9,2014 at 25 sites.In this study,the members of the darbepoetin alfa group underwent intravenous administration once per week or once every two weeks.The members of the control drug epoetin alfa group underwent intravenous administration two or three times per week.All subjects underwent epoetin alfa administration during the 8-week baseline period.After that,subjects were randomly assigned to the darbepoetin alfa group or epoetin alfa group.The noninferiority in the changes of the average Hb concentrations from the baseline to the end of the evaluation period(noninferiority threshold:-1.0 g/dl)was tested between the two treatments.The time-dependent hemoglobin(Hb)concentration and the maintenance rate of the target Hb concentration(the proportion of subjects with Hb concentrations between 10.0 and 12.0 g/dl)were also evaluated.Iron metabolism,including changes in the serum iron,total iron-binding capacity,ferritin,transferrin saturation,and comparisons of the dose adjustments between the two groups during the treatment period were analyzed further.Adverse events(AEs)were also observed and compared,and the safety was analyzed between the two treatment groups.The conversion rate switching from epoetin alfa to darbepoetin alfa was also discussed.SAS?software version 9.2 was used to perform all statistical analyses.Descriptive statistics were used for all efficacy,safety,and demographic variable analyses,including for the primary efficacy indicators.Results:Four hundred and sixty-six patients were enrolled in this study,and ultimately 384 cases were analyzed for safety,including 267 cases in the darbepoetin alfa group and 117 cases in the epoetin alfa group.There were 211 cases in the per-protocol set,including 152 cases in the darbepoetin alfa group and 59 cases in the epoetin alfa group.The changes in the average Hb concentrations from the baseline to the end of the evaluation period were-0.07 and-0.15 g/dl in the darbepoetin alfa group and epoetin alfa group respectively.The difference between the two groups was 0.08 g/dl(95%confidence interval[CI]:-0.22 to 0.39),and the lower limit of the 95%CI was-0.22>-1.0 g/dl.The average Hb concentrations of the two groups were 10.88-11.43 g/dl(darbepoetin alfa)and 10.91-11.38 g/dl(epoetin alfa)during the study period of Weeks 0-28,with the maintenance rates of the target Hb concentration ranging within 71%-87%and 78%-95%in the darbepoetin alfa group and epoetin alfa group respectively.During the period of comparison between the two groups,the incidence of AEs in the darbepoetin alfa group was 61.42%,while in the epoetin alfa group it was 56.41%.All of the adverse events and reactions in the study were those commonly associated with hemodialysis.Conclusion:The overall efficacy and safety of darbepoetin alfa for the treatment of Chinese renal anemia patients undergoing hemodialysis are consistent with those of epoetin alfa.

COVID-19 in the immunocompromised population:data from renal allograft recipients throughout full cycle of the outbreak in Hubei province,China

Coronavirus disease 2019(COVID-19)is an infectious disease caused by a newly discovered coronavirus and has rapidly spread to most of the world and resulted in a global pandemic.However,there is a paucity of information available to characterize the immunodeficient population in the COVID-19 pandemic,especially information that focuses on patients after renal transplantation as the typical representative of this population.