Avian metapneumovirus(aMPV) is a highly contagious pathogen that causes acute upper respiratory tract diseases in chickens and turkeys, resulting in serious economic losses. Subtype B aMPV has recently become the domi...Avian metapneumovirus(aMPV) is a highly contagious pathogen that causes acute upper respiratory tract diseases in chickens and turkeys, resulting in serious economic losses. Subtype B aMPV has recently become the dominant epidemic strain in China. We developed an attenuated aMPV subtype B strain by serial passaging in Vero cells and evaluated its safety and efficacy as a vaccine candidate. The safety test showed that after the 30th passage, the LN16-A strain was fully attenuated, as clinical signs of infection and histological lesions were absent after inoculation.The LN16-A strain did not revert to a virulent strain after five serial passages in chickens. The genomic sequence of LN16-A differed from that of the parent wild-type LN16(wtLN16) strain and had nine amino acid mutations. In chickens, a single immunization with LN16-A induced robust humoral and cellular immune responses, including the abundant production of neutralizing antibodies, CD4^(+) T lymphocytes, and the Th1(IFN-γ) and Th2(IL-4 and IL-6)cytokines. We also confirmed that LN16-A provided 100% protection against subtype B aMPV and significantly reduced viral shedding and turbinate inflammation. Our findings suggest that the LN16-A strain is a promising live attenuated vaccine candidate that can prevent infection with subtype B aMPV.展开更多
Recent research on the underlying mechanisms of cerebral ischemia indicates that the neurovascular unit can be used as a novel subject for general surveys of neuronal damage and protein mechanisms.Fingolimod(FTY-720)i...Recent research on the underlying mechanisms of cerebral ischemia indicates that the neurovascular unit can be used as a novel subject for general surveys of neuronal damage and protein mechanisms.Fingolimod(FTY-720)is a newly developed immunosuppressant isolated from Cordyceps sinensis that exhibits a wide range of biological activities,and has recently attracted much attention for the treatment of ischemic cerebrovascular diseases.In the current research,the role of FTY-720 and its possible mechanisms were assessed from an neurovascular unit perspective using a rat cerebral ischemia model.Our results revealed that FTY-720 markedly decreased infarct volume,promoted neurological function recovery,and weakened the blood-brain barrier permeability of ischemic rats.The protective roles of FTY-720 in ischemic stroke are ascribed to a combination of sphingosin-1-phosphate receptor-1 and reduced expression of sphingosin-1-phosphate receptor-1 in microvessels and reduction of interleukin-17A protein levels.These findings indicate that FTY-720 has promise as a new therapy for neurovascular protection and functional recovery after ischemic stroke.展开更多
Matrix vesicles(MVs)have shown strong effects in diseases such as vascular ectopic calcification and pathological calcified osteoarthritis and in wound repair of the skeletal system due to their membranous vesicle cha...Matrix vesicles(MVs)have shown strong effects in diseases such as vascular ectopic calcification and pathological calcified osteoarthritis and in wound repair of the skeletal system due to their membranous vesicle characteristics and abundant calcium and phosphorus content.However,the role of MVs in the progression of osteoporosis is poorly understood.Here,we report that annexin A5,an important component of the matrix vesicle membrane,plays a vital role in bone matrix homeostasis in the deterioration of osteoporosis.We first identified annexin A5 from adherent MVs but not dissociative MVs of osteoblasts and found that it could be sharply decreased in the bone matrix during the occurrence of osteoporosis based on ovariectomized mice.We then confirmed its potential in mediating the mineralization of the precursor osteoblast lineage via its initial binding with collagen type I to achieve MV adhesion and the subsequent activation of cellular autophagy.Finally,we proved its protective role in resisting bone loss by applying it to osteoporotic mice.Taken together,these data revealed the importance of annexin A5,originating from adherent MVs of osteoblasts,in bone matrix remodeling of osteoporosis and provided a new strategy for the treatment and intervention of bone loss.展开更多
In recent decades,the potential health hazards of microwave exposure have been attracting increasing attention.Our previous studies have demonstrated that microwave exposure impaired learning and memory in experimenta...In recent decades,the potential health hazards of microwave exposure have been attracting increasing attention.Our previous studies have demonstrated that microwave exposure impaired learning and memory in experimental animal models[1,2].展开更多
Objectives Endothelial senescence has been proposed to be involved in endothelial dysfunction and atherogenesis. This study investigates the effects of ginsenoside Rbl, a major constituent of ginseng,on H<sub>2&...Objectives Endothelial senescence has been proposed to be involved in endothelial dysfunction and atherogenesis. This study investigates the effects of ginsenoside Rbl, a major constituent of ginseng,on H<sub>2</sub>O<sub>2</sub>-induced endothelial senescence.Methods Primary human umbilical vein endothelial cells（HUVECs） senescence was induced by H<sub>2</sub>O<sub>2</sub> as judged by senescence-associated P-galactosidase assay （SA-P-gal）.Fntracellur superoxide dismutase（S0D1） activity and malondialdehyde（MDA） level were determined by commercial kit.S0D1 mRNA and protein expression were analyzed by real time PCR and Western blot.Reactive oxygen species（ROS） were determined by flow cytometry.Results Rb1 was found to reverse endothelial senescence,as witnessed by a significant decrease of senescent cell numbers. Rbl could markedly increase intracellular SOD activity, decrease the MDA level,and suppress the generation of intracellular ROS in H<sub>2</sub>O<sub>2</sub>-treated HUVECs.Consistent with these findings,Rbl can effectively restore SOD1 mRNA and protein expression which decreased in H<sub>2</sub>O<sub>2</sub> treated cells. Conclusions Our report demonstrates thatRbl can exert reversal effects on H<sub>2</sub>O<sub>2</sub>-induced cellular senescence through modulating cellular redox status.展开更多
AIM To investigate the pathogenic effect ofSEB and D-GalN on liver and the protection ofcyclosporin A, the relationship between hepaticapoptosis and necrosis and the possiblemechanism of acute hepatic necrosis.METHODS...AIM To investigate the pathogenic effect ofSEB and D-GalN on liver and the protection ofcyclosporin A, the relationship between hepaticapoptosis and necrosis and the possiblemechanism of acute hepatic necrosis.METHODS After staphylococcal enterotoxin B(SEB ) mixed with D--galactosamine (D-GaiN )were injected intraperitoneally into Balb/c miceand those previously treated with cyclosporin A,blood samples were collected and livers wereisolated at 2, 6, 12 and 24 h. Patterns othepatocellular death were studiedmorphologically and biochemically, circulatingcytokines (TNF-a, IFN--y ) and mice mortalitywithin 24h was assessed.RESU’LTS The SEB could induce the typicalapoptotic changes of hepatocytes, the D-GaiNcould induce hepatocytes apoptosis anddegeneration at the same time, and the micehaving received the SEB + D-GaiN injectionsdeveloped apoptosis at 2 and 6 h, but after 12 hhepatocytes were characterized by severein jury, whereas all the examinations in thecyclosporin A treated mice were normal.CONCLUSION Hepatic cell apoptosis might berelated to necrosis, and massive hepatocyteapoptosis is likely the initiating step of acutehepatic necrosis in mice. The effects induced bySEB and D--GaiN on hepatocytes might bemediated by T cells, and could be prevented bycyclosporin A.展开更多
Osteoarthritis(OA)is a prevalent joint disease with no effective treatment strategies.Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis.Although multiple studies have detected ...Osteoarthritis(OA)is a prevalent joint disease with no effective treatment strategies.Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis.Although multiple studies have detected potential regulatory mechanisms underlying OA and have concentrated on developing novel treatment strategies,the epigenetic control of OA remains unclear.Histone demethylase JMJD3 has been reported to mediate multiple physiological and pathological processes,including cell differentiation,proliferation,autophagy,and apoptosis.However,the regulation of JMJD3 in aberrant force-related OA and its mediatory effect on disease progression are still unknown.In this work,we confirmed the upregulation of JMJD3 in aberrant forceinduced cartilage injury in vitro and in vivo.Functionally,inhibition of JMJD3 by its inhibitor,GSK-J4,or downregulation of JMJD3 by adenovirus infection of sh-JMJD3 could alleviate the aberrant force-induced chondrocyte injury.Mechanistic investigation illustrated that aberrant force induces JMJD3 expression and then demethylates H3K27me3 at the NR4A1 promoter to promote its expression.Further experiments indicated that NR4A1 can regulate chondrocyte apoptosis,cartilage degeneration,extracellular matrix degradation,and inflammatory responses.In vivo,anterior cruciate ligament transection(ACLT)was performed to construct an OA model,and the therapeutic effect of GSK-J4 was validated.More importantly,we adopted a peptide-si RNA nanoplatform to deliver si-JMJD3 into articular cartilage,and the severity of joint degeneration was remarkably mitigated.Taken together,our findings demonstrated that JMJD3 is flow-responsive and epigenetically regulates OA progression.Our work provides evidences for JMJD3 inhibition as an innovative epigenetic therapy approach for joint diseases by utilizing p5RHH-si RNA nanocomplexes.展开更多
Epidermal growth factor receptor(EGFR)signaling has become an importanttarget for drug development becauseEGFR signaling enhances tumor cell proliferation,migration,and invasion and inhibits apoptosis.However,theresul...Epidermal growth factor receptor(EGFR)signaling has become an importanttarget for drug development becauseEGFR signaling enhances tumor cell proliferation,migration,and invasion and inhibits apoptosis.However,theresults of clinical trials using EGFR inhibitors in patients with solid tumors have been disappointing.Here,wereport a protective effect of the EGFR inhibitors AG1478 and PD153035 against cell death induced by acute hy-poxia,which contrasts with their proapoptotic effects under normoxia.Under hypoxic conditions,both agents re-展开更多
Acrylamide has been shown to be neurotoxic.Brain-derived neurotrophic factor(BDNF)can alleviate acrylamide-induced synaptic injury;however,the underlying mechanism remains unclear.In this study,dibutyryl-cyclic adenos...Acrylamide has been shown to be neurotoxic.Brain-derived neurotrophic factor(BDNF)can alleviate acrylamide-induced synaptic injury;however,the underlying mechanism remains unclear.In this study,dibutyryl-cyclic adenosine monophosphate-induced mature human neuroblastoma(NB-1)cells were exposed with 0–100μg/mL acrylamide for 24–72 hours.Acrylamide decreased cell viability and destroyed synapses.Exposure of co-cultured NB-1 cells and Schwann cells to 0–100μg/mL acrylamide for 48 hours resulted in upregulated expression of synapsin I and BDNF,suggesting that Schwann cells can activate self-protection of neurons.Under co-culture conditions,activation of the downstream TrkB-MAPK-Erk1/2 pathway strengthened the protective effect.Exogenous BDNF can increase expression of TrkB,Erk1/2,and synapsin I,while exogenous BDNF or the TrkB inhibitor K252a could inhibit these changes.Taken together,Schwann cells may act through the BDNF-TrkB-MAPK-Erk1/2 signaling pathway,indicating that BDNF plays an important role in this process.Therefore,exogenous BDNF may be an effective treatment strategy for acrylamide-induced nerve injury.This study was approved by the Laboratory Animal Welfare and Ethics Committee of the National Institute of Occupational Health and Poison Control,a division of the Chinese Center for Disease Control and Prevention(approval No.EAWE-2017-008)on May 29,2017.展开更多
Osteoporosis(OP)is a common skeletal disease involving low bone mineral density(BMD)that often leads to fragility fracture,and its development is affected by multiple cellular pathologies and associated with marked ep...Osteoporosis(OP)is a common skeletal disease involving low bone mineral density(BMD)that often leads to fragility fracture,and its development is affected by multiple cellular pathologies and associated with marked epigenetic alterations of osteogenic genes.Proper physical exercise is beneficial for bone health and OP and reportedly possesses epigenetic modulating capacities;however,whether the protective effects of exercise on OP involve epigenetic mechanisms is unclear.Here,we report that epigenetic derepression of nuclear factor erythroid derived 2-related factor-2(Nrf2),a master regulator of oxidative stress critically involved in the pathogenesis of OP,mediates the significant osteoprotective effects of running exercise(RE)in a mouse model of OP induced by ovariectomy.We showed that Nrf2 gene knockout(Nfe2l2^(−/−))ovariectomized mice displayed a worse BMD reduction than the controls,identifying Nrf2 as a critical antiosteoporotic factor.Further,femoral Nrf2 was markedly repressed with concomitant DNA methyltransferase(Dnmt)1/Dnmt3a/Dnmt3b elevations and Nrf2 promoter hypermethylation in both patients with OP and ovariectomized mice.However,daily 1-h treadmill RE significantly corrected epigenetic alterations,recovered Nrf2 loss and improved the femur bone mass and trabecular microstructure.Consistently,RE also normalized the adverse expression of major osteogenic factors,including osteoblast/osteoclast markers,Nrf2 downstream antioxidant enzymes and proinflammatory cytokines.More importantly,the RE-conferred osteoprotective effects observed in the wild-type control mice were largely abolished in the Nfe2l2^(−/−)mice.Thus,Nrf2 repression due to aberrant Dnmt elevation and subsequent Nrf2 promoter hypermethylation is likely an important epigenetic feature of the pathogenesis of OP,and Nrf2 derepression is essential for the antiosteoporotic effects of RE.展开更多
Runt-related transcription factor-1(Runxl)is required for chondrocyte-to-osteoblast lineage commitment by enhancing both chondrogenesis and osteogenesis during vertebrate development.However,the potential role of Runx...Runt-related transcription factor-1(Runxl)is required for chondrocyte-to-osteoblast lineage commitment by enhancing both chondrogenesis and osteogenesis during vertebrate development.However,the potential role of Runxl in joint diseases is not well known.In the current study,we aimed to explore the role of Runxl in osteoarthritis induced by anterior cruciate ligament transaction(ACLT)surgery.We showed that chondrocyte-specific Runxl knockout(Runx1f/fCol2a1-Cre)aggravated cartilage destruction by accelerating the loss of proteoglycan and collagen II in early osteoarthritis.Moreover,we observed thinning and ossification of the growth plate,a decrease in chondrocyte proliferative capacity and the loss of bone matrix around the growth plate in late osteoarthritis.We overexpressed Runxl by adeno-associated virus(AAV)in articular cartilage and identified its protective effect by slowing the destruction of osteoarthritis in cartilage in early osteoarthritis and alleviating the pathological progression of growth plate cartilage in late osteoarthritis.ChIP-seq analysis identified new targets that interacted with Runxl in cartilage pathology,and we confirmed the direct interactions of these factors with Runxl by ChIP-qPCR.This study helps us to understand the function of Runxl in osteoarthritis and provides new clues for targeted osteoarthritis therapy.展开更多
To determine passive haemagglutination (PHA) antibody titer that would protect chicks against Nigerian isolates of the Infectious Bursa Disease Virus (IBDV), five groups of chicks aged 30 days which had different anti...To determine passive haemagglutination (PHA) antibody titer that would protect chicks against Nigerian isolates of the Infectious Bursa Disease Virus (IBDV), five groups of chicks aged 30 days which had different antibody titers were challenged with a Nigerian isolate of virulent IBDV. Mortality rates of the different groups were plotted against their respective mean PHA antibody titers. A group with zero antibody titer had a mortality rate of 75% while those with PHA antibody titers of 185.6, 243.2, 256 and 307.2 had mortality rates of 40%, zero, zero and zero respectively. Linear equation generated for a line of best fit of the graph of mortality rates of the chicks on their IBD antibody titers gave antibody titer (X) at which mortality (Y) would be zero as 300. A mortality of 75% and the high antibody level needed to protect chicks suggest that the isolate may be a hypervirulent strain.展开更多
Bacterial infection is a common finding in patients,who develop medication-related osteonecrosis of the jaw(MRONJ)by the longterm and/or high-dose use of anti-resorptive agents such as bisphosphonate(BPs).However,path...Bacterial infection is a common finding in patients,who develop medication-related osteonecrosis of the jaw(MRONJ)by the longterm and/or high-dose use of anti-resorptive agents such as bisphosphonate(BPs).However,pathological role of bacteria in MRONJ development at the early stage remains controversial.Here,we demonstrated that commensal microbiota protects against MRONJ development in the pulp-exposed periapical periodontitis mouse model.C57/BL6 female mice were treated with intragastric broadspectrum antibiotics for 1 week.Zoledronic acid(ZOL)through intravenous injection and antibiotics in drinking water were administered for throughout the experiment.Pulp was exposed on the left maxillary first molar,then the mice were left for 5 weeks after which bilateral maxillary first molar was extracted and mice were left for additional 3 weeks to heal.All mice were harvested,and cecum,maxilla,and femurs were collected.ONJ development was assessed usingμCT and histologic analyses.When antibiotic was treated in mice,these mice had no weight changes,but developed significantly enlarged ceca compared to the control group(CTL mice).Periapical bone resorption prior to the tooth extraction was similarly prevented when treated with antibiotics,which was confirmed by decreased osteoclasts and inflammation.ZOL treatment with pulp exposure significantly increased bone necrosis as determined by empty lacunae and necrotic bone amount.Furthermore,antibiotics treatment could further exacerbate bone necrosis,with increased osteoclast number.Our findings suggest that the commensal microbiome may play protective role,rather than pathological role,in the early stages of MRONJ development.展开更多
This study is to explore the mechanisms underlying the protective effects of Lactobacillus casei(L.casei)on the intestinal mucosal barrier of chicks infected with Salmonella pullorum(S.pullorum)through histological,im...This study is to explore the mechanisms underlying the protective effects of Lactobacillus casei(L.casei)on the intestinal mucosal barrier of chicks infected with Salmonella pullorum(S.pullorum)through histological,immunological,and molecular biology methods.The results showed that L.casei significantly reduced the diarrhea rate,increased the daily weight gain,and maintained normal levels of IgA,IgM,and IgG in the serum of chicks infected with S.pullorum.Furthermore,we found that L.casei markedly improved the immunity of gut mucosa by regulating cytokine and chemokine receptor balance,elevating the number of intraepithelial lymphocytes.展开更多
Burkholderia mallei is the etiologic agent of glanders in solipeds and humans. Lipopolysaccharide (LPS) is a major component of cell envelop of this pathogen. O-antigen, the most external component of LPS, is a virule...Burkholderia mallei is the etiologic agent of glanders in solipeds and humans. Lipopolysaccharide (LPS) is a major component of cell envelop of this pathogen. O-antigen, the most external component of LPS, is a virulence factor and a protective antigen in many pathogenic bacteria. Two putative proteins named Wzm (integral membrane protein) and Wzt (hydrophilic ATP-binding protein) are believed to make up an ABC-2 transporter of B. mallei that facilitates transport of components of O-antigen from cytosol to outer-membrane. We studied the importance of wzt (encoding Wzt) to growth, LPS O-antigen profile, and pathogenicity of B. mallei. A wzt mutant strain was generated by deleting a portion of the wzt in B. mallei wild type strain ATCC 23344 by gene replacement. Compared to the wild type strain, the wzt mutant displayed slower growth in vitro and less lethality in CD1 mice when inoculated intraperitoneally. The 50% lethal doses (LD50) of the wild type and the wzt mutant strains were 5.9 × 105 and 9.1 × 105 cfu, respectively. CD1 mice inoculated with a non-lethal dose of the wzt mutant produced specific serum immunoglobulins IgG1 and IgG2a and were partially protected against challenge with 11.2 times LD50 of the wild type strain. These findings suggest that the wzt is required for optimal in vitro growth and pathogenesis of B. mallei, and a wzt mutant protects CD1 mice against glanders.展开更多
Monkeypox has been declared a public health emergency by the World Health Organization.There is an urgent need for efficient and safe vaccines against the monkeypox virus(MPXV)in response to the rapidly spreading monk...Monkeypox has been declared a public health emergency by the World Health Organization.There is an urgent need for efficient and safe vaccines against the monkeypox virus(MPXV)in response to the rapidly spreading monkeypox epidemic.In the age of COVID-19,mRNA vaccines have been highly successful and emerged as platforms enabling rapid development and large-scale preparation.Here,we develop two MPXV quadrivalent mRNA vaccines,named mRNA-A-LNP and mRNA-B-LNP,based on two intracellular mature virus specific proteins(A29L and M1R)and two extracellular enveloped virus specific proteins(A35R and B6R).By administering mRNA-A-LNP and mRNA-B-LNP intramuscularly twice,mice induce MPXV specific IgG antibodies and potent vaccinia virus(VACV)specific neutralizing antibodies.Further,it elicits efficient MPXV specific Th-1 biased cellular immunity,as well as durable effector memory T and germinal center B cell responses in mice.In addition,two doses of mRNA-A-LNP and mRNA-B-LNP are protective against the VACV challenge in mice.And,the passive transfer of sera from mRNA-A-LNP and mRNA-B-LNP-immunized mice protects nude mice against the VACV challenge.Overall,our results demonstrate that mRNA-A-LNP and mRNA-B-LNP appear to be safe and effective vaccine candidates against monkeypox epidemics,as well as against outbreaks caused by other orthopoxviruses,including the smallpox virus.展开更多
Pancreatitis is the leading cause of hospitalization in gastroenterology,and no medications are available for treating this disease in current clinical practice.FxR plays an anti-inflammatory role in diverse inflammat...Pancreatitis is the leading cause of hospitalization in gastroenterology,and no medications are available for treating this disease in current clinical practice.FxR plays an anti-inflammatory role in diverse inflammatory diseases,while its function in pancreatitis remains unknown.In this study,we initially observed a marked increase of nuclear FXR in pancreatic tissues of human patients ithpancratis eleting theFXRinpancreati acinar cels FXRicnara/a)ledto moreseverepancreatitis in mousemodels of caerulein-induced acute and chronic pancreatitis,while the FXR agonist GW4064 significantly attenuated pancreatitis in caerulein or arginine-induced acute pancreatitis and caerulein-induced chronic pancreatitis.FXR deletion impaired the viability and stress responses of pancreatic exocrine organoids(PEOs)in vitro.Utilizing RNA-seq and ChIP-seq of PEOs,we identified Osginl as a direct target of FxR in the exocrine pancreas,which was also increasingly expressed in human pancreatitis tissues compared to normal pancreatic tissues.Pancreatic knockdown of Osgin1 by AAV-pan abolished the therapeutic effects of FXR activation on pancreatitis,whereas pancreatic overexpression of Osginl effectively alleviated caerulein-induced pancreatitis.Mechanistically,we found that the FXR-OSGINl axis stimulated autophagic flux in the pancreatic tissues and cell lines,which was considered as the intrinsic mechanisms through which FXR-OSGINI protecting against pancreatitis.Our results highlight the protective role of the FXR-OSGIN1 axis in pancreatitis and provided a new target for the treatment of this disease.展开更多
The Compendium of Physical Activities(Compendium)was developed to address consistent assignment of physical activity(PA)intensity values used in PA epidemiology research of the association between PA and health outcom...The Compendium of Physical Activities(Compendium)was developed to address consistent assignment of physical activity(PA)intensity values used in PA epidemiology research of the association between PA and health outcomes.1The known protective effects of PA on incident health outcomes traces to the mid-1900s,with over 50 studies examining coronary heart disease(CHD)as the outcome of interest.展开更多
Dear Editor,Zika virus (ZIKV) is a mosquito-borne virus that belongs to the Flavivirus family along with dengue virus (DENV),yellow fever virus, West Nile virus, and Japanese encephalitis virus (Ming et al. 2016). ZIK...Dear Editor,Zika virus (ZIKV) is a mosquito-borne virus that belongs to the Flavivirus family along with dengue virus (DENV),yellow fever virus, West Nile virus, and Japanese encephalitis virus (Ming et al. 2016). ZIKV is a singlestranded positive-sense RNA virus encoding three structural proteins, including nucleocapsid protein C, prM/M,envelope glycoprotein E, and seven non-structural proteins.Since 2015.展开更多
This paper is investigating the use of composite armour reinforced by nanomaterials, for the protection of light armoured(LAV) and medium armoured military vehicles(MAV), and the interaction between the composite mate...This paper is investigating the use of composite armour reinforced by nanomaterials, for the protection of light armoured(LAV) and medium armoured military vehicles(MAV), and the interaction between the composite materials and high-performance ballistic projectiles. Four armour materials, consisted of front hybrid fibre reinforced polymer cover layer, ceramic strike-face, fibre reinforced polymer intermediate layer and the metal matrix composite reinforced backplate, were manufactured and assembled by adhesive technology. The proposed laminated protection system is suitable for armoured ground vehicles;however, it could be used as armour on ground, air and naval platforms. The design of the protection system, including material selection and thickness, was elaborated depending on the performance requirements of Level 4 + STANAG 4569 military standard(projectile 14.5 mm × 114 mm API B32) and especially on a design philosophy which is analysed with the specifications. The backplate of this new composite is a hybrid material of Metal Matrix Composite(MMC) reinforced with carbon nanotubes(CNTs), manufactured with the use of powder metallurgy technique. The composite backplate material was morphologically, mechanically and chemically analysed. Results show that all plates are presenting high mechanical properties and ballistic characteristics, compared to commonly used armour plates. Real military ballistic tests according to AEP-STANAG 4569 were carried out for the total composite armour systems. After the ballistic tests, AA2024-CNT3 showed the best protection results, compared with the other plates(AA2024-CNT1 and AA2024-CNT2), with the projectile being unable to fully penetrate the composite plate.展开更多
基金supported by the National Key Research and Development Program of China (2022YFD1800604)the China Agricultural Research System (CARS-41)the Heilongjiang Touyan Innovation Team Program of China
文摘Avian metapneumovirus(aMPV) is a highly contagious pathogen that causes acute upper respiratory tract diseases in chickens and turkeys, resulting in serious economic losses. Subtype B aMPV has recently become the dominant epidemic strain in China. We developed an attenuated aMPV subtype B strain by serial passaging in Vero cells and evaluated its safety and efficacy as a vaccine candidate. The safety test showed that after the 30th passage, the LN16-A strain was fully attenuated, as clinical signs of infection and histological lesions were absent after inoculation.The LN16-A strain did not revert to a virulent strain after five serial passages in chickens. The genomic sequence of LN16-A differed from that of the parent wild-type LN16(wtLN16) strain and had nine amino acid mutations. In chickens, a single immunization with LN16-A induced robust humoral and cellular immune responses, including the abundant production of neutralizing antibodies, CD4^(+) T lymphocytes, and the Th1(IFN-γ) and Th2(IL-4 and IL-6)cytokines. We also confirmed that LN16-A provided 100% protection against subtype B aMPV and significantly reduced viral shedding and turbinate inflammation. Our findings suggest that the LN16-A strain is a promising live attenuated vaccine candidate that can prevent infection with subtype B aMPV.
基金supported by grants from the National Natural Science Foundation of China,No.81971231(to JL)Liaoning Revitalization Talents Program,No.XLYC1907178(to JL)。
文摘Recent research on the underlying mechanisms of cerebral ischemia indicates that the neurovascular unit can be used as a novel subject for general surveys of neuronal damage and protein mechanisms.Fingolimod(FTY-720)is a newly developed immunosuppressant isolated from Cordyceps sinensis that exhibits a wide range of biological activities,and has recently attracted much attention for the treatment of ischemic cerebrovascular diseases.In the current research,the role of FTY-720 and its possible mechanisms were assessed from an neurovascular unit perspective using a rat cerebral ischemia model.Our results revealed that FTY-720 markedly decreased infarct volume,promoted neurological function recovery,and weakened the blood-brain barrier permeability of ischemic rats.The protective roles of FTY-720 in ischemic stroke are ascribed to a combination of sphingosin-1-phosphate receptor-1 and reduced expression of sphingosin-1-phosphate receptor-1 in microvessels and reduction of interleukin-17A protein levels.These findings indicate that FTY-720 has promise as a new therapy for neurovascular protection and functional recovery after ischemic stroke.
基金supported by the National Natural Science Foundation of China (Grant numbers 11932014 and 31971239)the Sichuan Science and Technology Program (Grant numbers 2022NSFSC0765 and 2022ZYD0079)。
文摘Matrix vesicles(MVs)have shown strong effects in diseases such as vascular ectopic calcification and pathological calcified osteoarthritis and in wound repair of the skeletal system due to their membranous vesicle characteristics and abundant calcium and phosphorus content.However,the role of MVs in the progression of osteoporosis is poorly understood.Here,we report that annexin A5,an important component of the matrix vesicle membrane,plays a vital role in bone matrix homeostasis in the deterioration of osteoporosis.We first identified annexin A5 from adherent MVs but not dissociative MVs of osteoblasts and found that it could be sharply decreased in the bone matrix during the occurrence of osteoporosis based on ovariectomized mice.We then confirmed its potential in mediating the mineralization of the precursor osteoblast lineage via its initial binding with collagen type I to achieve MV adhesion and the subsequent activation of cellular autophagy.Finally,we proved its protective role in resisting bone loss by applying it to osteoporotic mice.Taken together,these data revealed the importance of annexin A5,originating from adherent MVs of osteoblasts,in bone matrix remodeling of osteoporosis and provided a new strategy for the treatment and intervention of bone loss.
基金supported by National Science Foundation of China[No.81172620]。
文摘In recent decades,the potential health hazards of microwave exposure have been attracting increasing attention.Our previous studies have demonstrated that microwave exposure impaired learning and memory in experimental animal models[1,2].
文摘Objectives Endothelial senescence has been proposed to be involved in endothelial dysfunction and atherogenesis. This study investigates the effects of ginsenoside Rbl, a major constituent of ginseng,on H<sub>2</sub>O<sub>2</sub>-induced endothelial senescence.Methods Primary human umbilical vein endothelial cells（HUVECs） senescence was induced by H<sub>2</sub>O<sub>2</sub> as judged by senescence-associated P-galactosidase assay （SA-P-gal）.Fntracellur superoxide dismutase（S0D1） activity and malondialdehyde（MDA） level were determined by commercial kit.S0D1 mRNA and protein expression were analyzed by real time PCR and Western blot.Reactive oxygen species（ROS） were determined by flow cytometry.Results Rb1 was found to reverse endothelial senescence,as witnessed by a significant decrease of senescent cell numbers. Rbl could markedly increase intracellular SOD activity, decrease the MDA level,and suppress the generation of intracellular ROS in H<sub>2</sub>O<sub>2</sub>-treated HUVECs.Consistent with these findings,Rbl can effectively restore SOD1 mRNA and protein expression which decreased in H<sub>2</sub>O<sub>2</sub> treated cells. Conclusions Our report demonstrates thatRbl can exert reversal effects on H<sub>2</sub>O<sub>2</sub>-induced cellular senescence through modulating cellular redox status.
文摘AIM To investigate the pathogenic effect ofSEB and D-GalN on liver and the protection ofcyclosporin A, the relationship between hepaticapoptosis and necrosis and the possiblemechanism of acute hepatic necrosis.METHODS After staphylococcal enterotoxin B(SEB ) mixed with D--galactosamine (D-GaiN )were injected intraperitoneally into Balb/c miceand those previously treated with cyclosporin A,blood samples were collected and livers wereisolated at 2, 6, 12 and 24 h. Patterns othepatocellular death were studiedmorphologically and biochemically, circulatingcytokines (TNF-a, IFN--y ) and mice mortalitywithin 24h was assessed.RESU’LTS The SEB could induce the typicalapoptotic changes of hepatocytes, the D-GaiNcould induce hepatocytes apoptosis anddegeneration at the same time, and the micehaving received the SEB + D-GaiN injectionsdeveloped apoptosis at 2 and 6 h, but after 12 hhepatocytes were characterized by severein jury, whereas all the examinations in thecyclosporin A treated mice were normal.CONCLUSION Hepatic cell apoptosis might berelated to necrosis, and massive hepatocyteapoptosis is likely the initiating step of acutehepatic necrosis in mice. The effects induced bySEB and D--GaiN on hepatocytes might bemediated by T cells, and could be prevented bycyclosporin A.
基金supported by National Natural Science Foundation of China(11932012,81870790 and 31801233)Science and Technology Commission of Shanghai Municipality(18441903600)+1 种基金Clinical Research Plan of SHDC(No.SHDC2020CR3009A)Innovative Research Team of High-level Local Universities in Shanghai(SSMU-ZDCX20180902)。
文摘Osteoarthritis(OA)is a prevalent joint disease with no effective treatment strategies.Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis.Although multiple studies have detected potential regulatory mechanisms underlying OA and have concentrated on developing novel treatment strategies,the epigenetic control of OA remains unclear.Histone demethylase JMJD3 has been reported to mediate multiple physiological and pathological processes,including cell differentiation,proliferation,autophagy,and apoptosis.However,the regulation of JMJD3 in aberrant force-related OA and its mediatory effect on disease progression are still unknown.In this work,we confirmed the upregulation of JMJD3 in aberrant forceinduced cartilage injury in vitro and in vivo.Functionally,inhibition of JMJD3 by its inhibitor,GSK-J4,or downregulation of JMJD3 by adenovirus infection of sh-JMJD3 could alleviate the aberrant force-induced chondrocyte injury.Mechanistic investigation illustrated that aberrant force induces JMJD3 expression and then demethylates H3K27me3 at the NR4A1 promoter to promote its expression.Further experiments indicated that NR4A1 can regulate chondrocyte apoptosis,cartilage degeneration,extracellular matrix degradation,and inflammatory responses.In vivo,anterior cruciate ligament transection(ACLT)was performed to construct an OA model,and the therapeutic effect of GSK-J4 was validated.More importantly,we adopted a peptide-si RNA nanoplatform to deliver si-JMJD3 into articular cartilage,and the severity of joint degeneration was remarkably mitigated.Taken together,our findings demonstrated that JMJD3 is flow-responsive and epigenetically regulates OA progression.Our work provides evidences for JMJD3 inhibition as an innovative epigenetic therapy approach for joint diseases by utilizing p5RHH-si RNA nanocomplexes.
文摘Epidermal growth factor receptor(EGFR)signaling has become an importanttarget for drug development becauseEGFR signaling enhances tumor cell proliferation,migration,and invasion and inhibits apoptosis.However,theresults of clinical trials using EGFR inhibitors in patients with solid tumors have been disappointing.Here,wereport a protective effect of the EGFR inhibitors AG1478 and PD153035 against cell death induced by acute hy-poxia,which contrasts with their proapoptotic effects under normoxia.Under hypoxic conditions,both agents re-
基金This study was supported by the National Natural Science Foundation of China,Nos.81773474 and 81273110(to BL)the National Key Research and Development Project of China,No.2017YFF0211201(to BL).
文摘Acrylamide has been shown to be neurotoxic.Brain-derived neurotrophic factor(BDNF)can alleviate acrylamide-induced synaptic injury;however,the underlying mechanism remains unclear.In this study,dibutyryl-cyclic adenosine monophosphate-induced mature human neuroblastoma(NB-1)cells were exposed with 0–100μg/mL acrylamide for 24–72 hours.Acrylamide decreased cell viability and destroyed synapses.Exposure of co-cultured NB-1 cells and Schwann cells to 0–100μg/mL acrylamide for 48 hours resulted in upregulated expression of synapsin I and BDNF,suggesting that Schwann cells can activate self-protection of neurons.Under co-culture conditions,activation of the downstream TrkB-MAPK-Erk1/2 pathway strengthened the protective effect.Exogenous BDNF can increase expression of TrkB,Erk1/2,and synapsin I,while exogenous BDNF or the TrkB inhibitor K252a could inhibit these changes.Taken together,Schwann cells may act through the BDNF-TrkB-MAPK-Erk1/2 signaling pathway,indicating that BDNF plays an important role in this process.Therefore,exogenous BDNF may be an effective treatment strategy for acrylamide-induced nerve injury.This study was approved by the Laboratory Animal Welfare and Ethics Committee of the National Institute of Occupational Health and Poison Control,a division of the Chinese Center for Disease Control and Prevention(approval No.EAWE-2017-008)on May 29,2017.
基金supported by research grants from the National Nature and Science Foundation of China(NSFC)Key Program(81730067)the NSFC General Program(81670762 and 81970577)the NSFC Major Project(81991514).
文摘Osteoporosis(OP)is a common skeletal disease involving low bone mineral density(BMD)that often leads to fragility fracture,and its development is affected by multiple cellular pathologies and associated with marked epigenetic alterations of osteogenic genes.Proper physical exercise is beneficial for bone health and OP and reportedly possesses epigenetic modulating capacities;however,whether the protective effects of exercise on OP involve epigenetic mechanisms is unclear.Here,we report that epigenetic derepression of nuclear factor erythroid derived 2-related factor-2(Nrf2),a master regulator of oxidative stress critically involved in the pathogenesis of OP,mediates the significant osteoprotective effects of running exercise(RE)in a mouse model of OP induced by ovariectomy.We showed that Nrf2 gene knockout(Nfe2l2^(−/−))ovariectomized mice displayed a worse BMD reduction than the controls,identifying Nrf2 as a critical antiosteoporotic factor.Further,femoral Nrf2 was markedly repressed with concomitant DNA methyltransferase(Dnmt)1/Dnmt3a/Dnmt3b elevations and Nrf2 promoter hypermethylation in both patients with OP and ovariectomized mice.However,daily 1-h treadmill RE significantly corrected epigenetic alterations,recovered Nrf2 loss and improved the femur bone mass and trabecular microstructure.Consistently,RE also normalized the adverse expression of major osteogenic factors,including osteoblast/osteoclast markers,Nrf2 downstream antioxidant enzymes and proinflammatory cytokines.More importantly,the RE-conferred osteoprotective effects observed in the wild-type control mice were largely abolished in the Nfe2l2^(−/−)mice.Thus,Nrf2 repression due to aberrant Dnmt elevation and subsequent Nrf2 promoter hypermethylation is likely an important epigenetic feature of the pathogenesis of OP,and Nrf2 derepression is essential for the antiosteoporotic effects of RE.
基金This work was supported by the National Natural Science Foundation of China(81771047 to J.X.,81901040 to CZ.)the China Postdoctoral Science Foundation(2019M653440)+1 种基金the Sichuan Provincial Science and Technology Department(2019YJ0101)the Young Elite Scientist Sponsorship Program by CAST(2020QNR001).
文摘Runt-related transcription factor-1(Runxl)is required for chondrocyte-to-osteoblast lineage commitment by enhancing both chondrogenesis and osteogenesis during vertebrate development.However,the potential role of Runxl in joint diseases is not well known.In the current study,we aimed to explore the role of Runxl in osteoarthritis induced by anterior cruciate ligament transaction(ACLT)surgery.We showed that chondrocyte-specific Runxl knockout(Runx1f/fCol2a1-Cre)aggravated cartilage destruction by accelerating the loss of proteoglycan and collagen II in early osteoarthritis.Moreover,we observed thinning and ossification of the growth plate,a decrease in chondrocyte proliferative capacity and the loss of bone matrix around the growth plate in late osteoarthritis.We overexpressed Runxl by adeno-associated virus(AAV)in articular cartilage and identified its protective effect by slowing the destruction of osteoarthritis in cartilage in early osteoarthritis and alleviating the pathological progression of growth plate cartilage in late osteoarthritis.ChIP-seq analysis identified new targets that interacted with Runxl in cartilage pathology,and we confirmed the direct interactions of these factors with Runxl by ChIP-qPCR.This study helps us to understand the function of Runxl in osteoarthritis and provides new clues for targeted osteoarthritis therapy.
文摘To determine passive haemagglutination (PHA) antibody titer that would protect chicks against Nigerian isolates of the Infectious Bursa Disease Virus (IBDV), five groups of chicks aged 30 days which had different antibody titers were challenged with a Nigerian isolate of virulent IBDV. Mortality rates of the different groups were plotted against their respective mean PHA antibody titers. A group with zero antibody titer had a mortality rate of 75% while those with PHA antibody titers of 185.6, 243.2, 256 and 307.2 had mortality rates of 40%, zero, zero and zero respectively. Linear equation generated for a line of best fit of the graph of mortality rates of the chicks on their IBD antibody titers gave antibody titer (X) at which mortality (Y) would be zero as 300. A mortality of 75% and the high antibody level needed to protect chicks suggest that the isolate may be a hypervirulent strain.
基金supported National Institutes of Health/National Institute of Dental and Craniofacial Research(grant DE023348 to R.H.K.,grant DE025172 to D.W.W.)China Postdoctoral Science Foundation(grant 2019M663526 to W.D.)。
文摘Bacterial infection is a common finding in patients,who develop medication-related osteonecrosis of the jaw(MRONJ)by the longterm and/or high-dose use of anti-resorptive agents such as bisphosphonate(BPs).However,pathological role of bacteria in MRONJ development at the early stage remains controversial.Here,we demonstrated that commensal microbiota protects against MRONJ development in the pulp-exposed periapical periodontitis mouse model.C57/BL6 female mice were treated with intragastric broadspectrum antibiotics for 1 week.Zoledronic acid(ZOL)through intravenous injection and antibiotics in drinking water were administered for throughout the experiment.Pulp was exposed on the left maxillary first molar,then the mice were left for 5 weeks after which bilateral maxillary first molar was extracted and mice were left for additional 3 weeks to heal.All mice were harvested,and cecum,maxilla,and femurs were collected.ONJ development was assessed usingμCT and histologic analyses.When antibiotic was treated in mice,these mice had no weight changes,but developed significantly enlarged ceca compared to the control group(CTL mice).Periapical bone resorption prior to the tooth extraction was similarly prevented when treated with antibiotics,which was confirmed by decreased osteoclasts and inflammation.ZOL treatment with pulp exposure significantly increased bone necrosis as determined by empty lacunae and necrotic bone amount.Furthermore,antibiotics treatment could further exacerbate bone necrosis,with increased osteoclast number.Our findings suggest that the commensal microbiome may play protective role,rather than pathological role,in the early stages of MRONJ development.
文摘This study is to explore the mechanisms underlying the protective effects of Lactobacillus casei(L.casei)on the intestinal mucosal barrier of chicks infected with Salmonella pullorum(S.pullorum)through histological,immunological,and molecular biology methods.The results showed that L.casei significantly reduced the diarrhea rate,increased the daily weight gain,and maintained normal levels of IgA,IgM,and IgG in the serum of chicks infected with S.pullorum.Furthermore,we found that L.casei markedly improved the immunity of gut mucosa by regulating cytokine and chemokine receptor balance,elevating the number of intraepithelial lymphocytes.
文摘Burkholderia mallei is the etiologic agent of glanders in solipeds and humans. Lipopolysaccharide (LPS) is a major component of cell envelop of this pathogen. O-antigen, the most external component of LPS, is a virulence factor and a protective antigen in many pathogenic bacteria. Two putative proteins named Wzm (integral membrane protein) and Wzt (hydrophilic ATP-binding protein) are believed to make up an ABC-2 transporter of B. mallei that facilitates transport of components of O-antigen from cytosol to outer-membrane. We studied the importance of wzt (encoding Wzt) to growth, LPS O-antigen profile, and pathogenicity of B. mallei. A wzt mutant strain was generated by deleting a portion of the wzt in B. mallei wild type strain ATCC 23344 by gene replacement. Compared to the wild type strain, the wzt mutant displayed slower growth in vitro and less lethality in CD1 mice when inoculated intraperitoneally. The 50% lethal doses (LD50) of the wild type and the wzt mutant strains were 5.9 × 105 and 9.1 × 105 cfu, respectively. CD1 mice inoculated with a non-lethal dose of the wzt mutant produced specific serum immunoglobulins IgG1 and IgG2a and were partially protected against challenge with 11.2 times LD50 of the wild type strain. These findings suggest that the wzt is required for optimal in vitro growth and pathogenesis of B. mallei, and a wzt mutant protects CD1 mice against glanders.
基金supported by the National Key R&D Program of China (2021YFC2302405)the National Natural Science Foundation of China (Grant No.81830101).
文摘Monkeypox has been declared a public health emergency by the World Health Organization.There is an urgent need for efficient and safe vaccines against the monkeypox virus(MPXV)in response to the rapidly spreading monkeypox epidemic.In the age of COVID-19,mRNA vaccines have been highly successful and emerged as platforms enabling rapid development and large-scale preparation.Here,we develop two MPXV quadrivalent mRNA vaccines,named mRNA-A-LNP and mRNA-B-LNP,based on two intracellular mature virus specific proteins(A29L and M1R)and two extracellular enveloped virus specific proteins(A35R and B6R).By administering mRNA-A-LNP and mRNA-B-LNP intramuscularly twice,mice induce MPXV specific IgG antibodies and potent vaccinia virus(VACV)specific neutralizing antibodies.Further,it elicits efficient MPXV specific Th-1 biased cellular immunity,as well as durable effector memory T and germinal center B cell responses in mice.In addition,two doses of mRNA-A-LNP and mRNA-B-LNP are protective against the VACV challenge in mice.And,the passive transfer of sera from mRNA-A-LNP and mRNA-B-LNP-immunized mice protects nude mice against the VACV challenge.Overall,our results demonstrate that mRNA-A-LNP and mRNA-B-LNP appear to be safe and effective vaccine candidates against monkeypox epidemics,as well as against outbreaks caused by other orthopoxviruses,including the smallpox virus.
基金supported by the National Key R&D Program of China(2018YFC2000500/3and2018YFC2000202)the National Natural Science Foundation of China(NSFC no.82070391(N.S.),no.321711175(X.L.),and no.81900791(Z.W.).
文摘Pancreatitis is the leading cause of hospitalization in gastroenterology,and no medications are available for treating this disease in current clinical practice.FxR plays an anti-inflammatory role in diverse inflammatory diseases,while its function in pancreatitis remains unknown.In this study,we initially observed a marked increase of nuclear FXR in pancreatic tissues of human patients ithpancratis eleting theFXRinpancreati acinar cels FXRicnara/a)ledto moreseverepancreatitis in mousemodels of caerulein-induced acute and chronic pancreatitis,while the FXR agonist GW4064 significantly attenuated pancreatitis in caerulein or arginine-induced acute pancreatitis and caerulein-induced chronic pancreatitis.FXR deletion impaired the viability and stress responses of pancreatic exocrine organoids(PEOs)in vitro.Utilizing RNA-seq and ChIP-seq of PEOs,we identified Osginl as a direct target of FxR in the exocrine pancreas,which was also increasingly expressed in human pancreatitis tissues compared to normal pancreatic tissues.Pancreatic knockdown of Osgin1 by AAV-pan abolished the therapeutic effects of FXR activation on pancreatitis,whereas pancreatic overexpression of Osginl effectively alleviated caerulein-induced pancreatitis.Mechanistically,we found that the FXR-OSGINl axis stimulated autophagic flux in the pancreatic tissues and cell lines,which was considered as the intrinsic mechanisms through which FXR-OSGINI protecting against pancreatitis.Our results highlight the protective role of the FXR-OSGIN1 axis in pancreatitis and provided a new target for the treatment of this disease.
文摘The Compendium of Physical Activities(Compendium)was developed to address consistent assignment of physical activity(PA)intensity values used in PA epidemiology research of the association between PA and health outcomes.1The known protective effects of PA on incident health outcomes traces to the mid-1900s,with over 50 studies examining coronary heart disease(CHD)as the outcome of interest.
基金supported by the National Natural Science Foundation of China (31470848, 31470880, 31670898, and 31870867)Open Research Fund Program of the State Key Laboratory of Virology of China (2017IOV003)Jiangsu Provincial Innovative Research Team
文摘Dear Editor,Zika virus (ZIKV) is a mosquito-borne virus that belongs to the Flavivirus family along with dengue virus (DENV),yellow fever virus, West Nile virus, and Japanese encephalitis virus (Ming et al. 2016). ZIKV is a singlestranded positive-sense RNA virus encoding three structural proteins, including nucleocapsid protein C, prM/M,envelope glycoprotein E, and seven non-structural proteins.Since 2015.
基金the Research and Development department of EODH SA and has been co-financed by the European Regional Development Fund of the European Union and Greek national funds through the Operational Program Competitiveness,Entrepreneurship and Innovation,under the call RESEARCH-CREATE-INNOVATE(project code:T1EDK-04429).
文摘This paper is investigating the use of composite armour reinforced by nanomaterials, for the protection of light armoured(LAV) and medium armoured military vehicles(MAV), and the interaction between the composite materials and high-performance ballistic projectiles. Four armour materials, consisted of front hybrid fibre reinforced polymer cover layer, ceramic strike-face, fibre reinforced polymer intermediate layer and the metal matrix composite reinforced backplate, were manufactured and assembled by adhesive technology. The proposed laminated protection system is suitable for armoured ground vehicles;however, it could be used as armour on ground, air and naval platforms. The design of the protection system, including material selection and thickness, was elaborated depending on the performance requirements of Level 4 + STANAG 4569 military standard(projectile 14.5 mm × 114 mm API B32) and especially on a design philosophy which is analysed with the specifications. The backplate of this new composite is a hybrid material of Metal Matrix Composite(MMC) reinforced with carbon nanotubes(CNTs), manufactured with the use of powder metallurgy technique. The composite backplate material was morphologically, mechanically and chemically analysed. Results show that all plates are presenting high mechanical properties and ballistic characteristics, compared to commonly used armour plates. Real military ballistic tests according to AEP-STANAG 4569 were carried out for the total composite armour systems. After the ballistic tests, AA2024-CNT3 showed the best protection results, compared with the other plates(AA2024-CNT1 and AA2024-CNT2), with the projectile being unable to fully penetrate the composite plate.
