Conservation of T cell epitopes between seasonal influenza viruses and the novel influenza A H7N9 virus

A novel avian influenza A(H7N9) virus recently emerged in the Yangtze River delta and caused diseases, often severe, in over 130 people. This H7N9 virus appeared to infect humans with greater ease than previous avian influenza virus subtypes such as H5N1 and H9N2. While there are other potential explanations for this large number of human infections with an avian influenza virus, we investigated whether a lack of conserved T-cell epitopes between endemic H1N1 and H3N2 influenza viruses and the novel H7N9 virus contributes to this observation. Here we demonstrate that a number of T cell epitopes are conserved between endemic H1N1 and H3N2 viruses and H7N9 virus. Most of these conserved epitopes are from viral internal proteins. The extent of conservation between endemic human seasonal influenza and avian influenza H7N9 was comparable to that with the highly pathogenic avian influenza H5N1. Thus, the ease of inter-species transmission of H7N9 viruses(compared with avian H5N1 viruses) cannot be attributed to the lack of conservation of such T cell epitopes. On the contrary, our findings predict significant T-cell based cross-reactions in the human population to the novel H7N9 virus. Our findings also have implications for H7N9 virus vaccine design.

Growth arrest-specific gene 2 suppresses hepatocarcinogenesis by intervention of cell cycle and p53-dependent apoptosis

BACKGROUND Growth arrest-specific gene 2(GAS2)plays a role in modulating in reversible growth arrest cell cycle,apoptosis,and cell survival.GAS2 protein is universally expressed in most normal tissues,particularly in the liver,but is depleted in some tumor tissues.However,the functional mechanisms of GAS2 in hepatocellular carcinoma(HCC)are not fully defined.AIM To investigate the function and mechanism of GAS2 in HCC.METHODS GAS2 expression in clinic liver and HCC specimens was analyzed by real-time PCR and western blotting.Cell proliferation was analyzed by counting,MTS,and colony formation assays.Cell cycle analysis was performed by flow cytometry.Cell apoptosis was investigated by Annexin V apoptosis assay and western blotting.RESULTS GAS2 protein expression was lower in HCC than in normal tissues.Overexpression of GAS2 inhibited the proliferation of HCC cells with wide-type p53,while knockdown of GAS2 promoted the proliferation of hepatocytes(P<0.05).Furthermore,GAS2 overexpression impeded the G1-to-S cell cycle transition and arrested more G1 cells,particularly the elevation of sub G1(P<0.01).Apoptosis induced by GAS2 was dependent on p53,which was increased by etoposide addition.The expression of p53 and apoptosis markers was further enhanced when GAS2 was upregulated,but became diminished upon downregulation of GAS2.In the clinic specimen,GAS2 was downregulated in more than 60%of HCCs.The average fold changes of GAS2 expression in tumor tissues were significantly lower than those in paired non-tumor tissues(P<0.05).CONCLUSION GAS2 plays a vital role in HCC cell proliferation and apoptosis,possibly by regulating the cell cycle and p53-dependent apoptosis pathway.

Predictive value of red cell distribution width on left atrial thrombus or left atrial spontaneous echo contrast in patients with non-valvular atrial fibrillation

Objective To evaluate the predictive value of red cell distribution width （RDW） on left atrial thrombus （LAT） or left atrial spontane- ous echo contrast （LASEC） in patients with non-valvular atrial fibrillation （AF）. Methods We reviewed 692 patients who were diagnosed as non-valvular AF and underwent transesophageal echocardiography （TEE） in Guangdong Cardiovascular Institute from April 2014 to December 2015. The baseline clinical characteristics, laboratory test of blood routine, electrocardiograph measurements were analyzed. Results Eighty-four patients were examined with LAT/LASEC under TEE. The mean RDW level was significantly higher in LAT/LASEC patients compared with the non-LAT/LASEC patients （13.59% ± 1.07% ws. 14.34% ± 1.34%; P 〈 0.001）. Receiver-operating characteristic curve analysis was performed and indicated the best RDW cut point was 13.16%. Furthermore, multivariate logistic regression analysis indicated that RDW level 〉 13.16% could be an independent risk factor for LAT/LASEC in patients with AF. Conclusion Elevated RDW level is associated with the presence of LAT/LASEC and could be with moderate predictive value for LAT/LASEC in patients with non-valvular AF.

Human embryonic stem cells as an in vitro model for studying developmental origins of type 2 diabetes

The developmental origins of health and diseases(DOHaD)is a concept stating that adverse intrauterine environments contribute to the health risks of offspring.Since the theory emerged more than 30 years ago,many epidemiological and animal studies have confirmed that in utero exposure to environmental insults,including hyperglycemia and chemicals,increased the risk of developing noncommunicable diseases(NCDs).These NCDs include metabolic syndrome,type 2 diabetes,and complications such as diabetic cardiomyopathy.Studying the effects of different environmental insults on early embryo development would aid in understanding the underlying mechanisms by which these insults promote NCD development.Embryonic stem cells(ESCs)have also been utilized by researchers to study the DOHaD.ESCs have pluripotent characteristics and can be differentiated into almost every cell lineage;therefore,they are excellent in vitro models for studying early developmental events.More importantly,human ESCs(hESCs)are the best alternative to human embryos for research because of ethical concerns.In this review,we will discuss different maternal conditions associated with DOHaD,focusing on the complications of maternal diabetes.Next,we will review the differentiation protocols developed to generate different cell lineages from hESCs.Additionally,we will review how hESCs are utilized as a model for research into the DOHaD.The effects of environmental insults on hESC differentiation and the possible involvement of epigenetic regulation will be discussed.

Puerarin@Chitosan composite for infected bone repair through mimicking the bio-functions of antimicrobial peptides

It is important to eliminate lipopolysaccharide(LPS)along with killing bacteria in periprosthetic joint infection(PJI)therapy for promoting bone repair due to its effect to regulate macrophages response.Although natural antimicrobial peptides(AMPs)offer a good solution,the unknown toxicity,high cost and exogenetic immune response hamper their applications in clinic.In this work,we fabricated a nanowire-like composite material,named P@C,by combining chitosan and puerarin via solid-phase reaction,which can finely mimic the bio-functions of AMPs.Chitosan,serving as the bacteria membrane puncture agent,and puerarin,serving as the LPS target agent,synergistically destroy the bacterial membrane structure and inhibit its recovery,thus endowing P@C with good antibacterial property.In addition,P@C possesses good osteoimmunomodulation due to its ability of LPS elimination and macrophage differentiation modulation.The in vivo results show that P@C can inhibit the LPS induced bone destruction in the Escherichia coli infected rat.P@C exhibits superior bone regeneration in Escherichia coli infected rat due to the comprehensive functions of its superior antibacterial property,and its ability of LPS elimination and immunomodulation.P@C can well mimic the functions of AMPs,which provides a novel and effective method for treating the PJI in clinic.

Surface defect engineered-Mg-based implants enable the dual functions of superhydrophobic and synergetic photothermal/chemodynamic therapy

Promoting metallic magnesium(Mg)-based implants to treat bone diseases in clinics,such as osteosarcoma and bacterial infection,remains a challenging topic.Herein,an iron hydroxide-based composite coating with a twostage nanosheet-like structure was fabricated on Mg alloy,and this was followed by a thermal reduction treatment to break some of the surface Fe–OH bonds.The coating demonstrated three positive changes in properties due to the defects.First,the removal of–OH made the coating superhydrophobic,and it had self-cleaning and antifouling properties.This is beneficial for keeping the implants clean and for anti-corrosion before implantation into the human body.Furthermore,the superhydrophobicity could be removed by immersing the implant in a 75%ethanol solution,to further facilitate biological action during service.Second,the color of the coating changed from yellow to brown-black,leading to an increase in the light absorption,which resulted in an excellent photothermal effect.Third,the defects increased the Fe2+content in the coating and highly improved peroxidase activity.Thus,the defect coating exhibited synergistic photothermal/chemodynamic therapeutic effects for bacteria and tumors.Moreover,the coating substantially enhanced the anti-corrosion and biocompatibility of the Mg alloys.Therefore,this study offers a novel multi-functional Mg-based implant for osteosarcoma therapy.

Corrigendum to“Magnesium cationic cue enriched interfacial tissue microenvironment nurtures the osseointegration of gamma-irradiated allograft bone”[Bioact.Mater.10C(April 2022)32-47]

The authors regret a mistake of funding numbers in the Acknowledgment Section failed to be corrected during proof reading.Below is the corrected funding statement in Acknowledgment SECTION This work was supported by the National Natural Science Foundation of China(NSFC)(Nos.81902189,81772354,82002303,31570980),Clinical Innovation Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory(2018GZR0201002),National Key Research and Development Plan(2018YFC1105103).

The modulation of stem cell behaviors by functionalized nanoceramic coatings on Ti-based implants

Nanoceramic coating on the surface of Ti-based metallic implants is a clinical potential option in orthopedic surgery.Stem cells have been found to have osteogenic capabilities.It is necessary to study the influences of functionalized nanoceramic coatings on the differentiation and proliferation of stem cells in vitro or in vivo.In this paper,we summarized the recent advance on the modulation of stem cells behaviors through controlling the properties of nanoceramic coatings,including surface chemistry,surface roughness and microporosity.In addition,mechanotransduction pathways have also been discussed to reveal the interaction mechanisms between the stem cells and ceramic coatings on Ti-based metals.In the final part,the osteoinduction and osteoconduction of ceramic coating have been also presented when it was used as carrier of BMPs in new bone formation.

Nanograins on Ti-25Nb-3Mo-2Sn-3Zr alloy facilitate fabricating biological surface through dual-ion implantation to concurrently modulate the osteogenic functions of mesenchymal stem cells and kill bacteria

Surface mechanical attrition treatment(SMAT)method is an effective way to generate nanograined(NG)surface on Ti-25 Nb-3 Mo-2 Sn-3 Zr(wt.%)(named as TLM),a kind ofβ-type titanium alloy,and the achieved nanocrystalline surface was proved to promote positive functions of osteoblastic cells.In this work,to further endow the NG TLM alloy with both good osteogenic and antibacterial properties,magnesium(Mg),silver(Ag)ion or both were introduced onto the NG TLM surface by ion implantation process,as a comparison,the Mg and Ag ions were also co-implanted onto coarsegrained(CG)TLM surface.The obtained results show that subsequent ion implantation does not remarkably induce the surface roughness and topography alteration of the SMAT-treated layers,and it also has little impact on the microstructure of the SMAT-derivedβ-Ti nanograins.In addition,the implanted Mg and Ag ions are observed to exist as MgO and metallic Ag na noparticles(NPs)embedding tightly in theβ-Ti matrix with grain size of about 15 and 7 nm,respectively.Initial cell adhesion and functions(including proliferation,osteo-differentiation and extracellular matrix mineralization)of rabbit bone marrow mesenchymal stem cells(rBMMSCs)and the bacterial colonization of Staphylococcus aureus(S.aureus)on the different surfaces were investigated.The in-vitro experimental results reveal that the Mg and Ag single-ion implanted NG surface either significantly promotes the rBMMSCs response or inhibits the growth ofS.aureus,whereas the Mg/Ag coimplanted NG surface could concurrently enhance the rBMMSCs functions as well as inhibit the bacterial growth compared to the NG surface,and this efficacy is more pronounced as compared to the Mg/Ag co-implantation in the CG surface.The SMAT-achieved nanograins in the TLM surface layer are identified to not only play a leading role in determining the fate of rBMMSCs but also facilitate fabricating dualfunctio nal surface with both good osteogenic and antibacterial activities through co-implantation of Mg and Ag ions.Our investigation provides a new strategy to develop high-performance Ti-based implants for clinical application.

The perivascular niche of endometrial mesenchymal stromal/stem-like cells

Human endometrium is a unique adult tissue that undergoes cyclical shedding,repair,and regeneration during a woman’s reproductive life.Over the past 2 decades,tremendous progress has been made towards the identification and characterization of endometrial stromal stem/progenitor cells.The substantial regeneration of vascularized stroma in the endometrium during the proliferative stages of each menstrual cycle is likely to be mediated by endometrial mesenchymal stromal/stem cells.This review focuses on the perivascular niche for CD140b^(+)CD146^(+)pericytes and SUSD2^(+)perivascular cells.The identity,characteristics,and underlying mechanisms of uterine regeneration are also discussed.

Enhancement of critical-sized bone defect regeneration by magnesium oxide-reinforced 3D scaffold with improved osteogenic and angiogenic properties

The healing of critical-sized bone defects(CSD)remains a challenge in orthopedic medicine.In recent years,scaffolds with sophisticated microstructures fabricated by the emerging three-dimensional(3D)printing technology have lighted up the treatment of the CSD due to the elaborate microenvironments and support they may build.Here,we established a magnesium oxide-reinforced 3D-printed biocompos-ite scaffold to investigate the effect of magnesium-enriched 3D microenvironment on CSD repairing.The composite was prepared using a biodegradable polymer matrix,polycaprolactone(PCL),and the disper-sion phase,magnesium oxide(MgO).With the appropriate surface treatment by saline coupling agent,the MgO dispersed homogeneously in the polymer matrix,leading to enhanced mechanical performance and steady release of magnesium ion(Mg^(2+))for superior cytocompatibility,higher cell viability,advanced osteogenic differentiation,and cell mineralization capabilities in comparison with the pure PCL.The in-vivo femoral implantation and critical-sized cranial bone defect studies demonstrated the importance of the 3D magnesium microenvironment,as a scaffold that released appropriate Mg^(2+) exhibited remarkably increased bone volume,enhanced angiogenesis,and almost recovered CSD after 8-week implantation.Overall,this study suggests that the magnesium-enriched 3D scaffold is a potential candidate for the treatment of CSD in a cell-free therapeutic approach.

Evaluating the application of next generation sequencing techniques in endoscopic retrograde cholangiopancreatography (ERCP) to improve diagnostic accuracy in patients with malignant biliary strictures

Malignant biliary obstruction is a sinister condition that require radical treatment in order to provide the hope of a cure.Apart from complex surgery,the major clinical challenge remains the difficulty in making a conclusive diagnosis(1).There is a long list of differential diagnosis for obstruction of the bile duct including benign condition like primary sclerosing cholangitis,iatrogenic injury,infection and IgG 4 related conditions to malignant condition like carcinoma involving the whole course of bile duct,pancreatic carcinoma and adenocarcinoma in the periampullary regions(2-5).

A construct of adipose-derived mesenchymal stem cells—laden collagen scaffold for fertility restoration by inhibiting fibrosis in a rat model of endometrial injury

Severe endometrium damage causes pathological conditions such as thin endometrium and intrauterine adhesion,resulting in uterine factor infertility.Mesenchymal stem cell(MSC)therapy is a promising strategy in endometrial repair;yet,exogenous MSCs still raise concerns for safety and ethical issues.Human adipose-derived mesenchymal stem cells(ADMSCs)residing in adipose tissue have high translational potentials due to their autologous origin.To harness the high translation potentials of ADMSC in clinical endometrium regeneration,here we constructed an ADMSCs composited porous scaffold(CS/ADMSC)and evaluated its effectiveness on endometrial regeneration in a rat endometrium-injury model.We found that CS/ADMSC intrauterine implantation(i)promoted endometrial thickness and gland number,(ii)enhanced tissue angiogenesis,(iii)reduced fibrosis and(iv)restored fertility.We ascertained the pro-proliferation,pro-angiogenesis,immunomodulating and anti-fibrotic effects of CS/ADMSC in vitro and revealed that the CS/ADMSC influenced extracellular matrix composition and organization by a transcriptomic analysis.Our results demonstrated the effectiveness of CS/ADMSC for endometrial regeneration and provided solid proof for our future clinical study.

Regulation of extracellular bioactive cations in bone tissue microenvironment induces favorable osteoimmune conditions to accelerate in situ bone regeneration

The design of orthopedic biomaterials has gradually shifted from“immune-friendly”to“immunomodulatory,”in which the biomaterials are able to modulate the inflammatory response via macrophage polarization in a local immune microenvironment that favors osteogenesis and implant-to-bone osseointegration.Despite the well-known effects of bioactive metallic ions on osteogenesis,how extracellular metallic ions manipulate immune cells in bone tissue microenvironments toward osteogenesis and subsequent bone formation has rarely been studied.Herein,we investigate the osteoimmunomodulatory effect of an extracellular bioactive cation(Mg^(2+))in the bone tissue microenvironment using custom-made poly lactic-co-glycolic acid(PLGA)/MgO-alendronate microspheres that endow controllable release of magnesium ions.The results suggest that the Mg^(2+)-controlled tissue microenvironment can effectively induce macrophage polarization from the M0 to M2 phenotype via the enhancement of anti-inflammatory(IL-10)and pro-osteogenic(BMP-2 and TGF-β1)cytokines production.It also generates a favorable osteoimmune microenvironment that facilitates the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells.The in vivo results further verify that a large amount of bony tissue,with comparable bone mineral density and mechanical properties,has been generated at an early post-surgical stage in rat intramedullary bone defect models.This study demonstrates that the concept of in situ immunomodulated osteogenesis can be realized in a controlled magnesium tissue microenvironment.

Fabrication of a bio-instructive scaffold conferred with a favorable microenvironment allowing for superior implant osseointegration and accelerated in situ vascularized bone regeneration via type H vessel formation

The potential translation of bio-inert polymer scaffolds as bone substitutes is limited by the lack of neovascularization upon implantation and subsequently diminished ingrowth of host bone,most likely resulted from the inability to replicate appropriate endogenous crosstalk between cells.Human umbilical vein endothelial cell-derived decellularized extracellular matrix(HdECM),which contains a collection of angiocrine biomolecules,has recently been demonstrated to mediate endothelial cells(ECs)-osteoprogenitors(OPs)crosstalk.We employed the HdECM to create a PCL(polycaprolactone)/fibrin/HdECM(PFE)hybrid scaffold.We hypothesized PFE scaffold could reconstitute a bio-instructive microenvironment that reintroduces the crosstalk,resulting in vascularized bone regeneration.Following implantation in a rat femoral bone defect,the PFE scaffold demonstrated early vascular infiltration and enhanced bone regeneration by microangiography(μ-AG)and micro-computational tomography(μ-CT).Based on the immunofluorescence studies,PFE mediated the endogenous angiogenesis and osteogenesis with a substantial number of type H vessels and osteoprogenitors.In addition,superior osseointegration was observed by a direct host bone-PCL interface,which was likely attributed to the formation of type H vessels.The bio-instructive microenvironment created by our innovative PFE scaffold made possible superior osseointegration and type H vessel-related bone regeneration.It could become an alternative solution of improving the osseointegration of bone substitutes with the help of induced type H vessels,which could compensate for the inherent biological inertness of synthetic polymers.

Fracture of Extensively Porous-Coated Cylindrical Femoral Stem Following Revision Total Hip Arthroplasty

Total hip arthroplasty （THA） is one of the most clinically successful surgeries. Despite the prevalence of THA, the number of revisions for septic or aseptic reasons continues to increase.

Next-Generation Sequencing-Based Diagnosis of Bacteremic Listeria monocytogenes Meningitis in a Patient with Anti-Interferon Gamma Autoantibodies:A Case Report

Although various opportunistic infections have been described in patients with anti-interferon gamma autoantibodies,so far there is no Listeria monocytogenes infection reported to be associated with this primary immunodeficiency.Here,we describe the first case of bacteremic L.monocytogenes meningitis in a 59-year-old Chinese man with anti-interferon gamma autoantibodies,who presented with acute onset of fever and severe headache.Blood culture was positive but culture of the cerebrospinal fluid was negative,although it showed features suggestive of partially treated bacterial meningitis.The presence of L.monocytogenes in the cerebrospinal fluid was confirmed by next-generation sequencing.Avoidance of high-risk food items in these patients is important for the prevention of listeriosis.The use of antibiotic regimens that cover Listeria is crucial for empirical treatment,particularly if such patients develop acute or subacute meningitis.Next-generation sequencing is becoming an important diagnostic modality for culture-negative infections.

P21-activated kinase 1 (PAK1)-mediated cytoskeleton rearrangement promotes SARS-CoV-2 entry and ACE2 autophagic degradation

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent of coronavirus disease 2019(COVID-19),has had a significant impact on healthcare systems and economies worldwide.The continuous emergence of new viral strains presents a major challenge in the development of effective antiviral agents.Strategies that possess broad-spectrum antiviral activities are desirable to control SARS-CoV-2 infection.ACE2,an angiotensin-containing enzyme that prevents the overactivation of the renin angiotensin system,is the receptor for SARS-CoV-2.ACE2 interacts with the spike protein and facilitates viral attachment and entry into host cells.Yet,SARS-CoV-2 infection also promotes ACE2 degradation.Whether restoring ACE2 surface expression has an impact on SARS-CoV-2 infection is yet to be determined.Here,we show that the ACE2-spike complex is endocytosed and degraded via autophagy in a manner that depends on clathrin-mediated endocytosis and PAK1-mediated cytoskeleton rearrangement.In contrast,free cellular spike protein is selectively cleaved into S1 and s2 subunits in a lysosomal-dependent manner.Importantly,we show that the pan-PAK inhibitor FRAX-486 restores ACE2 surface expression and suppresses infection by different SARS-CoV-2 strains.FRAX-486-treated Syrian hamsters exhibit significantly decreased lung viral load and alleviated pulmonary inflammation compared with untreated hamsters.In summary,our findings have identified novel pathways regulating viral entry,as well as therapeutic targets and candidate compounds for controlling the emerging strains of SARS-CoV-2 infection.

Corrigendum to‘Fabrication of a bio-instructive scaffold conferred with a favorable microenvironment allowing for superior implant osseointegration and accelerated in situ vascularized bone regeneration via type H vessel formation’[Bioactive Materials,Volume 9(March 2022)Page 491-507]

The authors regret a mistake of funding numbers in the Acknowledgment Section failed to be corrected during proofreading.Below is the corrected funding statement in ACKNOWLEDGMENT SECTION:This work was supported by the National Natural Science Foundation of China(NSFC)(Nos.82072415,81772354,81902189),Clinical Innovation Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory(2018GZR0201002),Science Technology Project of Guangzhou City(2019ZD15).

等离子体聚合改性对医用钛表面性能的影响

采用低温等离子体聚合改性技术在医用钛表面聚合丙烯胺单体,沉积一层聚合物改性层,在此过程中,以氮等离子体注入作为预处理,研究等离子体预处理对表面丙烯胺聚合改性层的性能影响。采用扫描电子显微镜、原子力显微镜、以及能谱分析、傅里叶红外光谱分析仪对不同条件下等离子体聚合物表面改性层的形貌、拓扑结构、官能团结构及化学成分进行研究,以及通过表面接触角测试仪分析表面亲水性能。结果显示,低温表面等离子体聚合手段能够在钛合金表面形成一层厚度可以调节的纳米聚合物改性层,电化学测试表明,聚合物改性层能够提高表面耐腐蚀性能;接触角测试表明表面聚合物改性层能够提高钛合金表面的亲水性能;FTIR分析表明低温表面等离子体聚合手段能够很好的保留丙烯胺中的氨基官能团,因此能够改善聚合物层的生物活性,有利于细胞的生长。同时,氮的注入之所以能够提高丙烯胺表面聚合物层与基体的结合效率,是因为氮等离子体注入预处理能够在钛合金表面形成梯度结构的过度TiN层,能够有利于等离子聚合过程中–C–N、C–H、–C–NH2、–O=C–NH2等官能团与基体之间的键合。