Synthesis of the Biomimetic Polymer: Aliphatic Diamine and RGDS Modified Poly(d,l-lactic acid)

A novel poly（d, /-lactic acid） （PDLLA） based biomimetic polymer was synthesized by grafting maleic anhydride, butanediamine and arg-gly-asp-ser （RGDS） peptides onto the backbone of PDLLA, aiming to overcome the acidity and auto-accelerating degradation of PDLLA during degradation and to improve its biospecificity and biocompatibility. The synthetic copolymer was characterized by FTIR, ^13C NMR and amino acid analyzer （AAA）.

Synthesis and characterization of biodegradable polymer:Poly (ethene maleic acid ester-co-D,L-lactide acid)

A novel biodegradable polymer--poly （ethene maleic acid ester-co-D,L-lactide acid） was synthesized by copolymerizing lactide and prepolymer, which was prepared by the condensation of maleic anhydride and glycol, using p-toluene sulphonic acid as a catalyst, attempting to improve the hydrophilicity, increase flexibility and modulate the degradation rate. FTIR,^1H NMR, MALLS and DSC were employed to characterize these polymers.

Effects of rotational culture on morphology,nitric oxide production and cell cycle of endothelial cells

Devices for the rotational culture of cells and the study of biological reactions have been widely applied in tissue engineering.However,there are few reports exploring the effects of rotational culture on cell morphology,nitric oxide(NO)production,and cell cycle of the endothelial cells from human umbili-cal vein on the stent surface.This study focuses on these parameters after the cells are seeded on the stents.Results showed that covering of stents by endothelial cells was improved by rotational culture.NO produc-tion decreased within 24 h in both rotational and static culture groups.In addition,rotational culture signifi-cantly increased NO production by 37.9%at 36 h and 28.9%at 48 h compared with static culture.Flow cytometry showed that the cell cycle was not obviously influenced by rotational culture.Results indicate that rotational culture may be helpful for preparation of cell-seeded vascular grafts and intravascular stents,which are expected to be the most frequently implanted materials in the future.

Recent advances of mechanosensitive genes in vascular endothelial cells for the formation and treatment of atherosclerosis

Atherosclerotic cardiovascular disease and its complications are a high-incidence disease worldwide.Numerous studies have shown that blood flow shear has a huge impact on the function of vascular endothelial cells,and it plays an important role in gene regulation of pro-inflammatory,pro-thrombotic,pro-oxidative stress,and cell permeability.Many impor-tant endothelial cell mechanosensitive genes have been discovered,including KLK10,CCN gene family,NRP2,YAP,TAZ,HIF-1α,NF-kB,FOS,JUN,TFEB,KLF2/KLF4,NRF2,and ID1.Some of them have been intensively studied,whereas the relevant regulatory mechanism of other genes remains unclear.Focusing on these mechanosensitive genes will provide new strategies for therapeutic intervention in atherosclerotic vascular disease.Thus,this article reviews the mechanosensitive genes affecting vascular endothelial cells,including classical pathways and some newly screened genes,and summarizes the latest research progress on their roles in the pathogenesis of atherosclerosis to reveal effective therapeutic targets of drugs and provide new insights foranti-atherosclerosis.

A Novel Poly(3-hexylthiophene) Engineered Interface for Electrochemical Monitoring of Ascorbic Acid During the Occurrence of Glutamate-Induced Brain Cytotoxic Edemas

Although neuroelectrochemical sensing technology offers unique benefits for neuroscience research,its application is limited by substantial interference in complex brain environments while ensuring biosafety requirements.In this study,we introduced poly(3-hexylthiophene)(P3HT)and nitrogen-doped multiwalled carbon nanotubes(N-MWCNTs)to construct a composite membrane-modified carbon fiber microelectrode(CFME/P3HT-N-MWCNTs)for ascorbic acid(AA)detection.The microelectrode presented good linearity,selectivity,stability,antifouling,and biocompatibility and exhibited great performance for application in neuroelectrochemical sensing.Subsequently,we applied CFME/P3HT-N-MWCNTs to monitor AA release from in vitro nerve cells,ex vivo brain slices,and in vivo living rat brains and determined that glutamate can induce cell edema and AA release.We also found that glutamate activated the N-methyl-d-aspartic acid receptor,which enhanced Na^(+) and Cl^(−) inflow to induce osmotic stress,resulting in cytotoxic edema and ultimately AA release.This study is the first to observe the process of glutamate-induced brain cytotoxic edema with AA release and to reveal the mechanism.Our work can benefit the application of P3HT in in vivo implant microelectrode construction to monitor neurochemicals,understand the molecular basis of nervous system diseases,and discover certain biomarkers of brain diseases.

Effects of COVID-19 pandemic on human fertility:A scientometric and visualized evaluation

CovID-19,also known as coronavirus disease 2019,is a novel coronavirus disease with high infectivity,strong heterogeneity,and long incubation period(generally 3-14 days).Its main symptoms and signs include fever,dry cough,nasal congestion,fatigue,disorientation,lymphopenia,and dyspnea.The short-term and long-term impacts of covID-19 on human health,particularly its effects on human reproduction and offspring development,continue to receive significant concerns,as they may lead to potential sequelae for several decades or even centuries.

Small molecules facilitate single factor-mediated sweat gland cell reprogramming

Background: Large skin defects severely disrupt the overall skin structure and can irreversibly damage sweat glands(SGs), thus impairing the skin’s physiological function. This study aims to develop a stepwise reprogramming strategy to convert fibroblasts into SG lineages, which may provide a promising method to obtain desirable cell types for the functional repair and regeneration of damaged skin.Methods: The expression of the SG markers cytokeratin 5(CK5), cytokeratin 10(CK10), cytokeratin 18(CK18), carcinoembryonic antigen(CEA), aquaporin 5(AQP5) and α-smooth muscle actin(α-SMA) was assessed with quantitative PCR(qPCR), immunofluorescence and flow cytometry. Calcium activity analysis was conducted to test the function of induced SG-like cells(iSGCs). Mouse xenograft models were also used to evaluate the in vivo regeneration of iSGCs.BALB/c nude mice were randomly divided into normal group, SGM treatment group and iSGC transplantation group.Immunocytochemical analyses and starch-iodine sweat tests were used to confirm the in vivo regeneration of iSGCs.Results: Ectodermal dysplasia antigen(EDA) overexpression drove human dermal fibroblast(HDF) conversion into i SGCs in SG culture medium(SGM). qPCR indicated significantly increased mRNA levels of the SG markers CK5, CK18and CEA in iSGCs, and flow cytometry data demonstrated(4.18±0.04)% of iSGCs were CK5 positive and(4.36±0.25)%of iSGCs were CK18 positive. The addition of chemical cocktails greatly accelerated the SG fate program. qPCR results revealed significantly increased mRNA expression of CK5, CK18 and CEA in iSGCs, as well as activation of the duct marker CK10 and luminal functional marker AQP5. Flow cytometry indicated, after the treatment of chemical cocktails,(23.05±2.49)% of iSGCs expressed CK5^(+) and(55.79±3.18)% of iSGCs expressed CK18^(+), respectively. Calcium activity analysis indicated that the reactivity of iSGCs to acetylcholine was close to that of primary SG cells [(60.79±7.71)% vs.(70.59±0.34)%, ns]. In vivo transplantation experiments showed approximately(5.2±1.1)% of the mice were sweat test positive, and the histological analysis results indicated that regenerated SG structures were present in iSGCs-treated mice.Conclusions: We developed a SG reprogramming strategy to generate functional iSGCs from HDFs by using the single factor EDA in combination with SGM and small molecules. The generation of iSGCs has important implications for future in situ skin regeneration with SG restoration.

The Janus-faced role of Piezo1 in cardiovascular health under mechanical stimulation

In recent years,cardiovascular health problems are becoming more and more serious.At the same time,mechanical stimulation closely relates to cardiovascular health.In this context,Piezo1,which is very sensitive to mechanical stimulation,has attracted our attention.Here,we review the critical significance of Piezo1 in mechanical stimulation of endothelial cells,NO production,lipid metabolism,DNA damage protection,the development of new blood vessels and maturation,narrowing of blood vessels,blood pressure regulation,vascular permeability,insulin sensitivity,and maintenance of red blood cell function.Besides,Piezo1 may participate in the occurrence and development of atherosclerosis,diabetes,hypertension,and other cardiovascular diseases.It is worth noting that Piezo1 has dual effects on maintaining cardiovascular health.On the one hand,the function of Piezo1 is necessary to maintain cardiovascular health;on the other hand,under some extreme mechanical stimulation,the overexpression of Piezo1 may bring adverse factors such as inflammation.Therefore,this review discusses the Janus-faced role of Piezo1 in maintaining cardiovascular health and puts forward new ideas to provide references for gene therapy or nanoagents targeting Piezo1.

Ectopic mineralization-inspired cell membrane-based matrix vesicle analogs for in-depth remineralization of dentinal tubules for treating dentin hypersensitivity

The invasion of etched dentinal tubules(DTs)by external substances induces dentin hypersensitivity(DH).The deep and compact occlusion of DTs is highly desirable for treating DH but still challenging due to the limited penetrability and mineralization capacities of most current desensitizers.Matrix vesicles(MVs)participate in the regulation of ectopic mineralization.Herein,ectopic MV analogs are prepared by employing natural cell membranes to endow mineral precursors with natural biointerfaces and integrated biofunctions for stimulating dentin remineralization.The analogs quickly access DTs(>20μm)in only 5 min and further penetrate deep into the interior of DTs(an extraordinary~200μm)in 7 days.Both in vitro and in vivo studies confirm that the DTs are efficiently sealed by the newly formed minerals(>50μm)with excellent resistance to wear and acid erosion,which is significantly deeper than most reported values.After repair,the microhardness of the damaged dentin can be recovered to those of healthy dentin.For the first time,cell membrane coating nanotechnology is used as a facile and efficient therapy for in-depth remineralization of DTs in treating DH with thorough and long-term effects,which provides insights into their potential for hard tissue repair.

Effect of ultrasound with methylene blue as sound sensitive agent on virus inactivation

The goal of this paper is to explore a method for virus inactivation based on ultrasonic treatment,and on this basis,to explore the synergistic effect of methylene blue as a sonosensitizer in virus inactivation.The titer of human parainfluenza virus type 3(HPIV3),Autographacaliforinica nuclear polyhedrosis virus carried a green fluorescent reporter gene(AcNPV-GFP)and Enterovirus group D 68(EV-D68)were determined by plaque assays or TCID50 methods after treatment by MB combined with illumination(MB photochemical,MBP)or ultrasonic excitation.Different ultrasonic power and time,MB concentration gradient were set to determine the best antiviral combination.For the enveloped virus HPIV3 and AcNPV-GFP,pure ultrasonic or MBP treatment could reduce viral titer more than 104,and ultrasonic combined with MB could completely inactivate HPIV3 and AcNPV-GFP in 5min while traditional MBP methods could only reduce viral titer about 10X.For the nonenveloped virus EV-D68,pure ultrasonic or MBP treatment only reduced the viral titer about 102,but ultrasonic combined with MB treatment could reduce the viral titer about 103 in 5min and completely inactive EV-D68 in 10min(reduced 105).Compared with MBP method and pure ultrasonic inactivation,ultrasonic combined with MB has better inactivation effect on either enveloped or non-enveloped viruses,and the appropriate combination of parameters is expected to be a new blood transfusion transmitted virus inactivation method.

Fibroblast membrane-camouflaged nanoparticles for inflammation treatment in the early stage

Unrestrained inflammation is harmful to tissue repair and regeneration.Immune cell membrane-camouflaged nanoparticles have been proven to show promise as inflammation targets and multitargeted inflammation controls in the treatment of severe inflammation.Prevention and early intervention of inflammation can reduce the risk of irreversible tissue damage and loss of function,but no cell membrane-camouflaged nanotechnology has been reported to achieve stage-specific treatment in these conditions.In this study,we investigated the prophylactic and therapeutic efficacy of fibroblast membrane-camouflaged nanoparticles for topical treatment of early inflammation(early pulpitis as the model)with the help of in-depth bioinformatics and molecular biology investigations in vitro and in vivo.Nanoparticles have been proven to act as sentinels to detect and competitively neutralize invasive Escherichia coli lipopolysaccharide(E.coli LPS)with resident fibroblasts to effectively inhibit the activation of intricate signaling pathways.Moreover,nanoparticles can alleviate the secretion of multiple inflammatory cytokines to achieve multitargeted anti-inflammatory effects,attenuating inflammatory conditions in the early stage.Our work verified the feasibility of fibroblast membrane-camouflaged nanoparticles for inflammation treatment in the early stage,which widens the potential cell types for inflammation regulation.

The recent advances and future perspectives of genetic compensation studies in the zebrafish model

Genetic compensation is a remarkable biological concept to explain the genetic robustness in an organism to maintain its fitness and viability if there is a disruption occurred in the genetic variation by mutation.However,the underlying mechanism in genetic compensation remain unsolvable.The initial concept of genetic compensation has been studied in model organisms when there was a discrepancy between knockout-mediated and knockdown-mediated phenotypes.In the zebrafish model,several studies have reported that zebrafish mutants did not exhibit severe phenotype as shown in zebrafish morphants for the same genes.This phenomenon in zebrafish mutants but not morphants is due to the response of genetic compensation.In 2019,two amazing works partially uncovered genetic compensation could be triggered by the upregulation of compensating genes through regulating NMD and/or PTC-bearing mRNA in collaboration with epigenetic machinery in mutant zebrafish.In this review,we would like to update the recent advances and future perspectives of genetic compensation studies,which including the hypothesis of time-dependent involvement and addressing the discrepancy between knockout-mediated and knockdown-mediated to study gene function in the zebrafish model.At last,the study of genetic compensation could be a potential therapeutic strategy to treat human genetic disorder related diseases.

Development of a molecular feature-based survival prediction model of ovarian cancer using the deep neural network

Ovarian cancer(OC)is one of the most lethal gynecologic cancer worldwide,and survival prediction is meaningful for personalized treatment.^(1)The survival outcome of cancer patients mainly depended on the malignancy of the primary tumor which is tightly linked with the expression profile of the molecular features.^(2)Therefore,in this study,we developed a molecular feature-based survival prediction model of OC using a deep neural network(DNN).

FaSRnet:a feature and semantics refinement network for human pose estimation

Due to factors such as motion blur,video out-of-focus,and occlusion,multi-frame human pose estimation is a challenging task.Exploiting temporal consistency between consecutive frames is an efficient approach for addressing this issue.Currently,most methods explore temporal consistency through refinements of the final heatmaps.The heatmaps contain the semantics information of key points,and can improve the detection quality to a certain extent.However,they are generated by features,and feature-level refinements are rarely considered.In this paper,we propose a human pose estimation framework with refinements at the feature and semantics levels.We align auxiliary features with the features of the current frame to reduce the loss caused by different feature distributions.An attention mechanism is then used to fuse auxiliary features with current features.In terms of semantics,we use the difference information between adjacent heatmaps as auxiliary features to refine the current heatmaps.The method is validated on the large-scale benchmark datasets PoseTrack2017 and PoseTrack2018,and the results demonstrate the effectiveness of our method.

Effect of intraplaque angiogenesis to atherosclerotic rupture-prone plaque induced by high shear stress in rabbit model

Atherosclerotic prone-rupture plaque is mainly localized in the region of the entrance to the stenosiswith high shear stress and the reasons are largely unknown. Our hypothesis is that such a distributionof cells in atherosclerotic plaque may depend on the angiogenesis. Silastic collars inducedregions of high shear stress (20.6865.27 dynes/cm2) in the upstream flow and low shear stress(12.2561.28 dynes/cm2) in the downstream flow in carotid arteries. Compared with the low shearstress region, plaques in the high shear stress region showed more intraplaque haemorrhaging,less collagen and higher apoptotic rates of vascular smooth muscle cells;endothelial cells (ECs) inthe high shear stress region were characterized with integrity and high endothelial nitric oxidesynthase (eNOS) expression (1570.36345.5% vs 172.9649.9%). The number of intraplaque microvesselsis very high in the high shear stress region (1561.8 n/mm2 vs 3.560.4 n/mm2), and themicrovessels in the plaque show ECs were abnormal, with membrane blebs, intracytoplasmic vacuolesand leukocyte infiltration. Our current study reveals that the integrity of the endothelium andthe vulnerability of atherosclerotic plaques are simultaneously localized in high shear stress regions,and we provide evidence for the first time that microvessels in the intraplaque maybe responsiblefor rupture-prone plaque formation in the high shear stress region.

Impurity analysis of gentamicin bulk samples by improved liquid chromatography-ion trap mass spectrometry

Several gentamicin bulk samples from different origins were investigated using an LC/MS method.LC equipped with ion trap MS with positive ionization was performed on a Capcell Pak C18(AQ) column with the mobile phase containing 50 mM trifluoroacetic(TFA) and methanol.Impurities present in batches of gentamicin bulk samples were elucidated and compared according to their fragmentation behavior.In total seventeen impurities present in samples,five impurities were not elucidated and two compounds were identified preliminarily.It was observed that the impurity profiles were different in samples from different origins which indicate necessity in the quality control of gentamicin.

A novel mechanism of inhibiting in-stent restenosis with arsenic trioxide drug-eluting stent: Enhancing contractile phenotype of vascular smooth muscle cells via YAP pathway

Objective:Arsenic trioxide(ATO or As2O3)has beneficial effects on suppressing neointimal hyperplasia and restenosis,but the mechanism is still unclear.The goal of this study is to further understand the mechanism of ATO's inhibitory effect on vascular smooth muscle cells(VSMCs).Methods and results:Through in vitro cell culture and in vivo stent implanting into the carotid arteries of rabbit,a synthetic-to-contractile phenotypic transition was induced and the proliferation of VSMCs was inhibited by ATO.F-actin filaments were clustered and the elasticity modulus was increased within the phenotypic modulation of VSMCs induced by ATO in vitro.Meanwhile,Yes-associated protein(YAP)nuclear translocation was inhibited by ATO both in vivo and in vitro.It was found that ROCK inhibitor or YAP inactivator could partially mask the phenotype modulation of ATO on VSMCs.Conclusions:The interaction of YAP with the ROCK pathway through ATO seems to mediate the contractile phenotype of VSMCs.This provides an indication of the clinical therapeutic mechanism for the beneficial bioactive effect of ATO-drug eluting stent(AES)on in-stent restenosis(ISR).

Uptake of oxidative stress-mediated extracellular vesicles by vascular endothelial cells under low magnitude shear stress

Extracellular vesicles(EVs)are increasingly used as delivery vehicles for drugs and bioactive molecules,which usually require intravascular administration.The endothelial cells covering the inner surface of blood vessels are susceptible to the shear stress of blood flow.Few studies demonstrate the interplay of red blood cell-derived EVs(RBCEVs)and endothelial cells.Thus,the phagocytosis of EVs by vascular endothelial cells during blood flow needs to be elucidated.In this study,red blood cell-derived extracellular vesicles(RBCEVs)were constructed to investigate endothelial cell phagocytosis in vitro and animal models.Results showed that low magnitude shear stress including low shear stress(LSS)and oscillatory shear stress(OSS)could promote the uptake of RBCEVs by endothelial cells in vitro.In addition,in zebrafish and mouse models,RBCEVs tend to be internalized by endothelial cells under LSS or OSS.Moreover,RBCEVs are easily engulfed by endothelial cells in atherosclerotic plaques exposed to LSS or OSS.In terms of mechanism,oxidative stress induced by LSS is part of the reason for the increased uptake of endothelial cells.Overall,this study shows that vascular endothelial cells can easily engulf EVs in areas of low magnitude shear stress,which will provide a theoretical basis for the development and utilization of EVs-based nano-drug delivery systems in vivo.

Inhibition of in-stent restenosis after graphene oxide double-layer drug coating with good biocompatibility

In this study,we designed a double layer-coated vascular stent of 316L stainless steel using an ultrasonic spray system to achieve both antiproliferation and antithrombosis.The coating included an inner layer of graphene oxide(GO)loaded with docetaxel(DTX)and an outer layer of carboxymethyl chitosan(CMC)loaded with heparin(Hep).The coated surface was uniform without aggregation and shedding phenomena before and after stent expanded.The coating treatment was able to inhibit the adhesion and activation of platelets and the proliferation and migration of smooth muscle cells,indicating the excellent biocompatibility and antiproliferation ability.The toxicity tests showed that the GO/DTX and CMC/Hep coating did not cause deformity and organ abnormalities in zebrafish under stereomicroscope.The stents with GO double-layer coating were safe and could effectively prevent thrombosis and in-stent restenosis after the implantation into rabbit carotid arteries for 4–12 weeks.