Integration of Theory and Practice in Medical Morphology Curriculum in Postgraduate Training:A Flipped Classroom and Case-based Learning Exercise

Objective:The integration of training in theory and practice across the medical education spectrum is being encouraged to increase student understanding and skills in the sciences.This study aimed to determine the deciding factors that drive students'perceived advantages in class to improve precision education and the teaching model.Methods:A mixed strategy of an existing flipped classroom(FC)and a case-based learning(CBL)model was conducted in a medical morphology curriculum for 575 postgraduate students.The subjective learning evaluation of the individuals(learning time,engagement,study interest and concentration,and professional integration)was collected and analyzed after FC-CBL model learning.Results:The results from the general evaluation showed promising results of the medical morphology in the FC-CBL model.Students felt more engaged by instructors in person and benefited in terms of time-saving,flexible arrangements,and professional improvement.Our study contributed to the FC-CBL model in Research Design in postgraduate training in 4 categories:1)advancing a guideline of precision teaching according to individual characteristics;2)revealing whether a learning background is needed for a Research Design course to guide setting up a preliminary course;3)understanding the perceived advantages and their interfaces;and 4)barriers and/or improvement to implement the FC-CBL model in the Research Design class,such as a richer description of e-learning and hands-on practice.Conclusion:Undertaking a FC-CBL combined model could be a useful addition to pedagogy for medical morphology learning in postgraduate training.

Gasdermin D-mediated hepatocyte pyroptosis expands inflammatory responses that aggravate acute liver failure by upregulating monocyte chemotactic protein 1/CC chemokine receptor-2 to recruit macrophages

BACKGROUND Massive hepatocyte death is the core event in acute liver failure(ALF).Gasdermin D(GSDMD)-mediated pyroptosis is a type of highly inflammatory cell death.However,the role of hepatocyte pyroptosis and its mechanisms of expanding inflammatory responses in ALF are unclear.AIM To investigate the role and mechanisms of GSDMD-mediated hepatocyte pyroptosis through in vitro and in vivo experiments.METHODS The expression of pyroptosis pathway-associated proteins in liver tissues from ALF patients and a hepatocyte injury model was examined by Western blot.GSDMD short hairpin RNA(shRNA)was used to investigate the effects of downregulation of GSDMD on monocyte chemotactic protein 1(MCP1)and its receptor CC chemokine receptor-2(CCR2)in vitro.For in vivo experiments,we used GSDMD knockout mice to investigate the role and mechanism of GSDMD in a D-galactose/lipopolysaccharide(D-Galn/LPS)-induced ALF mouse model.RESULTS The levels of pyroptosis pathway-associated proteins in liver tissue from ALF patients and a hepatocyte injury model increased significantly.The level of GSDMD-N protein increased most obviously(P<0.001).In vitro,downregulation of GSDMD by shRNA decreased the cell inhibition rate and the levels of MCP1/CCR2 proteins(P<0.01).In vivo,GSDMD knockout dramatically eliminated inflammatory damage in the liver and improved the survival of DGaln/LPS-induced ALF mice(P<0.001).Unlike the mechanism of immune cell pyroptosis that involves releasing interleukin(IL)-1βand IL-18,GSDMDmediated hepatocyte pyroptosis recruited macrophages via MCP1/CCR2 to aggravate hepatocyte death.However,this pathological process was inhibited after knocking down GSDMD.CONCLUSION GSDMD-mediated hepatocyte pyroptosis plays an important role in the pathogenesis of ALF,recruiting macrophages to release inflammatory mediators by upregulating MCP1/CCR2 and leading to expansion of the inflammatory responses.GSDMD knockout can reduce hepatocyte death and inflammatory responses,thus alleviating ALF.

Fluoxetine ameliorates depressive symptoms by regulating lncRNA expression in the mouse hippocampus

Depression is a prevalent mental disorder that is associated with aging and contributes to increased mortality and morbidity.The overall prevalence of geriatric depression with clinically significant symptoms is currently on the rise.Recent studies have demonstrated that altered expressions of long non-coding RNAs(lncRNAs)in the brain affect neurodevelopment and manifest modulating functions during the depression.However,most lncRNAs have not yet been studied.Herein,we analyzed the transcriptome of dysregulated lncRNAs to reveal their expressions in a mouse model exhibiting depressive-like behaviors,as well as their corresponding response following antidepressant fluoxetine treatment.A chronic unpredictable mild stress(CUMS)mouse model was applied.A sixweek fluoxetine intervention in CUMS-induced mice attenuated depressive-like behaviors.In addition,differential expression analysis of lncRNAs was performed following RNA-sequencing.A total of 282 lncRNAs(134 up-regulated and 148 down-regulated)were differentially expressed in CUMS-induced mice relative to non-stressed counterparts(P<0.05).Moreover,370 differentially expressed lncRNAs were identified in CUMS-induced mice after fluoxetine intervention.Gene Ontology(GO)analyses showed an association between significantly dysregulated lncRNAs and protein binding,oxygen binding,and transport activity,while the Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis indicated that these dysregulated lncRNAs might be involved in inflammatory response pathways.Fluoxetine effectively ameliorated the symptoms of depression in CUMS-induced mice by regulating the expression of lncRNAs in the hippocampus.The findings herein provide valuable insights into the potential mechanism underlying depression in elderly people.

Phonon Focusing Effect in an Atomic Level Triangular Structure

The rise of artificial microstructures has made it possible to modulate propagation of various kinds of waves,such as light,sound and heat.Among them,the focusing effect is a modulation function of particular interest.We propose an atomic level triangular structure to realize the phonon focusing effect in single-layer graphene.In the positive incident direction,our phonon wave packet simulation results confirm that multiple features related to the phonon focusing effect can be controlled by adjusting the height of the triangular structure.More interestingly,a completed different focusing pattern and an enhanced energy transmission coefficient are found in the reverse incident direction.The detailed mode conversion physics is discussed based on the Fourier transform analysis on the spatial distribution of the phonon wave packet.Our study provides physical insights to achieving phonon focusing effect by designing atomic level microstructures.

Do pyroptosis, apoptosis, and necroptosis (PANoptosis) exist in cerebral ischemia? Evidence from cell and rodent studies

Some scholars have recently developed the concept of PANoptosis in the study of infectious diseases where pyroptosis,apoptosis and necroptosis act in consort in a multimeric protein complex,PANoptosome.This allows all the components of PANoptosis to be regulated simultaneously.PANoptosis provides a new way to study the regulation of cell death,in that different types of cell death may be regulated at the same time.To test whether PANoptosis exists in diseases other than infectious diseases,we chose cerebral ischemia/reperfusion injury as the research model,collected articles researching cerebral ischemia/reperfusion from three major databases,obtained the original research data from these articles by bibliometrics,data mining and other methods,then integrated and analyzed these data.We selected papers that investigated at least two of the components of PANoptosis to check its occurrence in ischemia/reperfusion.In the cell model simulating ischemic brain injury,pyroptosis,apoptosis and necroptosis occur together and this phenomenon exists widely in different passage cell lines or primary neurons.Pyroptosis,apoptosis and necroptosis also occurred in rat and mouse models of ischemia/reperfusion injury.This confirms that PANoptosis is observed in ischemic brain injury and indicates that PANoptosis can be a target in the regulation of various central nervous system diseases.

Bone morphogenetic protein-7 represses hepatic stellate cell activation and liver fibrosis via regulation of TGF-β/Smad signaling pathway

BACKGROUND Liver fibrosis is a refractory disease whose persistence can eventually induce cirrhosis or even liver cancer.Early liver fibrosis is reversible by intervention.As a member of the transforming growth factor-beta(TGF-β)superfamily,bone morphogenetic protein 7(BMP7)has anti-liver fibrosis functions.However,little is known about BMP7 expression changes and its potential regulatory mechanism as well as the relationship between BMP7 and TGF-βduring liver fibrosis.In addition,the mechanism underlying the anti-liver fibrosis function of BMP7 needs to be further explored.AIM To investigate changes in the dynamic expression of BMP7 during liver fibrosis,interactions between BMP7 and TGF-β1,and possible mechanisms underlying the anti-liver fibrosis function of BMP7.METHODS Changes in BMP7 expression during liver fibrosis and the interaction between BMP7 and TGF-β1 in mice were observed.Exogenous BMP7 was used to treat mouse primary hepatic stellate cells(HSCs)to observe its effect on activation,migration,and proliferation of HSCs and explore the possible mechanism underlying the anti-liver fibrosis function of BMP7.Mice with liver fibrosis received exogenous BMP7 intervention to observe improvement of liver fibrosis by using Masson’s trichrome staining and detecting the expression of the HSC activation indicator alpha-smooth muscle actin(α-SMA)and the collagen formation associated protein type I collagen(Col I).Changes in the dynamic expression of BMP7 during liver fibrosis in the human body were further observed.RESULTS In the process of liver fibrosis induced by carbon tetrachloride(CCl4)in mice,BMP7 protein expression first increased,followed by a decrease;there was a similar trend in the human body.This process was accompanied by a sustained increase in TGF-β1 protein expression.In vitro experiment results showed that TGF-β1 inhibited BMP7 expression in a time-and dose-dependent manner.In contrast,high doses of exogenous BMP7 inhibited TGF-β1-induced activation,migration,and proliferation of HSCs;this inhibitory effect was associated with upregulation of pSmad1/5/8 and downregulation of phosphorylation of Smad3 and p38 by BMP7.In vivo experiment results showed that exogenous BMP7 improved liver fibrosis in mice.CONCLUSION During liver fibrosis,BMP7 protein expression first increases and then decreases.This changing trend is associated with inhibition of BMP7 expression by sustained upregulation of TGF-β1 in a time-and dose-dependent manner.Exogenous BMP7 could selectively regulate TGF-β/Smad pathway-associated factors to inhibit activation,migration,and proliferation of HSCs and exert antiliver fibrosis functions.Exogenous BMP7 has the potential to be used as an antiliver fibrosis drug.

Deficit of mitochondria-derived ATP during oxidative stress impairs mouse MII oocyte spindles

Although the role of oxidative stress in maternal aging and infertility has been suggested, the underlying mechanisms are not fully understood. The present study is designed to determine the relationship between mitochondrial function and spindle stability in metaphase II (MII) oocytes under oxidative stress. MII mouse oocytes were treated with H2O2 in the presence or absence of permeability transition pores (PTPs) blockers cyclosporin A (CsA). In addition, antioxidant N-acetylcysteine (NAC), F0/F1 synthase inhibitor oligomycin A, the mitochondria uncoupler carbonyl cyanide 4-trifluoro- methoxyphenylhydrazone (FCCP) or thapsigargin plus 2.5 mM Ca^2+ (Th+2.5 mM Ca^2+) were used in mechanistic studies. Morphologic analyses of oocyte spindles and chromosomes were performed and mitochondrial membrane potential (AWm), cytoplasmic free calcium concentration ([Ca^2+]c) and cytoplasmic ATP content within oocytes were also assayed. In a time- and H202 dose-dependent manner, disruption of meiotic spindles was found after oocytes were treated with H202, which was prevented by pre-treatment with NAC. Administration of H2O2 led to a dissipation of AWm, an increase in [Ca^2+]c and a decrease in cytoplasmic ATP levels. These detrimental responses of oocytes to H2O2 treatment could be blocked by pre-incubation with CsA. Similar to H2O2, both oligomycin A and FCCP dissipated AWm, decreased cytoplasmic ATP contents and disassembled MII oocyte spindles, while high [Ca^2+]c alone had no effects on spindle morphology. In conclusion, the decrease in mitochondria-derived ATP during oxidative stress may cause a disassembly of mouse MII oocyte spindles, presumably due to the opening of the mitochondrial PTPs.

Research trends, hot spots and prospects for necroptosis in the field of neuroscience

There are two types of cell death-apoptosis and necrosis. Apoptosis is cell death regulated by cell signaling pathways, while necrosis has until recently been considered a passive mechanism of cell death caused by environmental pressures. However, recent studies show that necrosis can also be regulated by specific cell signaling pathways. This mode of death, termed necroptosis, has been found to be related to the occurrence and development of many diseases. We used bibliometrics to analyze the global output of literature on necroptosis in the field of neuroscience published in the period 2007–2019 to identify research hotspots and prospects. We included 145 necroptosisrelated publications and 2239 references published in the Web of Science during 2007–2019. Visualization analysis revealed that the number of publications related to necroptosis has increased year by year, reaching a peak in 2019. China is the country with the largest number of publications. Key word and literature analyses demonstrated that mitochondrial function change, stroke, ischemia/reperfusion and neuroinflammation are likely the research hotspots and future directions of necroptosis research in the nervous system. The relationship between immune response-related factors, damage-associated molecular patterns, pathogen-associated molecular patterns and necroptosis may become a potential research hotspot in the future. Taken together, our findings suggest that although the inherent limitations of bibliometrics may affect the accuracy of the literature-based prediction of research hotspots, the results obtained from the included publications can provide a reference for the study of necroptosis in the field of neuroscience.

Alkyl group functionalization-induced phonon thermal conductivity attenuation in graphene nanoribbons

We calculated the room-temperature phonon thermal conductivity and phonon spectrum of alkyl group-functionalized zigzag graphene nanoribbons(ZGNRs) with molecular dynamics simulations. The increase in both chain length and concentration of alkyl groups caused remarkable reduction of phonon thermal conductivity in functionalized ZGNRs. Phonon spectra analysis showed that functionalization of ZGNR with alkyl functional groups induced phonon–structural defect scattering, thus leading to the reduction of phonon thermal conductivity of ZGNR. Our study showed that surface functionalization is an effective routine to tune the phonon thermal conductivity of GNRs, which is useful in graphene thermal-related applications.

Analysis and Optimization of Passenger Side Knee Slider Compression in Front Impact

The influences of different design factors,as well as dummy posture,on an occupants' knee slider compression,were studied in this paper.Based on the vehicle geometry data,the simulation model,including both the multi-rigid-body and finite element(FE)part,was built up and validated with China New Car Assessment Program(C-NCAP)full impact to ensure the accuracy of the model.By adjusting the design parameters and the posture of the femur and lower leg,different factors affecting the passengers' knee slider compression were evaluated,with the help of MAthematical DYnamic MOdel(MADYMO)simulations.The study indicated that the leg posture,the stiffness of the IP and angles of the carpet have significant effects on the knee slider compression in this case.By decreasing the angle between the femur and lower leg from 133° to 124°,the maximum knee slider compression was decreased by 17.3% and by scaling the IP stiffness from 1 to 0.7,it could be decreased by 18.6%.Also,decreasing the angles of the carpet from 28° to 37°can help reduce the knee slider compression by 18.3%.

Protein-based nanocarriers for efficient Etoposide delivery and cancer therapy

Etoposide,a DNA damage-inducing agent,is widely used for malignant tumors.However,insufficient solubility,poor bioavailability and adverse events limited the treatment outcomes and prognosis.To address this,we here developed a novel biosynthetic and unfolded protein nanocarrier to load and deliver Etoposide.Compared with the pristine agent,the loading efficiency of the nanoformulated drug increased four times and the half-life time increased to 17.6 h with controlled release of the Etoposide for 6 days.The half-maximal inhibitory concentration at 48 h was lower than that at 24 h,suggesting a long-acting anti-tumor property.Moreover,the anti-tumor performance in rat models was significantly enhanced by improving solubility and cellular internalization.Additionally,immunogenicity and adverse toxicologic effects such as kidney and liver toxicity were significantly weakened.Therefore,the assembly strategy enables etoposide with higher efficacy,bioavailability,and safety,and has great potential in the comprehensive treatment of malignant tumors.

Carbon honeycomb structure with high axial thermal transport and strong robustness

Thermal transport properties of low-dimensional nanomaterials are highly anisotropic and sensitive to the structural disorder,which can greatly limit their applications in heat dissipation.In this work,we unveil that the carbon honeycomb structures which have high in-plane thermal conductivity simultaneously possess high axial thermal conductivity.Based on non-equilibrium molecular dynamics simulations,we find that the intrinsic axial thermal conductivity of carbon honeycomb structure reaches 746 W·m^(-1)·K^(-1)at room temperature,comparable to that of good heat dissipation materials such as hexagonal boron nitride.By comparing the phonon transmission spectrum between carbon honeycombs and few layer graphene,the physical mechanism responsible for the high axial thermal conductivity of carbon honeycombs is discussed.More importantly,our simulation results further demonstrate that the high axial thermal conductivity of carbon honeycomb structure is robust to the structural disorder,which is a common issue during the mass production of the carbon honeycomb structure.Our study suggests that the carbon honeycomb structure has unique advantages to serve as the thermal management material for practical applications.

Collective cell behaviors manipulated by synthetic DNA nanostructures

Cellular collective motion in confluent epithelial monolayers is involved in many processes such as embryo development,carcinoma invasion,and wound healing.The development of new chemical strategies to achieve largescale control of cells’collective motion is essential for biomedical applications.Here a series of DNA nanostructures with different dimensions were synthesized and their influences on cells’collective migration and packing behaviors in epithelial monolayers were investigated.We found that the framed DNA nanoassemblies effectively reduced the cells’speed by increasing the rigidity of cells,while the lipid-DNA micelles had a more pronounced effect on cells’projection area and shape factor.These DNA nanostructures all significantly enhanced the dependence of cells’speed on their shape factor.Our results indicate that cells’mobility in monolayers can be manipulated by chemical intercellular interactions without any genetic intervention.This may provide a new chemical strategy for tissue engineering and tumor therapy.

DNA辅助纳米金三角片的高效纯化与信息编码

针对目前纳米金三角片的分离纯化手段仍不够成熟这一问题,提出借助巯基修饰的DNA分子,对混有类球形颗粒等杂质的纳米金三角片粗产物,进行形状选择性分离纯化的新思路.纳米金表面修饰的DNA分子,一方面屏蔽了金与溶液环境的直接接触,提高了颗粒的稳定性;另一方面,形貌粒径以及表面DNA修饰量的差异,造成不同纳米金颗粒在电场中的迁移速度不同,因而可通过凝胶电泳手段分离纯化金颗粒.该方法获得的纳米金三角片纯度在80%以上,并对于不同粒径的三角片纯化具有普适性.更为重要的是,表面修饰的DNA同时实现了对纳米金三角片的信息编码,通过设计修饰DNA序列信息,可以实现后续的可控组装,构建更高级结构.

Progress in synthesis and application of zwitterionic Gemini surfactants

Zwitterionic Gemini surfactants have the Gemini molecular structure in which there are both multiple lipophilic groups and multiple hydrophilic groups.However,their hydrophilic groups have different charges.Due to the special molecular structure,this kind of surfactants possesses excellent properties,including high surface activities,isoelectric point(IP),low critical micelle concentration(CMC),less toxicity,low irritating,biodegradability,bioactive,interface modification,and so on.In this review,synthetic strategies of three kinds of zwitterionic Gemini surfactants,i.e.,an ioniccationic,cationic-nonionic and anionic-nonionic Gemini surfactants,are discussed,and their potential applications in life sciences,chemical industry and enhanced oil recovery(EOR)are illustrated.Their future development is also prospected.

精准肝脏外科联合ERAS理念在复杂肝囊型包虫病手术中的应用

目的探讨精准肝脏外科联合加速康复外科(ERAS)理念在复杂肝囊型包虫病患者手术中的应用价值。方法回顾性分析2012年1月至2021年1月在新疆维吾尔自治区人民医院行手术治疗的42例复杂肝囊型包虫病患者临床资料。其中男23例,女19例;年龄23~61岁,中位年龄39岁。患者均签署知情同意书,符合医学伦理学规定。根据围手术期管理模式的不同将患者分为传统外科治疗组(传统组,23例)和精准外科联合ERAS组(联合组,19例)。比较两组患者围手术期情况、术后并发症发生情况及疗效。两组手术时间、术中出血量等数据比较采用t检验或秩和检验,并发症发生率比较采用χ2检验。结果患者均无围手术期死亡。联合组术前均采用三维重建精准评估,手术方式与评估相吻合。联合组术中出血量、术后肝功能恢复时间中位数分别为200(900)ml、3(4)d,明显少于传统组的400(850)ml、4(10)d(Z=-2.74,-2.25;P<0.05)。联合组平均手术时间、术后肛门排气时间、术后进食时间、腹腔引流管留置时间、术后住院时间分别为(182±25)min、(17.2±3.0)h、(18.6±3.8)h、(3.0±1.0)d、(6.0±2.0)d,亦明显少于传统组的(204±31)min、(20.4±2.4)h、(22.7±3.2)h、(5.0±1.0)d、(8.0±1.0)d(t=-2.51,-3.88,-3.78,-4.14,-2.55;P<0.05)。联合组术后并发症发生率为26%(5/19),明显低于传统组的57%(13/23)(χ2=3.88,P<0.05)。结论精准肝脏外科联合ERAS理念可减少术中出血,降低术后并发症发生率,并有助于患者术后恢复,能有效提高复杂肝囊型包虫病手术疗效。

Rare-earth based materials:an effective toolbox for brain imaging,therapy,monitoring and neuromodulation

Brain diseases, including tumors and neurodegenerative disorders, are among the most serious health problems. Non-invasively high-resolution imaging methods are required to gain anatomical structures and information of the brain. In addition, efficient diagnosis technology is also needed to treat brain disease. Rare-earth based materials possess unique optical properties, superior magnetism, and high X-ray absorption abilities, enabling high-resolution imaging of the brain through magnetic resonance imaging, computed tomography imaging, and fluorescence imaging technologies. In addition, rare-earth based materials can be used to detect, treat, and regulate of brain diseases through fine modulation of their structures and functions. Importantly, rare-earth based materials coupled with biomolecules such as antibodies, peptides, and drugs can overcome the blood-brain barrier and be used for targeted treatment. Herein, this review highlights the rational design and application of rare-earth based materials in brain imaging, therapy, monitoring, and neuromodulation. Furthermore, the development prospect of rare-earth based materials is briefly introduced.

Lack of association between integrin αvβ3 gene polymorphisms and hemorrhagic fever with renal syndrome in Han Chinese from Hubei, China

Hantaviruses belong to the family Bunyaviridae and cause hemorrhagic fever with renal syndrome （HFRS） in humans. 133 integrins, including αvβ3 and αⅡbβ3 integrins, act as receptors on endothelial cells and play key roles in cellular entry during the pathogenesis of hantaviruses. Previous study demonstrated that the polymorphisms of integrin αⅡbβ3 are associated with susceptibility to hantavirus infection and the disease severity of HFRS in Shaanxi Province of China, rather than in Finland. However, the polymorphisms of integrin av133 in patients with HFRS was incompletely understood. Here, we aimed to investigate the associations between polymorphisms in human integrin αvβ3 and HFRS in Han Chinese individuals. Ninety patients with HFRS and 101 healthy controls were enrolled in this study. Analysis of five single nucleotide polymorphism （SNP） sites （rs3768777 and rs3738919 on ITGAV; rs13306487, rs5921, and rs5918 on ITGB3） was performed by TaqMan SNP genotyping assays and bi-directional PCR allele-specific amplification method. No significant differences were observed between the HFRS group and controls regarding the genotype and allele frequency distributions of any of the five SNP sites, and no associations were found between ITGAV polymorphisms/genotypes and disease severity. In conclusion, our results implied that these five SNPs in the integrin αvβ3 gene were not associated with HFRS susceptibility or severity in Han Chinese individuals in Hubei Province.

Regulatory perspectives of combination products

Combination products with a wide range of clinical applications represent a unique class of medical products that are composed of more than a singular medical device or drug/biological product.The product research and development,clinical translation as well as regulatory evaluation of combination products are complex and challenging.This review firstly introduced the origin,definition and designation of combination products.Key areas of systematic regulatory review on the safety and efficacy of device-led/supervised combination products were then presented.Preclinical and clinical evaluation of combination products was discussed.Lastly,the research prospect of regulatory science for combination products was described.New tools of computational modeling and simulation,novel technologies such as artificial intelligence,needs of developing new standards,evidence-based research methods,new approaches including the designation of innovative or breakthrough medical products have been developed and could be used to assess the safety,efficacy,quality and performance of combination products.Taken together,the fast development of combination products with great potentials in healthcare provides new opportunities for the advancement of regulatory review as well as regulatory science.