Facile Approach to Synthesize Gold Nanorod@Polyacrylic Acid/Calcium Phosphate Yolk–Shell Nanoparticles for Dual-Mode Imaging and pH/NIR-Responsive Drug Delivery

A facile strategy to fabricate gold nanorod@polyacrylic acid/calcium phosphate(Au NR@-PAA/Ca P) yolk–shell nanoparticles(NPs) composed with a PAA/Ca P shell and an Au NR yolk is reported. The asobtained Au NR@PAA/Ca P yolk–shell NPs possess ultrahigh doxorubicin(DOX) loading capability(1 mg DOX/mg NPs), superior photothermal conversion property(26%)and p H/near-infrared(NIR) dual-responsive drug delivery performance. The released DOX continuously increased due to the damage of the Ca P shell at low p H values. When the DOX-loaded Au NR@PAA/Ca P yolk–shell NPs wereexposed to NIR irradiation, a burst-like drug release occurs owing to the heat produced by the Au NRs. Furthermore,Au NR@PAA/Ca P yolk–shell NPs are successfully employed for synergic dual-mode X-ray computed tomography/photoacoustic imaging and chemo-photothermal cancer therapy. Therefore, this work brings new insights for the synthesis of multifunctional nanomaterials and extends theranostic applications.

关节镜下半月板成形术与康复训练治疗中年退行性内侧半月板撕裂的疗效比较

目的对比分析关节镜下半月板成形术与康复治疗中年单纯退行性膝内侧半月板撕裂的临床疗效。方法回顾性分析2017年1月至2020年1月首都医科大学附属北京天坛医院骨科收治的90例中年内侧半月板撕裂患者资料,依据不同治疗方式,分为半月板成形组(48例),康复治疗组(42例),于术前、术后3个月、术后2年采集患者一般情况、膝关节功能评分量表(KOOS)、膝关节影像学评估(KL分级),比较两组患者的临床疗效。结果半月板成形组与康复治疗组在年龄、性别、体质量指数(BMI)方面组间差异无统计学意义;半月板成形组术前KOOS评分[(36.61±7.14)分]与康复治疗组[(36.7±11.59)分]相比差异无统计学意义;半月板成形组术后3个月KOOS评分[(64.3±14.39)分]显著高于康复治疗组[(44.65±1.66)分](P<0.05);半月板成形组术后2年KOOS评分[(71.2±14.37)分]与康复治疗组[(72.7±12.15)分]相比差异无统计学意义;术后2年膝骨关节炎进展半月板成形组(术前KL 0级3例,1级24例,2级21例;术后2年0级0例,1级12例,2级36例)显著快于康复治疗组(治疗前KL 0级4例,1级18例,2级20例;治疗后2年0级0例,1级16例,2级26例)(P<0.05)。结论相对于康复治疗方案,单纯退行性膝内侧半月板撕裂患者接受半月板成形术在早期可显著改善临床症状和膝关节功能,尤其是疼痛和日常生活能力,在中期临床随访中无显著差异,半月板成形术加速膝骨关节炎进展。与康复治疗相比,关节镜下半月板成形术治疗退行性膝内侧半月板撕裂并无明显优势,应采取谨慎态度。

Coupled single-cell and bulk RNA-seq analysis reveals the engulfment role of endothelial cells in atherosclerosis

The clearance of apoptotic cell debris,containing professional phagocytosis and non-professional phagocytosis,is essential for maintaining the homeostasis of healthy tissues.Here,we discovered that endothelial cells could engulf apoptotic cell debris in atherosclerotic plaque.Single-cell RNA sequencing(RNA-seq)has revealed a unique endothelial cell subpopulation in atherosclerosis,which was strongly associated with vascular injury-related pathways.Moreover,integrated analysis of three vascular injury-related RNA-seq datasets showed that the expression of scavenger receptor class B type 1(SR-B1)was up-regulated and specifically enriched in the phagocytosis pathway under vascular injury circumstances.Single-cell RNA-seq and bulk RNA-seq indicate that SR-B1 was highly expressed in a unique endothelial cell subpopulation of mouse aorta and strongly associated with the reorganization of cellular adherent junctions and cytoskeleton which were necessary for phagocytosis.Furthermore,SR-B1 was strongly required for endothelial cells to engulf apoptotic cell debris in atherosclerotic plaque of both mouse and human aorta.Overall,this study demonstrated that apoptotic cell debris could be engulfed by endothelial cells through SR-B1 and associated with the reorganization of cellular adherent junctions and cytoskeleton.

trans-2-Enoyl-CoA Reductase Tecr-Driven Lipid Metabolism in Endothelial Cells Protects against Transcytosis to Maintain Blood-Brain Barrier Homeostasis

The transport and metabolism of lipids in cerebrovascular endothelial cells(ECs)have been hypothesized to regulate blood-brain barrier(BBB)maturation and homeostasis.Long-chain polyunsaturated fatty acids(LCPUFAs)as the important lipids components of cell membranes are essential for the development and function of BBB,but the direct links of lipid metabolism and ECs barrier function remain to be established.Here,we comprehensively characterize the transcriptomic phenotype of developmental cerebrovascular ECs in single-cell resolution and firstly find that trans-2-enoyl-CoA reductase(Tecr),a verylong-chain fatty acid synthesis,is highly expressed during barriergenesis and decreased after BBB maturation.EC-specific knockout of Tecr compromises angiogenesis due to delayed vascular sprouting.Importantly,EC-specific deletion of Tecr loss restrictive quality of vascular permeability from neonatal stages to adulthood,with high levels of transcytosis,but maintains the vascular tight junctions.Moreover,lipidomic analysis shows that the expression of Tecr in ECs is associated with the containing of omega-3 fatty acids,which directly suppresses caveolae vesicles formation.These results reveal a protective role for Tecr in BBB integrity and suggest that Tecr as a novel therapeutic target in the central nervous system(CNS)diseases associated with BBB dysfunction.

Cathepsin K contributed to disturbed flow-induced atherosclerosis is dependent on integrin-actin cytoskeleton–NF–κB pathway

Atherosclerosis is a chronic inflammatory disease, occurring preferentially in bifurcation, branching, and bending of blood vessels exposed to disturbed flow. Disturbed flow in atheroprone areas activates elevated proteases, degrading elastin lamellae and collagenous matrix, resulting in endothelial dysfunction and vascular remodeling. As a mediator for extracellular matrix protein degradation, cathepsin K (CTSK) was directly regulated by hemodynamics and contributed to atherosclerosis. The mechanism of CTSK responding to disturbed flow and contributing to disturbed flow-induced atherosclerosis is unclear. In this study, the partial carotid ligation model of mice and in vitro disturbed shear stress model were constructed to explore the contribution and potential mechanism of CTSK in atherosclerosis. Our results indicated that CTSK elevated in the disturbed flow area in vivo and in vitro along with endothelial inflammation and atherogenesis. Additionally, the expression of integrin αvβ3 was upregulated in these atheroprone areas. We found that inhibition of the integrin αvβ3-cytoskeleton pathway could significantly block the activation of NF-κB and the expression of CTSK. Collectively, our findings unraveled that disturbed flow induces increased CTSK expression, and contributes to endothelial inflammation and vascular remodeling, leading to atherogenesis eventually. This study is helpful to provide new enlightenment for the therapy of atherosclerosis.

Hybrid Optical-Electrical Perovskite Can Be a Ferroelastic Semiconductor

Organic–inorganic hybrid perovskites(OIHPs)have been a hot research topic due to their advanced structural and functional features that cover almost all the research fields of intelligent materials including ferroelectric,photovoltaic,fluorescent,and dielectric.However,the development of the construction of an OIHP ferroelastic semiconductor with optical-electrical response has been a huge challenge and infrequently reported.In this work,a rare and interesting hybrid perovskite ferroelastic semiconductor,[BFDA]PbBr_(3)(BFDA=benzyl-(2-fluoro-ethyl)-dimethyl-ammonium),was synthesized,which benefits from the structural advantage of a long tail BFDA to be balanced by the suitable inorganic framework.[BFDA]PbBr_(3) shows a high-temperature ferroelastic phase transition at 365 K and a direct band gap of 3.33 eV.In addition,it can emit charming orange-pink light under a 365 nm UV lamp.To combine this with the ferroelastic,optical,and dielectric properties,[BFDA]PbBr_(3) can be identified as a very rarely reported ferroelastic semiconductor.The above-mentioned synthesis strategy is also helpful for the enrichment and development of the hybrid perovskite family.

TAPP1 inhibits the differentiation of oligodendrocyte precursor cells via suppressing the Mek/Erk pathway

Oligodendrocytes（OLs） are glial cells that form myelin sheaths around axons in the central nervous system（CNS）.Loss of the myelin sheath in demyelinating and neurodegenerative diseases can lead to severe impairment of movement.Understanding the extracellular signals and intracellular factors that regulate OL differentiation and myelination during development can help to develop novel strategies for enhancing myelin repair in neurological disorders.Here,we report that TAPP1 was selectively expressed in differentiating OL precursor cells（OPCs）.TAPP1 knockdown promoted OL differentiation and myelin gene expression in culture.Conversely,over-expression of TAPP1 in immature OPCs suppressed their differentiation.Moreover,TAPP1 inhibition in OPCs altered the expression of Erk1/2 but not AKT.Taken together,our results identify TAPP1 as an important negative regulator of OPC differentiation through the Mek/Erk signaling pathway.

气候变化情景下中国因高温造成的劳动生产力损失预估

气候变化背景下,高温会影响职业人群的工作效率并造成劳动生产力损失.本研究基于区域气候模式并采用本土化的暴露-反应函数,预估了未来气候变化情景下中国因高温造成的劳动时间损失.研究发现,与基线期的213亿小时高温相关劳动时间损失相比,到21世纪末在RCP2.6、RCP4.5和RCP8.5情景下,损失将分别增加-17.8%、10.8%及121.1%.损失主要集中在华南、华中和华东地区,其中广东与河南将占到全国总损失的四分之一.因为这些区域的温度将更高、人口更密集、户外工作者在总人群中的比例较大.与RCP2.6、RCP4.5和RCP8.5情景相比,若能实现1.5℃温控目标,将分别能够避免11.8%、33.7%和53.9%的劳动时间损失,相当于避免了全中国21世纪中叶的0.1%、0.6%及1.4%的年均GDP损失.本研究显示未来气候变化会给中国造成严重的热相关劳动生产力损失,并强调亟需采取因地制宜的气候减缓及适应策略以保护职业人群健康.本研究对其他与中国相似的发展中国家同样具有重要意义.

Desulfovibrio desulfuricans aggravates atherosclerosis by enhancing intestinal permeability and endothelial TLR4/NF-kB pathway in Apoe^(-/-) mice

It is increasingly aware that gut microbiota is closely associated with atherosclerosis.However,which and how specific gut bacteria regulate the progression of atherosclerosis is still poorly understood.In this study,modified linear discriminant analysis was performed in comparing the gut microbiota structures of atherosclerotic and non-atherosclerotic mice,and Desulfovibrio desulfuricans(D.desulfuricans)was found to be associatedwith atherosclerosis.D.desulfuricans-treated Apoe^(-/-) mice showed significantly aggravated atherosclerosis.The proatherogenic effect of D.desulfuricans was attributed to its ability to increase intestinal permeability and subsequent raise in the transit of lipopolysaccharide(LPS)from the intestine to the bloodstream.Excessive LPS in the blood can elicit local and systemic inflammation and activate Toll-like receptor 4(TLR4)/nuclear factor-kB(NF-kB)signaling of endothelial cells.TAK-242,a specific inhibitor of TLR4,can ameliorate the development of D.desulfuricansinduced atherosclerosis by blocking the LPS-induced activation of TLR4/NF-kB signaling.

In vitro gastrointestinal model for the elderly: Effect of high hydrostatic pressure on protein structures and antioxidant activities of whey protein isolate

With the increase in global life expectancy,the research on the specific digestive patterns of the elderly is becoming highly essential.We simulated the digestion process of older individuals in vitro and investigated the effects of various high hydrostatic pressure(HHP)treatments on the protein structure,digestibility,and antioxidant activity of whey protein isolate(WPI),as well as the antioxidant peptides produced from its digest.The HHP treatment specifically affected on the secondary and tertiary protein structures along with the free sulfhydryl content of WPI.Protein microstructure revealed a significant increase in the number and depth of pores.Highest in vitro digestibility and cellular antioxidant activity was observed after HHP treatment at 600 MPa for 30 min.In the intestinal digest,15 antioxidant peptides were identified whose characteristics matched those of bioactive peptides.Of these,the LGSDMEDLR peptide sequence had the highest"-CDOCKER Energy"and formed the salt bridge,attractive charge,conventional hydrogen bond,carbon hydrogen bond,and van der Waals with Arg380,Arg415,Arg483,Tyr334 and Asn382,which all located in the binding site of the Keap1-Nrf2 interaction.Overall,HHP appeared to be a potential method for the application of dairy products among the elderly.

Recent advances of natural and bioengineered extracellular vesicles and their application in vascular regeneration

The progression of cardiovascular diseases such as atherosclerosis and myocardial infarction leads to serious vascular injury,highlighting the urgent need for targeted regenerative therapy.Extracellular vesicles(EVs)composed of a lipid bilayer containing nuclear and cytosolic materials are relevant to the progression of cardiovascular diseases.Moreover,EVs can deliver bioactive cargo in pathological cardiovascular and regulate the biological function of recipient cells,such as inflammation,proliferation,angiogenesis and polarization.However,because the targeting and bioactivity of natural EVs are subject to several limitations,bioengineered EVs have achieved wide advancements in biomedicine.Bioengineered EVs involve three main ways to acquire including(i)modification of the EVs after isolation;(ii)modification of producer cells before EVs’isolation;(iii)synthesize EVs using natural or modified cell membranes,and encapsulating drugs or bioactive molecules into EVs.In this review,we first summarize the cardiovascular injury-related disease and describe the role of different cells and EVs in vascular regeneration.We also discuss the application of bioengineered EVs from different producer cells to cardiovascular diseases.Finally,we summarize the surface modification on EVs which can specifically target abnormal cells in injured vascular.

Alterations in gut microbiota and physiological factors associated with abdominal aortic aneurysm

Abdominal aortic aneurysm(AAA)is a progressive focal dilatation and weakening of the abdominal aorta,causing 1.3%of all deaths among men aged 65–85 years worldwide.The formation of AAA is a complex process with multiple risk factors.Therefore,this study aimed to determine the relationship of disease severity and physiological factors,and gut microbiota structures in AAA patients.Physiological indicators and fecal 16S rRNA gene sequences from healthy controls and patients with AAA were collected.The correlations between the diameter of the AAA and clinical parameters,and gut microbiota composition were then analyzed separately using multivariable analysis.The diameter of AAA was extremely positively correlated with smoking index,alkaline phosphatase,blood glucose,and blood triglycerides and negatively correlated with prealbumin and Cystatin C.As the diameter of AAA increased,the α-diversity,including Chao 1,Shannon,and Simpson indices,of the gut microbiota decreased and presented a negative linear relationship.Patients with AAA with more severe disease had significantly increased relative abundance of Enterobacteriaceae and decreased relative abundance of Veillonellaceae.A strong correlation was observed between the diameter and physiological data,as well as between diameter and gut microbiota composition.This study could improve the understanding of AAA,and gut microbiota may be a potential target to prevent and treat this deadly disease.