Overexpression of low-density lipoprotein receptor prevents neurotoxic polarization of astrocytes via inhibiting NLRP3 inflammasome activation in experimental ischemic stroke

Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.

SAR Image Change Detection Algorithm Based on Different Empirical Mode Decomposition

Empirical mode decomposition (EMD) is a data-driven and multi-scale transform theory, and it is a nonlinear and non-stationary signal processing theory. But each EMD decomposition theory has its advantages and disadvantages. Synthetic aperture radar (SAR) imaging is an important remote sensing technique to obtain the change information, and SAR image data belongs to non-stationary signal. So EMD is very suitable for SAR image processing. There are two kinds of typical EMD theories, which are the ensemble empirical mode decomposition (EEMD) and bidimensional empirical mode decomposition (BEMD). Based on the deep study of the two methods, this paper proposed a new SAR image change detection algorithm, which is called the FCD-EMD algorithm, i.e. fusion change detection based on EMD. So FCD-EMD algorithm can obtain more accurate information, which not only includes the directional information obtained by EEMD, but also can contain the spatial information got by BEMD. The main contribution of the FCD-EMD algorithm is to fuse the detail information in different directions, so that the results obtained are more accurate than the individual method. On the other hand, it can reduce the influence of speckle noise in SAR images by feature selections. The actual SAR image data verify the algorithm proposed in this paper and good experimental results are obtained, which show that the new method is feasible.

Metabolic reprogramming of proinflammatory macrophages by target delivered roburic acid effectively ameliorates rheumatoid arthritis symptoms

Rheumatoid arthritis(RA)is a common chronic inflammatory disorder that usually affects joints.It was found that roburic acid(RBA),an ingredient from anti-RA herb Gentiana macrophylla Pall.,displayed strong anti-inflammatory activity.However,its medical application is limited by its hydrophobicity,lack of targeting capability and unclear functional mechanism.Here,we constructed a pH responsive dual-target drug delivery system hitchhiking RBA(RBA-NPs)that targeted both CD44 and folate receptors,and investigated its pharmacological mechanism.In rat RA model,the nanocarriers effectively delivered RBA to inflammatory sites and significantly enhanced the therapeutic outcomes compared with free RBA,as well as strongly reducing inflammatory cytokine levels and promoting tissue repair.Following analysis revealed that M1 macrophages in the joints were reprogrammed to M2 phenotype by RBA.Since the balance of pro-and anti-inflammatory macrophages play important roles in maintaining immune homeostasis and preventing excessive inflammation in RA,this reprogramming is likely responsible for the anti-RA effect.Furthermore,we revealed that RBA-NPs drove M1-to-M2 phenotypic switch by down-regulating the glycolysis level via blocking ERK/HIF-1α/GLUT1 pathway.Thus,our work not only developed a targeting delivery system that remarkably improved the anti-RA efficiency of RBA,but also identified a potential molecular target to reversely reprogram macrophages though energy metabolism regulation.

The Yanshan orogeny and late Mesozoic multi-plate convergence in East Asia—Commemorating 90th years of the “Yanshan Orogeny”

The Yanshan movement/orogeny has been proposed for 90 years, which is of special significance in the history of geological research in China. This study conducted a review by synthesizing major achievements regarding episodic deformation features, sedimentary and magmatic records of the Yanshan orogeny in China, and clarified the episodic tectono-magmatism and its geodynamic origins. The tectonic implications of the Yanshan orogeny are discussed in the context of global plate tectonics and supercontinent reconstruction. Lines of evidence from structural, sedimentary and magmatic data suggest that the Yanshan orogeny represents a regional-scale tectonic event that affected the entire China continent in late Mesozoic period. Numerous age and structural constraints consistently indicate that the Yanshan orogeny was initiated in the Jurassic(at ～170±5 Ma). and was characterized by alternating stages of crustal shortening at ～170–136 Ma, crustal extension at ～135–90 Ma, and weak shortening at ～80 Ma. The 170–136 Ma crustal shortening was reflected in the generation of two regional stratigraphic unconformities(the Tiaojishan and Zhangjiakou unconformities), which were initially named the A and B episodes of "the Yanshan Orogeny" by Mr.Wong Wenhao in 1928. Geodynamically, the Yanshan orogeny in East Asia was associated with nearly coeval oceanic subduction and continental convergence in the Paleo-Pacific, Neo-Tethys, and Mongol-Okhotsk tectonic domains. As a consequence, three giant accretionary-collisional tectonic systems were formed along the continental margins of East Asia, i.e., the Mongol-Okhotsk, Bangonghu-Nujiang, and SE China subduction-and collision-related accretionary systems. The Yanshan orogeny induced widespread crustal-scale folding and thrusting, tectonic reactivation of long-lived zones of crustal weakness,and extensive magmatism and mineralization in intraplate regions. Based on the time principle of supercontinent assembly and break-up, we propose that the mid-Late Jurassic multi-plate convergence in East Asia might represent the initiation of the assembly of the Amasia supercontinent, and the Yanshan orogeny might be the first "stirrings" that is a prerequisite for the birth of the Amasia supercontinent.

Novel fibronectin-targeted nanodisk drug delivery system displayed superior efficacy against prostate cancer compared with nanospheres

Currently,prostate cancer is the most frequently diagnosed cancer in males and chemotherapy is often essential for treating advaneed prostate cancer.However,common chemotherapies for prostate cancer suffer from serious adverse effects due to poor drug targeting ability and tissue penetration,even with the help of conventional drug delivery systems.Here,encouraged by recent studies showing possible drug retention and tissue pen etration advan tages of unconventional non-spherical nan oparticles over conventional spherical nan oparticles,we design and construct a novel non-spherical nano disk drug delivery system for treating prostate cancer.norder to enhance tumor-targeting capability,these nanodisks are further modified with targeting peptide,Cys-Arg-Glu丄ys?Ala peptide with N-methylated Glu(CR(NMe)EKA),which recognizes extracellular matrix fibronectin and its complexes specifically expressed on the walls of tumor vessels and in tumor stroma.Compared with conventional nano spheres,the nano disks achieve much higher drug accumulati on at prostate tumor sites.When loaded with paclitaxel,the CR(NMe)EKA-modified nan odisks display superior an titumor efficacy to free paclitaxel,unmodified nan odisks and nano spheres.In summary,our study provides an attractive therapeutic strategy for targeted therapy against prostate cancer with simple preparation,high efficiency and low toxicity,and supplements a theoretical support for treatments realized by different shaped nano platforms.Our study also offers valuable data for understa nding biological effects of non-spherical nano disks and highlights the great pote ntial of unconventional nan oparticles in biomedical applicati ons.

Co-delivery of TRAIL and paclitaxel by fibronectin-targeting liposomal nanodisk for effective lung melanoma metastasis treatment

Melanoma is a highly aggressive cancer which often forms metastatic tumors in the lung,leading to sharply reduced patients'survival rate.Effectively treating these tumors thus could improve late stage melanoma with lung metastasis.In this study,we fabricated a Cys-Arg-Glu-Lys-Ala with N-methylated Glu(CR(NMe)EKA)decorated disk shaped nano vehicle to co-deliver tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)and paclitaxel(PTX)to lung melanoma tumor sites(TRAIL-[ND-PTX]^(CR(NMe)EKA)).These nanodisks displayed better tumor-targeting and penetration capability than spherical nanoparticles,while the fibronectin-targeting CR(NMe)EKA motif also increased the tumor accumulation of loaded drugs.The combined usage of TRAIL and PTX both killed tumor cells and reduced local nutrition supply,leading to stronger overall anti-tumor effect.This TRAIL-[ND-PTX]^(CR(NMe)EKA)system performed remarkably better than free paclitaxel and also significantly elongated survival rate of melanoma lung metastasis bearing mice,without displaying significant toxicity.Hence,this designing strategy and the fabricated nanoplatform possess potential for further development.

Paper‑like Polyphenylene Sulfide/Aramid Fiber Electrode with Excellent Areal Capacitance and Flame‑Retardant Performance

In this paper,an aramid chopped fiber,so-called(ACF)/polyphenylene sulfide(PPS)composite,containing multi-walled carbon nanotubes(MWCNT),and in situ polymerized polypyrrole(PPy)was designed and fabricated,to be applied as a paper based electrode.The ACF/PPS/MWCNT-PPy electrode features highly porous paper-like structure with excel-lent electrochemical activity,rendering it a high areal capacitance of~3205 mF cm^(-2) at a current density of 5 mA cm^(-2).After 5000 charge-discharge cycles,the areal capacitance still maintains 93%and 70%at high current densities of 20 and 80 mA cm^(-2),respectively.Moreover,the ACF/PPS/MWCNT-PPy electrode displays over 50%the areal capacitance and maintains it's mechanical stability after annealing at 300℃.The UL-94 test reveals that the highest V-0 flame-retardant performance can be achieved.All these results suggest that the ACF/PPS/MWCNT-PPy composite is a promising material to be used as electrode for supercapacitor with high energy-storage capability and noninflammability.

Single-cell transcriptomics of cardiac progenitors reveals functional subpopulations and their cooperative crosstalk in cardiac repair

Dear Editor,Myocardial infarction is one of the leading causes of morbidity and mortality.Stem/progenitor cells therapy has emerged as a promising strategy for the cardiac repair,especially those derived from cardiac tissue,have attracted worldwide attention(Tompkins et al.,2018).However,challenges and controversies remain in characterizing functional progenitors and explaining their mechanisms of action.