HSPA12A Attenuates Lipopolysaccharide-Induced Liver Injury Through Inhibiting Caspase-11-Mediated Hepatocyte Pyroptosis via PGC-1α-Dependent Acyloxyacyl Hydrolase Expression

Liver dysfunction is strongly associated with poor survival of sepsis patients. Cytosolic lipopolysaccharide (LPS) sensing by Caspase-4/5/11 for pyroptosis activation is a major driver of the development of sepsis. Studies in macrophages and endothelial cells have demonstrated that LPS is inactivated by acyloxyacyl hydrolase (AOAH) and leading to desensitizing Caspase-4/5/11 to LPS. However, little is known about the cytosolic LPS-induced pyroptosis in hepatocytes during sepsis. Heat shock protein 12A (HSPA12A) is a novel member of the HSP70 family. Here, we report that LPS increased HSPA12A nuclear translocation in hepatocytes, while knockout of HSPA12A (Hspa12a−/−) in mice promoted LPS-induced acute liver injury. We also noticed that the LPS-induced Caspase-11 activation and its cleavage of gasdermin D (GSDMD) to produce the membrane pore-forming GSDMDNterm (markers of pyroptosis) were greater in livers of Hspa12a−/− mice compared with its wild type controls. Loss- and gain-of-function studies showed that HSPA12A deficiency promoted, whereas HSPA12A overexpression inhibited, cytosolic LPS accumulation, Caspase-11 activation and GSDMDNterm generation in primary hepatocytes following LPS incubation. Notably, LPS-induced AOAH expression was suppressed by HSPA12A deficiency, whereas AOAH overexpression reversed the HSPA12A deficiency-induced promotion of LPS-evoked and Caspase-11-mediated pyroptosis of hepatocytes. In-depth molecular analysis showed that HSPA12A interacted directly with peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and increased its nuclear translocation, thereby inducing AOAH expression for cytosolic LPS inactivation, which ultimately leading to inhibition of the Caspase-11 mediated pyroptosis of hepatocytes. Taken together, these findings revealed HSPA12A as a novel player against LPS-induced liver injury by inhibiting cytosolic LPS-induced hepatocyte pyroptosis via PGC-1α-mediated AOAH expression. Therefore, targeting hepatocyte HSPA12A represents a viable strategy for the management of liver injury in sepsis patients

Comparative analysis of drag reduction characteristics of two-type riblets based on numerical simulation

Turbulent drag reduction has always been a hot issue in fluid mechanics. Among various turbulent drag reduction methods, riblets has attracted wide attention due to its simple structure and convenient application. In order to investigate the effect of the riblets shape on the drag reduction, the effect of the triangular and trapezoidal riblets on the turbulent boundary layer flow field and drag reduction characteristics has been studied numerically by adopting the CFD method and based on the large eddy simulation (LES). The numerical simulation of turbulent channel flow was conducted by RANS, DES and LES methods respectively, and their results were compared with the results of direct numerical simulation (DNS) to verify the accuracy and feasibility of the large eddy simulation method. According to the experimental results in references, the flow field parameters such as integral statistics, first-order statistics and second-order statistics of the triangular and trapezoidal riblets on the turbulent boundary layer flow fields were compared and analyzed. The drag reduction characteristics of two-type riblets were investigated by studying the variation in physical parameters such as drag reduction rate, time-averaged velocity, root mean square velocity fluctuation, shear stress, turbulent kinetic energy generation and contour of spanwise velocity fluctuation, and it was concluded that the trapezoidal riblets have better drag reduction effect than the triangular riblets under the same dimensionless condition

Phylogeographic Analyses of a Widely Distributed Populus davidiana: Further Evidence for the Existence of Glacial Refugia of Cool‐Temperate Deciduous Trees in Northern East Asia

Despite several phylogeographic studies had provided evidence to support the existence of glacial refugia of cool‐temperate deciduous trees in northeast China, the species used in these studies were limited by the species ranges, which could not exclude the possibility that northern populations were the colonists from southern refugial populations during the last glacial maximum (LGM). Here, we estimated the nucleotide variation in Populus davidiana, a widespread species distributed in Eurasia. Three groups in northeast, central, and southwest China were constructed according to the simulation results from SAMOVA, composition of chloroplast haplotypes and structure results. We revealed that the northeast China had endemic haplotypes, the haplotypes and nucleotide diversity in northern regions were not lower than that in southern China, and this species has not experienced population expansion base on the estimation of Bayesian skyline plots. Ecological niche modeling (ENM) indicated that the northeast China had a high suitability score during the last glacial maximum. The combined evidence clearly demonstrated that northeastern and southwestern refugia were maintained across the current distributional range of P. davidiana during the LGM. The genetic differentiation between these two refugia might be mainly caused by differences of climate among these areas. The phylogeographic analyses of a widely distributed P. davidiana provided robust evidence to clarify the issue of refugia in northeast China, and these results are of great importance for understanding the influence of Quaternary glaciations on the distribution and evolution of species in East Asia

Estimation of hydrodynamic size distribution of magnetic nanoparticles based on AC magnetization harmonics for magnetic immunoassay

Magnetic nanoparticles (MNPs) have been widely studied for use in biomedical applications such as magnetic immunoassay. The hydrodynamic size distribution is an important physical characteristic for estimating the binding behavior in magnetic immunoassay. In this study, we proposed a method to estimate the hydrodynamic size distribution of MNPs based on the AC magnetization harmonics. The matrix equation of hydrodynamic size distribution was constructed based on the Fokker-Planck equation dominated by Brownian relaxation, and inversed by a Tikhonov regularization least squares algorithm. The simulation results show that the proposed method can accurately estimate the hydrodynamic size distribution, which is expected to useful for biosensor applications

TAT Nanobody Exerts Antiviral Effect against PRRSV In Vitro by Targeting Viral Nucleocapsid Protein

Porcine reproductive and respiratory syndrome (PRRS) is caused by the PRRS virus (PRRSV), which has brought huge economic losses to the pork industry worldwide since its first discovery in the late 1980s in North America. To date, there are no effective commercial vaccines or therapeutic drugs available for controlling the spread of PRRSV. Due to their unique advantages of high affinity and high specificity, nanobodies (Nbs) have received increasing attention in the process of disease diagnosis and treatment. Trans-activator transcription (TAT) can serve as a vector to carry specific proteins into cells by passing through cell membranes. In our previous study, a specific Nb against the PRRSV nucleocapsid (N) protein was screened using phage display technology. For this study, we developed a novel recombinant protein constituting a TAT-conjugated Nb, which we call TAT-Nb1. The target cell entry efficiency of TAT-Nb1 and its effect on PRRSV infection and replication were then investigated. Our results indicate that TAT delivered Nb1 into Marc-145 cells and porcine alveolar macrophages (PAMs) in a dose- and time-dependent manner. Furthermore, TAT-Nb1 dose-dependently suppressed PRRSV infection and replication, where this antiviral effect was independent of PRRSV strain. Co-immunoprecipitation results revealed that Nb1 efficiently interacted with the N protein of PRRSV. Taken together, the presented results suggest that TAT-Nb1 can effectively suppress PRRSV replication, and it may be considered as a new anti-PRRSV candidate drug

Cardiomyocyte-Specific Deficiency of HSPB1 Worsens Cardiac Dysfunction by Activating NFκB-Mediated Leucocyte Recruitment After Myocardial Infarction

Aims Inadequate healing after myocardial infarction (MI) leads to heart failure and fatal ventricular rupture, while optimal healing requires timely induction and resolution of inflammation. This study tested the hypothesis that heat shock protein B1 (HSPB1), which limits myocardial inflammation during endotoxemia, modulates wound healing after MI. Methods and results To test this hypothesis, cardiomyocyte-specific HSPB1 knockout (Hspb1-/-) mice were generated using the Cre-LoxP recombination system. MI was induced by ligation of the left anterior descending coronary artery in Hspb1-/- and wild-type (WT) littermates. HSPB1 was up-regulated in cardiomyocytes of WT animals in response to MI, and deficiency of cardiomyocyte HSPB1 increased MI-induced cardiac rupture and mortality within 21 days after MI. Serial echocardiography showed more aggravated remodelling and cardiac dysfunction in Hspb1-/- mice than in WT mice at 1, 3, and 7 days after MI. Decreased collagen deposition and angiogenesis, as well as increased MMP2 and MMP9 activity, were also observed in Hspb1-/- mice compared with WT controls after MI, using immunofluorescence, polarized light microscopy, and zymographic analyses. Notably, Hspb1-/- hearts exhibited enhanced and prolonged leucocyte infiltration, enhanced expression of inflammatory cytokines, and enhanced TLR4/MyD88/NFκB activation compared with WT controls after MI. In-depth molecular analyses in both mice and primary cardiomyocytes demonstrated that cardiomyocyte-specific knockout of HSPB1 increased nuclear factor-κB (NFκB) activation, which promoted the expression of proinflammatory mediators. This led to increased leucocyte recruitment, thereby to excessive inflammation, ultimately resulting in adverse remodelling, cardiac dysfunction, and cardiac rupture following MI. Conclusion These data suggest that HSPB1 acts as a negative regulator of NFκB-mediated leucocyte recruitment and the subsequent inflammation in cardiomyocytes. Cardiomyocyte HSPB1 is required for wound healing after MI and could be a target for myocardial repair in MI patients

RETRACTED: Forensic characteristics and phylogenetic analyses of one branch of Tai‐Kadai language‐speaking Hainan Hlai (Ha Hlai) via 23 autosomal STRs included in the Huaxia™ Platinum System

Abstract Background Hainan Island, located in the South China Sea and separated from the Leizhou Peninsula by Qiongzhou Strait, is the second largest island after Taiwan in China. With the expansion of Han Chinese and the gradual formation of “South Hlai and North Han”, nowadays, Hainan Hlai is the second largest population after Han Chinese in Hainan Island. Ha Hlai, distributed in southwest and southern Hainan Island, is the dominant branch of Hlai and speaks Ha localism. Methods We utilized the Huaxia™ Platinum PCR Amplification System (including 23 autosomal STRs and 2 sex‐linked markers) to obtain the first STR profiling batch of 657 Ha Hlai individuals (497 males and 160 females). In order to explore the genetic relationships between the studied Ha Hlai and other reference populations with different language families, population genetic analyses, including PCA, MDS, STRUCTURE, and phylogenetic analysis, were conducted based upon the raw data and allelic frequencies of the polymorphic autosomal STR markers. Results In total, 271 distinct alleles were observed at the 23 STR loci. The number of diverse alleles ranged from 7 at TPOX locus to 23 at FGA locus, and the allelic frequencies varied from 0.0008 to 0.5533. In addition, the CPE and CPD were 1‐7.39 × 10−10 and 1‐3.13 × 10−28, respectively. The phylogenetic analyses indicated that Ha Hlai is a Tai‐Kadai language‐speaking and relatively isolated population which has a close genetic and geographical relationship with Hainan Hlai, and M95 is the dominant haplogroup in Ha Hlai (56.18%). Conclusion The 23 autosomal STR genetic markers were highly polymorphic as well as potentially useful for forensic applications in Hainan Ha Hlai population. The phylogenetic analyses demonstrated that small geographic scale gene flows could not be ignored and the shaping of the unique gene pool for each population was the combination effects of geographic, language, and cultural isolations