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Background: Hypertension can lead to podocyte damage and subsequent apoptosis, eventually resulting in glomerulosclerosis. Although alleviating podocyte apoptosis has clinical significance for the treatment of hypertensive nephropathy, an effective therapeutic target has not yet been identified. The function of septin4, a proapoptotic protein and an important marker of organ damage, is regulated by post-translational modification. However, the exact role of septin4 in regulating podocyte apoptosis and its connection to hypertensive renal damage remains unclear. Methods: We investigated the function and mechanism of septin4 in hypertensive nephropathy to discover a theoretical basis for targeted treatment. Mouse models including Rosa 26 (Gt(ROSA)26Sor)- SIRT2 (silent mating type information regulation 2 homolog-2)-Flag-TG (transgenic) ( SIRT2 -TG) mice SIRT2 -knockout, and septin4 -K174Q mutant mice, combined with proteomic and acetyl proteomics analysis, followed by multiple molecular biological methodologies, were used to demonstrate mechanisms of SIRT2-mediated deacetylation of septin4-K174 in hypertensive nephropathy. Results: Using transgenic septin4 -K174Q mutant mice treated with the antioxidant Tempol, we found that hyperacetylation of the K174 site of septin4 exacerbates Ang II (angiotensin II)– induced hypertensive renal injury resulting from oxidative stress. Proteomics and Western blotting assays indicated that septin4-K174Q activates the cleaved-PARP1 (poly [ADP-ribose] polymerase family, member 1)-cleaved-caspase3 pathway. In septin4-knockdown human renal podocytes, septin4-K174R, which mimics deacetylation at K174, rescues podocyte apoptosis induced by Ang II. Immunoprecipitation and mass spectrometry analyses identified SIRT2 as a deacetylase that interacts with the septin4 GTPase domain and deacetylates septin4-K174. In Sirt2 -deficient mice and SIRT2-knockdown renal podocytes, septin4-K174 remains hyperacetylated and exacerbates hypertensive renal injury. By contrast, in Rosa26-Sirt2-Flag (SIRT2-TG) mice and SIRT2-knockdown renal podocytes reexpressing wild-type SIRT2, septin4-K174 is hypoacetylated and mitigates hypertensive renal injury. Conclusions: Septin4, when activated through acetylation of K174 (K174Q), promotes hypertensive renal injury. Septin4-K174R, which mimics deacetylation by SIRT2, inhibits the cleaved-PARP1-cleaved-caspase3 pathway. Septin4-K174R acts as a renal protective factor, mitigating Ang II–induced hypertensive renal injury. These findings indicate that septin4-K174 is a potential therapeutic target for the treatment of hypertensive renal injury.

Colibacillosis is one of the most common and economically devastating infectious diseases in poultry production worldwide. Innovative universal vaccines are urgently needed to protect chickens from the infections caused by genetically diverse avian pathogenic Escherichia coli (APEC). Enterobactin (Ent) is a highly conserved siderophore required for E. coli iron acquisition and pathogenesis. The Ent-specific antibodies induced by a novel Ent conjugate vaccine significantly inhibited the in vitro growth of diverse APEC strains. In this study, White Leghorn chickens were immunized with the Ent conjugate vaccine using a crossed design with two variables, vaccination (with or without) and APEC challenge (O1, O78, or PBS control), resulting in six study groups (9 to 10 birds/group). The chickens were subcutaneously injected with the vaccine (100 μg per bird) at 7 days of age, followed by booster immunization at 21 days of age. The chickens were intratracheally challenged with an APEC strain (10

Mortality in coronavirus disease 2019 (COVID-19) patients has been linked to the presence of a "cytokine storm" induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which involves elevated levels of circulating cytokines and immune-cell hyperactivation. Targeting cytokines during the management of COVID-19 patients has the potential to improve survival rates and reduce mortality. Although cytokine blockers and immune-host modulators are currently being tested in severely ill COVID-19 patients to cope with the overwhelming systemic inflammation, there is not too many successful cases, thus finding new cytokine blockers to attenuate the cytokine storm syndrome is meaningful. In this paper, we significantly attenuated the inflammatory responses induced by mouse hepatitis viruses A59 and SARS-CoV-2 through a soluble DR5-Fc (sDR5-Fc) chimeric protein that blocked the TNF-related apoptosis-inducing ligand-death receptor 5 (TRAIL-DR5) interaction. Our findings indicates that blocking the TRAIL-DR5 pathway through the sDR5-Fc chimeric protein is a promising strategy to treat COVID-19 severe patients requiring intensive care unit admission or with chronic metabolic diseases.

If gentrification is occurring globally, we must understand the uneven intervention of globalisation in the production of a (global) gentrifier class. This paper adopts a comparative perspective to investigate the ‘new middle class’ within China’s urban context. Through the critical examination of subtle retailing changes, it discusses how recent place-making strategies have fabricated the aura of ‘authenticity’ built upon the history of traditional residential neighbourhoods, attracting gentrifiers, whose consumption practices have transformed the retail space of a gentrified historic neighbourhood. Using Nanjing as a case study by employing qualitative research methods, this study shows that the Chinese new middle classes have yearned for modern and elitist lifestyles, with a preference for consuming Western-style goods to manifest their distinctive tastes and social status. This paper’s research findings propose the concept of Xiaozi consumption, a specific term that challenges Western-developed concepts of ‘consuming authenticity’ by highlighting the planetary indigeneity of gentrification in the Global South.

We report a preliminary study of stress corrosion cracking (SCC) of a 13Cr-5Ni-2Mo martensitic stainless steel (UNS S41426), 110 ksi grade in methanol at 82°C. SCC was predominantly intergranular, although transgranular cracking also occurred at low chloride solutions. SCC was eliminated by the absence of oxygen and/or the presence of water. The presence of copper exacerbated the cracking slightly.

Background Endothelial injury caused by Type 2 diabetes mellitus (T2DM) is considered as a mainstay in the pathophysiology of diabetic vascular complications (DVCs). However, the molecular mechanism of T2DM-induced endothelial injury remains largely unknown. Here, we found that endothelial WW domain-containing E3 ubiquitin protein ligase 2 (WWP2) act as a novel regulator for T2DM-induced vascular endothelial injury through modulating ubiquitination and degradation of DEAD-box helicase 3 X-linked (DDX3X). Methods Single-cell transcriptome analysis was used to evaluate WWP2 expression in vascular endothelial cells of T2DM patients and healthy controls. Endothelial-specific Wwp2 knockout mice were used to investigate the effect of WWP2 on T2DM-induced vascular endothelial injury. In vitro loss- and gain-of-function studies were performed to assess the function of WWP2 on cell proliferation and apoptosis of human umbilical vein endothelial cells. The substrate protein of WWP2 was verified using mass spectrometry, coimmunoprecipitation assays and immunofluorescence assays. The mechanism of WWP2 regulation on substrate protein was investigated by pulse-chase assay and ubiquitination assay. Results The expression of WWP2 was significantly down-regulated in vascular endothelial cells during T2DM. Endothelial-specific Wwp2 knockout in mice significantly aggravated T2DM-induced vascular endothelial injury and vascular remodeling after endothelial injury. Our in vitro experiments showed that WWP2 protected against endothelial injury by promoting cell proliferation and inhibiting apoptosis in ECs. Mechanically, we found that WWP2 is down-regulated in high glucose and palmitic acid (HG/PA)-induced ECs due to c-Jun N-terminal kinase (JNK) activation, and uncovered that WWP2 suppresses HG/PA-induced endothelial injury by catalyzing K63-linked polyubiquitination of DDX3X and targeting it for proteasomal degradation. Conclusion Our studies revealed the key role of endothelial WWP2 and the fundamental importance of the JNK-WWP2-DDX3X regulatory axis in T2DM-induced vascular endothelial injury, suggesting that WWP2 may serve as a new therapeutic target for DVCs.

Oncogenic stress induces DNA damage repair (DDR) that permits escape from mitotic catastrophe and allows early precursor lesions during the evolution of cancer. SAMHD1, a dNTPase protecting cells from viral infections, has been recently found to participate in DNA damage repair process. However, its role in tumorigenesis remains largely unknown. Here, we show that SAMHD1 is up-regulated in early-stage human carcinoma tissues and cell lines under oxidative stress or genotoxic insults. We further demonstrate that de-ubiquitinating enzyme USP7 interacts with SAMHD1 and de-ubiquitinates it at lysine 421, thus stabilizing SAMHD1 protein expression for further interaction with CtIP for DDR, which promotes tumor cell survival under genotoxic stress. Furthermore, SAMHD1 levels positively correlates with USP7 in various human carcinomas, and is associated with an unfavorable survival outcome in patients who underwent chemotherapy. Moreover, USP7 inhibitor sensitizes tumor cells to chemotherapeutic agents by decreasing SAMHD1 in vitro and in vivo. These findings suggest that de-ubiquitination of SAMHD1 by USP7 promotes DDR to overcome oncogenic stress and affect chemotherapy sensitivity.

Figure S1. Cellular senescence, expression profiling and the SASP development in human stromal cells upon genotoxic treatment. Figure S2. SIRT1 decline is not related with single strand breaks, proteasome degradation or autophagy deficiency upon cellular senescence. Figure S3. Senescent stromal sEVs enhance the malignancy of prostate cancer cells. Figure S4. Transcriptomic profiling of prostate cancer cells upon exposure to senescent stromal sEVs and establishment of protein-protein interaction network involving ABCB4. Figure S5. Senescent stromal sEV-conferred malignancy is diminished upon elimination of ABCB4 from cancer cells. Figure S6. Pharmacological targeting SIRT1 minimizes senescent stromal sEV production and prevents ABCB4 upregulation in prostate cancer cells.

Cellular senescence is a potent tumor-suppressive program that prevents neoplastic events. Paradoxically, senescent cells develop an inflammatory secretome, termed the senescence-associated secretory phenotype, which is implicated in age-related pathologies including cancer. Here, we report that senescent cells actively synthesize and release small extracellular vesicles (sEV) with a distinctive size distribution. Mechanistically, SIRT1 loss supported accelerated sEV production despite enhanced proteome-wide ubiquitination, a process correlated with ATP6V1A downregulation and defective lysosomal acidification. Once released, senescent stromal sEVs significantly altered the expression profile of recipient cancer cells and enhanced their aggressiveness, specifically drug resistance mediated by expression of ATP-binding cassette subfamily B member 4 (ABCB4). Targeting SIRT1 with agonist SRT2104 prevented development of cancer resistance by restraining sEV production by senescent stromal cells. In clinical oncology, sEVs in peripheral blood of posttreatment cancer patients were readily detectable by routine biotechniques, presenting an exploitable biomarker to monitor therapeutic efficacy and predict long-term outcome. Together, this study identifies a distinct mechanism supporting pathologic activities of senescent cells and provides a potent avenue to circumvent advanced human malignancies by cotargeting cancer cells and their surrounding microenvironment, which contributes to drug resistance via secretion of sEVs from senescent stromal cells.Significance:Senescent stromal cells produce a large number of sEVs to promote cancer resistance in therapeutic settings, a process driven by SIRT1 decline in stromal cells and ABCB4 augmentation in cancer cells.See related commentary by Wiley, p. 3193

Supplementary Figure 1 from Absence of the Full-Length Breast Cancer–Associated Gene-1 Leads to Increased Expression of Insulin-Like Growth Factor Signaling Axis Members

The tumor suppressor BRCA1 interacts with many proteins and undergoes multiple modifications on DNA damage. ATM, a key molecule of the DNA damage response, phosphorylates S1189 of BRCA1 after γ-irradiation. S1189 of BRCA1 is known as a unique ATM phosphorylation site in BRCA1 exon 11. To study the functions of ATM-dependent phosphorylation of BRCA1-S1189, we generated a mouse model carrying a mutation of S1152A (S1152 in mouse Brca1 corresponds to S1189 in human BRCA1) by gene targeting. Brca1S1152A/S1152A mice were born at the expected ratio, unlike that seen in previous studies of Brca1-null mice. However, 36% of Brca1S1152A/S1152A mice exhibited aging-like phenotypes including growth retardation, skin abnormalities, and delay of the mammary gland morphogenesis, with an increase in apoptosis. Mutant mice were hypersensitive to high doses of γ-irradiation, displaying shortened life span and reduction in intestinal villus size, associated with increased apoptosis. Aging-unaffected 18-month-old Brca1S1152A/S1152A female mice also showed mammary gland abnormalities with increased levels of cyclin D1 and phospho-ER-α, such as Brca1-Δ11 mutation. On low-dose γ-irradiation, they suffered a marked increase in tumor formation with an abnormal coat pattern. Furthermore, Brca1S1152A/S1152A embryonic fibroblasts failed to accumulate p53 on γ-irradiation with delayed phosphorylation of p53-S23. These observations indicate that ATM-mediated phosphorylation of S1189 is required for BRCA1 functions in the modulation of DNA damage response and in the suppression of tumor formation by regulating p53 and apoptosis. [Cancer Res 2009;69(24):9291–300]

The breast cancer–associated gene-1 (BRCA1) plays many important functions in multiple biological processes/pathways. Mice homozygous for a targeted deletion of full-length BRCA1 (Brca1Δ11/Δ11) display both increased tumorigenesis and premature aging, yet molecular mechanisms underlying these defects remain elusive. Here, we show that Brca1 deficiency leads to increased expression of several insulin-like growth factor (IGF) signaling axis members in multiple experimental systems, including BRCA1-deficient mice, primary mammary tumors, and cultured human cells. Furthermore, we provide evidence that activation of IGF signaling by BRCA1 deficiency can also occur in a p53-independent fashion. Our data indicate that BRCA1 interacts with the IRS-1 promoter and inhibits its activity that is associated with epigenetic modification of histone H3 and histone H4 to a transcriptional repression chromatin configuration. We further show that BRCA1-deficient mammary tumor cells exhibit high levels of IRS-1, and acute suppression of Irs-1 using RNA interference significantly inhibits growth of these cells. Those observations provide a molecular insight in understanding both fundamental and therapeutic BRCA1-associated tumorigenesis and aging. (Cancer Res 2006; 66(14): 7151-7)

Supplementary Methods and Figure 1 from Impaired Skin and Mammary Gland Development and Increased γ-Irradiation–Induced Tumorigenesis in Mice Carrying a Mutation of S1152-ATM Phosphorylation Site in Brca1

Microvascular basement membrane (BM) plays a pivotal role in the interactions of astrocyte with endothelium to maintain the blood–brain barrier (BBB) homeostasis; however, the significance and precise regulation of the endothelial cell–derived BM component in the BBB remain incompletely understood. Here, we report that conditional knockout of Atg7 in endothelial cells (Atg7-ECKO) leads to astrocyte–microvascular disassociation in the brain. Our results reveal astrocytic endfeet detachment from microvessels and BBB leakage in Atg7-ECKO mice. Furthermore, we find that the absence of endothelial Atg7 downregulates the expression of fibronectin, a major BM component of the BBB, causing significantly reduced coverage of astrocytes along cerebral microvessels. We reveal Atg7 triggers the expression of endothelial fibronectin via regulating PKA activity to affect the phosphorylation of cAMP-responsive element-binding protein. These results suggest that Atg7-regulated endothelial fibronectin production is required for astrocytes adhesion to microvascular wall for maintaining the BBB homeostasis. Thus, endothelial Atg7 plays an essential role in astrocyte–endothelium interactions to maintain the BBB integrity.

Public participation is an emergent feature of urban governance in Nanjing, China. Though introduced to address social conflicts around urban redevelopment, the fact is that government-led public participation did not successfully soothe tensions, but resistance instead played a role like ‘public participation’ which influenced the governing processes. This Chinese case thus requires us to rethink the limitations of Western governance theories in explaining this Chinese story. With the purpose to research urban political studies beyond the West to have more plural and heterodox voices to depict a diversity of urban knowledge, this paper focuses on this heterodox phenomenon in China to understand how Chinese insurgent urbanism reconfigured and made a new form of urban governance. Through critical investigation of public participation in Nanjing, this paper argues that public participation is the buffer that mediates and ‘repairs’ the inconsistencies between different levels of governmental agencies, while also because of this disjointed and stratified administrative feature, resisting by appropriating government policies thus can influence the governing processes and become a way of ‘informal public participation’. By introducing the concept of ‘informal public participation’, this paper’s research findings shed light on governance studies about how participatory governance is made through both governmental approaches and bottom-up insurgent urbanism, and also illustrates how resistance can reshuffle power dominance in urban politics to make a new form of urban governance.

In this study, we aimed to evaluate phthalate metabolite levels in pregnant women, to explore the factors influencing exposure, and to assess phthalate metabolite levels in relation to thyroid hormone synthesis. We recruited 463 pregnant women and collected urine, blood, and questionnaire data at participant's first prenatal examination. Ten phthalate metabolites were analyzed: mono-isobutyl phthalate (MiBP); mono-methyl phthalate (MMP); mono-ethyl phthalate (MEP); mono-n-butyl phthalate (MnBP); mono-n-octyl phthalate (MOP); mono-benzyl phthalate (MBzP); and the metabolite of di-2-ethylhexyl phthalate (DEHP), which were mono (2-ethylhexyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, and mono-(2-ethyl-5-carboxypentyl) phthalate. Multivariable generalized estimating equation models and linear mixed models were used to predict urinary biomarker concentrations and to assess the associations between phthalate exposure and thyroid hormones. Positive associations were found between phthalate metabolites and lower education (MEP and MOP), living near the road (MEP, MnBP, and ∑DEHP), and consuming more puffed food (MEP and MBzP). In addition, MnBP (percent change [%△] = 4.25; 95% confidence interval [CI] = 0.32, 8.18) and ∑DEHP (%△ = 5.12; 95% CI = 1.25, 8.99) were positively associated with thyroid-stimulating hormones, although MEP and MnBP were inversely associated with free thyroxine and total triiodothyronine. Our findings suggest that certain habits and behaviors were predictive of the positive presence of phthalate metabolites and that certain phthalate esters are associated with altered thyroid hormone levels.

It is emerging that autophagy-related proteins regulate the adaptive response to DNA damage in maintaining genome stability at multiple pathways. Here, we discuss recent insights into how autophagy-related proteins participate in DNA damage repair processes, influence chromosomal instability, and regulate the cell cycle through autophagy-dependent and independent actions. There is increasing awareness of the importance of these pathways mediated by autophagy-related proteins to DNA damage response (DDR), and disturbances in these regulatory connections may be linked to genomic instability participated in various human diseases, such as cancer and aging.

The input files of BSH molecular dynamics simulations, and simulation trajectories analysis are provided., Bile Salt Hydrolases (BSHs) are currently investigated as target enzymes for metabolic regulators in humans and growth promoters in farm animals. Understanding structural features underlying substrate specificity is necessary for inhibitor design. Here, we built a quantitative structure-activity model correlating our mass spectrometry hydrolysis rates of seventeen substrates for Lactobacillus salivarius BSH and its seventeen mutants with the residue-substrate interaction energies derived from molecular dynamics (MD) simulations of the substrate-enzyme complexes. The interpretation of the model led to the identification of residues involved in substrate specificity. Subsequent MD simulations explained the preference for taurocholic over lithocholic substrates and highlighted the role of water in hydrolysis. The first X-ray structure of BSH bound to taurocholate was solved confirming the interactions of the substrate taurine head observed in the simulations. The X-ray structures and mutagenesis indicated the regulatory role of T208 from another BSH monomer in hydrolysis.

International audience; Combined chemo/gene therapy of cancer through different action mechanisms has been emerging to enhance the therapeutic efficacy towards cancer, and still remains a challenging task due to the lack of highly effective and biocompatible nanocarriers. In this work, we report a new nanosystem based on amphiphilic phosphorus dendron (1-C12G1) micelles to co-deliver microRNA-21 inhibitor (miR-21i) and doxorubicin (DOX) for combination therapy of triple negative breast cancer. The amphiphilic phosphorus dendron bearing a long linear alkyl chain and ten protonated pyrrolidine surface groups was prepared and was demonstrated to form micelles in water solution and have a hydrodynamic size of 103.2 nm. The micelles are shown to be stable, enable encapsulation of an anticancer drug DOX with optimal loading content (80%) and encapsulation efficiency (98%), and can compress miR-21i to form polyplexes to render it with good stability against degradation. The co-delivery system of 1-C12G1@DOX/miR-21i polyplexes has a pH-dependent DOX release profile, and can be readily phagocytosed by cancer cells to inhibit them due to the different anticancer mechanisms, which was further validated after intravenous injection to treat an orthotopic triple-negative breast tumor model in vivo. With the proven biocompatibility under the studied doses, the developed amphiphilic phosphorus dendron micelles could be developed as an effective nanomedicine formulation for synergistic cancer therapy.

In multiple types of cancer, decreased tumour cell apoptosis during chemotherapy is indicative of decreased chemosensitivity. Forkhead box K2 (FOXK2), which is essential for cell fate, regulates cancer cell apoptosis through several post‐translational modifications. However, FOXK2 acetylation has not been extensively studied. Here, we evaluated the effects of sirtiun 1 (SIRT1) on FOXK2 deacetylation. Our findings demonstrated that SIRT1 inhibition increased FOXK2‐induced chemosensitivity to cisplatin and that K223 in FOXK2 was acetylated. Furthermore, FOXK2 K223 deacetylation reduced chemosensitivity to cisplatin in vitro and in vivo. Mechanistically, FOXK2 was acetylated by the acetyltransferase cAMP response element binding protein and deacetylated by SIRT1. Furthermore, cisplatin attenuated the interaction between FOXK2 and SIRT1. Cisplatin or SIRT1 inhibition enhanced FOXK2 acetylation, thereby reducing the nuclear distribution of FOXK2. Additionally, FOXK2 K223 acetylation significantly affected the expression of cell cycle–related and apoptosis‐related genes in cisplatin‐stimulated cancer cells, and FOXK2 K223 hyperacetylation promoted mitotic catastrophe, which enhanced chemosensitivity to cisplatin. Overall, our results provided insights into the mechanisms of SIRT1‐mediated FOXK2 deacetylation, which was involved in chemosensitivity to cisplatin.

Antibiotic contamination from animal production and wastewater treatment process will release antibiotic resistant genes to the environment and potentially threaten human health. Meanwhile, the residual antibiotic in manure could have inactive impacts on anaerobic digestion (AD). This study explores the effect of sulfamethazine on manure AD mediated by biochar. The results show that biochar weakens the adverse effects of sulfamethazine on AD by adsorption sulfamethazine during the initial stage (0-3 days) of AD and promoting the growth of hydrolytic bacteria (especially Firmicutes and Bacteroidetes) and methanogens (especially Methanothrix and Methanosarcina). Besides, the presence of biochar improves the biogas production capacity of AD and promotes microbial diversity and community richness. Thus, the addition of biochar greatly reduces sulfamethazine and is testified to be a desirable strategy to mitigate the inhibition of sulfamethazine on AD.

Wnt/β-catenin signaling is a conserved pathway crucially governing development, homeostasis and oncogenesis. Discovery of novel regulators holds great values in both basic and translational research. Through screening, we identified a deubiquitinase (DUB) USP10 as a novel and critical modulator of β-catenin. Mechanistically, USP10 binds to key scaffold Axin1 via conserved motifs and stabilizes Axin1 through K48-linked deubiquitination, and surprisingly, tethers Axin1 and β-catenin physically while promoting phase separation for β-catenin suppression regardless of its enzymatic activity. Functionally, USP10 prominently regulates embryonic development and intestinal homeostasis by antagonizing β-catenin via DUB activity. In colorectal cancer, USP10 substantially represses cancer growth mainly through physical binding compensation and phase separation promotion and correlates with Wnt/β-catenin magnitude clinically. Collectively, we discovered USP10 functioning in multiple biological processes against β-catenin and unearthed a novel enzyme-dependent and -independent “dual-regulating” mechanism by which USP10 utilizes parallelly and context-dependently. USP10 inhibitor was suggested in treating certain Wnt-related diseases.

For propulsion systems using gel fuels, reducing the gel fuel viscosity is essential for achieving better atomization and combustion. In this paper, we investigate the flow and heat transfer in a water-gel with a temperature and shear dependent viscosity. We consider several different channels, mimicking the transport of gelled fuels in propulsion systems, and we also look at corrugation, which is a way of enhancing fluid mixing and thus improving the heat transfer characteristics. The rheological parameters in the constitutive model of the gel are fitted with experimental data. The influence of different corrugation profiles, corrugation configuration parameters and the Reynolds number on the mean apparent viscosity and the pressure drop are investigated. It was found that the flow recirculation formed in the valley of the corrugations enhances the heat transfer and thus the temperature of the main flow. We also noticed an increase in the pressure drop due to the stronger viscous dissipation. Furthermore, it was observed that the sinusoidal corrugation can achieve lower viscosity with a lower pressure drop compared with triangular and trapezoidal corrugations. A shorter wavelength and a deeper wave amplitude of the corrugation seemed to be better for reducing the gel fuel viscosity, while we must consider the adverse consequence of increased pressure drop. A larger Reynolds number was helpful for both lowering the pressure drop and for reducing the viscosity. In addition, compared with a smooth straight pipe, a Y-shape corrugated channel with a constant inlet velocity reduced the mean apparent viscosity by 70.8%, and this value increased to 72.6% by further applying a pulsed inlet velocity, which can greatly enhance the gel fuel atomization and thus improve the combustion efficiency.

Heparin-binding protein (HBP), as a granule protein secreted by polymorphonuclear neutrophils, participates in the pathophysiological process of sepsis. It has been reported that HBP is a biomarker of sepsis related to the severity of septic shock and organ dysfunction. HBP binds to vascular endothelial cells as a primary target site. However, it is still unclear whether HBP-binding protein receptors exist on the surface of endothelial cells. The effect of HBP on vascular permeability in sepsis and its mechanism needs to be explored. We conducted in vivo and in vitro studies and demonstrated that HBP binds to transforming growth factor-β receptor type 2 (TGF-β-R2) as a ligand. Glutathione S-transferase pull-down analysis revealed that HBP mainly interacts with the extracellular domain of TGF-β-R2. HBP induces acute lung injury and vascular leakage via activation of the TGF-β/SMAD2/3 signaling pathway. A permeability assay suggested that TGF-β-R2 is necessary for HBP-induced increased permeability. We also defined the role of HBP and its potential membrane receptor TGF-β-R2 in the blood-gas barrier in the pathogenesis of HBP-related acute lung injury.

316L stainless steel is currently one of the most critical stainless-steel materials due to its excellent corrosion resistance and comprehensive mechanical properties. Selective laser melting (SLM), as an additive manufacturing technology for directly forming complex metal parts, has been applied in the production of 316L stainless steel components. By introducing reasonable and comprehensive equivalent processing models (e.g., gasification pressure, gasification heat dissipation, and equivalent physical parameters), a predictive model of the dynamic behavior of the molten pool on the workpiece scale (two-phase flow model) was established for the SLM process of 316L stainless steel. The related equivalent processing models were customized by secondary development means based on the commercial software Fluent. By comparing and analyzing the different calculation schemes, it was found that surface tension stabilizes the liquid metal surface, while the Marangoni effect and the gasification recoil force cause the liquid metal surface to appear concave. The tangential movement of the liquid metal surface, caused by the Marangoni effect, causes the molten metal to accumulate around the central region, forming a liquid surface morphology resembling a crater. The influence of different processing parameters (scanning speed and laser power) on the SLM process of 316L stainless steel was analyzed. The simulated and experimentally obtained solidified track sizes were in good agreement.

Reactive oxygen species (ROS) are generally small, short-lived and highly reactive molecules, initially thought to be a pathological role in the cell. A growing amount of evidence in recent years argues for ROS functioning as a signaling intermediate to facilitate cellular adaptation in response to pathophysiological stress through the regulation of autophagy. Autophagy is an essential cellular process that plays a crucial role in recycling cellular components and damaged organelles to eliminate sources of ROS in response to various stress conditions. A large number of studies have shown that DNA damage response (DDR) transducer ataxia-telangiectasia mutated (ATM) protein can also be activated by ROS, and its downstream signaling pathway is involved in autophagy regulation. This review aims at providing novel insight into the regulatory mechanism of ATM activated by ROS and its molecular basis for inducing autophagy, and revealing a new function that ATM can not only maintain genome homeostasis in the nucleus, but also as a ROS sensor trigger autophagy to maintain cellular homeostasis in the cytoplasm.

Nucleic acid-based systems play important roles in antiviral defense, including CRISPR/Cas that adopts RNA-guided DNA cleavage to prevent DNA phage infection and RNA interference (RNAi) that employs RNA-guided RNA cleavage to defend against RNA virus infection. Here, we report a novel type of nucleic acid-based antiviral system that exists in mouse embryonic stem cells (mESCs), which suppresses RNA virus infection by DNA-mediated RNA cleavage. We found that the viral RNA of encephalomyocarditis virus can be reverse transcribed into complementary DNA (vcDNA) by the reverse transcriptase (RTase) encoded by endogenous retrovirus-like elements in mESCs. The vcDNA is negative-sense single-stranded and forms DNA/RNA hybrid with viral RNA. The viral RNA in the heteroduplex is subsequently destroyed by cellular RNase H1, leading to robust suppression of viral growth. Furthermore, either inhibition of the RTase activity or depletion of endogenous RNase H1 results in the promotion of virus proliferation. Altogether, our results provide intriguing insights into the antiviral mechanism of mESCs and the antiviral function of endogenized retroviruses and cellular RNase H. Such a natural nucleic acid-based antiviral mechanism in mESCs is referred to as ERASE (endogenous RTase/RNase H-mediated antiviral system), which is an addition to the previously known nucleic acid-based antiviral mechanisms including CRISPR/Cas in bacteria and RNAi in plants and invertebrates.

Gel fuel potentially combines the advantages of solid fuel and liquid fuel due to its special rheological properties, which have essential impacts on the application of gel fuel in propulsion systems. In this paper, we study the rheological property of organic kerosene gel through a series of measurements on its viscosity as a function of the shear rate, temperature, and shear history. The measured datasets are then fitted with constitutive relationships between the viscosity and shear rate at three different levels: the power law shear-thinning model, the power law dependency on both the temperature and shear rate, and the thixotropic property. It is found that intense pre-shear could exhaust thixotropy and reduce viscosity of the kerosene gel. For the power law shear-thinning model, the consistency index increases with the gellant mass fraction, whereas the power law exponent remains constant. The dependence of viscosity on temperature could be well approximated by an empirical power law relationship. As for the thixotropic property of the kerosene gel, the fitted second-order kinetic model corresponds accurately to the viscosity at different shear rates and shear times. The constitutive models fitted in this work at different levels are consistent with each other and provide useful tools for further applications of organic kerosene gel fuel.

Acute lymphoblastic leukemia (ALL) has been huge threaten for people health and finding effective target therapy is urgent and important. WWP2, as one of E3 ubiquitin ligase, is involved in many biological processes by specifically binding to substrates. PARP1 plays a role in cell apoptosis and is considered as a therapeutic target of certain cancers. In this study, we firstly tested WWP2 expression in patients and normal people and analyzed the relationship with clinicopathologic factors. We demonstrated WWP2 was involved in ALL apoptosis and knockout WWP2 alleviated ALL apoptosis induced by Dox in vitro and vivo. WWP2 negatively regulated and interacted with PARP1 in vitro and vivo and WWP2 mechanically degraded PARP1 through polyubiquitin-proteasome pathway. These findings suggested WWP2 played a role in ALL apoptosis and displayed a regulatory pathway of PARP1, which provide a new potential therapeutic target for the treatment of ALL.

Progerin, a product of LMNA mutation, leads to multiple nuclear abnormalities in patients with Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disorder. Progerin also accumulates during physiological aging. Here, we demonstrate that impaired insulin-like growth factor 1 receptor (IGF-1R)/Akt signaling pathway results in severe growth retardation and premature aging in Zmpste24 −/− mice, a mouse model of progeria. Mechanistically, progerin mislocalizes outside of the nucleus, interacts with the IGF-1R, and down-regulates its expression, leading to inhibited mitochondrial respiration, retarded cell growth, and accelerated cellular senescence. Pharmacological treatment with the PTEN (phosphatase and tensin homolog deleted on chromosome 10) inhibitor bpV (HOpic) increases Akt activity and improves multiple abnormalities in Zmpste24-deficient mice. These findings provide previously unidentified insights into the role of progerin in regulating the IGF-1R/Akt signaling in HGPS and might be useful for treating LMNA -associated progeroid disorders.

Acute lymphoblastic leukemia (ALL) has been a huge threat for people's health and finding effective target therapy is urgent and important. WWP2, as one of E3 ubiquitin ligase, is involved in many biological processes by specifically binding to substrates. PARP1 plays a role in cell apoptosis and is considered as a therapeutic target of certain cancers. In this study, we firstly found that WWP2 expressed higher in newly diagnosed ALL patients comparing with complete remission (CR) ALL patients and normal control people, and WWP2 in relapse ALL patients expressed higher than normal control people. WWP2 expression was related with the FAB subtype of ALL and the proportion of blast cells in bone marrow blood tested by flow cytometry. We demonstrated knockout WWP2 inhibited the ALL growth and enhanced apoptosis induced by Dox in vitro and vivo for the first time. WWP2 negatively regulated and interacted with PARP1 and WWP2 mechanically degraded PARP1 through polyubiquitin-proteasome pathway in ALL. These findings suggested WWP2 played a role in ALL development as well as growth and apoptosis, and also displayed a regulatory pathway of PARP1, which provided a new potential therapeutic target for the treatment of ALL.

Hybridization is one of the primary methods used to cultivate farmed grouper species. The hybrid grouper derived from crossing Epinephelus fuscoguttatus (♀) and E. polyphekadion (♂) exhibits growth superiority over its parents. The genetic characteristics and growth patterns of the hybrid grouper have not yet been defined. This study confirms the ploidy level of the hybrid grouper (2n = 48) using chromosome count analysis and flow cytometry. The 5S rDNA family was used to evaluate genetic diversity. Only one 5S class (~400 bp) was detected in the hybrid grouper, which could be used to distinguish between two different types based on nucleotide sequences, likely representing homologous unit classes from the female and male parental species. Growth patterns of 5-8-month-old hybrid groupers were also monitored. In this phase, a positive allometric growth pattern in body mass with total length was found. Body height and body mass were significantly correlated based on correlation and path coefficient, suggesting that body height could serve as an excellent index to increase body mass. These results aid our understanding of the genetic evolution of the hybrid grouper and inform the development of improved rearing techniques.