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Hydrophiine sea snakes represent ecologically significant and species-rich marine predatory reptiles, many of which inhabit marine environments throughout their entire lifecycles. However, due to morphological variability and limited molecular phylogenetic studies, the taxonomic relationships within this group remain unclear. In this study, we present the first complete mitochondrial genome of Aipysurus sea snakes, specifically Aipysurus eydouxii Gray 1849. The mitogenome comprises 17,228 base pairs and contains a total of 37 genes, plus a putative control region. This study provides valuable genetic data that will contribute to the future taxonomic classification and ecological protection of hydrophiine sea snakes.

Abstract The intracellular bacterial pathogen Legionella pneumophila utilizes the Dot/Icm system to translocate over 330 effectors into the host cytosol. These virulence factors modify a variety of cell processes, including pathways involved in cell death and survival, to promote bacterial proliferation. Here, we show that the effector LegK3 is a eukaryotic-like Ser/Thr kinase that functions to suppress host apoptosis. Mechanistically, LegK3 directly phosphorylates multiple caspases involved in apoptosis signaling, including Caspase-3, Caspase-7, and Caspase-9. LegK3-induced phosphorylation of these caspases occurs at serine (Ser29 in Caspase-3 and Ser199 in Caspase-7) or threonine (Thr102 in Caspase-9) residues located in the prodomain or interdomain linkers. These modifications interfere with the suitability of the caspases as the substrates of initiator caspases or upstream regulators without impacting their proteolytic activity. Collectively, our study reveals a novel strategy used by L. pneumophila to maintain the integrity of infected cells for its intracellular growth.

Ultrafine grained (UFG) n-C/Al composite bulk was obtained by mechanical milling and hot extrusion with petroleum coke utilized as carbon source. After extrusion, n-C sheets got dispersed and distributed in grain interiors or at grain boundaries. The tensile strength and corresponding thermal conductivity reached 407 ± 3 MPa and 216 ± 1.6 W m−1 K−1.

Infections caused by intracellular bacterial pathogens are difficult to treat since most antibiotics have low cell permeability and undergo rapid degradation within cells. The rapid development and dissemination of antimicrobial–resistant strains have exacerbated this dilemma. With the increasing knowledge of host–pathogen interactions, especially bacterial strategies for survival and proliferation within host cells, host-directed therapy (HDT) has attracted increased interest and has emerged as a promising anti-infection method for treating intracellular infection. Herein, we applied a cell-based screening approach to a US Food and Drug Administration (FDA)-approved drug library to identify compounds that can inhibit the intracellular replication of Salmonella Typhimurium (S. Typhimurium). This screening allowed us to identify the antidiarrheal agent loperamide (LPD) as a potent inhibitor of S. Typhimurium intracellular proliferation. LPD treatment of infected cells markedly promoted the host autophagic response and lysosomal activity. A mechanistic study revealed that the increase in host autophagy and elimination of intracellular bacteria were dependent on the high expression of glycoprotein nonmetastatic melanoma protein B (GPNMB) induced by LPD. In addition, LPD treatment effectively protected against S. Typhimurium infection in Galleria mellonella and mouse models. Thus, our study suggested that LPD may be useful for the treatment of diseases caused by intracellular bacterial pathogens. Moreover, LPD may serve as a promising lead compound for the development of anti-infection drugs based on the HDT strategy.

Abstract Background Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality. Although multi-kinase inhibitors can prolong the overall survival of late-stage HCC patients, the emergence of drug resistance diminishes these benefits, ultimately resulting in treatment failure. Therefore, there is an urgent need for novel and effective drugs to impede the progression of liver cancer. Methods This study employed a concentration gradient increment method to establish acquired sorafenib or regorafenib-resistant SNU-449 cells. Cell viability was assessed using the cell counting kit-8 assay. A library of 793 bioactive small molecules related to metabolism screened compounds targeting both parental and drug-resistant cells. The screened compounds will be added to both the HCC parental cells and the drug-resistant cells, followed by a comprehensive assessment. Intracellular adenosine triphosphate (ATP) levels were quantified using kits. Flow cytometry was applied to assess cell apoptosis and reactive oxygen species (ROS). Real-time quantitative PCR studied relative gene expression, and western blot analysis assessed protein expression changes in HCC parental and drug-resistant cells. A xenograft model in vivo evaluated Mito-LND and (E)-Akt inhibitor-IV effects on liver tumors, with hematoxylin and eosin staining for tissue structure and immunohistochemistry staining for endoplasmic reticulum stress protein expression. Results From the compound library, we screened out two novel compounds, Mito-LND and (E)-Akt inhibitor-IV, which could potently kill both parental cells and drug-resistant cells. Mito-LND could significantly suppress proliferation and induce apoptosis in HCC parental and drug-resistant cells by upregulating glycolytic intermediates and downregulating those of the tricarboxylic acid (TCA) cycle, thereby decreasing ATP production and increasing ROS. (E)-Akt inhibitor-IV achieved comparable results by reducing glycolytic intermediates, increasing TCA cycle intermediates, and decreasing ATP synthesis and ROS levels. Both compounds trigger apoptosis in HCC cells through the interplay of the AMPK/MAPK pathway and the endoplasmic reticulum stress response. In vivo assays also showed that these two compounds could significantly inhibit the growth of HCC cells and induce endoplasmic reticulum stress. Conclusion Through high throughput screening, we identified that Mito-LND and (E)-Akt inhibitor-IV are two novel compounds against both parental and drug-resistant HCC cells, which could offer new strategies for HCC patients.

Yellowfin tuna (Thunnus albacares) is popular with consumers due to its delicious meat and high nutritional value. It is a globally recognized high-end marine economic fish. With the advancement of fishing equipment and the increase in fishing efforts, the amount of tuna resources has decreased significantly. To make up for the insufficient supply of tuna in the market and protect wild populations, it is essential to carry out research on artificial aquaculture technology for tuna and to gradually establish full-cycle cultures of tuna. In order to study the differences in the nutritional components and quality of yellowfin tuna muscles of different sizes, three different-sized yellowfin tuna, J1 (4.2±1.2) kg, J2 (22.5± 2.5) kg, and J3 (50.8±3.9) kg, were used as the research subjects, and conventional biochemical analysis methods were used to compare and analyze the proximate compositions, amino acids, fatty acids, and mineral elements of tuna muscle. The results showed that (1) the moisture level of the J1 group was significantly higher than that of the J2 and J3 groups (PJ2>J1. The content of nonessential amino acids was J3>J2>J1 (P0.05). The fatty acids in yellowfin tuna muscle were mainly PUFAs, and the content of DHA accounted for 37.46%~39.18% of the total fatty acid content. The DHA content of the J3 group was significantly higher than that of the J1 and J2 groups (PJ2>J1 (PJ2>J1 (P

IntroductionDepression is a common psychological disorder, accompanied by a disturbance of the gut microbiota and its metabolites. Recently, microbiota-derived tryptophan metabolism and AMPK/mTOR pathway were found to be strongly linked to the development of depression. Shugan Hewei Decoction (SHD) is a classical anti-depression traditional Chinese medicine formula. Although, we have shown that SHD exerted antidepressant effects via cecal microbiota and cecum NLRP3 inflammasome, the specific mechanism of SHD on metabolism driven by gut microbiota is unknown. In this study, we focus on the tryptophan metabolism and AMPK/mTOR pathway to elucidate the multifaceted mechanisms of SHD.MethodsMale rats were established to the chronic unpredictable stress (CUS)/social isolation for 6 weeks, and SHD-L (7.34 g/kg/d), SHD-H (14.68 g/kg/d), Fructooligosaccharide (FOS) (3.15 g/kg/d) were given by intragastric administration once daily during the last 2 weeks. Behavioral experiments were carried out to evaluate the model. The colonic content was taken out for shotgun metagenomic sequencing combined with the untargeted metabolomics, the targeted tryptophan metabolomics. ELISA was used to detect the levels of zonula occludens 1 (ZO-1), Occludin in colon, as well as lipopolysaccharide (LPS), diamine oxidase (DAO), D-lactate (DLA) in serum. The expressions of mRNA and proteins of adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway of autophagy were examined using RT-qPCR and Western blot in colon.ResultsSHD modulated gut microbiota function and biological pathways, which were related to tryptophan metabolism. In addition, SHD could regulate microbiota-derived tryptophan production (such as reduction of 3-HK, 3-HAA etc., increment of ILA, IAA etc.), which metabolites belong to kynurenine (KYN) and indole derivatives. Further, SHD reduced intestinal permeability and enhanced the intestinal barrier function. Moreover, SHD could upregulate the levels of AMPK, microtubule associated protein light chain 3 (LC3), autophagy related protein 5 (ATG5) and Beclin1, downregulate the levels of mTOR, p62, promoted autophagy in colon. Spearman’s analysis illustrated the close correlation between tryptophan metabolites and intestinal barrier, AMPK/mTOR pathway.ConclusionSHD may exert antidepressant-like effects by regulating microbiota-derived tryptophan metabolism, and triggering the AMPK/mTOR pathway of autophagy, enhancing the intestinal barrier function.

The formation of residual coal pillars and void areas after mining of the upper seam close to the coal seam will affect the layout of the lower seam roadway. In this paper, taking 231101 working face of Xinliu Mine as engineering background, the comprehensive research means of theoretical analysis and numerical simulation is used to study and analyze the stress evolution law of mining stress field after overlying coal seam mining, and conduct an in-depth investigation on the asymmetric deformation damage mechanism of lower coal roadway, so as to arrive at the reasonable location of lower coal roadway layout. The research results show that: ① the overlying coal seam mining changes the principal stress magnitude, principal stress ratio and stress deflection angle at the location of the roadway, and the change of stress vector is the main reason for the asymmetric damage of the roadway. ② At 11 m from the center of the coal pillar, the maximum principal stress of the surrounding rock of the roadway reaches 14.43 MPa, the principal stress ratio is 2.74, and the stress deflection angle is 52.33°. At this time, the roadway is in a poor stress environment, resulting in butterfly-shaped damage of the surrounding rock and the rotation of the butterfly leaf to the right side of the roof of the roadway, and the right side of the roof of the roadway is prone to roofing accidents. ③ In order to make the roadway in a relatively stable area, this paper divides the working area into four zones based on three main influencing factors, and suggests that the best layout area is H–IV after considering the economic and safety factors of the coal mine, with the main stress deflection angle in the range of 0°−38° or 45°−90°.

Ultra-fine grained magnesium alloys are usually prepared by severe deformation and medium-low temperature deformation. In this work, it has been found that the binary Mg-1.2Ce alloy with the uniform distributed Mg12Ce precipitates smaller than 3 μm is a good candidate to obtain ultra-fine grains by conventional one-step extrusion at high temperatures. All the three Mg-1.2Ce samples extruded at 300 °C, 350 °C and 400 °C show a bimodal microstructure with high-density dislocations, whose average grain sizes are 1.19 ± 0.92 μm, 1.32 ± 1.30 μm, and 1.44 ± 1.33 μm, respectively. A linear relation of ln(d) = -0.05ln(Z)+1.27 was determined relating the average grain size (d) to the Zener-Hollomon parameter (Z). The alloy extruded at 300 °C exhibits an exceptionally high ultimate tensile strength (UTS) of 412.3 ± 5.3 MPa and yield strength (TYS) of 387.6 ± 3.2 MPa, but a low elongation after fracture (El) of 4.9 ± 0.8 %. With the extrusion temperature increasing, the tensile strength gradually decreases. For the 1.2E-400 sample, the TYS and the UTS drop to 347.2 ± 2.1 MPa and 349.4 ± 2.8 MPa, while the El increases to a more acceptable value of 12.6 ± 1.4 %. The microstructure analysis reveals that Ce atoms segregate along grain boundaries and dislocations in the Mg-1.2Ce alloy, which can limit the gliding of GBs or the slipping and climbing of dislocations. Additionally, dislocations can be pinned by Mg12Ce precipitates, thereby also restricting dislocation and grain boundary mobility. Consequently, the dynamic recrystallization (DRX) process is delayed, leading to the formation of a bimodal microstructure.

Abstract Holothuria scabra, a commercially valuable yet ecologically vulnerable tropical holothuroid, has experienced a severe decline in its wild populations, especially in China. Genomic resources are crucial for the development of effective genomic breeding projects and stock conservation strategies to restore these natural populations. Until now, a high-quality, chromosome-level reference genome for H. scabra has not been available. Here, we employed Oxford Nanopore and Hi-C sequencing technologies to assemble and annotate a high-quality, chromosome-level reference genome of H. scabra. The final genome comprised 31 scaffolds with a total length of 1.19 Gb and a scaffold N50 length of 53.52 Mb. Remarkably, 1,191.67 Mb (99.95%) of the sequences were anchored to 23 pseudo-chromosomes, with the longest one spanning 79.75 Mb. A total of 34,418 protein-coding genes were annotated in the final genome, with BUSCO analysis revealing 98.01% coverage of metazoa_odb10 genes, marking a significant improvement compared to the previous report. These chromosome-level sequences and annotations will provide an essential genomic basis for further investigation into molecular breeding and conservation management of H. scabra.

Abstract Graphene photodetectors have exhibited high bandwidth and capability of being integrated with silicon photonics (SiPh), holding promise for future optical communication devices. However, they usually suffer from a low photoresponsivity due to weak optical absorption. In this work, we have implemented SiPh-integrated twisted bilayer graphene (tBLG) detectors and reported a responsivity of 0.65 A W–1 for telecom wavelength 1,550 nm. The high responsivity enables a 3-dB bandwidth of >65 GHz and a high data stream rate of 50 Gbit s–1. Such high responsivity is attributed to the enhanced optical absorption, which is facilitated by van Hove singularities in the band structure of high-mobility tBLG with 4.1o twist angle. The uniform performance of the fabricated photodetector arrays demonstrates a fascinating prospect of large-area tBLG as a material candidate for heterogeneous integration with SiPh.

Aim at the mechanism and risk assessment of rockburst of mine roadways, the energy release laws of roadway surrounding rock in different regional stress fields are analyzed. Combined with the impact of dynamic load events, the mechanical relationship between the initial stress field, the transient stress field generated by dynamic load events, and the failure of roadway surrounding rock is established. A calculation equation for the final boundary of the plastic zone of the roadway surrounding rock under the disturbance of dynamic load events is proposed, and the mechanism of rockburst induced by the joint action of dynamic load events and initial stress fields is explained. The risk of roadway rockburst under different factors is analyzed, and the risk intensity is divided into different locations where dynamic load events occurred based on the angle of occurrence of dynamic load events. The research results indicate that with the increasing differentiation of the regional stress field, the energy release of the roadway system after disturbance equilibrium will also increase, and the main area of the energy release is the direction of the maximum stress of the regional stress field. The roadway rockburst is the result of the joint action of the initial stress field and the transient stress field of the dynamic load event on the surrounding rock of the roadway. The impact of the dynamic load event will cause the final stress field of the roadway system to deflect, and the energy released by the coordination of the surrounding rock is the main cause of the rockburst. When the initial stress field is in the butterfly risk area, the risk of roadway rockburst is greater after being affected by dynamic load events, and the increase of the effective release energy of dynamic load events, the decrease of the event distance, and the increase of the proportion of shear wave energy will increase the risk of roadway rockburst. The angle of occurrence of dynamic load events affects the risk of roadway rock-burst. When dynamic load events occur in some strong risk areas and sub-strong risk areas, small dynamic load events are also highly possible to induce rockburst, and the risk of roadway rockburst is high. When dynamic load events occur in some weak risk areas, larger dynamic load events are also less likely to cause rockburst, and the risk of roadway rockburst is lower.

Abstract Vertical semiconducting fins integrated with high-κ oxide dielectrics have been at the centre of the key device architecture that has promoted advanced transistor scaling during the last decades. Single-fin channels based on two-dimensional (2D) semiconductors are expected to offer unique advantages in achieving sub-1 nm fin-width and atomically flat interfaces, resulting in superior performance and potentially high-density integration. However, multi-fin structures integrated with high-κ dielectrics are commonly required to achieve higher electrical performance and integration density. Here we report a ledge-guided epitaxy strategy for growing high-density, mono-oriented 2D Bi2O2Se fin arrays that can be used to fabricate integrated 2D multi-fin field-effect transistors. Aligned substrate steps enabled precise control of both nucleation sites and orientation of 2D fin arrays. Multi-channel 2D fin field-effect transistors based on epitaxially integrated 2D Bi2O2Se/Bi2SeO5 fin-oxide heterostructures were fabricated, exhibiting an on/off current ratio greater than 106, high on-state current, low off-state current, and high durability. 2D multi-fin channel arrays integrated with high-κ oxide dielectrics offer a strategy to improve the device performance and integration density in ultrascaled 2D electronics.

Based on existing triaxial compression experimental data, a new empirical failure criterion with wide applicability was proposed considering hydrostatic pressure, second stress invariance, and maximum shear stress. Four fitting evaluation indicators were used to verify the consistency of the new failure criterion, and the differences with the other 6 failure criteria were discussed. The characteristics of the new failure criteria in the principal stress space were finally analyzed. The results indicate that (1) the new failure criterion exhibits strong predictive ability for triaxial experiments and has good applicability for both intact and jointed rocks; (2) the influence of hydrostatic pressure on the failure surface exhibits a non-linear trend, and different hydrostatic pressure also exhibits different distribution patterns on the deviatoric stress plane, with a distribution characteristic pattern of hexagonal snowflake-regular hexagon. The maximum shear stress has a torsional effect on the new criterion, in the three-dimensional failure surface. The parameters a and b of the rock have an impact on the failure surface morphology of the new criterion function on the offset surface.

Fully mechanized top-coal caving mining with large mining height is easy to form strong strata behavior, and the fracture evolution law of overlying strata is very important for safe production of working face. Taking the 160206 working face of Yangchangwan Coal Mine as the engineering background, the comprehensive research methods of similar simulation test, numerical simulation and theoretical analysis are used to systematically study the overburden fracture process and overburden migration law of the fully mechanized top coal caving working face with large mining height. The research shows that the strata in the water flowing fracture zone show “bench sinking” with the advance of the working face, and the subsidence trend of the same strata along the strike shows “sharp decline - stability (maximum) - rapid rise - stability (minimum)”. The overburden movement field of the working face has evolved from two areas (accelerated subsidence area and slow subsidence area) to three areas (accelerated subsidence area, slow subsidence area and stable area). The evolution of abscission layer and the law of surface subsidence are quantitatively described, and the dynamic subsidence mechanism of the surface and its related factors are deeply analyzed by using theoretical calculation expressions. Combined with the experimental results of similar simulation and numerical simulation, the morphological change characteristics of overburden fracture evolution are proposed: the overburden fracture morphology evolves from “single isosceles trapezoid” to “double isosceles trapezoid”, and the influence area of topsoil layer evolves from “rectangle” to “inverted trapezoid”. The dynamic evolution process of collapse area, separation area, compaction area and fracture enrichment area in overburden is analyzed: The caving zone gradually increases to a certain extent, the height decreases slightly and tends to be stable, the separation zone gradually develops from bottom to top and moves forward with the working face, the separation zone gradually closes to form a compaction zone, and the compaction zone gradually increases and finally remains stable, and the fracture enrichment zone is located at the front and back ends of goaf and moves forward with the working face.

Abstract Cellular entry of the hepatitis B and D viruses (HBV/HDV) requires binding of the viral surface polypeptide preS1 to the hepatobiliary transporter Na+-taurocholate co-transporting polypeptide (NTCP). This interaction can be blocked by bulevirtide (BLV, formerly Myrcludex B), a preS1 derivative and approved drug for treating HDV infection. Here, to elucidate the basis of this inhibitory function, we determined a cryo-EM structure of BLV-bound human NTCP. BLV forms two domains, a plug lodged in the bile salt transport tunnel of NTCP and a string that covers the receptor’s extracellular surface. The N-terminally attached myristoyl group of BLV interacts with the lipid-exposed surface of NTCP. Our structure reveals how BLV inhibits bile salt transport, rationalizes NTCP mutations that decrease the risk of HBV/HDV infection, and provides a basis for understanding the host specificity of HBV/HDV. Our results provide opportunities for structure-guided development of inhibitors that target HBV/HDV docking to NTCP.

Heat-resistant Al alloys used in such as aerospace, transportation fields are attracting more and more attention in recent years. Within Al alloy families, Al–Cu–Mg alloys have shown promising heat resistance properties. This work aims to investigate the influence of Cu/Mg ratio and content on the heat resistance of Al–Cu–Mg alloys, based on alloys of Al–4.5Cu–2.5 Mg (referred to as alloy A), Al–4.0Cu–2.2 Mg (alloy B) and Al–4.5Cu–1.6 Mg (alloy C). The alloys A and B possessed approximate Cu/Mg ratio, and they also exhibited nearly identical hardness retention rate during exposure at 200 °C. After 200 h, the rate is ∼75 %, though alloy A showed higher hardness (105 vs. 102 HBW) due to higher Cu, Mg content. In contrast, alloy C with a higher Cu/Mg ratio was less heat-resistant, with hardness retention rate of ∼70.5 % after 200 h exposure. Nano-sized S′(Al2CuMg) precipitate was main strengthening phase for the three alloys. Also, micron and submicron Al2CuMg particles could be formed with increase of Cu and Mg contents, which contributed a lot to yield strength for T6 heat-treated alloys, but slight contribution after exposure at 200 °C for 200 h. The degradation of mechanical properties during heat exposure can be attributed to the transformation and coarsening of S′ precipitates. In alloys with lower Cu/Mg ratio, there was excess Mg dissolved in Al matrix, which reduced Cu solubility in α-Al, and then slowed diffusion flux of Cu element, thus inhibited coarsening of Al2CuMg phase.

Vine tea is a traditional Chinese tea that has been used for centuries. It is rich in flavonoids and has excellent health benefits, especially for liver. The aim of this study was to investigate the hepatoprotective mechanism of dihydromyricetin (DMY), a flavonoid mainly contained in vine tea. Six-week-old male C57BL/6J mice were administered different doses of DMY by oral gavage for two weeks. Liver function and physiological indices of mice were assessed, while changes in gut microbiota following DMY treatment were monitored through 16S rDNA gene sequencing. Additionally, metabolic pathways and mechanisms were further explored using RT-qPCR and Western blot analysis. The results showed that aspartate aminotransferase and alanine aminotransferase levels were significantly reduced after DMY intervention in mice. Meanwhile, the diversity and abundance of gut microbiota was increased by DMY. Moreover, DMY enhanced gut microbiota-mediated primary and secondary bile acid synthesis pathways. It inhibited the expression of bile acid synthesis rate-limiting enzymes, such as cyp7a1 and cyp27a1, in mouse liver tissue. However, bile acid-related receptors including fxr, FGFR4, and TGR5 were significantly activated, indicating that DMY inhibited bile acid synthesis in the liver. This negative feedback regulation mechanism, in which DMY participated, maintained bile acid homeostasis in the liver and intestine of mice. In conclusion, DMY modulated the composition of intestinal microbiota and its mediated bile acid homeostasis in mice, thereby exhibiting a protective effect on liver tissue.

Anchor cables in water-rich roadways frequently experience severe corrosion and resultant fractures due to the combined effects of mine water and high stress. However, the precise factors influencing corrosion on these cables remain ambiguous, presenting challenges to roadway support safety. This study investigated the impact of major ions present in weakly alkaline mine water on anchor cable corrosion using salt spray corrosion experiments. The results indicated that major anions such as Cl- notably influence anchor cable corrosion, which primarily manifested as pitting corrosion. The nominal yield strength decreased by 95.68–156.01 MPa, and the nominal tensile strength decreased by 133.44–202.77 MPa because of a decrease in the cross-sectional area. During the corrosion process, major anions such as Cl- continuously degraded the passivation film on the surface of the anchor cable, exposing its internal metal structure and exacerbating corrosion until eventual fracture failure occurred. Therefore, this paper proposes a corrosion protection technique for mine anchor cables to realize superior protective effects compared to conventional anchor cables used concurrently in field applications.

ABSTRACT Streptococcus suis type 2 (SS2) is a zoonotic pathogen capable of eliciting meningitis, presenting significant challenges to both the swine industry and public health. Suilysin (Sly), one of SS2 most potent virulence determinants, releases a surfeit of inflammatory agents following red blood cell lysis. Notably, while current research on Sly role in SS2-induced meningitis predominantly centers on its interaction with the blood-brain barrier (BBB), the repercussions of Sly hemolytic products on BBB function have largely been sidestepped. In this vein, our study delves into the ramifications of Sly-induced hemolysis on BBB integrity. We discern that Sly hemolytic derivatives exacerbate the permeability of Sly-induced in vitro BBB models. Within these Sly hemolytic products, Interleukin-33 (IL-33) disrupts the expression and distribution of Claudin-5 in brain microvascular endothelial cells, facilitating the release of Interleukin-6 (IL-6) and Interleukin-8 (IL-8), thereby amplifying BBB permeability. Preliminary mechanistic insights suggest that IL-33-driven expression of IL-6 and IL-8 is orchestrated by the p38-mitogen-activated protein kinase signaling, whereas matrix metalloproteinase 9 mediates IL-33-induced suppression of Claudin-5. To validate these in vitro findings, an SS2-infected mouse model was established, and upon intravenous administration of growth stimulation expressed gene 2 (ST2) antibodies, in vivo results further underscored the pivotal role of the IL-33/ST2 axis during SS2 cerebral invasion. In summation, this study pioneerly illuminates the involvement of Sly hemolytic products in SS2-mediated BBB compromise and spotlights the instrumental role and primary mechanism of IL-33 therein. These insights enrich our comprehension of SS2 meningitis pathogenesis, laying pivotal groundwork for therapeutic advancements against SS2-induced meningitis.IMPORTANCEThe treatment of meningitis caused by Streptococcus suis type 2 (SS2) has always been a clinical challenge. Elucidating the molecular mechanisms by which SS2 breaches the blood-brain barrier (BBB) is crucial for the development of meningitis therapeutics. Suilysin (Sly) is one of the most important virulence factors of SS2, which can quickly lyse red blood cells and release large amounts of damage-associated molecular patterns, such as hemoglobin, IL-33, cyclophilin A, and so on. However, the impact of these hemolytic products on the function of BBB is unknown and ignored. This study is the first to investigate the effect of Sly hemolytic products on BBB function. The data are crucial for the study of the pathogenesis of SS2 meningitis and can provide an important reference for the development of meningitis therapeutics.

Diabetic wounds are serious clinical complications which manifest wet condition due to the mass exudate, along with disturbed regulation of inflammation, severe oxidative stress and repetitive bacterial infection. Existing treatments for diabetic wounds remain unsatisfactory due to the lack of ideal dressings that encompass mechanical performance, adherence to moist tissue surfaces, quick repair, and diverse therapeutic benefits. Herein, we fabricated a wet adhesive, self-healing, glucose-responsive drug releasing hydrogel with efficient antimicrobial and pro-healing properties for diabetic wound treatment. PAE hydrogel was constructed with poly(acrylic acid-co-acrylamide) (AA-Am) integrated with a dynamic E-F crosslinker, which consisted of epigallocatechin gallate (EGCG) and 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AFPBA). Due to the dynamic crosslinking nature of boronate esters, abundant catechol groups and hydrogen bonding, PAE hydrogel demonstrated excellent mechanical properties with about 1000 % elongation, robust adhesion to moist tissues, fast self-healing, and absorption of biofluids of 10 times of its own weight. Importantly, PAE hydrogel exhibited sustained and glucose-responsive release of EGCG. Together, the bioactive PAE hydrogel had effective antibacterial, antioxidative, and anti-inflammatory properties in vitro, and accelerated diabetic wound healing in rats via reducing tissue-inflammatory response, enhancing angiogenesis, and reprogramming of macrophages. Overall, this versatile hydrogel provides a straightforward solution for the treatment of diabetic wound, and shows potential for other wound-related application scenarios.

Salinity and dissolved oxygen concentration are two of the most important factors affecting the geographic distribution, survival, and physiological processes of estuarine and mariculture organisms. In this study, the effects of low salinity and hypoxia on survival and physiology were evaluated for two populations of Babylonia areolata, a Thailand population (TT) and a Hainan population (HH), and their reciprocal hybrids TH (TT♀ × HH♂), HT (HH♀ × TT♂). HH was more sensitive to low salinity, with a survival rate close to zero after 54 h of low salinity stress, while the survival rates of the other three populations remained above 50%, and the median lethal times (LT50) of the four populations after 72-h low salinity stress were in the order TT > TH > HT > HH. In addition, comparing the heterosis levels calculated from the 72 h-LT50 and the 48-h and 72-h survival rates of TH and HT under low salinity stress, the mid-parent heterosis (HMP) values of the three indicators of TH were 24.56%, 79.56%, and 80.97%, respectively, and the HMP values of the corresponding indicators of HT were 19.67%, 70.47%, and −42.88%, respectively. Moreover, with the increase in time under hypoxia, TH and HT began to die, and the survival rates of TH and HT were lower than those of their parental populations. The oxygen consumption rates (OCR) of TH and HT under hypoxic conditions were lower than those of TT and HH. The results showed that the crossbreeding between TT and HH improved the low salinity tolerance of their hybrids but decreased their tolerance to hypoxia. This study provides information concerning this ivory shell hybrid system that could aid in the application of heterosis in ivory shell aquaculture.

IntroductionPeriodontitis, a common chronic inflammatory disease, significantly impacted oral health. To provide novel biological indicators for the diagnosis and treatment of periodontitis, we analyzed public microarray datasets to identify biomarkers associated with periodontitis.MethodThe Gene Expression Omnibus (GEO) datasets GSE16134 and GSE106090 were downloaded. We performed differential analysis and robust rank aggregation (RRA) to obtain a list of differential genes. To obtain the core modules and core genes related to periodontitis, we evaluated differential genes through enrichment analysis, correlation analysis, protein-protein interaction (PPI) network and competing endogenous RNA (ceRNA) network analysis. Potential biomarkers for periodontitis were identified through comparative analysis of dual networks (PPI network and ceRNA network). PPI network analysis was performed in STRING. The ceRNA network consisted of RRA differentially expressed messenger RNAs (RRA_DEmRNAs) and RRA differentially expressed long non-coding RNAs (RRA_DElncRNAs), which regulated each other’s expression by sharing microRNA (miRNA) target sites.ResultsRRA_DEmRNAs were significantly enriched in inflammation-related biological processes, osteoblast differentiation, inflammatory response pathways and immunomodulatory pathways. Comparing the core ceRNA module and the core PPI module, C1QA, CENPK, CENPU and BST2 were found to be the common genes of the two core modules, and C1QA was highly correlated with inflammatory functionality. C1QA and BST2 were significantly enriched in immune-regulatory pathways. Meanwhile, LINC01133 played a significant role in regulating the expression of the core genes during the pathogenesis of periodontitis.ConclusionThe identified biomarkers C1QA, CENPK, CENPU, BST2 and LINC01133 provided valuable insight into periodontitis pathology.

In order to explore the metabolic process of caffeic acid in vivo, two strains that could metabolize caffeic acid were isolated and screened from human intestinal feces, their strain characteristics were analyzed by cell morphology, 16S rDNA sequence and phylogenetic tree, and the total number of bacteria and pH changes in the process of caffeic acid metabolism in the two strains were studied, and finally the metabolites were determined by thin layer chromatography and high performance liquid chromatography to elucidate the caffeic acid metabolism process. The results showed that the two strains were Staphylococcus xylosus strain and Proteus mirabilis strain. The content of caffeic acid metabolized by Staphylococcus xylosus strain decreased from 0.539 mg/mL to 0.087 mg/mL after 6 h and was completely metabolized after 12 h. However, the content of caffeic acid metabolized by Proteus mirabilis strain decreased from 0.543 mg/mL to 0.352 mg/mL after 6 h, and was completely metabolized after 24 h. Caffeic acid inhibited the proliferation of intestinal bacteria, and the ability of Staphylococcus xylosus strain to metabolize caffeic acid was better than that of Proteus mirabilis strain, and the product of caffeic acid metabolized by intestinal bacteria was m-coumaric acid. The results of the study provided a basis for further research on the interaction between caffeic acid and intestinal bacteria.

IGBT modules are core components of power electronic converters, and their reliability has gained significant attention. Among various reliability concerns, bond wire fatigue is a prominent issue. Bond wire fatigue can alter the electrical characteristics of IGBT modules, affecting the turn-off process of the IGBT. Consequently, it leads to changes in the collector-emitter voltage spike and the auxiliary emitter-emitter voltage spike during the turn-off process. The paper proposes the utilization of the K factor parameter which is not affected by the collector current and junction temperature, based on the collector-emitter voltage spike and the auxiliary emitter-emitter voltage spike, for bond wire fatigue monitoring of IGBT modules. Additionally, the monitoring of bond wire fatigue and junction temperature of IGBT modules was achieved based on the K factor parameter and the auxiliary emitter-emitter voltage spike. This provides a basis for the reliability assessment of IGBT modules.

Abstract Background Cadmium (Cd) exposure has been found to have detrimental effects on the development of the central nervous system and cognitive ability in children. However, there is ongoing debate regarding the impact of maternal Cd exposure on the cognitive ability of offspring. In this study, we aimed to investigate the mechanisms underlying the influence of maternal Cd exposure on the cognitive ability of offspring rats. Methods Here, we constructed a model of cadmium poisoning in first-generation rats through gavage. The cognitive and memory abilities of its offspring were evaluated by water maze experiment. Then, we used the gene chip to find out the key genes, and we performed qRT-PCR detection of these genes. Subsequently, enrichment analysis was employed to identify pathways. Finally, we constructed a co-expression network consisting of LncRNAs and mRNAs to elucidate the biological functions and regulatory mechanisms of LncRNAs. Results The results of the water maze trial demonstrated that the offspring of rats exposed to cadmium in the first generation had reduced cognitive and memory abilities. Through an analysis of gene expression in the hippocampus of the cadmium-treated rats' offspring and the control group, we identified a correlation between the islet secretion pathway and the cognitive impairment observed in the offspring. Utilizing various algorithms, we identified Cpa1 and Prss1 as potential key genes associated with the cognitive impairment caused by cadmium. The results of qRT-PCR demonstrated a decrease in the expression levels of these genes in the hippocampus of the cadmium-treated rats’ offspring. In addition, in the co-expression network, we observed that Cpa1 was co-expressed with 11 LncRNAs, while Prss1 was associated with 4 unexplored LncRNAs. Furthermore, we conducted an analysis to examine the relationship between Cpa1, Prss1-related transcription factors, and LncRNAs. Conclusion Overall, this study provides novel insights into the molecular effects of first generation Cd exposure on the cognitive ability of offspring. The target genes and signaling pathways investigated in this study could serve as potential targets for improving neurodevelopment and cognitive ability in children.

An investigation into the spatial–temporal distribution characteristics of ancient settlements and their relationship with the environment in the Sichuan Basin can enhance our understanding of the evolution of the regional human–land relationship. Utilizing kernel density analysis by GIS, this paper obtained the spatial distribution characteristics of 1100 settlements in the Neolithic, Shang–Zhou, and Qin to Southern Dynasties periods. Subsequently, a GIS spatial analysis was performed to examine the distribution of these settlements in relation to the natural environment, focusing on four aspects: elevation, slope, aspect, and water buffer zone. The results demonstrate that: (1) The distribution of settlements from the Neolithic to the Southern Dynasties has expanded from the Chengdu Plain in the west and the Xiajiang Area in the east to the hilly areas in the center. (2) The settlements in the Neolithic and Shang–Zhou periods are predominantly located at elevations between 300–600 m, slopes between 0–3°, aspects between 135–225°, distances to rivers between 0–1000 m, and soil choice on Luvisols, Cambisols, Regosols, and Anthrosols. The influence of aspect on settlements during the Qin–Southern Dynasties period was notably reduced. The settlements mainly grow in the Chengdu Plain and the smaller plains along the river from the Neolithic to the Southern Dynasties in the Sichuan Basin. (3) The emergence and advancement of primitive agriculture, the construction of early water conservancy facilities, commercial and trade exchanges, and the establishment of regimes led to a shift from a double core to a more dispersed distribution in the Sichuan Basin from the Neolithic to the Southern Dynasties periods. The evolution of settlements reflects the adaption and competition of the residents to the natural environment in the Sichuan Basin. Furthermore, it provides insights into the complex social development in the region, ranging from the formation of early states to the establishment of the Qin and Han Empires.

Reinforcement learning (RL) has been shown to be effective in path planning. However, it usually requires exploring a sufficient number of state–action pairs, some of which may be unsafe when deployed in practical obstacle environments. To this end, this paper proposes an end-to-end planning method based model-free RL framework with optimization, which can achieve better learning performance with a safety guarantee. Firstly, for second-order drone systems, a differentiable high-order control barrier function (HOCBF) is introduced to ensure the output of the planning algorithm falls in a safe range. Then, a safety layer based on the HOCBF is proposed, which projects RL actions into a feasible solution set to guarantee safe exploration. Finally, we conducted a simulation for drone obstacle avoidance and validated the proposed method in the simulation environment. The experimental results demonstrate a significant enhancement over the baseline approach. Specifically, the proposed method achieved a substantial reduction in the average cumulative number of collisions per drone during training compared to the baseline. Additionally, in the testing phase, the proposed method realized a 43% improvement in the task success rate relative to the MADDPG.

Parkinson's disease (PD) is a neurodegenerative disorder commonly accompanied by gut dysfunction. EA has shown anti-inflammatory and neuroprotective effects. Here, we aim to explore whether EA can treat Parkinson's disease by restoring the intestinal barrier and modulating NLRP3 inflammasome. We applied 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to establish a PD mouse model and EA at the GV16, LR3, and ST36 for 12 consecutive days. The open-field test results indicated that EA alleviated depression and behavioral defects, upregulated the expressions of tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF), and blocked the accumulation of α-synuclein (α-syn) in the midbrain. Moreover, EA blocked the damage to intestinal tissues of PD mice, indicative of suppressed NLRP3 inflammasome activation and increased gut barrier integrity. Notably, the antibiotic-treated mouse experiment validated that the gut microbiota was critical in alleviating PD dyskinesia and intestinal inflammation by EA. In conclusion, this study suggested that EA exhibited a protective effect against MPTP-induced PD by alleviating behavioral defects, reversing the block of motor dysfunction, and improving the gut barrier by modulating intestinal NLRP3 inflammasome. Above all, this study could provide novel insights into the pathogenesis and therapy of PD.

Cancer stem cells (CSCs) are considered key contributors to tumor progression, and ferroptosis has been identified as a potential target for CSCs. We have previously shown that butyrate enhances the ferroptosis induced by erastin in lung cancer cell, this study aimed to investigate the impact of butyrate on the progression of lung CSCs. To investigate these effects, we constructed a series of in vitro experiments, including 3D non-adherent sphere-formation, cytometry analysis, assessment of CSC marker expression, cell migration assay, and in vivo tumorigenesis analyses. Additionally, the influence of butyrate on chemotherapeutic sensitivity were determined through both in vitro and in vivo experiments. Mechanistically, immunofluorescence analysis was employed to examine the localization of biotin-conjugated butyrate. We identified that butyrate predominantly localized in the lysosome and concurrently recruited Fe2+ in lysosome. Moreover, butyrate reduced the stability of SLC7A11 protein stability in lung cancer cells through ubiquitination and proteasome degradation. Importantly, the effects of butyrate on lung CSCs were found to be dependent on lysosome Fe2+- and SLC7A11-mediated ferroptosis. In summary, our results demonstrate that butyrate could induce the ferroptosis in lung CSCs by recruiting Fe2+ in lysosome and promoting the ubiquitination-lysosome degradation of SLC7A11 protein.

Abstract BSEP (ABCB11) is an ATP-binding cassette transporter that is expressed in hepatocytes and extrudes bile salts into the canaliculi of the liver. BSEP dysfunction, caused by mutations or induced by drugs, is frequently associated with severe cholestatic liver disease. We report the cryo-EM structure of glibenclamide-bound human BSEP in nanodiscs, revealing the basis of small-molecule inhibition. Glibenclamide binds the apex of a central binding pocket between the transmembrane domains, preventing BSEP from undergoing conformational changes, and thus rationalizing the reduced uptake of bile salts. We further report two high-resolution structures of BSEP trapped in distinct nucleotide-bound states by using a catalytically inactivated BSEP variant (BSEPE1244Q) to visualize a pre-hydrolysis state, and wild-type BSEP trapped by vanadate to visualize a post-hydrolysis state. Our studies provide structural and functional insight into the mechanism of bile salt extrusion and into small-molecule inhibition of BSEP, which may rationalize drug-induced liver toxicity.

Abstract Nitrogen has five valence electrons and can form a maximum of three shared electron-pair bonds to complete its octet, which suggests that its maximum bond order is three. With a joint anion photoelectron spectroscopy and quantum chemistry investigation, we report herein that nitrogen presents a quadruple bonding interaction with thorium in ThN. The quadruple Th≣N bond consists of two electron-sharing Th-N π bonds formed between the Th-6d xz/6d yz and N 2p x/2p y orbitals, one dative Th←N σ bond and one weak Th←N σ bonding interaction formed between Th-6d z 2 and N 2s/2p z orbitals. The ThC molecule has also been investigated and proven to have a similar bonding pattern as ThN. Nonetheless, due to one singly occupied σ-bond, ThC is assigned a bond order of 3.5. Moreover, ThC has a longer bond length as well as a lower vibrational frequency in comparison with ThN.

In order to obtain candidate strains with strong colonization ability and excellent fermentation performance of goji berry juice, 3 strains of lactic acid bacteria were isolated and screened from human intestinal tract. They were identified by morphological, physiological and biochemical, 16S rDNA sequence analysis and phylogenetic tree construction, and their acid resistance, bile salt resistance, artificial gastric fluid, intestinal fluid resistance and fermentation performance were studied. The results showed that all three strains were identified as Pediococcus lactis, numbered NXU_220218, NXU_220219 and NXU_220220, respectively. The growth rate from 2 to 8 h, the ability of NXU 220218 to produce acid was stronger, and the tolerance to acid, bile salt and artificial gastric juice was better than NXU 220219 and NXU 220220. The survival rate of NXU_220218 was 67% at pH2, 65% in bovine bile salt at 0.3% concentration, 72% tolerance to artificial gastric juice, and 95% tolerance to artificial intestinal juice. Finally, the NXU_220218 strain was inoculated and used in the preparation of fermented goji berry juice. It was found that the reducing sugar content and the free radical scavenging rate in the fermented goji berry juice were significantly reduced and increased, respectively, compared with the unfermented goji berry juice, indicating that the NXU_220218 strain had good fermentation performance for goji berry juice and could be used as a candidate strain of lactic acid bacteria for the fermentation of goji berry juice.

In order to study the boundary of plastic zone of surrounding rock of a roadway considering axial stress, based on Mohr-Coulomb criterion, the implicit equation of plastic zone boundary of surrounding rock of circular roadway considering axial stress is derived by introducing Lode angle parameter. The size and shape of plastic zone of surrounding rock under different stress fields are analyzed by changing the horizontal stress σx and axial stress σy of roadway, and the reliability of theoretical analysis is further illustrated by numerical simulation. In addition, the influence of cohesion C, internal friction angle φ, roadway radius R and Poisson’s ratio v on the stability of surrounding rock is studied. The results show that : ① Under the condition of fixed axial lateral pressure while changing horizontal lateral pressure, the size change of plastic zone of surrounding rock can be divided into sensitive zone and insensitive zone, and in the changing process of horizontal lateral pressure, the plastic zone of surrounding rock shows three forms: circular, elliptical and butterfly-shaped. ② Under the condition of fixed horizontal lateral pressure while changing axial lateral pressure, the plastic zone at each position of surrounding rock shows a strong interval effect. By comparing the size of plastic zone under plane strain problem, the region is divided into axial stress-affected zone and axial stress-unaffected zone. In the influence zone of axial stress, the change of axial lateral pressure has great influence on the size of plastic zone of surrounding rock. ③ The failure mode of roadway surrounding rock is determined by the horizontal lateral pressure η1, and the axial lateral pressure η2 has little effect on the shape of plastic zone, but has great influence on the size. ④ The increase of surrounding rock C and φ will reduce the size of plastic zone of roadway surrounding rock to varying degrees, and the increase of R will increase the plastic zone at different positions of surrounding rock in an equal number sequence. In the axial stress-unaffected zone, v has no effect on the size of plastic zone of surrounding rock. In the axial stress-affected zone, the size of plastic zone at the wing corner is not affected by v, and the size of plastic zone at other locations is affected to different degrees.

Aiming at the problems of serious asymmetric damage phenomenon of roadway on the side of stope and unclear rotation law of principal stress around roadway, the relationship between the rotation of principal stress around roadway and the asymmetric damage of roadway is expounded based on boundary equation of plastic zone around non-isobaric circular hole under the rotation of principal stress and butterfly failure theory. A theoretical model of stope equivalent hole is established to study the evolution laws of the rotation of stope lateral principal stress under different initial lateral stress coefficients. Under the engineering background of the 22205 working face in the Buertai Colliery, equivalent hole fitting is carried out for different positions of stope along the advancing direction. The reliability of the stope equivalent hole has been proved through theoretical analysis and numerical simulation, providing a new idea for determining the rotation angle of the principal stress on the side of the stope. The results show that: ① When the roadway is in the butterfly risk zone, the rotation of the principal stress direction around it will cause the rotation of the butterfly plastic zone, which affects the stability of the roadway. A theoretical model of stope equivalent hole is established, which can be used to calculate the rotation angle of stope lateral principal stress. The numerical simulation results are in good agreement with the theoretical calculation. ② The direction of stope lateral principal stress in a certain range before and after the stope will rotate, and the rotation angle of principal stress is determined by the original state around the stope and the equivalent hole radius of the stope. When the initial lateral stress coefficient is greater than 1, the maximum principal stress gradually rotates from vertical direction to horizontal direction, and the hidden equation of principal stress rotation 45° can be used to determine the position of rotation 45° on the side of the stope. When the initial lateral stress coefficient is less than 1, the maximum principal stress first rotates to the horizontal direction by a certain angle from the vertical direction, and then turns to the vertical direction. The radius of stope equivalent hole represents the influence range of stope. The larger the radius, the larger the influence range of stope will be.

The aim of this study was to determine the microstructural evolution, tensile characteristics, and strain-hardening response of AZ31B magnesium alloy welds as influenced by post-weld heat treatment (PWHT). Thus, the AZ31B alloy was welded by using a low-power pulsed Nd:YAG laser-arc hybrid welding equipped on the six-axis welding robot in the present study. Microstructure, mechanical properties and strain-hardening behaviors of the AZ31B joints under various post-weld heat treatment (PWHT) temperatures were characterized. As the heat treatment temperature increases, the grain size of the welded joint gradually increases, and the amount of β-Mg17AI12 phase noticeably decreases. The mechanical properties of the welded joint specimens showed a significant enhancement when subjected to heat treatment at 300 °C and 350 °C for 20 min. Especially, after 350 °C heat treatment for 20 min, the ultimate tensile strength (UTS) and elongation (EL) of specimen were 339.6 MPa and 20.1%, respectively, which were up to 99.5% and 98.5% of the AZ31B base material (BM). The strain-hardening capacity of specimens is significantly influenced by the grain size. Due to having the largest grain size, the 400–20 min specimen exhibited the highest hardening capacity and strain hardening exponent. In Kocks-Mecking type curves, both stage III and stage IV were observed in BM and joint specimens. At higher net flow stresses, the strain hardening rate in the 400–20 min joint specimen was higher due to the larger grains, which allowed for more dislocation accommodation and improved the capacity for dislocation storage.

Uveal melanoma (UM) represents a rare tumor of the uveal tract and is associated with a poor prognosis due to the high risk of metastasis. Despite advances in the treatment of UM, the mortality rate remains high, dictating an urgent need for novel therapeutic strategies. The current study introduces the first in vivo analysis of the therapeutic potential of calcium electroporation (CaEP) compared with electrochemotherapy (ECT) with bleomycin in a patient-derived xenograft (PDX) model based on the chorioallantoic membrane (CAM) assay. The experiments were conducted as monotherapy with either 5 or 10 mM calcium chloride or 1 or 2.5 µg/mL bleomycin in combination with EP or EP alone. CaEP and ECT induced a similar reduction in proliferative activity, neovascularization, and melanocytic expansion. A dose-dependent effect of CaEP triggered a significant induction of necrosis, whereas ECT application of 1 µg/mL bleomycin resulted in a significantly increased apoptotic response compared with untreated tumor grafts. Our results outline the prospective use of CaEP and ECT with bleomycin as an adjuvant treatment of UM, facilitating adequate local tumor control and potentially an improvement in metastatic and overall survival rates.

Uveal melanoma (UM) is the most common intraocular tumor in adults, and nearly 50% of patients develop metastatic disease with a high mortality rate. Therefore, the development of relevant preclinical in vivo models that accurately recapitulate the metastatic cascade is crucial. We exploited the chick embryo chorioallantoic membrane (CAM) xenograft model to quantify both experimental and spontaneous metastasis by qPCR analysis. Our study found that the transplanted UM cells spread predominantly and early in the liver, reflecting the primary site of metastasis in patients. Visible signs of pigmented metastasis were observed in the eyes, liver, and distal CAM. Lung metastases occurred rarely and brain metastases progressed more slowly. However, UM cell types of different origins and genetic profiles caused an individual spectrum of organ metastases. Metastasis to multiple organs, including the liver, was often associated with risk factors such as high proliferation rate, hyperpigmentation, and epithelioid cell type. The severity of liver metastasis was related to the hepatic metastatic origin and chromosome 8 abnormalities rather than monosomy 3 and BAP1 deficiency. The presented CAM xenograft model may prove useful to study the metastatic potential of patients or to test individualized therapeutic options for metastasis in different organs.

To explore the inhibitory effect of myristic acid against suilysin biological activity and the interactive mechanism, pore-forming assay, oligomerization assay, molecular docking, molecular dynamics simulation, minimal inhibitory concentration assay and lactate dehydrogenase activity assays were performed. The results showed that the formation of suilysin oligomer significant decreased when the concentration of myristic acid was 16 μg/mL, thereby inhibiting the pore-forming activity of suilysin, the release of hemoglobin was 8.88% of the control group, and the inhibition rate reached 91.12%. The results of molecular docking and molecular dynamics simulation showed that myristic bound to the junction of domain one, two and three，and 82Asn，83Asn，84Ser，87Ile，88Ala，90Ile，193Phe，194Gly，275Phe，372Ile，373Leu，374Ser contributed higher energy which were the critical residues during the binding. Myristic did not showed anti-Streptococcus suis character (MIC values was 128 μg/mL), and the release of lactic dehydrogenase in suilysin or Streptococcus suis treatment group was 67.84% and 45.72% of the control group when the cells received 16 μg/mL myristic treatment. Taken together, myristic inhibited the pore-forming of suilysin by affecting the formation of its oligomer based on a direct binding and protected cells from suilysin or Streptococcus suis cytotoxicity which promised it a candidate for developing anti-Streptococcus suis infection drug.

Abstract Nuclear factor I B (NFIB) plays an important role in tumors. Our previous study found that NFIB can promote colorectal cancer (CRC) cell proliferation in acidic environments. However, its biological functions and the underlying mechanism in CRC are incompletely understood. Nicotinamide adenine dinucleotide (NAD+) effectively affects cancer cell proliferation. Nevertheless, the regulatory mechanism of NAD+ synthesis in cancer remains to be elucidated. Here we show NFIB promotes CRC proliferation in vitro and growth in vivo, and down-regulation of NFIB can reduce the level of NAD+. In addition, supplementation of NAD+ precursor NMN can recapture cell proliferation in CRC cells with NFIB knockdown. Mechanistically, we identified that NFIB promotes CRC cell proliferation by inhibiting miRNA-182-5p targeting and binding to NAMPT, the NAD+ salvage synthetic rate-limiting enzyme. Our results delineate a combination of high expression of NFIB and NAMPT predicted a clinical poorest prognosis. This work provides potential therapeutic targets for CRC treatment.

In contrast to polymer bioresorbable stents (BRS) that exhibited suboptimal performance in clinical trials due to their deficient mechanical properties, metallic BRS with improved mechanical strength have made their way into the clinic and have demonstrated more promising results. In the roadmap of research and development of metallic BRS, magnesium and iron based biodegradable metal stents had been clinically used, and the zinc based biodegradable metal stents had been trailed in Mini-Pigs. In this mini-review paper, we demonstrate the current technology levels and point out the future R&D direction of metallic BRS. Magnesium based BRS should target for decreasing struct thickness meanwhile balancing with enough supporting strength. Iron based BRS should move towards high efficient absorption, conversion, metabolism, elimination of its degradation products. Zn based BRS should strive to improve mechanical stability, creep resistance and biocompatibility. Future R&D directions of metallic BRS should move towards new materials such as Molybdenum, intelligent stent integrated with degradable biosensors, and new stent with multiple biofunctions, such as NO release.

This study aimed to isolate oligosaccharides from P. sibiricum, analyze its structure, and elucidate the pharmacological mechanism for colitis improvement. First, a homogeneous oligosaccharide PSO-A was isolated and its structure was characterized. Then, the colitis model was induced with 3 % dextran sulfate sodium (DSS) and intervened with PSO-A. The results show that PSO-A was an agavin-type acetylated fructooligosaccharide with a molecular weight of 2.12 kDa. PSO-A consisted of (2 → 6)-β-D-Fruf residue backbone with an internal α-D-Glcp residue and (2 → 1)-β-D-Fruf residue side chains. Further, PSO-A increased mucin content, protected intestinal barrier integrity of colitis mice, and significantly inhibited the levels of inflammatory factors. Moreover, the protein expressions of NLRP3, ASC, and Caspase-1 in colitis mice was statistically inhibited by PSO-A. In summary, PSO-A could alleviate colitis by inhibiting NLRP3 inflammasome pathway, which provides a basis for the development and application of P. sibiricum oligosaccharides as drug or functional food to relieve colitis.

Nickel-iron batteries (NIBs) as typical aqueous batteries have ideal electrochemical performance in theory, making them potential candidates for power supply in specific conditions. However, they still face numerous thorny practical problems, including unsatisfactory durability and undesirable lifespan of anodes. Here, we put forward a new “island-bridge” design for building up rational anode networks by architecting active nanoparticle “islands” and conductive nanosheet “bridges” to realize trade-off strategy in electrochemistry. In comparison with normally-designed metal-graphene composites which are composed of dominate graphene substrates with metal-based additives, “island-bridge” design leads to optimized balance of abundant redox sites and enough conductive connections. As a result, the aerogels stemmed from “island-bridge” design display outstanding anode performance for NIBs with large capacity, high rate capability and long lifespan, which are far more superior than graphene-dominated composite anodes and neat metal oxides anodes. Additionally, theoretical calculations validate the mechanism of advantageous “island-bridge” design that it endows the anodes with numerous active sites, high-speed electron pathways and suitable ion-penetrable nanosized-pores. This work paves a way to take insights into micro-nano structured composite electrodes, providing a feasible way to prepare high-performance anodes for practical aqueous energy storage.

ABSTRACT Salmonella enterica is an important zoonotic intracellular bacterial pathogen that is capable of causing infections ranging from localized gastroenteritis to fatal systemic infection in humans and food-producing animals. The increasing antibiotic resistance in Salmonella isolates, especially the emergence of MDR and newer XDR strains, has compromised the efficacy of conventional antimicrobial therapy for Salmonella infections. Hence, it is desirable to develop alternative therapeutic means to tackle the antimicrobial resistance crisis. In this study, we screened plant-derived compounds to identify inhibitors of Salmonella invasion of host cells. These efforts identified fisetin as a possible protector against infection. Further mechanistic studies revealed that fisetin suppressed the function of type III secretion system 1 (T3SS-1), the virulence determinant critical for Salmonella invasion. Fisetin appears to interfere with the interaction between HilD and its relevant promoters, thereby decreasing the transcription of hilA, the central transcriptional regulator that functions to activate the expression of T3SS-1 effector proteins and structural elements. In addition, administration of fisetin in the Salmonella murine infection model resulted in reduced bacterial colonization, alleviation of histopathological destruction, and decreased proinflammatory cytokine levels. Taken together, our study establishes that the natural compound fisetin can be used as a lead compound for the development of anti-Salmonella drugs targeting T3SS-1. IMPORTANCE Salmonella spp. remains a major worldwide health concern that causes significant morbidity and mortality in both humans and animals. The spread of antimicrobial resistant strains has declined the efficacy of conventional chemotherapy. Thus, novel anti-infection drugs or strategies are needed. Anti-virulence strategy represents one of the promising means for the treatment of bacterial infections. In this study, we found that the natural compound fisetin could inhibit Salmonella invasion of host cells by targeting SPI-1 regulation. Fisetin treatment impaired the interaction of the regulatory protein HilD with the promoters of its target genes, thereby suppressing the expression of T3SS-1 effectors as well as structural proteins. Moreover, fisetin treatment could reduce pathology in the Salmonella murine infection model. Collectively, our results suggest that fisetin may serve as a promising lead compound for the development of anti-Salmonella drugs.

To solve the problem of poor heat transfer effect in the subcooled region of integrated condenser, a combined condenser for instant heat pump water heater (IHPWH) was proposed and designed based on the condenser design model, aiming at obtaining an optimal design method of condenser. The off-design performances of heat pump water heater (HPWH) with a combined condenser (HPWHCC) and HPWH with an integrated condenser (HPWHIC) were investigated and compared based on the Mopt IHPWH test unit, aiming at verifying the feasibility of using a combined condenser replacement of an integrated condenser in the IHPWH. The results show that the heat transfer area of combined condenser is only 83.33 % of that of integrated condenser. Compared with the HPWHIC, the HPWHCC achieves basically equivalent COP and heating capacities and slightly higher discharge temperatures under variable heat sink outlet temperature (HSOT) condition and variable heat sink inlet temperature (HSIT) condition. Therefore, the combined condenser has the obvious potential to replace the integrated condenser in the IHPWH. The HSOT has a remarkable influence on the COP of HPWHIC and HPWHCC but a small influence on their heat capacities, while the HSIT has a small influence on their COP and heat capacities.

This study aimed to evaluate the preventive effect of Bi Xie Fen Qing Yin (BXFQY) decoction on hyperuricemic nephropathy (HN). Using an HN mouse model induced by oral gavage of potassium oxonate and adenine, we found that BXFQY significantly reduced plasma uric acid levels and improved renal function. Further study shows that BXFQY suppressed the activation of the NLRP3 inflammasome and decreased the mRNA expressions of pro-inflammatory and fibrosis-associated factors in renal tissues of HN mice. Also, BXFQY prevented the damage to intestinal tissues of HN mice, indicative of suppressed colonic inflammation and increased gut barrier integrity. By 16 S rDNA sequencing, BXFQY significantly improved gut microbiota dysbiosis of HN mice. On the one hand, BXFQY down-regulated the abundance of some harmful bacteria, like Desulfovibrionaceae, Enterobacter, Helicobacter, and Desulfovibrio. On the other hand, BXFQY up-regulated the contents of several beneficial microbes, such as Ruminococcaceae, Clostridium sensu stricto 1, and Streptococcus. Using gas or liquid chromatography-mass spectrometry (GC/LC-MS) analysis, BXFQY reversed the changes in intestinal bacterial metabolites of HN mice, including indole and BAs. The depletion of intestinal flora from HN or HN plus BXFQY mice confirmed the significance of gut microbiota in BXFQY-initiated treatment of HN. In conclusion, BXFQY can alleviate renal inflammation and fibrosis of HN mice by modulating gut microbiota and intestinal metabolites. This study provides new insight into the underlying mechanism of BXFQY against HN.

Objective: All forms of diabetes result from insufficient functional β-cell mass. Thus, achieving the therapeutic goal of expanding β-cell mass requires a better mechanistic understanding of how β-cells proliferate. Glucose is a natural β-cell mitogen that mediates its effects in part through the glucose-responsive transcription factor, carbohydrate response element binding protein (ChREBP) and the anabolic transcription factor, MYC. However, mechanistic details by which glucose activates Myc at the transcriptional level are poorly understood. Methods: Here, siRNA was used to test the role of ChREBP in the glucose response of MYC, ChIP and ChIPseq to identify potential regulatory binding sites, chromatin conformation capture to identify DNA/DNA interactions, and an adenovirus was constructed to expresses x-dCas9 and an sgRNA that specifically disrupts the recruitment of ChREBP to a specific targeted ChoRE. Results: We found that ChREBP is essential for glucose-mediated transcriptional induction of Myc, and for increases in Myc mRNA and protein abundance. Further, ChIPseq revealed that the carbohydrate response element (ChoRE) nearest to the Myc transcriptional start site (TSS) is immediately upstream of the gene encoding the lncRNA, Pvt1, 60,000 bp downstream of the Myc gene. Chromatin Conformation Capture (3C) confirmed a glucose-dependent interaction between these two sites. Transduction with an adenovirus expressing x-dCas9 and an sgRNA specifically targeting the highly conserved Pvt1 ChoRE, attenuates ChREBP recruitment, decreases Myc-Pvt1 DNA/DNA interaction, and decreases expression of the Pvt1 and Myc genes in response to glucose. Importantly, isolated and dispersed rat islet cells transduced with the ChoRE-disrupting adenovirus also display specific decreases in ChREBP-dependent, glucose-mediated expression of Pvt1 and Myc, as well as decreased glucose-stimulated β-cell proliferation. Conclusions: The mitogenic glucose response of Myc is mediated via glucose-dependent recruitment of ChREBP to the promoter of the Pvt1 gene and subsequent DNA looping with the Myc promoter.

ABSTRACTLegionella pneumophila is a facultative intracellular pathogen that causes legionellosis. The key to its virulence is the delivery of hundreds of effector proteins into host cells via the defective in organelle trafficking/intracellular multiplication type IV secretion system. These effectors modulate numerous host signaling pathways to create a niche called the Legionella-containing vacuole (LCV) permissive for its intracellular replication. Previous investigation revealed that exploitation of the host ubiquitin system is among the most important strategies used by L. pneumophila to coopt host processes for its benefit. Here, we show that the effector Legionella ubiquitin ligase gene 15 (Lug15) (Lpg2327), which has no detectable homology with any enzyme involved in ubiquitin signaling, is an E3 ligase. In L. pneumophila-infected cells, Lug15 is localized on the LCV and impacts its association with polyubiquitinated proteins. We also demonstrate that Sec22b is ubiquitinated and recruited to the LCV by Lug15. Thus, our results establish Lug15 as a novel E3 ligase that functions to recruit a SNARE protein to remodel the L. pneumophila phagosome.IMPORTANCEProtein ubiquitination is one of the most important post-translational modifications that plays critical roles in the regulation of a wide range of eukaryotic signaling pathways. Many successful intracellular bacterial pathogens can hijack host ubiquitination machinery through the action of effector proteins that are injected into host cells by secretion systems. Legionella pneumophila is the etiological agent of legionellosis that is able to survive and replicate in various host cells. The defective in organelle trafficking (Dot)/intracellular multiplication (Icm) type IV secretion system of L. pneumophila injects over 330 effectors into infected cells to create an optimal environment permissive for its intracellular proliferation. To date, at least 26 Dot/Icm substrates have been shown to manipulate ubiquitin signaling via diverse mechanisms. Among these, 14 are E3 ligases that either cooperate with host E1 and E2 enzymes or adopt E1/E2-independent catalytic mechanisms. In the present study, we demonstrate that the L. pneumophila effector Legionella ubiquitin ligase gene 15 (Lug15) is a novel ubiquitin E3 ligase. Lug15 is involved in the remodeling of LCV with polyubiquitinated species. Moreover, Lug15 catalyzes the ubiquitination of host SNARE protein Sec22b and mediates its recruitment to the LCV. Ubiquitination of Sec22b by Lug15 promotes its noncanonical pairing with plasma membrane-derived syntaxins (e.g., Stx3). Our study further reveals the complexity of strategies utilized by L. pneumophila to interfere with host functions by hijacking host ubiquitin signaling.