Pathogenic ubiquitination of GSDMB inhibits NK cell bactericidal functions.

Gasdermin B (GSDMB) belongs to a large family of pore-forming cytolysins that execute inflammatory cell death programs. While genetic studies have linked GSDMB polymorphisms to human disease, its function in the immunological response to pathogens remains poorly understood. Here, we report a dynamic host-pathogen conflict between GSDMB and the IpaH7.8 effector protein secreted by enteroinvasive Shigella flexneri. We show that IpaH7.8 ubiquitinates and targets GSDMB for 26S proteasome destruction. This virulence strategy protects Shigella from the bacteriocidic activity of natural killer cells by suppressing granzyme-A-mediated activation of GSDMB. In contrast to the canonical function of most gasdermin family members, GSDMB does not inhibit Shigella by lysing host cells. Rather, it exhibits direct microbiocidal activity through recognition of phospholipids found on Gram-negative bacterial membranes. These findings place GSDMB as a central executioner of intracellular bacterial killing and reveal a mechanism employed by pathogens to counteract this host defense system.

Ultrathin quantum light source with van der Waals NbOCl2 crystal.

Interlayer electronic coupling in two-dimensional materials enables tunable and emergent properties by stacking engineering. However, it also results in significant evolution of electronic structures and attenuation of excitonic effects in two-dimensional semiconductors as exemplified by quickly degrading excitonic photoluminescence and optical nonlinearities in transition metal dichalcogenides when monolayers are stacked into van der Waals structures. Here we report a van der Waals crystal, niobium oxide dichloride (NbOCl2), featuring vanishing interlayer electronic coupling and monolayer-like excitonic behaviour in the bulk form, along with a scalable second-harmonic generation intensity of up to three orders higher than that in monolayer WS2. Notably, the strong second-order nonlinearity enables correlated parametric photon pair generation, through a spontaneous parametric down-conversion (SPDC) process, in flakes as thin as about 46 nm. To our knowledge, this is the first SPDC source unambiguously demonstrated in two-dimensional layered materials, and the thinnest SPDC source ever reported. Our work opens an avenue towards developing van der Waals material-based ultracompact on-chip SPDC sources as well as high-performance photon modulators in both classical and quantum optical technologies1-4.

SNP-based and haplotype-based genome-wide association on drug dependence in Han Chinese.

BACKGROUND: Drug addiction is a serious problem worldwide and is influenced by genetic factors. The present study aimed to investigate the association between genetics and drug addiction among Han Chinese. METHODS: A total of 1000 Chinese users of illicit drugs and 9693 healthy controls were enrolled and underwent single nucleotide polymorphism (SNP)-based and haplotype-based association analyses via whole-genome genotyping. RESULTS: Both single-SNP and haplotype tests revealed associations between illicit drug use and several immune-related genes in the major histocompatibility complex (MHC) region (SNP association: log10BF = 15.135, p = 1.054e-18; haplotype association: log10BF = 20.925, p = 2.065e-24). These genes may affect the risk of drug addiction via modulation of the neuroimmune system. The single-SNP test exclusively reported genome-wide significant associations between rs3782886 (SNP association: log10BF = 8.726, p = 4.842e-11) in BRAP and rs671 (SNP association: log10BF = 7.406, p = 9.333e-10) in ALDH2 and drug addiction. The haplotype test exclusively reported a genome-wide significant association (haplotype association: log10BF = 7.607, p = 3.342e-11) between a region with allelic heterogeneity on chromosome 22 and drug addiction, which may be involved in the pathway of vitamin B12 transport and metabolism, indicating a causal link between lower vitamin B12 levels and methamphetamine addiction. CONCLUSIONS: These findings provide new insights into risk-modeling and the prevention and treatment of methamphetamine and heroin dependence, which may further contribute to potential novel therapeutic approaches.

Highly Efficient Spin Injection and Readout Across Van Der Waals Interface.

Spin injection, transport, and detection across the interface between a ferromagnet and a spin-carrying channel are crucial for energy-efficient spin logic devices. However, interfacial conductance mismatch, spin dephasing, and inefficient spin-to-charge conversion significantly reduce the efficiency of these processes. In this study, it is demonstrated that an all van der Waals heterostructure consisting of a ferromagnet (Fe3GeTe2) and Weyl semimetal enables a large spin readout efficiency. Specifically, a nonlocal spin readout signal of 150 mΩ and a local spin readout signal of 7.8 Ω is achieved, which reach the signal level useful for practical spintronic devices. The remarkable spin readout signal is attributed to suppressed spin dephasing channels at the vdW interfaces, long spin diffusion, and efficient charge-spin interconversion in Td-MoTe2. These findings highlight the potential of vdW heterostructures for spin Hall effect-enabled spin detection with high efficiency, opening up new possibilities for spin-orbit logic devices using vdW interfaces.

Identification of the serum metabolites associated with cow milk consumption in Chinese Peri-/Postmenopausal women.

Cow milk consumption (CMC) and downstream alterations of serum metabolites are commonly considered important factors regulating human health status. Foods may lead to metabolic changes directly or indirectly through remodelling gut microbiota (GM). We sought to identify the metabolic alterations in Chinese Peri-/Postmenopausal women with habitual CMC and explore if the GM mediates the CMC-metabolite associations. 346 Chinese Peri-/Postmenopausal women participants were recruited in this study. Fixed effects regression and partial least squares discriminant analysis (PLS-DA) were applied to reveal alterations of serum metabolic features in different CMC groups. Spearman correlation coefficient was computed to detect metabolome-metagenome association. 36 CMC-associated metabolites including palmitic acid (FA(16:0)), 7alpha-hydroxy-4-cholesterin-3-one (7alphaC4), citrulline were identified by both fixed effects regression (FDR < 0.05) and PLS-DA (VIP score > 2). Some significant metabolite-GM associations were observed, including FA(16:0) with gut species Bacteroides ovatus, Bacteroides sp.D2. These findings would further prompt our understanding of the effect of cow milk on human health.

The regulatory metabolic networks of the Brassica campestris L. hairy roots in response to cadmium stress revealed from proteome studies combined with a transcriptome analysis.

Brassica campestris L., a cadmium (Cd) hyperaccumulating herbaceous plant, is considered as a promising candidate for the bioremediation of Cd pollution. However, the molecular mechanisms regulating these processes remain unclear. The present work, using proteome studies combined with a transcriptome analysis, was carried out to reveal the response mechanisms of the hairy roots of Brassica campestris L. under Cd stress. Significant tissue necrosis and cellular damage occurred, and Cd accumulation was observed in the cell walls and vacuoles of the hairy roots. Through quantitative proteomic profiling, a total of 1424 differentially expressed proteins (DEPs) were identified, and are known to be enriched in processes including phenylalanine metabolism, plant hormone signal transduction, cysteine and methionine metabolism, protein export, isoquinoline alkaloid biosynthesis and flavone biosynthesis. Further studies combined with a transcriptome analysis found that 118 differentially expressed genes (DEGs) and their corresponding proteins were simultaneously up- or downregulated. Further Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of the 118 shared DEGs and DEPs indicated their involvement in calcium, ROS and hormone signaling-mediated response, including regulation of carbohydrate and energy metabolism, biosynthesis of GSH, PCs and phenylpropanoid compounds that play vital roles in the Cd tolerance of Brassica campestris L. Our findings contribute to a better understanding of the regulatory networks of Brassica campestris L. under Cd stress, as well as provide valuable information on candidate genes (e.g., BrPAL, BrTAT, Br4CL, BrCDPK, BrRBOH, BrCALM, BrABCG1/2, BrVIP, BrGCLC, BrilvE, BrGST12/13/25). These results are of particular importance to the subsequent development of promising transgenic plants that will hyperaccumulate heavy metals and efficient phytoremediation processes.

Electron Transport Properties of Graphene/WS2 Van Der Waals Heterojunctions.

Van der Waals heterojunctions of two-dimensional atomic crystals are widely used to build functional devices due to their excellent optoelectronic properties, which are attracting more and more attention, and various methods have been developed to study their structure and properties. Here, density functional theory combined with the nonequilibrium Green's function technique has been used to calculate the transport properties of graphene/WS2 heterojunctions. It is observed that the formation of heterojunctions does not lead to the opening of the Dirac point of graphene. Instead, the respective band structures of both graphene and WS2 are preserved. Therefore, the heterojunction follows a unique Ohm's law at low bias voltages, despite the presence of a certain rotation angle between the two surfaces within the heterojunction. The transmission spectra, the density of states, and the transmission eigenstate are used to investigate the origin and mechanism of unique linear I-V characteristics. This study provides a theoretical framework for designing mixed-dimensional heterojunction nanoelectronic devices.

Controllable Coalescence Dynamics of Nanodroplets on Textured Surfaces Decorated with Well-Designed Wrinkled Nanostructures: A Molecular Dynamics Study.

The control of coalescence and motion of droplets play a significant role in advanced technology and our daily life, and one of the most important approaches is surface design. Here, the microtextured surfaces decorated with wrinkled substrates are designed and studied for coalescence behaviors. The simulation results show that the coalescence speed would be slower on such surfaces due to the downward movement of the droplets induced by the penetration of atoms into the grooves that delays their movement along the coalescence direction, which is considered as a restriction effect. With the increase of the angles and the interval distance of wrinkled structures, the coalescence time becomes longer and the coalescing process becomes unfavorable, resulting from the enhanced restriction effect. More importantly, a composite substrate possessing the original and sub-wrinkled structures has been designed to tune the coalescence dynamics. The results of this work may not only help shed light on understanding the coalescence behaviors on the wrinkled substrates but also propose a feasible method for controlling the liquid coalescence behavior, which is expected to provide some useful implications for practical applications.

Odd-Even Effects on Transport Properties of Polycyclic Arene Molecular Devices with Decreasing Numbers of Benzene Rings.

The electron transport properties of polycyclic aromatic hydrocarbons (PAHs) with different numbers of benzene rings tethered to narrow zigzag graphene nanoribbon (ZGNR) electrodes have been investigated. Results show that the transport properties of PAHs are dependent on whether the number of benzene rings in the width direction is odd or even. This effect is strong for narrow width PAHs, but its strength decreases as the width of the PAH is increased. PAHs with an odd number of rings exhibit poor transport properties, whereas the ones having an even number of rings show excellent transport properties coupled with a negative differential resistance (NDR) effect. Moreover, the linkage points and the structure of the molecules have a noticeable effect on the transport properties of the PAH, making the odd-even effect weaker or disappear entirely. Although the PAH with three benzene rings displays poor transport capabilities, it shows excellent rectification behavior compared to the other examined molecules. These studies present a feasible avenue for designing molecular devices with enhanced performance by the careful manipulation of the PAH molecular structure.

An assessment of sensitivity biomarkers for urinary cadmium burden.

BACKGROUND: Excess cadmium (Cd) intake poses a general risk to health and to the kidneys in particular. Among indices of renal dysfunction under Cd burden measures are the urinary N-acetyl-ß-D-glucosidase (UNAG) and urinary ß2-microglobulin (Uß2-MG) enzymes. However, the end-pointed values and the Cd burden threshold remain controversial because the scopes fluctuate widely. METHODS: To ascertain the clinical benchmark dose of urinary Cd (UCd) burden for renal dysfunction, 1595 residents near a Cd site were surveyed. Urine was sampled and assayed. A benchmark dose low (BMDL) was obtained by fitting UCd levels and index levels. RESULTS: We found that over 50% of the subjects were suffering from Cd exposure as their UCd levels far exceeded the national standard threshold of 5.000 µg/g creatinine (cr). Further analysis indicated that Uß2-MG was more sensitive than UNAG for renal dysfunction. The BMDL for UCd was estimated as 3.486 U/g cr (male, where U is unit of enzyme) and 2.998 U/g cr (female) for UNAG. The BMDL for Uß2-MG, which is released into urine from glomerulus after Cd exposure, was found to be 2.506 µg/g cr (male, where µg is the unit of microglobulin) and 2.236 µg/g cr (female). CONCLUSIONS: Uß2-MG is recommended as the sensitivity index for renal dysfunction, with 2.2 µg/g cr as the threshold for clinical diagnosis. Our findings suggest that Uß2-MG is the better biomarker for exposure to Cd.

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist.

The secreted Wnt signaling molecules are essential to the coordination of cell-fate decision making in multicellular organisms. In adult animals, the secreted Wnt proteins are critical for tissue regeneration and frequently contribute to cancer. Small molecules that disable the Wnt acyltransferase Porcupine (Porcn) are candidate anticancer agents in clinical testing. Here we have systematically assessed the effects of the Porcn inhibitor (WNT-974) on the regeneration of several tissue types to identify potentially unwanted chemical effects that could limit the therapeutic utility of such agents. An unanticipated observation from these studies is proregenerative responses in heart muscle induced by systemic chemical suppression of Wnt signaling. Using in vitro cultures of several cell types found in the heart, we delineate the Wnt signaling apparatus supporting an antiregenerative transcriptional program that includes a subunit of the nonfibrillar collagen VI. Similar to observations seen in animals exposed to WNT-974, deletion of the collagen VI subunit, COL6A1, has been shown to decrease aberrant remodeling and fibrosis in infarcted heart tissue. We demonstrate that WNT-974 can improve the recovery of heart function after left anterior descending coronary artery ligation by mitigating adverse remodeling of infarcted tissue. Injured heart tissue exposed to WNT-974 exhibits decreased scarring and reduced Col6 production. Our findings support the development of Porcn inhibitors as antifibrotic agents that could be exploited to promote heart repair following injury.

Tuning electronic properties of boron phosphide nanoribbons by edge passivation and deformation.

There is a growing awareness that the structures of boron phosphide (BP) nanoribbons have a significant impact on their electronic transport properties, which will further affect their application in many fields, including energy conversion and nanoelectronic devices. By using the first principle density functional theory and non-equilibrium Green's function calculations, we investigate the electronic transport properties of graphene-like hexagonal zigzag BP nanoribbons with edges terminated by hydrogen atoms (-H) or hydroxyl groups (-OH) and the effect of twisting and bending deformations on their transport properties. Our results show that the electronic transport properties of the BP-H nanoribbons become poor after twisting to 45°, while twisting does not reduce the electronic transport properties of BP-OH nanoribbons. When we combine BP-H and BP-OH nanoribbons into a heterosheet, the effect of twist angle is similar to that for the BP-H nanoribbon. Another interesting finding is that for the BP-OH nanoribbons, there is a significant negative differential resistance (NDR) with a giant peak-to-valley ratio (PVR) of up to 90 when it is curled into an arch, which can be applied as an electric switch. Our detailed insights may provide a novel strategy to tune the electronic transport properties of BP nanoribbon-based structures.

Synthesis of Fe-Fe3O4/rGO Composite with Heterostructure Through Room-Temperature Reduction as Photo-Fenton Catalyst.

A Fe-Fe3O4/rGO nanocomposite with heterostructure has been successfully synthesized by a highyield, low-cost, and easily operated room-temperature reduction method. The novel Fe-Fe3O4/rGO composite exhibits an excellent activity for the degradation of Orange II under visible light by the Photo-Fenton process, which is 92.06% after 180 minutes. Moreover, magnetic analysis indicated that the prepared Fe-Fe3O4/rGO composite possesses ferromagnetic properties, which enable it to be magnetically separated for recycling purposes.

Inhibitory effect and molecular mechanism of mesenchymal stem cells on NSCLC cells.

Non-small-cell lung cancer (NSCLC) is still the main threat of cancer-associated death. Current treatment of NSCLC has limited effectiveness, and unfortunately, the prognosis of NSCLC remains poor. Therefore, a novel strategy for cancer therapy is urgently needed. Stem cell therapy has significant potential for cancer treatment. Mesenchymal stem cells (MSCs) with capacity for self-renewal and differentiation into various cells types exhibit the feature of homing to tumor site and immunosuppression, have been explored as a new treatment for various cancers. Studies revealed that the broad repertoire of trophic factors secreted by MSCs extensively involved in the interplay between MSCs and tumor cells. In this study, we confirmed that MSCs do have the paracrine effect on proliferation and migration of NSCLC cells (A549, NCI-H460, and SK-MES-1). Co-culture system and conditioned medium experiments results showed that soluble factors secreted by MSCs inhibited the proliferation of NSCLC cells in vitro. The scratch assay showed that conditioned medium of MSCs could suppress the migration of NSCLC cells in vitro. Western blot results showed that the expression of proteins relevant to cell proliferation, anti-apoptosis, and migration was remarkably decreased via MAPK/eIF4E signaling pathway. We speculated that soluble factors secreted by MSCs might be responsible for inhibitory mechanism of NSCLC cells. By Human Gene Expression Microarray Assay and recombinant Vascular Endothelial Growth Factor 165 (VEGF165) neutralizing experiment, we verified that VEGF might be responsible for the down-regulation of proteins related to cell proliferation, anti-apoptosis, and migration by suppressing translation initiation factor eIF4E via MAPK signaling pathway. Taken together, our study demonstrated that a possible trophic factor secreted by MSCs could manipulate translation initiation of NSCLC cells via MAPK signaling pathway, and significantly affect the fate of tumor cells, which will be a new strategy for cancer therapy.

Bouncing dynamics of liquid drops impact on ridge structure: an effective approach to reduce the contact time.

Surfaces designed so that liquid metals do not stick to them but instead rebound as soon as possible have received considerable attention due to their significant importance in many practical technologies. We herein design a ridge structure that can induce the drop to rapidly rebound through the combination effect of centre-drawing recoil and the resulting faster retraction velocity. The suitable sharp-angle of the ridge for minimizing the contact time is determined as 20-30°. Further analysis reveals that multi-ridge structure or two-ridge structure with gaps can reduce more contact time. We also highlight the role the impact velocity played in minimizing the contact time, which has been a neglected parameter previously. Our studies would open up a new way to reduce the contact time and control the bouncing dynamics of metal drops, which provides guidance for some potential applications, such as preventing splashing molten drops from depositing on clean surface.

Contributions of Bioactive Molecules in Stem Cell-Based Periodontal Regeneration.

Periodontal disease is a widespread disease, which without proper treatment, may lead to tooth loss in adults. Because stem cells from the inflammatory microenvironment created by periodontal disease exhibit impaired regeneration potential even under favorable conditions, it is difficult to obtain satisfactory therapeutic outcomes using traditional treatments, which only focus on the control of inflammation. Therefore, a new stem cell-based therapy known as cell aggregates/cell sheets technology has emerged. This approach provides sufficient numbers of stem cells with high viability for treating the defective site and offers new hope in the field of periodontal regeneration. However, it is not sufficient for regenerating periodontal tissues by delivering cell aggregates/cell sheets to the impaired microenvironment in order to suppress the function of resident cells. In the present review, we summarize some promising bioactive molecules that act as cellular signals, which recreate a favorable microenvironment for tissue regeneration, recruit endogenous cells into the defective site and enhance the viability of exogenous cells.

Multistage genome-wide association meta-analyses identified two new loci for bone mineral density.

Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10(-8)) level: 14q24.2 (rs227425, P-value 3.98 × 10(-13), SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10(-9), CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n = 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis.

Development of a triazole class of highly potent Porcn inhibitors.

The acyltransferase Porcupine (Porcn) is essential for the secretion of Wnt proteins which contribute to embryonic development, tissue regeneration, and tumorigenesis. We have previously discovered four molecular scaffolds harboring Porcn-inhibitory activity. Comparison of their structures led to the identification of a general scaffold that can be readily assembled by modular synthesis. We report herein the development of a triazole version of this new class of Porcn inhibitors. This study yielded IWP-O1, a Porcn inhibitor with an EC50 value of 80pM in a cultured cell reporter assay of Wnt signaling. Additionally, IWP-O1 has significantly improved metabolic stability over our previously reported Porcn inhibitors.

MicroRNA-124 suppresses the transactivation of nuclear factor of activated T cells by targeting multiple genes and inhibits the proliferation of pulmonary artery smooth muscle cells.

Abnormal proliferation and phenotypic modulation of pulmonary artery smooth muscle cells (PASMC) contributes to the pathogenesis of numerous cardiovascular disorders, including pulmonary arterial hypertension (PAH). The nuclear factor of activated T cells (NFAT) signaling pathway is linked to PASMC proliferation and PAH. MicroRNAs (miRNAs) are small non-coding RNAs that function in diverse biological processes. To systemically identify the specific miRNAs that regulate the NFAT pathway, a human primary miRNA library was applied for cell-based high throughput screening with the NFAT luciferase reporter system. Eight miRNAs were found to modulate NFAT activity efficiently. Of them, miR-124 robustly inhibited NFAT reporter activity and decreased both the dephosphorylation and the nuclear translocation of NFAT. miR-124 also inhibited NFAT-dependent transcription of IL-2 in Jurkat T cells. miR-124 exerted its effects by targeting multiple genes, including a known component of the NFAT pathway, NFATc1, and two new regulators of NFAT signaling, CAMTA1 (calmodulin-binding transcription activator 1) and PTBP1 (polypyrimidine tract-binding protein 1). Physiologically, miR-124 was down-regulated by hypoxia in human PASMC, consistent with the activation of NFAT during this process. Down-regulation of miR-124 was also observed in 3-week hypoxia-treated mouse lungs. Furthermore, the overexpression of miR-124 not only inhibited human PASMC proliferation but also maintained its differentiated phenotype by repressing the NFAT pathway. Taken together, our data provide the first evidence that miR-124 acts as an inhibitor of the NFAT pathway. Down-regulation of miR-124 in hypoxia-treated PASMC and its antiproliferative and prodifferentiation effects imply a potential value for miR-124 in the treatment of PAH.

Synthesis of a thin-layer MnO2 nanosheet-coated Fe3O4 nanocomposite as a magnetically separable photocatalyst.

A facile hydrothermal method combined with a mild ultrasonic means has been developed for the fabrication of a magnetically recyclable thin-layer MnO2 nanosheet-coated Fe3O4 nanocomposite. The photocatalytic studies suggest that the MnO2/Fe3O4 nanocomposite shows excellent photocatalytic efficiency and stability simultaneously for the degradation of methylene blue under UV-vis light irradiation. Moreover, its good acid resistance and stable recyclability are very important for its future practical application as a photocatalyst. Magnetic measurements verify that the MnO2/Fe3O4 nanocomposite possesses a ferromagnetic nature, which can be effectively separated for reuse by simply applying an external magnetic field after the photocatalytic reaction. This novel composite material may have potential applications in water treatment, degradation of dye pollutants, and environmental cleaning.