Jolkinolide B synergistically potentiates the antitumor activity of GPX4 inhibitors via inhibiting TrxR1 in cisplatin-resistant bladder cancer cells.

Glutathione peroxidase 4 (GPX4) is a promising anticancer therapeutic target; however, the application of GPX4 inhibitors (GPX4i) is limited owing to intrinsic or acquired drug resistance. Hence, understanding the mechanisms underlying drug resistance and discovering molecules that can overcome drug resistance are crucial. Herein, we demonstrated that GPX4i killed bladder cancer cells by inducing lipid reactive oxygen species-mediated ferroptosis and apoptosis, and cisplatin-resistant bladder cancer cells were also resistant to GPX4i, representing a higher half-maximal inhibitory concentration value than that of parent bladder cancer cells. In addition, thioredoxin reductase 1 (TrxR1) overexpression was responsible for GPX4i resistance in cisplatin-resistant bladder cancer cells, and inhibiting TrxR1 restored the sensitivity of these cells to GPX4i. In vitro and in vivo studies revealed that Jolkinolide B (JB), a natural diterpenoid and previously identified as a TrxR1 inhibitor, potentiated the antiproliferative efficacy of GPX4i (RSL3 and ML162) against cisplatin-resistant bladder cancer cells. Furthermore, GPX4 knockdown and inhibition could augment JB-induced paraptosis and apoptosis. Our results suggest that inhibiting TrxR1 can effectively improve GPX4 inhibition-based anticancer therapy. A combination of JB and GPX4i, which is well-tolerated and has several anticancer mechanisms, may serve as a promising therapy for treating bladder cancer.

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Immune-related nephropathy (IRN) refers to immune-response-mediated glomerulonephritis and is the main cause of end-stage renal failure. The pathogenesis of IRN is not fully understood; therefore, treatment is challenging. Traditional Chinese medicines (TCMs) have potent clinical effects in the treatment of the IRN conditions immunoglobulin A nephropathy, lupus nephropathy, and diabetic nephropathy. The underlying mechanisms mainly include its inhibition of inflammation; improvements to renal interstitial fibrosis, oxidative stress, autophagy, apoptosis; and regulation of immunity. In this review, we summarize the clinical symptoms of the three IRN subtypes and the use of TCM prescriptions, herbs, and bioactive compounds in treating IRN, as well as the potential mechanisms, intending to provide a reference for the future study of TCM as IRN treatments.

Simultaneously Cationic and Anionic Dyes Elimination via Magnetic Hydrochar Prepared from Copper Slag and Pinewood Sawdust.

In practical wastewater, cationic and anionic dyes usually coexist, while synergistic removal of these pollutants is difficult due to their relatively opposite properties. In this work, copper slag (CS) modified hydrochar (CSHC) was designed as functional material by the one-pot method. Based on characterizations, the Fe species in CS can be converted to zero-valent iron and loaded onto a hydrochar substrate. The CSHC exhibited efficient removal rates for both cationic dyes (methylene blue, MB) and anionic dyes (methyl orange, MO), with a maximum capacity of 278.21 and 357.02 mg·g-1, respectively, which was significantly higher than that of unmodified ones. The surface interactions of MB and MO between CSHC were mimicked by the Langmuir model and the pseudo-second-order model. In addition, the magnetic properties of CSHC were also observed, and the good magnetic properties enabled the adsorbent to be quickly separated from the solution with the help of magnets. The adsorption mechanisms include pore filling, complexation, precipitation, and electrostatic attraction. Moreover, the recycling experiments demonstrated the potential regenerative performance of CSHC. All these results shed light on the co-removal of cationic and anionic contaminates via these industrial by-products derived from environmental remediation materials.

Vapor-Phase Indium Intercalation in van der Waals Nanofibers of Atomically Thin W6Te6 Wires.

One-dimensional (1D) conducting materials are of great interest as potential building blocks for integrated nanocircuits. Ternary 1D transition-metal chalcogenides, consisting of M6X6 wires with intercalated A atoms (M = Mo or W; X = S, Se, or Te; A = alkali or rare metals, etc.), have attracted much attention due to their 1D metallic behavior, superconductivity, and mechanical flexibility. However, the conventional solid-state reaction usually produces micrometer-scale bulk crystals, limiting their potential use as nanoscale conductors. Here we demonstrate a versatile method to fabricate indium (In)-intercalated W6Te6 (In-W6Te6) bundles with a nanoscale thickness. We first prepared micrometer-long, crystalline bundles of van der Waals W6Te6 wires using chemical vapor deposition and intercalated In into the crystal via a vapor-phase reaction. Atomic-resolution electron microscopy revealed that In atoms were surrounded by three adjacent W6Te6 wires. First-principles calculations suggested that their wire-by-wire stacking can transform through postgrowth intercalation. Individual In-W6Te6 bundles exhibited metallic behavior, as theoretically predicted. We further identified the vibrational modes by combining polarized Raman spectroscopy and nonresonant Raman calculations.

Compound heterozygous mutations in PMFBP1 cause acephalic spermatozoa syndrome: A case report.

BACKGROUND: Acephalic spermatozoa syndrome (ASS) is an extremely rare form of severe teratozoospermia, where in most of the sperm either appear to lack heads or have disconnected or poorly connected heads and tails. CASE SUMMARY: We reported the case of a male patient with secondary infertility whose sperm showed typical ASS upon morphological analysis. Whole-exome sequencing was performed on the patient's peripheral blood, which revealed two heterozygous variants of the PMFBP1 gene: PMFBP1c.414+1G>T (p.?) and PMFBP1c.393del (p.C132Afs*3). CONCLUSION: It is speculated that the compound homozygous mutation of PMFBP1 may be the cause of ASS. We conducted a literature review in order to provide the basis for genetic counseling and clinical diagnosis of patients with ASS.

Continuous Color-Tunable Light-Emitting Devices Based on Compositionally Graded Monolayer Transition Metal Dichalcogenide Alloys.

The diverse series of transition metal dichalcogenide (TMDC) materials has been employed in various optoelectronic applications, such as photodetectors, light-emitting diodes, and lasers. Typically, the detection or emission range of optoelectronic devices is unique to the bandgap of the active material. Therefore, to improve the capability of these devices, extensive efforts have been devoted to tune the bandgap, such as gating, strain, and dielectric engineering. However, the controllability of these methods is severely limited (typically ≈0.1 eV). In contrast, alloying TMDCs is an effective approach that yields a composition-dependent bandgap and enables light emissions over a wide range. In this study, a color-tunable light-emitting device using compositionally graded TMDC alloys is fabricated. The monolayer WS2 /WSe2 alloy grown by chemical vapor deposition shows a spatial gradient in the light-emission energy, which varies from 2.1 to 1.7 eV. This alloy is incorporated in an electrolyte-based light-emitting device structure that can tune the recombination zone laterally. Thus, a continuous and reversible color-tunable light-emitting device is successfully fabricated by controlling the light-emitting positions. The results provide a new approach for exploring monolayer semiconductor-based broadband optical applications.

Large-Scale 1T'-Phase Tungsten Disulfide Atomic Layers Grown by Gas-Source Chemical Vapor Deposition.

The control of crystal polymorphism and exploration of metastable, two-dimensional, 1T'-phase, transition-metal dichalcogenides (TMDs) have received considerable research attention. 1T'-phase TMDs are expected to offer various opportunities for the study of basic condensed matter physics and for its use in important applications, such as devices with topological states for quantum computing, low-resistance contact for semiconducting TMDs, energy storage devices, and as hydrogen evolution catalysts. However, due to the high energy difference and phase change barrier between 1T' and the more stable 2H-phase, there are few methods that can be used to obtain monolayer 1T'-phase TMDs. Here, we report on the chemical vapor deposition (CVD) growth of 1T'-phase WS2 atomic layers from gaseous precursors, i.e., H2S and WF6, with alkali metal assistance. The gaseous nature of the precursors, reducing properties of H2S, and presence of Na+, which acts as a countercation, provided an optimal environment for the growth of 1T'-phase WS2, resulting in the formation of high-quality submillimeter-sized crystals. The crystal structure was characterized by atomic-resolution scanning transmission electron microscopy, and the zigzag chain structure of W atoms, which is characteristic of the 1T' structure, was clearly observed. Furthermore, the grown 1T'-phase WS2 showed superconductivity with the transition temperature in the 2.8-3.4 K range and large upper critical field anisotropy. Thus, alkali metal assisted gas-source CVD growth is useful for realizing large-scale, high-quality, phase-engineered TMD atomic layers via a bottom-up synthesis.

UBE2W Improves the Experimental Colitis by Inhibiting the NF-κB Signaling Pathway.

BACKGROUND: The NF-κB signaling cascade regulates immune response and is often dysregulated in tumor development. UBE2W is a novel type I ubiquitin-conjugating enzyme (E2) whose biological function is still unclear. AIMS: This study was designed to investigate whether UBE2W regulates NF-κB signaling pathway and is involved in the progression of experimental colitis. METHODS: At the cellular level, the effect of UBE2W on NF-κB transcriptional activity was measured using a dual-luciferase reporter assay. The influence of UBE2W on NF-κB pathway activation and the entry of p65 into the nucleus were determined by Western blot and immunofluorescence analyses, respectively. Moreover, the colitis model was established by administering 2.5% dextran sulfate sodium (DSS)/water to UBE2W overexpression, UBE2W-knockdown and control mice. Body weight, stool consistency, colon length and clinical severity were examined. Expression of pro-inflammatory cytokines and phosphorylation of p65 and IκB in the colon tissue were measured by qRT-PCR and Western blot, respectively. RESULTS: UBE2W inhibited TNFα-induced NF-κB transcription activity, attenuated IκB and p65 phosphorylation, downregulated TNFα and IL-8 expression and blocked the entry of p65 into the nucleus. In the DSS-induced colitis model, UBE2W-knockdown mice had increased weight loss, more serious diarrhea and mucosal injures compared with the control mice. Moreover, phosphorylation of IκB and p65 and the expression of pro-inflammatory mediators such as TNFα, IL-6 were significantly increased in UBE2W knockdown mice. However, these changes were completely reversed in UBE2W overexpression mice. CONCLUSIONS: The overexpression of UBE2W ameliorates the severity of DSS-induced colitis, which may be mediated by inhibiting the expression of pro-inflammatory mediators and activation of the NF-κB signaling pathway. These findings provide evidence that UBE2W might have potential therapeutic implications in IBD.

Transient receptor potential vanilloid 4 promotes the growth of non-small cell lung cancer by regulating Foxp3.

OBJECTIVE(S): Transient receptor potential vanilloid 4 (TRPV4) participates in malignant tumor. However, the role of TRPV4 in non-small cell lung cancer (NSCLC) remains unclear. In this study, we demonstrated TRPV4 was upregulated in NSCLC tissues and NSCLC cell lines. MATERIALS AND METHODS: TRPV4 level in the NSCLC patients and cell lines were detected, and its function was studied both in vivo and vitro. RESULTS: The level of TRPV4 showed a positive correlation with tumor size of NSCLC patients. Activation TRPV4 by agonist GSK1016790A promoted cell proliferation and decreased apoptosis in A549 cells, and these effects were enhanced when the cells have overexpressed TRPV4. Moreover, GSK1016790A induced inhibitory effects on apoptosis of A549 cells was impaired when GSK1016790A used together with TRPV4 selective antagonist HC-067047, or impaired when the cells have already downregulated TRPV4 expression by TRPV4 siRNA. In vivo study, pharmacological inhibition of TRPV4 prevented A549 cells transplanted tumor growth. It was showed Foxp3 level was significantly increased in the NSCLC tissues, and showed a positive correlation with the level of TRPV4. Deactivation of TRPV4 using TRPV4 siRNA or HC-067047 significantly reduced expression of Foxp3 in GSK1016790A treated NSCLC cells. Moreover, downregulation Foxp3 by transfection of Foxp3 siRNA significantly impaired TRPV4 induced NSCLC cells proliferations in vitro. CONCLUSIONS: Antitumor effects caused by TRPV4 inhibition in NSCLC might be attributed to the suppression of Foxp3 which induced subsequent cell apoptosis. Thus, pharmacological inhibition of TRPV4 may be a promising option for NSCLC treatment.

Sensitivity, Specificity, and Safety of a Novel ESAT6-CFP10 Skin Test for Tuberculosis Infection in China: 2 Randomized, Self-Controlled, Parallel-Group Phase 2b Trials.

BACKGROUND: Diagnostics to identify tuberculosis infection are limited. We aimed to assess the diagnostic accuracy and safety of ESAT6-CFP10 (EC) skin test for tuberculosis infection in Chinese adults. METHODS: We conducted 2 randomized, parallel-group clinical trials in healthy participants and tuberculosis patients. All participants were tested with the T-SPOT.TB test, then received an EC skin test and tuberculin skin test (TST). The diameter of skin indurations and/or redness at injection sites were measured at different time periods. A bacillus Calmette Guerin (BCG) model was established to assess the diagnosis of tuberculosis infection using an EC skin test. RESULTS: In total, 777 healthy participants and 96 tuberculosis patients were allocated to receive EC skin test at 1.0 µg/0.1 mL or 0.5 µg/0.1 mL. The area under the curve was 0.95 (95% confidence interval [CI], .91-.97) for the EC skin test at 1.0 µg/0.1 mL at 24-72 hours. Compared with the T-SPOT.TB test, the EC skin test demonstrated similar sensitivity (87.5, 95% CI, 77.8-97.2 vs 86.5, 95% CI, 79.5-93.4) and specificity (98.9, 95% CI, 96.0-99.9 vs 96.1, 95% CI, 93.5-97.8). Among BCG vaccinated participants, the EC skin test had high consistency with the T-SPOT.TB test (96.3, 95% CI, 92.0-100.0). No serious adverse events related to the EC skin test were observed. CONCLUSIONS: The EC skin test demonstrated both high specificity and sensitivity at a dose of 1.0 µg/0.1 mL, comparable to the T-SPOT.TB test. The diagnostic accuracy of the EC skin test was not impacted by BCG vaccination. CLINICAL TRIALS REGISTRATION: NCT02389322 and NCT02336542.

Room-Temperature Chiral Light-Emitting Diode Based on Strained Monolayer Semiconductors.

Room-temperature chiral light sources whose optical helicity can be electrically switched are one of the most important devices for future optical quantum information processing. The emerging valley degree of freedom in monolayer semiconductors allows generation of chiral luminescence via valley polarization. However, relevant valley-polarized light-emitting diodes (LEDs) have only been achieved at low temperatures (typically below 80 K). Here, a room-temperature chiral LED with strained transition metal dichalcogenide monolayers is realized. Spatially resolved polarization spectroscopy reveals that strain effects are crucial to yielding robust valley-polarized electroluminescence. The broken threefold rotational symmetry of strained monolayers induce inequivalent valley drifts at the K/K' valleys, resulting in different amounts of spin recombination driven by electric fields. Based on this scenario, ideally strained conditions are designed for LEDs on flexible substrates, in which the helicity of room-temperature valley-polarized electroluminescence is electrically tuned. The results provide a new pathway for practical chiral light sources based on monolayer semiconductors.

Spatial Control of Dynamic p-i-n Junctions in Transition Metal Dichalcogenide Light-Emitting Devices.

Emerging transition metal dichalcogenides (TMDCs) offer an attractive platform for investigating functional light-emitting devices, such as flexible devices, quantum and chiral devices, high-performance optical modulators, and ultralow threshold lasers. In these devices, the key operation is to control the light-emitting position, that is, the spatial position of the recombination zone to generate electroluminescence, which permits precise light guides/passes/confinement to ensure favorable device performance. Although various structures of TMDC light-emitting devices have been demonstrated, including the transistor configuration and heterostructured diodes, it is still difficult to tune the light-emitting position precisely owing to the structural device complexity. In this study, we fabricated two-terminal light-emitting devices with chemically synthesized WSe2, MoSe2, and WS2 monolayers, and performed direct observations of their electroluminescence, from which we discovered a divergence in their light-emitting positions. Subsequently, we propose a method to associate spatial electroluminescence imaging with transport properties among different samples; consequently, a common rule for determining the locations of recombination zones is revealed. Owing to dynamic carrier accumulations and p-i-n junction formations, the light-emitting positions in electrolyte-based devices can be tuned continuously. The proposed method will expand the device applicability for designing functional optoelectronic applications based on TMDCs.

Air-stable and efficient electron doping of monolayer MoS2 by salt-crown ether treatment.

To maximize the potential of transition-metal dichalcogenides (TMDCs) in device applications, the development of a sophisticated technique for stable and highly efficient carrier doping is critical. Here, we report the efficient n-type doping of monolayer MoS2 using KOH/benzo-18-crown-6, resulting in a doped TMDC that is air-stable. MoS2 field-effect transistors show an increase in on-current of three orders of magnitude and degenerate the n-type behaviour with high air-stability for ∼1 month as the dopant concentration increases. Transport measurements indicate a high electron density of 3.4 × 1013 cm-2 and metallic-type temperature dependence for highly doped MoS2. First-principles calculations support electron doping via surface charge transfer from the K/benzo-18-crown-6 complex to monolayer MoS2. Patterned doping is demonstrated to improve the contact resistance in MoS2-based devices.

Wafer-Scale Growth of One-Dimensional Transition-Metal Telluride Nanowires.

The development of bulk synthetic processes to prepare functional nanomaterials is crucial to achieve progress in fundamental and applied science. Transition-metal chalcogenide (TMC) nanowires, which are one-dimensional (1D) structures having three-atom diameters and van der Waals surfaces, have been reported to possess a 1D metallic nature with great potential in electronics and energy devices. However, their mass production remains challenging. Here, a wafer-scale synthesis of highly crystalline transition-metal telluride nanowires is demonstrated by chemical vapor deposition. The present technique enables formation of either aligned, atomically thin two-dimensional (2D) sheets or random networks of three-dimensional (3D) bundles, both composed of individual nanowires. These nanowires exhibit an anisotropic 1D optical response and superior conducting properties. The findings not only shed light on the controlled and large-scale synthesis of conductive thin films but also provide a platform for the study on physics and device applications of nanowire-based 2D and 3D crystals.

MiR-654-3p Suppresses Non-Small Cell Lung Cancer Tumourigenesis by Inhibiting PLK4.

PURPOSE: MiR-654-3p plays important roles in many types of malignant tumours. However, the biological function of miR-654-3p in non-small cell lung cancer (NSCLC) remains unknown. In this study, the role of miR-654-3p in NSCLC was investigated. METHODS: qRT-PCR was used to evaluate the level of miR-654-3p in NSCLC tissues and cell lines, while Cell Counting Kit-8, Annexin V/propidium iodide dual staining or TUNEL staining were used to investigate proliferation and apoptosis of NSCLC cells. Luciferase assays and Western blotting were performed to validate potential targets of miR-654-3p. RESULTS: MiR-654-3p levels were significantly decreased in NSCLC patients and cell lines and were significantly correlated with the tumour size and tumour node metastasis stage of NSCLC patients. In A549 cells, miR-654-3p overexpression significantly increased apoptosis and inhibited growth both in vivo and in vitro, while downregulation of miR-654-3p had the opposite effects. In addition, polo-like kinase 4 (PLK4) was shown to be a target gene of miR-654-3p that is negatively regulated by miR-654-3p in A549 cells. Furthermore, PLK4 was observed to be highly expressed in NSCLC tissues and cells, and PLK4 overexpression abolished the inhibitory effects of miR-654-3p overexpression on NSCLC cell proliferation. Finally, the animal experiment results further demonstrated that miR-654-3p inhibits tumour growth and regulates PLK4 expression. CONCLUSION: Our results demonstrate that miR-654-3p functions as a growth-suppressing miRNA by targeting PLK4 in NSCLC.

CVD growth of large-area InS atomic layers and device applications.

Group-III monochalcogenides of two-dimensional (2D) layered materials have attracted widespread attention among scientists due to their unique electronic performance and interesting chemical and physical properties. Indium sulfide (InS) is attracting increasing interest from scientists because it has two distinct crystal structures. However, studies on the synthesis of highly crystalline, large-area, and atomically thin-film InS have not been reported thus far. Here, the chemical vapor deposition (CVD) synthesis method of atomic InS crystals has been reported in this paper. The direct chemical vapour phase reaction of metal oxides with chalcogen precursors produces a large-sized hexagonal crystal structure and atomic-thickness InS flakes or films. The InS atomic films are merged with a plurality of triangular InS crystals that are uniform and entire and have surface areas of 1 cm2 and controllable thicknesses in bilayers or trilayers. The properties of the as-grown highly crystalline samples were characterized by spectroscopic and microscopic measurements. The ion-gel gated InS field-effect transistors (FETs) reveal n-type transport behavior, and have an on-off current ratio of >103 and a room-temperature electron mobility of ∼2 cm2 V-1 s-1. Moreover, our CVD InS can be transferred from mica to any substrates, so various 2D materials can be reassembled into vertically stacked heterostructures, thus facilitating the development of heterojunctions and exploration of the properties and applications of their interactions.

[Regulation of Chrysophanol-mediated TLR4/NF-κB Pathway on Renal Injury and Immune Response in IgA Nephropathy Rats].

OBJECTIVE: To investigate the regulatory effect and its mechanism of chrysophanol (CP) on renal injury and immune response in immunoglobin A (IgA) nephropathy rats. METHODS: IgA nephropathy rat model was established by the method of lipopolysaccharide + bovine serum protein + carbon tetrachloride. Then the rats were randomly divided into 5 groups: control group, IgA group, IgA+low, medium and high dose of CP groups(2.5, 5 and 10 mg/kg for each group respectively). IgA+CP groups were intraperitoneally injected with different doses of chrysophanol once a day for 4 weeks, and the control group and IgA group were given isovolumetric saline. Urine protein content, serum creatinine and urea nitrogen were detected at 24 h after the administration of drugs. Kidney histopathological damage and apoptosis were measured by HE and TUNEL staining. The expression levels of Caspase-3 and Caspase-9 were detected by RT-PCR and Western blot; The contents of malondialdehyde (MDA), superoxide dismutase (SOD) and (glutathione peroxidase, Gpx) were detected by enzyme-linked immunosorbent assay (ELISA). The expression of interleukin-1ß, -6 (IL-1ß, IL-6) and tumor necrosis factor (TNF-α) in serum and kidney tissue were measured by ELISA and Western blot, respectively. The mRNA and protein expression levels of toll-like receptro 4 (TLR4), nuclear factor-κB P65 (NF-κB P65) were also detected by RT-PCR and Western blot, and vascular cell adherin molecule (VCAM-1) protein level was deteted by Western blot. RESULTS: In IgA nephropathy rats, the administration of CP reduced proteinuria, serum creatinine and urea nitrogen in a dose-dependent manner (P < 0.01). It also improved the pathological damage of kidney tissue, reduced the apoptosis rate (P < 0.01), and decreased the mRNA and protein expression levels of apoptosis-related proteins Caspase-3 and Caspase-9 (P < 0.01). CP inhibited MDA production while increased the activities of antioxidant enzymes Gpx and SOD (P < 0.01), and decreased the levels of serum and protein expression of IL-1ß, IL-6 and TNF-α (P < 0.01), as well as the expression levels of TLR4, NF-κB P65 and VCAM-1 (P < 0.01). CONCLUSION: Chrysophanol could play a protective role in IgA nephropathy rats, and its mechanism may be related to alleviating kidney injury and regulating immune response.