Potential Correlation between Tea Intake and the Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study.

INTRODUCTION: There were limited observation studies on the association between tea intake and amyotrophic lateral sclerosis (ALS) with inconsistent results. This study aimed to determine the potential relationship between tea intake and ALS by a two-sample Mendelian randomization (MR) analysis. METHODS: We identified 41 independent SNPs strongly associated with tea intake from 448,060 participants of European ancestry in the UK Biobank. Summary statistics associated with ALS were also obtained from the UK Biobank including 20,806 cases and 59,804 controls. The study used MR analysis to assess the potential effect of tea consumption on ALS, and several methods such as sensitivity analyses and MR-pleiotropy residual sum and outlier method were performed to further test the robustness of our findings. RESULTS: The F statistic was more than 10 in each SNP, which meets the first assumption for the MR study. Using the inverse variance weighted MR analysis as the primary method, we found that a one standard deviation increase in tea consumption was associated with a 14% lower risk of ALS (OR = 0.86, 95% CI = 0.74-0.99, p < 0.05). Sensitivity analyses detected no potential pleiotropy and directional heterogeneity. CONCLUSION: Our MR study supported the potential relationship between tea intake and ALS risk, suggesting the potential advantages of tea intake for preventing ALS. Future clinical trials and research are needed to further validate the results and elucidate possible mechanisms.

NADP modulates RNA m6A methylation and adipogenesis via enhancing FTO activity.

Metabolism is often regulated by the transcription and translation of RNA. In turn, it is likely that some metabolites regulate enzymes controlling reversible RNA modification, such as N6-methyladenosine (m6A), to modulate RNA. This hypothesis is at least partially supported by the findings that multiple metabolic diseases are highly associated with fat mass and obesity-associated protein (FTO), an m6A demethylase. However, knowledge about whether and which metabolites directly regulate m6A remains elusive. Here, we show that NADP directly binds FTO, independently increases FTO activity, and promotes RNA m6A demethylation and adipogenesis. We screened a set of metabolites using a fluorescence quenching assay and NADP was identified to remarkably bind FTO. In vitro demethylation assays indicated that NADP enhances FTO activity. Furthermore, NADP regulated mRNA m6A via FTO in vivo, and deletion of FTO blocked NADP-enhanced adipogenesis in 3T3-L1 preadipocytes. These results build a direct link between metabolism and RNA m6A demethylation.

Liquid Exfibration and Optoelectronic Devices of Fibrous Phosphorus.

Quasi-one-dimensional (Q1D) semiconductor materials, such as carbon nanotubes, SbSI, MP15 (M = Li, Na, K), and selenium and tellurium nanowires, show amazing potential for applications in future nanoelectronic and optoelectronic devices. However, intricate chirality in the structure of carbon nanotubes limits their applications. Also, the performance of MP15 in optoelectronics has yet to be extensively explored. One new Q1D semiconductor material, fibrous phosphorus (FP), has recently received attention because its raw material is less toxic. However, the ability to characterize FP by phase identification is limited in the assessment of micro/nano-thickness, such as exfibrated FP. So, identifying a precise Raman spectrum will allow for much better characterization. Here, a sufficiently sharp Raman spectrum of FP was obtained and analyzed. Moreover, we demonstrated that high-quality, few-layer FP fibers with thicknesses as low as 5.55 nm can be produced by liquid-phase exfibration under ambient conditions in solvents. More importantly, an optoelectronic detector based on a single FP fiber field-effect-transistor configuration was investigated. A rise time as short as about 40 ms was obtained for the FP transistors, illustrating the potential of FP single bundle crystals as a new one-dimensional material for optoelectronic device applications.

Mast cells-derived MiR-223 destroys intestinal barrier function by inhibition of CLDN8 expression in intestinal epithelial cells.

BACKGROUND: Mast cells (MCs) have been found to play a critical role during development of inflammatory bowel disease (IBD) that characterized by dysregulation of inflammation and impaired intestinal barrier function. However, the function of MCs in IBD remains to be fully elucidated. RESULTS: In our study, we used exosomes isolated from human mast cells-1 (HMCs-1) to culture with NCM460, HT-29 or CaCO2 of intestinal epithelial cells (IECs) to investigate the communication between MCs and IECs. We found that MCs-derived exosomes significantly increased intestinal epithelial permeability and destroyed intestinal barrier function, which is attributed to exosome-mediated functional miRNAs were transferred from HMCs-1 into IECs, leading to inhibit tight junction-related proteins expression, including tight junction proteins 1 (TJP1, ZO-1), Occludin (OCLN), Claudin 8 (CLDN8). Microarray and bioinformatic analysis have further revealed that a panel of miRNAs target different tight junction-related proteins. Interestingly, miR-223 is enriched in mast cell-derived exosome, which inhibit CLDN8 expression in IECs, while treatment with miR-223 inhibitor in HT-29 cells significantly reversed the inhibitory effect of HMCs-1-derived exosomes on CLDN 8 expression. Most importantly, enrichment of MCs accumulation in intestinal mucosa of patients with IBD compared with those healthy control. CONCLUSIONS: These results indicated that enrichment of exosomal miR-223 from HMCs-1 inhibited CLDN8 expression, leading to destroy intestinal barrier function. These finding provided a novel insight of MCs as a new target for therapeutic treatment of IBD.

Crosstalk of protein kinase C ε with Smad2/3 promotes tumor cell proliferation in prostate cancer cells by enhancing aerobic glycolysis.

Protein kinase C ε (PKCε) has emerged as an oncogenic protein kinase and plays important roles in cancer cell survival, proliferation, and invasion. It is, however, still unknown whether PKCε affects cell proliferation via glucose metabolism in cancer cells. Here we report a novel function of PKCε that provides growth advantages for cancer cells by enhancing tumor cells glycolysis. We found that either PKCε or Smad2/3 promoted aerobic glycolysis, expression of the glycolytic genes encoding HIF-1α, HKII, PFKP and MCT4, and tumor cell proliferation, while overexpression of PKCε or Smad3 enhanced aerobic glycolysis and cell proliferation in a protein kinase D- or TGF-ß-independent manner in PC-3M and DU145 prostate cancer cells. The effects of PKCε silencing were reversed by ectopic expression of Smad3. PKCε or Smad3 ectopic expression-induced increase in cell growth was antagonized by inhibition of lactate transportation. Furthermore, interaction of endogenous PKCε with Smad2/3 was primarily responsible for phosphorylation of Ser213 in the Samd3 linker region, and resulted in Smad3 binding to the promoter of the glycolytic genes, thereby promoting cell proliferation. Forced expression of mutant Smad3 (S213A) attenuated PKCε-stimulated protein overexpression of the glycolytic genes. Thus, our results demonstrate a novel PKCε function that promotes cell growth in prostate cancer cells by increasing aerobic glycolysis through crosstalk between PKCε and Smad2/3.

[Effect of Junction Temperature on EL Spectra of GaN-Based White High Voltage LEDs].

High voltage light emitting diodes (HV-LEDs) have potential advantages on general lighting application for their special features. But as novel power LEDs, their optical, electrical and thermal characteristics still need to be further studied. In this paper, 6 and 9 V GaN-based HV-LEDs were packaged in the same package structure and process conditions. The optical characteristics of two samples were investigated under different temperatures range from 10 to 70 ℃ which were calibrated to junction temperatures using thermal impedance measurement. To ensure the same current density, working current was set to 150 mA for 6 V sample and 100 mA for 9 V sample respectively. Results show that the increasing junction temperature has a great effect on EL spectra of two samples, such as peak wavelength red-shifting, full width at half maximum (FWHM) broadening, luminous efficiency reducing and color rendering index (CRI) increasing. The junction temperature of 9V sample is lower than that of 6 V sample in the same platform temperature and injection power. With temperature increasing, the extended quantitative value of FWHM for 9 V sample is 1.3 nm less than that of 6 V sample, the reduced quantitative value of luminous efficiency is 1.13 lm·W(-1) less than that of 6 V sample, while the increased quantitative value of CRI is 0.28 less than that of 6 V sample. Those data suggest that EL spectra of HV-LEDs is less affected by junction temperature than traditional LEDs. It is because HV-LEDs perform better in current spreading and generate less heat. This conclusion has reference value for study, development and applications of GaN-based HV-LEDs. In addition, peak wavelength still has a good linear relationship with junction temperature and it can be a temperature-sensitive parameter when the spectra measurement accuracy is enough.

Validation for the function of protein C in mouse models.

Objectives: Protein C (PC) is an anticoagulant that is encoded by the PROC gene. Validation for the function of PC was carried out in mouse models. Methods: In this study, autosomal recessive PC deficiency (PCD) was selected as the target, and the specific mutation site was chromosome 2 2q13-q14, PROC c.1198G>A (p.Gly400Ser) which targets G399S (GGT to AGC) in mouse models. To investigate the role of hereditary PC in mice models, we used CRISPR/Cas9 gene editing technology to create a mouse model with a genetic PCD mutation. Results: The two F0 generation positive mice produced using the CRISPR/Cas9 gene editing technique were chimeras, and the mice in F1 and F2 generations were heterozygous. There was no phenotype of spontaneous bleeding or thrombosis in the heterozygous mice, but some of them were blind. Blood routine results showed no significant difference between the heterozygous mice and wild-type mice (P > 0.05). Prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT) were prolonged in the heterozygous mice, while the level of fibrinogen content (FIB) decreased, suggesting secondary consumptive coagulation disease. The protein C activity of heterozygous mice was significantly lower than that of wild-type mice (P < 0.001), but there was no significant difference in protein C antigen levels (P > 0.05). H&E staining showed steatosis and hydrodegeneration in the liver of heterozygous mice. Necrosis and exfoliated epithelial cells could be observed in renal tubule lumen, forming cell or granular tubules. Hemosiderin deposition was found in the spleen along with splenic hemorrhage. Immunohistochemistry demonstrated significant fibrin deposition in the liver, spleen, and kidney of heterozygous mice. Conclusion: In this study, heterozygotes of the mouse model with a PC mutation were obtained. The function of PC was then validated in a mouse model through genotype, phenotype, and PC function analysis.

m5C methylation modification guides the prognostic value and immune landscapes in acute myeloid leukemia.

The development, incidence, and metastasis of tumors are all intimately correlated with 5-methylcytosine (m5C). However, uncertainty surrounds the function of m5C in acute myeloid leukemia (AML). In this study, multicenter AML data were collected and analyzed comprehensively to grasp the gene expression level, clinicopathological characteristics, prognostic significance of m5C in AML and its relationship with the tumor microenvironment (TME). The m5C gene-mediated scoring system (m5CSS) was created using principal component analysis, and multiple cox regression analyses were utilized to determine the prognostic relevance of the m5C score. The investigation of the correlation among m5C, immune characteristics, clinical characteristics, immune infiltration level, as well as drug reaction at immune checkpoints, and immunotherapy efficacy confirmed that the change of the characteristics of immune cell infiltration and patient prognosis are linked with the m5C gene. Moreover, the m5CSS was employed to assess the pattern of m5C modification. Further analyses showed that the m5C score can served as a reliable indicator of AML prognosis. Crucially, the prognostic value of the m5C score was validated in terms of drug resistance and immunotherapy. This work reveals that AML diversity and the generation of complex TMEs are both impacted by m5C modifications. Therefore, understanding the m5C modification pattern will improve grasp of TME infiltration characteristics and assist exploring more efficient immunotherapeutic approaches.

An all-two-dimensional Fe-FET retinomorphic sensor based on the novel gate dielectric In2Se3-xOx.

Two-dimensional (2D) ferroelectric field-effect transistors (Fe-FETs) have attracted extensive interest as a competitive platform for implementing future-generation functional electronics, including digital memory and brain-inspired computing circuits. In 2D Fe-FETs, the 2D ferroelectric materials are more suitable as gate dielectric materials compared to 3D ferroelectric materials. However, the current 2D ferroelectric materials (represented by α-In2Se3) need to be integrated with other 3D gate dielectric layers because of their high conductivity as a ferroelectric semiconductor. This 2D/3D hybrid structure can lead to compatibility problems in practical devices. In this study, a new 2D gate dielectric material that is compatible with the complementary metal-oxide semiconductor process was found by using oxygen plasma treatment. The 2D gate dielectric material obtained shows excellent performance, with an equivalent oxide thickness of less than 0.15 nm, and excellent insulation, with a leakage current of less than 2 × 10-5 A cm-2 (under a 1 V gate voltage). Based on this dielectric layer and the α-In2Se3 ferroelectric gate material, we fabricated an all-2D Fe-FET high-performance photodetector with a high on/off ratio (∼105) and detectivity (>1013 Jones). Moreover, the photoelectric device integrates perception, memory and computing characteristics, indicating that it can be applied to an artificial neural network for visual recognition.

Cyclovirobuxine D, a cardiovascular drug from traditional Chinese medicine, alleviates inflammatory and neuropathic pain mainly via inhibition of voltage-gated Cav3.2 channels.

Cyclovirobuxine D (CVB-D), the main active constituent of traditional Chinese medicine Buxus microphylla, was developed as a safe and effective cardiovascular drug in China. B. microphylla has also been used to relieve various pain symptoms for centuries. In this study, we examined and uncovered strong and persistent analgesic effects of cyclovirobuxine D against several mouse models of pain, including carrageenan- and CFA-induced inflammatory pain and paclitaxel-mediated neuropathic hypersensitivity. Cyclovirobuxine D shows comparable analgesic effects by intraplantar or intraperitoneal administration. Cyclovirobuxine D potently inhibits voltage-gated Cav2.2 and Cav3.2 channels but has negligible effects on a diverse group of nociceptive ion channels distributed in primary afferent neurons, including Nav1.7, Nav1.8, TRPV1, TPRA1, TRPM8, ASIC3, P2X2 and P2X4. Moreover, inhibition of Cav3.2, rather than Cav2.2, plays a dominant role in attenuating the excitability of isolated dorsal root ganglion neurons and pain relieving effects of cyclovirobuxine D. Our work reveals that a currently in-use cardiovascular drug has strong analgesic effects mainly via blockade of Cav3.2 and provides a compelling rationale and foundation for conducting clinical studies to repurpose cyclovirobuxine D in pain management.

Research Status and Prospect for Vibration, Noise and Temperature Rise-Based Effect of Food Transport Pumps on the Characteristics of Liquid Foods.

In the field of food processing, the processing of liquid foods has always played an important role. Liquid foods have high requirements for the processing environment and equipment. As the core equipment in liquid foods processing, food transport pumps are widely used in liquid foods production, processing and transportation. Most liquid foods are non-Newtonian and vulnerable to vibration, noise, and temperature rise produced by rotary motions of food transport pumps in operation, which can finally affect foods safety. Therefore, this review summarizes the impact of mechanical vibration, noise, and temperature rise on liquid food products, with the aim of ensuring food safety while designing a cleaner, safer and more reliable food transport pumps in the future.

Caged polycyclic polyprenylated acylphloroglucinols as Cav3.2 low voltage-gated Ca2+ channel inhibitors from Hypericum curvisepalum.

Five caged polycyclic polyprenylated acylphloroglucinols including an unprecedented octahydro-2,5-methanoindene skeleton (1) were discovered from Hypericum curvisepalum. Biologically, 1 and 2 are potent Cav3.2 T-type Ca2+ channel inhibitors with negligible effect on the cardiovascular antitarget, the human ether-à-go-go-related gene potassium channel. Additionally, 2 indicates strong antinociception in the mouse acetic acid writhing test.

Strain-Tunable Electronic and Transport Properties of One-Dimensional Fibrous Phosphorus Nanotubes.

The one-dimensional van der Waals (1D vdW) material fibrous red phosphorus (FRP) nanotubes are a promising direct-bandgap semiconductor with high carrier mobility and anisotropic optical responses because of low deformation potential and dangling-bond-free anisotropic interface. Employing first-principles calculations, we captured the potential of 1D FRP nanotubes. The thermal stability of 1D FRP nanotubes was confirmed by phonon calculation. Meanwhile, Raman spectroscopy indicated the strong vibration mode (366 cm-1) is along the phosphorus nanotube. Interestingly, spatial anisotropy bandgaps were found along with various stacking orientations. The charge transport calculations showed that the 1D FRP nanotube has a high hole mobility (499.2 cm2 V-1 s-1), considering the weak acoustic phonon scattering. More importantly, we found that the hole mobility changes dramatically (down to 7.1 cm2 V-1 s-1) under the strain, and the strain-dependent charge transport property of 1D FRP nanotubes could be considered to have many potential applications for electronics, optoelectronics, and switching devices.

Temperature-Dependent Luminescence and Anisotropic Optical Properties of Centimeter-Sized One-Dimensional Perovskite Trimethylammonium Lead Iodide Single Crystals.

Low-dimensional hybrid halide perovskite materials with self-trapped exciton (STE) emissions and anisotropic properties are highly attractive for their great potential in many applications. However, to date, reports on large one-dimensional (1D) perovskite single crystals have been limited. Here, centimeter-sized 1D single crystals of trimethylammonium lead iodide (TMAPbI3) with typical STE emission are synthesized by an antisolvent vapor-assisted crystallization method. Thermal quenching and antiquenching with a high relative sensitivity of photoluminescence (PL) are observed and studied via temperature-dependent photoluminescence spectroscopy. Further analysis indicates that the temperature-dependent PL behaviors are influenced by the self-trapping of the free exciton and the migrations between self-trapped excitons and intermediate nonradiative states. The TMAPbI3 single crystal also exhibits a linearly polarized emission and a large birefringence that is higher than those of commercial birefringent crystals. This 1D perovskite with high structural anisotropy has promise for applications in versatile optical- and luminescence-related fields.

A High-Performance In-Memory Photodetector Realized by Charge Storage in a van der Waals MISFET.

The emerging data-intensive applications in optoelectronics are driving innovation toward the fused integration of sensing, memory, and computing to break through the restrictions of the von Neumann architecture. However, the present photodetectors with only optoelectronic conversion functions cannot satisfy the growing demands of the multifunctions required in single devices. Here, a novel route for the integration of non-volatile memory into a photodetector is proposed, with a WSe2 /h-BN van der Waals heterostructure on a Si/SiO2 substrate to realize in-memory photodetection. This photodetector exhibits an ultrahigh readout photocurrent of 3.4 µA and photoresponsivity of 337.8 A W-1 in the solar-blind wavelength region, together with an extended retention time of more than 10 years. Furthermore, the charge-storage-based non-volatile mechanism of h-BN/SiO2 is successfully proven through a novel analysis of in situ optoelectronic electron energy-loss spectroscopy. These results represent a leap forward to future applications and insightful mechanisms of in-memory photodetection.

Electrically tunable two-dimensional heterojunctions for miniaturized near-infrared spectrometers.

Miniaturized spectrometers are of considerable interest for their portability. Most designs to date employ a photodetector array with distinct spectral responses or require elaborated integration of micro & nano optic modules, typically with a centimeter-scale footprint. Here, we report a design of a micron-sized near-infrared ultra-miniaturized spectrometer based on two-dimensional van der Waals heterostructure (2D-vdWH). By introducing heavy metal atoms with delocalized electronic orbitals between 2D-vdWHs, we greatly enhance the interlayer coupling and realize electrically tunable infrared photoresponse (1.15 to 1.47 µm). Combining the gate-tunable photoresponse and regression algorithm, we achieve spectral reconstruction and spectral imaging in a device with an active footprint < 10 µm. Considering the ultra-small footprint and simple fabrication process, the 2D-vdWHs with designable bandgap energy and enhanced photoresponse offer an attractive solution for on-chip infrared spectroscopy.

High-fat diet impairs ferroptosis and promotes cancer invasiveness via downregulating tumor suppressor ACSL4 in lung adenocarcinoma.

BACKGROUND: Long-chain acyl-CoA synthetase-4 (ACSL4) is involved in fatty acid metabolism, and aberrant ACSL4 expression could be either tumorigenic or tumor-suppressive in different tumor types. However, the function and clinical significance of ACSL4 in lung adenocarcinoma remain elusive. RESULTS: ACSL4 was frequently downregulated in lung adenocarcinoma when analyzing both the TCGA database and the validation samples, and the lower ACSL4 expression was correlated with a worse prognosis. Using gene set enrichment analysis, we found that high ACSL4 expression was frequently associated with the oxidative stress pathway, especially ferroptosis-related proteins. In vitro functional studies showed that knockdown of ACSL4 increased tumor survival/invasiveness and inhibited ferroptosis, while ACSL4 overexpression exhibited the opposite effects. Moreover, high-fat treatment could also inhibit erastin-induced ferroptosis by affecting ACSL4 expression. The anti-tumor effects of ferroptosis inducers and the anti-ferroptosis effects of the high-fat diet were further validated using the mouse xenograft model. CONCLUSIONS: ACSL4 plays a tumor-suppressive role in lung adenocarcinoma by suppressing tumor survival/invasiveness and promoting ferroptosis. Our study provided a theoretical reference for the application of ferroptotic inducers and dietary guidance for lung adenocarcinoma patients.

Diterpenoid Alkaloids from the Aerial Parts of Aconitum flavum Hand.-Mazz.

Sixteen diterpenoid alkaloids (DAs), including six aconitine-type alkaloids (5 and 9 - 13), seven 7,17-seco-aconitine-type alkaloids (1 - 4, 6 - 8), two napelline-type alkaloids (14 and 15) as well as one veatchine-type alkaloid (16), were isolated from the aerial parts of Aconitum flavum Hand.-Mazz. In which, flavumolines A - D (1 - 4) were four new ones, and flavumoline E (5) was reported as natural compound for the first time. Their chemical structures were elucidated by the analysis of extensive spectroscopic data. The inhibitory activities of these isolates on Cav3.1 low voltage-gated Ca2+ channel, NO production in LPS-activated RAW264.7cells, five human tumor cell lines, as well as acetylcholinesterase (AChE) were tested.

Isoprenylated Flavonoids as Cav3.1 Low Voltage-Gated Ca2+ Channel Inhibitors from Salvia digitaloides.

Saldigones A-C (1, 3, 4), three new isoprenylated flavonoids with diverse flavanone, pterocarpan, and isoflavanone architectures, were characterized from the roots of Salvia digitaloides, together with a known isoprenylated flavanone (2). Notably, it's the first report of isoprenylated flavonoids from Salvia species. The structures of these isolates were elucidated by extensive spectroscopic analysis. All of the compounds were evaluated for their activities on Cav3.1 low voltage-gated Ca2+ channel (LVGCC), of which 2 strongly and dose-dependently inhibited Cav3.1 peak current.