Earliest Prepared core technology in Eurasia from Nihewan (China): Implications for early human abilities and dispersals in East Asia.

Organized flaking techniques to obtain predetermined stone tools have been traced back to the early Acheulean (also known as mode 2) in Africa and are seen as indicative of the emergence of advanced technical abilities and in-depth planning skills among early humans. Here, we report one of the earliest known examples of prepared core technology in the archaeological record, at the Cenjiawan (CJW) site in the Nihewan basin of China, dated 1.1 Mya. The operational schemes reconstructed from the CJW refit sets, together with shaping patterns observed in the retouched tools, suggest that Nihewan basin toolmakers had the technical abilities of mode 2 hominins, and developed different survival strategies to adapt to local raw materials and environments. This finding predates the previously earliest known prepared core technology from Eurasia by 0.3 My, and the earliest known mode 2 sites in East Asia by a similar amount of time, thus suggesting that hominins with advanced technologies may have migrated into high latitude East Asia as early as 1.1 Mya.

PDIA3 orchestrates effector T cell program by serving as a chaperone to facilitate the non-canonical nuclear import of STAT1 and PKM2.

Dysregulated T cell activation underpins the immunopathology of rheumatoid arthritis (RA), yet the machineries that orchestrate T cell effector program remain incompletely understood. Herein, we leveraged bulk and single-cell RNA sequencing data from RA patients and validated protein disulfide isomerase family A member 3 (PDIA3) as a potential therapeutic target. PDIA3 is remarkably upregulated in pathogenic CD4 T cells derived from RA patients and positively correlates with C-reactive protein level and disease activity score 28. Pharmacological inhibition or genetic ablation of PDIA3 alleviates RA-associated articular pathology and autoimmune responses. Mechanistically, T cell receptor signaling triggers intracellular calcium flux to activate NFAT1, a process that is further potentiated by Wnt5a under RA settings. Activated NFAT1 then directly binds to the Pdia3 promoter to enhance the expression of PDIA3, which complexes with STAT1 or PKM2 to facilitate their nuclear import for transcribing T helper 1 (Th1) and Th17 lineage-related genes, respectively. This non-canonical regulatory mechanism likely occurs under pathological conditions, as PDIA3 could only be highly induced following aberrant external stimuli. Together, our data support that targeting PDIA3 is a vital strategy to mitigate autoimmune diseases, such as RA, in clinical settings.

Genome-wide analysis and expression profiling of the HD-ZIP gene family in kiwifruit.

The homeodomain-leucine zipper (HD-Zip) gene family plays a pivotal role in plant development and stress responses. Nevertheless, a comprehensive characterization of the HD-Zip gene family in kiwifruit has been lacking. In this study, we have systematically identified 70 HD-Zip genes in the Actinidia chinensis (Ac) genome and 55 in the Actinidia eriantha (Ae) genome. These genes have been categorized into four subfamilies (HD-Zip I, II, III, and IV) through rigorous phylogenetic analysis. Analysis of synteny patterns and selection pressures has provided insights into how whole-genome duplication (WGD) or segmental may have contributed to the divergence in gene numbers between these two kiwifruit species, with duplicated gene pairs undergoing purifying selection. Furthermore, our study has unveiled tissue-specific expression patterns among kiwifruit HD-Zip genes, with some genes identified as key regulators of kiwifruit responses to bacterial canker disease and postharvest processes. These findings not only offer valuable insights into the evolutionary and functional characteristics of kiwifruit HD-Zips but also shed light on their potential roles in plant growth and development.

γ-Tocotrienol enhances autophagy of gastric cancer cells by the regulation of GSK3ß/ß-Catenin pathway.

γ-Tocotrienol (γ-T3) is a major subtype of vitamin E, mainly extracted from palm trees, barley, walnuts, and other plants. γ-T3 has effects on anti-inflammation, anti-oxidation, and potential chemoprevention against malignancies. It is still uncompleted to understand the effect of γ-T3 on the inhibitory mechanism of cancer. This study aimed to investigate whether γ-T3 enhanced autophagy in gastric cancer and the underlying molecular mechanism. The results showed that γ-T3 (0-90 µmol/L) inhibited the proliferation of gastric cancer MKN45 cells and AGS cells, and arrested the cell cycle at the G0/G1 phase in a dose-dependent manner. Autophagy was increased in MKN45 cells treated with γ-T3 (0-45 µmol/L), especially at a dose of 30 µmol/L for 24 h. These effects were reversed by 3-methyladenine pretreatment. Furthermore, γ-T3 (30 µmol/L) also significantly downregulated the expression of pGSK-3ß (ser9) and ß-catenin protein in MKN45 cells, and γ-T3 (20 mg/kg b.w.) effectively decreased the growth of MKN45 cell xenografts in BABL/c mice. GSK-3ß inhibitor-CHIR-99021 reversed the negative regulation of GSK-3ß/ß-Catenin signaling and autophagy. Our findings indicated that γ-T3 enhances autophagy in gastric cancer cells mediated by GSK-3ß/ß-Catenin signaling, which provides new insights into the role of γ-T3 enhancing autophagy in gastric cancer.

New Phenol Derivatives from the Haima Cold Seep-Derived Fungus Aspergillus subversicolor CYH-17.

Seven new phenol derivatives, subversins A-E (1-5), subversic acid A (6) and epi-wortmannine G (7); one new natural product, 4-hydroxy-7-methoxyphthalide (8); and five known compounds (9-13) were isolated from the fungus Aspergillus subversicolor CYH-17 collected from the Haima cold seep. The structures and absolute configurations of these compounds were determined via NMR, MS, optical rotation, electronic circular dichroism (ECD) calculation, X-ray diffraction analysis and comparison with the literature. Compounds 2 and 5 were two pairs of enantiomers. All compounds were tested for their α-glucosidase and acetylcholinesterase (AChE) inhibitory activity, antioxidant activity and antibacterial activity, but no obvious activity was observed among these studied compounds.

Synthesis, Structural Characterization, and Biological Activities of 1,3,4- Thiadiazole Derivatives Containing Sulfonylpiperazine Structures.

To develop novel bacterial biofilm inhibiting agents, a series of 1,3,4-thiadiazole derivatives containing sulfonylpiperazine structures were designed, synthesized, and characterized using 1H nuclear magnetic resonance (1H NMR), 13C nuclear magnetic resonance (13C NMR), and high-resolution mass spectrometry. Meanwhile, their biological activities were evaluated, and the ensuing structure-activity relationships were discussed. The bioassay results showed the substantial antimicrobial efficacy exhibited by most of the compounds. Among them, compound A24 demonstrated a strong efficacy with an EC50 value of 7.8 µg/mL in vitro against the Xanthomonas oryzae pv. oryzicola (Xoc) pathogen, surpassing commercial agents thiodiazole copper (31.8 µg/mL) and bismerthiazol (43.3 µg/mL). Mechanistic investigations into its anti-Xoc properties revealed that compound A24 operates by increasing the permeability of bacterial cell membranes, inhibiting biofilm formation and cell motility, and inducing morphological changes in bacterial cells. Importantly, in vivo tests showed its excellent protective and curative effects on rice bacterial leaf streak. Besides, molecular docking showed that the hydrophobic effect and hydrogen-bond interactions are key factors between the binding of A24 and AvrRxo1-ORF1. Therefore, these results suggest the utilization of 1,3,4-thiadiazole derivatives containing sulfonylpiperazine structures as a bacterial biofilm inhibiting agent, warranting further exploration in the realm of agrochemical development.

[Treatment of hypoxia-induced ED in high-altitude areas by transcutaneous low-frequency electrical stimulation based on the parameters obtained from visualized precision electrophysiological diagnosis].

OBJECTIVE: To investigate the effects of visualized precision electrophysiological diagnosis and transcutaneous low-frequency electrical stimulation (TES) on hypoxia-induced ED in high-altitude areas. METHODS: This study included 152 ED patients from high-altitude hypoxic areas treated by TES based on the parameters obtained from visualized precision electrophysiological diagnosis. We followed up the patients for 1 to 3 months and compared their IIEF-5 scores, nocturnal penile tumescence and rigidity (NPTR) and infrared thermal metabolic technology (TMT)-based temperature of the whole body and diseased parts before and after treatment. RESULTS: All the patients successfully completed 1 to 3 courses of TES. There were no statistically significant differences in the IIEF-5 scores (P<0.05) and penile tip optimal erection rigidity and duration (P<0.01) of the patients before and after treatment. TMT images indicated a temperature change of >1.5 ℃ in the penis and bilateral inguinal regions after treatment, suggesting the effectiveness of electrical stimulation. No recurrence was observed during the follow-up. CONCLUSION: TES based on the parameters obtained from visualized precision electrophysiological diagnosis has a definite effect on hypoxia-induced ED by enhancing oxygen supply to the penile corpus cavernosum and improving its function and structure.

Description of two new Megistophylla Burmeister, 1855 species from China, with a redescription of M. andrewesi Moser, 1913 (Coleoptera: Scarabaeidae: Melolonthinae).

This study presents descriptions and illustrations of two new melolonthine species: Megistophylla brevivirgata Wang & Gao, new species and M. keithi Wang & Gao, new species from Yunnan province in China. Additionally, a detailed redescription and illustration of the male of M. andrewesi Moser, 1913, and a description of its previously unknown female are provided. Finally, a key to identification of Megistophylla Burmeister, 1855 species from China is added.

Optimizing brand loyalty through user-centric product package design: A study of user experience in dairy industry.

Objective: With the arrival of the experience economy era, changes in the marketing environment, and the evolution of consumer psychological needs, a good user experience will bring them freshness. Based on user experience, this paper analyzes the relationship among product brand image, brand trust, and brand loyalty, aiming to promote product values and improve brand loyalty and trust. Methods: Through case analysis, consumers' favorite brands were selected and conducted positioning analysis on brand color, image, package form, and so on. The study proposed a hypothetical model of user experience on brand loyalty and performed a questionnaire survey on 357 consumers. The relational model of the impact of user experience on consumers was verified using the SEM (Structural Equation Model) method. Results: It is shown that sensory experience, emotional experience, behavioral experience, and thinking experience have significant impacts on brand image; brand image apparently affects brand trust; and brand trust and image remarkably influence brand loyalty. Conclusions: Extending the concept of user experience to the fast-moving consumer goods industry will contribute to the package design of products and the theory and practice of brand loyalty. The research findings can provide effective strategies and approaches for marketers to improve product market competitiveness and enhance consumer brand stickiness.

[Effects of Microplastics on the Leaching of Nutrients and Cadmium from Soil].

The environmental effects of microplastics, which are considered a type of emerging contaminants, have attracted increasing concern due to their small size, large specific surface area, strong adsorption capacity, and low degradability. Microplastics can change soil properties and affect the migration ability of nutrients and pollutants in soil, but their effects on the leaching of soil nutrients and heavy metals have not been sufficiently studied. A soil column leaching experiment was conducted to explore the effects of polystyrene (PS) and polylactic acid (PLA) microplastics at different mass fractions (0%, 0.2%, and 2%) on the leaching of nutrients and cadmium under simulated rainfall scenarios. The results showed that increasing rainfall intensity enhanced the leaching of nutrients and cadmium from soil. During downpour conditions, 2% PS significantly increased the leaching of total nitrogen and the content of available phosphorus in soil and reduced the leaching of inorganic phosphorus and the content of ammonium nitrogen in the soil, whereas it increased the content of available potassium during heavy rain. By comparison, 2% PLA reduced the leaching of nitrate nitrogen during heavy rain and intense rainfall and decreased the content of ammonium nitrogen in soil during intense rainfall and downpour conditions and the content of total nitrogen in soil during downpours. In addition, 0.2% PLA significantly increased cadmium leaching during downpours. To conclude, the effects of microplastics on the leaching of nutrients and cadmium were dependent on the type and concentration of microplastics, as well as the rainfall level. Our findings showed that the microplastics derived from both nondegradable PS and biodegradable PLA could affect the leaching of nutrients and heavy metals from soil.

Anderson critical metal phase in trivial states protected by average magnetic crystalline symmetry.

Transitions between distinct obstructed atomic insulators (OAIs) protected by crystalline symmetries, where electrons form molecular orbitals centering away from the atom positions, must go through an intermediate metallic phase. In this work, we find that the intermediate metals will become a scale-invariant critical metal phase (CMP) under certain types of quenched disorder that respect the magnetic crystalline symmetries on average. We explicitly construct models respecting average C2zT, m, and C4zT and show their scale-invariance under chemical potential disorder by the finite-size scaling method. Conventional theories, such as weak anti-localization and topological phase transition, cannot explain the underlying mechanism. A quantitative mapping between lattice and network models shows that the CMP can be understood through a semi-classical percolation problem. Ultimately, we systematically classify all the OAI transitions protected by (magnetic) groups P m , P 2 ' , P 4 ' , and P 6 ' with and without spin-orbit coupling, most of which can support CMP.

Two-Photon Photodegradation of E3 Ubiquitin Ligase Cereblon by a Ru(II) Complex: Inducing Ferroptosis in Cisplatin-Resistant Tumor Cells.

Using photodynamic therapy (PDT) to trigger nonconventional cell death pathways has provided a new scheme for highly efficient and non-side effects to drug-resistant cancer therapies. Nonetheless, the unclear targets of available photosensitizers leave the manner of PDT-induced tumor cell death relatively unpredictable. Herein, we developed a novel Ru(II)-based photosensitizer, Ru-Poma. Possessing the E3 ubiquitin ligase CRBN-targeting moiety and high singlet oxygen yield of 0.96, Ru-Poma was demonstrated to specifically photodegrade endogenous CRBN, increase lipid peroxide, downregulate GPX4 and GAPDH expression, and consequently induce ferroptosis in cisplatin-resistant cancerous cells. Furthermore, with the deep penetration of two-photon excitation, Ru-Poma achieved drug-resistant circumvention in a 3D tumor cell model. Thus, we describe the first sample of the CRBN-targeting Ru(II) complex active in PDT.

Sulfonate derivatives bearing an amide unit: design, synthesis and biological activity studies.

Pest disasters which occurs on crops is a serious problem that not only cause crop yield loss or even crop failure but can also spread a number of plant diseases.Sulfonate derivatives have been widely used in insecticide and fungicide research in recent years. On this basis, a series of sulfonate derivatives bearing an amide unit are synthesized and the biological activities are evaluated. The bioassay results showed that compounds A8, A13, A16, B1, B3, B4, B5, B10, B12 - 20, C3, C5, C9, C10, C14, C15, C17 and C19 showed 100% activity at a concentration of 500 µg/mL against the Plutella xylostella (P. xylostella). Among them, B15 which contains a thiadiazole sulfonate structure still shows 100% activity at 50 µg/mL concentration against P. xylostella and had the lowest median lethal concentration (LC50) (7.61 µg/mL) among the target compounds. Further mechanism studies are conducted on compounds with better insecticidal activity. Molecular docking results shows that B15 formed hydrophobic interactions π-π and hydrogen bonds with the indole ring of Trp532 and the carboxyl group of Asp384, respectively, with similar interaction distances or bond lengths as those of diflubenzuron. Moreover, chitinase inhibition assays are performed to further demonstrate its mode of action. In addition, the anti-bacterial activity of the series of compounds is also tested and the results showed that the series of compounds has moderate biological activity against Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas oryzae pv. oryzicola (Xoc), with inhibition rates of 91%, 92% and 92%, 88% at the concentration of 100 µg/mL, respectively. Our study indicates that B15 can be used as a novel insecticide for crop protection.

[Research progress on structure and hydrological processes in the karst critical zone of southwest China]. / è¥¿å—å–€æ–¯ç‰¹å ³é”®å¸¦ç»“æž„åŠå ¶æ°´æ–‡è¿‡ç¨‹ç ”ç©¶è¿›å±•.

The southwestern region of China is the largest exposed karst area in the world and serves as an important ecological security barrier for the upstream of Yangtze River and Pearl River. Different from the critical zone of non-karst areas, the epikarst, formed by an interwoven network of denudation pores, is the core area of karst critical zone. Water is the most active component that participates in internal material cycle and energy flow within the critical zone. We reviewed relevant research conducted in the southwestern region from three aspects: the characte-rization of critical zone structure, the hydrological processes of soil-epikarst system, and their model simulations. We further proposed potential research hotpots. The main approach involved multi-scale and multi-method integrated observations, as well as interdisciplinary collaboration. Precisely characterizing the eco-hydrological processes of the vegetation-soil-epikarst coupling system was a new trend in the future research. This review would provide scientific reference for further studies on hydrological processes in critical zones and regional hydrological water resource management in karst areas.

Near-Infrared In Vivo Imaging of Claudin-1 Expression by Orthotopically Implanted Patient-Derived Colonic Adenoma Organoids.

BACKGROUND: Claudin-1 becomes overexpressed during the transformation of normal colonic mucosa to colorectal cancer (CRC). METHODS: Patient-derived organoids expressed clinically relevant target levels and genetic heterogeneity, and were established from human adenoma and normal colons. Colonoids were implanted orthotopically in the colon of immunocompromised mice. This pre-clinical model of CRC provides an intact microenvironment and representative vasculature. Colonoid growth was monitored using white light endoscopy. A peptide specific for claudin-1 was fluorescently labeled for intravenous administration. NIR fluorescence images were collected using endoscopy and endomicroscopy. RESULTS: NIR fluorescence images collected using wide-field endoscopy showed a significantly greater target-to-background (T/B) ratio for adenoma versus normal (1.89 ± 0.35 and 1.26 ± 0.06) colonoids at 1 h post-injection. These results were confirmed by optical sections collected using endomicroscopy. Optical sections were collected in vivo with sub-cellular resolution in vertical and horizontal planes. Greater claudin-1 expression by individual epithelial cells in adenomatous versus normal crypts was visualized. A human-specific cytokeratin stain ex vivo verified the presence of human tissues implanted adjacent to normal mouse colonic mucosa. CONCLUSIONS: Increased claudin-1 expression was observed from adenoma versus normal colonoids in vivo using imaging with wide field endoscopy and endomicrosopy.

First-principles calculations to investigate the impact of fluorine doping on electrochemical properties of Li-rich Li2MnO3 layered cathode materials.

Li-rich layered oxides are promising candidates for high-capacity Li-ion battery cathode materials. In this study, we employ first-principles calculations to investigate the effect of F doping on Li-rich Li2MnO3 layered cathode materials. Our findings reveal that both Li2MnO3 and Li2MnO2.75F0.25 exhibit significant volume changes (greater than 10%) during deep delithiation, which could hinder the cycling of more Li ions from these two materials. For Li2MnO3, it is observed that oxygen ions lose electrons to compensate for charge during the delithiation process, leading to a relatively high voltage plateau. After F doping, oxidation occurs in both the cationic (Mn) and anionic (O) components, resulting in a lower voltage plateau at the beginning of the charge, which can be attributed to the oxidation of Mn3+ to Mn4+. Additionally, F doping can somewhat suppress the release of oxygen in Li2MnO3, improving the stability of anionic oxidation. However, the increase of the activation barriers for Li diffusion can be observed after F doping, due to stronger electrostatic interactions between F- and Li+, which adversely affects the cycling kinetics of Li2MnO2.75F0.25. This study enhances our understanding of the impact of F doping in Li2MnO3 based on theoretical calculations.

SFN promotes renal fibrosis via binding with MYH9 in chronic kidney disease.

Chronic kidney disease (CKD) is a clinical syndrome characterized by persistent renal function decline. Renal fibrosis is the main pathological process in CKD, but an effective treatment does not exist. Stratifin (SFN) is a highly-conserved, multi-function soluble acidic protein. Therefore, this study explored the effects of SFN on renal fibrosis. First, we found that SFN was highly expressed in patients with CKD, as well as in renal fibrosis animal and cell models. Next, transforming growth factor-beta 1 (TGF-ß1) induced injury and fibrosis in human renal tubule epithelial cells, and SFN knockdown reversed these effects. Furthermore, SFN knockdown mitigated unilateral ureteral obstruction (UUO)-induced renal tubular dilatation and renal interstitial fibrosis in mice. Liquid chromatography-tandem mass spectrometry/mass spectrometry (LC-MS/MS), co-immunoprecipitation (Co-IP), and immunofluorescence co-localization assays demonstrated that SFN bound the non-muscle myosin-encoding gene, myosin heavy chain 9 (MYH9), in the cytoplasm of renal tubular epithelial cells. MYH9 knockdown also reduced Col-1 and α-SMA expression, which are fibrosis markers. Finally, silencing SFN decreased MYH9 expression, alleviating renal fibrosis. These results suggest that SFN promotes renal fibrosis in CKD by interacting with MYH9. This study may provide potential strategies for the treatment of CKD.

GSK2334470 attenuates high salt-exacerbated rheumatoid arthritis progression by restoring Th17/Treg homeostasis.

High salt (HS) consumption is a risk factor for multiple autoimmune disorders via disturbing immune homeostasis. Nevertheless, the exact mechanisms by which HS exacerbates rheumatoid arthritis (RA) pathogenesis remain poorly defined. Herein, we found that heightened phosphorylation of PDPK1 and SGK1 upon HS exposure attenuated FoxO1 expression to enhance the glycolytic capacity of CD4 T cells, resulting in strengthened Th17 but compromised Treg program. GSK2334470 (GSK), a dual PDPK1/SGK1 inhibitor, effectively mitigated the HS-induced enhancement in glycolytic capacity and the overproduction of IL-17A. Therefore, administration of GSK markedly alleviated HS-exacerbated RA progression in collagen-induced arthritis (CIA) model. Collectively, our data indicate that HS consumption subverts Th17/Treg homeostasis through the PDPK1-SGK1-FoxO1 signaling, while GSK could be a viable drug against RA progression in clinical settings.

Antiviral Therapy Favors a Lower Risk of Liver Cirrhosis in HBeAg-negative Chronic Hepatitis B with Normal Alanine Transaminase and HBV DNA Positivity.

Background and Aims: Direct evidence on the outcomes of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients with normal alanine transaminase after long-term antiviral treatment is lacking. Methods: HBeAg-negative patients with normal ALT and positive HBV DNA (≥20 IU/mL) were retrospectively enrolled. The endpoints included virological response (HBV DNA<100 IU/mL), changes in aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 index (FIB-4), and the incidence of liver nodules, cirrhosis, and hepatocellular carcinoma (HCC). Results: This cohort (n=194) was divided into three subgroups, untreated (n=67), treatment-continued (n=87), and treatment-discontinued patients (n=40), with a median follow-up of 54 months. The treatment-continued group achieved 100% (95% CI: 94.7-100) virological response, and significantly reduced APRI and FIB-4 scores (both p<0.001). The risk of liver nodules and cirrhosis in that group was reduced by 76% (HR: 0.24, 95% CI: 0.11-0.54, p<0.001) and 89% (HR: 0.11, 95% CI: 0.14-0.91, p=0.041) vs. the untreated group and by 77% (HR: 0.23, 95% CI: 0.10-0.49, p<0.001) and 95% (HR: 0.05, 95% CI: 0.01-0.44, p=0.006) vs. the treatment-discontinued group. For patients with HBV DNA≥2,000 IU/mL, adherence to treatment lowered the risks of liver cirrhosis by 92% (95% CI: 0.01-0.67) and 93% (95% CI: 0.01-0.53) vs. the untreated and treatment-discontinued patients, respectively. No patient adhering to treatment developed HCC, but one in each of the remaining groups did. Conclusions: Continuous nucleos(t)ide analog (NA) treatment has a satisfactory effectiveness and helps to lower the risk of liver cirrhosis in HBeAg-negative CHB patients with normal alanine transaminase, especially in those with HBV DNA≥2,000 IU/mL.

8R-methoxy-9R-hydroxyl-fumitremorgin C, a new diketopiperazine alkaloid from Haima cold seep-derived fungus Aspergillus fumigatus CYH-5.

One novel diketopiperazine derivative 8R-methoxy-9R-hydroxyl-fumitremorgin C (1), together with twelve known compounds, was separated from the fungus Aspergillus fumigatus CYH-5 collected from Haima cold seep. The structures of the compounds were identified by NMR, MS, optical rotation, hydrolysis reaction and comparing with literatures. Among them, compounds 10 and 11 exhibited inhibitory effect against bacteria. Compound 11 showed inhibitory activity on α-glucosidase and compound 8 displayed acetylcholinesterase (AchE) inhibitory activity.