Strongly plasticized gelatin-based hydrogel for flexible encapsulation of complex-shaped electronic devices.

The growth of environmentally sensitive complex-shaped electronic devices (ECEDs) has led to a surging demand for flexible electromagnetic wave (EMW) absorbers. Herein, the water loss property of hydrogel was ingeniously applied for the flexible encapsulation (FE) of ECEDs. To be specific, saturated state (SGT) hydrogels were prepared by chemical cross-linking, and the hydrogen bond dissipation network promoted FE. Additionally, SGT has an effective absorption bandwidth (EAB) of 6.04 GHz at 1.65 mm due to the presence of dipole polarization. With the loss of water, SGT transitions to its natural state (NGT), and the decreasing conductivity leads to better impedance matching. NGT exhibited a broader EAB (9.20 GHz at 2.65 mm) and also strength and lightness (density of 0.3 g cm-3). Furthermore, the semi-automatic reversible cyclic transformation between SGT and NGT gels further broadens application scenarios. GT gel combines self-encapsulation and self-optimized performance as a potential EMW absorber for FE.

PHLDA2 overexpression facilitates senescence and apoptosis via the mitochondrial route in human nucleus pulposus cells by regulating Wnt/ß-catenin signalling pathway.

Low back pain is a common clinical symptom of intervertebral disc degeneration (IVDD), which seriously affects the quality of life of the patients. The abnormal apoptosis and senescence of nucleus pulposus cells (NPCs) play important roles in the pathogenesis of IVDD. PHLDA2 is an imprinted gene related to cell apoptosis and tumour progression. However, its role in NPC degeneration is not yet clear. Therefore, this study was set to explore the effects of PHLDA2 on NPC senescence and apoptosis and the underlying mechanisms. The expression of PHLDA2 was examined in human nucleus pulposus (NP) tissues and NPCs. Immunohistochemical staining, magnetic resonance imaging imaging and western blot were performed to evaluate the phenotypes of intervertebral discs. Senescence and apoptosis of NPCs were assessed by SA-ß-galactosidase, flow cytometry and western blot. Mitochondrial function was investigated by JC-1 staining and transmission electron microscopy. It was found that the expression level of PHLDA2 was abnormally elevated in degenerated human NP tissues and NPCs. Furthermore, knockdown of PHLDA2 can significantly inhibit senescence and apoptosis of NPCs, whereas overexpression of PHLDA2 can reverse senescence and apoptosis of NPCs in vitro. In vivo experiment further confirmed that PHLDA2 knockdown could alleviate IVDD in rats. Knockdown of PHLDA2 could also reverse senescence and apoptosis in IL-1ß-treated NPCs. JC-1 staining indicated PHLDA2's knockdown impaired disruption of the mitochondrial membrane potential and also ameliorated superstructural destruction of NPCs as showed by transmission electron microscopy. Finally, we found the PHLDA2 knockdown promoted Collagen-II expression and suppressed MMP3 expression in NPCs by repressing wnt/ß-catenin pathway. In conclusion, the results of the present study showed that PHLDA2 promotes IL-1ß-induced apoptosis and senescence of NP cells via mitochondrial route by activating the Wnt/ß-catenin pathway, and suggested that therapy targeting PHLDA2 may provide valuable insights into possible IVDD therapies.

Trends in temporal and spatial changes of Japanese encephalitis in Chinese mainland, 2004-2019: A population-based surveillance study.

BACKGROUND: Japanese encephalitis (JE) is a serious health concern in China, with approximately 80 % of global infections occurring in China. To develop effective prevention and control strategies, this study explored the epidemiological characteristics of JE in China based on spatiotemporal data, to understand the patterns and trends of JE incidence in different regions and time periods. METHOD: The incidence and mortality rates of JE were extracted from the Public Health Data Center, the official website of the National Health Commission of the People's Republic of China, and the National Notifiable Infectious Disease Surveillance System from 2004 to 2019. Joinpoint regression was applied to examine the spatiotemporal patterns and annual percentage change in incidence and mortality of the JE. RESULTS: From 2004 to 2019, a total of 43,569 cases of JE were diagnosed, including 2081 deaths. The annual incidence rate of JE decreased from 0.4171/100,000 in 2004 to 0.0298/100,000 in 2019, with an annual percentage change (APC) of -13.5 % (P < 0.001). The annual mortality rate of JE showed three stages of change, with inflection points in 2006 and 2014. The incidence and mortality rates of JE have declined in all provinces of China, and more cases were reported in 0-14 years of age, accounting for nearly 80 % of all patients. CONCLUSIONS: The morbidity and mortality rates of JE in China are generally on a downward trend, and emphasis should be placed on strengthening disease surveillance in special areas and populations, popularizing vaccination, and increasing publicity.

eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer.

The majority of human breast cancers are dependent on hormone-stimulated estrogen receptor alpha (ER) and are sensitive to its inhibition. Treatment resistance arises in most advanced cancers due to genetic alterations that promote ligand independent activation of ER itself or ER target genes. Whereas re-targeting of the ER ligand binding domain (LBD) with newer ER antagonists can work in some cases, these drugs are largely ineffective in many genetic backgrounds including ER fusions that lose the LBD or in cancers that hyperactivate ER targets. By identifying the mechanism of ER translation, we herein present an alternative strategy to target ER and difficult to treat ER variants. We find that ER translation is cap-independent and mTOR inhibitor insensitive, but dependent on 5' UTR elements and sensitive to pharmacologic inhibition of the translation initiation factor eIF4A, an mRNA helicase. EIF4A inhibition rapidly reduces expression of ER and short-lived targets of ER such as cyclin D1 and other components of the cyclin D-CDK complex in breast cancer cells. These effects translate into suppression of growth of a variety of ligand-independent breast cancer models including those driven by ER fusion proteins that lack the ligand binding site. The efficacy of eIF4A inhibition is enhanced when it is combined with fulvestrant-an ER degrader. Concomitant inhibition of ER synthesis and induction of its degradation causes synergistic and durable inhibition of ER expression and tumor growth. The clinical importance of these findings is confirmed by results of an early clinical trial ( NCT04092673 ) of the selective eIF4A inhibitor zotatifin in patients with estrogen receptor positive metastatic breast cancer. Multiple clinical responses have been observed on combination therapy including durable regressions. These data suggest that eIF4A inhibition could be a useful new strategy for treating advanced ER+ breast cancer.

Continuous estimation of respiratory system compliance and airway resistance during pressure-controlled ventilation without end-inspiration occlusion.

BACKGROUND: Assessing mechanical properties of the respiratory system (Cst) during mechanical ventilation necessitates an end-inspiration flow of zero, which requires an end-inspiratory occlusion maneuver. This lung model study aimed to observe the effect of airflow obstruction on the accuracy of respiratory mechanical properties during pressure-controlled ventilation (PCV) by analyzing dynamic signals. METHODS: A Hamilton C3 ventilator was attached to a lung simulator that mimics lung mechanics in healthy, acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD) models. PCV and volume-controlled ventilation (VCV) were applied with tidal volume (VT) values of 5.0, 7.0, and 10.0 ml/kg. Performance characteristics and respiratory mechanics were assessed and were calibrated by virtual extrapolation using expiratory time constant (RCexp). RESULTS: During PCV ventilation, drive pressure (DP) was significantly increased in the ARDS model. Peak inspiratory flow (PIF) and peak expiratory flow (PEF) gradually declined with increasing severity of airflow obstruction, while DP, end-inspiration flow (EIF), and inspiratory cycling ratio (EIF/PIF%) increased. Similar estimated values of Crs and airway resistance (Raw) during PCV and VCV ventilation were obtained in healthy adult and mild obstructive models, and the calculated errors did not exceed 5%. An underestimation of Crs and an overestimation of Raw were observed in the severe obstruction model. CONCLUSION: Using the modified dynamic signal analysis approach, respiratory system properties (Crs and Raw) could be accurately estimated in patients with non-severe airflow obstruction in the PCV mode.

The efficacy and safety of ketamine in the treatment of super-refractory status epilepticus: a systematic review.

BACKGROUND: Ketamine, as an anesthetic, has been considered for terminating status epilepticus (SE); however, due to the urgency and severity of the condition, there are currently no randomized controlled trials internationally assessing the efficacy of ketamine for treating super-refractory status epilepticus. Similarly, there appears to be a lack of systematic reviews addressing this topic in the literature. Therefore, this systematic review aims to explore the effectiveness and safety of ketamine for terminating super-refractory status epilepticus. METHODS: We conducted a systematic search on PubMed, EMBASE, and Web of Science databases. Manuscripts unrelated to the research on super-refractory status epilepticus were excluded, as were manuscripts published in non-English languages. The quality assessment and risk of bias were evaluated using the MINORS criteria. Data extraction was limited to qualitative synthesis due to the unsuitability of the data for meta-analysis. RESULTS: Out of 782 studies retrieved from electronic databases, 11 met the inclusion criteria. Among them, 10 studies were retrospective, and 1 study was prospective. Patient data for inclusion were sourced from the case registries of the researchers' respective hospitals. Across all included studies, the administration of ketamine significantly reduced the duration of status epilepticus and demonstrated higher safety compared to patients not receiving ketamine treatment for super-refractory status epilepticus. Additionally, early administration of ketamine correlated with improved treatment outcomes. The risk of bias across all studies was deemed low. CONCLUSION: This systematic review suggests that ketamine may be a feasible treatment option for super-refractory status epilepticus. However, given the critical nature of super-refractory status epilepticus, clinicians should prioritize its termination over evaluating the efficacy of specific medications, ensuring patient safety remains paramount. If feasible in real-world medical settings, future research should focus on designing randomized controlled trials to observe the specific efficacy and mechanisms of ketamine. Careful validation is necessary before considering ketamine as a first-line treatment for super-refractory status epilepticus.

Ethylene-responsive VviERF003 modulates glycosylated monoterpenoid synthesis by upregulating VviGT14 in grapes.

Terpenoids are important contributors to the aroma of grapes and wines. Grapes contain terpenoids in both volatile free form and non-volatile glycosidic form, with the latter being more abundant. Glycosylated terpenoids are deemed as latent aromatic potentials for their essential role in adding to the flowery and fruity bouquet of wines. However, the transcriptional regulatory mechanism underlying glycosylated terpenoid biosynthesis remains poorly understood. Our prior study identified an AP2/ERF transcription factor, VviERF003, through DNA pull-down screening using the promoter of terpenoid glycosyltransferase VviGT14 gene. This study demonstrated that both genes were co-expressed and synchronized with the accumulation of glycosylated monoterpenoids during grape maturation. VviERF003 can bind to the VviGT14 promoter and promote its activity according to yeast one-hybrid and dual-luciferase assays. VviERF003 upregulated VviGT14 expression in vivo, leading to increased production of glycosylated monoterpenoids based on the evidence from overexpression or RNA interference in leaves, berry skins, and calli of grapes, as well as tomato fruits. Additionally, VviERF003 and VviGT14 expressions and glycosylated monoterpenoid levels were induced by ethylene in grapes. The findings suggest that VviERF003 is ethylene-responsive and stimulates glycosylated monoterpenoid biosynthesis through upregulating VviGT14 expression.

Mercury contamination is an invisible threat to declining migratory shorebirds along the East Asian-Australasian Flyway.

Exposure to pollutants is a potentially crucial but overlooked driver of population declines in shorebirds along the East Asian-Australasian Flyway. We combined knowledge of moult strategy and life history with a standardised sampling protocol to assess mercury (Hg) contamination in 984 individuals across 33 migratory shorebird species on an intercontinental scale. Over one-third of the samples exceeded toxicity benchmarks. Feather Hg was best explained by moulting region, while habitat preference (coastal obligate vs. non-coastal obligate), the proportion of invertebrates in the diet and foraging stratum (foraging mostly on the surface vs. at depth) also contributed, but were less pronounced. Feather Hg was substantially higher in South China (Mai Po and Leizhou), Australia and the Yellow Sea than in temperate and Arctic breeding ranges. Non-coastal obligate species (Tringa genus) frequently encountered in freshwater habitats were at the highest risk. It is important to continue and expand biomonitoring research to assess how other pollutants might impact shorebirds.

A prospective cohort-based artificial intelligence evaluation system for the protective efficacy and immune response of SARS-CoV-2 inactivated vaccines.

BACKGROUND: Novel coronaviruses constitute a significant health threat, prompting the adoption of vaccination as the primary preventive measure. However, current evaluations of immune response and vaccine efficacy are deemed inadequate. OBJECTIVES: The study sought to explore the evolving dynamics of immune response at various vaccination time points and during breakthrough infections. It aimed to elucidate the synergistic effects of epidemiological factors, humoral immunity, and cellular immunity. Additionally, regression curves were used to determine the correlation between the protective efficacy of the vaccine and the stimulated immune response. METHODS: Employing LASSO for high-dimensional data analysis, the study utilised four machine learning algorithms-logistical regression, random forest, LGBM classifier, and AdaBoost classifier-to comprehensively assess the immune response following booster vaccination. RESULTS: Neutralising antibody levels exhibited a rapid surge post-booster, escalating to 102.38 AU/mL at one week and peaking at 298.02 AU/mL at two weeks. Influential factors such as sex, age, disease history, and smoking status significantly impacted post-booster antibody levels. The study further constructed regression curves for neutralising antibodies, non-switched memory B cells, CD4+T cells, and CD8+T cells using LASSO combined with the random forest algorithm. CONCLUSION: The establishment of an artificial intelligence evaluation system emerges as pivotal for predicting breakthrough infection prognosis after the COVID-19 booster vaccination. This research underscores the intricate interplay between various components of immunity and external factors, elucidating key insights to enhance vaccine effectiveness. 3D modelling discerned distinctive interactions between humoral and cellular immunity within prognostic groups (Class 0-2). This underscores the critical role of the synergistic effect of humoral immunity, cellular immunity, and epidemiological factors in determining the protective efficacy of COVID-19 vaccines post-booster administration.

Multi-Interface Electromagnetic Wave Absorbing Material Based on Liquid Marble Microstructures Anchored to SEBS.

The direct application of liquid marbles in electromagnetic wave (EMW) absorption is challenging due to their poor stability, susceptibility to gravitational collapse, and shaping difficulties. To address this issue, a novel strategy is proposed to incorporate liquid marble microstructures (NaCl/nano-SiO2) encapsulated in organic phases (Octadecane) into the rubber-matrix (SEBS) using the ultrasound-assisted emulsion blending method. The resulting NaCl/SiO2/Octadecane microstructures anchored to SEBS offer a substantial solid-liquid interface consisting of NaCl solution and SiO2. When subjected to an alternating electromagnetic (EM) field, the water molecules and polysorbate within SiO2 exhibit heightened responsiveness to the EM field, and the movement of Na+ and Cl- within these microstructures leads to their accumulation at the solid-liquid interface, creating an asymmetric ion distribution. This phenomenon facilitates enhanced interfacial polarization, thereby contributing to the material's EMW absorption properties. Notably, the latex with 16 wt% SEBS (E-3), exhibiting a surface morphology similar to human cell tissues, achieves complete absorption of X-band (fE = 4.20 GHz, RLmin = -33.87 dB). Moreover, the latex demonstrates light density (0.78 g cm-3) and environmental stability. This study not only highlights the predominant loss mechanism in rubber-based wave-absorbing materials but also provides valuable insights into the design of multifunctional wave-absorbing materials.

Solvent and monomer regulation synthesis of core-shelled magnetic ß-cyclodextrin microporous organic network for efficient extraction of estrogens in biological samples prior to HPLC analysis.

The abnormal estrogens levels in human body can cause many side effects and diseases, but the quantitative detection of the trace estrogens in complex biological samples still remains great challenge. Here we reported the fabrication of a novel core-shell structured magnetic cyclodextrin microporous organic network (Fe3O4@CD-MON) for rapid magnetic solid phase extraction (MSPE) of four estrogens in human serum and urine samples prior to HPLC-UV determination. The uniform spherical core-shell Fe3O4@CD-MONs was successfully regulated by altering the reactive monomers and solvents. The Fe3O4@CD-MONs owned high specific surface area, good hydrophobicity, large superparamagnetism, and abundant extraction sites for estrogens. Under optimal conditions, the proposed MSPE-HPLC-UV method provided wide linearity range (2.0-400 µg L-1), low limits of detection (0.5-1.0 µg L-1), large enrichment factors (183-198), less adsorbent consumption (3 mg), short extraction time (3 min), and good stability and reusability (at least 8 cycles). The established method had also been successfully applied to the enrichment and detection of four estrogens in serum and urine samples with a recovery of 88.4-105.1 % and a relative standard deviation of 1.0-5.9 %. This work confirmed the feasibility of solvent and monomer regulation synthesis of Fe3O4@CD-MON composites, and revealed the great prospects of magnetic CD-MONs for efficient enrichment of trace estrogens in complex biological samples.

BJLD-CMI: a predictive circRNA-miRNA interactions model combining multi-angle feature information.

Increasing research findings suggest that circular RNA (circRNA) exerts a crucial function in the pathogenesis of complex human diseases by binding to miRNA. Identifying their potential interactions is of paramount importance for the diagnosis and treatment of diseases. However, long cycles, small scales, and time-consuming processes characterize previous biological wet experiments. Consequently, the use of an efficient computational model to forecast the interactions between circRNA and miRNA is gradually becoming mainstream. In this study, we present a new prediction model named BJLD-CMI. The model extracts circRNA sequence features and miRNA sequence features by applying Jaccard and Bert's method and organically integrates them to obtain CMI attribute features, and then uses the graph embedding method Line to extract CMI behavioral features based on the known circRNA-miRNA correlation graph information. And then we predict the potential circRNA-miRNA interactions by fusing the multi-angle feature information such as attribute and behavior through Autoencoder in Autoencoder Networks. BJLD-CMI attained 94.95% and 90.69% of the area under the ROC curve on the CMI-9589 and CMI-9905 datasets. When compared with existing models, the results indicate that BJLD-CMI exhibits the best overall competence. During the case study experiment, we conducted a PubMed literature search to confirm that out of the top 10 predicted CMIs, seven pairs did indeed exist. These results suggest that BJLD-CMI is an effective method for predicting interactions between circRNAs and miRNAs. It provides a valuable candidate for biological wet experiments and can reduce the burden of researchers.

Metal-Loaded Synthetic Melanin via Oxidative Polymerization of Neurotransmitter Norepinephrine Exhibiting High Photothermal Conversion.

Polydopamine (PDA)-derived melanin-like materials exhibit significant photothermal conversion owing to their broad-spectrum light absorption. However, their low near-infrared (NIR) absorption and inadequate hydrophilicity compromise their utilization of solar energy. Herein, we developed metal-loaded poly(norepinephrine) nanoparticles (PNE NPs) by predoping metal ions (Fe3+, Mn3+, Co2+, Ca2+, Ga3+, and Mg2+) with norepinephrine, a neuron-derived biomimetic molecule, to address the limitations of PDA. The chelation between catechol and metal ions induces a ligand-to-metal charge transfer (LMCT) through the formation of donor-acceptor pairs, modulating the light absorption behavior and reducing the band gap. Under 1 sun illumination, the Fe-loaded PNE coated wood evaporator achieved a high seawater evaporation rate and efficiency of 1.75 kg m-2 h-1 and 92.4%, respectively, owing to the superior hydrophilicity and photothermal performance of PNE. Therefore, this study offers a comprehensive exploration of the role of metal ions in enhancing the photothermal properties of synthetic melanins.

Endoscopic resection of extra-luminal gastric gastrointestinal stromal tumors using a snare assisted external traction technique (with video).

OBJECTIVE: The primary purpose of the study was to explore the clinical efficacy of the novel snare assisted endoscopic resection of extraluminal growing gastric gastrointestinal stromal tumors (gastric GISTs) using external traction, and the secondary purpose was to compare the novel snare assisted endoscopic resection of extraluminal GISTs with the standard laparoscopic procedure. METHODS: We retrospectively analyzed the patients who underwent novel external traction assisted endoscopic resection or laparoscopic resection for their extraluminal gastric GIST ≤5 cm in diameter. RESULTS: A total of 111 patients (27 in the endoscopic group and 84 in the laparoscopic group) were included in this study. There was no significant difference in tumor diameter and complication rate between the two groups. The overall procedure time was slightly higher in the endoscopic group compared to the laparoscopic group (P = 0.034). However, postoperative hospitalization time (P < 0.001) and postoperative fasting time (P = 0.005) were shorter in the endoscopic group compared to the laparoscopic group. CONCLUSION: Snare external traction-assisted endoscopic resection of extraluminal growing gastric GISTs is safe and effective, and it provides a new adjunctive method for endoscopic resection of GIST.

Joint association of serum urate and healthy diet with chronic obstructive pulmonary disease incidence: results from the UK Biobank study.

Background: The role of serum urate (SU) levels in the development of chronic obstructive pulmonary disease (COPD) remains a topic of debate, and it is unclear whether a healthy diet can mitigate the impact of SU on COPD risk. The objective of this study is to examine whether and to what extent a healthy diet can reduce the risk of COPD in relation to SU levels. Methods: The cohort analysis included 155 403 participants from the UK Biobank. SU levels were measured at the time of recruitment. A healthy diet score was calculated based on the consumption of vegetables, fruits, fish, processed meats, unprocessed red meat, whole grains, and refined grains. The Cox proportional hazards model was used to analyze the associations between SU levels, a healthy diet score, and the risk of COPD. Results: During a follow-up period of 1 409 969 person-years, 2918 incident cases of COPD were identified. Compared with the lowest SU level group, the hazard ratio (HR) and 95% confidence interval (CI) for COPD were 1.17 (1.03, 1.34) for participants with the highest SU level (hyperuricemia), indicating a positive association. Additionally, a dose-response relationship was observed between SU levels and the incidence of COPD (P-value for overall <0.0001). In the combined effect analysis, compared to individuals with high SU (hyperuricemia) + a low diet score (diet score <4), those with normal SU + a high diet score (diet score ≥4) had a HR (95% CI) of 0.75 (0.65, 0.87) for COPD. Conclusions: In summary, there is a positive association between SU levels and the risk of COPD. Furthermore, a healthier diet can mitigate the risk of COPD associated with high SU levels.

The Association of Circulating Glucagon-Like Peptide-1 with Cognitive Functions and Biomarkers in Alzheimer's Disease.

Background: Alzheimer's disease (AD) is an age-related neurodegenerative disease that is clinically characterized by progressive cognitive decline. Glucagon-like peptide-1 (GLP-1) is a hormone that belongs to the incretin family and is released in response to nutrient intake. It plays a role in maintaining metabolic homeostasis and has been suggested to be involved in maintaining the brain microenvironment. However, the role of GLP-1 in AD pathogenesis has not been fully illustrated. Objective: This study aims to investigate the clinical relevance of GLP-1 in AD and the effects of GLP-1 in amyloid-ß (Aß) metabolism in vitro. Methods: In this study, 39 AD patients and 120 cognitively intact controls were included. Plasma levels of GLP-1 were measured using ELISA. SH-SY5Y cells overexpressing human amyloid precursor protein (APP) were treated with GLP-1. Western blot analysis was used to assess the effects of GLP-1 on the metabolism of Aß. Results: Plasma GLP-1 levels were decreased with aging. Plasma GLP-1 levels were lower in AD patients in comparison with healthy older adults. Plasma GLP-1 levels were positively associated with Mini-Mental State Examination scores but negatively associated with plasma pTau181 levels. GLP-1 dose-dependently increased the area fraction of mitochondrial staining in vitro. Furthermore, GLP-1 dose-dependently promoted the α-cleavage of APP, thus reducing the generation of Aß. Conclusions: GLP-1 has neuroprotective effects in AD, and therefore the decrease in GLP-1 levels during aging might contribute to the development of AD.

Lead-free Perovskite with Distorted [InX6]3- Octahedron Induced by Organic Cation and Enhanced PLQY by Sb Doping.

In-based halide perovskites have attracted a lot of attention because of their unique broadband emission properties. Herein, a series of In-based hybrid perovskites of (H2MP)2InCl7·H2O (1), (H2EP)2InCl7·H2O (2), (H2MP)2InBr7·H2O (3), and (H2EP)2InBr7·H2O (4) were synthesized under the control of halogen ions and organic cations. 1, 2, and 4 exhibit obvious photoluminescence properties with peaks at 392, 442, and 652 nm, respectively. The effects of the different components on the crystal structure and photoluminescence properties are discussed by calculating the structural distortion of the [InX6]3- octahedron. The photoluminescence properties of 1 and 4 were significantly improved after Sb3+ doping with PLQY values of 57.12 and 41.53%. Finally, a white LED was successfully fabricated with the two doped compounds coated onto the 365 nm blue LED chip.

Sugar types, genetic predictors of the gut microbiome, and the risk of chronic kidney disease: a prospective cohort study.

Background: Emerging studies suggest that focusing on the intake of specific types or sources of sugars may yield greater benefits in preventing chronic kidney disease (CKD). Objective: We aimed to investigate the associations between free and non-free sugar intakes and CKD risk as well as the potential sugar type-gut microbiome interactions. Methods: A total of 138 064 participants from the UK Biobank were included in this prospective study. The free and non-free sugar intakes were assessed using repeated web-based 24-hour dietary recalls. A cause-specific competing risk model was used to estimate hazard ratios (HRs) and the corresponding confidence intervals (CIs) of incident CKD, treating deaths before incident CKD as competing events. Results: During a median follow-up of 10.5 years, 2,923 participants (2.1%) developed CKD. The free sugar intake was positively associated with the risk of CKD (HRquartile 4 vs. quartile 1 = 1.32, 95% CI = 1.18, 1.47), with a nonlinear relationship (P for nonlinearity = 0.01, the risk increased rapidly after free sugars made up 10% of the total energy). The non-free sugar intake was inversely associated with CKD risk (HRquartile 4 vs. quartile 1 = 0.68, 95% CI = 0.60, 0.77), with an L-shaped nonlinear curve (p for nonlinearity = 0.01, the turning point was at 13.5% of the total energy). We found that the associations between free sugar and non-free sugar intakes and CKD risk were more pronounced in participants with high genetically predicted gut microbial abundance. Furthermore, a significant interaction was observed between the genetically predicted gut microbial abundance and non-free sugar intake (P for interaction = 0.04). Conclusion: A higher intake of free sugars was associated with an elevated risk of CKD, whereas a higher intake of non-free sugars was associated with a reduced risk of CKD. The impact of free sugar intake and non-free sugar intake may be modified by the gut microbial abundance.

Tumorigenesis driven by the BRAFV600E oncoprotein requires secondary mutations that overcome its feedback inhibition of migration and invasion.

BRAFV600E mutation occurs in 46% of melanomas and drives high levels of ERK activity and ERK-dependent proliferation. However, BRAFV600E is insufficient to drive melanoma in GEMM models, and 82% of human benign nevi harbor BRAFV600E mutations. We show here that BRAFV600E inhibits mesenchymal migration by causing feedback inhibition of RAC1 activity. ERK pathway inhibition induces RAC1 activation and restores migration and invasion. In cells with BRAFV600E, mutant RAC1, overexpression of PREX1, PREX2, or PTEN inactivation restore RAC1 activity and cell motility. Together, these lesions occur in 48% of BRAFV600E melanomas. Thus, although BRAFV600E activation of ERK deregulates cell proliferation, it prevents full malignant transformation by causing feedback inhibition of cell migration. Secondary mutations are, therefore, required for tumorigenesis. One mechanism underlying tumor evolution may be the selection of lesions that rescue the deleterious effects of oncogenic drivers.

Insights into the Roles of Natural Killer Cells in Osteoarthritis.

Osteoarthritis (OA) is now widely acknowledged as a low-grade inflammatory condition, in which the intrinsic immune system plays a significant role in its pathogenesis. While the involvement of macrophages and T cells in the development of OA has been extensively reviewed, recent research has provided mounting evidence supporting the crucial contribution of NK cells in both the initiation and advancement of OA. Accumulated evidence has emerged in recent years indicating that NK cells play a critical role in OA development and progression. This review will outline the ongoing understanding of the utility of NK cells in the etiology of OA, focusing on how NK cells interact with chondrocytes, synoviocytes, osteoclasts, and other immune cells to influence the course of OA disease.