Correlation between diameter of esophageal varices and early rebleeding following endoscopic variceal ligation: a multicenter retrospective study based on artificial intelligence-based endoscopic virtual rule.

Background and objective: Bleeding following endoscopic variceal ligation (EVL) may occur as a result of numerous factors, including a diameter of esophageal varices (EV) that is too large to be completely ligated. The present study aimed to develop an artificial intelligence-based endoscopic virtual ruler (EVR) to measure the diameter of EV with a view to finding more suitable cases for EVL. Methods: The present study was a multicenter retrospective study that included a total of 1,062 EVLs in 727 patients with liver cirrhosis with EV, who underwent EVL from April 2016 to March 2023. Patients were divided into early rebleeding (n = 80) and non-rebleeding groups (n = 982) according to whether postoperative bleeding occurred at 6 weeks. The characteristics of patient baseline data, the status of rebleeding at 6 weeks after surgery and the survival status at 6 weeks after rebleeding were analyzed. Results: The early rebleeding rate following 1,062 EVL procedures was 7.5%, and the mortality rate at 6 weeks after bleeding was 16.5%. Results of the one-way binary logistic regression analysis demonstrated that the risk factors for early rebleeding following EVL included: high TB (P = 0.009), low Alb (P = 0.001), high PT (P = 0.004), PVT (P = 0.026), HCC (P = 0.018), high Child-Pugh score (P < 0.001), Child-Pugh grade C(P < 0.001), high MELD score(P = 0.004), Japanese variceal grade F3 (P < 0.001), diameter of EV (P < 0.001), and number of ligature rings (P = 0.029). Results of the multifactorial binary logistic regression analysis demonstrated that Child-Pugh grade C (P = 0.007), Japanese variceal grade F3 (P = 0.009), and diameter of EV (P < 0.001) may exhibit potential in predicting early rebleeding following EVL. ROC analysis demonstrated that the area under curve (AUC) for EV diameter was 0.848, and the AUC for Japanese variceal grade was 0.635, which was statistically significant (P < 0.001). Thus, results of the present study demonstrated that EV diameter was more optimal in predicting early rebleeding following EVL than Japanese variceal grade criteria. The cut-off value of EV diameter was calculated to be 1.35 cm (sensitivity, 70.0%; specificity, 89.2%). Conclusion: If the diameter of EV is ≥1.4 cm, there may be a high risk of early rebleeding following EVL surgery; thus, we recommend caution with EVL.

Clinical application of robots in dentistry: A scoping review.

PURPOSE: The surge in digitalization and artificial intelligence has led to the wide application of robots in various fields, but their application in dentistry started relatively late. This scoping review aimed to comprehensively explore and map the current status of the clinical application of robots in dentistry. STUDY SELECTION: An iterative approach was used to gather as much evidence as possible from four online databases, including PubMed, the China National Knowledge Infrastructure, the Japan Science and Technology Information Aggregator, Electronic, and the Institute of Electrical and Electronics Engineers, from January 1980 to December 2022. RESULTS: A total of 113 eligible articles were selected from the search results, and it was found that most of the robots were developed and applied in the United States (n = 56; 50%). Robots were clinically applied in oral and maxillofacial surgery, oral implantology, prosthodontics, orthodontics, endodontics, and oral medicine. The development of robots in oral and maxillofacial surgery and oral implantology is relatively fast and comprehensive. About 51% (n = 58) of the systems had reached clinical application, while 49% (n = 55) were at the pre-clinical stage. Most of these are hard robots (90%; n = 103), and their invention and development were mainly focused on university research groups with long research periods and diverse components. CONCLUSIONS: There are still limitations and gaps between research and application in dental robots. While robotics is threatening to replace clinical decision-making, combining it with dentistry to gain maximum benefit remains a challenge for the future.

Copper/Ruthenium Relay Catalysis for Stereodivergent Access to δ-Hydroxy α-Amino Acids and Small Peptides.

An atom- and step-economical and redox-neutral cascade reaction enabled by asymmetric bimetallic relay catalysis by merging a ruthenium-catalyzed asymmetric borrowing-hydrogen reaction with copper-catalyzed asymmetric Michael addition has been realized. A variety of highly functionalized 2-amino-5-hydroxyvaleric acid esters or peptides bearing 1,4-non-adjacent stereogenic centers have been prepared in high yields with excellent enantio- and diastereoselectivity. Judicious selection and rational modification of the Ru catalysts with careful tuning of the reaction conditions played a pivotal role in stereoselectivity control as well as attenuating undesired α-epimerization, thus enabling a full complement of all four stereoisomers that were otherwise inaccessible in previous work. Concise asymmetric stereodivergent synthesis of the key intermediates for biologically important chiral molecules further showcases the synthetic utility of this methodology.

A promising predictive biomarker combined EBV NDA with PNI for nasopharyngeal carcinoma in nonendemic area of China.

In endemic areas, EBV DNA is used to guide diagnosis, detect recurrence and distant metastasis of NPC. Until now, the importance of EBV DNA in the prediction of NPC has received little attention in non-endemic regions. To explore the prognostic value of EBV DNA alone or in combination with PNI in NPC patients from a non-endemic area of China. In this retrospective study, 493 NPC patients were enrolled. Clinical pathologic data, pre-treatment plasma EBV DNA, and laboratory tests were all performed. A standard anticancer treatment was prescribed, and follow up data were collected. EBV DNA was found to be positively related to clinical stage (r = 0.357, P < 0.001), T stage (r = 0.193, P < 0.001), N stage (r = 0.281, P < 0.001), and M stage (r = 0.215, P < 0.001). The difference in EBV DNA loads between clinical stage, T, N and M stage was statistically significant (P < 0.001). In this study, the best cutoff value for EBV-DNA to distinguish the prognosis of NPC was 262.7 copies/ml. The 5-year OS of patients in the EBV-DNA ≤ 262.7 copies/ml group and EBV-DNA > 262.7 copies/ml group was 88% and 65.3%, respectively (P < 0.001). EBV-DNA and PNI were found to be independent prognostic factors for OS in multivariate analysis (P < 0.05). EBV-DNA was independent prognostic factors for PFS. In predicting NPC patients OS, the novel combination marker of EBV DNA and PNI outperformed TNM staging (AUC: 0.709 vs. 0.675). In addition, the difference between EBV + PNI and EBV + TNM was not statistically significant for OS or PFS (P > 0.05). This novel combination biomarker was a promising biomarker for predicting NPC survival and may one day guide treatment option.

Dietary Components and Nutritional Strategies for Dementia Prevention in the Elderly.

BACKGROUND: For decades, evidence from observational studies and randomized controlled trials has converged to suggest associations of dietary components, foods, and dietary patterns with dementia. With population aging and a projected exponential expansion of people living with dementia, formulating nutritional strategies for dementia prevention has become a research hotspot. OBJECTIVE: This review aimed to summarize available data on the roles of specific dietary components, food groups, and dietary patterns in dementia prevention among the elderly. METHODS: Database search was carried out using PubMed, the Cochrane Library, EMBASE, and Medline. RESULTS: Polyphenols, folate, vitamin D, omega-3 fatty acids, and ß-carotene might decrease the risk of dementia. Consumption of green leafy vegetables, green tea, fish, and fruits is recommended. However, saturated fat, a diet rich in both dietary copper and saturated fat, aluminum from drinking water, and heavy drinking might increase dementia risk. Healthy dietary patterns, especially the Mediterranean diet, were proven to bring more cognitive benefits than single dietary components. CONCLUSION: We discussed and summarized the evidence on the roles of dietary components and patterns in dementia prevention among the elderly and found that some factors were closely associated with dementia risk in elderly. This may pave the way for the identification of dietary components and patterns as new therapeutic targets for dementia prevention in the elderly population.

Resveratrol inhibits LPS-induced apoptosis in bovine mammary epithelial cells: the role of PGC1α-SIRT3 axis.

Resveratrol (Res) is a bioactive dietary component and alleviates apoptosis in multiple cell types. However, its effect and mechanism on lipopolysaccharide (LPS)-induced bovine mammary epithelial cells (BMEC) apoptosis, which commonly happens in dairy cows with mastitis, is unknown. We hypothesized that Res would inhibit LPS-induced apoptosis in BMEC through SIRT3, a NAD + -dependent deacetylase activated by Res. To test the dose-response effect on apoptosis, 0-50 µM Res were incubated with BMEC for 12 h, followed by 250 µg/mL LPS treatment for 12 h. To investigate the role of SIRT3 in Res-mediated alleviation of apoptosis, BMEC were pretreated with 50 µM Res for 12 h, then incubated with si-SIRT3 for 12 h and were finally treated with 250 µg/mL LPS for 12 h. Res dose-dependently promoted the cell viability and protein levels of Bcl-2 (Linear P < 0.001) but decreased protein levels of Bax, Caspase-3 and Bax/Bcl-2 (Linear P < 0.001). TUNEL assays indicated that cellular fluorescence intensity declined with the rising doses of Res. Res also dose-dependently upregulated SIRT3 expression, but LPS had the opposite effect. SIRT3 silencing abolished these results with Res incubation. Mechanically, Res enhanced the nuclear translocation of PGC1α, the transcriptional cofactor for SIRT3. Further molecular docking analysis revealed that Res could directly bind to PGC1α by forming a hydrogen bond with Tyr-722. Overall, our data suggested that Res relieved LPS-induced BMEC apoptosis through the PGC1α-SIRT3 axis, providing a basis for further in vivo investigations of applying Res to relieve mastitis in dairy cows.

Clinical relevance of plasma EBV DNA as a biomarker for nasopharyngeal carcinoma in non-endemic areas: A multicenter study in southwestern China.

BACKGROUND: Numerous clinical studies have validated plasma EBV DNA as a reliable biomarker for nasopharyngeal carcinoma (NPC) screening, tumor load monitoring, and prognosis prediction in endemic regions. However, the clinical relevance of plasma EBV DNA as a biomarker for NPC in non-endemic areas is still unclear. METHOD: The pretreatment plasma EBV DNA of 1405 newly diagnosed NPC patients from three major regional hospitals in non-endemic areas were analyzed retrospectively. The medical records of 244 age- and gender-matched healthy individuals were reviewed. EBV DNA was detected using Polymerase Chain Reaction (PCR). Based on the baseline of 400 and 0 copies/mL, the distribution characteristics of the pretreatment EBV DNA load in different clinical stages and geographic regions were analyzed. The diagnostic value of pretreatment plasma EBV DNA for NPC with two baselines was evaluated using the ROC curve. RESULTS: NPC patients had a significantly higher pretreatment EBV DNA level than healthy controls (P＜0.001). Pretreatment EBV DNA was closely associated with clinical and TNM stages in non-endemic areas, as it was in endemic areas. However, when 400 copies/mL set as the detection baseline, the sensitivity and specificity for NPC diagnosis were 40.8 % and 100 %, respectively (AUC = 0.704, cut off = 200.5 copies/mL). This sensitivity was lower than that reported in endemic regions (41.5 % - 97.1 %). Lower sensitivity may result in false negatives, missing diagnoses during NPC screening. Further investigation revealed that 39.7 % (558/1405) of NPC patients had detectable EBV DNA and S amplification curves. Optimizing the detection limit to 0 copies/mL, the sensitivity could be improved to 80.5 % (AUC = 0.901). CONCLUSIONS: In non-endemic areas, the clinical significance of plasma EBV DNA as a biomarker for NPC was restricted due to the low detection limit of 400 copies/mL. More efficient nucleic acid extraction and detection methods are needed to optimize the detection limit and increase the clinical application of plasma EBV DNA for NPC.

Association between Kidney Function and the Burden of Cerebral Small Vessel Disease: An Updated Meta-Analysis and Systematic Review.

INTRODUCTION: Due to anatomical and functional similarities in microvascular beds, the brain and kidney share distinctive susceptibilities to vascular injury and common risk factors of small vessel disease. The aim of this updated meta-analysis is to explore the association between kidney function and the burden of cerebral small vessel disease (CSVD). METHODS: PubMed, EMBASE, and Cochrane Library were systematically searched for observational studies that explored the association between the indicators of kidney function and CSVD neuroimaging markers. The highest-adjusted risk estimates and their 95% confidence intervals (CIs) were aggregated using random-effect models. RESULTS: Twelve longitudinal studies and 51 cross-sectional studies with 57,030 subjects met the inclusion criteria of systematic review, of which 52 were included in quantitative synthesis. According to the pooled results, we found that low estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m2) was associated with cerebral microbleeds (odds ratio (OR) = 1.55, 95% CI = 1.26-1.90), white matter hyperintensities (OR = 1.40, 95% CI = 1.05-1.86), and lacunar infarctions (OR = 1.50, 95% CI = 1.18-1.92), but not with severe perivascular spaces (OR = 1.20, 95% CI = 0.77-1.88). Likewise, patients with proteinuria (OR = 1.75, 95% CI = 1.47-2.09) or elevated serum cystatin C (OR = 1.51, 95% CI = 1.25-1.83) also had an increased risk of CSVD. CONCLUSION: The association between kidney function and CSVD has been comprehensively updated through this study, that kidney insufficiency manifested as low eGFR, proteinuria, and elevated serum cystatin C was independently associated with CSVD burden.

Alantolactone inhibits oesophageal adenocarcinoma cells through nuclear factor erythroid 2-related factor 2-mediated reactive oxygen species increment.

BACKGROUND: Oesophageal adenocarcinoma (EAC) is a highly lethal cancer associated with a rapidly rising incidence and a poor prognosis. Alantolactone, a sesquiterpene lactone isolated from inula helenium, has anti-inflammatory, antimicrobial, neuroprotective activities, and anticancer properties. OBJECTIVE: In the present study, the anticancer effects of alantolactone on the human EAC cells were investigated in vitro and in vivo. METHODS AND FINDINGS: After treated with alantolactone, the cell viability of KYAE-1, KYAE-2, OE19, and OE33 cells reduced significantly compared with that of the control cells. Alantolactone induced apoptosis of the EAC cell lines by inhibiting the protein expression levels of nuclear factor erythroid2-related factor 2 (Nrf2). Furthermore, the apoptosis-inducing effect of alantolactone was enhanced by Nrf2 knockdown while reduced by overexpression of Nrf2. Antioxidant α-tocopherol and glutathione can protect EAC cell lines against alantolactone. A xenograft nude mice model showed that alantolactone can inhibit EAC growth in vivo. CONCLUSIONS: Alantolactone inhibits oesophageal adenocarcinoma cells through Nrf2-mediated reactive oxygen species (ROS) increment. Alantolactone maybe a potential therapeutical candidate for treating EAC.

Analysis of phellinus igniarius effects on gastric cancer cells by atomic force microscopy.

Gastric cancer is one of the common malignant tumors in the world, which originates from the gene mutation of human cells. In this work, an atomic force microscope was used to quantitatively detect the changes of multiple physical parameters such as the cell morphology, surface roughness, elasticity modulus and adhesion force before and after Phellinus linteus stimulation. The experimental results show that Phellinus linteus can change the shape of gastric cancer cells (SGC-7901) from flat to spherical, and increase their height and surface roughness values. The adhesion force of cells is reduced and the elasticity modulus is increased. But there are no significant differences in the morphology and mechanical properties of gastric epithelial cells (GES-1). The results indicate that Phellinus linteus has a high anticancer effect on the gastric cancer cells, but has less toxic side effects on the gastric epithelial cells. This work proves that Phellinus linteus can be used as a preferred anticancer drug for the treatment of gastric cancer cells.

Ferroptosis contributes to nickel-induced developmental neurotoxicity in zebrafish.

Nickel (Ni) is a widely utilized heavy metal that can cause environmental pollution and health hazards. Its safety has attracted the attention of both the environmental ecology and public health fields. While the central nervous system (CNS) is one of the main targets of Ni, its neurotoxicity and the underlying mechanisms remain unclear. Here, by taking advantage of the zebrafish model for live imaging, genetic analysis and neurobehavioral studies, we reveal that the neurotoxic effects induced by exposure to environmentally relevant levels of Ni are closely related to ferroptosis, a newly-described form of iron-mediated cell death. In vivo two-photon imaging, neurobehavioral analysis and transcriptome sequencing consistently demonstrate that early neurodevelopment, neuroimmune function and vasculogenesis in zebrafish larvae are significantly affected by environmental Ni exposure. Importantly, exposure to various concentrations of Ni activates the ferroptosis pathway, as demonstrated by physiological/biochemical tests, as well as the expression of ferroptosis markers. Furthermore, pharmacological intervention of ferroptosis via deferoxamine (DFO), a classical iron chelating agent, strongly implicates iron dyshomeostasis and ferroptosis in these Ni-induced neurotoxic effects. Thus, this study elucidates the cellular and molecular mechanisms underlying Ni neurotoxicity, with implications for our understanding of the physiologically damaging effects of other environmental heavy metal pollutants.

Association between multimorbidity status and incident dementia: a prospective cohort study of 245,483 participants.

Multimorbidity (the presence of two or more long-term conditions [LTCs]) was suggested to exacerbate the neuronal injuries. The impact of multimorbidity on dementia has not been fully elucidated. We aimed to investigate the association between multimorbidity and dementia risk. We used the prospective data from 245,483 UK Biobank participants during a 9-year follow-up. Multimorbidity status was evaluated based on the LTC counts and multimorbidity patterns. Cox regression models adjusted for potential confounders were used to examine the associations of multimorbidity status with all-cause dementia (ACD), Alzheimer's disease (AD) and vascular dementia (VD). Participants with multimorbidity at baseline had higher risks of ACD and VD, and the risks were elevated with the increase of LTC counts (ACD: hazard ratios [HR] = 1.15, 95% confidence intervals [CI] = 1.01-1.31 with 2 LTCs; HR = 1.18, CI = 1.01-1.39 with 3 LTCs; HR = 1.65, CI = 1.44-1.88 with ≥4 LTCs; VD: HR = 1. 66, CI = 1.24-2.21 with 2 LTCs; HR = 2.10, CI = 1.53-2.88 with 3 LTCs; HR = 3.17, CI = 2.43-4.13 with ≥4 LTCs). Participants with ≥4 LTCs also had a higher risk of AD (HR = 1.34, CI = 1.08-1.66]. Participants with the cardio-cerebrovascular/respiratory/metabolic/musculoskeletal/depressive multimorbidity were 1.46, 1.28, and 2.50 times more likely to develop ACD (HR = 1.46, 95% CI = 1.28-1.67), AD (HR = 1.28, CI = 1.04-1.58), and VD (HR = 2.50, CI = 1.90-3.27), respectively. Those with tumor/genitourinary/digestive disorders had a 11% higher hazard of ACD (HR = 1.11, CI = 1.00-1.24) and a 73% elevated risk of VD (HR = 1.73, CI = 1.37-2.18). The prevention of LTC accumulation and the identification of specific multimorbidity patterns might be beneficial to the prevention of dementia and its subtypes, AD as well as VD.

Modified dementia risk score as a tool for the prediction of dementia: a prospective cohort study of 239745 participants.

Based on risk profiles, several approaches for predicting dementia risk have been developed. Predicting the risk of dementia with accuracy is a significant clinical challenge. The goal was to create a modified dementia risk score (MDRS) based on a big sample size. A total of 239,745 participants from UK Biobank were studied (mean follow-up of 8.7 years). The score value of each risk factor was estimated according to the ß coefficient in the logistic regression model. The total dementia risk score was the sum of each risk score. Kaplan Meier survival curves and Cox proportional hazards analyses were used to assess the associations between total score and dementia. Among all participants included, 3531 incident cases of all-cause dementia (ACD), 1729 cases of Alzheimer's disease (AD), and 925 cases of vascular dementia (VD) were identified. Several vascular risk factors (physical activity, current smoking status, and glycemic status) and depressive symptoms were found to be significantly related to dementia risk. The modified dementia risk scores predicted dementia well (model 1, area under curve 0.810; model 2, area under curve 0.832). In model 1, the cut-off value for high risk (HR) was 81 or higher, and in model 2 (including the APOE4), it was 98 or higher. According to Kaplan-Meier survival analyses, patients in the HR group had faster clinical progression (p < 0.0001) in either model 1 or 2. Cox regression analyses for HR versus low risk (LR) revealed that the Hazard radio for ACD was 7.541 (6.941 to 8.193) in model 1 and 8.348 (7.727 to 9.019) in model 2. MDRS is appropriate for dementia primary prevention, and may help quickly identify individuals with elevated risk of dementia.

Tannic acid supplementation in the diet of Holstein bulls: Impacts on production performance, physiological and immunological characteristics, and ruminal microbiota.

This study was conducted to evaluate the influences of supplementing tannic acid (TA) at different doses on the production performance, physiological and immunological characteristics, and rumen bacterial microbiome of cattle. Forty-eight Holstein bulls were randomly allocated to four dietary treatments: the control (CON, basal diet), the low-dose TA treatment [TAL, 0.3% dry matter (DM)], the mid-dose TA treatment (TAM, 0.9% DM), and the high-dose TA treatment (TAH, 2.7% DM). This trial consisted of 7 days for adaptation and 90 days for data and sample collection, and samples of blood and rumen fluid were collected on 37, 67, and 97 d, respectively. The average daily gain was unaffected (P > 0.05), whilst the ruminal NH3-N was significantly decreased (P < 0.01) by TA supplementation. The 0.3% TA addition lowered (P < 0.05) the levels of ruminal isobutyrate, valerate, and tumor necrosis factor alpha (TNF-α), and tended to (P < 0.1) increase the gain to feed ratio. The digestibility of DM, organic matter (OM), and crude protein, and percentages of butyrate, isobutyrate, and valerate were lower (P < 0.05), while the acetate proportion and acetate to propionate ratio in both TAM and TAH were higher (P < 0.05) than the CON. Besides, the 0.9% TA inclusion lessened (P < 0.05) the concentrations of glucagon and TNF-α, but enhanced (P < 0.05) the interferon gamma (IFN-γ) level and Simpson index of ruminal bacteria. The 2.7% TA supplementation reduced (P < 0.05) the intake of DM and OM, and levels of malondialdehyde and thyroxine, while elevated (P < 0.05) the Shannon index of the rumen bacterial populations. Moreover, the relative abundances of the phyla Fibrobacteres and Lentisphaerae, the genera Fibrobacter and Bradyrhizobium, and the species Bradyrhizobium sp., Lachnospiraceae bacterium RM29, and Lachnospiraceae bacterium CG57 were highly significantly (q < 0.01) or significantly (q < 0.05) raised by adding 2.7% TA. Results suggested that the TA addition at 0.3% is more suitable for the cattle, based on the general comparison on the impacts of supplementing TA at different doses on all the measured parameters.

Wnt/ß-Catenin Signaling Pathway Is Strongly Implicated in Cadmium-Induced Developmental Neurotoxicity and Neuroinflammation: Clues from Zebrafish Neurobehavior and In Vivo Neuroimaging.

Cadmium (Cd) is a toxic heavy metal and worldwide environmental pollutant which seriously threatens human health and ecosystems. It is easy to be adsorbed and deposited in organisms, exerting adverse effects on various organs including the brain. In a very recent study, making full use of a zebrafish model in both high-throughput behavioral tracking and live neuroimaging, we explored the potential developmental neurotoxicity of Cd2+ at environmentally relevant levels and identified multiple connections between Cd2+ exposure and neurodevelopmental disorders as well as microglia-mediated neuroinflammation, whereas the underlying neurotoxic mechanisms remained unclear. The canonical Wnt/ß-catenin signaling pathway plays crucial roles in many biological processes including neurodevelopment, cell survival, and cell cycle regulation, as well as microglial activation, thereby potentially presenting one of the key targets of Cd2+ neurotoxicity. Therefore, in this follow-up study, we investigated the implication of the Wnt/ß-catenin signaling pathway in Cd2+-induced developmental disorders and neuroinflammation and revealed that environmental Cd2+ exposure significantly affected the expression of key factors in the zebrafish Wnt/ß-catenin signaling pathway. In addition, pharmacological intervention of this pathway via TWS119, which can increase the protein level of ß-catenin and act as a classical activator of the Wnt signaling pathway, could significantly repress the Cd2+-induced cell cycle arrest and apoptosis, thereby attenuating the inhibitory effects of Cd2+ on the early development, behavior, and activity, as well as neurodevelopment of zebrafish larvae to a certain degree. Furthermore, activation and proliferation of microglia, as well as the altered expression profiles of genes associated with neuroimmune homeostasis triggered by Cd2+ exposure could also be significantly alleviated by the activation of the Wnt/ß-catenin signaling pathway. Thus, this study provided novel insights into the cellular and molecular mechanisms of Cd2+ toxicity on the vertebrate central nervous system (CNS), which might be helpful in developing pharmacotherapies to mitigate the neurological disorders resulting from exposure to Cd2+ and many other environmental heavy metals.

Hinokitiol functions as a ferroptosis inhibitor to confer neuroprotection.

The intrinsic link of ferroptosis to neurodegeneration, such as Parkinson's disease and Alzheimer's disease, has set promises to apply ferroptosis inhibitors for treatment of neurodegenerative disorders. Herein, we report that the natural small molecule hinokitiol (Hino) functions as a potent ferroptosis inhibitor to rescue neuronal damages in vitro and in vivo. The action mechanisms of Hino involve chelating irons and activating cytoprotective transcription factor Nrf2 to upregulate the antioxidant genes including solute carrier family 7 member 11, glutathione peroxidase 4 and Heme oxygenase-1. In vivo studies demonstrate that Hino rescues the deficits of locomotor activity and neurodevelopment in zebrafishes. In addition, Hino shows the efficient blood-brain barrier permeability in mice, supporting the application of Hino for brain disorders. Paclitaxel is one of the most widely used broad-spectrum antineoplastic agents. However, its neurotoxic side effect is a severe concern. We demonstrate that the neurotoxicity of paclitaxel is ferroptosis-related and Hino also alleviates the paclitaxel-induced neurotoxicity without compromising its cytotoxicity to cancer cells. Hino also salvages the neurobehavioral impairment by paclitaxel in zebrafishes. Collectively, the discovery of Hino as a novel ferroptosis inhibitor and disclosure of its action mechanisms establish a foundation for the further development of Hino as a neuroprotective agent.

Amorphous Precursor-Mediated Calcium Phosphate Coatings with Tunable Microstructures for Customized Bone Implants.

Calcium phosphate (CaP) is frequently used as coating for bone implants to promote osseointegration. However, commercial CaP coatings via plasma spraying display similar microstructures, and thus fail to provide specific implants according to different surgical conditions or skeletal bone sites. Herein, inspired by the formation of natural biominerals with various morphologies mediated by amorphous precursors, CaP coatings with tunable microstructures mediated by an amorphous metastable phase are fabricated. The microstructures of the coatings are precisely controlled by both polyaspartic acid and Mg2+ . The cell biological behaviors, including alkaline phosphatase activity, mineralization, and osteogenesis-related genes expression, on the CaP coatings with different microstructures, exhibit significant differences. Furthermore, in vivo experiments demonstrate the osseointegration in different types of rats and bones indeed favors different CaP coatings. This biomimetic strategy can be used to fabricate customized bone implants that can meet the specific requirements of various surgery conditions.

Metabolomics Analysis Across Multiple Biofluids Reveals the Metabolic Responses of Lactating Holstein Dairy Cows to Fermented Soybean Meal Replacement.

This experiment was performed to reveal the metabolic responses of dairy cows to the replacement of soybean meal (SBM) with fermented soybean meal (FSBM). Twenty-four lactating Chinese Holstein dairy cattle were assigned to either the SBM group [the basal total mixed ration (TMR) diet containing 5.77% SBM] or the FSBM group (the experimental TMR diet containing 5.55% FSBM), in a completely randomized design. The entire period of this trial consisted of 14 days for the adjustment and 40 days for data and sample collection, and sampling for rumen liquid, blood, milk, and urine was conducted on the 34th and 54th day, respectively. When SBM was completely replaced by FSBM, the levels of several medium-chain FA in milk (i.e., C13:0, C14:1, and C16:0) rose significantly (p < 0.05), while the concentrations of a few milk long-chain FA (i.e., C17:0, C18:0, C18:1n9c, and C20:0) declined significantly (p < 0.05). Besides, the densities of urea nitrogen and lactic acid were significantly (p < 0.05) higher, while the glucose concentration was significantly (p < 0.05) lower in the blood of the FSBM-fed cows than in the SBM-fed cows. Based on the metabolomics analysis simultaneously targeting the rumen liquid, plasma, milk, and urine, it was noticed that substituting FSBM for SBM altered the metabolic profiles of all the four biofluids. According to the identified significantly different metabolites, 3 and 2 amino acid-relevant metabolic pathways were identified as the significantly different pathways between the two treatments in the rumen fluid and urine, respectively. Furthermore, glycine, serine, and threonine metabolism, valine, leucine, and isoleucine biosynthesis, and cysteine and methionine metabolism were the three key integrated different pathways identified in this study. Results mainly implied that the FSBM replacement could enhance nitrogen utilization and possibly influence the inflammatory reactions and antioxidative functions of dairy cattle. The differential metabolites and relevant pathways discovered in this experiment could serve as biomarkers for the alterations in protein feed and nitrogen utilization efficiency of dairy cows, and further investigations are needed to elucidate the definite roles and correlations of the differential metabolites and pathways.

The future of stem cell therapies of Alzheimer's disease.

Alzheimer's disease (AD) places a heavy burden on the global economy. There is no effective disease-modifying treatment available at present. Since the advent of induced pluripotent stem cells (iPSCs) reprogrammed from human somatic cells, new approaches using iPSC-derived products provided novel insights into AD pathogenesis and drug candidates for AD treatment. Multiple recent studies using animal models have increased the possibility of reducing pathology and improving cognitive function through cell replacement therapies. In this review, we summarized the advantages, limitations, and future directions of cell replacement therapy, discussed the safety and ethical concerns of this novel therapeutic approach and the possibility of translation to clinical practice.

Caspase-1 variant influencing CSF tau and FDG PET levels in non-demented elders from the ADNI cohort.

BACKGROUND: Genetic variations in the inflammatory Caspase-1 gene have been shown associated with cognitive function in elderly individuals and in predisposition to Alzheimer's disease (AD), but its detailed mechanism before the typical AD onset was still unclear. Our current study evaluated the impact of Caspase-1 common variant rs554344 on the pathological processes of brain amyloidosis, tauopathy, and neurodegeneration. METHODS: Data used in our study were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We examined the relationship between Caspase-1 rs554344 allele carrier status with AD-related cerebrospinal fluid (CSF), PET, and MRI measures at baseline by using a multiple linear regression model. We also analyzed the longitudinal effects of this variant on the change rates of CSF biomarkers and imaging data using a mixed effect model. RESULTS: We found that Caspase-1 variant was significantly associated with FDG PET levels and CSF t-tau levels at baseline in total non-demented elderly group, and especially in mild cognitive impairment (MCI) subgroup. In addition, this variant was also detected associated with CSF p-tau levels in MCI subgroup. The mediation analysis showed that CSF p-tau partially mediated the association between Caspase-1 variant and CSF t-tau levels, accounting for 80% of the total effect. CONCLUSIONS: Our study indicated a potential role of Caspase-1 variant in influencing cognitive function might through changing tau related-neurodegeneration process.