PICK1 regulates the trafficking of ASIC1a and acidotoxicity in a BAR domain lipid binding-dependent manner

<p>Abstract</p> <p>Background</p> <p>Acid-sensing ion channel 1a (ASIC1a) is the major ASIC subunit determining acid-activated currents in brain neurons. Recent studies show that ASIC1a play critical roles in acid-induced cell toxicity. While these studies raise the importance of ASIC1a in diseases, mechanisms for ASIC1a trafficking are not well understood. Interestingly, ASIC1a interacts with PICK1 (protein interacting with C-kinase 1), an intracellular protein that regulates trafficking of several membrane proteins. However, whether PICK1 regulates ASIC1a surface expression remains unknown.</p> <p>Results</p> <p>Here, we show that PICK1 overexpression increases ASIC1a surface level. A BAR domain mutant of PICK1, which impairs its lipid binding capability, blocks this increase. Lipid binding of PICK1 is also required for PICK1-induced clustering of ASIC1a. Consistent with the effect on ASIC1a surface levels, PICK1 increases ASIC1a-mediated acidotoxicity and this effect requires both the PDZ and BAR domains of PICK1.</p> <p>Conclusions</p> <p>Taken together, our results indicate that PICK1 regulates trafficking and function of ASIC1a in a lipid binding-dependent manner.</p

Ketogenic Diets and Hepatocellular Carcinoma.

The ketogenic diet (KD) is a low-carbohydrate, high-fat diet regarded as a potential intervention for cancers owing to its effects on tumor metabolism and behavior. Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer, and its management is worth investigating because of the high fatality rate. Additionally, as the liver is the glucose and lipid metabolism center where ketone bodies are produced, the application of KD to combat HCC is promising. Prior studies have reported that KD could reduce the energy supply and affect the proliferation and differentiation of cancer cells by lowering the blood glucose and insulin levels. Furthermore, KD can increase the expression of hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) in hepatocytes and regulate lipid metabolism to inhibit the progression of HCC. In addition, β-hydroxybutyrate can induce histone hyperacetylation and reduce the expression of inflammatory factors to alleviate damage to hepatocytes. However, there are few relevant studies at present, and the specific effects and safety of KD on HCC warrant further research. Optimizing the composition of KD and combining it with other therapies to enhance its anti-cancer effects warrant further exploration

Toll-like receptor 2 -196 to -174 del polymorphism influences the susceptibility of Han Chinese people to Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Toll-like receptor 2 (<it>TLR2</it>) represents a reasonable functional and positional candidate gene for Alzheimer's disease (AD) as it is located under the linkage region of AD on chromosome 4q, and functionally is involved in the microglia-mediated inflammatory response and amyloid-β clearance. The -196 to -174 del polymorphism affects the <it>TLR2 </it>gene and alters its promoter activity.</p> <p>Methods</p> <p>We recruited 800 unrelated Northern Han Chinese individuals comprising 400 late-onset AD (LOAD) patients and 400 healthy controls matched for gender and age. The -196 to -174 del polymorphism in the <it>TLR2 </it>gene was genotyped using the polymerase chain reaction (PCR) method.</p> <p>Results</p> <p>There were significant differences in genotype (P = 0.026) and allele (P = 0.009) frequencies of the -196 to -174 del polymorphism between LOAD patients and controls. The del allele was associated with an increased risk of LOAD (OR = 1.31, 95% CI = 1.07-1.60, Power = 84.9%). When these data were stratified by apolipoprotein E (<it>ApoE</it>) ε4 status, the observed association was confined to <it>ApoE </it>ε4 non-carriers. Logistic regression analysis suggested an association of LOAD with the polymorphism in a recessive model (OR = 1.64, 95% CI = 1.13-2.39, Bonferroni corrected P = 0.03).</p> <p>Conclusions</p> <p>Our data suggest that the -196 to -174 del/del genotype of <it>TLR2 </it>may increase risk of LOAD in a Northern Han Chinese population.</p

Identification and pharmacokinetics of saponins in Rhizoma Anemarrhenae after oral administration to rats by HPLC-Q-TOF/MS and HPLC-MS/MS

Rhizoma Anemarrhenae is a well-known herbal medicine with saponins as its commonly regarded major bioactive components. It is essential to classify the properties of saponins which are associated with their toxicity and efficacy. In this study, 25 compounds were identified by HPLC-Q-TOF/MS in the extract of Rhizoma Anemarrhenae and 8 saponins were detected in rat plasma by HPLC-MS/MS after oral administration of this extract. These were neomangiferin, mangiferin, timosaponin E1, timosaponin E, timosaponin B-II, timosaponin B-III, timosaponin A-III and timosaponin A-I. A sensitive and accurate HPLC-MS/MS method was developed and successfully applied to a pharmacokinetic study of the abovementioned eight saponins after oral administration of the Rhizoma Anemarrhenae extract to rats. The method validation, including specificity, linearity, precision, accuracy, recovery, matrix effect and robustness, met the requirements of the intended use. The pharmacokinetic parameter, Tmax value, ranged from 2 to 8 h for these eight saponins whereas their elimination half-life (t1/2) ranged from 4.06 to 9.77 h, indicating slow excretion. The plasma concentrations of these eight saponins were all very low, indicating a relatively low oral bioavailability. All these results provide support for further clinical studies

Phase-Adjusted Estimation of the COVID-19 Outbreak in South Korea Under Multi-Source Data and Adjustment Measures: A Modelling Study

Based on the reported data from February 16, 2020 to March 9, 2020 in South Korea including confirmed cases, death cases and recovery cases, the control reproduction number was estimated respectively at different control measure phases using Markov chain Monte Carlo method and presented using the resulting posterior mean and 95% credible interval (CrI). At the early phase from February 16 to February 24, we estimate the basic reproduction number R0 of COVID-19 to be 4.79(95% CrI 4.38 - 5.2). The estimated control reproduction number dropped rapidly to Rc ≈ 0.32(95% CrI 0.19 - 0.47) at the second phase from February 25 to March 2 because of the voluntary lockdown measures. At the third phase from March 3 to March 9, we estimate Rc to be 0.27 (95% CrI 0.14 - 0.42). We predict that the final size of the COVID-19 outbreak in South Korea is 9661 (95% CrI 8660 - 11100) and the whole epidemic will be over by late April. It is found that reducing contact rate and enhancing the testing speed will have the impact on the peak value and the peak time

Efficient dealkalization of red mud and recovery of valuable metals by a sulfur-oxidizing bacterium

Red mud (RM) is a highly alkaline polymetallic waste generated via the Bayer process during alumina production. It contains metals that are critical for a sustainable development of modern society. Due to a shortage of global resources of many metals, efficient large-scale processing of RM has been receiving increasing attention from both researchers and industry. This study investigated the solubilization of metals from RM, together with RM dealkalization, via sulfur (S(0)) oxidation catalyzed by the moderately thermophilic bacterium Sulfobacillus thermosulfidooxidans. Optimization of the bioleaching process was conducted in shake flasks and 5-L bioreactors, with varying S(0):RM mass ratios and aeration rates. The ICP analysis was used to monitor the concentrations of dissolved elements from RM, and solid residues were analyzed for surface morphology, phase composition, and Na distribution using the SEM, XRD, and STXM techniques, respectively. The results show that highest metal recoveries (89% of Al, 84% of Ce, and 91% of Y) were achieved with the S(0):RM mass ratio of 2:1 and aeration rate of 1 L/min. Additionally, effective dealkalization of RM was achieved under the above conditions, based on the high rates (>95%) of Na, K, and Ca dissolution. This study proves the feasibility of using bacterially catalyzed S(0) oxidation to simultaneously dealkalize RM and efficiently extract valuable metals from the amassing industrial waste

User-adaptive sketch-based 3D CAD model retrieval

3D CAD models are an important digital resource in the manufacturing industry. 3D CAD model retrieval has become a key technology in product lifecycle management enabling the reuse of existing design data. In this paper, we propose a new method to retrieve 3D CAD models based on 2D pen-based sketch inputs. Sketching is a common and convenient method for communicating design intent during early stages of product design, e.g., conceptual design. However, converting sketched information into precise 3D engineering models is cumbersome, and much of this effort can be avoided by reuse of existing data. To achieve this purpose, we present a user-adaptive sketch-based retrieval method in this paper. The contributions of this work are twofold. Firstly, we propose a statistical measure for CAD model retrieval: the measure is based on sketch similarity and accounts for users’ drawing habits. Secondly, for 3D CAD models in the database, we propose a sketch generation pipeline that represents each 3D CAD model by a small yet sufficient set of sketches that are perceptually similar to human drawings. User studies and experiments that demonstrate the effectiveness of the proposed method in the design process are presented

Ethyl 5-methyl­imidazo[1,2-a]pyridine-2-carboxyl­ate

The title compound, C11H12N2O2, was synthesized from the reaction of 6-methyl­pyridin-2-amine and ethyl 3-bromo-2-oxopropionate. In the mol­ecular structure, the six- and five-membered rings are individually almost planar with r.m.s. deviations of 0.003 and 0.002 Å, respectively. The two rings are almost coplanar, the dihedral angle between their planes being 1.4 (3)°. Inter­molecular C—H⋯O and C—H⋯N hydrogen bonds are present in the crystal structure

EGFR-mutated squamous cell lung cancer and its association with outcomes

Background: The therapeutic efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced EGFR-mutant lung squamous cell carcinoma (SCC) patients remains uncertain. Furthermore, the factors underlying the responsiveness have not been fully investigated. We therefore investigated the link between genomic profiles and EGFR-TKI efficacy. Material and Methods: We consecutively enrolled stage IV, EGFR-mutant, and EGFR-TKI-treated patients with SCC. Patients with EGFR wild-type lung SCC and EGFR-mutant lung adenocarcinoma were consecutively enrolled as controls, and next-generation sequencing (NGS) was performed. Results: In total, 28 EGFR-mutant lung SCC, 41 EGFR-mutant lung adenocarcinoma, and 40 EGFR wild-type lung SCC patients were included. Among the patients with EGFR mutations, shorter progression-free survival (PFS) was observed in SCC compared to adenocarcinoma (4.6 vs. 11.0 months, P<0.001). Comparison of the genomic profiles revealed that EGFR-mutant SCC patients had similar mutation characteristics to EGFR-mutant adenocarcinoma patients, but differed from those with EGFR wild-type SCC. Further exploration of EGFR-mutant SCC revealed that mutations in CREBBP (P = 0.005), ZNF217 (P = 0.016), and the Wnt (P = 0.027) pathway were negatively associated with PFS. Mutations in GRM8 (P = 0.025) were associated with improved PFS. Conclusions: EGFR-mutant lung SCC has a worse prognosis than EGFR-mutant adenocarcinoma. Mutations in other genes, such as CREBBP, ZNF217, GRM8, or Wnt that had implications on PFS raise the possibility of understanding mechanisms of resistance to EGFR-TKI in lung SCC, which will aid identification of potential beneficial subgroups of patients with EGFR-mutant SCCs receiving EGFR-TKIs

Bispecific antibodies revolutionizing breast cancer treatment: a comprehensive overview

Breast cancer (BCa) is known as a complex and prevalent disease requiring the development of novel anticancer therapeutic approaches. Bispecific antibodies (BsAbs) have emerged as a favorable strategy for BCa treatment due to their unique ability to target two different antigens simultaneously. By targeting tumor-associated antigens (TAAs) on cancer cells, engaging immune effector cells, or blocking critical signaling pathways, BsAbs offer enhanced tumor specificity and immune system involvement, improving anti-cancer activity. Preclinical and clinical studies have demonstrated the potential of BsAbs in BCa. For example, BsAbs targeting human epidermal growth factor receptor 2 (HER2) have shown the ability to redirect immune cells to HER2-positive BCa cells, resulting in effective tumor cell killing. Moreover, targeting the PD-1/PD-L1 pathway by BsAbs has demonstrated promising outcomes in overcoming immunosuppression and enhancing immune-mediated tumor clearance. Combining BsAbs with existing therapeutic approaches, such as chemotherapy, targeted therapies, or immune checkpoint inhibitors (ICIs), has also revealed synergistic effects in preclinical models and early clinical trials, emphasizing the usefulness and potential of BsAbs in BCa treatment. This review summarizes the latest evidence about BsAbs in treating BCa and the challenges and opportunities of their use in BCa