Association of lipid-lowering drugs with the risk of type 2 diabetes and its complications: a mendelian randomized study.

BACKGROUND: The pathogenesis of type 2 diabetes mellitus is somewhat associated with lipid metabolism. We aim to assess the impact of lipid-lowering drugs (HMGCR inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitors) on type 2 diabetes mellitus and its complications through a two-sample Mendelian randomization (MR) study. METHOD: We identified suitable genetic instruments from the GWAS database that represent the expression levels of three genes, interpreting reduced genetically proxied gene expression as indicative of lipid-lowering drug use. We evaluated the causal relationships among these variables employing a two-sample Mendelian randomization approach, with the Inverse Variance Weighted (IVW) analysis serving as the primary method. Coronary artery disease was utilized as a positive control to validate the reliability of the selected genetic instruments. RESULT: Increased genetically proxied HMGCR expression is significantly associated with a reduced risk of type 2 diabetes mellitus (OR = 0.64, 95%CI = 0.55-0.74), which was replicated in the FinnGen study with consistent results (OR = 0.65, 95%CI = 0.53-0.80). Increased genetically proxied HMGCR expression is associated with a reduced risk of diabetic retinopathy (OR = 0.23, 95%CI = 0.12-0.44) and diabetic nephropathy (OR = 0.35, 95%CI = 0.17-0.71). In contrast, increased genetically proxied PCSK9 expression is associated with a decreased risk of diabetic coma (OR = 0.70, 95%CI = 0.50-0.98), diabetic neuropathy (OR = 0.24, 95%CI = 0.14-0.42), diabetic retinopathy (OR = 0.67, 95%CI = 0.48-0.96), diabetic cardiovascular diseases (OR = 0.62, 95%CI = 0.38-0.99), and diabetic nephropathy (OR = 0.62, 95%CI = 0.41-0.95). CONCLUSIONS: This Mendelian randomization study suggests an association between HMGCR and the pathogenesis of type 2 diabetes mellitus, with increased genetically proxied HMGCR expression reducing the risk of type 2 diabetes mellitus, while PCSK9 and NPC1L1 show no significant association with type 2 diabetes mellitus. These findings may offer more reasonable lipid-lowering drug options for patients with dyslipidemia.

Number of lymph nodes retrieved in patients with locally advanced rectal cancer after total neoadjuvant therapy: post-hoc analysis from the STELLAR trial.

BACKGROUND: The current gold standard for extraperitoneal locally advanced rectal cancer is total neoadjuvant therapy (TNT) followed by total mesorectal excision. This research explored the number of lymph nodes in patients with locally advanced rectal cancer after TNT and its correlation with survival. MATERIALS AND METHODS: This is a post-hoc analysis based on the STELLAR trial, including patients with locally advanced rectal cancer from 16 tertiary centres who were randomized for short-term radiotherapy followed by chemotherapy (TNT group) or long-term concurrent chemotherapy group followed by total mesorectal excision between 2015 and 2018. This lymph node-related analysis is based on the TNT group. Subgroups were differentiated based on the lymph node harvest (below the median number: limited lymphadenectomy group, and greater than/equal to the median number: extended lymphadenectomy group). The primary outcomes were overall survival and disease-free survival (DFS). Correlations with clinical/pathological variables, lymphadenectomy categories and use of adjuvant chemotherapy were explored. RESULTS: Among the 451 patients enrolled in the STELLAR trial, 227 patients (50.3%) were assigned to the TNT group, including 29.5% females. The median number of lymph nodes retrieved in the TNT group was 11.0. Patients in the limited lymphadenectomy subgroup exhibited worse overall survival than those with extended lymphadenectomy (HR 2.95 (95% c.i. 1.47 to 5.92), P = 0.001). The overall survival was similar in the ypN0-limited and ypN1-extended subgroups (HR 0.38 (95% c.i. 0.11 to 1.30), P = 0.109). Adjuvant chemotherapy was associated with better overall survival and DFS than no adjuvant chemotherapy overall (P < 0.001) and in the limited lymphadenectomy subgroup (P < 0.001). However, there was no significant difference in overall survival or DFS with or without adjuvant chemotherapy in the extended lymphadenectomy subgroup (P = 0.887 and P = 0.192, respectively). CONCLUSION: In the STELLAR trial, the median number of lymph nodes harvested was 11. In patients with limited lymphadenectomy, the use of adjuvant therapy after TNT was beneficial and correlated with better prognosis compared with patients who did not receive adjuvant chemotherapy.

Single-cell exome sequencing reveals polyclonal seeding and TRPS1 mutations in colon cancer metastasis.

Liver metastasis remains the primary cause of mortality in patients with colon cancer. Identifying specific driver gene mutations that contribute to metastasis may offer viable therapeutic targets. To explore clonal evolution and genetic heterogeneity within the metastasis, we conducted single-cell exome sequencing on 150 single cells isolated from the primary tumor, liver metastasis, and lymphatic metastasis from a stage IV colon cancer patient. The genetic landscape of the tumor samples revealed that both lymphatic and liver metastases originated from the same region of the primary tumor. Notably, the liver metastasis was derived directly from the primary tumor, bypassing the lymph nodes. Comparative analysis of the sequencing data for individual cell pairs within different tumors demonstrated that the genetic heterogeneity of both liver and lymphatic metastases was also greater than that of the primary tumor. This finding indicates that liver and lymphatic metastases arose from clusters of circulating tumor cell (CTC) of a polyclonal origin, rather than from a single cell from the primary tumor. Single-cell transcriptome analysis suggested that higher EMT score and CNV scores were associated with more polyclonal metastasis. Additionally, a mutation in the TRPS1 (Transcriptional repressor GATA binding 1) gene, TRPS1 R544Q, was enriched in the single cells from the liver metastasis. The mutation significantly increased CRC invasion and migration both in vitro and in vivo through the TRPS1R544Q/ZEB1 axis. Further TRPS1 mutations were detected in additional colon cancer cases, correlating with advanced-stage disease and inferior prognosis. These results reveal polyclonal seeding and TRPS1 mutation as potential mechanisms driving the development of liver metastases in colon cancer.

The Puccinia striiformis effector Pst11215 manipulates mitochondria to suppress host immunity by promoting TaVDIP1-mediated ubiquitination of TaVDAC1.

Mitochondria-induced cell death is closely correlated with plant immune responses against pathogens. However, the molecular mechanisms by which pathogens manipulate mitochondria to suppress host resistance remain poorly understood. In this study, a haustorium-specific effector Pst11215 from the wheat stripe rust pathogen Puccinia striiformis f. sp. tritici (Pst) was characterized by host-induced gene silencing. The interaction partners regulated by Pst11215 were screened using the yeast two-hybrid system. In addition, Pst11215-mediated immune regulation modes were further determined. The results showed that Pst11215 was required for Pst virulence. Pst11215 interacted with the wheat voltage-dependent anion channel TaVDAC1, the negative regulator of wheat resistance to stripe rust, in mitochondria. Furthermore, the E3 ubiquitin ligase TaVDIP1 targeted and ubiquitinated TaVDAC1, which can be promoted by Pst11215. TaVDIP1 conferred enhanced wheat susceptibility to Pst by cooperating with TaVDAC1. Overexpression of TaVDIP1 reduced reactive oxygen species (ROS) accumulation and abnormal mitochondria. Our study revealed that Pst11215 functions as an important pathogenicity factor secreted to the host mitochondria to compromise wheat resistance to Pst possibly by facilitating TaVDIP1-mediated ubiquitination of TaVDAC1, thereby protecting mitochondria from ROS-induced impairment. This research unveils a novel regulation mode of effectors hijacking host mitochondria to contribute to pathogen infection.

Biomechanical model of minimally invasive hallux valgus surgery.

Hallux valgus is a common foot deformity characterized by outward tilting and twisting of the big toe, often accompanied by a medial prominence at the base. Minimally invasive surgical techniques are widely utilized for treating metatarsus adductus due to their advantages of smaller incisions, faster recovery, and early weight-bearing. However, due to individual variations and limited sample size, the biomechanical effects of different Kirschner wire fixation methods and the underlying mechanisms of postoperative metatarsalgia remain unclear. In this study, a finite element method was employed to develop a biomechanical model of metatarsus adductus. The influence of various Kirschner wire entry points and angles on foot loading characteristics was investigated. Six different Kirschner wire fixation models, including two entry methods (along the adjacent fracture line and proximal-biased entry at the midshaft of the metatarsal) with different entry angles, were analyzed. Mechanical parameters such as metatarsal stress distribution, plantar pressure distribution, and displacement of the first metatarsal osteotomy plane were assessed. This research aims to enhance understanding of minimally invasive surgery and its fixation methods for metatarsus adductus. By providing scientific support and reliable evidence, it seeks to contribute to the development of minimally invasive surgical techniques and the improvement of clinical practice in metatarsus adductus surgery. Ultimately, the goal is to reduce complications, increase surgical success rates, and enhance patient satisfaction.

Associations of Diet and Lifestyle with Mortality and Stroke: The China Cardiometabolic Disease and Cancer Cohort (4C) Study.

OBJECTIVE: This study aimed to examine the individual and combined associations between dietary habits and lifestyle factors concerning all-cause mortality and stroke in Chinese adults. METHOD: We conducted a nationwide, multicenter, prospective cohort study involving 10,008 participants, gathering baseline data on lifestyle, metabolic status, dietary habits, and living behaviors. Subsequently, a 10-year follow-up was performed, resulting in the inclusion of 7,612 participants in this study. We employed Spearman correlation analysis, restricted cubic spline regression, and Cox regression analysis to evaluate the connections between outcome events, dietary habits, and lifestyle. RESULT: For each additional serving of pulses consumed per week, there was a slight decrease in the risk of all-cause mortality (HR: 0.91, 95% CI: 0.83-0.99). The hazard ratios for stroke were 2.24 (1.48, 3.37) for current smokers, in comparison to individuals who had never smoked. Appropriate intake of specific dietary factors and certain lifestyle habits were associated with reduced stroke: fruit drinks at 0.51 (0.34, 0.87), and animal viscera at 0.58 (0.32, 1.04). Weekly consumption of at least 21 servings of vegetables (0.72, 0.53-0.98), 0-1 serving of fried food (0.58, 0.38-0.90), and at least 1 serving of carbonated beverages (0.51, 0.28-0.92) was associated with a reduced risk of stroke. CONCLUSION: Smoking was found to be linked to an increased risk of stroke. A higher intake of fruit drinks and animal viscera was associated with a reduced risk of stroke. In contrast, a higher intake of beans was associated with a decreased risk of overall mortality. Consuming an appropriate amount of vegetables, fried foods, and carbonated drinks was found to potentially lower the risk of stroke. Collectively, these findings underscore the importance of developing tailored dietary interventions conducive to the Chinese populace's health.

Lactyllysine Esterification Enables Efficient Lactylprotein Expression via Genetic Code Expansion and Supports Functional Proteomics Studies.

Lysine lactylation has recently been discovered and demonstrated to be an essential player in immunity, cancer and neurodegenerative diseases. Genetic code expansion (GCE) technique is powerful in uncovering lactylation functions, since it allows site-specific incorporation of lactyllysine (Klac) into proteins of interest (POIs) in living cells. However, the inefficient uptake of Klac into cells, due to its high hydrophilicity, results in limited expression of lactylated POIs. To address this challenge, here we designed esterified Klac derivatives, exemplified by ethylated Klac (KlacOEt), to enhance Klac's lipophilicity and improve its cellular uptake. The expression level of site-specifically lactylated POIs was doubled using KlacOEt in both Escherichia coli and HEK293T cells. Immunoprecipitation mass spectrometry analysis verified the significantly increased yield of the precisely lactylated fructose-bisphosphate aldolase A using KlacOEt. Furthermore, in conjunction with the Target Responsive Accessibility Profiling approach, we found that lactylation at ALDOA-K147 altered the protein's conformation, which may explain the lactylation-induced reduction in enzyme activity. Together, we demonstrate that, through enhancing the yield of lactylated proteins with Klac esters via GCE, we are able to site-specifically reveal the effects of lactylation on POIs' interactions, conformations and activities using a suite of functional proteomics and biochemical tools.

Intestinal probiotic-based nanoparticles for cytotoxic siRNA delivery in immunotherapy against cancer.

Immunogene therapy has emerged as strategy against cancer by introducing immune-stimulating components into gene therapy. However, there is still a need for an ideal platform to achieve both immune stimulation and efficient gene delivery. Lactobacillus reuteri has potential immunomodulatory activity owing to its unique antigenicity, which is potentially relevant to cancer progression. Here, we designed a novel non-viral siRNA vector (DMPLAC) by encapsulating Lactobacillus reuteri lysate in DMP. DMPLAC can promote maturation and activation of immune cells, increase infiltration of APC and cytotoxic T cells in tumor microenvironment, and exhibit tumor suppressive effects. Loading of siRNA targeting Stat3, DMPLAC/siStat3 further inhibits tumor in multiple models. We designed a strategy that combines immune activation with Stat3 silencing, triggering an immune response and tumor killing. This dual-functional design provides a new choice in development of effective immunogene therapy.

Lateral pelvic lymph nodes dissection of rectal neuroendocrine neoplasms: A prospective case-series and literature review.

BACKGROUND: Rectal neuroendocrine neoplasms are relatively rare. Patients with rectal neuroendocrine neoplasms undergoing radical surgery have a higher rate of lymph node metastases. Robust evidence on the status of lateral pelvic lymph node metastases and the role of lateral pelvic lymph node dissection in those patients is lacking. This case-series study aimed to explore and address these issues. METHODS: This single-center, prospective case series consecutively enrolled patients with biopsy-proven rectal neuroendocrine neoplasms in a tertiary referral hospital between June 2022 and January 2024. All eligible patients underwent laparoscopic total mesorectal excision surgery and bilateral lateral pelvic lymph node dissection under general anesthesia. The clinicopathologic features, surgical outcomes, and postoperative complications were presented. The last follow-up was conducted in March 2024. RESULTS: A total of 11 patients with rectal neuroendocrine neoplasms-3 female and 8 male-were enrolled. The average age was 60.0 years (range, 53.5-65.5 years), and the median tumor size was 2.0 cm (range, 1.6-2.5 cm). Tumors invaded the muscularis propria in 7 patients. There were 3 cases of neuroendocrine tumor G1, 6 cases of neuroendocrine tumor G2, and 2 cases of neuroendocrine carcinoma. Among these patients, 11 (100.0%) had lymph node metastases, and 6 (54.5%) had lateral pelvic lymph node metastases. In addition, in 2 patients, only lateral pelvic lymph node metastases were observed, without involvement of the mesenteric lymph nodes. Five patients had tumors located on the left wall of the rectum, and only left-sided lateral pelvic lymph node metastases were observed. The other patient had both sides of lateral pelvic lymph node metastases due to circumferential growth of the tumor around the rectum. Anal preservation was achieved in all patients. The median operating time was 235.0 minutes (range, 210.5-335.5 minutes), and the median estimated blood loss was 50.0 mL (range, 45.0-75.0 mL). Two patients experienced postoperative dysuria and recovered spontaneously within 2-4 months after surgery. CONCLUSION: On the basis of a prospective case series, we demonstrate, for the first time, the lateral pelvic lymph node metastasis status in patients with rectal neuroendocrine neoplasms requiring radical total mesorectal excision surgery. Simultaneous bilateral lateral pelvic lymph node dissection may be a feasible and beneficial procedure for preventing local recurrence in these patients due to the lack of definitive neoadjuvant or adjuvant therapy options.

Real-space energy decomposition analysis method for qualitative and quantitative interpretations.

In the work, a real-space energy decomposition analysis method, called DM-EDA(RS), is introduced based on our recently developed DM-EDA method [Zhang et al., J. Chem. Phys. 160, 174101 (2024)]. The EDA terms in DM-EDA(RS), including electrostatic, exchange, repulsion, polarization, and correlation, are expressed as the summations of grid-based energy density in real-space. This method is able to interpret intermolecular interactions in a unified qualitative and quantitative way. DM-EDA(RS) results provide not only comprehensive explanations for intermolecular interactions but also insights for sub-region interactions involving different functional groups.

The causal relationship between plasma protein-to-protein ratios and type 2 diabetes and its complications: Proteomics mendelian randomization study.

AIM: In recent years, proteomics research has surged, with numerous observational studies identifying associations between plasma proteins and type 2 diabetes. However, research specifically focusing on the ratios of plasma proteins in type 2 diabetes remains relatively scarce. METHODS: This study primarily employed a two-sample, two-step Mendelian randomization (MR) approach, leveraging genetic data from several large, publicly accessible genome-wide association studies, wherein single nucleotide polymorphisms served as proxies for exposures and diseases. Within this framework, we applied two-sample MR to assess the associations between the 2821 plasma protein-to-protein ratios and type 2 diabetes along with its complications and utilized reverse MR to confirm the unidirectionality of these causal relationships. In addition, we employed two-step MR to investigate the potential mediating role of body mass index in these associations. To augment the robustness of our findings, we systematically implemented a series of sensitivity analyses. RESULTS: The results gleaned from the inverse-variance weighted method elucidated that a cumulative sum of 23 protein-to-protein ratios bore a causal nexus with type 2 diabetes across both sample cohorts. With each incremental elevation of 1 standard deviation in the genetically anticipated protein-to-protein ratio, the susceptibility to type 2 diabetes oscillated from 0.93 (95% confidence interval: 0.87, 1.00) for the CNTN3/NCSS1 protein level ratio to 1.13 (1.06, 1.22) for the DBNL/NCK2 protein level ratio. Moreover, a tally of eight protein-to-protein ratios correlated with a minimum of one complication linked to type 2 diabetes. Diverse sensitivity analyses corroborated the robustness of these observations. CONCLUSIONS: The outcomes of our investigation unveiled correlations between 23 plasma protein-to-protein ratios and type 2 diabetes, with eight of these ratios entwined with complications of type 2 diabetes. These discoveries offer novel perspectives on the diagnosis and management of type 2 diabetes and its associated complications.

Design of a photocatalyst combining graphdiyne (g-CnH2n-2) nanosheets with a PVP-modified co-metal coordination polymer and its hydrogen-evolution performance.

Metal coordination polymers are organometallic frameworks in which a metal and an organic ligand are linked via a dative bond. The material in question exhibits ultra-high porosity, large specific surface area, and abundant active sites, which can be customised in terms of morphology, size, and electronic structure through rational design. Graphdiyne, a novel two-dimensional carbon allotrope, boasts structural stability and enhanced electrical conductivity due to its hybridization of sp2 and sp carbons. A metal-organic framework of Co (MOF-67) was synthesized via hydrothermal synthesis. The introduction of polyvinyl pyrrolidone (PVP) served as a structural regulator and surfactant to obtain a more active metal coordination polymer (Co-MCPS). PVP, in its dual role, significantly amplified the catalytic performance of metal coordinate polymers, as demonstrated in a number of experiments. The incorporation of GDY onto the surfaces of MOF-67 and Co-MCPS induced an electron-rich isolation layer, which could effectively sequester oxidation sites, thereby enhancing the rate of charge carrier separation and hydrogen precipitation evolution efficiency.

Association between gut microbiota and adrenal disease: a two-sample Mendelian randomized study.

Background: Some observational studies and clinical experiments suggest a close association between gut microbiota and metabolic diseases. However, the causal effects of gut microbiota on adrenal diseases, including Adrenocortical insufficiency, Cushing syndrome, and Hyperaldosteronism, remain unclear. Methods: This study conducted a two-sample Mendelian randomization analysis using summary statistics data of gut microbiota from a large-scale genome-wide association study conducted by the MiBioGen Consortium. Summary statistics data for the three adrenal diseases were obtained from the FinnGen study. The study employed Inverse variance weighting, MR-Egger, and MR-PRESSO methods to assess the causal relationship between gut microbiota and these three adrenal diseases. Additionally, a reverse Mendelian randomization analysis was performed for bacteria found to have a causal relationship with these three adrenal diseases in the forward Mendelian randomization analysis. Cochran's Q statistic was used to test for heterogeneity of instrumental variables. Results: The IVW test results demonstrate that class Deltaproteobacteria, Family Desulfovibrionaceae, and Order Desulfovibrionales exhibit protective effects against adrenocortical insufficiency. Conversely, Family Porphyromonadaceae, Genus Lachnoclostridium, and Order MollicutesRF9 are associated with an increased risk of adrenocortical insufficiency. Additionally, Family Acidaminococcaceae confers a certain level of protection against Cushing syndrome. In contrast, Class Methanobacteria, Family Lactobacillaceae, Family Methanobacteriaceae, Genus. Lactobacillus and Order Methanobacteriales are protective against Hyperaldosteronism. Conversely, Genus Parasutterella, Genus Peptococcus, and Genus Veillonella are identified as risk factors for Hyperaldosteronism. Conclusions: This two-sample Mendelian randomization analysis revealed a causal relationship between microbial taxa such as Deltaproteobacteria and Desulfovibrionaceae and Adrenocortical insufficiency, Cushing syndrome, and Hyperaldosteronism. These findings offer new avenues for comprehending the development of adrenal diseases mediated by gut microbiota.

LW-1 induced resistance to TMV in tobacco was mediated by nitric oxide and salicylic acid pathway.

The objective of this study was to investigate the mechanism underlying LW-1-induced resistance to TMV in wild-type and salicylic acid (SA)-deficient NahG transgenic tobacco plants. Our findings revealed that LW-1 failed to induce antivirus infection activity and increase SA content in NahG tobacco, indicating the crucial role of SA in these processes. Meanwhile, LW-1 triggered defense-related early-signaling nitric oxide (NO) generation, as evidenced by the emergence of NO fluorescence in both types of tobacco upon treatment with LW-1, however, NO fluorescence was stronger in NahG compared to wild-type tobacco. Notably, both of them were eliminated by the NO scavenger cPTIO, which also reversed LW-1-induced antivirus activity and the increase of SA content, suggesting that NO participates in LW-1-induced resistance to TMV, and may act upstream of the SA pathway. Defense-related enzymes and genes were detected in tobacco with or without TMV inoculation, and the results showed that LW-1 regulated both enzyme activity (ß-1,3-glucanase [GLU], catalase [CAT] and phenylalanine ammonia-lyase [PAL]) and gene expression (PR1, PAL, WYKY4) through NO signaling in both SA-dependent and SA-independent pathways.

Toxicokinetics Explain Differential Freshwater Ecotoxicity of Nanoencapsulated Imidacloprid Compared to Its Conventional Active Ingredient.

Agricultural applications of nanotechnologies necessitate addressing safety concerns associated with nanopesticides, yet research has not adequately elucidated potential environmental risks between nanopesticides and their conventional counterparts. To address this gap, we investigated the risk of nanopesticides by comparing the ecotoxicity of nanoencapsulated imidacloprid (nano-IMI) with its active ingredient to nontarget freshwater organisms (embryonic Danio rerio, Daphnia magna, and Chironomus kiinensis). Nano-IMI elicited approximately 5 times higher toxicity than IMI to zebrafish embryos with and without chorion, while no significant difference was observed between the two invertebrates. Toxicokinetics further explained the differential toxicity patterns of the two IMI analogues. One-compartmental two-phase toxicokinetic modeling showed that nano-IMI exhibited significantly slower elimination and subsequently higher bioaccumulation potential than IMI in zebrafish embryos (dechorinated), while no disparity in toxicokinetics was observed between nano-IMI and IMI in D. magna and C. kiinensis. A two-compartmental toxicokinetic model successfully simulated the slow elimination of IMI from C. kiinensis and confirmed that both analogues of IMI reached toxicologically relevant targets at similar levels. Although nanopesticides exhibit comparable or elevated toxicity, future work is of utmost importance to properly understand the life cycle risks from production to end-of-life exposures, which helps establish optimal management measures before their widespread applications.

A novel selenium nanocomposite modified by AANL inhibits tumor growth by upregulating CLK2 in lung cancer.

Lung cancer is a malignant tumor with high mortality and drug resistance. Therefore, it is urgent to explore natural and nontoxic drugs to treat lung cancer. In this study, the natural active ingredient AANL extracted from Agrocybe aegirita was used to modify nanoselenium by an oxidation-reduction method. Transmission electron microscope detection and infrared spectroscopy showed that a novel selenium nanocomposite named AANL-SeNPs was successfully prepared. The results of nanoscale characterization showed that AANL-SeNPs had good stability and uniform dispersion in aqueous solution by zeta potential and spectrum analysis. At the cellular level, we found that AANL-SeNPs significantly inhibited the cell viability of lung cancer cells, and the cell inhibition rate of 60 nM AANL-SeNPs was 39 % in H157 cells, 67 % in H147 cells, and 62 % in A549 cells. The IC50 value of AANL-SeNPs was 51.85 nM in A549 cells and 81.57 nM in H157 cells. Moreover, AANL-SeNPs could inhibit the cell proliferation and migration, and enhance the sensitivity of lung cancer cells to osimertinib and has no toxic to normal cells. In vivo, AANL-SeNPs significantly slowed tumor growth in tumor-bearing mice by establishing a subcutaneous transplantation tumor model for lung cancer, and the tumor size was smaller and was reduced about 79 % in 2 mg/kg AANL-SeNPs group compared with PBS group. Mechanistically, a total of 38 differentially expressed proteins were identified by data-independent acquisition mass spectrometry. A significantly upregulated protein, CDC-like kinase 2 (CLK2), was screened and validated for further analysis, which showed that the expression levels of CLK2 were increased in H157 and H1437 cells after AANL-SeNPs treatment. The results obtained in this study suggest that a novel selenium nanocomposite AANL-SeNPs, which inhibits lung cancer by upregulating the expression of CLK2.

Energy decomposition analysis method using density matrix formulation.

In this work, an energy decomposition analysis (EDA) method with the strategy of density matrix, called DM-EDA, is proposed on the basis of single reference electronic structure calculations. Different from traditional EDA methods, instead of an intermediate state wave function, the EDA terms in DM-EDA are expressed in the forms of the density matrix. This method can be carried out with various kinds of density matrices. With the efficient implementation, DM-EDA not only greatly improves the computational efficiency but also provides quantitative knowledge of intermolecular interactions with a large number of monomers.

A de novo PKD1 mutation in a Chinese family with autosomal dominant polycystic kidney disease.

BACKGROUND: PKD1, which has a relatively high mutation rate, is highly polymorphic, and the role of PKD1 is incompletely defined. In the current study, in order to determine the molecular etiology of a family with autosomal dominant polycystic kidney disease, the pathogenicity of an frameshift mutation in the PKD1 gene, c.9484delC, was evaluated. METHODS: The family clinical data were collected. Whole exome sequencing analysis determined the level of this mutation in the proband's PKD1, and Sanger sequencing and bioinformatics analysis were performed. SIFT, Polyphen2, and MutationTaster were used to evaluate the conservation of the gene and pathogenicity of the identified mutations. SWISS-MODEL was used to predict and map the protein structure of PKD1 and mutant neonate proteins. RESULTS: A novel c.9484delC (p.Arg3162Alafs*154) mutation of the PKD1 gene was identified by whole exome sequencing in the proband, which was confirmed by Sanger sequencing in his sister (II7). The same mutation was not detected in the healthy pedigree members. Random screening of 100 normal and end-stage renal disease patients did not identify the c.9484delC mutation. Bioinformatics analysis suggested that the mutation caused the 3162 nd amino acid substitution of arginine by alanine and a shift in the termination codon. As a result, the protein sequence was shortened from 4302 amino acids to 3314 amino acids, the protein structure was greatly changed, and the PLAT/LH2 domain was destroyed. Clustal analysis indicated that the altered amino acids were highly conserved in mammals. CONCLUSION: A novel mutation in the PKD1 gene has been identified in an affected Chinese family. The mutation is probably responsible for a range of clinical manifestations for which reliable prenatal diagnosis and genetic counseling may be provided.

Simulation study on functional group-modified Ni-MOF-74 for CH4/N2 adsorption separation.

This study employs grand canonical Monte Carlo (GCMC) simulations to investigate the impact of functional group modifications (CH3, OH, NH2, and OLi) on the adsorption performance of CH4/N2 on Ni-MOF-74. The results revealed that functional group modifications significantly increased the adsorption capacity of Ni-MOF-74 for both CH4 and N2. The packed methyl groups in CH3-Ni-MOF-74 create an environment conducive to CH4, leading to the highest CH4 adsorption capacity. The electrostatic potential distribution indicates that the strong electron-donating effect introduced by the alkali metal Li results in the highest electrostatic potential gradient in Li-O-Ni-MOF-74, leading to the strongest adsorption of N2, this is unfavorable for CH4/N2 separation. At 1500 kPa the selectivity order of adsorbents for mixed gases was as follows: CH3-Ni-MOF-74 > NH2-Ni-MOF-74 > OH-Ni-MOF-74 > Ni-MOF-74 > Li-O-Ni-MOF-74. This study highlights that CH3-Ni-MOF-74 possesses optimal CH4 selectivity and adsorption performance. Given the current lack of research on functionalized MOF-74 for the separation of CH4 and N2, the findings of this study will serve as a theoretical guide and provide references for the applications of CH4 adsorption and CH4/N2 separation.