In this paper, a memetic algorithm with competition ( MAC ) is proposed to solve the capacitated green vehicle routing problem ( CGVRP ). Firstly, the permutation array called ...traveling salesman problem ( TSP ) route is used to encode the solution, and an effective decoding method to construct the CGVRP route is presented accordingly. Secondly, the k-nearest neighbor ( kNN ) based initialization is presented to take use of the location information of the customers. Thirdly, according to the characteristics of the CGVRP, the search operators in the variable neighborhood search ( VNS ) framework and the simulated annealing ( SA ) strategy are executed on the TSP route for all solutions. Moreover, the customer adjustment operator and the alternative fuel station ( AFS ) adjustment operator on the CGVRP route are executed for the elite solutions after competition. In addition, the crossover operator is employed to share information among different solutions. The effect of parameter setting is investigated using the Taguchi method of design-of-experiment to suggest suitable values. Via numerical tests, it demonstrates the effectiveness of both the competitive search and the decoding method. Moreover, extensive comparative results show that the proposed algorithm is more effective and efficient than the existing methods in solving the CGVRP.
Abstract
With great interest, we have read the recent article “Age at menarche, age at natural menopause, and risk of rheumatoid arthritis — a Mendelian randomization study” by Zhu et al. While we ...have a great appreciation for the work conducted by the authors, there are some methodological issues that need to be reconsidered. First, the gender description of the sample for age at first birth in this study is wrong according to the original genome-wide association study. Second, the study exploited sex-specific SNPs for age at menarche (AAM) and age at natural menopause (ANM) but sex-combined effects of the SNPs on rheumatoid arthritis (RA) that possibly lead no evidence for the causation of AAM and ANM on RA. We suggested the author add the possible biases due to the issue in the limitations. With problems mentioned above, we recommend solutions to make this article more perfect.
Increasing evidence shows that systemic inflammation is an embedded mechanism of proliferative diabetic retinopathy (PDR). However, the specific systemic inflammatory factors involved in this process ...remained obscure. The study aimed to identify the upstream and downstream systemic regulators of PDR by using Mendelian randomization (MR) analyses.
We performed a bidirectional two-sample MR analysis implementing the results from genome-wide association studies for 41 serum cytokines from 8,293 Finnish individuals, and PDR from FinnGen consortium (2,025 cases vs. 284,826 controls) and eight cohorts of European ancestry (398 cases vs. 2,848 controls), respectively. The inverse-variance-weighted method was adopted as the main MR method, and four additional MR methods (MR-Egger, weighted-median, MR-pleiotropy residual sum and outlier (MR-PRESSO), and MR-Steiger filtering methods) were used for the sensitivity analyses. Results from FinnGen and eight cohorts were pooled into a meta-analysis.
Our results showed that genetically predicted higher stem cell growth factor-β (SCGFb) and interleukin-8 were positively associated with an elevated risk of PDR, with a combined effect of one standard deviation (SD) increase in SCGFb and interleukin-8 causing 11.8% 95% confidence interval (CI): 0.6%, 24.2%) and 21.4% 95% CI: 3.8%, 41.9%) higher risk of PDR, respectively. In contrast, genetically predisposition to PDR showed a positive association with the increased levels of growth-regulated oncogene-α (GROa), stromal cell-derived factor-1 alpha (SDF1a), monocyte chemotactic protein-3 (MCP3), granulocyte colony-stimulating factor (GCSF), interleukin-12p70, and interleukin-2 receptor subunit alpha (IL-2ra).
Our MR study identified two upstream regulators and six downstream effectors of PDR, providing opportunities for new therapeutic exploitation of PDR onset. Nonetheless, these nominal associations of systemic inflammatory regulators and PDR require validation in larger cohorts.
Inorganic CsPbX3 (X = Cl, Br, I, or hybrid among them) perovskite quantum dots (IPQDs) are promising building blocks for exploring high performance optoelectronic applications. In this work, the ...authors report a new hybrid structure that marries CsPbX3 IPQDs to silicon nanowires (SiNWs) radial junction structures to achieve ultrafast and highly sensitive ultraviolet (UV) detection in solar‐blind spectrum. A compact and uniform deployment of CsPbX3 IPQDs upon the sidewall of low‐reflective 3D radial junctions enables a strong light field excitation and efficient down‐conversion of the ultraviolet incidences, which are directly tailored into emission bands optimized for a rapid photodetection in surrounding ultrathin radial p‐i‐n junctions. A fast solar‐blind UV detection has been demonstrated in this hybrid IPQD‐NW detectors, with rise/fall response time scales of 0.48/1.03 ms and a high responsivity of 54 mA W−1@200 nm (or 32 mA W−1@270 nm), without the need of any external power supply. These results pave the way toward large area manufacturing of high performance Si‐based perovskite UV detectors in a scalable and low‐cost procedure.
Ultrafast solar‐blind ultraviolet (UV) detection is enabled by a hybrid inorganic perovskite CsPbX3‐quantum‐dot radial junction architecture, achieving a fast solar‐blind UV detection with rise/fall response times of 0.48/1.03 ms and a high responsivity of 54 mA W−1@200 nm, without the need of an external power supply. These results pave the way toward large‐area manufacturing of high‐performance Si‐based perovskite UV detectors in a low‐cost procedure.
Background Multiple myeloma (MM) is a severely debilitating and fatal B-cell neoplastic disease. The discovery of disease-associated proteins with causal genetic evidence offers a chance to uncover ...novel therapeutic targets. Methods First, we comprehensively investigated the causal association between 2994 proteins and MM through two-sample mendelian randomization (MR) analysis using summary-level data from public genome-wide association studies of plasma proteome (N = 3301 healthy individuals) and MM (598 cases and 180,756 controls). Sensitivity analyses were performed for these identified causal proteins. Furthermore, we pursued the exploration of enriched biological pathways, prioritized the therapeutic proteins, and evaluated their druggability using the KEGG pathway analysis, MR-Bayesian model averaging analysis, and cross-reference with current databases, respectively. Results We identified 13 proteins causally associated with MM risk (false discovery rate corrected P < 0.05). Six proteins were positively associated with the risk of MM, including nicotinamide phosphoribosyl transferase (NAMPT; OR 95% CI: 1.35 1.18, 1.55), tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1; 1.14 1.06, 1.22), neutrophil cytosol factor 2 (NCF2; 1.27 1.12, 1.44), carbonyl reductase 1, cAMP-specific 3',5'-cyclic phosphodiesterase 4D (PDE4D), platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B2). Seven proteins were inversely associated with MM, which referred to suppressor of cytokine signaling 3 (SOCS3; 0.90 0.86, 0.94), Fc-gamma receptor III-B (FCGR3B; 0.75 0.65,0.86), glypican-1 (GPC1; 0.69 0.58,0.83), follistatin-related protein 1, protein tyrosine phosphatase non-receptor type 4 (PTPN4), granzyme B, complement C1q subcomponent subunit C (C1QC). Three of the causal proteins, SOCS3, FCGR3B, and NCF2, were enriched in the osteoclast differentiation pathway in KEGG enrichment analyses while GPC1 (marginal inclusion probability (MIP):0.993; model averaged causal effects (MACE): - 0.349), NAMPT (MIP:0.433; MACE: - 0.113), and NCF2 (MIP:0.324; MACE:0.066) ranked among the top three MM-associated proteins according to MR-BMA analyses. Furthermore, therapeutics targeting four proteins are currently under evaluation, five are druggable and four are future breakthrough points. Conclusions Our analysis revealed a set of 13 novel proteins, including six risk and seven protective proteins, causally linked to MM risk. The discovery of these MM-associated proteins opens up the possibility for identifying novel therapeutic targets, further advancing the integration of genome and proteome data for drug development. Keywords: Plasma proteome, Multiple myeloma, Drug target, Bayesian model, Mendelian randomization, Enrichment pathway analysis
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dyslipidemia has long been implicated in elevating mortality risk; yet, the precise associations between lipid traits and mortality remained undisclosed. Our study aimed to explore the causal effects ...of lipid traits on both all-cause and cause-specific mortality. One-sample Mendelian randomization (MR) with linear and nonlinear assumptions was conducted in a cohort of 407,951 European participants from the UK Biobank. Six lipid traits, consisting of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein(a), were included to investigate the causal associations with mortality. Two-sample MR was performed to replicate the association between each lipid trait and all-cause mortality. Univariable MR results showed that genetically predicted higher ApoA1 was significantly associated with a decreased all-cause mortality risk (HR95% CI:0.93 0.89–0.97, P value = 0.001), which was validated by the two-sample MR analysis. Higher lipoprotein(a) was associated with an increased risk of all-cause mortality (1.03 1.01–1.04, P value = 0.002). Multivariable MR confirmed the direct causal effects of ApoA1 and lipoprotein(a) on all-cause mortality. Meanwhile, nonlinear MR found no evidence for nonlinearity between lipids and all-cause mortality. Our examination into cause-specific mortality revealed a suggestive inverse association between ApoA1 and cancer mortality, a significant positive association between lipoprotein(a) and cardiovascular disease mortality, and a suggestive positive association between lipoprotein(a) and digestive disease mortality. High LDL-C was associated with an increased risk of cardiovascular disease mortality but a decreased risk of neurodegenerative disease mortality. The findings suggest that implementing interventions to raise ApoA1 and decrease lipoprotein(a) levels may improve overall health outcomes and mitigate cancer and digestive disease mortality.
Hearing is an extremely delicate sense that is particularly vulnerable to insults from environment, including drugs and noise. Unsurprisingly, mice of different genetic backgrounds show different ...susceptibility to hearing loss. In particular, CBA/CaJ (CBA) mice maintain relatively stable hearing over age while C57BL/6J (B6) mice show a steady decline of hearing, making them a popular model for early onset hearing loss. To reveal possible underlying mechanisms, we examined cellular differences in the cochlea of these two mouse strains. Although the ABR threshold and Wave I latency are comparable between them, B6 mice have a smaller Wave I amplitude. This difference is probably due to fewer spiral ganglion neurons found in B6 mice, as the number of ribbon synapses per inner hair cell (IHC) is comparable between the two mouse strains. Next, we compared the outer hair cell (OHC) function and we found OHCs from B6 mice are larger in size but the prestin density is similar among them, consistent with the finding that they share similar hearing thresholds. Lastly, we examined the IHC function and we found IHCs from B6 mice have a larger Ca
current, release more synaptic vesicles and recycle synaptic vesicles more quickly. Taken together, our results suggest that excessive exocytosis from IHCs in B6 mice may raise the probability of glutamate toxicity in ribbon synapses, which could accumulate over time and eventually lead to early onset hearing loss.
Observational studies have suggested that women's reproductive factors (age at menarche (AAM), age at first birth (AFB), age at first sexual intercourse (AFS), age at natural menopause (ANM), and ...pregnancy loss) may influence the risk of cerebral small-vessel disease (CSVD) although the causality remains unclear.
We conducted two-sample univariable Mendelian randomization (UVMR) and multivariable MR (MVMR) to simultaneously investigate the causal relationships between five women's reproductive traits and CSVD clinical intracerebral hemorrhage (ICH) by location or small-vessel ischemic stroke (SVS) and subclinical measures white matter hyperintensities (WMH), fractional anisotropy (FA), and mean diffusivity (MD), utilizing data from large-scale genome-wide association studies of European ancestry. For both UVMR and MVMR, the inverse-variance-weighted (IVW) estimates were reported as the main results. The MR-Egger, weighted median, generalized summary-data-based MR (GSMR), and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods for UVMR and MVMR-Egger, and the MVMR-robust methods for MVMR were used as sensitivity analyses. Sex-combined instruments for AFS and AFB were used to assess the impact of sex instrumental heterogeneity. Positive control analysis was implemented to measure the efficacy of selected genetic instruments.
We found no evidence to support causal associations between genetic liability for women's reproductive factors and the risk of CSVD in UVMR (all
-values > 0.05). Using MVMR, the results were consistent with the findings of UVMR after accounting for body mass index and educational attainment (all
-values > 0.05). Sensitivity analyses also provided consistent results. The putative positive causality was observed between AAM, ANM, and ovarian cancer, ensuring the efficacy of selected genetic instruments.
Our findings do not convincingly support a causal effect of women's reproductive factors on CSVD. Future studies are warranted to investigate specific estrogen-related physiological changes in women, which may inform current researchers on the causal mechanisms involved in cerebral small-vessel disease progression.
Abstract
The laws and regulations in human history can be revealed by computational models. From 221 before Christ (BC) to 1912 Anno Domini (AD), the unification pattern has dominated the main part ...of Chinese history for 2132 years. Before the emergence of the first unified empire, the Qin Empire in 221 BC, there existed the Eastern Zhou dynasty (770 BC to 221 BC). This long dynasty has two stages, and here we focus on the first stage. This Spring–Autumn stage was from 770 BC (with 148 states) to 476 BC (with 32 states). The whole country (China) is modelled as a multi‐agent system, which contains multiple local states. They behave autonomously under certain action rules (wars and conflicts), which forms the main reason for the annexations and disappearance of most states. Key factors (power, loyalty, bellicosity and alliance) have been considered in our model settings, and simulation outcomes will be monitored and collected. Eventually, an optimal solution is obtained, which well unveils the internal mechanism and statistical features of real big history. Furthermore, counterfactuals are used to explore the non‐linear effects of the key factors, which deepens the authors’ understanding of civilisation evolutions in human history.
In flowering plants, RNA editing is a post-transcriptional process that selectively deaminates cytidines (C) to uridines (U) in organellar transcripts. Pentatricopeptide repeat (PPR) proteins have ...been identified as site-specific recognition factors for RNA editing. Here, we report the map-based cloning and molecular characterization of the defective kernel mutant
in maize. Loss of
function leads to delayed embryogenesis and endosperm development, which produce small and collapsed kernels.
encodes an E+-type PPR protein targeted to the mitochondria, which is required for RNA editing of mitochondrial NADH dehydrogenase 3 at the
-317 and
-44 sites. Biochemical analysis of mitochondrial protein complexes revealed a significant reduction in the mitochondrial NADH dehydrogenase complex I activity, indicating that the alteration of the amino acid sequence at
-44 and
-317 through RNA editing is essential for NAD3 function. Moreover, the amino acids are highly conserved in monocots and eudicots, whereas the events of C-to-U editing are not conserved in flowering plants. Thus, our results indicate that
is essential for RNA editing of
, which is critical for NAD3 function, mitochondrial complex I stability, and seed development in maize.