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A simple method that doubles learning speed for mice in touchscreen-based visual discrimination
Evaluation of dihydropyranocoumarins as potent inhibitors against triple-negative breast cancer: An integrated of in silico, quantum & molecular modeling approaches
Triple-negative breast cancer (TNBC) characterizes one of the most antagonistic subtypes of breast hostilities, due to lacking targeted and potential therapies. In this study, it is investigated and performed an integrative in silico investigation into the pharmacological potential of a series of dihydropyranocoumarins (Visnadine (L01), Pteryxin (L02), Isosamidin (L03), and Suksdorfin (L04)) as forthcoming TNBC therapeutics. A many-sided computational workflow was employed encompassing quantum chemical calculations, drug-likeness profiling, in silico, molecular docking, and molecular dynamics (MD) simulations. First of all, all ligands were sourced from the PubChem database and performed the geometry optimization with calculating the quantum descriptors using Density Functional Theory (DFT) via the DMol³ module in BIOVIA Materials Studio, applying the B3LYP functional and DNP basis set. Frontier molecular orbital (FMO) analyses in terms of HOMO–LUMO energy gaps and associated global reactivity descriptors, were evaluated to ascertain electronic stability and reactivity trends. Subsequent, PASS prediction, drug-likeness and ADMET assessments, performed using way2drug, SwissADME and pkCSM platforms, revealed favorable pharmacokinetic profiles, with all candidates exhibiting high gastrointestinal absorption, acceptable aqueous solubility, and minimal cytochrome P450 inhibition. Next, Target-based molecular docking against key TNBC-related proteins (PDB IDs: 5HA9 and 7L1X) was conducted using AutoDock Vina within PyRx. These complexes were further validated through 100-ns all-atom MD simulations using Desmond software under the AMBER14 force field, demonstrating stable RMSD values and compact, persistent protein–ligand interactions throughout the simulation period. For resulting, to begin with, PASS prediction suggested high probabilities for antineoplastic activity, substantiating their biological relevance, and initially, it was revealed that the ligands showed the anti-cancer properties. Next, despite predicted hepatotoxicity, the compounds showed no AMES mutagenicity or genotoxicity, indicating an acceptable safety profile. Overall, dihydropyranocoumarins, especially L03, emerge as promising TNBC leads. Docking analysis revealed strong binding affinities across the ligand set, with Isosamidin (L03) showing the most pronounced interaction (−9.1 kcal/mol), primarily mediated through hydrogen bonding and π-stacking interactions within the active sites. On based on quantum calculation, among the derivatives, L01 exhibited the highest chemical stability, while L04 showed greater electrophilic reactivity, as reflected in the MEP surface and charge distribution profiles. Lastly, the MD indicates indicative of strong conformational stability under physiological conditions of docked complex by RMSD, RMSF, SASA, H bonding and interactions. However, these in silico studies and computational approaches warrant to the future scope for experimental validation through in-vitro assays such as MTT cytotoxicity, apoptosis induction, and cell migration studies to confirm the anti-TNBC potential of these compounds.
Multi-criteria decision making approach for solar energy implementation using N-cubic fuzzy interaction aggregation operators
Correction: Navigating groundlessness: An interview study on dealing with ontological shock and existential distress following psychedelic experiences
Parameters estimation of stochastic finite fault ground motion simulation method and its application in North China
The stochastic finite-fault method based on dynamic corner frequency has been widely applied to simulate high-frequency ground motion of near-fault field. The model input parameters include source term, path term and site condition, many of which exhibit strong regional properties and are particularly sensitive to the site. Based on strong-motion stations drilling data and recordings within North China, some region-specific key parameters including local site amplification and high-frequency decay factor kappa are examined and analyzed. The local amplification function over versus frequency for class II and III site are computed using the quarter-wavelength approximation. The kappa in North China Plain and Mountain regions are calculated by employing the spectral decay method, respectively. In addition, the calibration of stress drop is achieved by adopting the trial-and-error method, which can be also applicable to the determination of other uncertain model parameters. After input parameters are determined and model bias is evaluated, we applied the region-specific parameters in North China to simulate and analyze time history, peak ground acceleration, Fourier amplitude spectrum, acceleration response spectrum, ShakeMap of PGA for the Dezhou earthquake. Overall, the simulated results coincide well with observed recordings. The validation of region-specific parameters demonstrates that they could be applied to the synthetic high-frequency ground motions in North China.
Relationship between saturation and contrast during internal limiting membrane peeling in 3D digital vitreoretinal surgery: A retrospective study
This retrospective comparative study aimed to investigate the relationship between saturation and contrast when using Brilliant Blue G (BBG) staining in internal limiting membrane (ILM) peeling during vitreoretinal surgery using the NGENUITY® 3D Visual System (NGENUITY), a three-dimensional digital monitor. Participants were individuals undergoing vitreoretinal surgeries involving ILM peeling with BBG staining, performed by the same surgeon at Juntendo University Urayasu Hospital, from October 2022 to June 2023, using the NGENUITY system. After ILM peeling, the contrast ratio between the ILM-peeled area and stained area was calculated using normal color tone (Normal group) and color tone set to yellow, with saturation set to 0 (Monochrome-0 group) or 20 (Monochrome-20 group). The visibility of retinal hemorrhage was also examined. The findings were compared among the groups. The contrast ratios of surgical screens with different color settings were used as the main outcome measure. We included 27 patients (27 eyes; 16 female individuals; age: 68.9 ± 9.8 years). The contrast ratios were 1.62 ± 0.15, 2.05 ± 0.44, and 2.00 ± 0.51 in the Normal, Monochrome-0, and Monochrome-20 groups, respectively. The contrast ratios were significantly higher in the Monochrome-0 and Monochrome-20 groups than in the Normal group (both p < 0.01), whereas these ratios were similar in the Monochrome-0 and Monochrome-20 groups (p = 0.554). Although distinguishing retinal hemorrhage was difficult in the Monochrome-0 group, this distinction was possible in the Monochrome-20 group. In BBG staining of the ILM, using the monochromatic mode with the NGENUITY system improves contrast visibility; however, using slight saturation facilitates distinction of retinal hemorrhage and allows safe ILM peeling.
Participants reporting greater desire to have children demonstrate weaker preferences for younger adult faces
The tendency for men to find younger adult women more attractive has been hypothesised to reflect preferences for cues of reproductive potential. To further test this hypothesis, we investigated the possible relationship between heterosexual men and women’s reported desire to have children and their preferences for cues of youth in face images of potential mates. Contrary to our expectation that reported desire to have children would be correlated with stronger preferences for younger adult faces, and that this pattern of results would be particularly pronounced when men judged women’s attractiveness, both men and women who reported greater desire to have children actually demonstrated weaker preferences for the faces of younger potential mates. Follow-up work suggested that this pattern of results was unlikely to have occurred because individuals with older faces were perceived as more likely to be better parents (Study 2) or wealthier (Study 3). While the role of individual differences in desire to have children in preferences for facial cues of age remains somewhat unclear, our results show no evidence for the widely held view that strong reliable sex differences exist in preferences for cues of youth.
Genetic evaluation of growth rate and efficiency-related traits in Menz sheep
Growth efficiency traits are economically important and their genetic improvement is essential in small ruminants, particularly under conditions of limited feed availability. Data on body weights of Menz sheep collected from 2009 through 2023 in Menz sheep community-based breeding programs (CBBPs) were used to estimate genetic parameters for six months weight (WT6), average daily gain from birth to weaning (ADG1), average daily gain from weaning to six months (ADG2), and average daily gain from six months to yearling (ADG3), and corresponding kleiber ratios (KR1, KR2, KR3), efficiency of growth (GE1, GE2, GE3), and relative growth rate (RGR1, RGR2, RGR3). Least-squares analysis was performed using the PROC GLM procedure in SAS 9.4. (Co)variance components and corresponding genetic parameters were estimated using the Average Information Restricted Maximum Likelihood (AI-REML) method in WOMBAT software by fitting six univariate animal models that incorporated various combination of direct additive, maternal genetic, and permanent environmental effects. The year of birth, season and villages of CBBP contributed significantly (P < 0.001) to the variation of all the considered traits. The model with direct additive genetic effect alone provided the best fit for all traits except WT6 and ADG1, for which the model including direct and maternal genetic effects performed best. Direct heritability estimates (h 2 a ) were 0.46 ± 0.02, 0.44 ± 0.02, 0.35 ± 0.02, 0.21 ± 0.02, 0.38 ± 0.02, 0.36 ± 0.02, 0.23 ± 0.02, 0.39 ± 0.02, 0.39 ± 0.02, 0.48 ± 0.03, 0.36 ± 0.02, 0.42 ± 0.02, and 0.47 ± 0.03 for WT6, ADG1, ADG2, ADG3, KR1, KR2, KR3, GE1, GE2, GE3, RGR1, RGR2, and RGR3, respectively. Maternal heritability (h 2 m ) for WT6 and ADG1 was 0.02 ± 0.01 and 0.02 ± 0.01. Moderate to high direct heritability estimates for the studied traits revealed that direct selection would be yield significant genetic progress. Genetic correlation estimates between the traits raged from −0.66 for ADG1-RGR2 and KR1-RGR2 to 0.98 for KR2-RGR2. Traits measured within the same growth period showed strong positive genetic and phenotypic correlations. Since Menz sheep are raised under harsh environmental conditions, incorporating efficiency related traits into the selection program can enhance the overall efficiency of the breeding program. Selection for WT6 would be more effective and increase efficiency-related traits due to their positive genetic correlations.
SELEX-HTCFQ Platform: Developing DNA Enhancers of ADAR1 to Suppress ZBP1-Dependent Immunopathology
Comparison of Atezolizumab plus Aevacizumab and Atezolizumab plus Aabozantinib for advanced hepatocellular carcinoma: A cost-effectiveness analysis
Background Atezolizumab combined with either bevacizumab (atezo-beva) or cabozantinib (atezo-cabo) has been granted approval for the treatment of advanced hepatocellular carcinoma (HCC). Given the current uncertainty among physicians and patients regarding the optimal choice between these two strategies, it becomes imperative to conduct a cost-effectiveness analysis to compare their relative benefits. Objective Assessing the cost-effectiveness of atezo-beva compared to atezo-cabo in the treatment of advanced HCC. Methods Both the network treatment comparison and cost-effectiveness analysis included patients from the IMbrave150 and the COSMIC-312 phase 3 randomized clinical trials. The network treatment comparison which included 761 patients was carried out, and a cost-effectiveness analysis that included 487 patients was conducted by developing a Markov model, both between February and November 2020. The robustness of the model was assessed via one-way and probabilistic sensitivity analyses. life-years, quality-adjusted life-years (QALYs), overall costs, and incremental cost-effectiveness ratios (ICERs) were measured. Results Compared with the atezo-cabo group, atezo-beva group respectively increased 0.528 life years and 0.365 QALYs, with costs per patient increasing by $506,639, and the ICER was $1,388,052.054 per QALY. The one-way sensitivity analysis results indicated that the hazard ratios of OS and HR of PFS were the most sensitive factors in the model. In probabilistic sensitivity analysis, when the WTP threshold is $150,000 per QALY, the cost-effectiveness probabilities of the atezo-beva group and atezo-cabo group were 7.09% and 92.91% respectively. Conclusions Findings from this cost-effectiveness analysis suggested that, compared to atezo-cabo, atezo-beva brought better OS benefits to advanced HCC patients, but also brought higher economic burden, considering the willingness-to-pay threshold was $150 000 per QALY, atezo-beva was not considered cost-effective.
The emergence of nitrification during DOM processing by marine microbial assemblages
Dissolved organic matter (DOM) production, its degradation, and nitrification, are crucial interconnected processes in the ocean. Nitrate produced by nitrification supports oceanic primary production. Primary production is the main source of DOM which, when remineralised by heterotrophic bacteria, liberates ammonium, the substrate supporting activities of nitrifying bacteria and archaea. However, the mechanisms underpinning the interplay between these processes, their succession and feedback, remain poorly understood. To elucidate these dynamics, we conducted two distinct DOM degradation experiments where natural marine microbial communities were exposed to microalgal-derived DOM. After 150 d of DOM degradation, we observed a strong consumption of ammonium and an increase in nitrate concomitantly with increased presence of nitrifying prokaryotes. The time course of this event suggests that, when ammonium is not limiting, nitrification in the oceans is regulated by competition between nitrifiers and heterotrophic bacteria with growth of the latter being more efficient when sufficient labile DOM is available. However, carbon limitation due to progressive consumption of labile DOM and enrichment of recalcitrant compounds transfers competitive advantage to nitrifiers, in this way contributing to the emergence of nitrification. This hypothesis is supported by numerical simulations showing an increasing dominance of nitrifying groups concomitantly with increasing DOM recalcitrance.
Skeletal Editing by Tip-Induced Chemistry
A bioavailable 87Sr/86Sr isoscape of Mongolia: Implications for the reconstruction of past human and animal mobility
Understanding past human and animal mobility is essential for reconstructing the social and cultural dynamics of ancient societies. Strontium isotope analysis ( 87 Sr/ 86 Sr) offers a powerful tool to investigate provenance and movement. The bioavailable 87 Sr/ 86 Sr follows the underlying lithology, and increasing efforts have been made to map its spatial distribution across the landscape and produce 87 Sr/ 86 Sr isoscapes at local and more global scales. Mongolia’s steppe landscapes have long supported highly mobile pastoralist societies whose movements were central to the formation of major polities, including Late Bronze Age cultures, Xiongnu first nomadic state and Mongol Empire. Despite the growing use of 87 Sr/ 86 Sr isotopic analysis to investigate past mobility, the lack of a robust 87 Sr/ 86 Sr baseline has hindered large-scale interpretations. Here, we generated a regionally-calibrated bioavailable 87 Sr/ 86 Sr isoscape for Mongolia by analysing modern plants collected at 534 sites, mostly from Arkhangai, central Mongolia. We used two machine learning approaches: the random forest regression (RF) and the ensemble machine learning (EML). Both methods produced comparable isoscapes with RF slightly outperforming EML. Three major regions have been identified, reflecting the complex geology of Mongolia: a western intermediate-to-high 87 Sr/ 86 Sr region (0.710–0.722), a central low 87 Sr/ 86 Sr region (0.707–0.711), and an eastern intermediate 87 Sr/ 86 Sr region (0.709–0.712). Comparison of archaeological 87 Sr/ 86 Sr data from 25 sites across Mongolia from the Late Bronze Age to the Medieval period with local isoscape predictions suggest that human, animal and plant samples are mainly of local origins for most of the sites, regardless of the period. This isoscape provides a strong baseline in Mongolia and not only enhances archaeological interpretations of past mobility but also holds significant potential for ecological monitoring and the authentication of regional products, such as cashmere.
Dual Catalytic Enantioconvergent Carbamoylation of Aziridines
Correction: Based on PCA and SSA-LightGBM oil-immersed transformer fault diagnosis method
Human Substance P Interactions with G Protein-Coupled Receptor NK1R Observed by NMR in Solution
Evogliptin prevents ceramide-induced pyroptosis during calcification via modulation of NLRP3/GSDM-D mediated pathway in Vascular Smooth Muscle Cells
Evogliptin, an anti-diabetic drug had positive impact on various cardiovascular events including inflammation and vascular calcification (VC), an active process driven by vascular smooth muscle cell (VSMC) phenotypic transition. Sphingolipids such as ceramide (CER) mediates inflammation and VC in the vascular tissue. We investigated whether evogliptin ameliorate phenotypic transition and pyroptosis in VSMCs as underlying cause of VC. In cultured VSMCs, isolated from the aorta of (C57/BL6) mouse, we observed more severe calcification with prior treatment of CER in P i -treated VSMCs as detected by Alizarin Red Staining. Prior CER- stimulation led to a marked upregulation of osteogenic markers such as RUNX2, OPN, BMP2 and decreased contractile markers SM22-α and α- SMA in P i -treated VSMCs as compared to control cells. In addition, increased expression of pyroptotic markers such as NLRP3, GSDM-D, IL-1 β , IL-18, and LDH release was observed with prior treatment of CER in P i -treated VSMCs as compared to control cells. Furthermore, MCC950 (NLRP3 inhibitor), disulfiram (GSDM-D inhibitor) and evogliptin significantly downregulated osteogenic and pyroptotic markers including LDH release in both P i ‐induced only and CER + P i -treated VSMCs. Moreover, GW4869 (SMase inhibitor) and evogliptin significantly reduced SMase activity in sphingomyelin (SM)-induced VSMCs as compared to both P i and SM only-treated groups. Also, the cleavage efficiency of GSDM-D was high in P i and CER + P i groups which was reduced with prior treatment of evogliptin. Hence, our data demonstrate that evogliptin alleviates VC by blocking phenotypic transition and associated pyroptosis via modulation of NLRP3/GSDM-D mediated pathway in CER-induced VSMCs.
Kinetics and Mechanism of Enantioselective Cu-Catalyzed Alcohol Silylation
Phonemic composition influences words’ aesthetic appeal and memorability
Positive emotional responses from pleasant experiences are known to enhance memory, yet the relationship between aesthetic appeal and linguistic memory remains understudied. To investigate this relationship, we designed pseudowords of varying appeal based on Crystal’s [1] phoneme rankings. Native English-speaking participants actively memorized these pseudowords and completed a free recall test, followed by two rounds of appeal ratings. Our results showed that, contrary to our predictions, pseudowords designed to be of intermediate appeal were rated as more appealing than those designed to be highly appealing or unappealing. Nevertheless, pseudowords designed to be highly appealing were recalled most frequently – even though participants themselves did not rate them as highly appealing. Also, overall, recalled words received higher appeal ratings from participants than non-recalled ones. These findings suggest that the phonemic and phonotactic composition of words may, indeed, have aesthetic value that correlates with words’ memorability. This encourages further exploration into how appeal interacts with other factors influencing linguistic cognition, including occurrence frequency or complexity. Our findings can inform applications in language learning, teaching, and marketing, while also offering theoretical contributions to our understanding of language evolution and change.