Browse Articles

Synthesis and antidiabetic evaluation of novel Tetrahydroacridine derivatives with computational insights

Abstract A new series of thirty-two tetrahydroacridine (THA) derivatives were rationally designed and synthesized via efficient multistep reactions involving nucleophilic aromatic substitution and Mannich condensation. The structural integrity and purity of the obtained compounds were confirmed by their spectroscopic techniques including 1 H-NMR, 13 C-NMR, mass spectroscopy and elemental analyses. The synthesized tetrahydroacridine (THA) derivatives were initially screened for antidiabetic potential through a glucose diffusion assay, where compound 4b (100 mg/kg) exhibited the highest inhibition rate (34.00%) at the lowest concentration tested, outperforming the reference drug Gliclazide. To deepen biological understanding, molecular docking studies were conducted against key diabetic targets: DPP-IV, SGLT1, and GLUT2. The docking results demonstrated that several compounds, particularly compound 4a , compound 5a , and compound 4c , achieved excellent binding affinities and interactions with critical active-site residues, showing potential as dual or triple inhibitors. ADMET and drug-likeness evaluations based on Lipinski’s rule of five and computational pharmacokinetic modeling indicated acceptable oral bioavailability, metabolic stability, and low toxicity for selected lead candidates. In-vivo studies were conducted in streptozotocin-induced diabetic Wistar rats over a 4-week period. Compounds 5b , 7a , and 8b (100 mg/kg) significantly decreased blood glucose level during fasting, approaching or surpassing the efficacy of Gliclazide. Compound 5b showed the most pronounced effect, lowering glucose to 180.5 ± 12.3 mg/dL by week 4. These integrated findings highlight the potential of tetrahydroacridine derivatives as promising scaffolds for the development of new antidiabetic candidates with multitarget activity, favorable drug-like properties and minimal toxicity risk. Further in-depth SAR, enzyme inhibition, and pharmacodynamic studies are warranted to advance these candidates toward clinical relevance.

Immunological and transcriptomic profile of chimeric live-attenuated Zika vaccine linked to protection in non-human primates

Synthesis of 2′-fucosyllactose using multi-enzyme cascade with cofactor regeneration

Parental socioeconomic composition of birth cohorts changed during the COVID-19 pandemic

Abstract The COVID-19 pandemic offers opportunities to study effects of in-utero and early life exposure to environmental changes. However, inferences from such studies may be flawed if the pandemic has changed the socioeconomic composition of parents. Analysing over 77.9 million live births from 15 countries, we estimate changes in the socioeconomic composition of the cohort born between December 2020 and December 2021 using interrupted time series analysis. We find that, compared with their counterfactual compositions, the December 2020-December 2021 birth cohort has a higher proportion of babies born to socioeconomically advantaged parents in Austria, England, Finland, the Netherlands, Scotland, Spain, Wales, and the United States while we observe the opposite change for Brazil, Colombia, Ecuador, and Mexico. These changes in cohort composition may cause between-cohort differences in life course outcomes that are influenced by parental socioeconomic circumstances even if early life exposure to the pandemic had no direct effect on this birth cohort.

Utilization of psychotherapy, pharmacotherapy, and their combination by individuals with current or residual depression: results from five annual nationally representative German surveys

Abstract Depression is a common and burdensome mental disorder affecting more than 320 million people worldwide. Clinical practice guidelines recommend psychotherapy, antidepressant pharmacotherapy, or their combination as the cornerstones of evidence-based treatment. Despite these well-established therapeutic options, a substantial proportion of individuals with depression remain untreated. In Germany, available estimates of the current treatment gap are outdated. The present study therefore aims to examine report the utilization of psychotherapy, antidepressant pharmacotherapy, or their combination among adults in Germany who self-reported a diagnosis of depression. In addition, we explore potential differences in treatment utilization according to sociodemographic characteristics, specifically sex and age. Between 2018 and 2022, annual population-representative surveys were conducted in Germany. A total of N  = 3,416 individuals who self-reported having been professionally diagnosed with depression at least once in their lifetime and who indicated current acute or residual symptoms were included in the present analysis. Overall, 63.4% of participants reported using at least one guideline-based treatment for their current depressive episode or residual symptoms. Specifically, 13.5% reported receiving psychotherapy, 26.5% pharmacotherapy, and 23.4% a combination of both. The likelihood of utilizing psychotherapy decreased with age ( 18–29 years: OR = 1.22 , 95% CI = 0.91–1.64; 60–69 years: OR = 0.36 , 95% CI = 0.24–0.52) , whereas the likelihood of pharmacotherapy use increased with age ( 18–29 years: OR = 0 . 74 , 95% CI = 0.54–1.01; 60–69 years: OR = 2 . 46 , 95% CI = 1.89–3.23) . Although self-reported utilization of guideline-based treatment for depression was higher than previously reported, depression in adulthood likely remains undertreated. These findings highlight the need to strengthen access to evidence-based interventions and to promote long-term treatment adherence and self-management strategies.

Photothermal skyrmion tweezer: programmable optical manipulation of magnetic topological quasiparticles

Predictors of anemia among lactating women in ethiopia: Using 2016 EDHS; application of ordinal logistic regression model

Norepinephrine-mediated arousal fluctuations drive inverted U-shaped functional connectivity dynamics

Efferent control of hair cells mechanically coupled by artificial membranes

Abstract The efferent system has been proposed to play a vital function in auditory and vestibular systems, by protecting the sensory hair cells from injury and preserving signal detection sensitivity. We report that the activation of efferents has strong modulatory effects on systems of coupled hair cell bundles. In this study, we use direct electrical stimulation of efferent neurons to probe its effects on the hair cells’ internal dynamics, by means of optically tracking the hair bundle motility. In vivo , hair bundles of auditory and vestibular epithelia are connected via overlying membranes; to address this physiological characteristic, we investigate the impact of efferent activity on the collective response of coupled hair bundles. We use a preparation from the American bullfrog sacculus which preserves the active motility of hair bundles, and achieve inter-cell coupling by connecting the cells to artificial mica structures. We found that efferent stimulation impacts hair-bundle dynamics, affecting the amplitude, frequency, and temporal profile of spontaneous oscillations, and altering the dynamical state of the system. Furthermore, efferent activation decreased synchronization among coupled hair bundles, suggesting a mechanism by which neural modulation may reduce the overall sensitivity of the system.

Pressure and bias dependence of the rate-limiting steps of the oxygen reduction reaction

Abstract The oxygen reduction reaction limits the energy efficiency of H 2 fuel cells and Li-air batteries, yet, it remains poorly understood within popular kinetic frameworks. Here, we study the oxygen reduction reaction on Pt/C, Ir/C, Ru/C and Rh/C nanoparticles as a function of electrochemical bias, temperature and O 2 pressure at industrially-relevant conditions in membrane electrode assemblies. Bias-, and pressure-dependent Arrhenius analysis reveals distinct changes in the (apparent) activation energy and pre-exponential factor that we relate to kinetics that cascade through a series of rate-limiting steps and transition states. Further, while the kinetics are accelerated by the pressure and bias, they remain pinned to pseudo-capacitive reduction processes and structural changes at the water-solid interface. Collectively, our study informs on how the free energy driving force and pressure tune the degree of rate control of rate-limiting steps and transition states of (electro)catalytic multi-step reactions and how this is related to structural and chemical changes at the interface. This is at the very heart of catalysis.

Intraoperative 3D reconstruction from sparse arbitrarily posed real X-rays

Experimental determination of structural motifs of interference-free water undecamer cluster (H2O)11

Pharmacokinetic and bioequivalence of two formulations of Valsartan/Amlodipine Tablet(I) in healthy Chinese volunteers: A randomized, three-period, partially replicated crossover study

Abstract Valsartan/amlodipine combination tablets can exert synergistic antihypertensive effects through different mechanisms, significantly lowering blood pressure while also addressing multiple risk factors and comorbidities in patients. This study designed a single-center, randomized, open-label, two-formulations, single-dose, three-cycle, three-sequence, partially repeated crossover controlled trial design. A total of 72 healthy Chinese volunteers participated in the fasting and fed trials, of whom 69 completed the trial process. This study employed a methodologically validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to determine the concentrations of valsartan and amlodipine in plasma. Phoenix WinNonlin software (version 7.0) was used to calculate pharmacokinetic parameters using a non-compartmental model. Equivalence analysis was performed using the average bioequivalence (ABE) method and the reference-scaled average bioequivalence (RSABE) method. The trial results showed that the test drug was bioequivalent to the reference drug, and no suspected serious adverse reactions or serious adverse events occurred throughout the trial. The results of this study support the launch of the new generic Valsartan/Amlodipine Tablet(I) in China. As a representative antihypertensive fixed-dose combination (FDC), these methodological insights can be directly applied to clinical trials of similar drug products, thereby enhancing success rates while mitigating development risks. Clinical trial registration : CTR20221889, ( http://www.chinadrugtrials.org.cn/clinicaltrials.searchlist.dhtml.28/07/2022 )

In-situ physical adjoint computing in multiple-scattering electromagnetic environments for wave control

Abstract Controlling electromagnetic wave propagation in multiple scattering systems is a challenging endeavor due to the extraordinary sensitivity generated by strong multi-path contributions at any given location. Overcoming such complexity has emerged as a central research theme in recent years, motivated both by a wide range of applications – from wireless communications and imaging to optical micromanipulations – and by the fundamental principles underlying these efforts. Here, we show that an in-situ manipulation of the myriad scattering events, achieved through time- and energy-efficient adjoint optimization (AO) methodologies, enables real time wave-driven functionalities such as targeted channel emission, coherent perfect absorption, and camouflage. Our paradigm shift exploits the highly multi-path nature of these complex environments, where repeated wave-scattering dramatically amplifies small local AO-informed system variations. Our approach can be immediately applied to in-door wireless technologies and incorporated into diverse wave-based frameworks including imaging, power electronic and optical neural networks.

Infants’ empathic concern responses moderate the association between maternal and child depressive symptoms

Reshaping reservoirs with unsupervised Hebbian adaptation

Abstract Reservoir Computing (RC) is a lightweight way to model time-dependent data, yet its reliance on static, randomly initialized network architectures often limits performance on challenging real-world problems. We introduce Hebbian Architecture Generation (HAG), an unsupervised rule that grows connections between neurons that frequently activate together–embodying the biological maxim “neurons that fire together wire together.” Starting from an almost empty reservoir, HAG progressively sculpts a task-specific wiring. Across a diverse set of classification and forecasting tasks, reservoirs reshaped by HAG are consistently more accurate than traditional Echo State Networks and reservoirs tuned with popular plasticity rules such as Intrinsic Plasticity or Anti-Oja learning. In other words, letting the network rewire itself from data turns a once-static RC model into a flexible, high-performance learner without a single gradient step. By coupling the efficiency of RC with the adaptability of Hebbian plasticity, HAG moves reservoir computing closer to its biological inspiration and shows that structural self-organization is a practical route to robust, task-aware processing of real-world time-series data.

Multi-task learning identifies shared genetic risk for late-onset epilepsy and alzheimer’s disease

Abstract Aging populations face increasing incidence of neurological disorders, including Alzheimer’s disease (AD) and late-onset epilepsy (LOE), which demonstrate a bidirectional relationship where AD is a risk factor for LOE and LOE is a risk factor for AD. While the APOE gene is a known shared risk factor, comprehensive genetic studies for LOE remain limited. This study employed a multi-task learning framework using Elastic Net modeling to systematically identify shared genetic risk factors between AD and LOE. We analyzed electronic health records from UCLA Health System ( N  = 416,212; genetic subset N  = 16,500) and validated findings in the All of Us dataset ( N  = 52,493). Longitudinal analyses confirmed strong bidirectional associations between AD and LOE. The multi-task learning approach identified eight shared-risk single nucleotide polymorphisms mapping to key genes including the APOE-TOMM40-APOC1 cluster, BIN1 , CLU , PVRL2 , and TRAPPC6A . These shared-risk genes were enriched in pathways related to lipid metabolism, amyloid catabolic processes, and tau protein binding. A shared genetic risk score effectively stratified patients into distinct AD-LOE risk groups. This study represents an initial systematic identification of potential shared genetic factors between AD and LOE using multi-task learning. While our findings suggest possible shared genetic contributions, particularly in the APOE region, and highlight tau-mediated mechanisms as potential therapeutic targets, further validation is needed to establish the extent of genetic overlap between these conditions.

Targeted CRISPR-Cas9 screening identifies core transcription factors controlling murine haemato-endothelial fate commitment

Abstract During development, blood generation begins in the yolk sac with the differentiation of haemato-endothelial mesoderm forming haematopoietic progenitors. This study aims to identify the crucial molecular regulators of haemato-endothelial mesoderm formation and to extend our knowledge of the process in an unbiased way. We employ a murine embryonic stem cell model that recapitulates embryonic blood development, and perform targeted CRISPR-Cas9 knock out screens focusing on transcription factors and chromatin regulators. We identify the transcription factors ETV2, LDB1, SMAD1, SIX4 and ZBTB7b as regulators of haemato-endothelial mesoderm commitment. Embryonic stem cells lacking these regulators give rise to mesodermal subsets with a defined lineage differentiation bias, while transcriptome analysis of these cells uncovers the precise impact of each factor on gene expression in the developing mesoderm. Our study reveals molecular pathways governing mesodermal development crucial to allow endothelial and haematopoietic lineage specification and paves the way for future advances in haematopoietic stem cell applications.

Phytochemical composition and biological activities of selected essential oils and their discrimination through principal component analysis

Metabolomic profiling, antioxidant activity, and skin cell viability of citrus peel flavonoids extracted via ultrasonic-assisted aqueous two-phase system

Citrus peels, often considered agricultural waste, are rich in flavonoids with potent antioxidant properties. This study utilized ultrasonic-assisted aqueous two-phase extraction (UA-ATPE) to obtain flavonoid-rich upper phase extracts (UPEs) from the peels of four citrus varieties sourced from different cultivars and regions. Targeted metabolomics was used to analyze the flavonoid compositions in the UPEs, revealing distinct metabolic profiles among the varieties. The antioxidant activities of the UPEs were evaluated through hydroxyl, superoxide, and ABTS radical scavenging assays, while their effects on skin cell viability were assessed using HaCaT and BJ cells. Multivariate statistical analyses, including principal component analysis (PCA) and hierarchical clustering analysis (HCA), identified six key differential metabolites (naringenin, p-coumaric acid, luteolin, butin, vitexin/isovitexin, and ferulic acid) that effectively distinguished the citrus varieties. Among the UPEs, Guangxi mandarin orange exhibited the highest total flavonoid content and the most potent superoxide anion and ABTS radical scavenging activities. However, Meizhou shatian pomelo demonstrated the strongest overall antioxidant capacity, as indicated by the lowest IC 50 values for the antioxidant potential composite (APC). Cell viability assays confirmed that none of the UPEs exhibited cytotoxicity at concentrations of 0.06--1.00% (v/v). These findings highlight significant varietal differences in flavonoid content and antioxidant activity, providing a scientific basis for the utilization of citrus peels in functional cosmetics and other industries.