Nab-paclitaxel plus S-1 versus nab-paclitaxel plus gemcitabine in patients with advanced pancreatic cancer: a multicenter, randomized, phase II study.

BACKGROUND: Encouraging antitumor activity of nab-paclitaxel plus S-1 (AS) has been shown in several small-scale studies. This study compared the efficacy and safety of AS versus standard-of-care nab-paclitaxel plus gemcitabine (AG) as a first-line treatment for advanced pancreatic cancer (PC). METHODS: In this multicenter, randomized, phase II trial, eligible patients with unresectable, locally advanced, or metastatic PC were recruited and randomly assigned (1:1) to receive AS (nab-paclitaxel 125 mg/m2 on days 1 and 8; S-1 twice daily on days 1 through 14) or AG (nab-paclitaxel 125 mg/m2 on days 1 and 8; gemcitabine 1000 mg/m2 on days 1 and 8) for 6 cycles. The primary endpoint was progression-free survival (PFS). RESULTS: Between July 16, 2019, and September 9, 2022, 62 patients (AS, n = 32; AG, n = 30) were treated and evaluated. With a median follow-up of 8.36 months at preplanned interim analysis (data cutoff, March 24, 2023), the median PFS (8.48 vs 4.47 months; hazard ratio [HR], 0.402; P = .002) and overall survival (OS; 13.73 vs 9.59 months; HR, 0.226; P < .001) in the AS group were significantly longer compared to the AG group. More patients had objective response in the AS group than AG group (37.50% vs 6.67%; P = .005). The most common grade 3-4 adverse events were neutropenia and leucopenia in both groups, and gamma glutamyl transferase increase was observed only in the AG group. CONCLUSION: The first-line AS regimen significantly extended both PFS and OS of Chinese patients with advanced PC when compared with the AG regimen, with a comparable safety profile. (ClinicalTrials.gov Identifier: NCT03636308).

The role of Foxo3a in neuron-mediated cognitive impairment.

Cognitive impairment (COI) is a prevalent complication across a spectrum of brain disorders, underpinned by intricate mechanisms yet to be fully elucidated. Neurons, the principal cell population of the nervous system, orchestrate cognitive processes and govern cognitive balance. Extensive inquiry has spotlighted the involvement of Foxo3a in COI. The regulatory cascade of Foxo3a transactivation implicates multiple downstream signaling pathways encompassing mitochondrial function, oxidative stress, autophagy, and apoptosis, collectively affecting neuronal activity. Notably, the expression and activity profile of neuronal Foxo3a are subject to modulation via various modalities, including methylation of promoter, phosphorylation and acetylation of protein. Furthermore, upstream pathways such as PI3K/AKT, the SIRT family, and diverse micro-RNAs intricately interface with Foxo3a, engendering alterations in neuronal function. Through several downstream routes, Foxo3a regulates neuronal dynamics, thereby modulating the onset or amelioration of COI in Alzheimer's disease, stroke, ischemic brain injury, Parkinson's disease, and traumatic brain injury. Foxo3a is a potential therapeutic cognitive target, and clinical drugs or multiple small molecules have been preliminarily shown to have cognitive-enhancing effects that indirectly affect Foxo3a. Particularly noteworthy are multiple randomized, controlled, placebo clinical trials illustrating the significant cognitive enhancement achievable through autophagy modulation. Here, we discussed the role of Foxo3a in neuron-mediated COI and common cognitively impaired diseases.

An Enhanced Indoor Three-Dimensional Localization System with Sensor Fusion Based on Ultra-Wideband Ranging and Dual Barometer Altimetry.

Accurate three-dimensional (3D) localization within indoor environments is crucial for enhancing item-based application services, yet current systems often struggle with localization accuracy and height estimation. This study introduces an advanced 3D localization system that integrates updated ultra-wideband (UWB) sensors and dual barometric pressure (BMP) sensors. Utilizing three fixed UWB anchors, the system employs geometric modeling and Kalman filtering for precise tag 3D spatial localization. Building on our previous research on indoor height measurement with dual BMP sensors, the proposed system demonstrates significant improvements in data processing speed and stability. Our enhancements include a new geometric localization model and an optimized Kalman filtering algorithm, which are validated by a high-precision motion capture system. The results show that the localization error is significantly reduced, with height accuracy of approximately ±0.05 m, and the Root Mean Square Error (RMSE) of the 3D localization system reaches 0.0740 m. The system offers expanded locatable space and faster data output rates, delivering reliable performance that supports advanced applications requiring detailed 3D indoor localization.

First report of pepper yellow leaf curl Thailand virus infecting hot chili in central Vietnam and Laos.

Hot chili pepper (Capsicum annuum) cultivation has been on the rise in South East Asia to meet export demands. In Thailand, the top chili exporter in South East Asia, chili production has been severely hampered by pepper yellow leaf curl disease (YLCD) caused by the begomovirus pepper yellow leaf curl Thailand virus (PepYLCThV) (Chiemsombat et al., 2018; Suwor et al., 2021). In the neighbouring countries of Laos and Vietnam, a limited survey of chili fields (200 plants in total) in Savannakhet (Savannakhet University campus, n = 150), Laos and Quang Nam province (Ka Dang commune, Dong Giang district, n = 50), central Vietnam in 2023 led to the finding of eight plants (5 in Laos and 3 in Vietnam) exhibiting YLCD-like symptoms, which included bright yellow color in young leaves and leaf curl and mosaic chlorosis in mature leaves (Fig. S1). Total DNA was extracted from leaves of two symptomatic plants (one from Savannakhet and one from Quang Nam) using a cetyltrimethylammonium bromide-based DNA extraction protocol (Doyle & Doyle, 1987; Nguyen et al., 2023). Next, PCR were performed using newly designed PepYLCThV-specific primers based on PepYLCThV sequences in GenBank (Table 1). PCR products of expected sizes were observed in samples with disease symptoms, but not from DNA extracted from C. annuum (cv. VA.99999) grown at the Institute of Biotechnology in Thua Thien Hue, Vietnam (Fig. S2). The amplicons were Sanger sequenced (Apical Scientific, Selangor, Malaysia) and the complete bipartite genome sequence of two isolates ('Sava01' from Laos and 'QNam01' from Vietnam) were obtained. The sequences of the DNA-A component from isolates 'Sava01' (GenBank PP437580) and 'QNam01' (GenBank PP437581) exhibited the highest sequence identity of 99.2% and 94.7% with the PepYLCThV isolate 'ChiangDaoS1' (GenBank OM677627), respectively (Table 2). Conversely, the sequences of the DNA-B component from the isolates 'Sava01' (GenBank PP437579) and 'QNam01' (GenBank PP437582) exhibited the highest similarity of 91.8% and 90.9% with the PepYLCThV isolate 'KKN601' (GenBank MW715820), respectively (Table 2). These results confirmed the presence of PepYLCThV in hot chili pepper plants exhibiting YLCD-like symptoms in central Vietnam and Laos. Infectious clones of PepYLCThV DNA-A and DNA-B (isolate 'QNam01') were created based on the pLX-AS vector as described by Pasin (2022), and transformed into Agrobacterium tumefaciens EHA105. The resulting bacteria were cultured in LB broth containing rifampicin (25 µg/mL) and kanamycin (50 µg/mL) at 28°C and used for agroinoculation of Nicotiana benthamiana (n = 6) and C. annuum (cv. VA.99999, n = 6) (4-6 leaf plants) as described by Pasin (2022). In all N. benthamiana plants, agroinoculation with both DNA-A and DNA-B infectious clones caused stunted growth, severe leaf curl, with yellow and white patches 21 days post inoculation (Fig. S3). In C. annuum plants, symptom expression, which included leaf curl and stunted leaves with yellow mosaic patterns, was observed in two out of six inoculated plants six weeks postinoculation (Fig. S3). PCR assays confirmed the presence of PepYLCThV DNA in N. benthamiana and C. annuum symptomatic leaves (Fig. S4). To our knowledge, this is the first report of pepper yellow leaf curl Thailand virus in hot chili pepper in Laos and central Vietnam. Appropriate containment and management strategies should be developed and implemented to control the spread of this disease in hot chili pepper crops in both countries.

Challenges and Opportunities in Big Data Science to Address Health Inequities and Focus the HIV Response.

PURPOSE OF REVIEW: Big Data Science can be used to pragmatically guide the allocation of resources within the context of national HIV programs and inform priorities for intervention. In this review, we discuss the importance of grounding Big Data Science in the principles of equity and social justice to optimize the efficiency and effectiveness of the global HIV response. RECENT FINDINGS: Social, ethical, and legal considerations of Big Data Science have been identified in the context of HIV research. However, efforts to mitigate these challenges have been limited. Consequences include disciplinary silos within the field of HIV, a lack of meaningful engagement and ownership with and by communities, and potential misinterpretation or misappropriation of analyses that could further exacerbate health inequities. Big Data Science can support the HIV response by helping to identify gaps in previously undiscovered or understudied pathways to HIV acquisition and onward transmission, including the consequences for health outcomes and associated comorbidities. However, in the absence of a guiding framework for equity, alongside meaningful collaboration with communities through balanced partnerships, a reliance on big data could continue to reinforce inequities within and across marginalized populations.

Construction of Monolayer Ti3C2Tx MXene on Nickel Foam under High Electrostatic Fields for High-Performance Supercapacitors.

Ti3C2Tx MXene, as a common two-dimensional material, has a wide range of applications in electrochemical energy storage. However, the surface forces of few-layer or monolayer Ti3C2Tx MXene lead to easy agglomeration, which hinders the demonstration of its performance due to the characteristics of layered materials. Herein, we report a facile method for preparing monolayer Ti3C2Tx MXene on nickel foam to achieve a self-supporting structure for supercapacitor electrodes under high electrostatic fields. Moreover, the specific capacitance varies with the deposition of different-concentration monolayer Ti3C2Tx MXene on nickel foam. As a result, Ti3C2Tx/NF has a high specific capacitance of 319 mF cm-2 at 2 mA cm-2 and an excellent long-term cycling stability of 94.4% after 7000 cycles. It was observed that the areal specific capacitance increases, whereas the mass specific capacitance decreases with the increasing loading mass. Attributable to the effect of the high electrostatic field, the self-supporting structure of the Ti3C2Tx/NF becomes denser as the concentration of the monolayer Ti3C2Tx MXene ink increases, ultimately affecting its electrochemical performance. This work provides a simple way to overcome the agglomeration problem of few-layer or monolayer MXene, then form a self-supporting electrode exhibiting excellent electrochemical performance.

Effects of Laser Scanning Strategy on Bending Behavior and Microstructure of DP980 Steel.

Laser bending is a kind of cumulative forming technology and bending efficiency is one of its most important indexes. This study investigates the bending behavior and the microstructure of DP980 steel plates under different laser scanning strategies, using an IPG laser system. Two sets of experiments varied the accumulated line energy density (AED) by altering the laser scanning velocity and number of scans. The results show that, for the single laser scanning process, the bending angle of the plate increases with AED, due to a larger temperature gradient through the thickness direction; however, this relationship is nonlinear. A higher AED led to a sharper initial increase in bending angle, which then plateaued. Under the same AED conditions, the bending angle of the plate undergoing multiple laser scans increases by at least 26% compared to the single one, due to the microstructure changes. It is revealed that the bending efficiency is affected by both the AED and the resultant microstructure evolution in the DP980 steel. Higher AED values and appropriate peak temperatures facilitate better bending behavior due to the formation of uniform martensite and grain refinement. Conversely, excessive peak temperatures can hinder bending due to grain growth.

Transarterial chemoembolization with 125I seed insertion for multifocal hepatocellular carcinoma.

Background: A common treatment strategy for individuals with multifocal hepatocellular carcinoma (HCC) who are not candidates for surgical resection is transarterial chemoembolization (TACE). Combining TACE with 125I seed insertion (ISI) may offer a means of enhancing therapeutic efficacy. The purpose of this study was to compare the therapeutic efficacy of TACE administered with and without ISI for the treatment of multifocal HCC. Methods: The data from the two centers were analyzed retrospectively. The present study involved 85 consecutive patients with multifocal HCC who underwent TACE between January 2018 and December 2021. Of these patients, 43 were in the combined group, receiving TACE with ISI, and 42 were in the TACE-only group, receiving TACE without ISI. Comparisons of treatment outcomes were made between these groups. Results: No significant differences in baseline data were observed between these groups of patients. Higher rates of complete (60.5% vs. 33.3%, P = 0.016) and total (93.0% vs. 61.9%, P = 0.001) responses were evident in the combined group compared to the TACE-only group. Median progression-free survival (PFS, 13 vs. 10 months, P = 0.014) and overall survival (OS, 22 vs. 17 months, P = 0.035) were also significantly longer in the combined group than in the TACE-only group. Using a Cox regression analysis, risk variables associated with shorter PFS and OS included Child-Pugh B status (P = 0.027 and 0.004) and only TACE treatment (P = 0.011 and 0.022). Conclusion: In summary, these findings suggest that, as compared to TACE alone, combining TACE and ISI can enhance HCC patients' treatment outcomes and survival.

Genetically Predicted Apolipoprotein E Levels with the Risk of Panvascular Diseases: A Mendelian Randomization Study.

The aim of this study was to comprehensively assess the causal relationship between the overall genetic effect of circulating ApoE levels and panvascular lesions using newer genome-wide association data and two-sample bidirectional Mendelian randomization (MR) analysis. Two-way MR using single-nucleotide polymorphisms of circulating ApoE as instrumental variables was performed using the highest-priority Genome-wide association study (GWAS) data, with factor-adjusted and data-corrected statistics, to estimate causal associations between circulating ApoE levels and 10 pan-vascular diseases in > 500,000 UK Biobank participants, > 400,000 participants of Finnish ancestry, and numerous participants in a consortium of predominantly European ancestry. Meta-analysis was conducted to assess positive results. After correcting for statistical results, elevated circulating ApoE levels were shown to have a significant protective effect against Cerebral ischemia (CI) [IVW odds ratio (OR) 0.888, 95% Confidence Interval (CI): 0.823-0.958, p = 2.3 × 10-3], Coronary heart disease [IVW OR 0.950,95% CI: 0.924-0.976, p = 2.0 × 10-4] had a significant protective effect and potentially suggestive protective causality against Angina pectoris [IVW odds ratio (OR) 0.961, 95%CI: 0.931-0.991, p = 1.1 × 10-2]. There was a potential causal effect for increased risk of Heart failure (HF) [IVW ratio (OR) 1.040, 95%CI: 1.006-1.060, p = 1.8 × 10-2]. (Bonferroni threshold p < 0.0026, PFDR < 0.05) Reverse MR analysis did not reveal significant evidence of a causal effect of PVD on changes in circulating ApoE levels. Meta-analysis increases reliability of results. Elevated circulating ApoE levels were particularly associated with an increased risk of heart failure. Elevated ApoE levels reduce the risk of cerebral ischemia, coronary heart disease, and angina pectoris, reflecting a protective effect. The possible pathophysiological role of circulating ApoE levels in the development of panvascular disease is emphasized.

A Planar Multi-Inertial Navigation Strategy for Autonomous Systems for Signal-Variable Environments.

The challenge of precise dynamic positioning for mobile robots is addressed through the development of a multi-inertial navigation system (M-INSs). The inherent cumulative sensor errors prevalent in traditional single inertial navigation systems (INSs) under dynamic conditions are mitigated by a novel algorithm, integrating multiple INS units in a predefined planar configuration, utilizing fixed distances between the units as invariant constraints. An extended Kalman filter (EKF) is employed to significantly enhance the positioning accuracy. Dynamic experimental validation of the proposed 3INS EKF algorithm reveals a marked improvement over individual INS units, with the positioning errors reduced and stability increased, resulting in an average accuracy enhancement rate exceeding 60%. This advancement is particularly critical for mobile robot applications that demand high precision, such as autonomous driving and disaster search and rescue. The findings from this study not only demonstrate the potential of M-INSs to improve dynamic positioning accuracy but also to provide a new research direction for future advancements in robotic navigation systems.

Effects of Solitaire AB stent thrombectomy with tirofiban and butylphthalide on neurological function and inflammatory factors in acute cerebral infarction patients.

BACKGROUND: Acute cerebral infarction profoundly affects patients' neurological function and quality of life. This study explores the impact of Solitaire AB stent thrombectomy, combined with tirofiban and butylphthalide, on neurological function and inflammatory factors in patients with acute cerebral infarction. METHODS: Seventy-three eligible patients treated between 2021 and 2023 were divided into a control group (Solitaire AB stent thrombectomy) and a treatment group (Solitaire AB stent thrombectomy with tirofiban and butylphthalide). Postoperative neurological function scores and inflammatory factor levels were analyzed. RESULTS: The treatment group demonstrated a higher clinical effective rate, lower National Institutes of Health Stroke Scale scores at one day and seven days and higher Mini-Mental State Examination and Montreal Cognitive Assessment scores post-treatment. Inflammatory factor levels (Neuron Specific Enolase (NSE), S100-ß, TNF-α and IL-6) were lower in the treatment group. No significant differences in adverse outcomes were observed. CONCLUSION: Solitaire AB stent thrombectomy with tirofiban and butylphthalide shows superior efficacy, improving neurological function and inflammatory factors without increasing adverse outcomes. This offers valuable insights for clinical treatment of acute cerebral infarction.

Morphological, phytochemical and genetic characterization of Centella asiatica accessions collected throughout Vietnam and Laos.

Pennywort (Centella asiatica L.) is commonly grown in the tropical world for its nutritional and medicinal values. Valuable saponins in pennywort are extensively investigated for their anti-tumour activities. The diversity in morphology, phytochemical contents and genetics among pennywort accessions has been extensively studied to identify elite landraces for large-scale production. While pennywort is widely consumed in Vietnam, a systematic characterization of their diverse morphology, secondary metabolites and genetics is lacking. In this work, 26 pennywort accessions were collected across Vietnam and Laos. Their morphological features and yields were characterized under uniform agro-climatic conditions at Hue city in central Vietnam. The highest yield was obtained with HUIB_CA20 (478 g per tray), compared to the lowest yield in HUIB_CA19 (107 g per tray). Furthermore, a range of phytochemical markers, including vitamin C, reducing sugar, carotenoid, tannin, phenolic, flavonoid and saponin contents, were determined. Based on yield, phenolic and flavonoid contents, HUIB_CA20 and HUIB_CA27 were determined to be elite cultivars in this germplasm. Finally, microsatellite analysis was performed to explore the genetic diversity within the germplasm. Using fourteen SSR primer pairs, a total of 47 alleles were identified with 45 alleles (96 %) being polymorphic. These results will be useful for breeding programs aiming to create elite pennywort cultivars with enhanced properties.

A Correlated Network Scale-up Model: Finding the Connection Between Subpopulations.

Aggregated relational data (ARD), formed from "How many X's do you know?" questions, is a powerful tool for learning important network characteristics with incomplete network data. Compared to traditional survey methods, ARD is attractive as it does not require a sample from the target population and does not ask respondents to self-reveal their own status. This is helpful for studying hard-to-reach populations like female sex workers who may be hesitant to reveal their status. From December 2008 to February 2009, the Kiev International Institute of Sociology (KIIS) collected ARD from 10,866 respondents to estimate the size of HIV-related groups in Ukraine. To analyze this data, we propose a new ARD model which incorporates respondent and group covariates in a regression framework and includes a bias term that is correlated between groups. We also introduce a new scaling procedure utilizing the correlation structure to further reduce biases. The resulting size estimates of those most-at-risk of HIV infection can improve the HIV response efficiency in Ukraine. Additionally, the proposed model allows us to better understand two network features without the full network data: 1. What characteristics affect who respondents know, and 2. How is knowing someone from one group related to knowing people from other groups. These features can allow researchers to better recruit marginalized individuals into the prevention and treatment programs. Our proposed model and several existing NSUM models are implemented in the networkscaleup R package.

Probabilistic HIV recency classification-a logistic regression without labeled individual level training data.

Accurate HIV incidence estimation based on individual recent infection status (recent vs long-term infection) is important for monitoring the epidemic, targeting interventions to those at greatest risk of new infection, and evaluating existing programs of prevention and treatment. Starting from 2015, the Population-based HIV Impact Assessment (PHIA) individual-level surveys are implemented in the most-affected countries in sub-Saharan Africa. PHIA is a nationally-representative HIV-focused survey that combines household visits with key questions and cutting-edge technologies such as biomarker tests for HIV antibody and HIV viral load which offer the unique opportunity of distinguishing between recent infection and long-term infection, and providing relevant HIV information by age, gender, and location. In this article, we propose a semi-supervised logistic regression model for estimating individual level HIV recency status. It incorporates information from multiple data sources - the PHIA survey where the true HIV recency status is unknown, and the cohort studies provided in the literature where the relationship between HIV recency status and the covariates are presented in the form of a contingency table. It also utilizes the national level HIV incidence estimates from the epidemiology model. Applying the proposed model to Malawi PHIA data, we demonstrate that our approach is more accurate for the individual level estimation and more appropriate for estimating HIV recency rates at aggregated levels than the current practice - the binary classification tree (BCT).

Prevalence and Factors Affecting Appropriate Inhaler Use in Elderly Patients with Chronic Obstructive Pulmonary Disease: A Prospective Study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) mainly affects individuals aged 60 and older. The proper use of inhalers is crucial for managing COPD. This study aimed to evaluate the prevalence and factors affecting the appropriate use of inhalers among elderly patients with COPD. METHODS: We enrolled 91 elderly patients with COPD admitted to the Department of Respiratory, University Medical Center HCMC between October 2020 and May 2021. Patients who were capable of using the inhaler would have their inhaler usage recorded through video footage. Two respiratory experts carefully analyzed 133 video-recorded demonstrations for evaluation purposes. RESULTS: 18.7% of the patients demonstrated the correct inhaler technique. Pressurized metered dose inhaler (pMDI) and Turbuhaler had the lowest documented correct usage rates (11.9% and 10.0%, respectively). Two critical steps, namely "holding breath for about five seconds or as long as comfortable" and "breathing out gently," were commonly performed incorrectly when using pMDI, Respimat, Breezhaler, or Turbuhaler. Multivariable logistic regression analysis showed that lower mMRC scores (AOR = 5.3, CI 1.1-25.5, p = 0.037) and receiving inhaler instruction within the past three months (AOR = 5.2, CI 1.3-20.1, p = 0.017) were associated with increased odds of using the inhaler correctly. CONCLUSIONS: Our study found that less than 20% of elderly patients with COPD use inhalers correctly. Common errors include inadequate breath-holding and gentle exhalation. mMRC scores and recent inhaler instruction were predictors of proper use. These findings can aid clinicians in improving inhaler management for elderly patients with COPD.

Stability Constant and Potentiometric Sensitivity of Heavy Metal-Organic Fluorescent Compound Complexes: QSPR Models for Prediction and Design of Novel Coumarin-like Ligands.

Industrial wastewater often consists of toxic chemicals and pollutants, which are extremely harmful to the environment. Heavy metals are toxic chemicals and considered one of the major hazards to the aquatic ecosystem. Analytical techniques, such as potentiometric methods, are some of the methods to detect heavy metals in wastewaters. In this work, the quantitative structure-property relationship (QSPR) was applied using a range of machine learning techniques to predict the stability constant (logßML) and potentiometric sensitivity (PSML) of 200 ligands in complexes with the heavy metal ions Cu2+, Cd2+, and Pb2+. In result, the logßML models developed for four ions showed good performance with square correlation coefficients (R2) ranging from 0.80 to 1.00 for the training and 0.72 to 0.85 for the test sets. Likewise, the PSML displayed acceptable performance with an R2 of 0.87 to 1.00 for the training and 0.73 to 0.95 for the test sets. By screening a virtual database of coumarin-like structures, several new ligands bearing the coumarin moiety were identified. Three of them, namely NEW02, NEW03, and NEW07, showed very good sensitivity and stability in the metal complexes. Subsequent quantum-chemical calculations, as well as physicochemical/toxicological profiling were performed to investigate their metal-binding ability and developability of the designed sensors. Finally, synthesis schemes are proposed to obtain these three ligands with major efficiency from simple resources. The three coumarins designed clearly demonstrated capability to be suitable as good florescent chemosensors towards heavy metals. Overall, the computational methods applied in this study showed a very good performance as useful tools for designing novel fluorescent probes and assessing their sensing abilities.

Development of Activity Rules and Chemical Fragment Design for In Silico Discovery of AChE and BACE1 Dual Inhibitors against Alzheimer's Disease.

Multi-target drug development has become an attractive strategy in the discovery of drugs to treat of Alzheimer's disease (AzD). In this study, for the first time, a rule-based machine learning (ML) approach with classification trees (CT) was applied for the rational design of novel dual-target acetylcholinesterase (AChE) and ß-site amyloid-protein precursor cleaving enzyme 1 (BACE1) inhibitors. Updated data from 3524 compounds with AChE and BACE1 measurements were curated from the ChEMBL database. The best global accuracies of training/external validation for AChE and BACE1 were 0.85/0.80 and 0.83/0.81, respectively. The rules were then applied to screen dual inhibitors from the original databases. Based on the best rules obtained from each classification tree, a set of potential AChE and BACE1 inhibitors were identified, and active fragments were extracted using Murcko-type decomposition analysis. More than 250 novel inhibitors were designed in silico based on active fragments and predicted AChE and BACE1 inhibitory activity using consensus QSAR models and docking validations. The rule-based and ML approach applied in this study may be useful for the in silico design and screening of new AChE and BACE1 dual inhibitors against AzD.

Dearomatization-Rearomatization Reaction of Metal-Polarized Aza-ortho-Quinone Methides.

Metal-polarized aza-ortho-quinone methides (aza-o-QMs) are a unique and efficient handle for azaheterocycle synthesis. Despite great achievements, the potential of these reactive intermediates has not yet been fully exploited, especially the new reaction modes. Herein, we disclosed an unprecedented dearomatization process of metal-polarized aza-o-QMs, affording transient dearomatized spiroaziridine intermediates. Based on this serendipity, we accomplished three sequential dearomatization-rearomatization reactions of benzimidazolines with aza-sulfur ylides, enabling the divergent synthesis of bis-nitrogen heterocycles with high efficiency and flexibility. Moreover, experimental and theoretical studies were performed to explain the proposed mechanisms and observed selectivity. Further cellular evaluation of the dibenzodiazepine products identified a hit compound for new antitumor drugs.

A Theoretical Study of Interband Absorption Spectra of Spherical Sector Quantum Dots under the Effect of a Powerful Resonant Laser.

We explore the variation of interband absorption spectra of GaAs spherical sector quantum dots (QDs) in response to a strong resonant laser, using the renormalized wave function method. Even though a spherical sector QD appears identical to a section cut from a spherical QD, it contains a controllable additional spatial parameter, the apical angle, which results in radically different wave functions and energy levels of particles, and is anticipated to exhibit novel optical properties. The obtained findings reveal that the apical angle of the dot has a considerable effect on the interband absorption spectrum. With the increase in the dot apical angle, a significant redshift of the interband absorption peaks has been identified. Increasing the pump laser detuning and dot radius yields similar results. Especially when a powerful resonant laser with tiny detuning is utilized, a dynamical coupling between electron levels arises, resulting in the formation of new interband absorption peaks. These new peaks and the former ones were similarly influenced by the aforementioned parameters. Furthermore, it is thought that the new peaks, when stimulated by a suitable laser, will produce the entangled states necessary for quantum information.

Secondary metabolites as potential drug candidates against Zika virus, an emerging looming human threat: Current landscape, molecular mechanism and challenges ahead.

Nature has given us yet another wild card in the form of Zika virus (ZIKV). It was found in 1947, but has only recently become an important public health risk, predominantly to pregnant women and their unborn offspring. Currently, no specific therapeutic agent exists for ZIKV and treatment is mainly supportive. Natural products (NPs) can serve as a major source of potent antiviral drugs. To create this review, a comprehensive search was conducted from different databases (PubMed, ScienceDirect, Google scholar). A statistical analysis on the number of publications related to NPs and ZIKV was conducted to analyse the trend in research covering the period 1980-2020. From the data collated in this review, a number of NPs have been found to be inhibitive towards different stages of the ZIKV lifecycle in in vitro studies. For instance, baicalin, (-)-epigallocatechin gallate, curcumin, nanchangmycin, gossypol, cephaeline, emetine, resveratrol, berberine, amongst others, can prevent viral entry by attacking ZIKV E protein. Compounds luteolin, myricetin, astragalin, rutin, (-)-epigallocatechin gallate, carnosine, pedalitin, amongst others, inhibited NS2B-NS3 protease activity which consequently hamper replication. Interestingly, a few NPs had the ability to arrest both viral entry and replication, namely baicalin, (-)-epigallocatechin gallate, curcumin, cephaeline, emetine, and resveratrol. To the best of our knowledge, we obtained only one in vivo study conducted on emetine and results showed that it decreased the levels of circulating ZIKV by approximately 10-fold. Our understanding on NPs exhibiting anti-ZIKV effects in in vivo testing as well as clinical trials is limited. Our trend analysis showed that interest in searching for a cure or prevention against Zika in NPs is negligible and there are no publications yet covering the clinical evaluation. NPs with anti-ZIKV property can a winning strategy in controlling the bio-burden of an epidemic or pandemic. We therefore opine that in the future, more research should be devoted to ZIKV. This review attempts to provide baseline data and roadmap to pursuit detailed investigations for developing potent and novel therapeutic agents to prevent and cure ZIKV infection.