Unleashing the potential of cell painting assays for compound activities and hazards prediction.

The cell painting (CP) assay has emerged as a potent imaging-based high-throughput phenotypic profiling (HTPP) tool that provides comprehensive input data for in silico prediction of compound activities and potential hazards in drug discovery and toxicology. CP enables the rapid, multiplexed investigation of various molecular mechanisms for thousands of compounds at the single-cell level. The resulting large volumes of image data provide great opportunities but also pose challenges to image and data analysis routines as well as property prediction models. This review addresses the integration of CP-based phenotypic data together with or in substitute of structural information from compounds into machine (ML) and deep learning (DL) models to predict compound activities for various human-relevant disease endpoints and to identify the underlying modes-of-action (MoA) while avoiding unnecessary animal testing. The successful application of CP in combination with powerful ML/DL models promises further advances in understanding compound responses of cells guiding therapeutic development and risk assessment. Therefore, this review highlights the importance of unlocking the potential of CP assays when combined with molecular fingerprints for compound evaluation and discusses the current challenges that are associated with this approach.

Organoboron Polymorphs with Different Molecular Packing Modes for Optical Waveguides.

Organoboron compounds offer a new strategy to design optoelectronic materials with high fluorescence efficiency. In this paper, the organoboron compound B-BNBP with double B←N bridged bipyridine bearing four fluorine atoms as core unit is facilely synthesized and exhibits a narrowband emission spectrum and a high photoluminescence quantum yield (PLQY) of 86.53% in solution. Its polymorphic crystals were controllable prepared by different solution self-assembly methods. Two microcrystals possess different molecular packing modes, one-dimensional microstrips (1D-MSs) for H-aggregation and two-dimensional microdisks (2D-MDs) for J-aggregation, owing to abundant intermolecular interactions of four fluorine atoms sticking out conjugated plane. Their structure-property relationships were investigated by crystallographic analysis and theoretical calculation. Strong emission spectra with the full width at half maximum (FWHM) of less than 30 nm can also be observed in thin film and 2D-MDs. 1D-MSs possess thermally activated delayed fluorescence (TADF) property and exhibit superior optical waveguide performance with an optical loss of 0.061 dB/µm. This work enriches the diversity of polymorphic microcrystals and further reveals the structure-property relationship in organoboron micro/nano-crystals.

Play it again, but more sadly: Influence of timbre, mode, and musical experience in melody processing.

The emotional properties of music are influenced by a host of factors, such as timbre, mode, harmony, and tempo. In this paper, we consider how two of these factors, mode (major vs. minor) and timbre interact to influence ratings of perceived valence, reaction time, and recognition memory. More specifically, we considered the notion of congruence-that is, we used a set of melodies that crossed modes typically perceived as happy and sad (i.e., major and minor) in Western cultures with instruments typically perceived as happy and sad (i.e., marimba and viola). In a reaction-time experiment, participants were asked to classify melodies as happy or sad as quickly as possible. There was a clear congruency effect-that is, when the mode and timbre were congruent (major/marimba or minor/viola), reaction times were shorter than when the mode and timbre were incongruent (major/viola or minor/marimba). In Experiment 2, participants first rated the melodies for valence, before completing a recognition task. Melodies that were initially presented in incongruent conditions in the rating task were subsequently recognized better in the recognition task. The recognition advantage for melodies presented in incongruent conditions is discussed in the context of desirable difficulty.

Residue profiles of peptides with cholesterol esterase and pancreatic lipase inhibitory activities through virtual screening and sequence analysis.

The detailed characterization of the structural features of peptides targeting cholesterol esterase (CEase) or pancreatic lipase (PPL) will benefit the management of hyperlipidemia and obesity. This study employed the Glide SP (standard precision)-peptide method to predict the binding modes of 202 dipeptides and 203 tripeptides to these targets, correlating residue composition and position with binding energy. Strong preferences for Trp, Phe, and Tyr were observed at all positions of potential inhibitory peptides, whereas negatively charged residues Glu and Asp were disfavored. Notably, Arg and aromatic rings significantly influenced the peptide conformation at the active site. Tripeptide IWR demonstrated the high efficacy, with IC50 values of 0.214 mg/mL for CEase and 0.230 mg/mL for PPL. Five novel IWR scaffold-tetrapeptides exhibited promising inhibitory activity. Non-covalent interactions and energy contributions dominated the formation of stable complexes. Our results provide insights for the development of new sequences or peptide-like molecules with enhanced inhibitory activity.

Directive transportation in smart cities with line connectivity at distinctive points using mode control algorithm.

This article examines the operational functionality of intelligent transport systems to enhance smart cities by reducing traffic congestion. Given the increasing populations of smart cities, there is a growing demand for public transit systems to address the issue of traffic congestion. Therefore, the suggested system is developed using a few parametric design models, which combine point-to-point protocol and mode control optimization. The multi-objective parametric design for a smart transportation system is conducted using min-max functions to minimize the waiting time period for end users. Furthermore, customers are given the option to utilize a line following mechanism that offers suitable connectivity, along with independent identification and revitalize functions. The predicted model effectively eliminates the delay produced by transportation devices when positioning units are involved, ensuring that individual messages are delivered without any interruptions. In order to evaluate the results of the proposed system model, four different scenarios were examined. A comparison analysis revealed that the suggested method achieves a suitable directional flow for 96% of smart transport units. Additionally, it reduces delays and waiting periods by 2% and 6% respectively, while increasing energy consumption by 29%.

An ultrasensitive dual-mode aptasensor for patulin based on the upconversion particles and G-Quadruplex-hemin DNAzyme.

Patulin (PAT) is a mycotoxin-produced secondary metabolite that can contaminate foods, causing toxic effects on animal and human health. Therefore, for the first time, we have constructed a "turn-on" dual-mode aptamer sensor for PAT using oleic acid-coated upconversion nanomaterials (OA-UCNPs) and G-Quadruplex-hemin DNAzyme (G4-DNAzyme) as fluorescent and colorimetry probes. The sensor employs aptamers binding to PAT as recognition elements for specific molecule detection. Mxene-Au can be used as a biological inducer to assist OA-UCNPs in controlling fluorescence intensity. In addition, colorimetric signal amplification was performed using the trivalent G4-DNAzyme to increase detection sensitivity and reduce false positives. Under optimal conditions, the dual-mode aptasensor has a detection limit of 5.3 pg mL-1 in fluorescence and 2.4 pg mL-1 in colorimetric methods, respectively, with the wider linear range and limit of detection (LOD) of the colorimetric assay. The combination aptasensor can detect PAT with high sensitivity and high specificity and has broad application prospects in the field of food safety detection.

Altered effective connectivity of the default mode network in juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is associated with brain dysconnectivity in the default mode network (DMN). Most previous studies of patients with JME have assessed static functional connectivity in terms of the temporal correlation of signal intensity among different brain regions. However, more recent studies have shown that the directionality of brain information flow has a more significant regional impact on patients' brains than previously assumed in the present study. Here, we introduced an empirical approach incorporating independent component analysis (ICA) and spectral dynamic causal modeling (spDCM) analysis to study the variation in effective connectivity in DMN in JME patients. We began by collecting resting-state functional magnetic resonance imaging (rs-fMRI) data from 37 patients and 37 matched controls. Then, we selected 8 key nodes within the DMN using ICA; finally, the key nodes were analyzed for effective connectivity using spDCM to explore the information flow and detect patient abnormalities. This study found that compared with normal subjects, patients with JME showed significant changes in the effective connectivity among the precuneus, hippocampus, and lingual gyrus (p < 0.05 with false discovery rate (FDR) correction) with most of the effective connections being strengthened. In addition, previous studies have found that the self-connection of normal subjects' nodes showed strong inhibition, but the self-connection inhibition of the anterior cingulate cortex and lingual gyrus of the patient was decreased in this experiment (p < 0.05 with FDR correction); as the activity in these areas decreased, the nodes connected to them all appeared abnormal. We believe that the changes in the effective connectivity of nodes within the DMN are accompanied by changes in information transmission that lead to changes in brain function and impaired cognitive and executive function in patients with JME. Overall, our findings extended the dysconnectivity hypothesis in JME from static to dynamic causal and demonstrated that aberrant effective connectivity may underlie abnormal brain function in JME patients at early phase of illness, contributing to the understanding of the pathogenesis of JME. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-023-09994-4.

A smartphone-assisted portable dual-mode immunoassay of gentamicin based on curcumin nanoparticles and carbon dots.

A smartphone-assisted portable dual-mode immunoassay was constructed based on curcumin nanoparticles (CNPs) and carbon dots (CDs) for gentamicin (GEN) detection. CNPs were labeled with goat anti-mouse IgG (Ab2) to create a conjugation that coupled dual signals to concentrations of GEN antigens. CNPs were introduced to pH 7.4 water and showed insignificant color and optical responses. When exposed to the high pH environment, the structure of CNPs changed and color and optical properties were restored. Because of the inner filter effect (IFE) between CNPs and CDs, the fluorescence of CNPs at 550 nm quenched the fluorescence of CDs at 450 nm. Colorimetry and ratiometric fluorescence (F550 nm/F450 nm) dual-mode immunoassay linearly correlated with GEN ranged from 10-4 to 100 µg/mL with a detection limit (LOD) of 8.98 × 10-5 µg/mL and 4.66 × 10-5 µg/mL, respectively. This work supplied a portable, sensitive, and specific platform to detect GEN.

Pass the boron: benzoxaboroles as antiparasite drugs.

The development of new drug modalities has been facilitated recently by the introduction of boron as a component of organic compounds, and specifically within a benzoxaborale scaffold. This has enabled exploration of new chemical space and the development of effective compounds targeting a broad range of morbidities, including infections by protozoa, fungi, worms, and bacteria. Most notable is the recent demonstration of a single oral dose cure using acoziborole against African trypanosomiasis. Common and species-/structure-specific interactions between benzoxaboroles and parasite species have emerged and provide vital insights into the mechanisms of cidality, as well as potential challenges in terms of resistance and/or side effects. Here, we discuss the literature specific to benzoxaborole studies in parasitic protists and consider unanswered questions concerning this important new drug class.

Shear Wave Elastography in Breast Cancer: Unveiling Correlations With Histopathological Grades and Subtypes.

Objective This study explores the correlation between shear wave elastography (SWE) features and histopathological grades and subtypes in breast cancer, aiming to enhance diagnostic accuracy and personalized treatment strategies. Methods The study retrospectively analyzed 59 consecutive women with breast cancer who underwent breast ultrasound with SWE. SWE parameters and histopathologic information, including histological type and grade, were recorded. Qualitative and quantitative SWE findings were analyzed, and B-mode findings were evaluated. Sociodemographic and clinical factors and B-mode findings were assessed as predictors of elastography stiffness using logistic regression analysis. Results Of the 59 participants diagnosed with breast cancer, invasive ductal carcinoma of no special type (IDC-NST) was predominantly found in 50 (84.7%) cases, followed by invasive medullary carcinoma in 5 (8.5%) cases. The majority of participants belonged to the 50-59 age group, comprising 19 (32.2%) patients. Histopathological grading revealed grade II tumors in 27 (45.8%) cases and grade III tumors in 24 (40.7%) cases. Notably, grade III tumors exhibited higher tissue stiffness compared to grade II tumors. Out of 36 stiff lesions, 30 (83.3%%) were IDC-NST while 3 (8.3%) were invasive medullary carcinoma. A significant association was observed between higher histopathological grade (grade III) and increased tissue stiffness (p < 0.05). Furthermore, among participants with stiff lesions, 21 (58.3%) exhibited color defects while 4 (23.5%) cases with soft lesions also displayed color defects Conclusion The correlation between SWE findings and histopathological grades and subtypes underscores the potential of SWE as a valuable tool for predicting tumor aggressiveness and characterizing specific subtypes. SWE enhances diagnostic accuracy and complements traditional imaging modalities, holding promise for personalized treatment strategies.

Effect Analysis of the HFMEA Model Applied in Sputum Specimen Management Among Patients with Tuberculosis.

Objective: Accurate diagnosis is very important to block the transmission of tuberculosis. The quality of sputum culture affects the diagnostic accuracy. The quality of sputum samples is not optimistic. Therefore, this study investigated whether health care failure mode and effect analysis (HFMEA) can improve specimen quality and detection efficiency in sputum specimen management in tuberculosis departments. Methods: This study is a non-randomized controlled trial study. A convenience sampling method was used to select 110 patients who visited the Department of Tuberculosis of the Second Hospital of Nanjing from September to November 2022 and December 2022 to February 2023 as the control group and the experimental group. Control groups followed standard operating procedures for sputum specimen collection. In the experimental group, HFMEA model was used to control the quality on this basis. After 3 months of intervention, the qualified rate and positive detection rate of sputum samples were compared between the two groups. Results: A total of 634 sputum specimens were included in the experimental group and 647 in the control group. Compared with the control group, the qualification rate of sputum specimens was higher in the experimental group (84.54% vs 79.13%); the positive detection rates of the X-Pert assay (27.88% vs 16.19%), sputum culture (20.29% vs 12.68%), and sputum smear (22.29% vs 15.81%) were all higher in the experimental group (all P < 0.05). Patients in the experimental group had higher knowledge mastery and nurse sputum sample management scores (P < 0.05). However, patient satisfaction with sputum specimen management in the experimental group was lower than in the control group (7.72 ± 0.74 vs 8.38 ± 0.85, P < 0.001). Conclusion: The application of the HFMEA model in sputum specimen management can effectively improve specimen quality and positive detection rates.

Social disparities in delivery choice among patients with history of cesarean.

OBJECTIVE: Given the call to reduce rates of non-medically indicated cesarean deliveries (CDs) by encouraging trials of labor after cesarean (TOLAC), this study looks at social characteristics of patients choosing a TOLAC versus a scheduled repeat cesarean delivery (SRCD) to determine disparities regarding delivery method choice. METHODS: This was a retrospective cohort study of patients with a history of one CD between April 29, 2015-April 29, 2020. Patients were divided based on type of delivery chosen at admission. Chi-squared tests examined proportional differences between groups and logistic regression models examined odd ratios of choosing TOLAC versus SRCD according to socially dependent categories including race/ethnicity, health insurance, pre-pregnancy body mass index, and Social Vulnerability Index (SVI). RESULTS: 1,983 patients were included. Multivariable logistic regression models revealed that patients with a high SVI (reference: low/medium SVI) (AOR 2.0, CI: 1.5, 2.5), self-identified as Black/ African American (AOR: 2.4, CI: 1.6, 3.6) or Hispanic/Latina (AOR: 2.0, CI: 1.4, 2.8) (reference: White), had public insurance (reference: private insurance) (AOR: 3.7, CI: 2.8, 5.0), and who had an obese BMI (reference: non-obese BMI) were more likely to opt for a TOLAC rather than SRCD. CONCLUSION: These findings demonstrate differences in delivery method preferences. Specifically, more disadvantaged patients are more likely to choose TOLAC, suggesting that social and economic factors may play a role in delivery preferences. These findings have implications for improving individualized counselling and engaging in shared decision-making around mode of delivery.

Individualized prediction of online shopping addiction from whole-brain functional connectivity.

Online shopping addiction (OSA) is defined as a behavioral addiction where an individual exhibits an unhealthy and excessive attachment to shopping on the Internet. Since the OSA shown its adverse impacts on individuals' daily life and social functions, it is important to examine the neurobiological underpinnings of OSA that could be used in clinical practice to identify individuals with OSA. The present study addressed this question by employing a connectome-based prediction model approach to predict the OSA tendency of healthy subjects from whole-brain resting-state functional connectivity. The OSA connectome - a set of connections across multiple brain networks that contributed to predict individuals' OSA tendency was identified, including the functional connectivity between the frontal-parietal network (FPN) and cingulo-opercular network (CON) (i.e., positive network), as well as the functional connectivity within default mode network (DMN) and that between FPN and DMN (i.e., negative network). Key nodes that contributed to the prediction model included the middle frontal gyrus, inferior frontal gyrus, anterior cingulate cortex, and inferior temporal gyrus, which have been associated with impulsivity and emotional processing. Notably, this connectome has shown its specific role in predicting OSA by controlling for the influence of general Internet addiction. Moreover, the strength of the negative network mediated the relationship between OSA and impulsivity, highlighting that the negative network underlies the impulsivity characteristic of OSA. Together, these findings advanced our understanding of the neural correlates of OSA and provided a promising framework for diagnosing OSA.

[On the issues of additional public support of workers involved in medical care support during period of COVID-19].

The article considers issues of organizational and legal progress of social protection of workers involved in medical care during period of COVID-19. The purpose of the study is to analyze regulatory legal documents that define state guarantees that provide social protection for persons involved in the provision of medical care during COVID-19. The attempt was made to analyze international and national information on relevant morbidity, mortality and disability of health care workers, but respective data was not readily available in open admission. The analysis of international documents (the WHO, CDC, JHU reports), public documents of the Russian Federation, information from official websites of the President of the Russian Federation and the executive authorities of the Russian Federation (state reports on sanitary and epidemiological well-being of the population in the Russian Federation in 2020-2022) demonstrated the following. The whole world faced with the problem of protecting health care workers from contamination with new corona-virus infection. In the Russian Federation, unprecedented measures were taken to ensure social protection for this category of workers, including provision of additional social benefits.

Risk analysis applied to the process of managing medical devices in a hospital pharmacy department.

INTRODUCTION: During the COVID-19 pandemic, single use medical devices' supply (SUMD) was marked by repetitive and unforeseen interruptions. The present study aimed to determine the risks related to the processes of management of medical devices in our CHU according to a method of failure mode, effect and criticality analysis (FMECA). METHODS: Qualified healthcare professionals were recruited to form a multidisciplinary consensus committee. By analyzing the process map, all failure modes, causes and consequences were identified through brainstorming meetings. They were then classified taking into account the criticality index (CI) calculated according to three parameters: frequency, severity and detectability. The prioritization was carried out by considering the mean and the median values ​​of the CI as limits. Corrective and preventive actions were then proposed. RESULTS: A total of 49 failure modes were identified, accumulating 4466 criticality points. The most critical step is that relating to the inter-depot order with an IC equal to 783 points. An action plan was developed allows us to control 64% of the overall criticality of the risks linked to the process. Three main lines of action have been proposed: continuous training, especially for managerial and administrative tasks, logistical improvement (architectural reorganization and implementation of systems for securing the circuit of SUMDs) and support for the digitization of hospital pharmacy. CONCLUSION: The FMECA is a consensual method which makes it possible to propose actions in order to reduce the risks linked to the process of managing medical devices. Optimizing the estimation of needs, strengthening communication with stakeholders and securing the circuit are essential to guarantee the availability of SUMDs for the benefit of the patient.

Acaricide Flupentiofenox Inhibits the Mitochondrial ß-Oxidation Pathway of Fatty Acids.

A newly developed pesticide, flupentiofenox, has a unique trifluoroethyl phenylsulfoxide structure, and it powerfully affects spider mites, including those with resistance to multiple commercial acaricides. To clarify the mode of action of flupentiofenox, we investigated its effect on mitochondrial energy generation. We observed that flupentiofenox decreased adenosine triphosphate (ATP) levels in two-spotted spider mites (Tetranychus urticae) at a practical dose. Flupentiofenox potently inhibited mitochondrial oxygen consumption under conditions of palmitoyl-carnitine or octanoic acid supply, but not under conditions of pyruvate supply. These results show that flupentiofenox inhibits the mitochondrial fatty acid metabolic pathway between the uptake of long-chain acylcarnitine or medium-chain fatty acid and the synthesis of acetyl-CoA by ß-oxidation, resulting in suppressed mitochondrial energy generation. Our investigations have led us to conclude that flupentiofenox is a pesticide with a novel mode of action.

Research progress in tumor therapy of carrier-free nanodrug.

Carrier-free nanodrugs are a novel type of drug constructed by the self-assembly of drug molecules without carrier involvement. They have the characteristics of small particle size, easy penetration of various barriers, targeting tumors, and efficient release. In recent years, carrier-free nanodrugs have become a hot topic in tumor therapy as they solve the problems of low drug loading, poor biocompatibility, and low uptake efficiency of carrier nanodrugs. A series of recent studies have shown that carrier-free nanodrugs play a vital role in the treatment of various tumors, with similar or better effects than carrier nanodrugs. Based on the literature published in the past decades, this paper first summarizes the recent progress in the assembly modes of carrier-free nanodrugs, then describes common therapeutic modalities of carrier-free nanodrugs in tumor therapy, and finally depicts the existing challenges along with future trends of carrier-free nanodrugs. We hope that this review can guide the design and application of carrier-free nanodrugs in the future.

Causal effects of endometriosis stages and locations on menstruation, ovulation, reproductive function, and delivery modes: a two-sample Mendelian randomization study.

Background: Endometriosis is a chronic inflammatory disease of women during their reproductive years. The relationship between the severity and location of endometriosis and menstruation, ovulation, reproductive function, and mode of delivery remains unclear. Methods: We explored the association between the various phenotypes of endometriosis and menstruation, ovulation, reproductive function, and mode of delivery, using two-sample Mendelian randomization (MR) and summary data on endometriosis stages and locations from the FinnGen consortium and women's menstruation, ovulation, reproductive function, and mode of delivery from OpenGWAS and ReproGen. Inverse-variance weighting was used for the primary MR analysis. In addition, a series of sensitivity analyses, confounding analyses, co-localization analyses, and multivariate MR analyses were performed. Results: MR analysis showed a negative effect of moderate to severe endometriosis on age at last live birth (OR = 0.973, 95% CI: 0.960-0.986) and normal delivery (OR = 0.999, 95% CI: 0.998-1.000; values for endpoint were excluded), ovarian endometriosis on age at last live birth (OR = 0.976, 95% CI: 0.965-0.988) and normal delivery (OR = 0.999, 95% CI: 0.998-1.000; values for endpoint were excluded), and fallopian tubal endometriosis on excessive irregular menstruation (OR = 0.966, 95% CI: 0.942-0.990). Bidirectional MR analysis showed that age at menarche had a negative causal effect on intestinal endometriosis (OR = 0.417, 95% CI: 0.216-0.804). All MR analyses were confirmed by sensitivity analyses, and only the genetic effects of moderate to severe endometriosis on normal delivery and age at last live birth were supported by co-localization evidence. Conclusion: Our findings deepen the understanding of the relationship between various types of endometriosis and menstruation, ovulation, reproductive function, and mode of delivery and clarify the important role of moderate to severe endometriosis.

Tunable Stochastic State Switching in 2D MoS2 Nanomechanical Resonators with Nonlinear Mode Coupling and Internal Resonance.

Coupled nanomechanical resonators have unveiled fascinating physical phenomena, including phonon-cavity coupling, coupled energy decay pathway, avoided crossing, and internal resonance. Despite these discoveries, the mechanisms and control techniques of nonlinear mode coupling phenomena with internal resonances require further exploration. Here, we report on the observation of stochastic switching between the two resonance states with coupled 1:1 internal resonance, for resonant two-dimensional (2D) molybdenum disulfide (MoS2) nanoelectromechanical systems (NEMS), which is directly driven to the critical coupling regime without parametric pumping. We further demonstrate that the probability of state switching is linearly tunable from ∼0% to ∼100% by varying the driving voltage. Furthermore, we gradually increase the white noise amplitude and show that the probability of obtaining the higher-energy state decreases, and the stochastic switching phenomenon eventually disappears. The results provide insights into the dynamics of coupled NEMS resonators and open up new possibilities for sensing and stochastic computing.

Separation of astragaloside IV from Astragalus membranaceus based on high-speed countercurrent chromatography in continuous injection mode.

INTRODUCTION: Astragaloside IV (AS-IV) is an index for the quality evaluation of the traditional Chinese medicine Astragalus and an important material basis for Astragalus to exert its medicinal effects, and it is difficult to obtain a single AS-IV by ordinary separation methods. OBJECTIVE: To find a new isolation method that can prepare AS-IV quickly and efficiently. METHODOLOGY: AS-IV was isolated from Astragalus membranaceus extract by high-speed countercurrent chromatography using a two-phase solvent system consisting of ethyl acetate/n-butanol/water (4.2:0.8:5, v/v) at a speed of 950 rpm at a flow rate of 2 mL/min using one of the high-speed countercurrent chromatographic sequential injection models developed during the previous study. RESULTS: Compared with the common countercurrent chromatographic separation, this separation method increased the injection volume and yield by 4-fold and 4.47-fold, respectively, with only about 1.2-fold increase in solvent consumption and separation time, and the purity was basically not reduced, and 55.9 mg of AS-IV, with a purity of 96.95%, was finally prepared from 400 mg of the crude extract in 240 min. CONCLUSION: The continuous injection mode of high-speed countercurrent chromatography was able to successfully prepare a large amount of AS-IV with high purity at one time.