Subsequent Screening Research Articles

83 What is social paediatrics and how do we teach it? A scoping review of social medicine curricula in the child and youth health context across health disciplines

Abstract Background Social paediatrics is a field that focuses on addressing social and environmental factors that affect children’s health and wellbeing1. Over recent years in medical education, social paediatrics has become increasingly recognized as foundational to undergraduate and postgraduate paediatrics curricula. Paediatric residency programs worldwide have been developing and offering social paediatrics curricula, yet we lack understanding of effective strategies for teaching it to medical trainees. 1. Spencer N, Colomer C, Alperstein G, et al. Social paediatrics. J Epidemiol Community Health. 2005;59(2):106-108. doi:10.1136/jech.2003.017681 Objectives We conducted a scoping review to describe the various educational interventions used to teach content and practice related to social paediatrics. Design/Methods We conducted a scoping review to describe the various educational interventions used to teach content and practice related to social paediatrics. Our literature search first drew upon Ovid MEDLINE and MedEd PORTAL, with subsequent studies identified through reference searching in relevant articles. We included studies that described and/or evaluated educational interventions aimed to teach elements of social paediatrics. We excluded studies published before 2000. We extracted data from the selected articles and conducted thematic analysis. Results Our search yielded 443 articles. Initial screen by title and/or abstract and subsequent screen by abstract and/or full text yielded 28 papers. Where it was unclear if studies met inclusion criteria, two additional researchers reviewed the full text. With the addition of articles found in references of the provisional articles, a total of 36 papers were included in the review. Of those, 17 (47%) described curricular interventions at the level of paediatric residency, 7 (19%) described medical school curricula, and 8 (22%) included non-medicine fields such as dentistry, nursing, research, and others. Fifty percent of curricula required self-directed learning, while a different 50% subset had a formal reflection process as part of learning consolidation. We organized the literature thematically into the following themes: interdisciplinary collaboration, community partnership, advocacy training, and experiential learning. Conclusion Our scoping review describes a variety of curricular interventions aimed to teach elements of social paediatrics, with a large focus on social determinants of health, primarily poverty, and a relative lack of focus on the underlying structural, systemic, and social justice issues underpinning these health determinants. We need to consider how the pedagogical strategies on offer can be purposed towards the development of more robust social paediatrics curricula at the postgraduate level.

High‐Throughput Experimentation (HTE) Applied to the Synthesis of API Impurities: A Case Study in Oxidative Decarboxylation of Aryl Acetic Acids

AbstractHigh‐throughput experimentation (HTE) has dramatically impacted experimental reaction development by enabling the rapid exploration of a diverse set of reaction conditions. During the past few decades, HTE has evolved as a tool to expedite reaction discovery and optimization. This work details the application of HTE to synthesize impurities of active pharmaceutical ingredients (APIs) with ketone/aldehyde functionality, specially focusing on ibuprofen impurity E. Initial experiments using K2S2O8 as oxidant yielded moderate results. Subsequent HTE screens identified cerium ammonium nitrate (CAN) and RuCl3‐NaIO4 as new effective decarboxylative oxidants, with RuCl3‐NaIO4 in the presence of tetrabutylammonium bromide (TBAB) achieving the highest yield of 65 %. This optimized method was successfully applied to synthesize ibuprofen impurity E on a gram scale. Additionally, the applicability of these methods to obtain other API related substances, such as naproxen impurity L and ketoprofen impurity A, was demonstrated. This research highlights the potential of HTE to streamline the synthesis of API impurities, making them widely accessible for pharmaceutical development purposes.

Unveiling the Human Brain on a Chip: An Odyssey to Reconstitute Neuronal Ensembles and Explore Plausible Applications in Neuroscience.

The brain is an incredibly complex structure that consists of millions of neural networks. In developmental and cellular neuroscience, probing the highly complex dynamics of the brain remains a challenge. Furthermore, deciphering how several cues can influence neuronal growth and its interactions with different brain cell types (such as astrocytes and microglia) is also a formidable task. Traditional in vitro macroscopic cell culture techniques offer simple and straightforward methods. However, they often fall short of providing insights into the complex phenomena of neuronal network formation and the relevant microenvironments. To circumvent the drawbacks of conventional cell culture methods, recent advancements in the development of microfluidic device-based microplatforms have emerged as promising alternatives. Microfluidic devices enable precise spatiotemporal control over compartmentalized cell cultures. This feature facilitates researchers in reconstituting the intricacies of the neuronal cytoarchitecture within a regulated environment. Therefore, in this review, we focus primarily on modeling neuronal development in a microfluidic device and the various strategies that researchers have adopted to mimic neurogenesis on a chip. Additionally, we have presented an overview of the application of brain-on-chip models for the recapitulation of the blood-brain barrier and neurodegenerative diseases, followed by subsequent high-throughput drug screening. These lab-on-a-chip technologies have tremendous potential to mimic the brain on a chip, providing valuable insights into fundamental brain processes. The brain-on-chip models will also serve as innovative platforms for developing novel neurotherapeutics to address several neurological disorders.

Juvenile Hemochromatosis Connecting Cardiac Arrest and Hypogonadotropic Hypogonadism in a Young Woman

Abstract Juvenile hemochromatosis (JH) is a subtype of hereditary hemochromatosis, a genetic disorder characterized by excessive iron absorption and deposition in various organs, leading to cardiomyopathy, cirrhosis, and diabetes. Endocrine dysfunction is a common manifestation and may appear years before end-organ damage. This report describes a rare case of JH, emphasizing the consequences of delayed diagnosis. A 28-year-old woman with a history of hypogonadotropic hypogonadism presented with cardiac arrest complicated by acute renal failure and cerebral vascular accidents. She initially exhibited signs of severe cardiomyopathy and multiorgan failure, which led to workup for an underlying cause. Laboratory values showed significantly elevated ferritin and transferrin saturation. Subsequent genetic screening revealed HJV gene pathogenic variants consistent with juvenile hemochromatosis. Treatment involved aggressive iron chelation therapy and outpatient referral for cardiac transplant. This case calls for heightened awareness and early screening of JH, particularly among patients with unexplained endocrine dysfunction. Early diagnosis and treatment are paramount in preventing irreversible organ damage and improving patient outcomes.

The potential benefits of extra screening for glycated haemoglobin, total cholesterol and low-density lipoprotein cholesterol on donor health management and retention.

An extra health screening, including glycated haemoglobin (HbA1c), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), was initiated for regular donors aged over 40 in Taiwan in November 2015. This study aimed to determine its benefits on donor health management and retention. A stratified random mail survey was conducted among donors who received HbA1c, TC and LDL-C screening between November 2015 and June 2017 to investigate their awareness of the screening, medical histories and post-screening behaviours. Their subsequent screening results and donation records from 3 years before and after the initial screening were obtained up to December 2021. In total, 2070 donors participated in the mail survey, with participation rates ranging 15.7%-23.2% across study groups. The screening newly detected hyperglycaemia in 1.6% (95% confidence interval [CI]: 1.2%-2.0%) and hyperlipidaemia in 1.0% (95% CI: 0.7%-1.4%) of participants, with 42.7% (95% CI: 40.3%-45.2%) of participants unaware of the screening. Participants with initially abnormal or borderline TC or LDL-C results showed significant decreases in the subsequent screening (all p values<0.05). No difference was found in participants' awareness of the screening. However, those who sought medical consultation or made specific lifestyle changes tended to show greater improvements. Awareness of the screening was associated with increased whole blood donations and donated units. The extra health screening has limited benefits for donor health management without additional interventions, but it may motivate donors to donate more frequently. Raising donors' awareness of the screening is also crucial to maximize its benefits.

Multiparameter Method for Developer Screening of Molecular Glass Resists via Molecular Simulations.

Efficient and accurate developer screening is critical for high-resolution lithography. In this study, a multiparameter (MP) method simultaneously based on the Hansen solubility parameters (HSP), two-component solubility parameters (TSP), and order parameter (OP) is proposed for the developer screening of molecular glass resists via molecular dynamics simulation. A customized solvent database, including 80 organic solvents, is created for the subsequent developer screening. Two diagram forms of HSP (δD-δP-δH diagram and δV-δH diagram) were investigated, and the δV-δH diagram is utilized due to its higher solubility prediction consistency with OP. Then, two solubility prediction diagrams, i.e., HSP&OP and TSP&OP diagrams, were formed using the MP method. The developer screening scheme using the MP method is illustrated for a decomposable resist, AD10BOC, and a cross-linkable resist, AD4C. Meanwhile, the feasibility of the developer screening scheme is verified by practical lithography experiments. In addition, relative solvation free energy (RSFE) calculations and dissolution experiments of six resists are implemented to further confirm the accuracy of OP in reflecting the relative solubility of the resist in various solvents. This study presents a viable approach for developer screening, which will facilitate the development of resist materials.

Characterizing the Metabolism of Tire Rubber-Derived p-Phenylenediamine Quinones to Identify Potential Exposure Biomarkers in Humans.

There is growing evidence of the frequent detection of tire rubber-derived contaminants p-phenylenediamine-derived quinones (PPD-Qs) (e.g., highly toxic N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q)) in the environment and biota and the adverse impact on organisms. Hence, a better understanding of their biotransformation/metabolism in humans is essential. However, relevant data are lacking owing to recent discoveries. Herein, the biotransformation patterns of 6PPD-Q and other five commonly detected PPD-Qs were characterized via combined in vitro assay and maternal cord blood screening monitoring. Rapid metabolism was found for each PPD-Q incubated with human liver S9 fraction and microsomes, resulting in the formation of abundant phase I and phase II metabolites. The subsequent screening for potential PPD-Q metabolites in blood samples showed the presence of suspect metabolites. Three detected metabolites were confirmed by matching the mass spectra and retention times of in vitro metabolites. N-Dealkylated, carboxy, carbonyl, and reductive metabolites and glucose, cysteine, and methionine conjugates were observed for the first time. The semiquantitative concentrations of metabolites were higher than those of the parent PPD-Qs, and several metabolites such as carboxy products were proposed as candidate biomarkers of PPD-Q exposure to humans. 6PPD-Q and N,N'-diphenyl-p-phenylenediamine quinone were detected in maternal and/or cord whole blood samples for the first time. This study holds great importance in elucidating the potential risks and health effects of PPD-Qs.

Use of Specific T Lymphocytes in Treating Cytomegalovirus Infection in Hematopoietic Cell Transplant Recipients: A Systematic Review

Cytomegalovirus (CMV) poses a significant threat to post-hematopoietic cell transplantation (HCT). Control strategies include letermovir prophylaxis or ganciclovir pre-emptive therapy (PET). Without prophylaxis, 65–90% of seropositive recipients develop a clinically significant CMV infection. Due to PET drawbacks, letermovir prophylaxis is preferable, as it reduces CMV-related events and improves overall survival. However, refractory or resistant CMV-CS remains a challenge, with maribavir showing limited efficacy. This systematic review followed the Cochrane Manual and PRISMA guidelines and was registered in PROSPERO. Searches were conducted in PubMed, Scopus, Embase, and Web of Science. Out of 1895 identified records, 614 duplicates were removed, and subsequent screening excluded 1153 studies. Eleven included studies (2012–2024) involved 255 HCT recipients receiving adoptive immunotherapy (AI), primarily CMV-specific T-cell therapy. GvHD occurred in 1.82% of cases. Adverse events occurred in 4.4% of cases, while mild CRS was observed in 1.3% of patients. Efficacy, evaluated in 299 patients across eleven studies, showed an average response rate of 78.2%. CMV-CS recurrence was observed in 24.4% of 213 patients, and death due to CMV was reported in 9.7% of 307 patients across nine studies. Adoptive hCMV-specific T-cell immunotherapy appears to be a safe, effective alternative for refractory CMV-CS in HCT.

Shenmai injection improves lipid metabolism in post-myocardial infarction heart failure based on network pharmacology and experimental validation

BackgroundShenmai injection (SMI), a traditional Chinese medicine formulation derived from the herbal decoction Shenmai Yin, is widely used in treating cardiovascular disorders. This study extensively investigated the effects and mechanisms of action of SMI on lipid metabolism in post-myocardial infarction heart failure (pMIHF). MethodsNetwork pharmacology was employed to predict the key targets and associated pathways involved in lipid metabolism for potential SMI treatments in post-myocardial infarction heart failure (pMIHF). Subsequently, a pMIHF mouse model and an ischemia/reperfusion (I/R) cell model were established to delve deeper into and validate the underlying mechanism of action. ResultsWe performed network pharmacology analysis, which identified 48 active components in SMI and 201 common gene targets. Subsequent screening using the protein–protein interaction network identified 26 core targets, including interleukin (IL)-6, tumor necrosis factor (TNF)-α, peroxisome proliferator-activated receptor alpha (PPARα), and sirtuin 1 (SIRT1). Based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses, we predicted that SMI might act on lipid metabolism in pMIHF through the PPARα pathway, a hypothesis supported by the strong binding affinity between this receptor and the active components of SMI, as confirmed via molecular docking. In a left anterior descending artery-ligation mouse model, SMI significantly improved cardiac function, reduced serum free fatty acid levels, decreased inflammatory cell infiltration and myocardial fibrosis, and maintained myocardial mitochondrial morphology. In ischemia-reperfusion (I/R) cells, SMI reduced cell apoptosis, improved mitochondrial membrane potential, and decreased mRNA expression levels of IL-6 and TNF-α, while increasing protein levels of PPARα, SIRT1, and PPARα co-activator-1 alpha (PGC1α). ConclusionCollectively, our findings suggest that SMI enhances myocardial lipid metabolism and ameliorates pMIHF by upregulating the PPARα/SIRT1/PGC1α pathway.

A Next-Generation Combinatorial Genomic Strategy Scans Genomic Loci Governing Heat Stress Tolerance in Chickpea.

In the wake of rising earth temperature, chickpea crop production is haunted by the productivity crisis. Chickpea, a cool season legume manifests tolerance in several agro-physiological level, which is complex quantitative in nature, and regulated by multiple genes and genetic networks. Understanding the molecular genetic basis of this tolerance and identifying key regulators can leverage chickpea breeding against heat stress. This study employed a genomics-assisted breeding strategy utilizing multi-locus GWAS to identify 10 key genomic regions linked to traits contributing to heat stress tolerance in chickpea. These loci subsequently delineated few key candidates and hub regulatory genes, such as RAD23b, CIPK25, AAE19, CK1 and WRKY40, through integrated genomics, transcriptomics and interactive analyses. The differential transcript accumulation of these identified candidates in contrasting chickpea accessions suggests their potential role in heat stress tolerance. Differential ROS accumulation along with their scavengers' transcript abundance aligning with the expression of identified candidates in the contrasting chickpea accessions persuade their regulatory significance. Additionally, their functional significance is ascertained by heterologous expression and subsequent heat stress screening. The high confidence genomic loci and the superior genes and natural alleles delineated here has great potential for swift genomic interventions to enhance heat resilience and yield stability in chickpea.

Jieduquyuziyin prescription alleviates lupus development via inhibiting neddylation pathway to promote Bim-induced apoptosis of double negative T cells

Ethnopharmacological relevanceJieduquyuziyin prescription (JP) is an empirical prescription approved for application to treat systemic lupus erythematosus (SLE) in hospital within China. Despite the prominent treatment effect of JP clinically, further investigation is imperative to explore its underlying mechanisms. Aim of the studyWe aim to investigate the impact of JP on DN T cell apoptosis in the treatment of SLE and the specific regulation mechanisms. Materials and methodsFirstly, female MRL/lpr mice were treated with JP and the therapeutic efficacy of JP was evaluated via skin lesions, lymphoid organ enlargement, accumulation of autoantibodies and renal function. Then, flow cytometer analysis was performed to evaluate the proportions and the apoptosis of T cell subpopulations. Based on the above results, double-negative (DN) T cells were subjected to proteomic with subsequent differential screening. The expression of Ube2m and Bim was further validated using real-time PCR and Western blot. Subsequently, DN T cells were incubated with JP-contained serum in vitro, and cell apoptosis was quantified using flow cytometry. Additionally, the expression levels of Ube2m, Bim and other associated proteins were also assessed through western blotting. To further clarify whether Ube2m serves as the key target of JP in regulating DN T cell apoptosis, the mice that Ube2m was specific deleted in T cells with spontaneous lupus (Ube2m−/−lpr) were utilized. JP was administered to WTlpr or Ube2m−/−lpr mice, followed by assessment of the lupus condition and DN T cell apoptosis. ResultsJP administration effectively ameliorated the lupus phenotype. Then flow cytometry assay showed that JP treatment enhanced DN T cell apoptosis to reduce their accumulation and restored the immune homeostasis. Proteomic analysis revealed a significant inhibition of Ube2m for JP treatment, which is essential for maintaining homeostasis of DN T cells. Further experiments confirmed that JP treatment effectively downregulated the expression of Ube2m and subsequently upregulated the level of pro-apoptotic protein Bim with decreased Bim degradation. In vitro experiments also confirmed that JP-contained serum significantly facilitated DN T cell apoptosis and reduced DN T cell accumulation by inhibiting Ube2m expression. Furthermore, Ube2m−/−lpr mice were utilized and the impact of JP treatment on the apoptosis of DN T cells was found to be minimal in the absence of Ube2m. Mechanistic investigation reveals that JP exerts its effects by suppressing the expression of Ube2m, subsequently inhibiting CRL-dependent degradation of Bim, and ultimately promoting Bim-induced apoptosis in DN T cells. Furthermore, the blockade of Ube2m in T cells effectively prevents JP-induced apoptosis in DN T cells, underscoring Ube2m as one crucial therapeutic target of JP in mediating DN T cell apoptosis and managing SLE. ConclusionsOur findings indicate that JP treatment effectively restores the homeostasis of DN T cells in SLE by inhibiting Ube2m expression, thereby reducing Bim ubiquitination degradation. This ultimately enhanced DN T cell apoptosis and alleviated lupus phenotype.

Long-term trends of cardiometabolic risk factors in adolescents aged 14–18 years in Novosibirsk (1989–2024)

High prevalence of cardiovascular morbidity and mortality in the Russian population dictates the need to identify and prevent risk factors for these diseases from adolescence. Objective: to study the prevalence and long-term trends in cardiometabolic risk factors in an adolescent population sample of Novosibirsk (1989–2024).Methods. In 1989–2024, cross-sectional population studies of random representative samples of schoolchildren aged 14–18 of both sexes were conducted in Novosibirsk with an interval of 5 years. 8 screenings were conducted. A total of 5106 adolescents (43–46 % boys) were examined. Approval was received from the Local Ethics Committee of the Research Institute of Preventive and Internal Medicine – Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences; all children and their parents signed informed consent for the examination. The program was uniform for all screenings and included a survey using a standard questionnaire, 2-fold measurement of blood pressure, anthropometry (height, body weight, chest, waist and hip circumferences), and a biochemical blood test for lipid profile. The levels of cardiometabolic risk factors were assessed in accordance with the latest Russian and international recommendations. Statistical data processing was performed using the SPSS for Windows 13 package.Results. The prevalence of hypercholesterolemia in adolescents in Novosibirsk over 35 years decreased from 22.3 to 3.0 % in boys and from 31.8 to 10.6 % in girls (p &lt; 0.001). The highest prevalence of hypertension in adolescents was observed in 1989, then by 1994 its levels decreased and remained relatively stable until a decrease in 2014 with a subsequent increase, especially among boys, the prevalence of hypertension among whom in 2024 reached the 1989 level (17.3 % and 16.9 %, respectively). The greatest decrease in the frequency of excessive weight in adolescents relative to 1989 was observed in 1999: in boys – 2.7 times, in girls – 3.2 times. Since 2003, there has been a consistent increase in the prevalence of overweight among adolescents, primarily among boys, and by 2014 it exceeded the baseline values of the 1989 screening by 8 % in boys (21.6 versus 13.9 % (p &lt; 0.01)) and by 3 % in girls (14.3 versus 11.5 % (p = 0.05)). At subsequent screenings, the frequency of overweight remained unchanged. The frequency of smoking among adolescents of both sexes decreased almost 10-fold from 1989 to 2024: from 45 % in 1989 to 5.5 % in 2024 among boys, and from 19 % to 2% among girls (p &lt; 0.01), however, an increase in electronic smoking was noted. Over the past 5 years (2019–2024), the use of electronic cigarettes and gadgets among boys has doubled (from 6 up to 12 %) and three times among girls (from 3 to 9 %). The prevalence of reduced physical activity among adolescents remained high throughout the period, but in the last 15 years it has clearly decreased among boys (62 % in 2009 versus 37 % in 2024 (p &lt; 0.01). Since 2009, screen time has increased: from 18 hours/week in 2009 for boys and 15 for girls to 30 hours/week in 2014 and remained at the same level in 2019. In 2024, screen time of the computer decreased, but phone time increased, which in total did not exceed the figures for 2014 and 2019 (33–35 hours/ week).Conclusions. Based on population screening of adolescents conducted in Novosibirsk over 35 years, the prevalence and long-term trends of cardiometabolic risk factors (arterial hypertension, dyslipoproteinemia, overweight and obesity, smoking and low physical activity) were identified.

Mathematical Model of Drilling Mud Movement along a Shale Shaker Screen

Introduction. When drilling oil or gas wells, rock from the bottomhole is brought to the surface by drilling mud, which is cleaned of sludge by shale shakers at the first stage. Shale shakers are equipped with such a screen and create such trajectories of vibration of the frame in order to solve a dual problem: on the one hand, to provide the cleaning of the drilling mud coming from the well mouth, and on the other hand — to maintain the proper degree of cleaning. To correctly select the nomenclature of screens, it is necessary to reliably determine the throughput capacity of a shale shaker in the real-time setting. This will allow you to pre-order the required number of screens with the required cell size. Previously, studies were conducted by sieving a mixture of calibrated granules on a standard shaker or by straining mineral oil through a fixed screen. However, this does not fully correspond to the actual conditions of drilling mud screening. The objective of this article was to simulate the throughput of a drilling shale shaker under real conditions by calculating the movement of drilling mud along a vibrating screen using its previously obtained specific throughput capacity.Materials and Methods. When creating a mathematical model of the full throughput capacity of a shale shaker, a previously known mathematical model of fluid flow in an open channel and a finite-dimensional approximation in the form of a sequence of sections of concentrated containers connected by hydraulic conductivities (by analogy with the approximation of long electrical lines and extended gas pipelines by the finite element method) were used. The fluid flow rate over the screen was determined according to Chézy law. In this case, the cross-sectional area of the flow above the screen for a specific section was specified as the arithmetic mean between the initial and final values of the drilling mud height in the corresponding section.Results. A chain calculation scheme for sieving drilling mud was compiled. Based on the material balance, mathematical models were developed for determining the throughput and height of drilling mud above the screen: for the first section of the screen and the first nodal point of the screen; for subsequent screen sections and subsequent screen nodal points; for the last section of the screen and the last nodal point of the screen.A mathematical model of the drilling mud movement along the shale shaker screen has been obtained, which, due to the finite-dimensional representation of this flow along n sections of the screen length, is a system of n integral equations describing concentrated tanks, and n – 1 algebraic equations describing the flow of drilling mud between tanks.Discussion and Conclusion. The movement of drilling mud along the length of the shale shaker screen corresponds to the movement of a steady uneven flow in an open channel. However, in the first case, the volume flow along the length is variable (decreasing to zero), and in the second case, it is constant along the length. Therefore, the use of only one differential equation for steady uneven flow in an open channel is not sufficient in this case. The resulting mathematical model of the drilling mud movement along the shale shaker screen is a mathematical basis for the development of a modeling program to determine the throughput of the shale shaker for real operating conditions, i.e., for a specific drilling mud, a given screen or a given drive system of the shale shaker.

Miniaturized Modular Click Chemistry-enabled Rapid Discovery of Unique SARS-CoV-2 Mpro Inhibitors With Robust Potency and Drug-like Profile.

The COVID-19 pandemic has required an expeditious advancement of innovative antiviral drugs. In this study, focused compound libraries are synthesized in 96- well plates utilizing modular click chemistry to rapidly discover potent inhibitors targeting the main protease (Mpro) of SARS-CoV-2. Subsequent direct biological screening identifies novel 1,2,3-triazole derivatives as robust Mpro inhibitors with high anti-SARS-CoV-2 activity. Notably, C5N17B demonstrates sub-micromolar Mpro inhibitory potency (IC50 = 0.12 µM) and excellent antiviral activity in Calu-3 cells determined in an immunofluorescence-based antiviral assay (EC50 = 0.078 µM, no cytotoxicity: CC50 > 100 µM). C5N17B shows superior potency to nirmatrelvir (EC50 = 1.95 µM) and similar efficacy to ensitrelvir (EC50 = 0.11 µM). Importantly, this compound displays high antiviral activities against several SARS-CoV-2 variants (Gamma, Delta, and Omicron, EC50 = 0.13 - 0.26 µM) and HCoV-OC43, indicating its broad-spectrum antiviral activity. It is worthy that C5N17B retains antiviral activity against nirmatrelvir-resistant strains with T21I/E166V and L50F/E166V mutations in Mpro (EC50 = 0.26 and 0.15 µM, respectively). Furthermore, C5N17B displays favorable pharmacokinetic properties. Crystallography studies reveal a unique, non-covalent multi-site binding mode. In conclusion, these findings substantiate the potential of C5N17B as an up-and-coming drug candidate targeting SARS-CoV-2 Mpro for clinical therapy.

The Development and Application of KinomePro-DL: A Deep Learning Based Online Small Molecule Kinome Selectivity Profiling Prediction Platform.

Characterizing the kinome selectivity profiles of kinase inhibitors is essential in the early stages of novel small-molecule drug discovery. This characterization is critical for interpreting potential adverse events caused by off-target polypharmacology effects and provides unique pharmacological insights for drug repurposing development of existing kinase inhibitor drugs. However, experimental profiling of whole kinome selectivity is still time-consuming and resource-demanding. Here, we report a deep learning classification model using an in-house built data set of inhibitors against 191 well-representative kinases constructed based on a novel strategy by systematically cleaning and integrating six public data sets. This model, a multitask deep neural network, predicts the kinome selectivity profiles of compounds with novel structures. The model demonstrates excellent predictive performance, with auROC, prc-AUC, Accuracy, and Binary_cross_entropy of 0.95, 0.92, 0.90, and 0.37, respectively. It also performs well in a priori testing for inhibitors targeting different categories of proteins from internal compound collections, significantly improving over similar models on data sets from practical application scenarios. Integrated to subsequent machine learning-enhanced virtual screening workflow, novel CDK2 kinase inhibitors with potent kinase inhibitory activity and excellent kinome selectivity profiles are successfully identified. Additionally, we developed a free online web server, KinomePro-DL, to predict the kinome selectivity profiles and kinome-wide polypharmacology effects of small molecules (available on kinomepro-dl.pharmablock.com). Uniquely, our model allows users to quickly fine-tune it with their own training data sets, enhancing both prediction accuracy and robustness.

Abstract B007: Racial/ethnic and socioeconomic disparities in over- and under-screening of cervical cancer among a national sample of commercially insured individuals

Abstract In the United States (US), disparities in cervical cancer screening uptake persist by race/ethnicity and socioeconomic status (SES). However, few have examined how race/ethnicity and SES contribute to specific guideline adherence patterns, which can exacerbate existing disparities. We investigated the impact of race/ethnicity and SES (education and household net worth [HHN]) on the probability of over- and under-screening. Optum Clinformatics Data Mart from 2012-2021 was used to identify average-risk females aged 30-64 and ≥1 cervical cancer screening with continuous health plan enrollment and no history of hysterectomy/cervical cancer. Over- and under-screening were defined as intervals between the index and subsequent screening which were shorter and longer than the interval recommended by the 2012 US Preventive Services Task Force guideline, respectively. Multivariate logistic regression was used to evaluate the association of race/ethnicity (Non-Hispanic [NH]-White, NH-Asian, Hispanic, NH-Black) and SES including HHN (&amp;lt;$250,000, $250,000-$500,000, &amp;gt;$500,000) and education level (&amp;lt;Bachelor’s Degree, &amp;gt;Bachelor’s Degree) with over- and under-screening. We tested for interactions between race/ethnicity and SES. Of the 686,884 eligible patients, 72.8% were NH-White, 71.4% had &amp;lt;Bachelor's Degree and 43.3% had HHN &amp;lt;$250,000. Only 7.2% were guideline adherent, 30.7% were under-screened, and 62.1% were over-screened. After regression adjustment, the odds of under-screening were higher among NH-Asian (OR, 1.2; 95%CI, 1.1- 1.2), NH-Black (OR, 1.1; 95%CI, 1.0-1.1), and Hispanic (OR, 1.2; 95%CI, 1.1-1.2) vs NH-White, &amp;lt;Bachelor’s degree (OR, 1.1; 95%CI, 1.0-1.1) vs &amp;gt;Bachelor’s degree, and HHN &amp;lt;$250,000 (OR, 1.3 95%CI, 1.2-1.3) and $250,000-$499,000 (OR, 1.1; 95%CI, 1.0-1.1) vs &amp;gt;$500,000. Odds of over-screening were higher among NH-Black (OR, 1.3; 95%CI, 1.2-1.3), and Hispanic (OR, 1.2; 95%CI, 1.1-1.2) vs NH-White, and lower among &amp;lt;Bachelor’s degree (OR, 0.9; 95%CI, 0.8-0.9) vs &amp;gt;Bachelor’s degree, and HHN &amp;lt;$250,000 (OR, 0.9; 95%CI, 0.9-1.0) and $250,000-$499,000 (OR, 0.9; 95%CI, 0.9-1.0) vs &amp;gt;$500,000. For under-screening, the interaction between race/ethnicity and HHN was significant, and the predicted probability (PP) increased with higher HHN among Hispanic but not in other groups (p&amp;lt;0.01). For over-screening, the interaction between race/ethnicity and HHN was significant and the PP increased with higher HHN among Hispanic and NH-White but decreased for NH-Black and NH-Asian. The interaction between race/ethnicity and education was significant and the PP increased with higher education among Hispanic and NH-White but decreased among NH-Black and NH-Asian. Even within a commercially insured population, we observed that the majority of patients received non-guideline adherent screening and SES contributed to disparities differently among racial/ethnic groups. Findings indicate the need to tailor interventions and policies for subpopulations experiencing over- and under-screening to address the overall screening quality and disparities in outcomes. Citation Format: Michelle B. Shin, Sarah Axeen, Jennifer Tsui. Racial/ethnic and socioeconomic disparities in over- and under-screening of cervical cancer among a national sample of commercially insured individuals [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B007.

Preliminary In silico Analysis of Adenylate Kinase 1 (ADK1) of Echinococcus granulosus as a Candidate for Vaccination against Cystic Echinococcosis

Background: A neglected zoonosis, Cystic Echinococcosis (CE), is most common in developing nations worldwide. Vaccination is, therefore, helpful in preventing the disease. Objective: Predicting the main biochemical properties of E. granulosus Adenylate Kinase 1 (ADK1) and its possible B-cell and T-cell-binding epitopes as a valuable candidate for immunization was the goal of the current study. Methods: Predictions were made to determine biochemical, antigenic, structural, and subcellular characteristics, along with the immunogenic epitopes, using several online servers. Results: The extracellular 22 KDa protein had no allergenicity, while it possessed hydrophilicity (GRAVY: -0.286), stability (instability: 17.48), tolerance to a wide range of temperatures (aliphatic: 93.45), and 17 post-translational modification sites. The secondary structure mostly comprised helices and random coils and the 3D model was generated using Robetta server (confidence: 0.88). Common B-cell epitopes were discovered by three servers and screened for antigenic, allergenic, and solubility traits. Moreover, MHC-associated epitopes for mice and humans were predicted in E. granulosus ADK1 with subsequent screening. Conclusion: This work offers a foundation for further investigation on designing an effective vaccination against CE. Further empirical research study with the examined protein solely or combined with other antigens is needed.

A growth-based screening strategy for engineering the catalytic activity of an oxygen-sensitive formate dehydrogenase.

Enzyme engineering is a powerful tool for improving or altering the properties of biocatalysts for industrial, research, and therapeutic applications. Fast and accurate screening of variant libraries is often the bottleneck of enzyme engineering and may be overcome by growth-based screening strategies with simple processes to enable high throughput. The currently available growth-based screening strategies have been widely employed for enzymes but not yet for catalytically potent and oxygen-sensitive metalloenzymes. Here, we present a screening system that couples the activity of an oxygen-sensitive formate dehydrogenase to the growth of Escherichia coli. This system relies on the complementation of the E. coli formate hydrogenlyase (FHL) complex by Mo-dependent formate dehydrogenase H (EcFDH-H). Using an EcFDH-H-deficient strain, we demonstrate that growth inhibition by acidic glucose fermentation products can be alleviated by FHL complementation. This allows the identification of catalytically active EcFDH-H variants at a readily measurable cell density readout, reduced handling efforts, and a low risk of oxygen contamination. Furthermore, a good correlation between cell density and formate oxidation activity was established using EcFDH-H variants with variable catalytic activities. As proof of concept, the growth assay was employed to screen a library of 1,032 EcFDH-H variants and reduced the library size to 96 clones. During the subsequent colorimetric screening of these clones, the variant A12G exhibiting an 82.4% enhanced formate oxidation rate was identified. Since many metal-dependent formate dehydrogenases and hydrogenases form functional complexes resembling E. coli FHL, the demonstrated growth-based screening strategy may be adapted to components of such electron-transferring complexes.IMPORTANCEOxygen-sensitive metalloenzymes are highly potent catalysts that allow the reduction of chemically inert substrates such as CO2 and N2 at ambient pressure and temperature and have, therefore, been considered for the sustainable production of biofuels and commodity chemicals such as ammonia, formic acid, and glycine. A proven method to optimize natural enzymes for such applications is enzyme engineering using high-throughput variant library screening. However, most screening methods are incompatible with the oxygen sensitivity of these metalloenzymes and thereby limit their relevance for the development of biosynthetic production processes. A microtiter plate-based assay was developed for the screening of metal-dependent formate dehydrogenase that links the activity of the tested enzyme variant to the growth of the anaerobically grown host cell. The presented work extends the application range of growth-based screening to metalloenzymes and is thereby expected to advance their adoption to biosynthesis applications.

RNA-Binding Small Molecules in Drug Discovery and Delivery: An Overview from Fundamentals.

RNA molecules, similar to proteins, fold into complex structures to confer diverse functions in cells. The intertwining of functions with RNA structures offers a new therapeutic opportunity for small molecules to bind and manipulate disease-relevant RNA pathways, thus creating a therapeutic realm of RNA-binding small molecules. The ongoing interest in RNA targeting and subsequent screening campaigns have led to the identification of numerous compounds that can regulate RNAs from splicing, degradation to malfunctions, with therapeutic benefits for a variety of diseases. Moreover, along with the rise of RNA-based therapeutics, RNA-binding small molecules have expanded their application to the modification, regulation, and delivery of RNA drugs, leading to the burgeoning interest in this field. This Perspective overviews the emerging roles of RNA-binding small molecules in drug discovery and delivery, covering aspects from their action fundamentals to therapeutic applications, which may inspire researchers to advance the field.

Association of dietary diversity and weight change with cognitive impairment among Chinese elderly: A prospective national cohort study

BackgroundDietary diversity is reported to be beneficial for cognitive function, while the effect may be offset by weight change status. We aimed to examine the association of dietary diversity and weight change with cognitive impairment among older adults. MethodsWe used three waves from 2008 to 2014 of the Chinese Longitudinal Survey of Health and Longevity, which included 16,954 participants for the subsequent screening and analysis. Dietary diversity information was collected from the food frequency questionnaire. Cognitive function was assessed using the Mini Mental State Examination. The relation of dietary diversity and weight change with cognitive impairment was investigated using Cox proportional hazards models and cubic spline regression. ResultsCompared with those reported poor dietary diversity at baseline, participants with good dietary diversity had a 16 % (hazard ratio [HR] = 0.84, 95 % confidence interval [CI]: 0.71–0.99) lower risk of cognitive impairment. The HR and 95 % CI of participants with consistently good dietary diversity from 2008 to 2011 was 0.71 (0.57–0.89) for cognitive impairment compared to those with consistently poor dietary diversity. Compared with the weight stable group, the HRs and 95 % CI for cognitive impairment were 1.34 (1.10–1.64) in weight loss group, and 1.08 (0.88–1.33) in weight gain group. Restricted cubic splines showed the risk of cognitive impairment decreased with higher dietary diversity score or less weight change, though no significant interaction between dietary diversity and weight change was found. LimitationGiven the observational nature of this study, there might be a reverse causation for the observed association. ConclusionEstablishing and maintaining good dietary diversity were associated with a lower risk of cognitive impairment regardless of weight change status, whereas weight loss was associated with increased cognitive impairment risk independently among older Chinese adults.