Additive Effects Research Articles

Short-term efficiency of plasma exchange in combination with immunosuppressants and/or biologics in the treatment of idiopathic inflammatory myopathy with rapidly progressive interstitial lung disease: a systematic review and meta-analysis

Objective Rapidly progressive interstitial lung disease (RP-ILD) is a frequent and serious manifestation of idiopathic inflammatory myopathy (IIM) associated with poor outcomes. Plasma exchange (PE) can quickly remove pathogenic substances from the blood. Therefore, PE may be efficacious in IIM patients who have elevated levels of autoantibodies, cytokines and chemokines, fighting for time for immunosuppressive therapy. However, the value of adding PE to immunosuppressants remains unclear. The purpose of this study was to determine the short-term outcomes, including the survival rate at 6 months and change of the laboratory data, of PE in combination with immunosuppressants and/or biologics in the treatment of IIM-RP-ILD. Methods We searched PubMed, Embase and Cochrane Library to find reports of interest published from inception to March 4, 2024. STATA 15.1 was used for data analysis. A fixed or random-effects model with inverse-variance weighting was used to estimate the pooled risk ratio (RR) and 95% confidence interval (CI). Results Two hundred and thirty studies were identified. Eleven studies, including five retrospective cohort studies, four case-control studies and two case series, were included. PE was performed on 114 patients. The survival rate at 6 months was 80% (95%CI = 64%–92%), with moderate heterogeneity (I 2=63.45%, p < 0.05). Moreover, the 6-month survival rate was significantly better in the PE group than in the non-PE group (RR, 1.34; 95% CI = 1.05–1.71, I 2=30.7%; p = 0.194). ILD-related serum markers, including ferritin, KL-6 and anti-MDA-5 antibody titres, were significantly suppressed by a series of PE treatments (p < 0.05). Conclusion The application of PE therapy plus treatment with corticosteroids, immunosuppressants and/or biologics was effective for patients with IIM-RP-ILD. PE may have additional supportive effect in intractable disease.

Unveiling genetic basis of yield and salinity tolerance in rice (Oryza sativa L.) through insights from generation mean analysis

Abstract Rice (Oryza sativa L) serves as a primary food source for over a billion people worldwide and is encountering challenges in yield due to the increasing global population and climate changes. Understanding the genetic variations that underlie complex traits is crucial for its enhancement and this can be accomplished through generation mean analysis. In this study, investigation was made to study the genetic mechanisms governing important quantitative traits, specifically yield and salinity tolerance in rice. The study involved six generations (P1, P2, F1, F2, B1 and B2) resulting from two crosses between three parents. The investigation specifically focused on generation mean analysis, assessing twelve traits includes days to flowering, plant height , total number of tillers , number of productive tillers , panicle length, flag leaf length, flag leaf width, number of filled grains per panicle, total number of grains per panicle, spikelet fertility, thousand-grain weight and single plant yield in the two crosses. In Cross I (ADT 45 × APD 19002), traits such as plant height, days to fifty percent flowering, total number of tillers and total number of grains per panicle exhibited opposing signs for dominance × dominance (l) and dominance (h), indicating a prevalence of duplicate epistasis. At the same time, additive and additive × additive gene effects influenced total number of tillers, plant height, total number of grains per panicle, number of filled grains per panicle and spikelet fertility. In Cross II (CO 54 × APD 19002), total number of tillers, plant height, flag leaf length, total number of grains per panicle, spikelet fertility and single plant yield suggested a predominance of duplicate epistasis. Further, the total number of grains per panicle, total number of tillers per plant, spikelet fertility and thousand-grain weight were primarily governed by additive and additive × additive gene effects. These observations show the feasibility of enhancement through selection in subsequent generations, emphasizing the necessity of integrating selection with salinity tolerance screening for the development of high-yield, salinity-tolerant rice varieties. Keywords: Scaling test, genetic effects, salinity tolerance

Development of an intelligent model for management of the requirements of marketing projects of the pharmaceutical industry

The object of research is the processes of managing the requirements of the marketing project using means of intelligent data analysis and artificial intelligence systems. Marketing projects include a large number of projects of various types, formats and scales. The work considers projects that are initiated at an existing pharmaceutical enterprise that produces drugs for the local market. Over a period of time, the company needs to introduce new dosage forms to the market. It is not about the development of new innovative drugs. Usually, these are new mixtures of known components, but according to the results of global research, adding new components to the formulation gives a new, additional effect. Also, it can be a new form, for example, a spray or syrup for children, etc. Nevertheless, in order to produce such a new product and bring it to the market, to make a profit, it is necessary to conduct a study of the local market in order to find analogues, consumer expectations and predict future cash flows from sales of new drugs. In order to form requirements for the project of creating and manufacturing a new medicinal form, the company initiates marketing projects. Such marketing projects are the subject of research. As a result of the marketing project of the analysis of the drug market, it is necessary to form the contours of a new product and the requirements for the project of creating this product – a new medicinal product. Collecting and forming requirements is not a trivial task. Therefore, in the work, it is proposed to apply means of intelligent data analysis, which will be implemented on artificial intelligence systems. As a result, an intelligent model for managing the requirements of marketing projects of the pharmaceutical industry was developed. The non-triviality of the task of requirements formation is based on the fact that it is multi-criteria. The desired requirements and, accordingly, the future product of the project depend on: the lack of a similar dosage form on the local market, the presence of theoretical and practical pharmacological developments in this direction, the technical and financial capabilities of the enterprise, the expectations of stakeholders and consumers of the product. The use of intelligent tools will allow to avoid a conflict of requirements and to develop a medicine that will not only meet the expectations of all participants of the local pharmaceutical market, but also provide profit to the developing company.

The role of E-wave velocity in predicting early left ventricular dysfunction and significant decline in left ventricular ejection fraction after mitral valve repair for severe chronic primary mitral regurgitation.

Preoperative left ventricular (LV) ejection fraction (LVEF) and LV end-systolic dimension (LVESD) are established predictors of LV dysfunction (LVD) after mitral valve repair (MVr) for mitral regurgitation (MR). Although elevated estimated right ventricular systolic pressure (eRVSP) indicating pulmonary hypertension is the best proposed additional predictor, we hypothesized that transthoracic echocardiography (TTE) parameters more directly reflecting left atrial pressure (LAP) would more accurately predict LVD than eRVSP. Furthermore, predictors of a significant decline in LVEF remain unknown. We retrospectively studied 622 patients, aged 20-87years, who underwent MVr for severe chronic primary MR. As previously reported predictors of postoperative LVD, we collected seven preoperative TTE parameters, including LVESD, LVEF, eRVSP, LV end-diastolic dimension, left atrial volume index (LAVI), early transmitral annular (e') velocity, and atrial fibrillation. Furthermore, as LAP-related TTE parameters, we collected left atrial dimension, E-wave velocity, and E/e' ratio, in addition to eRVSP and LAVI. Using multivariate logistic regression and receiver operating characteristic curve analyses, we explored predictors of early postoperative LVD, defined as LVEF < 50% measured on postoperative day 7. We further explored predictors of a significant decline in LVEF, defined as an absolute decline in LVEF of > 12 percentage points, the third quintile of the data. Incidences of postoperative LVD and a significant LVEF decline were 12.9% and 23.2%, respectively. In addition to LVESD and LVEF, E-wave velocity, but not eRVSP, remained a significant predictor of postoperative LVD. E-wave velocity, LVESD, and LVEF had additive effects in risk prediction. Furthermore, E-wave velocity was the strongest predictor of a significant LVEF decline. E-wave velocities > 121.5cm/s and > 101.5cm/s were associated with increased risks of postoperative LVD (odds ratio [OR], 2.896; 95% confidence interval [95%CI], 1.792-4.681; p < 0.001) and a significant LVEF decline (OR, 6.345; 95%CI, 3.707-10.86; p < 0.001), respectively. After adjustment for multiple TTE parameters, E-wave velocity, but not eRVSP, remained significant predictors of postoperative LVD and a significant LVEF decline after MVr. These results were reproducible in 461 patients who underwent follow-up TTE at 1year, suggesting an important role of E-wave velocity in risk prediction.

Antibacterial Activity of Glycosylated Flavonoids Isolated from Ocotea notata Leaves.

Research into natural products has led to the discovery of new drugs. This work shows relevant data on the antibacterial activity of Ocotea notata leaves. Dichloromethane fraction (DF) from leaves of O. notata showed antibacterial activity at the concentration of 512 μg/mL against strains of Staphylococcus. The DF was fractionated to investigate bioactive compounds and yielded six subfractions (DF1-DF6). The DF3, DF5, and DF6 showed bacteriostatic activity and DF4 showed bactericidal activity at the concentration of 2048 μg/mL and additive effect when combined with the antibiotic oxacillin. The flavonoids miquelianin (1), isoquercitrin (2), reynoutrin (3), guaijaverin (4), and afzelin (5) were isolated from the DF4 and characterized via NMR and HPLC-DAD-MS/MS analyses. Flavonoids 1-5, especially reynoutrin (3), seem to be responsible for the DF4 antibacterial activity. Reynoutrin showed activity against Staphylococcus epidermidis ATCC 12228 and S. aureus methicillin-resistant ATCC 33591. This is the first report regarding the reynoutrin antibacterial activity and the first description of the flavonoid guaijaverin for O. notata.

Genetic inheritance studies in rice (Oryza sativa L.) for grain protein, quality and yield

The present study was undertaken to investigate the genetic parameters of yield component and quality traits of the F3 population from BPT 5204 and JAK-686 cross in rice. High heritability and high genetic advance as a percentage of the mean were recorded for productive tillers per plant, grains per panicle, panicle length and grain yield per plant indicating the effectiveness of direct phenotypic selection for improvement of these traits. For traits such as grains per panicle, 1000 grain weight, amylose content and grain protein content, the magnitude of additive (d) effects surpassed dominance (h) gene effects. This implies that phenotypic selection using methods like pureline selection, mass selection would be beneficial. Gel consistency exhibited complimentary gene interaction. Furthermore, duplicate gene interaction was prevalent in traits like days to 50% flowering, productive tillers per plant, plant height, panicle length, grain yield per plant, kernel length, kernel breadth, and kernel L/B ratio, making selection in later generations more effective. The inheritance studies highlighted the importance of selecting desired recombinants from the segregating population to enhance rice quality as well as grain yield. Keywords: Rice, Grain protein content, Quality, Variability, Heritability, Gene action

Preparation of Antimicrobial Agents: From Interpolyelectrolyte Complexes to Silver-Containing Metal–Polymer Complexes and Nanocomposites

In order to control pathogenic microorganisms, three polymer compositions were prepared and tested. First, a water-soluble positively charged polycomplex was synthesized via the electrostatic binding of anionic polyacrylic acid to an excess of polyethylenimine to enhance the biocidal activity of the polycation. Second, an aqueous solution of AgNO3 was added to the polycomplex, thus forming a ternary polycation-polyanion-Ag1+ complex with an additional antimicrobial effect. Third, the resulting ternary complex was subjected to UV irradiation, which ensured the conversion of Ag1+ ions into Ag nanoparticles ranging in size mainly from 10 to 20 nm. Aqueous solutions of the polymer compositions were added to suspensions of the Gram-positive bacteria S. aureus and the Gram-negative bacteria P. aeruginosa, with the following main results: (a) Upon the addition of the binary polycomplex, 30% or more of the cells survived after 20 h. (b) The ternary complex killed S. aureus bacteria but was ineffective against P. aeruginosa bacteria. (c) When the ternary complex with Ag nanoparticles was added, the percentage of surviving cells of both types did not exceed 0.03%. The obtained results are valuable for the development of antibacterial formulations.

Genotype by environment interaction across water regimes in relation to cropping season response of quinoa (Chenopodium quinoa).

Genotype × environment (GxE) interaction effects are one of the major challenges in identifying cultivars with stable performance across agri-environments. In this study we analysed GE interactions to identify quinoa (Chenopodium quinoa) cultivars with high and stable yields under different soil moisture regimes, representing control conditions, waterlogging and drought. Waterlogging and drought treatments were artificially induced using normoxia, a combination of hypoxia-normoxia, and 10% PEG (Polyethylene glycol) under hydroponic growth conditions, respectively. Both waterlogging and drought conditions significantly reduced the plant height (PH), number of leaves (NoL) and number of branches (NoB), stem diameter (SD), leaf area (LA) and dry weight (DW) of quinoa genotypes. The genotype, water regime, and genotype by water regime effects all significantly affected the measured quinoa traits. Based on the additive main effects and multiplicative interaction (AMMI) model for DW, the genotypes G18, Puno, Q4, 2-Want, Puno, Real1 x Ruy937 and Titicaca were found to exhibit tolerance and were stable across water regimes. A second-stage evaluation was conducted to test genotype × environment interaction effects in crop production field trials, selecting two contrasting seasons based on soil moisture conditions involving a diverse set of genotypes (58 varieties in total). Our results demonstrate significant variations in both growth and yield among the quinoa genotypes across the cropping seasons. The GGE analysis for grain yield indicate that field conditions matched to G × E under hydroponic experimental conditions and the cultivars G18, Q1, Q4, NL-3, G28, 42-Test, Atlas and 59-ALC were classified within a range of high productivity. Our findings provide a basis for understanding the mechanisms of wide adaptation, while identifying germplasm that enhances the water stress tolerance of quinoa cultivars at early growth stages.

The Impact of Healthcare Pressures on the COVID-19 Hospitalisation Fatality Risk in England.

As the impact of the SARS-CoV-2 pandemic extends into 2023 and beyond, the treatment and outcomes of infected patients continues to evolve. Unlike earlier in the pandemic there are now further infectious disease pressures placed on hospitals, which influence patient care and triage decisions. The manuscript uses individual patient records linked with associated hospital management information of system pressure characteristics to attribute COVID-19 hospitalisation fatality risks (HFR) to patients and hospitals, using generalised additive mixed effects models. Between 01 September 2022 and 09 October 2023, the COVID-19 hospitalisation fatality risk in England was estimated as 12.71% (95% confidence interval (CI) 12.53%, 12.88%). Staff absences had an adjusted odds ratio of 1.038 (95% CI 1.017, 1.060) associatedwith the HFR when accounting for patient and hospital characteristics. This observational research presents evidence that a range of local hospital effects can have a meaningful impact on the risk of death from COVID-19 once hospitalised and should be accounted for when reporting estimates. We show that both the patient case mix and hospital pressures impact estimates of patient outcomes.

Unveiling Phenotypic and Environmental Dynamics: Exploring Genetic Stability and Adaptability of Faba Bean Cultivars in Norwegian Climates

ABSTRACTThis study evaluated 22 spring‐type faba bean cultivars in the main areas for cultivation of faba bean in Norway to assess the variation of 14 faba bean traits due to cultivar (G), environment (E), and their interaction (G × E), and to assess their stability across environments by using the additive main effects and multiplicative interaction (AMMI) analysis and coefficient of variation (CV). Significant G, E, and G × E effects were found for most traits, with environment accounting for much of the variance in yield and the growing degree days (GDD) to different developmental stages. Yield was highly correlated with thousand kernel weight (TKW) and GDD to BBCH 89 (maturation). The stability of the cultivars was studied for yield, TKW, and GDD to BBCH 89. Stability analysis using the AMMI stability value, yield stability index, CV, and the average sum of ranks identified Birgit, Stella, Bobas, and Macho as the most stable high‐yielding cultivars across environments, achieving a mean yield of 6–6.4 tons ha−1. Bobas, Macho, Stella, and Yukon had the most stable TKW (612–699 g) and Bobas, Capri, Trumpet, and Vertigo were the most stable regarding GDD to BBCH 89 (1257°C days, with a base temperature of 5°C). These stable cultivars can be utilized in breeding programs to achieve high and stable faba bean yield in the main growing areas of Norway and other Nordic‐Baltic countries.

Genetic Analysis for Seed Yield and Yield‐Related Traits in Tepary Bean (Phaseolus acutifolius A. Gray) Under Drought‐Stress and Non‐stress Conditions

ABSTRACTTepary bean (Phaseolus acutifolius A. Gray) is an under‐utilized genetic resource with significant potential for food security and stress tolerance breeding. Expanding its cultivation in southern Africa requires high‐yielding, locally adapted and drought‐tolerant varieties. This study determined the combining ability and genetic components for seed yield and related traits in tepary bean genotypes under non‐stress (NS) and drought‐stress (DS) conditions. Seven parents were selected through rigorous phenotyping and crossed using a half‐diallel design. The 7 parents and 21 F2 progenies were evaluated in 2021/2022 season at Kasinthula and Bunda sites in Malawi under NS and DS conditions using a 4 × 7 lattice design with three replications. The specific combining ability (SCA) × location interaction effect was significant (p &lt; 0.05) for DTF, NPP, and SY, suggesting that the genetic effects of crosses were influenced by the test locations. General combining ability (GCA) and SCA mean squares were significant for the number of seeds per pod (NSP) and SY under DS conditions, indicating both additive and non‐additive gene effects. Baker's ratio (BR) &gt; 0.50 for NPP and NSP under DS conditions suggested a preponderance of additive gene effects. G40145, G40148 and G40150 parental lines were good combiners for NPP and SY. The F2 families from crosses such as Zimbabwe landrace/G40138, Zimbabwe landrace/G40150, G40059/G40145, G40059/G40148, G40138/G40150 and G40145/G40150 were identified as best specific combiners, with enhanced SY of 1.67 t/ha under DS conditions. The study recommends advancing high‐performing early‐generation families for selection across representative environments to facilitate variety release and commercialization.

Superlattice Assembly for Empowering Metal Nanoclusters.

ConspectusAtomically precise metal nanoclusters, serving as an aggregation state of metal atoms, display unique physicochemical properties owing to their ultrasmall sizes with discrete electronic energy levels and strong quantum size effects. Such intriguing properties endow nanoclusters with potential utilization as efficient nanomaterials in catalysis, electron transfer, drug delivery, photothermal conversion, optical control, etc. With the assistance of atomically precise operations and theoretical calculations on metal nanoclusters, significant progress has been accomplished in illustrating their structure-performance correlations at the single-molecule level. Such research achievements, in turn, have contributed to the rational design and customization of functional nanoclusters and cluster-based nanomaterials.Most previous studies have focused on investigating structure-property correlations of nanocluster monomers, while the exploration of electronic structures and physicochemical properties of hierarchical cluster-based assembled structures was far from enough. Indeed, from the application aspect, the nanoclusters with controllably assembly states (e.g., crystalline assembled materials, host-guest hybrid materials, amorphous powders, and so on) were more suitable for performance expression relative to those in the monomeric state and more directed to downstream solid-state applications. In this context, more attention should be paid to the state-correlated property variations of metal nanoclusters occurring in their aggregating and assembling processes for better applications in accordance with their aptitude.Crystalline aggregates are crucial in the structural determination of metal nanoclusters, also acting as a cornerstone to analyze the structure-property correlations by affording atomic-level information. The regular arrangement, uniform composition, and close intermolecular distance of the cluster molecules in their supercrystal lattices are beneficial for property retention and amplification from the molecule itself as a monomeric state. Besides, for these nanoparticles with strong quantum size effects, the intercluster distances in the supercrystal lattices are still located at the nanoscale level, wherein the quantum size effect is highly likely to take effect with additional intermolecular synergistic effects. Accordingly, it is expected that novel performances might occur in the crystalline aggregates of nanoclusters that are completely different from those in the monomolecular state.In this Account, we emphasize our efforts in exploring the performance enhancement of atomically precise metal nanoclusters in their crystalline aggregate states, such as thermal stability, photoluminescence, optical activity, and an optical waveguide. Such performance enhancements further supported the practical uses of metal nanoclusters in structure determination, a polarization switch, an optical waveguide device, and so on. We also demonstrated that the differences in physicochemical properties between crystalline aggregates and monomers of metal nanoclusters might be attributed to the change in electronic structures during the crystalline aggregation processes in the superlattice. The "superlattice assembly" is intended to customize the function of cluster-based aggregates for downstream solid-state applications.

Do human resource systems indeed have "system" effects? The dual internal fit model of a high-performance work system.

The configurational or "internal fit" perspective proposes that human resource (HR) systems are most effective when individual practices are configured such that they fit together and are mutually reinforcing. The Ability-Motivation-Opportunity (AMO) model has emerged as a predominant way to select and configure HR practices based on whether they attempt to enhance employee ability, motivation, or opportunities. Despite the widespread use of the configurational perspective and AMO model in building a high-performance work system (HPWS), researchers have not clearly articulated how HR practices across the AMO domains should be configured to maximize internal fit across the system. Moreover, research has overlooked the hierarchical nature of an HPWS, such that HR practices are nested within a particular AMO domain, and the AMO domains, in turn, are nested within the HPWS. To address these gaps, we develop and test a dual internal fit model that specifies synergistic interactions within and among AMO domains. Analyses of six-wave panel data from 640 firms reveal that internal fit effects of HR practices simultaneously exist within (i.e., HR practice-level interactions) and among AMO domains (i.e., AMO domain-level interactions) to predict workforce productivity and ultimately firm profitability. Moreover, the two sets of interactions predict outcomes beyond the additive effects of the HR practices on which prior research has typically focused. These findings show that HR practices can be configured to have "system" effects. They also highlight the value of the dual internal fit model to understand the performance benefits of optimally configured HR systems. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A randomized phase I study of BI 1820237, a novel neuropeptide Y receptor type 2 agonist, alone or in combination with low-dose liraglutide in otherwise healthy men with overweight or obesity.

Pharmacotherapeutic options for obesity treatment include glucagon-like peptide-1 receptor (GLP-1R) agonists, for example, liraglutide. However, an unmet need remains, particularly in patients with a high body mass index (BMI), as GLP-1R agonists are associated with gastrointestinal adverse events (AEs) and some patients do not respond to treatment. Neuropeptide Y (NPY) and peptide YY bind G-protein-coupled Y receptors and represent attractive targets for modulating bodyweight. This first-in-human, three-part, partially blinded phase I study (NCT04903509) investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of the peptidic NPY2R agonist BI 1820237, with/without low-dose liraglutide: part 1 (participants randomized to receive BI 1820237: 0.075-2.4 mg or placebo), part 2 (BI 1820237: 1.2 mg or placebo) and part 3 (BI 1820237: 0.025-1.2 mg + liraglutide 0.6 mg or placebo + liraglutide 0.6 mg). Primary endpoint is the proportion of participants with drug-related AEs. Secondary endpoints are tolerability, PK and PD. In total, 95 otherwise healthy men with increased BMI (25.0-34.9 kg/m2) were randomized. Drug-related AEs, mainly gastrointestinal events, were reported by 39.0% of participants (n = 23) in parts 1 + 2 and 30.6% of participants (n = 11) in part 3; one drug-related AE (11.1%, part 3) was reported in a participant receiving placebo with liraglutide. Post-dose paracetamol PK suggested that BI 1820237 and low-dose liraglutide exhibited additive effects on gastric emptying. BI 1820237 treatment was associated with transient nausea and vomiting at higher doses. No differences in tolerability were observed when combined with liraglutide; effects on gastric emptying appeared additive.

Effectiveness of neck-specific exercises with and without internet-based support on dizziness/unsteadiness in chronic whiplash-associated disorders: Secondary analyses of a randomised controlled trial.

To investigate the effectiveness in individuals with chronic whiplash-associated disorders (WADs) of neck-specific exercise (NSE) supervised by a physiotherapist twice a week for 12 weeks versus neck-specific exercise with internet support and four physiotherapy visits (NSEIT) regarding dizziness, unsteadiness and balance, and to investigate the differences between WAD grades. This is a secondary analysis of a prospective randomised multicentre study (RCT) with concealed allocation (ClinicalTrials.gov Protocol ID: NCT03022812). The outcomes were dizziness measured on the Dizziness Handicap Inventory (DHI); dizziness at rest and during activity and unsteadiness using visual analogue scales; and standing on one leg with eyes closed (SOLEC). Participants (n = 140) were randomised to NSE or NSEIT. Measurements were obtained at baseline, and at three- and 15-month follow-ups by assessor-blinded investigators. There were no significant differences between NSEIT and NSE in any of the outcomes (p>0.38). Both NSEIT and NSE improved over time (p<0.02; effect size (ES) = 0.74-1.01) in DHI score and dizziness during activity. There was a significant group-by-time interaction effect in dizziness (at rest: p = 0.035; ES: 0.66; and during activity: p = 0.016; ES: 1.24) between WAD grades. Individuals with WAD grade 3 had dizziness/unsteadiness to a greater extent and improved in all outcomes over time (p<0.04) compared to those with WAD grade 2, except for SOLEC. There were no significant group differences between NSEIT and NSE. Both groups decreased in terms of self-reported dizziness (DHI, dizziness during activity), with medium to large effect size. Those with WAD grade 3 have dizziness/unsteadiness to a greater extent than those with WAD grade 2. Despite improvements, many participants still reported dizziness at 15-month follow-up, and additional balance training and/or vestibular exercise may be investigated for potential additional effect.

Alkaloids solenopsins from fire ants display in vitro and in vivo activity against the yeast Candida auris

ABSTRACT The urgency surrounding Candida auris as a public health threat is highlighted by both the Center for Disease Control (CDC) and World Health Organization (WHO) that categorized this species as a priority fungal pathogen. Given the current limitations of antifungal therapy for C. auris, particularly due to its multiple resistance to the current antifungals, the identification of new drugs is of paramount importance. Some alkaloids abundant in the venom of the red invasive fire ant (Solenopsis invicta), known as solenopsins, have garnered attention as potent inhibitors of bacterial biofilms, and there are no studies demonstrating such effects against fungal pathogens. Thus, we herein investigated the antibiotic efficacy of solenopsin alkaloids against C. auris biofilms and planktonic cells. Both natural and synthetic solenopsins inhibited the growth of C. auris strains from different clades, including fluconazole and amphotericin B-resistant isolates. Such alkaloids also inhibited matrix deposition and altered cellular metabolic activity of C. auris in biofilm conditions. Mechanistically, the alkaloids compromised membrane integrity as measured by propidium iodide uptake in exposed planktonic cells. Additionally, combining the alkaloids with AMB yielded an additive antifungal effect, even against AMB-resistant strains. Finally, both extracted solenopsins and the synthetic analogues demonstrated protective effect in vivo against C. auris infection in the invertebrate model Galleria mellonella. These findings underscore the potent antifungal activities of solenopsins against C. auris and suggest their inclusion in future drug development. Furthermore, exploring derivatives of solenopsins could reveal novel compounds with therapeutic promise.

7765 Exploring the Synergistic Effect of GHRH Receptor Agonist MR-409 and Incretin-based Therapies in Type 1 Diabetes Using a Low-dose Streptozotocin Model

Abstract Disclosure: M. Gonzalez Medina: None. R. Louzada: None. V. Pita-Grisanti: None. M. Blandino: None. T. Cui: None. W. Sha: Owner/Co-Owner; Self; WS. is co-inventor on GHRH agonists MR-409 patent, assigned to the University of Miami and the Veterans Affairs. R. Cai: Owner/Co-Owner; Self; R.C. is co-inventor on GHRH agonists MR-409 patent, assigned to the University of Miami and the Veterans Affairs. A.V. Schally: Owner/Co-Owner; Self; A.V.S. is co-inventor on GHRH agonists MR-409 patent, assigned to the University of Miami and the Veterans Affairs.. E. Bernal-Mizrachi: None. Patients with type 1 diabetes (T1D) have decreased functional β-cell mass due to inflammatory cell infiltration and cytokine-induced β-cell death. Clinical trials using a combination of immunomodulatory agents and β-cell protecting medications such as GLP1-R agonists (GLP1-Ra) are being considered. A potential limitation for the clinical efficacy of GLP1-R agonists is the loss of GLP-1-R at the cell surface in states of hyperglycemia. Hence, novel agents that enhance β-cell survival and proliferation through parallel pathways could improve responses to GLP1-R agonists and/or synergistically potentiate β-cell responses. Previous studies have demonstrated beneficial effects of growth hormone-releasing hormone receptor agonists (GHRH-Ra), such as MR-409 on islet preconditioning in transplantation models. Our previous studies showed that GHRH-Ra protects β-cells from autoimmune injury in vitro and improves glucose levels in a model of high-dose streptozotocin-induced diabetes via stimulation of the cAMP/PKA/CREB/IRS2 axis. However, the effects of combination of incretin-based therapy with GHRHRa on β-cell survival in T1D models have not yet been explored. Using the low-dose STZ model in C57/B6 mice, we investigated how MR-409 alone or in combination with GLP1-R agonists (Exendin-4 or Ex-4) promotes β-cell survival and prevents T1D. Low-dose STZ treated mice received daily MR-409 and Ex-4 injections, either alone or in combination for six weeks. We found that, STZ-treated mice that received either MR-409, Ex-4 or combination exhibited better glucose homeostasis while the combination failed to induce any additional effect. Interestingly, glucose tolerance and insulin levels were improved only in the MR-409-treated mice. β-cell mass was similarly increased in mice that received MR-409, Ex-4 and combination groups compared to the vehicle-treated. Further, treatment of human islets with MR-409 and/or Ex-4 induced insulin receptor substrate 2 (IRS2) expression, a master regulator of survival and growth in β-cells, while the combination of both therapies did not have any additional effect. Experiments in human islets exposed to proinflammatory cytokines treatment demonstrated that MR-409 and/or Ex-4 was associated with a decrease in β-cell death and improved insulin secretory function by activation of the cAMP/PKA/CREB/IRS2 axis. These studies demonstrate that although there was no evidence for a synergistic effect between MR-409 and Ex-4, MR-409 appears to have more potent effects on improving glucose tolerance and insulin levels when compared to the long-term effect of Ex-4 in a low-dose STZ model, suggesting that MR-409 could be an alternative therapeutic agent in the treatment of β-cell death in T1D. Presentation: 6/2/2024

6826 Mevalonate Treatment Worsened Hypocholesterolemia During Prolonged Sepsis Without Affecting Adrenal And Muscle Function

Abstract Disclosure: L. De Bruyn: None. S. Derde: None. F. Van Beek: None. S. Vander Perre: None. I. Derese: None. L. Pauwels: None. G. Van den Berghe: None. L. Langouche: None. Introduction: Sepsis is hallmarked by an immediate and sustained reduction in total-, HDL- and LDL-cholesterol (-C), associated with illness severity and a potential contributor to the development of adrenal failure and muscle weakness. The underlying mechanisms that might be involved in sepsis-induced hypocholesterolemia are multifactorial and partly understood. We hypothesized that treatment with the cholesterol precursor mevalonate might improve cholesterol availability, thereby improving adrenal gland and skeletal muscle function. Our hypothesis was tested in a validated and clinically relevant mouse model of prolonged sepsis. Methods: In a catheterized mouse model of cecal ligation and puncture-induced, fluid resuscitated and antibiotics treated polymicrobial abdominal sepsis (5 d), septic mice received continuous infusion with either mevalonate (78 mg/d) or placebo solution, whereas healthy mice served as controls (N=50). Plasma total-C (HDL- + LDL-C), CORT and total bile acids were measured, in addition to ex vivo muscle force and adrenocortical cholesterol ester content. Gene expression markers of inflammation (Tnf-α, Il-6) were measured in the adrenal gland, as well as hepatic mRNA expression of cholesterol synthesis enzymes (Hmgcs1, Hmgcr, Fdft1). Metabolites of the mevalonate pathway (mevalonic acid, squalene, lanosterol, desmosterol and (7-dehydro) cholesterol) were quantified in the liver with LC-MS. Results: The sepsis-induced reduction in plasma total-C was further decreased in mevalonate-treated septic mice (26±3 mg/dL) as compared with placebo (53±3 mg/dL) and healthy controls (108±3 mg/dL) (p&amp;lt;0.0001). Metabolites of the mevalonate pathway were all increased in the liver after mevalonate treatment (p&amp;lt;0.01), whereas hepatic cholesterol content was decreased as compared with placebo (p&amp;lt;0.05). Also, gene expression markers of cholesterol synthesis enzymes were further decreased in the liver of mevalonate-treated septic mice as compared with placebo (p&amp;lt;0.05). In the context of the unexpected further reduction in plasma total-C, no additional effect on plasma CORT, total bile acids, and sepsis-induced loss of muscle force and depletion in adrenocortical cholesterol ester content was observed. In addition, the sepsis-induced rise in markers of adrenal inflammation (Tnf-α, Il-6) was not further affected by mevalonate treatment. Conclusion: Mevalonate treatment further reduced the sepsis-induced hypocholesterolemia in prolonged septic mice, potentially due to increased feedback inhibition on hepatic cholesterol biosynthesis, but without further affecting adrenal and muscle function. Other therapies such as substitution with bovine serum HDL-C are currently investigated to improve altered cholesterol availability during sepsis. Presentation: 6/2/2024

Screening and Site Adaptability Evaluation of Qi-Nan Clones (Aquilaria sinensis) in Southern China

In recent years, plantations of Aquilaria sinensis in China have been dominated by Qi-nan, yet there remains limited research on the growth evaluation and breeding of these clones. In this study, a multi-point joint variance analysis, an additive main effect and multiplicative interaction (AMMI) model, a weighted average of absolute scores (WAASB) stability index, and a genotype main effect plus a genotype-by-environment interaction (GGE) biplot were used to comprehensively analyze the yield, stability, and suitable environment of 25 3-year-old Qi-Nan clones from five sites in southern China. The results showed that all the growth traits exhibited significant differences in the clones, test sites, and interactions between the clones and test sites. The phenotypic variation coefficient (PCV) and genetic variation coefficient (GCV) of the clones’ growth traits at the different sites ranged from 16.56% to 32.09% and 5.24% to 27.06%, respectively, showing moderate variation. The medium–high repeatability (R) of tree height and ground diameter ranged from 0.50 to 0.96 and 0.69 to 0.98, respectively. Among the clones, Clones G04, G05, G10, G11 and G13 showed good growth performance and could be good candidates for breeding. Environmental effects were found to be the primary source of variation, with temperature and light primarily affecting growth, while rainfall influenced survival and preservation rates. Yangjiang (YJ) was found to be the most suitable experimental site for screening high-yield and stable clones across the different sites, whereas the tree height and ground diameter at the Chengmai (CM) site were significantly higher than at the other sites, and the Pingxiang (PX) and Zhangzhou (ZZ) sites showed poor growth performance. The findings suggest that Qi-nan clones are suitable for planting in southern China. There were also abundant genetic variations in germplasm resources for the Qi-nan clones. The five selected clones could be suitable for extensive planting. Therefore, large-scale testing is necessary for determining genetic improvements in Qi-nan clones, which will be conducive to the precise localization of their promotion areas.

7395 Developmental Programming: Adverse Effects Of Prenatal Exposure To A Real-Life Environmental Chemical Mixture Via Biosolids On Ovarian Folliculogenesis In Adult Sheep

Abstract Disclosure: Y. Zhou: None. K.M. Halloran: None. M. Bellingham: None. N.P. Evans: None. R.G. Lea: None. K.D. Sinclair: None. V. Padmanabhan: None. The ovarian capacity to provide fertilizable oocytes, regulate folliculogenesis as well as activate and progress primordial follicles into preovulatory follicles are key contributing factors to female fertility and reproductive aging. In sheep, as in humans, while genetics play a role in establishing the ovarian reserve during fetal development, developmental insults such as inappropriate exposure to native steroids or environmental chemicals (ECs) can adversely impact the establishment of the ovarian reserve and, additionally can affect folliculogenesis. Considering humans are exposed to multiple ECs simultaneously which could have additive, synergistic, or antagonistic effects, real-life EC exposure models are needed to assess risks posed by EC exposure. Offspring from sheep grazed on biosolids-treated pasture offers one such real-life exposure model. Studies with day 140 fetuses found maternal exposure to a real-life EC mixture via biosolids increased the proportion of unhealthy transitory follicles (Lea et al., Sci Rep. 2016;6:22279). The present study tested if biosolids exposure during fetal life would impact folliculogenesis, follicle activation and follicle atresia during their adult life. Ovaries were derived from adult EasyCare ewes (age 31.4 ± 0.5 months) whose mothers were grazed on biosolids-treated (BTP, n=10) or inorganic fertilizer-treated (Control, n=10) pastures from preconception through to birth. Ovarian morphometry was undertaken to assess the distribution and health status of follicles. Follicular atresia was evaluated via the expression of Caspase-3, an apoptosis marker. Data analysis utilized Student's t-test for normally distributed variables and Mann-Whitney U tests for non-parametric comparisons. There were no differences in the absolute counts or the percentages of follicle classes at all stages of folliculogenesis, the density of primordial follicles in cortical tissue, or the follicular activation rate. An increase in the percentage of unhealthy activated follicles (post-primordial) was noted in the BTP group (p = 0.014), predominantly in the transitory stage (p = 0.021). Consistent with this, a higher density of Caspase-3 positive primary follicles was observed in the BTP group (p = 0.033). These findings indicate the adverse impacts of fetal exposure to an EC mixture via maternal biosolid exposure on the survival of early-stage activated follicles in adult sheep. The lack of difference in ovarian reserve between the control and BTP groups suggests compensatory mechanisms may be in place to prevent premature depletion of the ovarian reserve. Whether EC mixture exposure via biosolids also has an adverse effect on the quality of the surviving activated follicles remains to be determined. Funding source: NIH R01 ES030374. Presentation: 6/3/2024