Moderate Accumulation Research Articles

Evaluation of the safety, tolerability, pharmacokinetics and pharmacodynamics of SM17 in healthy volunteers: results from pre-clinical models and a first-in-human, randomized, double blinded clinical trial

BackgroundAlarmins mediate type 2 T helper cell (Th2) inflammation and serve as upstream signaling elements in allergic inflammation and autoimmune responses. The alarmin interleukin (IL)-25 binds to a multi-domain receptor consisting of IL-17RA and IL-17RB subunits, resulting in the release of Th2 cytokines IL-4, IL-5, IL-9 and IL-13 to drive an inflammatory response. Therefore, the blockage of IL-17RB via SM17, a novel humanized monoclonal antibody, offers an attractive therapeutic target for Th2-mediated diseases, such as asthma.MethodsWild-type mice were stimulated with house dust mite (HDM) extracts for evaluation of SM17’s pre-clinical efficacy in allergic asthma. The safety, pharmacokinectics (PK), pharmacodynamics (PD), and immunogenicity of intravenous (IV) doses of SM17 were assessed in a 2-part clinical study in healthy adult subjects. In Part A, 53 healthy participants were enrolled to receive a single IV dose of SM17 (2, 20, 70, 200, 400, 600, 1200 mg) or placebo. In Part B, 24 healthy subjects were enrolled to receive a single IV dose of SM17 every two weeks (Q2W; 200, 400, 600 mg) or placebo for a total of 3 doses.ResultsAnimal studies demonstrated that SM17 significantly suppressed Th2 inflammation in the bronchoalveolar lavage fluid and infiltration of immune cells into the lungs. In the Phase I clinical study, no drug-related serious adverse events were observed. Total SM17 exposure increased by approximately 60- to 188-fold with a 60-fold increase in dose from 20 to 1200 mg SM17. Upon administration of the third dose, mean accumulation ratios over 200-600 mg was 1.5 to 2.1, which confirms moderate accumulation of SM17. After Q2W dosing of SM17 over 4 weeks, total exposure increased in a dose-proportional manner from 200 mg to 600 mg SM17.ConclusionIn the pre-clinical studies, we demonstrated that SM17 is a potential therapeutic agent to treat allergic asthma. In the Phase 1 clinical trial, a single IV dose of SM17 up to 1200 mg and three Q2W doses up to 600 mg were well tolerated in healthy participants and demonstrated a favorable safety profile. The pre-clinical efficacy and clinical PK and immunogenicity results of SM17 support further clinical development.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT05332834.

Even moderate liver fat accumulation below conventional fatty liver cutoffs is linked to multiple metabolomic alterations and gestational dysglycemia in Asian women of reproductive age

BackgroundIt is not clear if conventional liver fat cutoff of 5.56% weight which has been used for identifying fatty liver in western populations is also applicable for Asians. In Asian women of reproductive age, we evaluate the optimum metabolic syndrome (MetS)-linked liver fat cutoff, the specific metabolomic alterations apparent at this cutoff, as well as prospective associations of preconception liver fat levels with gestational dysglycemia.MethodsLiver fat (measured by magnetic resonance spectroscopy), MetS, and nuclear magnetic resonance (NMR)-based plasma metabolomic profiles were assessed in 382 Asian women, who were planning to conceive. Ninety-eight women went on to become pregnant and received an oral glucose tolerance test at week 26 of gestation.ResultsThe optimum liver fat cutoff for diagnosing MetS was 2.07%weight. Preconception liver fat was categorized into Low (liver fat < 2.07%), Moderate (2.07% ≤ liver fat < 5.56%), and High (liver fat ≥ 5.56%) groups. Individual MetS traits showed worsening trends, going from Low to Moderate to High groups. Multiple plasma metabolomic alterations, previously linked to incident type 2 diabetes (T2D), were already evident in the Moderate group (adjusted for ethnicity, age, parity, educational attainment, and BMI). Both a cross-sectional multi-metabolite score for incident T2D and mid-gestational glucose area under the curve showed increasing trends, going from Low to Moderate to High groups (p < 0.001 for both). Gestational diabetes incidence was 2-fold (p = 0.23) and 7-fold (p < 0.001) higher in the Moderate and High groups relative to the Low group.ConclusionsIn Asian women of reproductive age, moderate liver fat accumulation below the conventional fatty liver cutoff was not metabolically benign and was linked to gestational dysglycemia. The newly derived cutoff can aid in screening individuals before adverse metabolic phenotypes have consolidated, which provides a longer window for preventive strategies.

Adaptive peak price with lazy updates for short-term portfolio optimization

This paper introduces the novel Adaptive Peak Price with Lazy Updates (APPLU) approach for short-term portfolio optimization (SPO), a method that innovatively combines the Radial Basis Function (RBF) and a new lazy update approach to address the unique challenges of SPO. Our approach is tailored to balance the dual objectives of maximizing returns and minimizing transaction costs, which are critical concerns in dynamically allocating wealth among various assets over time. Unlike conventional methods that primarily rely directly on peak price information, APPLU introduces an adaptive peak price using RBFs to capture continuous depreciation information of assets, thereby alleviating the aggressive nature of traditional peak price strategies and avoiding frequent trades. Furthermore, we propose a new lazy update approach that employs unsquared l2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$l^{2}$$\\end{document}-norm regularization to represent portfolio changes. This approach contrasts with squared l2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$l^{2}$$\\end{document}-norm regularization, which disproportionately penalizes larger portfolio changes while being more lenient towards smaller changes. Thereby, our methodology offers a more balanced and effective approach to portfolio adjustment. Extensive experiments conducted on seven real datasets demonstrate that APPLU outperforms existing strategies in terms of cumulative return and risk-adjusted return, while effectively controlling transaction costs and maintaining a moderate wealth accumulation strategy.

Influence of Population Biomass Accumulation During Different Growth Periods on Agronomic Traits and Cotton Yield

Increased output per unit area is the main goal of cotton producers worldwide, and the determination of biomass for high-yield cotton production is most important index. Cotton plants were grown at five densities (2.25, 3.0, 3.75, 4.5, and 5.25 × 104 plants ha−1). The relationships between the lint yield, construction of vegetative and reproductive organs and the population biomass were investigated. The results indicated that the maximum lint yield could be obtained at an appropriate population biomass before peak flowering and that the maximum lint yield increased with the biomass after peak flowering. When a lint yield above 1875.0 kg ha−1 was achieved, the biomass was at 657.0, 2317.3 and 5398.0 kg ha−1 for peak squaring, early flowering and peak flowering, respectively, whereas it surpassed 11,977.4 kg ha−1 and 15,365.8 kg ha−1 for the biomass at peak boll-setting and during the boll open period, respectively. This study indicated that moderate biomass accumulation before peak flowering and higher population biomass accumulation after peak flowering could achieve high lint yield because of the construction of optimum plant height, maximum and suitable LAI, maximum fruiting branches and boll weight before peak flowering, the highest effective fruiting node number and the population boll number after peak flowering. The results suggest that agronomic measurements could be implemented according to population biomass dynamics of high yield during the main growth stages.

Vascular bundle cell-specific expression of a phosphate transporter improves phosphate use efficiency of transgenic Arabidopsis without detrimental effects

Constitutive overexpression of phosphate (Pi) transporter family 1 often results in the accumulation of toxic levels of Pi, which causes growth retardation in plants. In contrast, we had previously reported that root epidermis-specific overexpression of the phosphate transporter TaPT2 in Arabidopsis leads to improved growth and Pi use efficiency. In the present study, we used promoters AtHKT1;1 and SKOR, which are predominantly expressed in the vascular bundle tissues, to overexpress TaPT2. Transgenic lines exhibited increased shoot growth compared to wild type plants under normal- and low-Pi conditions, along with elevated root Pi and total P content, and higher xylem sap Pi concentration, specifically under low-Pi conditions. This was attributed to moderate Pi accumulation in the xylem parenchyma cells, enhancing the Pi uploading capacity to the xylem. SKOR-TaPT2, however, did not complement pho1 mutant, which was defective in uploading Pi to the xylem. The transcriptional levels of VPT1 and VPT3, which are responsible for transporting excess Pi into a vacuole, were upregulated in SKOR promoter lines under normal-Pi conditions. Our results suggested that root vascular bundle-specific expression of TaPT2 is another promising strategy for increasing biomass production, Pi uptake, and Pi use efficiency while preventing growth retardation in transgenic plants.

Assessment of transboundary macro-litter on the remote island of Andaman and Nicobar: Unveiling the governing factors and risk assessment

The increasing occurrence of mismanaged plastic litter along India's coastline and the ominous challenges it poses to biodiversity and ecosystem health is a growing environmental concern. To address this issue, we comprehensively investigated the abundance, composition, and probable sources of marine litter on North Cinque Island, a remote uninhabited island in the Andaman and Nicobar archipelago, Bay of Bengal. This island is a designated wildlife sanctuary and serves as an important nesting site for Green, Hawksbill and Leatherback turtles. A total of 6227 litter items were enumerated, with an average concentration of 0.12 items/m2, representing 20 diverse litter types, with plastic dominating the litter composition (86 %). The cleanliness and environmental hazards of the coast due to the litter were assessed using different indices such as the Clean Coast Index (CCI), Plastic Accumulation Index (PAI), Hazardous Item Index (HII), and Clean Environment Index (CEI). CCI indicates the moderately clean-to-clean status of the surveyed sites. PAI points to low to moderate accumulation of plastic litter. HII of all five coasts fell in category II, suggesting a moderate abundance of hazardous items that can inflict injuries to the foraging turtle and their hatchlings. The CEI articulates the moderately clean to very clean status of the sites. Litter brand audit suggests a considerable amount of stranded litter on the coasts was transboundary and originated from six Indian Ocean Rim Countries (IORC), namely Thailand, Myanmar, Malaysia, Indonesia, Sri Lanka, and UAE. Joint solid waste management by the IORC is the need of the hour to avert litter accumulation on the pristine, remote islands.

Beachrock: A chronological benchmark for Late Holocene build-up on the coast of Israel

Beachrock formations are proxies of coastal morphodynamics, and are thus commonly utilized for paleoenvironment interpretations. Linear beachrock outcrops parallel to the shoreline are typical of the Mediterranean coastline of Israel. A new geomorphic and sedimentological analysis of beachrock, integrated with relative and absolute geochronology, characterizes their clastic composition and determines their ages. In-situ beachrock outcrops in the sandy beaches of the Sharon coast of central Israel are composed of quartz sand, shells and shell fragments, and show a significant contribution of fragmented rocks from the coastal cliff. Sections of beachrocks analyzed using portable Optically Stimulated Luminescence (pOSL) provided a relative chronological framework within and between the sections. The results show a moderate optic signal accumulation, indicating a gradual beach build-up during initial beachrock formation stages. Optically Stimulated Luminescence (OSL) ages indicate deposition of unconsolidated beach sediments dated to about 1600–800 years before present (BP). The sediment burial at the former foreshore enabled rapid consolidation in the intertidal zone.

Moderate BMI accumulation modified associations between blood benzene, toluene, ethylbenzene and xylene (BTEX) and phenotypic aging: mediating roles of inflammation and oxidative stress

The associations between blood benzene, toluene, ethylbenzene, and xylenes (BTEX) and biological aging among general adults remain elusive. The present study comprised 5780 participants from the National Health and Nutrition Examination Survey 1999–2010. A novel measure of biological aging, phenotypic age acceleration (PhenoAge.Accel), derived from biochemical markers was calculated. Weighted generalized linear regression and weighted quantile sum regression (WQS) were utilized to assess the associations between BTEX components and mixed exposure, and PhenoAge.Accel. The mediating roles of systemic immune-inflammation index (SII) and oxidative stress indicators (serum bilirubin and gamma-glutamyl transferase), along with the modifying effects of body mass index (BMI) were also examined. In the single-exposure model, the highest quantile of blood benzene (b = 0.89, 95%CI: 0.58 to 1.20), toluene (b = 0.87, 95%CI: 0.52 to 1.20), and ethylbenzene (b = 0.80, 95%CI: 0.46 to 1.10) was positively associated with PhenoAge.Accel compared to quantile 1. Mixed-exposure analyses revealed a consistent positive association between BTEX mixed exposure and PhenoAge.Accel (b = 0.88, 95%CI: 0.56 to 1.20), primarily driven by benzene (92.78%). The association between BTEX and PhenoAge.Accel was found to be partially mediated by inflammation and oxidative stress indicators (ranging from 3.2% to 13.7%). Additionally, BMI negatively modified the association between BTEX mixed exposure and PhenoAge.Accel, with a threshold identified at 36.2 kg/m^2. Furthermore, BMI negatively moderated the direct effect of BTEX mixed exposure on PhenoAge.Accel in moderated mediation models, while positively modified the link between SII and PhenoAge.Accel in the indirect path (binteraction = 0.04, 95%CI: 0.01 to 0.06). Overall, BTEX mixed exposure was associated with PhenoAge.Accel among US adults, with benzene may have reported most contribution, and inflammation and oxidative damage processes may partially explain this underlying mechanism. The study also highlighted the potential benefits of appropriate BMI increased. Additional large-scale cohort studies and experiments were necessary to substantiate these findings.

Abstract CT184: First-in-human trial of TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa (BA) in patients (pts) with advanced solid unresectable tumors

Abstract Introduction: M6223 is an intravenous (IV), fully human, antagonistic, anti-TIGIT antibody with an Fc-mediated effector region. In preclinical studies, M6223 combined with BA (a bifunctional fusion protein that simultaneously targets the TGF-β and PD-(L)1 pathways) enhanced antitumor efficacy compared to either agent alone. Methods: This first-in-human, dose escalation study of M6223 as monotherapy (M6223; Part 1A) or in combination with BA (M6223+BA; Part 1B) included pts with advanced solid tumors (aged ≥18 years, ECOG PS ≤1) (NCT04457778). In Part 1A, pts received M6223 at 10 mg, 30 mg, 100 mg, 300 mg, 900 mg, 1600 mg, 2400 mg (all Q2W) or M6223 2400 mg Q3W. In Part 1B, pts received M6223 at 300 mg, 900 mg, or 1600 mg, all in combination with BA 1200 mg (both Q2W, IV). Dose escalation decisions by the Safety Monitoring Committee were assisted by a Bayesian 2-parameter logistic regression model. Primary objectives were safety, tolerability, maximum tolerated dose (MTD), and recommended dose for expansion (RDE). Additional objectives included pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity. Results: At final analysis, 40 pts (21 male, age range 24-79 years) had received M6223 (Q2W: n=32; Q3W: n=8), and 18 pts (7 male, age range 34-80 years) had received M6223+BA. Overall, two dose-limiting toxicities were observed: a grade 3 adrenal insufficiency (M6223, 900 mg) and a grade 3 anemia (M6223+BA, 300 mg; unrelated to M6223). In the M6223 group, grade ≥3 TEAEs were observed in 14 (35.0%) pts and M6223-related grade ≥3 TEAEs in 2 (5.0%) pts. In the M6223+BA group, grade ≥3 TEAEs were observed in 14 (77.8%) pts and M6223-related grade ≥3 TEAEs in 4 (22.2%) pts. No MTD was identified. RDEs were 1600 mg Q2W or 2400 mg Q3W for M6223 monotherapy, and 1600 mg+1200 mg Q2W for M6223+BA. Half-life for the two monotherapy RDEs were 9.0 and 14.6 days, respectively, with moderate accumulation at the selected RDEs. Linear PK was observed for M6223 at 100-2400 mg Q2W and at 2400 mg Q3W; co-administration with BA did not change the PK profile of M6223. PD analyses in blood showed full and sustained TIGIT target occupancy, and depletion of suppressive Tregs at M6223 ≥900 mg. Paired biopsies in the M6223 group (900 mg Q2W, 1600 mg Q2W, 2400 mg Q3W; n=12) showed a trend of decrease in TIGIT+ and increase in CD226+ cells. Median overall survival was 7.6 months (95% CI: 4.9, 12.0) and median progression-free survival was 1.4 months (95% CI: 1.3, 1.8). No pt achieved an objective response (per RECIST v1.1); stable disease as the best response was observed in 13 (32.5%) pts in M6223 and 5 (27.8%) pts in M6223+BA. Conclusion: M6223 monotherapy and in combination with BA had a manageable safety profile, and RDEs for both mono- and combination therapy were defined. Further evaluation of M6223 is ongoing in combination with PD-L1 inhibitor avelumab (JAVELIN Bladder Medley; NCT05327530). Citation Format: Aung Naing, Meredith McKean, Anthony Tolcher, Anja Victor, Ping Hu, Keyvan Tadjalli Mehr, Thomas Kitzing, Daniel Holland, Emilia Richter, Lillian Siu. First-in-human trial of TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa (BA) in patients (pts) with advanced solid unresectable tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT184.

Weathering Incongruence in Mountainous Mediterranean Climates Recorded by Stream Lithium Isotope Ratios

AbstractLithium isotope ratios (δ7Li) of rivers are increasingly serving as a diagnostic of the balance between chemical and physical weathering contributions to overall landscape denudation rates. Here, we show that intermediate weathering intensities and highly enriched stream δ7Li values typically associated with lowland floodplains can also describe small upland watersheds subject to cool, wet climates. This behavior is revealed by stream δ7Li between +22.4 and +23.5‰ within a Critical Zone observatory located in the Cévennes region of southern France, where dilute stream solute concentrations and significant atmospheric deposition otherwise mask evidence of incongruence. The water‐rock reaction pathways underlying this behavior are quantified through a multicomponent, isotope‐enabled reactive transport model. Using geochemical characterization of soil profiles, bedrock, and long‐term stream samples as constraints, we evolve the simulation from an initially unweathered granite to a steady state weathering profile which reflects the balance between (a) fluid infiltration and drainage and (b) bedrock uplift and soil erosion. Enriched stream δ7Li occurs because Li is strongly incorporated into actively precipitating secondary clay phases beyond what prior laboratory experiments have suggested. Chemical weathering incongruence is maintained despite relatively slow reaction rates and moderate clay accumulation due to a combination of two factors. First, reactive primary mineral phases persist across the weathering profile and effectively “shield” the secondary clays from resolubilization due to their greater solubility. Second, the clays accumulating in the near‐surface profile are relatively mature weathering byproducts. These factors promote characteristically low total dissolved solute export from the catchment despite significant input of exogenous dust.

Effects of Dietary Plant Protein Replacement with Insect and Poultry By-Product Meals on the Liver Health and Serum Metabolites of Sea Bream (Sparus aurata) and Sea Bass (Dicentrarchus labrax).

The liver health of Gilthead sea bream and European sea bass, fed with fish meal-free diets, including various proportions of plant proteins, as well as insect and poultry by-product meals, was investigated through biochemical and histological analyses using a new liver index (LI) formula. Four isoproteic (45% Dry Matter, DM) and isolipidic (20% DM) diets were compared, including a plant-based control diet (CV) and three other test diets, in which 40% of a plant protein-rich ingredient mixture was replaced with meals from Hermetia illucens (H40) or poultry by-product (P40) alone, or in combination (H10P30). The trials lasted 12 and 18 weeks for sea bream and sea bass, respectively. The results obtained thus far highlighted species-specific differences in the physiological response to dietary changes. In sea bream, the biochemical and histological responses suggest favorable physiological and liver health statuses, with higher serum cholesterol (CHO) and triglyceride (TAG) levels, as well as moderate hepatocyte lipid accumulation, with the H10P30 diet compared to the CV (p < 0.05). In sea bass, all diets resulted in elevated serum TAG levels and lipid accumulation in the liver, particularly in fish fed the P40 one (p < 0.05), which resulted in the highest LI, coupled with a higher frequency of severe lipid accumulation, hypertrophy, cord loss, peripheral nuclei displacement, and pyknosis. In conclusion, sea bream adapted well to the test diets, whereas sea bass exhibited altered hepatic lipid metabolism leading to incipient liver steatosis, likely due to the high lipid contents of the diets, including the insect and poultry meals. The LI formula developed in this study proved to be a reliable tool for assessing the effects of dietary changes on the liver health of sea bream and sea bass, consistent with biochemical and histological findings.

The effect of local millet drink (Kunu) on the testis and epididymis of adult male wistar rats

Background: Kunu is a local beverage drink that finds its origin in the northern part of Nigeria. This study was aimed at determining the effect of the liquid drink on the epididymis, testes, sperm parameters, and hormonal assay. Methods: A total of sixteen rats were used for this study and the animals were separated into four groups of four rats each (A-D). The animals were then sacrificed and the testes and epididymis were harvested and fixed in 10% formal saline. Group A was fed only rat feed and water. Groups B, C, and D were fed 0.2 ml, 0.9 ml, and 2.5 ml of Kunu respectively orally using a metal cannula for 21 days. Findings: There was a significant increase (P&lt;0.05) in the relative testicular weights of groups B, C, and D as compared with those of group A. There was a significant decrease (P&lt;0.05) in sperm count in groups B, C, and D when compared to group A. There was an insignificant increase (P&gt;0.05) in FSH in groups B, C, and D when compared to group A. The histopathological findings revealed that the group B rats of 0.2ml and group C rats of 0.9ml showed epididymal tissue with moderate accumulation of spermatozoa and testicular tubules with moderately enhanced spermatogenesis. The group D rats showed well-accumulated spermatozoa in the epididymal lumen and improved spermatogenesis in the testis as did group A. Conclusion: Kunu beverage may not be used as a natural male fertility booster since it does little to improve sperm count, motility, morphology, pH, and hormonal levels of FSH and testosterone.

No drug-drug interactions between selective prolyl-tRNA synthetase inhibitor, bersiporocin, and pirfenidone or nintedanib in healthy participants.

Bersiporocin, a potent and selective prolyl-tRNA synthetase inhibitor, is expected to show a synergistic effect with pirfenidone or nintedanib in patients with idiopathic pulmonary fibrosis. To validate the combination therapy of bersiporocin with pirfenidone or nintedanib, a randomized, open-label, two-part, one-sequence, three-period, three-treatment study was designed to evaluate the effect of drug-drug interactions (DDI) regarding their pharmacokinetics, safety, and tolerability in healthy participants. In addition, the pharmacokinetic profiles of the newly formulated, enteric-coated bersiporocin tablet were evaluated after single and multiple administrations. The potential effects of cytochrome P450 2D6 (CYP2D6) genotyping on bersiporocin pharmacokinetics and DDI were also explored. In Part 1, participants were sequentially administered a single dose of pirfenidone 600 mg, a single dose of bersiporocin 150 mg followed by multiple doses, and bersiporocin in combination with pirfenidone. In Part 2, participants were sequentially administered a single dose of nintedanib 150 mg, multiple doses of bersiporocin 150 mg, and bersiporocin in combination with nintedanib. Forty-six participants completed the study. There was no significant pharmacokinetic DDI between bersiporocin, and pirfenidone or nintedanib. All adverse events (AEs) were mild to moderate and did not include serious AEs, suggesting bersiporocin alone or in combination therapy were well-tolerated. The newly formulated bersiporocin 150 mg tablet showed a moderate accumulation index. There was no significant difference in the pharmacokinetic profiles after administration of bersiporocin alone or in combination therapy between CYP2D6 phenotypes. In conclusion, there are no significant DDI regarding the pharmacokinetics, safety, and tolerability of bersiporocin administration with pirfenidone or nintedanib.

MICROELEMENT COMPOSITION OF PATRINIA SCABIOSIFOLIA AND PATRINIA RUPESTRIS

Anthropogenic activity leads to an increased content of trace elements in environmental resources: air, water, land and biota. The accumulation of elements is influenced by the properties of the element, the characteristics of the environment, and the factors of the host organism. This necessitates monitoring of plant materials, especially in regions with a significant raw material base of medicinal plants, but actively exposed to anthropogenic impact, which currently includes the Russian Far East. The article presents the results of studying the elemental composition of plant raw materials of Patrinia rupestris and Patrinia scabiosifolia. It has been established that P. rupestris raw material contains 11-12 elements, P. scabiosifolia raw material contains 11-14 elements, depending on the habitat, 8 of them are essential, 4 are conditionally essential. The homogeneous elemental composition of the grass and roots of P. rupestris and P. scabiosifolia reflects the genetic closeness of the studied species. For most elements, both species exhibit the properties of moderate accumulation and strong capture. Mn, Cr, Ni maintain a constant concentration throughout the range, both for P. rupestris and P. scabiosifolia. Foliar uptake of Co, Br for both species, and Ba for P. rupestris was noted. For P. rupestris and P. scabiosifolia, an acropetal type of element accumulation is noted in Primorye; in the mainland areas of the ranges, a reverse strategy of element accumulation is observed.

Characterization of a phenotypically severe animal model for human AB-Variant GM2 gangliosidosis

AB-Variant GM2 gangliosidosis (ABGM2) is a rare and lethal genetic disorder caused by mutations in the GM2A gene that lead to fatal accumulation of GM2 gangliosides (GM2) in neurons of the central nervous system (CNS). GM2A encodes a transport protein known as GM2 activator (GM2A) protein, which is essential for degrading GM2 into their GM3 form. ABGM2 presents in infantile-, juvenile-, and adult-onset forms; of the three, the infantile-onset is the most prominent, and by far the most severe, as evidenced by high levels of GM2 accumulation, widespread neurodegeneration, and death by the age of 4. Gm2a−/− mice are commonly used as a model of ABGM2. These mice are characterized by phenotypes most representative of predicted adult-onset form of ABGM2, which include moderate GM2 accumulation and mild neurological defects. This mild phenotype has been attributed to compensation by alternative GM2 degradation pathways mediated by sialidase, neuraminidase 3 (NEU3), a pathway that is more prominent in mice than humans. To assess the extent to which NEU3 contributes to GM2 degradation, we generated double knock-out (Gm2a−/−Neu3−/−) mice. Compellingly, these mice present with a clinical phenotype resembling that of a more severe ABGM2, including ataxia, reduced mobility and coordination, weight loss, poor body scores, and lethality by 6–7 months. Furthermore, these phenotypes correlate with a dramatic increase in GM2 accumulation in the CNS compared to levels observed in either Gm2a−/− or Neu3−/− mice. Taken together, these studies, for the first-time, confirm that the mild neurological phenotype of Gm2a−/− mice is due to compensatory activity on GM2 catabolism through an alternate breakdown pathway involving NEU3. These studies support the use of double knockout mice as a novel and highly relevant model for pre-clinical drug studies in a more severe form of ABGM2.

Characterization of flue gas desulphurized (FGD) gypsum of a coal-fired plant and its relevant risk of associated potential toxic elements in sodic soil reclamation.

Thermal Power Plant generates FGD gypsum as by-product during coal combustion. This study evaluates the characterization (spectroscopic and elemental), potentially toxic elements (PTEs) distribution, and environmental risk assessment of FGD gypsum for safe and sustainable use in agriculture. The XRD and SEM analysis confirmed the dominance of crystalline CaSO4·2H2O in FGD gypsum. The order of concentrations of PTEs in FGD gypsum was Fe > Al > Mn > Zn > Ni > Co. The residual fraction was the dominant pool, sharing 80-90% of the total PTEs. The heavy metals (HMs) were below the toxic range in the leachates. The Co, Ni, Al, Fe Mn, Zn had low (< 10%) risk assessment code and the ecotoxicity was in the range of 0.0-7.46%. The contamination factor was also low (0.0-0.16) at the normal recommended doses of FGD gypsum application for sodicity reclamation. The enrichment factor was in the order of Al < Mn < Co < Zn < Ni. Mn [enrichment factor (Ef) 1.2-2.0] and Co (Ef 1.7-2.8) showed negligible enrichment of metals, whereas Ni (Ef 4.3-5.2) and Zn (Ef 4.5-5.6) reported moderate accumulation in soil. The application of FGD gypsum @ 10 t ha-1 for sodicity reclamation will develop a geo-accumulation index below the critical values indicating its safe and sustainable use to achieve land degradation neutrality (LDN) and UN's Sustainable Development Goals.

Association of the visceral adiposity index with femur bone mineral density and osteoporosis among the U.S. older adults from NHANES 2005-2020: a cross-sectional study.

The visceral adiposity index (VAI) is a marker of abdominal fat distribution and adipose tissue function. However, the association between VAI and femur bone mineral density (BMD) and osteoporosis is unclear among the U.S. older adults. Cross-sectional data for adults aged 60 years and older from the 2007-2020 National Health and Nutrition Examination Survey (NHANES) were included. Multivariable linear and logistic regression were used to evaluate the association between VAI and femur BMD and osteoporosis. We used the smooth curve fitting to address nonlinearity. Moreover, a two-piecewise linear regression model was used to explain the nonlinearity further. The findings of the multivariable logistic regression models showed that as the VAI value increased by one unit, the prevalence of osteoporosis decreased by 1.2% after adjusting for covariates associated with osteoporosis. The multivariable linear regression models demonstrated that VAI was positively correlated with femur BMD. Further analysis revealed an inverted L-shaped and inverted U-shaped relationship between VAI and femur BMD at different sites. Our findings indicated that an increased VAI is independently linked to a higher prevalence of osteoporosis among the U.S. older adults. Further analysis reveals that once VAI reaches a certain threshold, femur BMD no longer increases and may even decrease. This suggests that a moderate accumulation of visceral fat may be beneficial for bone health, while excessive visceral fat could potentially have detrimental effects.

Deglutition Assessment, Using Fiberoptic Endoscopic Evaluation of Swallowing in Patients underwent Frontolateral Laryngectomy

Objective: To assess the long-term deglutition in patients undergone frontolateral laryngectomy (FL) by fiberoptic endoscopic evaluation of swallowing (FEES) and to identify factors that might influence the swallowing outcomes of these patients Materials and Methods: A cross-sectional descriptive study in patients undergone FL between 2004 and 2014 with postoperative time of 6 months or more. Three parameters: premature spillage of material, retention/pooling of material, and the presence of penetration or aspiration were evaluated. All parameters were graded from one (severe) to five (normal). Results: Total of 36 patients, 31 male and 5 female, with mean age of 58±12.9 years were included in the present study. Twenty-nine cases (80.6%) presented with stage I glottis cancers and 7 cases (19.4%) presented with stage II glottis-subglottic cancers. For their treatment by surgery, 30 cases (83.3%) underwent FL and 6 cases (16.7%) underwent extended FL. Swallowing function was determined to be normal in 27 cases (75%), however, 6 cases (16.7%) had mild residue accumulation after food swallowing, whereas 3 cases (8.3%) had moderate symptoms of either minimal pharyngeal stasis plus unsafe airway or moderate pharyngeal residue accumulation. When considering each factor that may worsen post-operative swallowing function, the results suggested that there were significant associations with age of ≥65 years old (p=0.036), tumor stage II (p=0.049), and the presence of postoperative wound infection (p=0.012). Conclusion: In the present study, the authors confirmed that FL had minimal impacts on swallowing functions as the majority of patients who underwent FL recovered normal or near-normal swallowing function after 6 months as determined by FEES. However, long-term swallowing functions should be monitored especially in older patients (≥65 years of age), or patients with tumor stage II or postoperative wound infection. Keywords: Frontolateral laryngectomy; Glottic cancer; Fiberoptic endoscopic evaluation of swallowing; FEES; Penetration and aspiration; Deglutition

Fat crystallization and physical characteristics of mung bean protein-based frozen whipped emulsions: Effect of lipophilic surfactants and quinoa hydrolysate

Yogurt ice cream (acid frozen whipped emulsion) is a complex frozen emulsion-foam system. The study investigated the impact of three lipophilic surfactant emulsifiers [glyceryl monostearate (GMS), polyglycerol ester (PGE), and sucrose ester 970 (S970)] and quinoa hydrolysate (QH) on fat crystallization, physical properties, and morphology of frozen whipped emulsions containing fermented mung bean protein. QH serves as a sustainable and health-conscious alternative to traditional emulsifiers. pH12-shifting treatment was utilized to modulate fermentation performance of mung bean protein. Yogurt-like ice creams (10% coconut oil) were formulated using pre-whipped emulsions comprising fermented pH12-treated mung bean protein (FMP12) or native mung bean protein (NFMP), along with 0.5% (w/w) emulsifiers or QH. Pre-whipped FMP12 emulsions exhibited significantly higher emulsification stability (P < 0.05) compared to NFMP emulsions, owing to the better-balanced hydrophilic-lipophilic nature of FMP12. The individual addition of surfactants and QH promoted fat crystallization and improved the stability and viscous of FMP12 emulsion by competitively adsorbing with FMP12 at the O/W interface. Upon freezing, all three surfactants in whipped creams resulted in uniform and fine ice crystals with a moderate accumulation of oil droplets, showing a comparable effect to QH. Consequently, FMP12 frozen whipped emulsions with surfactants or QH both exhibited superior hardness and overrun, attributed to the presence of fine ice crystals and a stable fat crystal skeleton structure. These findings indicate the prospective utility of QH as a substitute for conventional small chemical emulsifiers, thereby enhancing the quality attributes of plant-based yogurt ice cream.

Source Analysis and Risk Assessment of Heavy Metals in Soil of County Scale Based on PMF Model

This study explores the pollution characteristics, risks, and sources of heavy metals in small-scale areas. Rongcheng District, Jieyang City, Guangdong Province was considered as the study area and enrichment factor (EF), pollution load index (PLI), potential ecological risk index (RI), and US EPA health risk assessment model were used to evaluate its environmental risk. Moreover, the source apportionment of heavy metals was analyzed through correlation analysis, the characteristic of spatial distribution, and a PMF model. The results showed that the mean concentrations of ω(Cr), ω(Hg), ω(As), ω(Pb), ω(Ni), ω(Cd), ω(Cu), and ω(Zn) were 54.87, 0.25, 8.35, 56.00, 15.38, 0.35, 30.56, and 124.23 mg·kg-1, respectively. The mean concentrations of all elements exceeded the local soil background value. In terms of EF level, Cr, As, Pb, and Ni showed negligible accumulation; Zn and Cu showed minor accumulation; and Hg and Cd showed moderate accumulation. The mean value of the pollution load index was 2.37, with a severe pollution level, and the eight elements were in different pollution levels. In total, the study region suffered severe ecological risk, Hg and Cd presented strong ecological risk, and other elements presented slight ecological risk. The non-carcinogenic risks under the three exposure paths were within the acceptable level. The carcinogenic risks (CR) of adults and children were 9.81E-05 and 5.59E-04, respectively, and Cr and As were the main contributors of CR. The results showed that the four sources of heavy metals were transportation sources (37.02%), parent material sources (18.53%), atmospheric deposition sources (26.49%), and industrial sources (17.96%).