Potency Ratio Research Articles

Acute toxicity assessment and QSAR modeling of zebrafish embryos exposed to methyl paraben and its halogenated byproducts

Halogenated methyl parabens are formed readily during water chlorination, with or without bromide ion presence. However, research gaps persist in in vivo toxicological assessments of vertebrates exposed to halo-MePs. To address this gap, this study evaluated acute toxicities at 24−96 h-post-fertilization in zebrafish embryos exposed to methyl paraben and its mono- or di-halogenated derivatives, using various apical endpoints. Significant enhanced toxic effects were confirmed for halo-MePs compared to MeP on embryo coagulation (3–19 fold), heartbeat rate decrement (11–80 fold), deformity rate increment (9–68 fold), and hatching failure (4–33 fold), with parentheses indicating the determined toxic potency ratios. Moreover, halo-MePs showed a significantly higher increase in biochemical levels of reactive oxygen species, catalase, superoxide dismutase, and malondialdehyde, while acetylcholinesterase activity was inhibited compared to NT and MeP. The experimental toxic potencies (log(1/EC50 or LC50)) were compared with the predicted ones (log(1/EC50 or LC50, baseline)) using the baseline toxicity Quantitative Structure-Activity Relationship previously established for zebrafish embryos. Halo-MePs were specific (or reactive) toxicants based on their toxic ratios of more than 10 for apical endpoints including heartbeat rate, deformity rate, and hatching rate, while MeP acted as a baseline toxicant. Overall, this study presents the comprehensive toxicological assessment of halo-MePs in zebrafish embryos, contributing to an essential in vivo toxicity database for halogenated phenolic contaminants in aquatic ecosystems.

Optimal Infusion Rate of Norepinephrine for Prevention of Spinal Hypotension for Cesarean Delivery: A Randomized Controlled Trial, Using Up-Down Sequential Allocation.

Norepinephrine has recently been suggested to be as effective as phenylephrine for the prevention of hypotension after spinal anesthesia for cesarean delivery. Moreover, compared to phenylephrine, norepinephrine may be superior in maintaining heart rate (HR) and consequently, cardiac output (CO). A recent study demonstrated that norepinephrine given as a single intravenous bolus is approximately 13 times more potent than phenylephrine. However, it is uncertain whether this finding can be applied when these vasopressors are administered as infusions. Therefore, the optimum infusion rate of norepinephrine remains unknown. We aimed to determine the median effective dose (ED50; defined as the rate of vasopressor infusion required to prevent spinal hypotension in 50% of subjects) of both drugs needed to maintain maternal systolic blood pressure within 20% of the baseline after spinal anesthesia for cesarean delivery and to derive the relative potency ratio. Sixty healthy patients undergoing elective cesarean delivery with standardized spinal anesthesia were randomized into 2 groups. The first patient in group 1 received phenylephrine 1200 µg in normal saline 0.9% w/v 60 mL at 60 mL/h infusion rate (20 µg.min-1). The first patient in group 2 received norepinephrine 96 µg in normal saline 0.9% w/v 60 mL at 60 mL/h infusion rate (1.6 µg.min-1). Using up-down sequential allocation technique, the vasopressor dose for every subsequent patient was determined by the response in the previous patient. If effective, the next patient received a dose reduced by 150 µg of phenylephrine (2.5 µg.min-1) or 12 µg (0.2 µg.min-1) of norepinephrine. If ineffective, the dose for the next patient was increased by the same amount. The ED50s were determined according to the Dixon-Massey formula. Stroke volume (SV), HR, and CO were also measured. The ED50 was 12.7 µg.min-1 (95% CI, 10.5-14.9) for phenylephrine and 1.01 µg.min-1 (95% CI, 0.84-1.18) for norepinephrine, giving a potency ratio of 12.6 (95% CI, 9.92-15.9). HR, SV, and CO did not differ between the groups. Norepinephrine is more potent than phenylephrine by a factor of approximately 13 when administered as infusion for equivalent maternal blood pressure control. Based on these findings, we recommend a variable rate prophylactic infusion of norepinephrine to be initiated at 1.9 to 3.8 µg.min-1 for the management of hypotension during cesarean delivery under spinal anesthesia.

Combining Ability, Heterosis and Potence Ratio for Yield and Yield Components in Korean Double-Haploid, Progenies and Improved Rice Varieties in Nigeria

Rice is the most widely consumed staple crop in Africa and consumption continues to grow at a rapid pace with increasing population. Success in breeding programs are largely dependent on the genetic diversity of a crop. Genetic variability occurs due to genetic differences in individuals within a given population, which is the basis of plant breeding. Thus, if the genetic variability is well managed, diversity can result to permanent gains in the performance of the crop. The objectives of this study were to determine the interaction between grain yield and yield components and to conduct genetic studies on selected rice genotypes. The research was carried out at the University of Port Harcourt Faculty of Agriculture teaching and research farm. Thirteen (13) varieties were used which comprised 7 adapted Nigerian varieties and 6 Korean rice varieties in a randomized complete block design (RCBD) in three replications was established. All agronomic practices were carried out at appropriately crop phenology. North Carolina II mating design was used to perform crosses. Data was collected on 10 agronomic traits. All means were subjected to ANOVA, combining ability, Heterosis and Potence ratio were determined. The progenies from UPIA 2 x UPN 234, FARO 52 X UPN 266 and UPIA 3 X UPN 266 had the best phenotypic and genotypic expression and most of the hybrids had heterotic values than their parents. The results also showed ranges of dominance for genotypes. UPIA 1, UPIA 2, UPN 223, UPN 234 and UPN266 should be included in breeding programs because they showed the best GCA’s across most traits.

A 7×7 diallel cross for developing high-yielding and saline-tolerant barley (Hordeum vulgare L.)

In this experiment, F1s produced from a 7 × 7 half-diallel cross along with their parents were evaluated to develop high yielding and saline-tolerant barley lines. The investigation focused on the general combining ability (GCA) of parents, specific combining ability (SCA) of offspring, genetic action, and heterosis of eight quantitative variables. Genetic analysis and potence ratio suggested that different degrees of dominance controlling the inheritance of the studied traits. Significant GCA and SCA variances suggested the presence of both additive and non-additive gene actions controlling the traits. However, a GCA:SCA ratio lower than 1 indicated the preponderance of the non-additive gene action involved in the expression of the traits. The parents P5 and P6 possess the genetic potential favorable for early and short stature in their F1s. Conversely, P2 and P4 were more likely to produce short F1s with high yield potential. Based on the mean performance, SCA, and heterobeltiosis, crosses P2 × P3, P2 × P7, P3 × P4, P4 × P5, P5 × P6, and P6 × P7 were selected as promising F1s for earliness, short stature, and high yield potential. These crosses are recommended for further breeding to obtain early-maturing and high-yielding segregants. To identify saline-tolerant F1s, screening was conducted in saline media prepared in half-strength Hoagland solution. The salinity stress involved exposing F1s to 100 mM NaCl for first 10 days, and followed by an increase to 150 mM until maturity. Among the F1s, five crosses (P1 × P2, P2 × P3, P3 × P5, P4 × P6, and P4 × P7) exhibited promising signs of saline tolerance based on a comprehensive evaluation of healthy seed set, K+/Na+ ratio, root volume, generation of reactive oxygen species (O2•− and H2O2), and activities of key antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), ascorbate peroxidase (APX), and glutathione reductase (GR). These crosses will undergo further evaluation in the next filial generation to confirm heritable saline tolerance.

Randomized Double-Blind Study of the Effect of Injectate Temperature on Intrathecal Bupivacaine Dose Requirement in Spinal Anesthesia for Cesarean Delivery.

Increasing the temperature of intrathecal local anesthetics has been shown to increase the speed of onset and block height of spinal anesthesia. However, how this influences dose requirement has not been fully quantified. The aim of this study was to determine and compare the effective dose for anesthesia for cesarean delivery in 50% of patients (ED50) of intrathecal bupivacaine given at temperatures of 37 °C (body temperature) or 24 °C (room temperature). Eighty healthy parturients having elective cesarean delivery under combined spinal-epidural anesthesia were randomly assigned to receive intrathecal hyperbaric bupivacaine stored at 37 °C (body temperature group) or 24 °C (room temperature group). The first subject in each group received a bupivacaine dose of 10 mg. The dose for each subsequent subject in each group was varied with an increment or decrement of 1 mg based on the response (effective or noneffective) of the previous subject. Patients for whom the dose was noneffective received epidural supplementation after data collection with lidocaine 2% as required until anesthesia was sufficient for surgery. Values for ED50 were calculated using modified up-down sequential analysis with probit analysis applied as a backup sensitivity analysis. These values were compared and the relative mean potency was calculated. The ED50 (mean [95% confidence interval, CI]) of intrathecal hyperbaric bupivacaine was lower in the body temperature group (6.7 [5.7-7.6] mg) compared with the room temperature group (8.1 [7.7-8.6] mg) (P < .05). The relative potency ratio for intrathecal bupivacaine for the room temperature group versus the body temperature group was 0.84 (95% CI, 0.77-0.93). Warming hyperbaric bupivacaine to body temperature reduced the dose requirement for spinal anesthesia for cesarean delivery by approximately 16% (95% CI, 7%-23%).

Insulin degludec in pregestational diabetes: evidence and perspectives

Pregestational diabetes is described when a woman with diabetes before the onset of pregnancy becomes pregnant and consequently she is vulnerable to higher risk for adverse outcomes in the embryo/foetus. Strict glycaemic control, with minimal glucose variability, starting from before conception and maintained throughout pregnancy decreases significantly adverse foetal and maternal outcomes; maternal hypoglycaemic episodes are the major barrier in achieving this goal. Insulin degludec is an ultralong-acting analogue, which has half-life of over 25 h and full duration of effect of more than 42 h, reaching a steady-state serum concentration after 2–3 days of its administration. It promotes flat, steady, peakless and predictable insulin concentrations, with minor intra-individual and inter-individual variability. It also exerts a low mitogenic/metabolic potency ratio. This review examines thoroughly all current evidence of the administration of insulin degludec in pregestational diabetes as well as its future role in this population.

The effects of Fc fusion protein glucagon-like peptide-1 and glucagon dual receptor agonist with different receptor selectivity in vivo studies

BackgroundGlucagon-like peptide-1 (GLP-1)/glucagon (GCG) dual receptor agonists with different receptor selectivity are under investigation and have shown significant improvement in both weight loss and glycemic control, but the optimal potency ratio between the two receptors to balance efficacy and safety remains unclear. Experimental approachWe designed and constructed several dual receptor agonists with different receptor potency ratios using Fc fusion protein technology. The long-term effects of the candidates on body weight and metabolic dysfunction-associated steatotic liver disease (MASLD) were evaluated in diet-induced obese (DIO) model mice, high-fat diet (HFD)-ob/ob mice and AMLN diet-induced MASLD mice. Repeat dose toxicity assays were performed to investigate the safety profile of the candidate (HEC-C070) in Sprague Dawley (SD) rats. Key resultsThe high GCG receptor (GCGR) selectivity of HEC-C046 makes it more prominent than other compounds for weight loss and most MASLD parameters but may lead to safety concerns. The weight change of HEC-C052 with the lowest GCG agonism was inferior to that of selective GLP-1 receptor agonist (GLP-1RA) semaglutide in DIO model mice. The GLP-1R selectivity of HEC-C070 with moderate GCG agonism has a significant effect on weight loss and liver function in obese mice, and its lowest observed adverse effect level (LOAEL) was 30 nmol/kg in the repeat dose toxicity study. ConclusionWe compared the potential of the Fc fusion protein GLP-1/GCG dual receptor agonists with different receptor selectivity to provide the setting for future GLP-1/GCG dual receptor agonists to treat obesity and MASLD.

The presence of erionite in North American geologies and the estimated mesothelioma potency by region

Objective Erionite is a naturally occurring fibrous mineral found in soils in some geographical regions. Known for its potency for causing mesothelioma in the Cappadocia region of Turkey, the erionite fiber has attracted interest in the United States due to its presence in a band of rock that extends from Mexico to Montana. There are few toxicology studies of erionite, but all show it to have unusually high chronic toxicity. Despite its high potency compared to asbestos fibers, erionite has no occupational or environmental exposure limits. This paper takes what has been learned about the chemical and physical characteristics of the various forms of asbestos (chrysotile, amosite, anthophyllite, and crocidolite) and predicts the potency of North American erionite fibers. Materials and Methods Based on the fiber potency model in Korchevskiy et al. (2019) and the available published information on erionite, the estimated mesothelioma potency factors (the proportion of mesothelioma mortality per unit cumulative exposure (f/cc-year)) for erionites in the western United States were determined. Results and Discussion The model predicted potency factors ranged from 0.19 to 11.25 (average ∼3.5), depending on the region. For reference, crocidolite (the most potent commercial form of asbestos) is assigned a potency factor ∼0.5. Conclusion The model predicted mesothelioma potency of Turkish erionite (4.53) falls in this same range of potencies as erionite found in North America. Although it can vary by region, a reasonable ratio of average mesothelioma potency based on this model is 3,000:500:100:1 comparing North American erionite, crocidolite, amosite, and chrysotile (from most potent to least potent).

The 50% effective dose of hydromorphone and morphine for epidural analgesia in the hemorrhoidectomy: a double-blind, sequential dose-finding study

BackgroundAlthough previous studies have showed that epidural morphine can be used as a complement to local anesthetics for analgesia after postcesarean delivery under spinal anesthesia, there is little known about the analgesic dosage of epidural morphine and hydromorphone for hemorrhoidectomy. Therefore, we conducted this study to examine the potency ratio of hydromorphone to epidural morphine as well as effective analgesic dose for 50% patients (ED50) undergoing elective hemorrhoidectomy.Methods80 patients under elective hemorrhoidectomy with combined spinal and epidural anesthesia(CSEA) in department of anesthesia, Dongguan Tungwah hospital. To assess the ED50, patients were treated with epidural morphine or epidural hydromorphone randomly using a biased coin method-determined dose with a sequential allocation procedure. Following surgery, standardized multimodal analgesia was administered to all patients. A pain response score of ≤ 3 (on a scale of 0–10) was determined to be the effective dose after 24 h following CSEA. The ED50 in both groups were determined using the probit regression and isotonic regression method. We also measured pain intensity by patient interview using a 10 point verbal numeric rating scale prospectively at 6, 12 and 24 h after CSEA, and adverse effects were also noted.ResultsThe ED50 was 0.350 mg (95% CI, 0.259–0.376 mg) in hydromorphone group and 1.129 mg (95% CI, 0.903–1.187 mg) in morphine group, respectively, estimated by isotonic regression method. Regression analysis with the probit, the ED50 of epidural hydromorphone was 0.366 mg (95% CI, 0.276–0.388 mg) and epidural morphine was 1.138 mg (95% CI, 0.910–1.201 mg). Exploratory findings showed that there was no difference between the most frequent dosages of epidural hydromorphone or epidural morphine in the occurrence of nausea, vomiting and pruritus. When administered with epidural opioids at ED50 doses or higher, 97.5% (39/40) of epidural morphine patients and 97.5% (39/40) epidural hydromorphone of patients were satisfied with their analgesia.ConclusionEffective hemorrhoidectomy analgesia requires a 3:1 ratio of epidural morphine to epidural hydromorphone. Both drugs provide excellent patient satisfaction.

Genetic assessment and potence ratio of various traits of okra (Abelmoschus esculentus) in mid hills of Himachal Pradesh

The selection of appropriate breeding strategies for achieving desired improvements in plant breeding necessitates a thorough understanding of the mechanism of gene expression implicated in the transmission of quantitative and biochemical characteristics. Line × tester study of 30 F1 hybrids obtained by crossing 13 parental lines was carried out to assess gene action and potence ratio of such traits in okra (Abelmoschus esculentus L.) during rainy (kharif) seasons of 2021 and 2022 at research farm of Dr. Yashwant Singh Parmar University of Horticulture and Forestry, Nauni, Solan, Himachal Pradesh. Out of 22 traits, 20 indicated the preponderance of non-additive gene action and additive gene action for plant height and inter-nodal length. UHFO-6 and UHFO-9 were the best general combiners, whereas, UHFO-2 × Pusa Bhindi-5 and UHFO-10 × Hisar Unnat were the best specific combiners. For 20 traits, proportional contribution of lines was higher than the testers for total variance. Potence ratio indicated that majority of the traits in the hybrids had over dominance gene effect. Over dominance was expressed for pod length, pod diameter, number of pods per plant, average pod weight, and pod yield per plant, etc. To maximize the entire genetic potential of hybrids and parents with excellent per se performance, okra crop development initiatives must include heterosis, combining ability, proportionate contribution of genotypes and potence ratio.

Endogenous Signaling Molecule Activating (ESMA) CARs: A Novel CAR Design Showing a Favorable Risk to Potency Ratio for the Treatment of Triple Negative Breast Cancer.

As chimeric antigen receptor (CAR) T cell therapy continues to gain attention as a valuable treatment option against different cancers, strategies to improve its potency and decrease the side effects associated with this therapy have become increasingly relevant. Herein, we report an alternative CAR design that incorporates transmembrane domains with the ability to recruit endogenous signaling molecules, eliminating the need for stimulatory signals within the CAR structure. These endogenous signaling molecule activating (ESMA) CARs triggered robust cytotoxic activity and proliferation of the T cells when directed against the triple-negative breast cancer (TNBC) cell line MDA-MB-231 while exhibiting reduced cytokine secretion and exhaustion marker expression compared to their cognate standard second generation CARs. In a NOD SCID Gamma (NSG) MDA-MB-231 xenograft mouse model, the lead candidate maintained longitudinal therapeutic efficacy and an enhanced T cell memory phenotype. Profound tumor infiltration by activated T cells repressed tumor growth, further manifesting the proliferative capacity of the ESMA CAR T cell therapy. Consequently, ESMA CAR T cells entail promising features for improved clinical outcome as a solid tumor treatment option.

Combining ability analysis of Cucurbita moschata D. in Côte d'Ivoire and classification of promising lines based on their gca effects.

Cucurbita moschata varieties grown in Africa have very low yield. They have been neglected, and totally ignored in agricultural research programs. However, interest in their fruits, seeds, flowers and leaves is growing nowadays due to their nutritional and medicinal potentials. That growing interest has prompted plant breeders and agronomists to develop research programs for their improvement. A complete diallel cross analysis of four parental lines, Long, Zouan-H, Oval, and Soubre and their twelve F1 hybrids, was carried out in a farming environment at the University Nangui Abrogoua, Abidjan, Côte d'Ivoire. The four parental lines and the F1 hybrids were evaluated for their general performances, combining abilities, potency ratio and heterosis effects. The investigated traits included plant height, and eleven fruit- and seed-related characters. The analysis of variance showed significant differences for all traits studied. In addition, the diallel model yielded highly significant gca effects of the female parents. The gca effects of the male parents were significant for all traits except plant height, length of the fruit, width of the fruit and length of the seed. Highly significant sca effects were observed in the crosses for all the traits. Strong maternal effects were observed for the weight and diameter of the fruit, weight of the pulp, number of seeds per fruit, weight of the fresh seeds and 100-seed weight. The general predictive ratio approached the value 1 for all the traits except weight of the fresh seed and width of the dry seed. Most of the characters under this study are predominantly determined by the effects of additive genes. But, weight of the fresh seed and width of the dry seed may be controlled by non-additive genes. Mid-parent heterosis was significant for all measured traits in the crosses, except the length of the fruit. And better-parent heterosis was significant for all traits except plant height, number of fruits per plant and length of the fruit. Gene expression is described by a super-dominance for many traits, and partial dominance for some other traits in all twelve F1 hybrids. Classification of the parental lines based on the effects of their general combining ability grouped the Soubre lines as promising contributors to fruit yield. The parental lines Long and Oval formed another group likely on the basis of the small size of their fruits, the small pulps, the smaller number of fruits per plant and the large number of seeds per fruit. However, Long would be a candidate parent for the development of cultivars with longer vegetative growth. The parental line Zouan-H formed the third group and it was mostly characterized by its large number of seeds per fruit and relatively large fruits.

Similarity Appearance of Parents with Progeny of Lombok Local Cantaloupe (Cucumis melo var. Cantalupensis) and Melon (Cucumis melo L.)

Crosses between local lombok cantaloupe and melon have produced the first progeny (F1). The F1 have a similar appearance to their parents. This study used two similarity assessments based on qualitative and quantitative traits. Qualitative characters are said to have similarities if their phenotypic appearance resembles one or both parents. The similarity of qualitative characters is visually observed using the munsell plant tissue color book and penetrometer. Meanwhile, the quantitative characters are said to have an appearance resembling one or both parents if the standard error line at the histogram between parents and offspring overlaps. In addition, analysis of gene action, heterosis, heterobeltiosis, and the maternal effect was carried out on quantitative character to obtain genetic information for producing superior local lombok cantaloupe varieties. The results of this study showed several changes in the appearance of F1 in qualitative and quantitative characters. The qualitative characters of F1 resemble the female parent, while the quantitative characters do not resemble both parents. Genetic information about potential ratio, heterosis, heterobeltiosis, and maternal effect varied. Gene action is dominated by potency ratio partial dominance and overdominance. Heterosis occurred in all treatments, while heterobeltiosis did not occur in all treatments. The maternal-effect was obtained on fruit weight, fruit diameter, and fruit length characters.

Quality Evaluation of Gentamicin Sulfate Reference Standards in Japanese Pharmacopoeia Using Hydrophilic Interaction Chromatography Combined With Tandem Mass Spectrometry.

Through the recent development of analytical technology, antibiotics quantification in the Japanese Pharmacopoeia (JP) has changed from traditional microbiological assays to physicochemical methods with high specificity and precision. However, for several multicomponent antibiotics without typical UV absorption, potency cannot be directly determined using instrumental methods such as high-performance liquid chromatography; therefore, traditional microbiological assays are still used. Gentamicin sulfate (GmS), which consists of three major components, C1, C1a, and C2, is such a typical antibiotic, and its antimicrobial potency continues to be assayed using microbiological methods in JP monographs. Introduction of a physicochemical assay for GmS is needed to help ensure its quality and quantity. This study aimed to develop quality control measures for GmS that could be complementary to quantitative assays and purity tests specified in the JP. For each gentamicin C component (C1, C2, and C1a), theoretical potencies were determined based on the quantitative relationship between purity and potency, as measured by quantitative 1H NMR and microbiological assays, respectively. Two lots of the JP reference standard (RS) were used as test samples, with the contents of each component and impurity (sisomicin and garamine) being determined using hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS). The ratios of theoretical potency for C1, C2, and C1a were 1.00, 1.21, and 1.80, respectively. The potencies of the GmS JP RSs, which were estimated based on the contents and theoretical potency of each C component, corresponded well with those determined through microbiological assays. Marked differences in impurities (%) between the two RS lots were highlighted by quantifying sisomicin and garamine. The developed analytical procedure enabled the characterization of two different JP RSs in terms of content ratio, potencies, and impurities. Novel analytical procedures useful for routine quality control of GmS were developed using HILIC-MS/MS.

Genetic architecture for yield and its components in castor (Ricinus communis L.)

The genetic analysis was done through line x tester design involving five pistillate lines and 13 pollen parents for the development of a set of 65 hybrids in castor, Ricinus communis. The combining ability analysis for yield and its components revealed that both the components, additive and non-additive of genetic variances were significantly influenced by environment. The preponderance of additive gene action was observed for the control of days to 50% flowering and days to 50% maturity of main raceme as well as number of nodes up to main raceme. For the characters plant height and oil content, non-additive gene effect was propounded. The parents SKP-8, 103745, 1379, SKP-93, TMV-5, Aruna, SH-72 and SK2-8A were good general combiners for imparting earliness, former three as well as VP-1 were good general combiner for short plant stature, whereas later two and SKP-82, JH-128, SH-41 and48-1 were good general combiners for oil content. The estimates of gca effects suggested that parents SKP-93, SKP-82, 48-1, Aruna, SPS-35-9B, JI-77 and JH-128 were good general combiners for seed yield and at least for two important yield attributes viz., 100-seed weight, effective branches/plant, number of capsules in main raceme and length of main raceme. The good specific cross combinations for yield were SKP-8 x TMV-5, VP-l x SKI-41 and SKP 25 x 1379, also identified as superior hybrid for earliness, high oil content and short plant stature, respectively. Hence, these may be exploited for commercial cultivation. The hybrids SKP-8 x TMV-5, SKP-25 x JH-128 and SKP-82 x 48-1 depicted significant positive sca effect for seed yield, these hybrids could be exploitedfor development of hybrids and new inbred as well as pistilate lines in castor. The potence ratio of genetic variance suggested preponderance of non-additive gene effect for inheritance of the seed yield/plant, number of capsules in main raceme and number of effective branches.

Development of a novel Fc fusion protein dual glucagon-like peptide-1 and gastric inhibitory polypeptide receptor agonists.

To develop and investigate an imbalanced dual gastric inhibitory polypeptide receptor (GIPR)/glucagon-like peptide-1 receptor (GLP-1 R) agonist with Fc fusion protein structure. We designed and constructed an Fc fusion protein that is a dual agonist (HEC-CG115) with an empirically optimized potency ratio for GLP-1R and GIPR. The long-term effects of HEC-CG115 on body weight and glycaemic control were evaluated in diet-induced obese mice and diabetic db/db mice. Repeat dose toxicity assays were performed to investigate the safety profile of HEC-CG115 in Sprague-Dawley rats. HEC-CG115 displayed high potency for GIPR and relatively low potency for GLP-1R, and we labelled it 'imbalanced'. In animal models, HEC-CG115 (3 nmol/kg) led to more weight loss than semaglutide at a higher dose (10 nmol/kg) in diet-induced obese model mice. HEC-CG115 (one dose every 3 days) reduced fasting blood glucose and glycated haemoglobin levels similar to those after semaglutide (once daily) at the same dose. In a 4-week subcutaneous toxicity study conducted to assess the biosafety of HEC-CG115, the no observed adverse effect level was determined to be 3 mg/kg. HEC-CG115 is a novel Fc fusion protein with imbalanced dual agonism that shows superior weight loss, glycaemic control and metabolic improvement in animal models, and has an optimal safety profile according to a repeat-dose toxicity study. Therefore, the use of HEC-CG115 appears to be safe and effective for the treatment of obesity and type 2 diabetes.

Aprocitentan: A new development of resistant hypertension.

As the blood pressure threshold for commencing antihypertensive treatment diminishes, the cohort suffering from resistant hypertension (RH) correspondingly expands. Notwithstanding the availability of known antihypertensive medications, there exists a conspicuous lacuna in therapeutic options specifically intended for the management of RH. Currently, aprocitentan is the sole endothelin receptor antagonist (ERA) under development for addressing this pressing clinical challenge. Aprocitentan (ACT-132577), deriving its active form as a metabolite of macitentan, demonstrates oral potency as a dual endothelin (ET) receptor antagonist. This compound effectively obstructs the binding of endothelin-1 (ET-1) to both ETA and ETB receptors, exhibiting an inhibitory potency ratio of 1:16. Clinical investigation of aprocitentan has advanced to phase 3 trials, yielding promising preliminary outcomes.

Assessing the effect of N-oxidation on the mutagenicity of 1-pyrazolines using the Ames assay.

N-Nitrosamines are well known as environmental carcinogens. We have reported that N-nitroso-N-methylbutylamine was oxidized by Fe2+-Cu2+-H2O2 to 5-methyl-5-nitro-1-pyrazoline, a direct-acting N-oxide. 1-Pyrazolines have not been reported to exhibit genotoxicity. In this study, we investigated the effect of N-oxidation on the mutagenicity of 1-pyrazolines using the Ames assay. The mutagenicity of 5-alkyl-5-nitro-1-pyrazoline 1-oxide (1a; methyl, 1b; ethyl), the N-oxide isomer (3-alkyl-3-nitro-1-pyrazoline 1-oxide; 2a; methyl, 2b; ethyl), and the corresponding nonoxides (3-alkyl-3-nitro-1-pyrazoline; 3a; methyl, 3b; ethyl) was assayed in Salmonella typhimurium TA1535 and Escherichia coli WP2uvrA. The ratios of mutagenic potency in S. typhimurium TA1535 versus E. coli WP2uvrA were compared with those of N-alkylnitrosoureas. To predict the reaction site on the pyrazolines with nucleophiles, the electron density of the pyrazolines was obtained by theoretical calculations. The pyrazolines were mutagenic in S. typhimurium TA1535 and E. coli WP2uvrA. The ratio of S. typhimurium TA1535 to E. coli WP2uvrA 1a (87:13) or 1b (90:10) was similar to that of N-ethyl-N-nitrosourea (70:30). In contrast, the mutagenic ratio of 2a (22:78) or 2b (52:48) was similar to that of N-propyl-N-nitrosourea (48:52) or N-butyl-N-nitrosourea (14:86). The ratio of 3a (53:47) or 3b (54:46) was similar to that of N-propyl-N-nitrosourea or N-butyl-N-nitrosourea. The pyrazolines exhibit genotoxicity, and the mutagenic potency of the 1-pyrazolines is influenced by N-oxidation. We estimated that the mutagenicity of 1a or 1b was caused by DNA ethylation, and the isomers or the nonoxides were mutagenic via formation of alkylated DNA, which contains an alkyl chain longer than the propyl.

Relationship between heterosis, potence ratio and genetic distance for yield traits in maize (Zea mays)

An experiment was conducted during 2014–18 at Agricultural Research Station, Professor Jayashankar Telangana State Agricultural University, Karimnagar, Telangana to find out the relationship between heterosis, potence ratio and genetic distance for yield contributing characters in maize (Zea mays L.). Heterosis was trait dependent exhibiting high level for plant height, ear height, ear length, kernels/row, 100-kernel weight, grain yield and fodder yield. Two hybrids BML-51 × BML-14 (22.1%) and BML-51 × BML-6 (13.2%) recorded heterosis of greater than 10% over the check NK6240 and exhibited negative heterosis for flowering and maturity traits and positive heterosis for the remaining traits. Potence ratio indicated that majority of the traits in the hybrids had over dominance gene effect and expressed over dominance for ear length, ear diameter, kernels/row, fodder yield and grain yield suggesting heterosis breeding is an appropriate strategy for improvement of these traits. Standard heterosis of greater than 5% was observed in 7 crosses and out of these 6 belonged to mid parental divergence group. Five crosses, viz. BML-51 × BML-14, BML-51 × BML-7, BML-51 × BML-6, BML-32 × BML-13 and BML-32 × BML-6 with yield ranging from 7637 to 8733 kg/ha belonged to the medium parental divergence group comprising of high yielding inbreds, viz. BML-51 or BML-32 as parents. Grain yield heterosis was found significant and positively correlated with heterosis for ear length and 100-kernel weight. Therefore to maximize the full genetic potential of hybrids, inbreds with high per se performance and intermediate genetic divergence are to be involved in maize crop improvement programmes.

Genetic assessments, dominance estimates of economic traits of gynoecious cucumber (Cucumis sativus) under Himalayas

In India generally monoecious and cross-pollinated cucumber (Cucumis sativus L.) hybrids/varieties are grown. The use of stable gynoecious cucumber varieties/hybrids would increase the productivity of cucumber in India. In the past, despite improvement in monoecious cucumber varieties/hybrids, little effort has been done into the development of stable gynoecious hybrids. To address this issue 3 genetically diverse gynoecious lines and improvement, and 6 testers were crossed in line × tester fashion to develop 18 crosses during 2017. These 18 crosses along with 9 parents evaluated at the Krishi Vigyan Kendra, Kandaghat, Himachal Pradesh and Dr. YSPUHF, Solan, Himachal Pradesh during pre-kharif season 2018–19 to determine the mode of gene action, combining ability, extent heterosis and potence ratio for 12 quantitative traits. Experimental results depicted that the dominant component of variance (σ2S) was found higher than the additive component of variance (σ2S) for all the traits indicating a predominant role of non-additive gene action governing yield and its contributing traits during both the years. Gynoecious inbred lines KTG-40, 2870G and testers K-90, UHF-16 were found most promising general combiners for fruit yield. The cross combination KTG-40 × K-90 and 2870G × K-90 isolated based on heterosis manifested and SCA effects. Further, the performance of top 7 heterotic crosses illustrate the presence of overdominance in most of the crosses for traits under study, suggesting the importance of heterosis breeding for the development of early, high-yielding, disease tolerance stable gynoecious hybrids in cucumber.