Enhanced soil carbon storage and arbuscular mycorrhizal fungal biomass in a long-term nutrient management under soybean-based cropping system.

To ensure the sustainability of crop production and ecosystem functioning, a thorough understanding of the mechanisms governing soil carbon (C) sequestration and soil health is essential. This study examined the effects of three nutrient management practices (organic, inorganic, and integrated) and two cropping systems (soybean-wheat and soybean-chickpea), on arbuscular mycorrhizal fungi (AMF) and soil C-sequestration in a long-term (12 years) field experiment. We measured the stocks of soil organic carbon, total glomalin-related soil protein, pertinent soil quality parameters such as microbial biomass carbon, and β-glucosidase activity along with AMF biomass [microscopic parameters and 16:1ω5cis phospholipid fatty acid (AM PLFA) and neutral lipid fatty acid (AM NLFA)].

Caregiving for China's one-child generation: a simulation study of caregiving responsibility and impact on women's time use.

Introduction: The introduction, strict enforcement and recent exit of China's one-child policy (OCP) resulted in China's demographical changes, and, alongside its epidemiological transition, disproportionately impacted caregiving needs and demands on women. This study examines women's caregiving responsibilities in contemporary China and evaluates how the OCP affected them.

Methods: We simulated the female population aged 25-54 years in 2020 in China and their caregiving responsibilities based on epidemiological and demographic data for women, their parents and parents-in-law, and children under 10.

Envirotype-based delineation of environmental effects and genotype × environment interactions in Indian soybean (Glycine max, L.).

Soybean is a rainfed crop grown across a wide range of environments in India. Its grain yield is a complex trait governed by many minor genes and influenced by environmental effects and genotype × environment interactions. In the current investigation, grain yield data of different sets of 41, 30 and 48 soybean genotypes evaluated during 2019, 2020 and 2021, respectively across 19 locations and twenty years' data on 19 different climatic parameters at these locations was used to study the environmental effects on grain yield, to understand the genotype × environment interactions and to identify the mega-environments.

Structure Guided Discovery of Novel Pan Metallo-β-Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration.

The use of β-lactam (BL) and β-lactamase inhibitor combination to overcome BL antibiotic resistance has been validated through clinically approved drug products. However, unmet medical needs still exist for the treatment of infections caused by Gram-negative (GN) bacteria expressing metallo-β-lactamases. Previously, we reported our effort to discover pan inhibitors of three main families in this class: IMP, VIM, and NDM.

First report of milkweed () as an alternative host for in soybean fields in India.

Soybean (Glycine max, L.), a major oilseed crop of India faces anthracnose disease caused by Colletotrichum truncatum (Nataraj et al. 2021).

Setbacks in the quest for universal health coverage in Mexico: polarised politics, policy upheaval, and pandemic disruption.

2023 marks the 20-year anniversary of the creation of Mexico's System of Social Protection for Health and the Seguro Popular, a model for the global quest to achieve universal health coverage through health system reform. We analyse the success and challenges after 2012, the consequences of reform ageing, and the unique coincidence of systemic reorganisation during the COVID-19 pandemic to identify strategies for health system disaster preparedness. We document that population health and financial protection improved as the Seguro Popular aged, despite erosion of the budget and absent needed reforms.

The feminization of medicine in Latin America: 'More-the-merrier' will not beget gender equity or strengthen health systems.

This viewpoint addresses the lack of gender diversity in medical leadership in Latin America and the gap in evidence on gender dimensions of the health workforce. While Latin America has experienced a dramatic change in the gender demographic of the medical field, the health sector employment pipeline is rife with entrenched and systemic gender inequities that continue to perpetuate a devaluation of women; ultimately resulting in an under-representation of women in medical leadership. Using data available in the public domain, we describe and critique the trajectory of women in medicine and characterize the magnitude of gender inequity in health system leadership over time and across the region, drawing on historical data from Mexico as an illustrative case.

Discovery of MK-1462: GLP-1 and Glucagon Receptor Dual Agonist for the Treatment of Obesity and Diabetes.

Peptide-based analogues of the gut-derived incretin hormone, glucagon-like peptide 1 (GLP1), stimulate insulin secretion in a glucose-dependent manner. Currently marketed GLP1 receptor (GLP1R) agonists are safe and effective in the management of Type 2 diabetes but often offer only modest weight loss. This has prompted the search for safe and effective alternatives to enhance the weight loss component of these treatments.

Discovery of Potent and Orally Bioavailable Pyridine N-Oxide-Based Factor XIa Inhibitors through Exploiting Nonclassical Interactions.

Activated factor XI (FXIa) inhibitors are promising novel anticoagulants with low bleeding risk compared with current anticoagulants. The discovery of potent FXIa inhibitors with good oral bioavailability has been challenging. Herein, we describe our discovery effort, utilizing nonclassical interactions to improve potency, cellular permeability, and oral bioavailability by enhancing the binding while reducing polar atoms.

Discovery of Insulin Receptor Partial Agonists MK-5160 and MK-1092 as Novel Basal Insulins with Potential to Improve Therapeutic Index.

We have identified a series of novel insulin receptor partial agonists (IRPAs) with a potential to mitigate the risk of hypoglycemia associated with the use of insulin as an antidiabetic treatment. These molecules were designed as dimers of native insulin connected via chemical linkers of variable lengths with optional capping groups at the N-terminals of insulin chains. Depending on the structure, the maximal activation level (%Max) varied in the range of ∼20-70% of native insulin, and EC values remained in sub-nM range.

Olefin oligomerization by main group Ga and Zn single site catalysts on SiO.

In heterogeneous catalysis, olefin oligomerization is typically performed on immobilized transition metal ions, such as Ni and Cr. Here we report that silica-supported, single site catalysts containing immobilized, main group Zn and Ga ion sites catalyze ethylene and propylene oligomerization to an equilibrium distribution of linear olefins with rates similar to that of Ni. The molecular weight distribution of products formed on Zn is similar to Ni, while Ga forms higher molecular weight olefins.

Multi-step parallel synthesis enabled optimization of benzofuran derivatives as pan-genotypic non-nucleoside inhibitors of HCV NS5B.

In a lead optimization effort towards NS5B NNI inhibitors, two multi-step parallel libraries were designed and successfully synthesized. Through this effort we discovered compound 9B, which achieved rigorous and delicate balance of inhibition across the common genotypes and mutants with <10 nM potency. In addition, the bicyclic compounds 9B exhibited improved FASSIF solubility over the tetracyclic compound MK-8876.

Design, synthesis and biological evaluation of indane derived GPR40 agoPAMs.

GPR40 (FFAR1 or FFA1) is a G protein-coupled receptor, primarily expressed in pancreatic islet β-cells and intestinal enteroendocrine cells. When activated by fatty acids, GPR40 elicits increased insulin secretion from islet β-cells only in the presence of elevated glucose levels. Towards this end, studies were undertaken towards discovering a novel GPR40 Agonist whose mode of action is via Positive Allosteric Modulation of the GPR40 receptor (AgoPAM).

Accelerating the discovery of DGAT1 inhibitors through the application of parallel medicinal chemistry (PMC).

The parallel medicinal chemistry (PMC) was effectively applied to accelerate the optimization of diacylglycerol O-acyltransferase I (DGAT-1) inhibitors. Through a highly collaborative and iterative library design, synthesis and testing, a benzimidazole lead was rapidly and systematically advanced to a highly potent, selective and bioavailable DGAT1 inhibitor with the potential for further development.

Benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety.

Previously disclosed benzimidazole-based DGAT1 inhibitors containing a cyclohexane carboxylic acid moiety suffer from isomerization at the alpha position of the carboxylic acid group, generating active metabolites which exhibit DGAT1 inhibition comparable to the corresponding parent compounds. In this report, we describe the design, synthesis and profiling of benzimidazole-based DGAT1 inhibitors with a [3.1.

Design and evaluation of novel tetracyclic benzofurans as palm site allosteric inhibitors of HCV NS5B polymerase.

Hepatitis C virus (HCV) NS5B polymerase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Several novel and potent HCV NS5B non-nucleoside inhibitors with unique tetracyclic bezonfuran-based structures were prepared and evaluated. Similar to clinical developmental compound MK-8876, N-linked (compounds 1 and 2) and C-linked (compounds 3 and 4) tetracyclic structures maintained broad spectrum anti-replicon potency profiles and demonstrated moderate to excellent oral bioavailability and pharmacokinetic parameters across the three preclinical animal species.

Discovery of MK-8318, a Potent and Selective CRTh2 Receptor Antagonist for the Treatment of Asthma.

A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overcome by exhaustive medicinal chemistry lead optimization through focused SAR studies on the tricyclic core.

Superior Glycemic Control With a Glucose-Responsive Insulin Analog: Hepatic and Nonhepatic Impacts.

We evaluated the hepatic and nonhepatic responses to glucose-responsive insulin (GRI). Eight dogs received GRI or regular human insulin (HI) in random order. A primed, continuous intravenous infusion of [3-H]glucose began at -120 min.

A glucose-responsive insulin therapy protects animals against hypoglycemia.

Hypoglycemia is commonly associated with insulin therapy, limiting both its safety and efficacy. The concept of modifying insulin to render its glucose-responsive release from an injection depot (of an insulin complexed exogenously with a recombinant lectin) was proposed approximately 4 decades ago but has been challenging to achieve. Data presented here demonstrate that mannosylated insulin analogs can undergo an additional route of clearance as result of their interaction with endogenous mannose receptor (MR), and this can occur in a glucose-dependent fashion, with increased binding to MR at low glucose.

The synthesis of 2,3,6-trisubstituted 1-oxo-1,2-dihydroisoquinolines as potent CRTh antagonists.

New synthetic methods were developed for the preparation of 2,3,6-trisubstituted 1-oxo-1,2-dihydroisoquinolines as CRTh antagonists. The isoquinolinone core could be constructed before the introduction of substitution groups or synthesized through a catalytic intramolecular cyclization reaction with desired substitution groups properly installed. These synthetic strategies have helped to accelerate the SAR development of this series, and potent lead compounds were identified in both the CRTh receptor binding assay and the CD11b biomarker assay.

Engineering Glucose Responsiveness Into Insulin.

Insulin has a narrow therapeutic index, reflected in a small margin between a dose that achieves good glycemic control and one that causes hypoglycemia. Once injected, the clearance of exogenous insulin is invariant regardless of blood glucose, aggravating the potential to cause hypoglycemia. We sought to create a "smart" insulin, one that can alter insulin clearance and hence insulin action in response to blood glucose, mitigating risk for hypoglycemia.