Structure-guided engineering of a receptor-agonist pair for inducible activation of the ABA adaptive response to drought.

Strategies to activate abscisic acid (ABA) receptors and boost ABA signaling by small molecules that act as ABA receptor agonists are promising biotechnological tools to enhance plant drought tolerance. Protein structures of crop ABA receptors might require modifications to improve recognition of chemical ligands, which in turn can be optimized by structural information. Through structure-based targeted design, we have combined chemical and genetic approaches to generate an ABA receptor agonist molecule (iSB09) and engineer a CsPYL1 ABA receptor, named CsPYL1, which efficiently binds iSB09.

Reactivity of a Recombinant Esterase from HB27 in Aqueous and Organic Media.

The thermoalkalophilic membrane-associated esterase E34Tt from HB27 was cloned and expressed in (KLEST-3S esterase). The recombinant enzyme was tested as a biocatalyst in aqueous and organic media. It displayed a high thermal stability and was active in the presence of 10% (/) organic solvents and 1% (/) detergents.

Discovery of V-0219: A Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor toward Oral Treatment for "Diabesity".

Peptidic agonists of the glucagon-like peptide-1 receptor (GLP-1R) have gained a prominent role in the therapy of type-2 diabetes and are being considered for reducing food intake in obesity. Potential advantages of small molecules acting as positive allosteric modulators (PAMs) of GLP-1R, including oral administration and reduced unwanted effects, could improve the utility of this class of drugs. Here, we describe the discovery of compound (4-{[1-({3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)piperidin-3-yl]methyl}morpholine, V-0219) that exhibits enhanced efficacy of GLP-1R stimulation, subnanomolar potency in the potentiation of insulin secretion, and no significant off-target activities.

Heritability of Locomotor Stereotypies in Chilean Horses.

The Chilean horse is a breed of closed registry. Stall-walking and weaving are locomotor stereotypies that affect this breed, and genetic predisposition has been suggested for both conditions. The objective of the present study was to estimate heritability of stall-walking and weaving in Chilean horses.

Retinal Proteomics of a Mouse Model of Dystroglycanopathies Reveals Molecular Alterations in Photoreceptors.

Mutations in the 1 gene, encoding a protein -mannosyltransferase essential for α-dystroglycan (α-DG) glycosylation, are frequently observed in a group of rare congenital muscular dystrophies, collectively known as dystroglycanopathies. However, it is hitherto unclear whether the effects seen in affected patients can be fully ascribed to α-DG hypoglycosylation. To study this, here we used comparative mass spectrometry-based proteomics and immunofluorescence microscopy and investigated the changes in the retina of mice in which 1 is specifically knocked out in photoreceptor cells.

Biochemical and Structural Characterization of a novel thermophilic esterase EstD11 provide catalytic insights for the HSL family.

A novel esterase, EstD11, has been discovered in a hot spring metagenomic library. It is a thermophilic and thermostable esterase with an optimum temperature of 60°C. A detailed substrate preference analysis of EstD11 was done using a library of chromogenic ester substrate that revealed the broad substrate specificity of EstD11 with significant measurable activity against 16 substrates with varied chain length, steric hindrance, aromaticity and flexibility of the linker between the carboxyl and the alcohol moiety of the ester.

Social Environment Ameliorates Behavioral and Immune Impairments in Tyrosine Hydroxylase Haploinsufficient Female Mice.

The social environment can influence the functional capacity of nervous and immune systems, and consequently the state of health, especially in aged individuals. Adult female tyrosine hydroxylase haploinsufficient (TH-HZ) mice exhibit behavioral impairments, premature immunosenescence and oxidative- inflammatory stress. All these deteriorations are associated with a lower lifespan than wild type (WT) counterparts.

The ratio of prematurely aging to non-prematurely aging mice cohabiting, conditions their behavior, immunity and lifespan.

Adult prematurely aging mice (PAM) show behavioral deterioration, premature immunosenescence and increased oxidative stress, impairments that are associated with their shorter lifespan, compared to the corresponding exceptional non-prematurely aging mice (ENPAM). When PAM live in a predominantly ENPAM environment (2/5, respectively) they exhibit an improvement of immunity and redox state in their spleen and thymus leukocytes, and an increased lifespan. Nevertheless, it is unknown if other PAM/ENPAM ratios could affect behavioral and peritoneal leukocyte functions of PAM and change their lifespan.

Improvement of Redox State and Functions of Immune Cells as Well as of Behavioral Response in Aged Mice After Two-Week Supplementation of Fermented Milk with Probiotics.

The homeostatic systems, such as the nervous and immune systems, show deterioration in aging as a consequence of the age-related oxidative-inflammatory stress establishment. The supplementation with fermented milk containing probiotic bacteria could be a good nutritional strategy to improve homeostatic system functions in aged individuals through the modulation of their redox state. The aim of the present study was to evaluate the effect of 2-week supplementation with a commercial fermented milk containing yogurt species (Lactobacillus delbrueckii subsp.

Oxidative-Inflammatory Stress in Immune Cells from Adult Mice with Premature Aging.

Oxidative and inflammatory stresses are closely related processes, which contribute to age-associated impairments that affect the regulatory systems such as the immune system and its immunosenescence. Therefore, the aim of this work was to confirm whether an oxidative/inflammatory stress occurs in immune cells from adult mice with premature aging, similar to that shown in leukocytes from chronologically old animals, and if this results in immunosenescence. Several oxidants/antioxidants and inflammatory/anti-inflammatory cytokines were analyzed in peritoneal leukocytes from adult female CD1 mice in two models of premature aging-(a) prematurely aging mice (PAM) and (b) mice with the deletion of a single allele (hemi-zygotic: HZ) of the tyrosine hydroxylase () gene (TH-HZ), together with cells from chronologically old animals.

Social environment improves immune function and redox state in several organs from prematurely aging female mice and increases their lifespan.

Aging is associated with a chronic oxidative stress (increase of oxidants and decrease of antioxidants), which contributes to immunosenescence and therefore shorter longevity. Nevertheless, a positive social network has been related to the adequate maintenance of health and deceleration of aging. Adult prematurely aging mice (PAM) are characterized by their inadequate stress response to a T-maze, showing premature immunosenescence and oxidative stress establishment.

Reemergence of H3N8 Equine Influenza A virus in Chile, 2018.

A new outbreak of equine Influenza A virus (IAV) was reported in Chile in January 2018, 6 years after its last report in 2012. Equine IAV was detected by rtRT-PCR, followed by virus isolation and full genome sequencing. Genetic characterization of equine IAV classified the virus within clade 1 of the Florida sublineage.

Adsorption of Pharmaceutical Pollutants from Water Using Covalent Organic Frameworks.

Capture of pharmaceutical pollutants from water was studied using a novel fluorine-bearing covalent organic framework TpBD-(CF ) , which showed ibuprofen adsorption capacity of 119 mg g at neutral pH. This value is further enhanced at pH 2, highlighting the potential of this class of materials to serve as adsorbents even under harsh conditions. The adsorbed pharmaceutical can be recovered from TpBD-(CF ) in high yield, offering the option of recycling both the adsorbent and the pharmaceutical.

Impairment of photoreceptor ribbon synapses in a novel Pomt1 conditional knockout mouse model of dystroglycanopathy.

Hypoglycosylation of α-dystroglycan (α-DG) resulting from deficiency of protein O-mannosyltransferase 1 (POMT1) may cause severe neuromuscular dystrophies with brain and eye anomalies, named dystroglycanopathies. The retinal involvement of these disorders motivated us to generate a conditional knockout (cKO) mouse experiencing a Pomt1 intragenic deletion (exons 3-4) during the development of photoreceptors, mediated by the Cre recombinase expressed from the cone-rod homeobox (Crx) gene promoter. In this mouse, retinal α-DG was unglycosylated and incapable of binding laminin.

Expression in retinal neurons of fukutin and FKRP, the protein products of two dystroglycanopathy-causative genes.

Purpose: Dystroglycanopathies are a heterogeneous group of recessive neuromuscular dystrophies that affect the muscle, brain and retina, and are caused by deficiencies in the O-glycosylation of α-dystroglycan. This post-translational modification is essential for the formation and maintenance of ribbon synapses in the retina. Fukutin and fukutin-related protein (FKRP) are two glycosyltransferases whose deficiency is associated with severe dystroglycanopathies.

Premature aging in behavior and immune functions in tyrosine hydroxylase haploinsufficient female mice. A longitudinal study.

Aging is accompanied by impairment in the nervous, immune, and endocrine systems as well as in neuroimmunoendocrine communication. In this context, there is an age-related alteration of the physiological response to acute stress, which is modulated by catecholamine (CA), final products of the sympathetic-adreno-medullary axis. The involvement of CA in essential functions of the nervous system is consistent with the neuropsychological deficits found in mice with haploinsufficiency (hemizygous; HZ) of tyrosine hydroxylase (TH) enzyme (TH-HZ).

A Positive Allosteric Modulator of the Serotonin 5-HT Receptor for Obesity.

The 5-HTR agonist lorcaserin, clinically approved for the treatment of obesity, causes important side effects mainly related to subtype selectivity. In the search for 5-HTR allosteric modulators as safer antiobesity drugs, a chemical library from Vivia Biotech was screened using ExviTech platform. Structural modifications of identified hit VA240 in synthesized analogues 6-41 afforded compound 11 (N-[(1-benzyl-1H-indol-3-yl)methyl]pyridin-3-amine, VA012), which exhibited dose-dependent enhancement of serotonin efficacy, no significant off-target activities, and low binding competition with serotonin or other orthosteric ligands.

Improved Measurement of Elastic Properties of Cells by Micropipette Aspiration and Its Application to Lymphocytes.

Mechanical deformability of cells is an important property for their function and development, as well as a useful marker of cell state. The classical technique of micropipette aspiration allows single-cell studies and we provide here a method to measure the two basic mechanical parameters, elastic modulus and Poisson's ratio. The proposed method, developed from finite-element analysis of micropipette aspiration experiments, may be implemented in future technologies for the automated measurement of mechanical properties of cells, based on the micropipette aspiration technique or on the cell transit through flow constrictions.

Immune function parameters as markers of biological age and predictors of longevity.

Chronological age is not a good indicator of how each individual ages and thus how to maintain good health. Due to the long lifespan in humans and the consequent difficulty of carrying out longitudinal studies, finding valid biomarkers of the biological age has been a challenge both for research and clinical studies. The aim was to identify and validate several immune cell function parameters as markers of biological age.

Cellular Viscosity in Prokaryotes and Thermal Stability of Low Molecular Weight Biomolecules.

Some low molecular weight biomolecules, i.e., NAD(P)H, are unstable at high temperatures.

Gallus gallus orthologous to human alpha-dystroglycanopathies candidate genes: Gene expression and characterization during chicken embryogenesis.

Alpha-dystroglycanopathies are a heterogenic group of human rare diseases that have in common defects of α-dystroglycan O-glycosylation. These congenital disorders share common features as muscular dystrophy, malformations on central nervous system and more rarely altered ocular development, as well as mutations on a set of candidate genes involved on those syndromes. Severity of the syndromes is variable, appearing Walker-Warburg as the most severe where mutations at protein O-mannosyl transferases POMT1 and POMT2 genes are frequently described.

Expression pattern in retinal photoreceptors of POMGnT1, a protein involved in muscle-eye-brain disease.

Purpose: The POMGNT1 gene, encoding protein O-linked-mannose β-1,2-N-acetylglucosaminyltransferase 1, is associated with muscle-eye-brain disease (MEB) and other dystroglycanopathies. This gene's lack of function or expression causes hypoglycosylation of α-dystroglycan (α-DG) in the muscle and the central nervous system, including the brain and the retina. The ocular symptoms of patients with MEB include retinal degeneration and detachment, glaucoma, and abnormal electroretinogram.