Impact of Minor Structural Modifications on Properties of a Series of mTOR Inhibitors.

Minor structural modifications-sometimes single atom changes-can have a dramatic impact on the properties of compounds. This is illustrated here on structures related to known mTOR inhibitor Sapanisertib. Subtle changes in the hinge binder lead to strikingly different overall profiles with changes in physical properties, metabolism, and kinase selectivity.

Atypical Cowpox Virus Infection in Smallpox-Vaccinated Patient, France.

We report a case of atypical cowpox virus infection in France in 2016. The patient sought care for thoracic lesions after injury from the sharp end of a metallic guardrail previously stored in the ground. We isolated a cowpox virus from the lesions and sequenced its whole genome.

Brimonidine displays anti-inflammatory properties in the skin through the modulation of the vascular barrier function.

Background: Rosacea is a chronic inflammatory skin disease. Characteristic vascular changes in rosacea skin include enlarged, dilated vessels of the upper dermis and blood flow increase. Brimonidine is approved for symptomatic relief of the erythema of rosacea.

Temporalis, a generic method and tool for dynamic Life Cycle Assessment.

The limitations of the static nature of Life Cycle Assessment (LCA) are well known. To overcome the loss of temporal information due to the aggregation of flows in the Life Cycle Inventory (LCI), several dynamic LCA methodologies have been proposed. In this paper we present a new generic and operational methodology for dynamic LCA that allows for the introduction of temporal information in both in the inventory and the Life Cycle Impact Assessment (LCIA) phases.

Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor-γ agonist trifarotene.

Background: First- and third-generation retinoids are the main treatment for acne. Even though efficacious, they lack full selectivity for retinoic acid receptor (RAR) γ, expressed in the epidermis and infundibulum.

Objectives: To characterize the in vitro metabolism and the pharmacology of the novel retinoid trifarotene.

Sulfoximines as potent RORγ inverse agonists.

Progress in the identification of suitable RORγ inverse agonists as clinical candidates has been hampered by the high lipophilicity that seems required for high potency on this nuclear receptor. In this context, we decided to focus on the replacement of the hydroxymethyl group found on known modulators to determine if more polarity could be tolerated in this position. SAR of the replacement of this moiety is presented in this article leading to the identification of sulfoximine derivatives as potent modulators with pharmacological activity in the in vivo mouse Imiquimod psoriasis model.

EFO-LCI: A New Life Cycle Inventory Database of Forestry Operations in Europe.

Life cycle assessment (LCA) has become a common methodology to analyze environmental impacts of forestry systems. Although LCA has been widely applied to forestry since the 90s, the LCAs are still often based on generic Life Cycle Inventory (LCI). With the purpose of improving LCA practices in the forestry sector, we developed a European Life Cycle Inventory of Forestry Operations (EFO-LCI) and analyzed the available information to check if within the European forestry sector national differences really exist.

Discovery and Characterization of CD12681, a Potent RORγ Inverse Agonist, Preclinical Candidate for the Topical Treatment of Psoriasis.

With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor RORγ has become a sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-[(tetrahydro-2H-pyran-4-yl)methyl]-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (CD12681), a potent inverse agonist with in vivo activity in an IL-23-induced mouse skin inflammation model.

Discovery and process development of a novel TACE inhibitor for the topical treatment of psoriasis.

Targeting the TNFα pathway is a validated approach to the treatment of psoriasis. In this pathway, TACE stands out as a druggable target and has been the focus of in-house research programs. In this article, we present the discovery of clinical candidate 26a.

Topical ivermectin improves allergic skin inflammation.

Background: Ivermectin (IVM) is widely used in both human and veterinary medicine to treat parasitic infections. Recent reports have suggested that IVM could also have anti-inflammatory properties.

Methods: Here, we investigated the activity of IVM in a murine model of atopic dermatitis (AD) induced by repeated exposure to the allergen Dermatophagoides farinae, and in standard cellular immunological assays.

Protective Effect of Dermal Brimonidine Applications Against UV Radiation-induced Skin Tumors, Epidermal Hyperplasia and Cell Proliferation in the Skin of Hairless Mice.

Brimonidine at 0.18%, 1% and 2% concentrations applied topically in hairless mice significantly decreased tumor burden and incidences of erythema, flaking, wrinkling and skin thickening induced by UVR. The unbiased median week to tumor ≥1 mm was increased by the 1% and 2% concentrations.

Will selenium increase lentil (Lens culinaris Medik) yield and seed quality?

Lentil (Lens culinaris Medik), a nutritious traditional pulse crop, has been experiencing a declining area of production in South East Asia, due to lower yields, and marginal soils. The objective of this study was to determine whether selenium (Se) fertilization can increase lentil yield, productivity, and seed quality (both seed Se concentration and speciation). Selenium was provided to five lentil accessions as selenate or selenite by foliar or soil application at rates of 0, 10, 20, or 30 kg Se/ha and the resulting lentil biomass, grain yield, seed Se concentration, and Se speciation was determined.

Combining two repurposed drugs as a promising approach for Alzheimer's disease therapy.

Alzheimer disease (AD) represents a major medical problem where mono-therapeutic interventions demonstrated only a limited efficacy so far. We explored the possibility of developing a combinational therapy that might prevent the degradation of neuronal and endothelial structures in this disease. We argued that the distorted balance between excitatory (glutamate) and inhibitory (GABA/glycine) systems constitutes a therapeutic target for such intervention.

Polytherapy with a combination of three repurposed drugs (PXT3003) down-regulates Pmp22 over-expression and improves myelination, axonal and functional parameters in models of CMT1A neuropathy.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited sensory and motor peripheral neuropathy. It is caused by PMP22 overexpression which leads to defects of peripheral myelination, loss of long axons, and progressive impairment then disability. There is no treatment available despite observations that monotherapeutic interventions slow progression in rodent models.

[Urban violence and social capital in a southern Brazilian city: a quantitative and qualitative study].

Objective: to study the relationship between reported urban violence and social capital in a medium-sized city in the state of Rio Grande do Sul, Brazil.

Methods: the study was carried out with adults living in the urban area of São Leopoldo. For the quantitative analysis, a structured questionnaire was answered by 1 100 individuals older than 20 years of age and in charge of the household at the moment of the interview.

[Prevalence of poor self-rated mastication and associated factors in Brazilian elderly].

We estimated the prevalence of poor self-rated mastication and associated factors among Brazilian elders. The study used data from a national survey of 5,124 Brazilian elderly in 250 cities. Data collection included dental examinations and household interviews with the elderly.

Major contribution of MEK1 to the activation of ERK1/ERK2 and to the growth of LS174T colon carcinoma cells.

Mammalian cells express two closely related MEK isoforms, MEK1 and MEK2, upstream of the ERK1/ERK2 MAPK module. Although genetic studies have suggested that MEK1 and MEK2 do not have overlapping functions in vivo, little is known about their specific contribution to the activation of ERKs and to tumor cell proliferation. We used Tet-inducible shRNA to investigate the independent role of MEK1 and MEK2 for the oncogenic and the serum-induced activation of ERK1 and ERK2 in LS174T colon carcinoma cells.

Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility.

Rho GTPases participate in various cellular processes, including normal and tumor cell migration. It has been reported that RhoA is targeted for degradation at the leading edge of migrating cells by the E3 ubiquitin ligase Smurf1, and that this is required for the formation of protrusions. We report that Smurf1-dependent RhoA degradation in tumor cells results in the down-regulation of Rho kinase (ROCK) activity and myosin light chain 2 (MLC2) phosphorylation at the cell periphery.

[Nursing in life re-significance on the face of disease].

The paper deals with the educational role played by the health care provider. The ideas exposed stem from a reflection made from a research on the resignification of life of individuals affected by diseases that entail changes to their lifestyle. The health care provider has a key role in this process, influencing the patient positively or negatively.

Elevated ERK-MAP kinase activity protects the FOS family member FRA-1 against proteasomal degradation in colon carcinoma cells.

The AP-1 (activator protein-1) complex, which consists of proteins of the Fos and Jun families, is thought to play an important role in the balance between cell proliferation and apoptosis, the response to genotoxic stress and cell transformation. In cells containing oncogenic Ras, the major components of AP-1 are Fra-1 and c-Jun. Signalling from Ras to AP-1 is through the Raf/MEK[mitogen-activated protein (MAP) kinase kinase]/ERK (extracellular signal-regulated kinase) MAP kinase pathway as sustained activation of Raf1 or Mek1 modifies AP-1 composition and activity.

ERK-MAPK signaling coordinately regulates activity of Rac1 and RhoA for tumor cell motility.

We describe two signaling events downstream of ERK-MAP kinase contributing to cell motility in colon carcinoma cells. The Fos family member Fra-1 is expressed in an ERK-dependent manner. Silencing of Fra-1 expression with short interfering RNAs leads to losses of cell polarization, motility, and invasiveness in vitro.

v-Jun downregulates the SPARC target gene by binding to the proximal promoter indirectly through Sp1/3.

Transformation of chick embryo fibroblasts by the v-Jun oncoprotein correlates with a downregulation of the extracellular matrix protein SPARC and repression of the corresponding mRNA. Repression of SPARC contributes to the oncogenic process by facilitating tumor development in vivo. A proximal promoter fragment, designated -124/+16, is responsible for high constitutive activity of the SPARC gene and is the target of repression by v-Jun.

Mapping of autosomal recessive chronic distal spinal muscular atrophy to chromosome 11q13.

Distal spinal muscular atrophy is a heterogeneous group of neuromuscular disorders caused by progressive anterior horn cell degeneration and characterized by progressive motor weakness and muscular atrophy, predominantly in the distal parts of the limbs. Here we report on chronic autosomal recessive distal spinal muscular atrophy in a large, inbred family with onset at various ages. Because this condition had some of the same clinical features as spinal muscular atrophy with respiratory distress, we tested the disease gene for linkage to chromosome 11q and mapped the disease locus to chromosome 11q13 in the genetic interval that included the spinal muscular atrophy with respiratory distress gene (D11S1889-D11S1321, Z(max) = 4.

Influence of the charge of low molecular weight proteins on their efficacy of filtration and/or adsorption on dialysis membranes with different intrinsic properties.

Hemodialysis membranes eliminate by filtration low-molecular-weight toxic metabolites (urea and creatinine) with minimum interactions between blood components and the membrane itself. However, the ability of a membrane to adsorb specific proteins could be beneficial if the accumulation of these same proteins is implicated in the genesis of a pathological condition. Beta-amyloidosis which accompanies the elevation of beta2-microglobulin (11.