A yeast-based tool for screening mammalian diacylglycerol acyltransferase inhibitors

Dysregulation of lipid metabolism is associated with obesity and metabolic diseases but there is also increasing evidence of a relationship between lipid body excess and cancer. Lipid body synthesis requires diacylglycerol acyltransferases (DGATs) which catalyze the last step of triacylglycerol synthesis from diacylglycerol and acyl-coenzyme A. The DGATs and in particular DGAT2, are therefore considered potential therapeutic targets for the control of these pathologies. Here, the murine and the human DGAT2 were overexpressed in the oleaginous yeast Yarrowia lipolytica deleted for all DGAT activities, to evaluate the functionality of the enzymes in this heterologous host and DGAT activity inhibitors. This work provides evidence that mammalian DGATs expressed in Y. lipolytica are a useful tool for screening chemical libraries to identify potential inhibitors or activators of these enzymes of therapeutic interest

Production of Long Chain Fatty Alcohols Found in Bumblebee Pheromones by Yarrowia lipolytica

Fatty alcohols (FA-OH) are aliphatic unbranched primary alcohols with a chain of four or more carbon atoms. Besides potential industrial applications, fatty alcohols have important biological functions as well. In nature, fatty alcohols are produced as a part of a mixture of pheromones in several insect species, such as moths, termites, bees, wasps, etc. In addition, FA-OHs have a potential for agricultural applications, for example, they may be used as a suitable substitute for commercial insecticides. The insecticides have several drawbacks associated with their preparation, and they exert a negative impact on the environment. Currently, pheromone components are prepared mainly through the catalytic hydrogenation of plant oils and petrochemicals, which is an unsustainable, ecologically unfriendly, and highly expensive process. The biotechnological production of the pheromone components using engineered microbial strains and through the expression of the enzymes participating in the biosynthesis of these components is a promising approach that ensures ecological sustenance as well. The present study was aimed at evaluating the production of FA-OHs in the oleaginous yeast, Yarrowia lipolytica, with different lengths of fatty-acyl chains by expressing the fatty acyl-CoA reductase (FAR) BlapFAR4 from B. lapidarius, producing C16:0-OH, C16:1Δ9-OH, and lower quantities of both C14:0-OH and C18:1Δ9-OH, and BlucFAR1 from B. lucorum, producing FA-OHs with a chain length of 18–26 carbon atoms, in this yeast. Among the different novel Y. lipolytica strains used in the present study, the best results were obtained with JMY7086, which carried several lipid metabolism modifications and expressed the BlucFAR1 gene under the control of a strong constitutive promoter 8UAS-pTEF. JMY7086 produced only saturated fatty alcohols with chain lengths from 18 to 24 carbon atoms. The highest titer and accumulation achieved were 166.6 mg/L and 15.6 mg/g DCW of fatty alcohols, respectively. Unlike JMY7086, the BlapFAR4-expressing strain JMY7090 produced only 16 carbon atom-long FA-OHs with a titer of 14.6 mg/L

Reasons and Means to Model Preferences as Incomplete

Literature involving preferences of artificial agents or human beings often assume their preferences can be represented using a complete transitive binary relation. Much has been written however on different models of preferences. We review some of the reasons that have been put forward to justify more complex modeling, and review some of the techniques that have been proposed to obtain models of such preferences

Equity, Envy and Efficiency under Asymmetric Information

The set of fair (i.e. envy free and efficient) allocation rules may be empty in wellbehaved pure exchange economies if the agents are asymmetrically informed at the time of contracting. In addition, there may exist efficient allocation rules such that every agent envies another

Welding dynamics in an atomistic model of an amorphous polymer blend with polymer-polymer interface

We consider an atomistic model of thermal welding at the polymer-polymer interface of a polyetherimide/polycarbonate blend, motivated by applications to 3D manufacturing in space. We follow diffusion of semiflexible chains at the interface and analyze strengthening of the samples as a function of the welding time tw by simulating the strain-stress and shear viscosity curves. The time scales for initial wetting, and for fast and slow diffusion, are revealed. It is shown that each component of the polymer blend has its own characteristic time of slow diffusion at the interface. Analysis of strainstress demonstrates saturation of the Young’s modulus at tw = 240 ns, while the tensile strength continues to increase. The shear viscosity is found to have a very weak dependence on the welding time for tw > 60 ns. It is shown that both strain-stress and shear viscosity curves agree with experimental data

Stage and treatment variation with age in postmenopausal women with breast cancer: compliance with guidelines

Breast cancer-specific mortality is static in older women despite having fallen in younger age groups, possibly due to lack of screening and differences in treatment. This study compared stage and treatment between two cohorts of postmenopausal women (55–69 vs 470 years) in a single cancer network over 6 months. A total of 378 patients were studied (470: N ¼ 167, 55–69 years: N ¼ 210). Older women presented with more advanced disease (470: metastatic/locally advanced 12%, 55–69 years: 3%, Po0.01). Those with operable cancer had a worse prognosis (Nottingham Prognostic Index (NPI) 470: median NPI 4.4, 55–69 years: 4.25, Po0.03). These stage differences were partially explained by higher screening rates in the younger cohort. Primary endocrine therapy was used in 42% of older patients compared with 3% in the younger group (Po0.001). Older women with cancers suitable for breast conservation were more likely to choose mastectomy (470: 57.5% mastectomy rate vs 55–69 years: 20.6%, Po0.01). Nodal surgery was less frequent in older patients (470: 6.7% no nodal surgery, 55–69 years: 0.5%, Po0.01) and was more likely to be inadequate (470: 10.7% o4 nodes excised, 55–69 years: 3.4%, Po0.02). In summary, older women presented with more advanced breast cancer, than younger postmenopausal women and were treated less comprehensively

Myasthenia gravis

Myasthenia gravis (MG) is a rare, autoimmune neuromuscular junction disorder. Contemporary prevalence rates approach 1/5,000. MG presents with painless, fluctuating, fatigable weakness involving specific muscle groups. Ocular weakness with asymmetric ptosis and binocular diplopia is the most typical initial presentation, while early or isolated oropharyngeal or limb weakness is less common. The course is variable, and most patients with initial ocular weakness develop bulbar or limb weakness within three years of initial symptom onset. MG results from antibody-mediated, T cell-dependent immunologic attack on the endplate region of the postsynaptic membrane. In patients with fatigable muscle weakness, the diagnosis of MG is supported by: 1. pharmacologic testing with edrophonium chloride that elicits unequivocal improvement in strength; 2. electrophysiologic testing with repetitive nerve stimulation (RNS) studies and/or single-fiber electromyography (SFEMG) that demonstrates a primary postsynaptic neuromuscular junctional disorder; and 3. serologic demonstration of acetylcholine receptor (AChR) or muscle-specific tyrosine kinase (MuSK) antibodies. Differential diagnosis includes congenital myasthenic syndromes, Lambert Eaton syndrome, botulism, organophosphate intoxication, mitochondrial disorders involving progressive external ophthalmoplegia, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), motor neuron disease, and brainstem ischemia. Treatment must be individualized, and may include symptomatic treatment with cholinesterase inhibitors and immune modulation with corticosteroids, azathioprine, cyclosporine, and mycophenolate mofetil. Rapid, temporary improvement may be achieved for myasthenic crises and exacerbations with plasma exchange (PEX) or intravenous immunoglobulin (IVIg). Owing to improved diagnostic testing, immunotherapy, and intensive care, the contemporary prognosis is favorable with less than five percent mortality and nearly normal life expectancy

COVID-19 pandemic: Impact caused by school closure and national lockdown on pediatric visits and admissions for viral and non-viral infections, a time series analysis.

A time series analysis of 871,543 pediatric emergency visits revealed that the COVID-19 lockdown and school closure were associated with a significant decrease in infectious diseases disseminated through airborne or fecal-oral transmissions: common cold, gastro-enteritis, bronchiolitis, acute otitis. No change was found for urinary tract infections