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

Revealing subthreshold motor contributions to perceptual confidence

Established models of perceptual metacognition, the ability to evaluate our perceptual judgements, posit that perceptual confidence depends on the strength or quality of feedforward sensory evidence. However, alternative theoretical accounts suggest the entire perception-action cycle, and not only variation in sensory evidence, is monitored when evaluating confidence in one’s percepts. Such models lead to the counterintuitive prediction that perceptual confidence should be directly modulated by features of motor output. To evaluate this proposal here we recorded electromyographic (EMG) activity of motor effectors while subjects performed a near-threshold perceptual discrimination task and reported their confidence in each response in a pre-registered experiment. A subset of trials exhibited subthreshold EMG activity in response effectors before a decision was made. Strikingly, trial-by-trial analysis showed that confidence, but not accuracy, was significantly higher on trials with subthreshold motor activation. These findings support a hypothesis that preparatory motor activity, or a related latent variable, impacts upon confidence over and above performance, consistent with models in which perceptual metacognition integrates information across the perception-action cycle

Does social context impact metacognition? Evidence from stereotype threat in a visual search task

While recent studies have emphasized the role of metacognitive judgments in social interactions, whether social context might reciprocally impact individuals’ metacognition remains an open question. It has been proposed that such might be the case in situations involving stereotype threat. Here, we provide the first empirical test of this hypothesis. Using a visual search task, we asked participants, on a trial-by-trial basis, to monitor the unfolding and accuracy of their search processes, and we developed a computational model to measure the accuracy of their metacognition. Results indicated that stereotype threat enhanced metacognitive monitoring of both outcomes and processes. Our study thus shows that social context can actually affect metacognition

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

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

Elicitation of Preferences under Ambiguity

This paper is about behaviour under ambiguity ‒ that is, a situation in which probabilities either do not exist or are not known. Our objective is to find the most empirically valid of the increasingly large number of theories attempting to explain such behaviour. We use experimentally-generated data to compare and contrast the theories. The incentivised experimental task we employed was that of allocation: in a series of problems we gave the subjects an amount of money and asked them to allocate the money over three accounts, the payoffs to them being contingent on a ‘state of the world’ with the occurrence of the states being ambiguous. We reproduced ambiguity in the laboratory using a Bingo Blower. We fitted the most popular and apparently empirically valid preference functionals [Subjective Expected Utility (SEU), MaxMin Expected Utility (MEU) and α­-MEU], as well as Mean-Variance (MV) and a heuristic rule, Safety First (SF). We found that SEU fits better than MV and SF and only slightly worse than MEU and α­-MEU

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

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

Analysis of incidence and prognostic factors for ipsilateral breast tumour recurrence and its impact on disease-specific survival of women with node-negative breast cancer: a prospective cohort study

INTRODUCTION: This study had three aims: to establish the incidence of ipsilateral breast tumour recurrence (IBTR) in a community treatment setting, to evaluate known factors – in particular younger age (< 40 years) – predictive for local recurrence, and to assess the impact of local recurrence on disease-specific survival (DSS). METHODS: A consecutive series of 1,540 women with node-negative breast cancer, diagnosed between the ages of 18–75 years, were prospectively accrued between September 1987 and September 1999. All had undergone a resection of the primary breast cancer with clear margins, an axillary lymph node dissection with a minimum of four sampled nodes, and breast-conserving surgery (of any type). RESULTS: During the study follow-up period, 98 (6.4%) IBTRs and 117 (7.6%) deaths from or with breast cancer were observed. The median time to IBTR was 3.1 years and to death from or with disease was 4.3 years. In the multivariate Cox proportional hazards (PH) regression model for IBTR with adjuvant therapy factors, independent risk factors included age < 40 years (relative risk (RR) = 1.89, 95% confidence interval (CI) of 1.00 – 3.58), presence of intraductal disease (RR = 1.81, 95% CI = 1.15–2.85) and histological grade ('G2' or G3 versus G1: RR = 1.59, 95% CI = 0.87–2.94). In the multivariate Cox PH regression model for DSS with adjuvant therapy factors, independent risk factors included previous IBTR (RR = 2.58, 95% CI = 1.41–4.72), tumor size (1–2 cm versus < 1 cm: RR = 1.95, 95% CI = 1.05–3.64, > 2 cm versus < 1 cm: RR = 2.94, 95% CI = 1.56–5.56), progesterone receptor status (negative or equivocal versus positive or unknown: RR = 2.15, 95% CI = 1.36–3.39), lymphatic invasion (RR = 1.78, 95% CI = 1.17–2.72), and histological grade ('G2' or G3 versus G1: RR = 8.59, 95% CI = 2.09–35.36). The effects of competing risks could be ignored. CONCLUSION: The Cox PH analyses confirmed the importance of known risk factors for IBTR and DSS in a community treatment setting. This study also revealed that the early occurrence of an IBTR is associated with a relatively poor five-year survival rate