Quality assessment of protein NMR structures

Biomolecular NMR structures are now routinely used in biology, chemistry, and bioinformatics. Methods and metrics for assessing the accuracy and precision of protein NMR structures are beginning to be standardized across the biological NMR community. These include both knowledge-based assessment metrics, parameterized from the database of protein structures, and model versus data assessment metrics. On line servers are available that provide comprehensive protein structure quality assessment reports, and efforts are in progress by the world-wide Protein Data Bank (wwPDB) to develop a biomolecular NMR structure quality assessment pipeline as part of the structure deposition process. These quality assessment metrics and standards will aid NMR spectroscopists in determining more accurate structures, and increase the value and utility of these structures for the broad scientific community

Community-linked maternal death review (CLMDR) to measure and prevent maternal mortality: a pilot study in rural Malawi.

In Malawi, maternal mortality remains high. Existing maternal death reviews fail to adequately review most deaths, or capture those that occur outside the health system. We assessed the value of community involvement to improve capture and response to community maternal deaths

Factors associated with public knowledge of and attitudes to dementia: A cross-sectional study

IntroductionDementia is a major public health concern but one that continues to be stigmatised. We examine lay knowledge of dementia and attitudes to people with dementia as potential precursors of public anxiety, focusing on the social characteristics associated with (a) the formation of these attitudes, and (b) the perception of the need for restriction and control for people with dementia.MethodsAnalysis of the 2014 Northern Ireland Life and Times survey, which included questions on knowledge of, attitudes to and personal experience with dementia. We used (a) latent class analysis and (b) logistic regression to examine factors associated with respondent attitudes towards dementia.ResultsRespondents (n = 1211) had relatively good general knowledge of dementia, but limited knowledge of specific risk factors. Negative perceptions of dementia were mitigated somewhat by personal contact. A high proportion of respondents felt that high levels of control were appropriate for people diagnosed with dementia, even at early stages of the disease.ConclusionPersonal antipathy to dementia was highly prevalent despite ongoing public campaigns to increase public awareness of developments in its prevention, treatment and consequent care pathways and hampering efforts to widen social inclusion. Fresh thinking and more resources may be needed to challenge persisting common misapprehension of the condition and the formation of entrenched stigma

Perceptron theory can predict the accuracy of neural networks

Multilayer neural networks set the current state of the art for many technical classification problems. But, these networks are still, essentially, black boxes in terms of analyzing them and predicting their performance. Here, we develop a statistical theory for the one-layer perceptron and show that it can predict performances of a surprisingly large variety of neural networks with different architectures. A general theory of classification with perceptrons is developed by generalizing an existing theory for analyzing reservoir computing models and connectionist models for symbolic reasoning known as vector symbolic architectures. Our statistical theory offers three formulas leveraging the signal statistics with increasing detail. The formulas are analytically intractable, but can be evaluated numerically. The description level that captures maximum details requires stochastic sampling methods. Depending on the network model, the simpler formulas already yield high prediction accuracy. The quality of the theory predictions is assessed in three experimental settings, a memorization task for echo state networks (ESNs) from reservoir computing literature, a collection of classification datasets for shallow randomly connected networks, and the ImageNet dataset for deep convolutional neural networks. We find that the second description level of the perceptron theory can predict the performance of types of ESNs, which could not be described previously. Furthermore, the theory can predict deep multilayer neural networks by being applied to their output layer. While other methods for prediction of neural networks performance commonly require to train an estimator model, the proposed theory requires only the first two moments of the distribution of the postsynaptic sums in the output neurons. Moreover, the perceptron theory compares favorably to other methods that do not rely on training an estimator model

A NMR study of the interaction of a three-domain construct of ATP7A with copper(I) and copper(I)-HAH1: the interplay of domains.

ATP7A is a P-type ATPase involved in copper(I) homeostasis in humans. It possesses a long N-terminal tail protruding into the cytosol and containing six copper(I)-binding domains, which are individually folded and capable of binding one copper(I) ion. ATP7A receives copper from a soluble protein, the metallochaperone HAH1. The exact role and interplay of the six soluble domains is still quite unclear, as it has been extensively demonstrated that they are strongly redundant with respect to copper(I) transport in vivo. In the present work, a three-domain (fourth to sixth, MNK456) construct has been investigated in solution by NMR, in the absence and presence of copper(I). In addition, the interaction of MNK456 with copper(I)-HAH1 has been studied. It is proposed that the fourth domain is the preferential site for the initial interaction with the partner. A significant dependence of the overall domain dynamics on the metallation state and on the presence of HAH1 is observed. This dependence could constitute the molecular mechanism to trigger copper(I) translocation and/or ATP7A relocalization from the trans-Golgi network to the plasmatic membrane

Liver biopsy in type 2 diabetes mellitus: steatohepatitis represents the sole feature of liver damage

Recent studies report a prevalence of non-alcoholic fatty liver disease (NAFLD) of between 70% and 80% in patients with metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM). Nevertheless, it is not possible to differentiate between simple steatosis and nonalcoholic steatohepatitis (NASH) with non-invasive tests. The aim of this study was to differentiate between simple steatosis and NASH by liver biopsy in patients with hypertransaminasemia and MS or T2DM. Two hundred and fifteen patients with increased ALT levels and MS, and 136 patients at their first diagnosis of T2DM regardless of ALT values were consecutively admitted to a tertiary hepatology center between January 2004 and November 2014. Exclusion criteria were other causes of liver disease/ALT increase. Each patient underwent a clinical, laboratory and ultrasound evaluation, and a liver biopsy. Gender distribution, age, and body mass index were similar in the two groups of patients, whereas cholesterol levels, glycemia and blood pressure were significantly different between the two groups. The prevalence of NAFLD was 94.82% in MS patients and 100% in T2DM patients. NASH was present in 58.52% of MS patients and 96.82% of T2DM. Consequently, this study reveals that, by using liver biopsy, almost all patients with T2DM or MS have NAFLD, which in patients with T2DM means NASH. Importantly, it suggests that NASH may be one of the early complications of T2DM due to its pathophysiological correlation with insulin resistance

Density waves and 1/f1/f density fluctuations in granular flow

We simulate the granular flow in a narrow pipe with a lattice-gas automaton model. We find that the density in the system is characterized by two features. One is that spontaneous density waves propagate through the system with well-defined shapes and velocities. The other is that density waves are so distributed to make the power spectra of density fluctuations as $1/f^{\alpha}$ noise. Three important parameters make these features observable and they are energy dissipation, average density and the rougness of the pipe walls.Comment: Latex (with ps files appended

Variational Approach to Hard Sphere Segregation Under Gravity

It is demonstrated that the minimization of the free energy functional for hard spheres and hard disks yields the result that excited granular materials under gravity segregate not only in the widely known "Brazil nut" fashion, i.e. with the larger particles rising to the top, but also in reverse "Brazil nut" fashion. Specifically, the local density approximation is used to investigate the crossover between the two types of segregation occurring in the liquid state, and the results are found to agree qualitatively with previously published results of simulation and of a simple model based on condensation.Comment: 10 pages, 3 figure

Non alcoholic fatty liver disease and eNOS dysfunction in humans

Background: NAFLD is associated to Insulin Resistance (IR). IR is responsible for Endothelial Dysfunction (ED) through the impairment of eNOS function. Although eNOS derangement has been demonstrated in experimental models, no studies have directly shown that eNOS dysfunction is associated with NAFLD in humans. The aim of this study is to investigate eNOS function in NAFLD patients. Methods: Fifty-four NAFLD patients were consecutively enrolled. All patients underwent clinical and laboratory evaluation and liver biopsy. Patients were divided into two groups by the presence of NAFL or NASH. We measured vascular reactivity induced by patients' platelets on isolated mice aorta rings. Immunoblot assays for platelet-derived phosphorylated-eNOS (p-eNOS) and immunohistochemistry for hepatic p-eNOS have been performed to evaluate eNOS function in platelets and liver specimens. Flow-mediated-dilation (FMD) was also performed. Data were compared with healthy controls. Results: Twenty-one (38, 8%) patients had NAFL and 33 (61, 7%) NASH. No differences were found between groups and controls except for HOMA and insulin (p < 0.0001). Vascular reactivity demonstrated a reduced function induced from NAFLD platelets as compared with controls (p < 0.001), associated with an impaired p-eNOS in both platelets and liver (p < 0.001). NAFL showed a higher impairment of eNOS phosphorylation in comparison to NASH (p < 0.01). In contrast with what observed in vitro, the vascular response by FMD was worse in NASH as compared with NAFL. Conclusions: Our data showed, for the first time in humans, that NAFLD patients show a marked eNOS dysfunction, which may contribute to a higher CV risk. eNOS dysfunction observed in platelets and liver tissue didn't match with FMD