Building nonparametric nn-body force fields using Gaussian process regression

Constructing a classical potential suited to simulate a given atomic system is a remarkably difficult task. This chapter presents a framework under which this problem can be tackled, based on the Bayesian construction of nonparametric force fields of a given order using Gaussian process (GP) priors. The formalism of GP regression is first reviewed, particularly in relation to its application in learning local atomic energies and forces. For accurate regression it is fundamental to incorporate prior knowledge into the GP kernel function. To this end, this chapter details how properties of smoothness, invariance and interaction order of a force field can be encoded into corresponding kernel properties. A range of kernels is then proposed, possessing all the required properties and an adjustable parameter $n$ governing the interaction order modelled. The order $n$ best suited to describe a given system can be found automatically within the Bayesian framework by maximisation of the marginal likelihood. The procedure is first tested on a toy model of known interaction and later applied to two real materials described at the DFT level of accuracy. The models automatically selected for the two materials were found to be in agreement with physical intuition. More in general, it was found that lower order (simpler) models should be chosen when the data are not sufficient to resolve more complex interactions. Low $n$ GPs can be further sped up by orders of magnitude by constructing the corresponding tabulated force field, here named "MFF".Comment: 31 pages, 11 figures, book chapte

Anti-Allergic Cromones Inhibit Histamine and Eicosanoid Release from Activated Human and Murine Mast Cells by Releasing Annexin A1

PMCID: PMC3601088This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Advancing the global public health agenda for NAFLD: a consensus statement

Non-alcoholic fatty liver disease (NAFLD) is a potentially serious liver disease that affects approximately one-quarter of the global adult population, causing a substantial burden of ill health with wide-ranging social and economic implications. It is a multisystem disease and is considered the hepatic component of metabolic syndrome. Unlike other highly prevalent conditions, NAFLD has received little attention from the global public health community. Health system and public health responses to NAFLD have been weak and fragmented, and, despite its pervasiveness, NAFLD is largely unknown outside hepatology and gastroenterology. There is only a nascent global public health movement addressing NAFLD, and the disease is absent from nearly all national and international strategies and policies for non-communicable diseases, including obesity. In this global Delphi study, a multidisciplinary group of experts developed consensus statements and recommendations, which a larger group of collaborators reviewed over three rounds until consensus was achieved. The resulting consensus statements and recommendations address a broad range of topics — from epidemiology, awareness, care and treatment to public health policies and leadership — that have general relevance for policy-makers, health-care practitioners, civil society groups, research institutions and affected populations. These recommendations should provide a strong foundation for a comprehensive public health response to NAFLD

Intercellular Transfer of Oncogenic H-Ras at the Immunological Synapse

Immune cells establish dynamic adhesive cell–cell interactions at a specific contact region, termed the immunological synapse (IS). Intriguing features of the IS are the formation of regions of plasma membrane fusion and the intercellular exchange of membrane fragments between the conjugated cells. It is not known whether upon IS formation, intact intracellular proteins can transfer from target cells to lymphocytes to allow the transmission of signals across cell boundaries. Here we show by both FACS and confocal microscopy that human lymphocytes acquire from the cells they scan the inner-membrane protein H-Ras, a G-protein vital for common lymphocyte functions and a prominent participant in human cancer. The transfer was cell contact-dependent and occurred in the context of cell-conjugate formation. Moreover, the acquisition of oncogenic H-RasG12V by natural killer (NK) and T lymphocytes had important biological functions in the adopting lymphocytes: the transferred H-RasG12V induced ERK phosphorylation, increased interferon-γ and tumor necrosis factor-α secretion, enhanced lymphocyte proliferation, and augmented NK-mediated target cell killing. Our findings reveal a novel mode of cell-to-cell communication—allowing lymphocytes to extend the confines of their own proteome—which may moreover play an important role in natural tumor immunity

The Promoter of the pri-miR-375 Gene Directs Expression Selectively to the Endocrine Pancreas

microRNAs (miRNAs) are known to play an essential role in controlling a broad range of biological processes including animal development. Accordingly, many miRNAs are expressed preferentially in one or a small number of cell types. Yet the mechanisms responsible for this selectivity are not well understood. The aim of this study was to elucidate the molecular basis of cell-specific expression of the pri-miR-375 gene, which is selectively expressed in pancreatic islets, and has been implicated both in the development of islets, and the function of mature pancreatic beta cells. An evolutionarily conserved 768 bp region of DNA upstream of the pri-miR-375 gene was linked to GFP and luciferase reporter genes, and expression monitored in transgenic mice and transfected cultured cells. Deletion and targeted mutagenesis analysis was used to evaluate the functional significance of sequence blocks within the upstream fragment. 5′-RACE analysis was used for mapping the pri-miR-375 gene transcription start site. The conserved 768 bp region was able to direct preferential expression of a GFP reporter gene to pancreatic islets in transgenic mice. Deletion analysis using a luciferase reporter gene in transfected cultured cell lines confirmed the cell specificity of the putative promoter region, and identified several key cis-elements essential for optimal activity, including E-boxes and a TATA sequence. Consistent with this, 5′-RACE analysis identified a transcription start site within this DNA region, 24 bp downstream of the TATA sequence. These studies define the promoter of the pri-miR-375 gene, and show that islet-specific expression of the pri-miR-375 gene is controlled at the transcriptional level. Detailed analysis of the transcriptional mechanisms controlling expression of miRNA genes will be essential to permit a comprehensive understanding of the complex role of miRNAs such as miR-375 in developmental processes

Salmonella enterica Serovar Typhimurium Lacking hfq Gene Confers Protective Immunity against Murine Typhoid

Salmonella enterica is an important enteric pathogen and its various serovars are involved in causing both systemic and intestinal diseases in humans and domestic animals. The emergence of multidrug-resistant strains of Salmonella leading to increased morbidity and mortality has further complicated its management. Live attenuated vaccines have been proven superior over killed or subunit vaccines due to their ability to induce protective immunity. Of the various strategies used for the generation of live attenuated vaccine strains, focus has gradually shifted towards manipulation of virulence regulator genes. Hfq is a RNA chaperon which mediates the binding of small RNAs to the mRNA and assists in post-transcriptional gene regulation in bacteria. In this study, we evaluated the efficacy of the Salmonella Typhimurium Δhfq strain as a candidate for live oral vaccine in murine model of typhoid fever. Salmonella hfq deletion mutant is highly attenuated in cell culture and animal model implying a significant role of Hfq in bacterial virulence. Oral immunization with the Salmonella hfq deletion mutant efficiently protects mice against subsequent oral challenge with virulent strain of Salmonella Typhimurium. Moreover, protection was induced upon both multiple as well as single dose of immunizations. The vaccine strain appears to be safe for use in pregnant mice and the protection is mediated by the increase in the number of CD4+ T lymphocytes upon vaccination. The levels of serum IgG and secretory-IgA in intestinal washes specific to lipopolysaccharide and outer membrane protein were significantly increased upon vaccination. Furthermore, hfq deletion mutant showed enhanced antigen presentation by dendritic cells compared to the wild type strain. Taken together, the studies in murine immunization model suggest that the Salmonella hfq deletion mutant can be a novel live oral vaccine candidate

Measuring macroscopic brain connections in vivo

Decades of detailed anatomical tracer studies in non-human animals point to a rich and complex organization of long-range white matter connections in the brain. State-of-the art in vivo imaging techniques are striving to achieve a similar level of detail in humans, but multiple technical factors can limit their sensitivity and fidelity. In this review, we mostly focus on magnetic resonance imaging of the brain. We highlight some of the key challenges in analyzing and interpreting in vivo connectomics data, particularly in relation to what is known from classical neuroanatomy in laboratory animals. We further illustrate that, despite the challenges, in vivo imaging methods can be very powerful and provide information on connections that is not available by any other means

Are luminescent bacteria suitable for online detection and monitoring of toxic compounds in drinking water and its sources?

Biosensors based on luminescent bacteria may be valuable tools to monitor the chemical quality and safety of surface and drinking water. In this review, an overview is presented of the recombinant strains available that harbour the bacterial luciferase genes luxCDABE, and which may be used in an online biosensor for water quality monitoring. Many bacterial strains have been described for the detection of a broad range of toxicity parameters, including DNA damage, protein damage, membrane damage, oxidative stress, organic pollutants, and heavy metals. Most lux strains have sensitivities with detection limits ranging from milligrams per litre to micrograms per litre, usually with higher sensitivities in compound-specific strains. Although the sensitivity of lux strains can be enhanced by various molecular manipulations, most reported detection thresholds are still too high to detect levels of individual contaminants as they occur nowadays in European drinking waters. However, lux strains sensing specific toxic effects have the advantage of being able to respond to mixtures of contaminants inducing the same effect, and thus could be used as a sensor for the sum effect, including the effect of compounds that are as yet not identified by chemical analysis. An evaluation of the suitability of lux strains for monitoring surface and drinking water is therefore provided