Mechanical food properties responsible for food breakdown in the human mouth

Abstract no. 2362published_or_final_versio

Earthquake source model using strong motion displacement as response of finite elastic media

The strong motion displacement records available during an earthquake can be treated as the response of the earth as the a structural system to unknown forces acting at unknown locations. Thus, if the part of the earth participating in ground motion is modelled as a known finite elastic medium, one can attempt to model the source location and forces generated during an earthquake as an inverse problem in structural dynamics. Based on this analogy, a simple model for the basic earthquake source is proposed. The unknown source is assumed to be a sequence of impulses acting at locations yet to be found. These unknown impulses and their locations are found using the normal mode expansion along with a minimization of mean square error. The medium is assumed to be finite, elastic, homogeneous, layered and horizontal with a specific set of boundary conditions. Detailed results are obtained for Uttarkashi earthquake. The impulse locations exhibit a linear structure closely associated with the causative fault. The results obtained are shown to be in good agreement with reported values. The proposed engineering model is then used to simulate the acceleration time histories at a few recording stations. The earthquake source in terms of a sequence of impulses acting at different locations is applied on a 2D finite elastic medium and acceleration time histories are found using finite element methods. The synthetic accelerations obtained are in close match with the recorded accelerations

Food properties that influence neuromuscular activity during human mastication

published_or_final_versio

A two-domain elevator mechanism for sodium/proton antiport

Sodium/proton (Na+/H+) antiporters, located at the plasma membrane in every cell, are vital for cell homeostasis1. In humans, their dysfunction has been linked to diseases, such as hypertension, heart failure and epilepsy, and they are well-established drug targets2. The best understood model system for Na+/H+ antiport is NhaA from Escherichia coli1, 3, for which both electron microscopy and crystal structures are available4, 5, 6. NhaA is made up of two distinct domains: a core domain and a dimerization domain. In the NhaA crystal structure a cavity is located between the two domains, providing access to the ion-binding site from the inward-facing surface of the protein1, 4. Like many Na+/H+ antiporters, the activity of NhaA is regulated by pH, only becoming active above pH 6.5, at which point a conformational change is thought to occur7. The only reported NhaA crystal structure so far is of the low pH inactivated form4. Here we describe the active-state structure of a Na+/H+ antiporter, NapA from Thermus thermophilus, at 3 Å resolution, solved from crystals grown at pH 7.8. In the NapA structure, the core and dimerization domains are in different positions to those seen in NhaA, and a negatively charged cavity has now opened to the outside. The extracellular cavity allows access to a strictly conserved aspartate residue thought to coordinate ion binding1, 8, 9 directly, a role supported here by molecular dynamics simulations. To alternate access to this ion-binding site, however, requires a surprisingly large rotation of the core domain, some 20° against the dimerization interface. We conclude that despite their fast transport rates of up to 1,500 ions per second3, Na+/H+ antiporters operate by a two-domain rocking bundle model, revealing themes relevant to secondary-active transporters in general

Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk

Predicting a small molecule-kinase interaction map: A machine learning approach

<p>Abstract</p> <p>Background</p> <p>We present a machine learning approach to the problem of protein ligand interaction prediction. We focus on a set of binding data obtained from 113 different protein kinases and 20 inhibitors. It was attained through ATP site-dependent binding competition assays and constitutes the first available dataset of this kind. We extract information about the investigated molecules from various data sources to obtain an informative set of features.</p> <p>Results</p> <p>A Support Vector Machine (SVM) as well as a decision tree algorithm (C5/See5) is used to learn models based on the available features which in turn can be used for the classification of new kinase-inhibitor pair test instances. We evaluate our approach using different feature sets and parameter settings for the employed classifiers. Moreover, the paper introduces a new way of evaluating predictions in such a setting, where different amounts of information about the binding partners can be assumed to be available for training. Results on an external test set are also provided.</p> <p>Conclusions</p> <p>In most of the cases, the presented approach clearly outperforms the baseline methods used for comparison. Experimental results indicate that the applied machine learning methods are able to detect a signal in the data and predict binding affinity to some extent. For SVMs, the binding prediction can be improved significantly by using features that describe the active site of a kinase. For C5, besides diversity in the feature set, alignment scores of conserved regions turned out to be very useful.</p

Hyperstable U1snRNA complementary to the K-ras transcripts induces cell death in pancreatic cancer cells

One of the critical steps that governs the inhibitory effect of antisense RNA on target gene expression is the association of the antisense RNA with the target RNA molecules. However, until now, no systematic method has been available to select the suitable parts of a gene as antisense targets. In this study, we utilised U1 small nuclear RNA (snRNA) that binds physiologically to the 5′ splice site (5′ss) of pre-mRNA, to develop a novel vector system that permits imposed binding of antisense RNA to its target. The 5′ free end of U1snRNA was replaced with the antisense sequence against the K-ras gene to generate a hyperstable U1snRNA, whose binding stability to 5′ss of the K-ras transcript is ten-fold higher than that of wild-type U1snRNA. The efficacy of such hyperstable U1snRNA was examined by transducing the expression plasmids into human pancreatic cancer cell lines. This revealed that two of the hyperstable U1snRNAs induced cell death after gene transduction, and significantly reduced the number of G418-resistant colonies to less than 10% of the controls. Furthermore, hyperstable U1snRNA suppressed intraperitoneal dissemination of pancreatic cancer cells in vivo. Hyperstable U1snRNA might be a novel approach to express effective antisense RNA in target cells

Induction of protective and therapeutic anti-pancreatic cancer immunity using a reconstructed MUC1 DNA vaccine

<p>Abstract</p> <p>Background</p> <p>Pancreatic cancer is a common, highly lethal disease with a rising incidence. MUC1 is a tumor-associated antigen that is over-expressed in pancreatic adenocarcinoma. Active immunotherapy that targets MUC1 could have great treatment value. Here we investigated the preventive and therapeutic effect of a MUC1 DNA vaccine on the pancreatic cancer.</p> <p>Methods</p> <p>MUC1-various tandem repeat units(VNTR) DNA vaccine was produced by cloning one repeat of VNTR and inserting the cloned gene into the pcDNA3.1. In the preventive group, female C57BL/6 mice were immunized with the vaccine, pcDNA3.1 or PBS; and challenged with panc02-MUC1 or panc02 cell. In the therapeutic group the mice were challenged with panc02-MUC1 or panc02 cell, and then immunized with the vaccine, pcDNA3.1 or PBS. The tumor size and the survival time of the animals were compared between these groups.</p> <p>Results</p> <p>The DNA vaccine pcDNA3.1-VNTR could raise cytotoxic T lymphocyte (CTL) activity specific for MUC1. In the preventive experiment, the mice survival time was significantly longer in the vaccine group than in the control groups (<it>P </it>< 0.05). In the therapeutic experiment, the DNA vaccine prolonged the survival time of the panc02-MUC1-bearing mice (<it>P </it>< 0.05). In both the preventive and therapeutic experiments, the tumor size was significantly less in the vaccine group than in the control groups (<it>P </it>< 0.05). This pcDNA3.1-VNTR vaccine, however, could not prevent the mice attacked by panc02 cells and had no therapeutic effect on the mice attacked by panc02 cells.</p> <p>Conclusion</p> <p>The MUC1 DNA vaccine pcDNA3.1-VNTR could induce a significant MUC1-specific CTL response; and had both prophylactic and therapeutic effect on panc02-MUC1 tumors. This vaccine might be used as a new adjuvant strategy against pancreatic cancer.</p

Herbivore Preference for Native vs. Exotic Plants: Generalist Herbivores from Multiple Continents Prefer Exotic Plants That Are Evolutionarily Naïve

Enemy release and biotic resistance are competing, but not mutually exclusive, hypotheses addressing the success or failure of non-native plants entering a new region. Enemy release predicts that exotic plants become invasive by escaping their co-adapted herbivores and by being unrecognized or unpalatable to native herbivores that have not been selected to consume them. In contrast, biotic resistance predicts that native generalist herbivores will suppress exotic plants that will not have been selected to deter these herbivores. We tested these hypotheses using five generalist herbivores from North or South America and nine confamilial pairs of native and exotic aquatic plants. Four of five herbivores showed 2.4–17.3 fold preferences for exotic over native plants. Three species of South American apple snails (Pomacea sp.) preferred North American over South American macrophytes, while a North American crayfish Procambarus spiculifer preferred South American, Asian, and Australian macrophytes over North American relatives. Apple snails have their center of diversity in South America, but a single species (Pomacea paludosa) occurs in North America. This species, with a South American lineage but a North American distribution, did not differentiate between South American and North American plants. Its preferences correlated with preferences of its South American relatives rather than with preferences of the North American crayfish, consistent with evolutionary inertia due to its South American lineage. Tests of plant traits indicated that the crayfish responded primarily to plant structure, the apple snails primarily to plant chemistry, and that plant protein concentration played no detectable role. Generalist herbivores preferred non-native plants, suggesting that intact guilds of native, generalist herbivores may provide biotic resistance to plant invasions. Past invasions may have been facilitated by removal of native herbivores, introduction of non-native herbivores (which commonly prefer native plants), or both