Deciphering the global roles of Cold shock proteins in Listeria monocytogenes nutrient metabolism and stress tolerance

Listeria monocytogenes (Lm) accounts for serious public health and food safety problems owing to its stress resilience and pathogenicity. Based on their regulatory involvement in global gene expression events, cold-shock domain family proteins (Csps) are crucial in expression of various stress fitness and virulence phenotypes in bacteria. Lm possesses three Csps (CspA, CspB, and CspD) whose regulatory roles in the context of the genetic diversity of this bacterium are not yet fully understood. We examined the impacts of Csps deficiency on Lm nutrient metabolism and stress tolerance using a set of csp deletion mutants generated in different genetic backgrounds. Phenotype microarrays (PM) analysis showed that the absence of Csps in ∆cspABD reduces carbon (C-) source utilization capacity and increases Lm sensitivity to osmotic, pH, various chemical, and antimicrobial stress conditions. Single and double csp deletion mutants in different Lm genetic backgrounds were used to further dissect the roles of individual Csps in these phenotypes. Selected PM-based observations were further corroborated through targeted phenotypic assays, confirming that Csps are crucial in Lm for optimal utilization of various C-sources including rhamnose and glucose as well as tolerance against NaCl, β-phenyethylamine (PEA), and food relevant detergent stress conditions. Strain and genetic lineage background-based differences, division of labour, epistasis, and functional redundancies among the Csps were uncovered with respect to their roles in various processes including C-source utilization, cold, and PEA stress resistance. Finally, targeted transcriptome analysis was performed, revealing the activation of csp gene expression under defined stress conditions and the impact of Csps on expression regulation of selected rhamnose utilization genes. Overall, our study shows that Csps play important roles in nutrient utilization and stress responses in Lm strains, contributing to traits that are central to the public health and food safety impacts of this pathogen

Crystal structure of Hop2-Mnd1 and mechanistic insights into its role in meiotic recombination

In meiotic DNA recombination, the Hop2−Mnd1 complex promotes Dmc1-mediated single-stranded DNA (ssDNA) invasion into homologous chromosomes to form a synaptic complex by a yet-unclear mechanism. Here, the crystal structure of Hop2−Mnd1 reveals that it forms a curved rod-like structure consisting of three leucine zippers and two kinked junctions. One end of the rod is linked to two juxtaposed winged-helix domains, and the other end is capped by extra α-helices to form a helical bundle-like structure. Deletion analysis shows that the helical bundle-like structure is sufficient for interacting with the Dmc1-ssDNA nucleofilament, and molecular modeling suggests that the curved rod could be accommodated into the helical groove of the nucleofilament. Remarkably, the winged-helix domains are juxtaposed at fixed relative orientation, and their binding to DNA is likely to perturb the base pairing according to molecular simulations. These findings allow us to propose a model explaining how Hop2−Mnd1 juxtaposes Dmc1-bound ssDNA with distorted recipient double-stranded DNA and thus facilitates strand invasio

The Effects of Two Planning Interventions on the Oral Health Behavior of Iranian Adolescents: A Cluster Randomized Controlled Trial.

PURPOSE: The aim of this study was to investigate the effectiveness of a planning intervention (specifying when, where, and how to act) and an implementation intention intervention (specifying the same in the format of an if-then plan) in increasing self-reported brushing in adolescents. METHODS: The study adopted a cluster randomized controlled trial design, and 1158 students in 48 schools were randomized to planning, implementation intention, or active control conditions. After baseline assessment, all participants received a leaflet containing information and recommendations on oral health and instructions on correct brushing behavior. After reading the leaflets, they were provided with a toothbrush and toothpaste plus a calendar in which to record their brushing. Participants in the planning condition and in the implementation intention condition also received instructions to form specific plans regarding brushing behavior. Self-reported brushing, perceived behavioral control, self-monitoring, intention, frequency of planning, oral health-related quality of life, and dental plaque and periodontal status were measured 1 and 6 months later. RESULTS: Both intervention conditions showed a significant improvement in the frequency of self-reported brushing, self-monitoring, frequency of planning, intention, perceived behavioral control, plaque index, periodontal health, and oral health-related quality of life compared to the control condition at both follow-ups. Comparing the two intervention conditions revealed that adolescents who received the implementation intention intervention had significantly greater improvement in the frequency of self-reported brushing, intention, frequency of planning, and periodontal health than those in planning condition. CONCLUSIONS: Taken together, the findings suggest that forming implementation intentions as well as planning has the potential to increase dental self-reported brushing rates in adolescents, but that forming implementation intentions has the strongest impact on dental hygiene behavior and is, therefore, recommended. TRIAL REGISTRATION NUMBER: The trial was registered with the ClinicalTrials.gov database (NCT02066987) https://www.clinicaltrials.gov/ct2/show/NCT02066987

Crystal structure of Hop2-Mnd1 and mechanistic insights into its role in meiotic recombination

In meiotic DNA recombination, the Hop2-Mnd1 complex promotes Dmc1-mediated single-stranded DNA (ssDNA) invasion into homologous chromosomes to form a synaptic complex by a yet-unclear mechanism. Here, the crystal structure of Hop2-Mnd1 reveals that it forms a curved rod-like structure consisting of three leucine zippers and two kinked junctions. One end of the rod is linked to two juxtaposed winged-helix domains, and the other end is capped by extra ?-helices to form a helical bundle-like structure. Deletion analysis shows that the helical bundle-like structure is sufficient for interacting with the Dmc1-ssDNA nucleofilament, and molecular modeling suggests that the curved rod could be accommodated into the helical groove of the nucleofilament. Remarkably, the winged-helix domains are juxtaposed at fixed relative orientation, and their binding to DNA is likely to perturb the base pairing according to molecular simulations. These findings allow us to propose a model explaining how Hop2-Mnd1 juxtaposes Dmc1-bound ssDNA with distorted recipient double-stranded DNA and thus facilitates strand invasion

Analysis of IL2/IL21 Gene Variants in Cholestatic Liver Diseases Reveals an Association with Primary Sclerosing Cholangitis

Background/Aims: The chromosome 4q27 region harboring IL2 and IL21 is an established risk locus for ulcerative colitis (UC) and various other autoimmune diseases. Considering the strong coincidence of primary sclerosing cholangitis (PSC) with UC and the increased frequency of other autoimmune disorders in patients with primary biliary cirrhosis (PBC), we investigated whether genetic variation in the IL2/IL21 region may also modulate the susceptibility to these two rare cholestatic liver diseases. Methods: Four strongly UC-associated single nucleotide polymorphisms (SNPs) within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block were genotyped in 124 PBC and 41 PSC patients. Control allele frequencies from 1,487 healthy, unrelated Caucasians were available from a previous UC association study. Results: The minor alleles of all four markers were associated with a decreased susceptibility to PSC (rs13151961: p = 0.013, odds ratio (OR) 0.34; rs13119723: p = 0.023, OR 0.40; rs6822844: p = 0.031, OR 0.41; rs6840978: p = 0.043, OR 0.46). Moreover, a haplotype consisting of the four minor alleles also had a protective effect on PSC susceptibility (p = 0.0084, OR 0.28). A haplotype of the four major alleles was independently associated with PSC when excluding the patients with concomitant inflammatory bowel disease (p = 0.033, OR 4.18). Conclusion: The IL2/IL21 region may be one of the highly suggestive but so far rarely identified shared susceptibility loci for PSC and UC. Copyright (C) 2011 S. Karger AG, Base

Harnessing Interpretable and Unsupervised Machine Learning to Address Big Data from Modern X-ray Diffraction

The information content of crystalline materials becomes astronomical when collective electronic behavior and their fluctuations are taken into account. In the past decade, improvements in source brightness and detector technology at modern x-ray facilities have allowed a dramatically increased fraction of this information to be captured. Now, the primary challenge is to understand and discover scientific principles from big data sets when a comprehensive analysis is beyond human reach. We report the development of a novel unsupervised machine learning approach, XRD Temperature Clustering (X-TEC), that can automatically extract charge density wave (CDW) order parameters and detect intra-unit cell (IUC) ordering and its fluctuations from a series of high-volume X-ray diffraction (XRD) measurements taken at multiple temperatures. We apply X-TEC to XRD data on a quasi-skutterudite family of materials, (Ca$_x$Sr$_{1-x}$)$_3$Rh$_4$Sn$_{13}$, where a quantum critical point arising from charge order is observed as a function of Ca concentration. We further apply X-TEC to XRD data on the pyrochlore metal, Cd$_2$Re$_2$O$_7$, to investigate its two much debated structural phase transitions and uncover the Goldstone mode accompanying them. We demonstrate how unprecedented atomic scale knowledge can be gained when human researchers connect the X-TEC results to physical principles. Specifically, we extract from the X-TEC-revealed selection rule that the Cd and Re displacements are approximately equal in amplitude, but out of phase. This discovery reveals a previously unknown involvement of $5d^2$ Re, supporting the idea of an electronic origin to the structural order. Our approach can radically transform XRD experiments by allowing in-operando data analysis and enabling researchers to refine experiments by discovering interesting regions of phase space on-the-fly

Output from VIP cells of the mammalian central clock regulates daily physiological rhythms

The suprachiasmatic nucleus (SCN) circadian clock is critical for optimising daily cycles in mammalian physiology and behaviour. The roles of the various SCN cell types in communicating timing information to downstream physiological systems remain incompletely understood, however. In particular, while vasoactive intestinal polypeptide (VIP) signalling is essential for SCN function and whole animal circadian rhythmicity, the specific contributions of VIP cell output to physiological control remains uncertain. Here we reveal a key role for SCN VIP cells in central clock output. Using multielectrode recording and optogenetic manipulations, we show that VIP neurons provide coordinated daily waves of GABAergic input to target cells across the paraventricular hypothalamus and ventral thalamus, supressing their activity during the mid to late day. Using chemogenetic manipulation, we further demonstrate specific roles for this circuitry in the daily control of heart rate and corticosterone secretion, collectively establishing SCN VIP cells as influential regulators of physiological timing

Comparison of hospital charge prediction models for gastric cancer patients: neural network vs. decision tree models

<p>Abstract</p> <p>Background</p> <p>In recent years, artificial neural network is advocated in modeling complex multivariable relationships due to its ability of fault tolerance; while decision tree of data mining technique was recommended because of its richness of classification arithmetic rules and appeal of visibility. The aim of our research was to compare the performance of ANN and decision tree models in predicting hospital charges on gastric cancer patients.</p> <p>Methods</p> <p>Data about hospital charges on 1008 gastric cancer patients and related demographic information were collected from the First Affiliated Hospital of Anhui Medical University from 2005 to 2007 and preprocessed firstly to select pertinent input variables. Then artificial neural network (ANN) and decision tree models, using same hospital charge output variable and same input variables, were applied to compare the predictive abilities in terms of mean absolute errors and linear correlation coefficients for the training and test datasets. The transfer function in ANN model was sigmoid with 1 hidden layer and three hidden nodes.</p> <p>Results</p> <p>After preprocess of the data, 12 variables were selected and used as input variables in two types of models. For both the training dataset and the test dataset, mean absolute errors of ANN model were lower than those of decision tree model (1819.197 vs. 2782.423, 1162.279 vs. 3424.608) and linear correlation coefficients of the former model were higher than those of the latter (0.955 vs. 0.866, 0.987 vs. 0.806). The predictive ability and adaptive capacity of ANN model were better than those of decision tree model.</p> <p>Conclusion</p> <p>ANN model performed better in predicting hospital charges of gastric cancer patients of China than did decision tree model.</p