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

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

A Novel Breast Cancer Diagnosis Scheme With Intelligent Feature and Parameter Selections.

BACKGROUND AND OBJECTIVE: Breast cancer is the most commonly occurring cancer among women, which contributes to the global death rate. The key to increasing the survival rate of affected patients is early diagnosis along with appropriate treatments. Manual methods for breast cancer diagnosis fail due to human errors, inaccurate diagnoses, and are time-consuming when demands are high. Intelligent systems based on Artificial Neural Network (ANN) for automated breast cancer diagnosis are powerful due to their strong decision-making capabilities in complicated cases. Artificial Bee Colony, Artificial Immune System, and Bacterial Foraging Optimization are swarm intelligence algorithms that solve combinatorial optimization problems. This paper proposes two novel hybrid Artificial Bee Colony (ABC) optimization algorithms that overcome the demerits of standard ABC algorithms. First, this paper proposes a hybrid ABC approach called HABC, in which the standard ABC optimization is hybridized with a modified clonal selection algorithm of the Artificial Immune System that eliminates the poor exploration capabilities of standard ABC optimization. Further, this paper proposes a novel hybrid Artificial Bee Colony (Hybrid ABC) optimization where the strong explorative capabilities of the chemotaxis phase of the bacterial foraging optimization are integrated with a spiral model-based exploitative phase of the ABC by which the proposed Hybrid ABC overcomes the demerits of poor exploration and exploitation of the standard ABC algorithm. METHODS: In this work, the two proposed hybrid approaches were used in concurrent feature selection and parameter optimization of an ANN model. The proposed algorithm is implemented using various back-propagation algorithms, including resilient back-propagation (HABC-RP and Hybrid ABC-RP), Levenberg Marquart (HABC-LM and Hybrid ABC-LM), and momentum-based gradient descent (HABC-MGD and Hybrid ABC-GD) for parameter tuning of ANN. The Wisconsin breast cancer dataset was used to evaluate the performance of the proposed algorithms in terms of accuracy, complexity, and computational time. RESULTS: The mean accuracy of the proposed HABC-RP was 99.14% and 99.54% for Hybrid ABC which is better than the results found in the existing literature. HABC-RP attained a sensitivity of 98.32%, a specificity of 99.63%, and a precision of 99.38% whereas Hybrid ABC attained sensitivity of 99.08% and Specificity of 99.81%. CONCLUSIONS: HABC-RP and Hybrid ABC-RP yielded high accuracy with a low complexity ANN structure compared to other variants. After evaluation, interestingly it is found that the Hybrid ABC-RP has achieved the highest mean accuracy of 99.54% with low complexity of 10.25 mean connections when compared to other variants proposed in this paper. It can be concluded that the concurrent selection of input features and tuning of parameters of ANN plays a vital role in increasing the accuracy of a breast cancer diagnosis. The proposed HABC-RP and Hybrid ABC-RP showed better results when compared to the existing breast cancer diagnosis systems taken for comparison. In the future, the proposed two-hybrid approaches can be used to generate optimal thresholds for the segmentation of tumors in abnormal images. HABC and Hybrid ABC can be used for tuning the parameters of various classifiers

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

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

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

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

Complement component 3 (C3) expression in the hippocampus after excitotoxic injury: role of C/EBPβ

[Background] The CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor implicated in the control of proliferation, differentiation, and inflammatory processes mainly in adipose tissue and liver; although more recent results have revealed an important role for this transcription factor in the brain. Previous studies from our laboratory indicated that CCAAT/enhancer-binding protein β is implicated in inflammatory process and brain injury, since mice lacking this gene were less susceptible to kainic acid-induced injury. More recently, we have shown that the complement component 3 gene (C3) is a downstream target of CCAAT/enhancer-binding protein β and it could be a mediator of the proinflammatory effects of this transcription factor in neural cells.[Methods] Adult male Wistar rats (8–12 weeks old) were used throughout the study. C/EBPβ+/+ and C/EBPβ–/– mice were generated from heterozygous breeding pairs. Animals were injected or not with kainic acid, brains removed, and brain slices containing the hippocampus analyzed for the expression of both CCAAT/enhancer-binding protein β and C3.[Results] In the present work, we have further extended these studies and show that CCAAT/enhancer-binding protein β and C3 co-express in the CA1 and CA3 regions of the hippocampus after an excitotoxic injury. Studies using CCAAT/enhancer-binding protein β knockout mice demonstrate a marked reduction in C3 expression after kainic acid injection in these animals, suggesting that indeed this protein is regulated by C/EBPβ in the hippocampus in vivo.[Conclusions] Altogether these results suggest that CCAAT/enhancer-binding protein β could regulate brain disorders, in which excitotoxic and inflammatory processes are involved, at least in part through the direct regulation of C3.This work was supported by MINECO, Grant SAF2014-52940-R and partially financed with FEDER funds. CIBERNED is funded by the Instituto de Salud Carlos III. JAM-G was supported by CIBERNED. We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).Peer reviewe