Helical Chirality: a Link between Local Interactions and Global Topology in DNA

DNA supercoiling plays a major role in many cellular functions. The global DNA conformation is however intimately linked to local DNA-DNA interactions influencing both the physical properties and the biological functions of the supercoiled molecule. Juxtaposition of DNA double helices in ubiquitous crossover arrangements participates in multiple functions such as recombination, gene regulation and DNA packaging. However, little is currently known about how the structure and stability of direct DNA-DNA interactions influence the topological state of DNA. Here, a crystallographic analysis shows that due to the intrinsic helical chirality of DNA, crossovers of opposite handedness exhibit markedly different geometries. While right-handed crossovers are self-fitted by sequence-specific groove-backbone interaction and bridging Mg2+ sites, left-handed crossovers are juxtaposed by groove-groove interaction. Our previous calculations have shown that the different geometries result in differential stabilisation in solution, in the presence of divalent cations. The present study reveals that the various topological states of the cell are associated with different inter-segmental interactions. While the unstable left-handed crossovers are exclusively formed in negatively supercoiled DNA, stable right-handed crossovers constitute the local signature of an unusual topological state in the cell, such as the positively supercoiled or relaxed DNA. These findings not only provide a simple mechanism for locally sensing the DNA topology but also lead to the prediction that, due to their different tertiary intra-molecular interactions, supercoiled molecules of opposite signs must display markedly different physical properties. Sticky inter-segmental interactions in positively supercoiled or relaxed DNA are expected to greatly slow down the slithering dynamics of DNA. We therefore suggest that the intrinsic helical chirality of DNA may have oriented the early evolutionary choices for DNA topology

Maximum tumor diameter is not an independent prognostic factor in high-risk localized prostate cancer

Contains fulltext : 69173.pdf (publisher's version ) (Closed access)OBJECTIVES: Previous studies suggest that maximum tumor diameter (MTD) is a predictor of recurrence in prostate cancer (PC). This study investigates the prognostic value of MTD for biochemical recurrence (BCR) in patients with PC, after radical prostatectomy (RP), with emphasis on high-risk localized prostate cancer. METHODS: RP specimens of 542 patients were evaluated with a median follow-up of 39.5 months (range 0.6-150 months). MTD was defined as the largest diameter of the largest tumor; high-risk as >or=T2c or PSA level>20 ng/ml or Gleason score>or=8 and BCR as two consecutive PSA levels>0.10 ng/ml. Proportional hazards multivariable regression models were composed to determine prognostic factors for BCR. RESULTS: Overall, 114 patients developed BCR after RP. The overall 5-year risk of BCR was 25% (95% CI=20.4-29.6), and median MTD was 24 mm (range 1-65). MTD in the total and high-risk group was associated with total tumor volume, volume of the largest tumor, pre-operative PSA levels, and Gleason score. In a univariable analyses, MTD was weakly associated with risk of BCR (HR=1.02 per mm increase, 95% CI=1.002-1.035, P=0.024) in the total group; in the high-risk group this association was lost (HR=1.01, 95%CI=0.99-1.03, P=0.18). Multivariable analyses indicated that positive surgical margins, higher Gleason score, advanced pathological stage, and multiple tumors were the main prognostic factors for BCR irrespective of the risk profile. MTD did not provide additional information. CONCLUSIONS: MTD is not an independent prognostic factor for BCR in patients treated with RP, irrespective of the risk profile

Evaluating the Peer Education Project in secondary schools

PURPOSE: The purpose of this paper is to determine the efficacy of the Peer Education Project (PEP), a school-based, peer-led intervention designed to support secondary school students to develop the skills and knowledge they need to safeguard their mental health and that of their peers. DESIGN/METHODOLOGY/APPROACH: Six schools from across England and the Channel Islands took part in an evaluation of the PEP across the 2016/2017 academic year. In total, 45 trained peer educators from the sixth form and 455 Year 7 students completed pre- and post-questionnaires assessing their emotional and behavioural difficulties, perceived school climate, and knowledge, skills and confidence related to mental health. FINDINGS: Results indicate that participation in the PEP is associated with significant improvement in key skills among both peer educators and student trainees, and in understanding of key terms and readiness to support others among trainees. Most students would recommend participation in the programme to other students. ORIGINALITY/VALUE: While peer education has been found to be effective in some areas of health promotion, research on the effectiveness of peer-led mental health education programmes in schools is limited. This study contributes evidence around the efficacy of a new peer education programme that can be implemented in secondary schools

Dimensionality of Carbon Nanomaterials Determines the Binding and Dynamics of Amyloidogenic Peptides: Multiscale Theoretical Simulations

Experimental studies have demonstrated that nanoparticles can affect the rate of protein self-assembly, possibly interfering with the development of protein misfolding diseases such as Alzheimer's, Parkinson's and prion disease caused by aggregation and fibril formation of amyloid-prone proteins. We employ classical molecular dynamics simulations and large-scale density functional theory calculations to investigate the effects of nanomaterials on the structure, dynamics and binding of an amyloidogenic peptide apoC-II(60-70). We show that the binding affinity of this peptide to carbonaceous nanomaterials such as C60, nanotubes and graphene decreases with increasing nanoparticle curvature. Strong binding is facilitated by the large contact area available for π-stacking between the aromatic residues of the peptide and the extended surfaces of graphene and the nanotube. The highly curved fullerene surface exhibits reduced efficiency for π-stacking but promotes increased peptide dynamics. We postulate that the increase in conformational dynamics of the amyloid peptide can be unfavorable for the formation of fibril competent structures. In contrast, extended fibril forming peptide conformations are promoted by the nanotube and graphene surfaces which can provide a template for fibril-growth

An improved parameter estimation and comparison for soft tissue constitutive models containing an exponential function

Motivated by the well-known result that stiffness of soft tissue is proportional to the stress, many of the constitutive laws for soft tissues contain an exponential function. In this work, we analyze properties of the exponential function and how it affects the estimation and comparison of elastic parameters for soft tissues. In particular, we find that as a consequence of the exponential function there are lines of high covariance in the elastic parameter space. As a result, one can have widely varying mechanical parameters defining the tissue stiffness but similar effective stress–strain responses. Drawing from elementary algebra, we propose simple changes in the norm and the parameter space, which significantly improve the convergence of parameter estimation and robustness in the presence of noise. More importantly, we demonstrate that these changes improve the conditioning of the problem and provide a more robust solution in the case of heterogeneous material by reducing the chances of getting trapped in a local minima. Based upon the new insight, we also propose a transformed parameter space which will allow for rational parameter comparison and avoid misleading conclusions regarding soft tissue mechanics

Use, acceptability and impact of booklets designed to support mental health self-management and help seeking in schools:Results of a large randomised controlled trial in England

Mental health booklets may provide a low-cost means of promoting mental health self-management and help seeking in schools. The aim of the study was to assess the (a) use, (b) acceptability and (c) impact of booklets for students in primary (10-11 years) and secondary school (12-13 years) alone and in conjunction with funding for targeted mental health support. This was a 2 × 2 factorial cluster randomized controlled trial, in which 846 schools in England were randomly allocated to receive/not receive: (1) booklets for students containing information on mental health self-management and help seeking, and (2) funding for mental health support as part of a national mental health initiative. 14,690 students (8139 primary, 6551 secondary) provided self-report on mental health, quality of life (baseline and 1 year follow-up) and help seeking (follow-up). (a) Approximately, 40 % primary school students and 20 % secondary school students reported seeing the booklets. (b) Of these, 87 % of primary school students reported that the booklet was 'very helpful' or 'quite helpful', compared with 73 % in secondary school. (c) There was no detectable impact of booklets on mental health, quality of life or help seeking, either alone or in conjunction with additional funding through the national mental health initiative. Lack of discernable impact of booklets underscores the need for caution in adopting such an approach. However, it is feasible that the impact was obscured by low uptake or that booklets may be more effective when used in a targeted way

Functional Genetic Variants in DC-SIGNR Are Associated with Mother-to-Child Transmission of HIV-1

BACKGROUND: Mother-to-child transmission (MTCT) is the main cause of HIV-1 infection in children worldwide. Given that the C-type lectin receptor, dendritic cell-specific ICAM-grabbing non-integrin-related (DC-SIGNR, also known as CD209L or liver/lymph node-specific ICAM-grabbing non-integrin (L-SIGN)), can interact with pathogens including HIV-1 and is expressed at the maternal-fetal interface, we hypothesized that it could influence MTCT of HIV-1. METHODS AND FINDINGS: To investigate the potential role of DC-SIGNR in MTCT of HIV-1, we carried out a genetic association study of DC-SIGNR in a well-characterized cohort of 197 HIV-infected mothers and their infants recruited in Harare, Zimbabwe. Infants harbouring two copies of DC-SIGNR H1 and/or H3 haplotypes (H1-H1, H1-H3, H3-H3) had a 3.6-fold increased risk of in utero (IU) (P = 0.013) HIV-1 infection and a 5.7-fold increased risk of intrapartum (IP) (P = 0.025) HIV-1 infection after adjusting for a number of maternal factors. The implicated H1 and H3 haplotypes share two single nucleotide polymorphisms (SNPs) in promoter region (p-198A) and intron 2 (int2-180A) that were associated with increased risk of both IU (P = 0.045 and P = 0.003, respectively) and IP (P = 0.025, for int2-180A) HIV-1 infection. The promoter variant reduced transcriptional activity in vitro. In homozygous H1 infants bearing both the p-198A and int2-180A mutations, we observed a 4-fold decrease in the level of placental DC-SIGNR transcripts, disproportionately affecting the expression of membrane-bound isoforms compared to infant noncarriers (P = 0.011). CONCLUSION: These results suggest that DC-SIGNR plays a crucial role in MTCT of HIV-1 and that impaired placental DC-SIGNR expression increases risk of transmission

Structure and function analyses of the purified GPCR human vomeronasal type 1 receptor 1

The vomeronasal system is one of several fine-tuned scent-detecting signaling systems in mammals. However, despite significant efforts, how these receptors detect scent remains an enigma. One reason is the lack of sufficient purified receptors to perform detailed biochemical, biophysical and structural analyses. Here we report the ability to express and purify milligrams of purified, functional human vomeronasal receptor hVN1R1. Circular dichroism showed that purified hVN1R1 had an alpha-helical structure, similar to that of other GPCRs. Microscale thermophoresis showed that hVN1R1 bound its known ligand myrtenal with an EC50 ∼1 µM. This expression system can enable structural and functional analyses towards understanding how mammalian scent detection works

Modelling study of dimerization in mammalian defensins

BACKGROUND: Defensins are antimicrobial peptides of innate immunity functioning by non-specific binding to anionic phospholipids in bacterial membranes. Their cationicity, amphipathicity and ability to oligomerize are considered key factors for their action. Based on structural information on human β-defensin 2, we examine homologous defensins from various mammalian species for conserved functional physico-chemical characteristics. RESULTS: Based on homology greater than 40%, structural models of 8 homologs of HBD-2 were constructed. A conserved pattern of electrostatics and dynamics was observed across 6 of the examined defensins; models backed by energetics suggest that the defensins in these 6 organisms are characterized by dimerization-linked enhanced functional potentials. In contrast, dimerization is not energetically favoured in the sheep, goat and mouse defensins, suggesting that they function efficiently as monomers. CONCLUSION: β-defensin 2 from some mammals may work as monomers while those in others, including humans, work as oligomers. This could potentially be used to design human defensins that may be effective at lower concentrations and hence have therapeutic benefits

A Comparative Approach Linking Molecular Dynamics of Altered Peptide Ligands and MHC with In Vivo Immune Responses

The recognition of peptide in the context of MHC by T lymphocytes is a critical step in the initiation of an adaptive immune response. However, the molecular nature of the interaction between peptide and MHC and how it influences T cell responsiveness is not fully understood.We analyzed the immunological consequences of the interaction of MHC class II (I-Au) restricted 11-mer peptides of myelin basic protein with amino acid substitutions at position 4. These mutant peptides differ in MHC binding affinity, CD4+ T cell priming, and alter the severity of peptide-induced experimental allergic encephalomyelitis. Using molecular dynamics, a computational method of quantifying intrinsic movements of proteins at high resolution, we investigated conformational changes in MHC upon peptide binding. We found that irrespective of peptide binding affinity, MHC deformation appears to influence costimulation, which then leads to effective T cell priming and disease induction. Although this study compares in vivo and molecular dynamics results for three altered peptide ligands, further investigation with similar complexes is essential to determine whether spatial rearrangement of peptide-MHC and costimulatory complexes is an additional level of T cell regulation