Pathways to folding, nucleation events and native geometry

We perform extensive Monte Carlo simulations of a lattice model and the Go potential to investigate the existence of folding pathways at the level of contact cluster formation for two native structures with markedly different geometries. Our analysis of folding pathways revealed a common underlying folding mechanism, based on nucleation phenomena, for both protein models. However, folding to the more complex geometry (i.e. that with more non-local contacts) is driven by a folding nucleus whose geometric traits more closely resemble those of the native fold. For this geometry folding is clearly a more cooperative process.Comment: Accepted in J. Chem. Phy

Truncated and Helix-Constrained Peptides with High Affinity and Specificity for the cFos Coiled-Coil of AP-1

Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promiscuously bind to proteins with low affinity and specificity. Here we combine structural stability and target specificity of proteins, with low cost and rapid synthesis of small molecules, towards meeting the significant challenge of binding coiled coil proteins in transcriptional regulation. By iteratively truncating a Jun-based peptide from 37 to 22 residues, strategically incorporating i-->i+4 helix-inducing constraints, and positioning unnatural amino acids, we have produced short, water-stable, alpha-helical peptides that bind cFos. A three-dimensional NMR-derived structure for one peptide (24) confirmed a highly stable alpha-helix which was resistant to proteolytic degradation in serum. These short structured peptides are entropically pre-organized for binding with high affinity and specificity to cFos, a key component of the oncogenic transcriptional regulator Activator Protein-1 (AP-1). They competitively antagonized the cJun–cFos coiled-coil interaction. Truncating a Jun-based peptide from 37 to 22 residues decreased the binding enthalpy for cJun by ~9 kcal/mol, but this was compensated by increased conformational entropy (TDS ≤ 7.5 kcal/mol). This study demonstrates that rational design of short peptides constrained by alpha-helical cyclic pentapeptide modules is able to retain parental high helicity, as well as high affinity and specificity for cFos. These are important steps towards small antagonists of the cJun-cFos interaction that mediates gene transcription in cancer and inflammatory diseases

Ultrafast nonlocal control of spontaneous emission

Solid-state cavity quantum electrodynamics systems will form scalable nodes of future quantum networks, allowing the storage, processing and retrieval of quantum bits, where a real-time control of the radiative interaction in the cavity is required to achieve high efficiency. We demonstrate here the dynamic molding of the vacuum field in a coupled-cavity system to achieve the ultrafast nonlocal modulation of spontaneous emission of quantum dots in photonic crystal cavities, on a timescale of ~200 ps, much faster than their natural radiative lifetimes. This opens the way to the ultrafast control of semiconductor-based cavity quantum electrodynamics systems for application in quantum interfaces and to a new class of ultrafast lasers based on nano-photonic cavities.Comment: 15 pages, 4 figure

WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Prostate cancer cells with stem cell characteristics were identified in human prostate cancer cell lines by their ability to form from single cells self-renewing prostaspheres in non-adherent cultures. Prostaspheres exhibited heterogeneous expression of proliferation, differentiation and stem cell-associated makers CD44, ABCG2 and CD133. Treatment with WNT inhibitors reduced both prostasphere size and self-renewal. In contrast, addition of Wnt3a caused increased prostasphere size and self-renewal, which was associated with a significant increase in nuclear Β-catenin, keratin 18, CD133 and CD44 expression. As a high proportion of LNCaP and C4-2B cancer cells express androgen receptor we determined the effect of the androgen receptor antagonist bicalutamide. Androgen receptor inhibition reduced prostasphere size and expression of PSA, but did not inhibit prostasphere formation. These effects are consistent with the androgen-independent self-renewal of cells with stem cell characteristics and the androgen-dependent proliferation of transit amplifying cells. As the canonical WNT signaling effector Β-catenin can also associate with the androgen receptor, we propose a model for tumour propagation involving a balance between WNT and androgen receptor activity. That would affect the self-renewal of a cancer cell with stem cell characteristics and drive transit amplifying cell proliferation and differentiation. In conclusion, we provide evidence that WNT activity regulates the self-renewal of prostate cancer cells with stem cell characteristics independently of androgen receptor activity. Inhibition of WNT signaling therefore has the potential to reduce the self-renewal of prostate cancer cells with stem cell characteristics and improve the therapeutic outcome.Peer reviewe

Implementation of Web-Based Respondent-Driven Sampling among Men who Have Sex with Men in Vietnam

Objective: Lack of representative data about hidden groups, like men who have sex with men (MSM), hinders an evidence-based response to the HIV epidemics. Respondent-driven sampling (RDS) was developed to overcome sampling challenges in studies of populations like MSM for which sampling frames are absent. Internet-based RDS (webRDS) can potentially circumvent limitations of the original RDS method. We aimed to implement and evaluate webRDS among a hidden population. Methods and Design: This cross-sectional study took place 18 February to 12 April, 2011 among MSM in Vietnam. Inclusion criteria were men, aged 18 and above, who had ever had sex with another man and were living in Vietnam. Participants were invited by an MSM friend, logged in, and answered a survey. Participants could recruit up to four MSM friends. We evaluated the system by its success in generating sustained recruitment and the degree to which the sample compositions stabilized with increasing sample size. Results: Twenty starting participants generated 676 participants over 24 recruitment waves. Analyses did not show evidence of bias due to ineligible participation. Estimated mean age was 22 year and 82% came from the two large metropolitan areas. 32 out of 63 provinces were represented. The median number of sexual partners during the last six months was two. The sample composition stabilized well for 16 out of 17 variables. Conclusion: Results indicate that webRDS could be implemented at a low cost among Internet-using MSM in Vietnam. WebRDS may be a promising method for sampling of Internet-using MSM and other hidden groups. Key words: Respondent-driven sampling, Online sampling, Men who have sex with men, Vietnam, Sexual risk behavio

Toward Sustainable Agriculture: An Evaluation of Mechanization Practices in Small-Scale Paddy Farming in the Mekong River Delta, Vietnam

This study evaluates mechanization practices in small-scale paddy farming in the Mekong River Delta, following several years of government policies and programs promoting mechanization. Primary data was collected from 1,170 farming households in Hau Giang, Kien Giang, An Giang, and Dong Thap provinces. The mechanization status was assessed based on four key criteria, and mechanization levels were quantified using a cost-based Mechanization Index (MI). The results show high mechanization rates (over 90%) in land preparation, irrigation, fertilization, and harvesting; however, adoption rates were lower in transplanting or sowing (41.2%) and transportation (15.7%). Furthermore, machinery investment has stagnated since 2016, reflecting limited farmer interest in acquiring additional equipment. Advanced mechanization techniques remain experimental as traditional labor-intensive methods continue to dominate farming practices. The calculated MI indicated that 64 percent of households fall into a very low mechanization category. These findings reveal significant limitations of current agricultural policies and underline the need for multidisciplinary and systematic interventions, particularly through the development of self-propelled spreaders, drone sprayers, enhanced linkages between combine harvesters and transportation vehicles, and training on skilled agricultural labor

Impact of socioeconomic deprivation on rate and cause of death in severe mental illness

Background: Socioeconomic status has important associations with disease-specific mortality in the general population. Although individuals with Severe Mental Illnesses (SMI) experience significant premature mortality, the relationship between socioeconomic status and mortality in this group remains under investigated.<p></p> Aims: To assess the impact of socioeconomic status on rate and cause of death in individuals with SMI (schizophrenia and bipolar disorder) relative to the local (Glasgow) and wider (Scottish) populations.<p></p> Methods: Cause and age of death during 2006-2010 inclusive for individuals with schizophrenia or bipolar disorder registered on the Glasgow Psychosis Clinical Information System (PsyCIS) were obtained by linkage to the Scottish General Register Office (GRO). Rate and cause of death by socioeconomic status, measured by Scottish Index of Multiple Deprivation (SIMD), were compared to the Glasgow and Scottish populations.<p></p> Results: Death rates were higher in people with SMI across all socioeconomic quintiles compared to the Glasgow and Scottish populations, and persisted when suicide was excluded. Differences were largest in the most deprived quintile (794.6 per 10,000 population vs. 274.7 and 252.4 for Glasgow and Scotland respectively). Cause of death varied by socioeconomic status. For those living in the most deprived quintile, higher drug-related deaths occurred in those with SMI compared to local Glasgow and wider Scottish population rates (12.3% vs. 5.9%, p = <0.001 and 5.1% p = 0.002 respectively). A lower proportion of deaths due to cancer in those with SMI living in the most deprived quintile were also observed, relative to the local Glasgow and wider Scottish populations (12.3% vs. 25.1% p = 0.013 and 26.3% p = <0.001). The proportion of suicides was significantly higher in those with SMI living in the more affluent quintiles relative to Glasgow and Scotland (54.6% vs. 5.8%, p = <0.001 and 5.5%, p = <0.001). Discussion and conclusions: Excess mortality in those with SMI occurred across all socioeconomic quintiles compared to the Glasgow and Scottish populations but was most marked in the most deprived quintiles when suicide was excluded as a cause of death. Further work assessing the impact of socioeconomic status on specific causes of premature mortality in SMI is needed

Search for Gravitational Waves from Primordial Black Hole Binary Coalescences in the Galactic Halo

We use data from the second science run of the LIGO gravitational-wave detectors to search for the gravitational waves from primordial black hole (PBH) binary coalescence with component masses in the range 0.2--$1.0 M_\odot$. The analysis requires a signal to be found in the data from both LIGO observatories, according to a set of coincidence criteria. No inspiral signals were found. Assuming a spherical halo with core radius 5 kpc extending to 50 kpc containing non-spinning black holes with masses in the range 0.2--$1.0 M_\odot$, we place an observational upper limit on the rate of PBH coalescence of 63 per year per Milky Way halo (MWH) with 90% confidence.Comment: 7 pages, 4 figures, to be submitted to Phys. Rev.

Search for resonant diphoton production with the D0 detector

We present a search for a narrow resonance in the inclusive diphoton final state using 2.7 fb-1 of data collected with the D0 detector at the Fermilab Tevatron ppbar Collider. We observe good agreement between the data and the background prediction, and set the first 95% C.L. upper limits on the production cross section times the branching ratio for decay into a pair of photons for resonance masses between 100 and 150 GeV. This search is also interpreted in the context of several models of electroweak symmetry breaking with a Higgs boson decaying into two photons.Comment: 7 pages, 3 figures

Search for the standard model Higgs boson in tau final states

We present a search for the standard model Higgs boson using hadronically decaying tau leptons, in 1 inverse femtobarn of data collected with the D0 detector at the Fermilab Tevatron ppbar collider. We select two final states: tau plus missing transverse energy and b jets, and tau+ tau- plus jets. These final states are sensitive to a combination of associated W/Z boson plus Higgs boson, vector boson fusion and gluon-gluon fusion production processes. The observed ratio of the combined limit on the Higgs production cross section at the 95% C.L. to the standard model expectation is 29 for a Higgs boson mass of 115 GeV.Comment: publication versio