Hydrogels for delivery of therapeutic compounds

In some aspects, methacrylate co-polymers crosslinked with an enzymatically cleavable peptide linker are provided and may be used for the oral delivery of a therapeutic. The peptide linker may be cleavable by an enzyme in the small intestine and may allow for the delivery of a therapeutic protein or nucleic acid to the small intestine. Also provided are methods of using the polymers for the treatment of a disease.Board of Regents, University of Texas Syste

Intimate partner violence, suicidality, and self-harm: a probability sample survey of the general population in England

BACKGROUND: Intimate partner violence (IPV) is a recognised risk factor for psychiatric disorders. There is little current evidence on IPV and self-harm and suicidality, and we therefore aimed to investigate the associations between experience of lifetime and past-year IPV with suicidal thoughts, suicide attempt, and self-harm in the past year. METHODS: We analysed the 2014 Adult Psychiatric Morbidity Survey, a cross-sectional survey of 7058 adults (aged ≥16 years) in England, which used a multistage random probability sampling design and involved face-to-face interviews. Participants were asked about experience of physical violence and sexual, economic, and emotional abuse from a current or former partner, and about suicidal thoughts, suicide attempts, and self-harm. Other adversities were recorded through an adapted version of the List of Threatening Experiences. Multivariable logistic regression models quantified associations between different indicators of lifetime and past-year IPV, with past-year non-suicidal self-harm, suicidal thoughts, and suicide attempts. All analyses were weighted. FINDINGS: Using weighted percentages, we found that a fifth (21·4%) of 7058 adults reported lifetime experience of IPV, and that 27·2% of women and 15·3% of men had experienced IPV. Among women, 19·6% had ever experienced emotional IPV, 18·7% physical IPV, 8·5% economic IPV, and 3·7% sexual IPV, which was higher than in men (8·6%, 9·3%, 3·6%, and 0·3%, respectively). Findings for ethnicity were unclear. Lifetime prevalence of IPV was higher in those living in rented accommodation or deprived neighbourhoods. Among people who had attempted suicide in the past year, 49·7% had ever experienced IPV and 23·1% had experienced IPV in the past year (including 34·8% of women and 9·4% of men). After adjusting for demographics, socioeconomics, and lifetime experience of adversities, the odds ratio of a past-year suicide attempt were 2·82 (95% CI 1·54–5·17) times higher in those who have ever experienced IPV, compared with those who had not. Fully adjusted odds ratios for past-year self-harm (2·20, 95% CI 1·37–3·53) and suicidal thoughts (1·85, 1·39–2·46) were also raised in those who had ever experienced IPV. INTERPRETATION: IPV is common in England, especially among women, and is strongly associated with self-harm and suicidality. People presenting to services in suicidal distress or after self-harm should be asked about IPV. Interventions designed to reduce the prevalence and duration of IPV might protect and improve the lives of people at risk of self-harm and suicide. FUNDING: UK Prevention Research Partnership

A Targeted RNA Interference Screen Reveals Novel Epigenetic Factors That Regulate Herpesviral Gene Expression

ABSTRACT Herpes simplex virus (HSV) utilizes and subverts host chromatin mechanisms to express its lytic gene products in mammalian cells. The host cell attempts to silence the incoming viral genome by epigenetic mechanisms, but the viral VP16 and ICP0 proteins promote active chromatin on the viral genome by recruiting other host epigenetic factors. However, the dependence on VP16 and ICP0 differs in different cell lines, implying cell type-dependent functional contributions of epigenetic factors for HSV gene expression. In this study, we performed a targeted RNA interference (RNAi) screen for cellular chromatin factors that are involved in regulation of herpes simplex virus (HSV) gene expression in U2OS osteosarcoma cells, a cell line that complements ICP0 mutant and VP16 mutant virus replication. In this screen, we found the same general classes of chromatin factors that regulate HSV gene expression in U2OS cells as in other cell types, including histone demethylases (HDMs), histone deacetylases (HDACs), histone acetyltransferases (HATs), and chromatin-remodeling factors, but the specific factors within these classes are different from those identified previously for other cell types. For example, KDM3A and KDM1A (LSD1) both demethylate mono- and dimethylated H3K9, but KDM3A emerged in our screen of U2OS cells. Further, small interfering RNA (siRNA) and inhibitor studies support the idea that KDM1A is more critical in HeLa cells, as observed previously, while KDM3A is more critical in U2OS cells. These results argue that different cellular chromatin factors are critical in different cell lines to carry out the positive and negative epigenetic effects exerted on the HSV genome

Minority and mode conversion heating in (3He)-H JET plasma

Radio frequency (RF) heating experiments have recently been conducted in JET (He-3)-H plasmas. This type of plasmas will be used in ITER's non-activated operation phase. Whereas a companion paper in this same PPCF issue will discuss the RF heating scenario's at half the nominal magnetic field, this paper documents the heating performance in (He-3)-H plasmas at full field, with fundamental cyclotron heating of He-3 as the only possible ion heating scheme in view of the foreseen ITER antenna frequency bandwidth. Dominant electron heating with global heating efficiencies between 30% and 70% depending on the He-3 concentration were observed and mode conversion (MC) heating proved to be as efficient as He-3 minority heating. The unwanted presence of both He-4 and D in the discharges gave rise to 2 MC layers rather than a single one. This together with the fact that the location of the high-field side fast wave (FW) cutoff is a sensitive function of the parallel wave number and that one of the locations of the wave confluences critically depends on the He-3 concentration made the interpretation of the results, although more complex, very interesting: three regimes could be distinguished as a function of X[He-3]: (i) a regime at low concentration (X[He-3] < 1.8%) at which ion cyclotron resonance frequency (ICRF) heating is efficient, (ii) a regime at intermediate concentrations (1.8 < X[He-3] < 5%) in which the RF performance is degrading and ultimately becoming very poor, and finally (iii) a good heating regime at He-3 concentrations beyond 6%. In this latter regime, the heating efficiency did not critically depend on the actual concentration while at lower concentrations (X[He-3] < 4%) a bigger excursion in heating efficiency is observed and the estimates differ somewhat from shot to shot, also depending on whether local or global signals are chosen for the analysis. The different dynamics at the various concentrations can be traced back to the presence of 2 MC layers and their associated FW cutoffs residing inside the plasma at low He-3 concentration. One of these layers is approaching and crossing the low-field side plasma edge when 1.8 < X[He-3] < 5%. Adopting a minimization procedure to correlate the MC positions with the plasma composition reveals that the different behaviors observed are due to contamination of the plasma. Wave modeling not only supports this interpretation but also shows that moderate concentrations of D-like species significantly alter the overall wave behavior in He-3-H plasmas. Whereas numerical modeling yields quantitative information on the heating efficiency, analytical work gives a good description of the dominant underlying wave interaction physics

The world's colonization and trade routes formation as imitated by slime mould

The plasmodium of Physarum polycephalum is renowned for spanning sources of nutrients with networks of protoplasmic tubes. The networks transport nutrients and metabolites across the plasmodium's body. To imitate a hypothetical colonization of the world and the formation of major transportation routes we cut continents from agar plates arranged in Petri dishes or on the surface of a three-dimensional globe, represent positions of selected metropolitan areas with oat flakes and inoculate the plasmodium in one of the metropolitan areas. The plasmodium propagates towards the sources of nutrients, spans them with its network of protoplasmic tubes and even crosses bare substrate between the continents. From the laboratory experiments we derive weighted Physarum graphs, analyze their structure, compare them with the basic proximity graphs and generalized graphs derived from the Silk Road and the Asia Highway networks. © 2012 World Scientific Publishing Company

RNA signatures allow rapid identification of pathogens and antibiotic susceptibilities

With rising rates of drug-resistant infections, there is a need for diagnostic methods that rapidly can detect the presence of pathogens and reveal their susceptibility to antibiotics. Here we propose an approach to diagnosing the presence and drug-susceptibility of infectious diseases based on direct detection of RNA from clinical samples. We demonstrate that species-specific RNA signatures can be used to identify a broad spectrum of infectious agents, including bacteria, viruses, yeast, and parasites. Moreover, we show that the behavior of a small set of bacterial transcripts after a brief antibiotic pulse can rapidly differentiate drug-susceptible and -resistant organisms and that these measurements can be made directly from clinical materials. Thus, transcriptional signatures could form the basis of a uniform diagnostic platform applicable across a broad range of infectious agents

HSV-1 Remodels Host Telomeres to Facilitate Viral Replication

SummaryTelomeres protect the ends of cellular chromosomes. We show here that infection with herpes simplex virus 1 (HSV-1) results in chromosomal structural aberrations at telomeres and the accumulation of telomere dysfunction-induced DNA damage foci (TIFs). At the molecular level, HSV-1 induces transcription of telomere repeat-containing RNA (TERRA), followed by the proteolytic degradation of the telomere protein TPP1 and loss of the telomere repeat DNA signal. The HSV-1-encoded E3 ubiquitin ligase ICP0 is required for TERRA transcription and facilitates TPP1 degradation. Small hairpin RNA (shRNA) depletion of TPP1 increases viral replication, indicating that TPP1 inhibits viral replication. Viral replication protein ICP8 forms foci that coincide with telomeric proteins, and ICP8-null virus failed to degrade telomere DNA signal. These findings suggest that HSV-1 reorganizes telomeres to form ICP8-associated prereplication foci and to promote viral genomic replication

Astrometric and Light-travel Time Orbits to Detect Low-mass Companions: A Case Study of the Eclipsing System R Canis Majoris

We discuss a method to determine orbital properties and masses of low-mass bodies orbiting eclipsing binaries. The analysis combines long-term eclipse timing modulations (light-travel time or LTT effect) with short-term, high-accuracy astrometry. As an illustration of the method, the results of a comprehensive study of Hipparcos astrometry and over a hundred years of eclipse timings of the Algol-type eclipsing binary R Canis Majoris are presented. A simultaneous solution of the astrometry and the LTTs yields an orbital period of P_12=92.8+/-1.3 yr, an LTT semiamplitude of 2574+/-57 s, an angular semi-major axis of a_12=117+/-5 mas, and values of the orbital eccentricity and inclination of e_12=0.49+/-0.05, and i_12=91.7+/-4.7 deg, respectively. Adopting the total mass of R CMa of M_12=1.24+/-0.05 Mo, the mass of the third body is M_3=0.34+/-0.02 Mo and the semi-major axis of its orbit is a_3=18.7+/-1.7 AU. From its mass, the third body is either a dM3-4 star or, more unlikely, a white dwarf. With the upcoming microarcsecond-level astrometric missions, the technique that we discuss can be successfully applied to detect and characterize long-period planetary-size objects and brown dwarfs around eclipsing binaries. Possibilities for extending the method to pulsating variables or stars with transiting planets are briefly addressed.Comment: 9 pages, 3 figures, accepted for publication in AJ (April 2002 issue