Glycotope structures and intramolecular affinity factors of plant lectins for Tn/T antigens

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Use of horseradish peroxidase for gene-directed enzyme prodrug therapy with paracetamol

Gene therapy is a potential method of treating cancer with a greater degree of targeting than conventional therapies. In addition, therapy can be directed towards cells within the tumour population that are traditionally resistant to current treatment schedules. Horseradish peroxidase (HRP) can oxidise paracetamol to N-acetyl-p-benzoquinoneimine via a one-electron pathway. Incubation of human cells expressing HRP with 0.5–10 mm paracetamol reduced clonogenic survival, but had little effect on control cells. A small increase in apoptosis was seen and a decrease in the number of cells undergoing mitosis, consistent with reports in hepatocytes using higher paracetamol concentrations. The cytotoxicity was also seen under conditions of severe hypoxia (catalyst induced anoxia), indicating that the HRP/paracetamol combination may be suitable for hypoxia-targeted gene therapy

Very high energy particle acceleration powered by the jets of the microquasar SS 433

SS 433 is a binary system containing a supergiant star that is overflowing its Roche lobe with matter accreting onto a compact object (either a black hole or neutron star). Two jets of ionized matter with a bulk velocity of $\sim0.26c$ extend from the binary, perpendicular to the line of sight, and terminate inside W50, a supernova remnant that is being distorted by the jets. SS 433 differs from other microquasars in that the accretion is believed to be super-Eddington, and the luminosity of the system is $\sim10^{40}$ erg s$^{-1}$. The lobes of W50 in which the jets terminate, about 40 pc from the central source, are expected to accelerate charged particles, and indeed radio and X-ray emission consistent with electron synchrotron emission in a magnetic field have been observed. At higher energies (>100 GeV), the particle fluxes of $\gamma$ rays from X-ray hotspots around SS 433 have been reported as flux upper limits. In this energy regime, it has been unclear whether the emission is dominated by electrons that are interacting with photons from the cosmic microwave background through inverse-Compton scattering or by protons interacting with the ambient gas. Here we report TeV $\gamma$-ray observations of the SS 433/W50 system where the lobes are spatially resolved. The TeV emission is localized to structures in the lobes, far from the center of the system where the jets are formed. We have measured photon energies of at least 25 TeV, and these are certainly not Doppler boosted, because of the viewing geometry. We conclude that the emission from radio to TeV energies is consistent with a single population of electrons with energies extending to at least hundreds of TeV in a magnetic field of $\sim16$~micro-Gauss.Comment: Preprint version of Nature paper. Contacts: S. BenZvi, B. Dingus, K. Fang, C.D. Rho , H. Zhang, H. Zho

What is the 'problem' that outreach work seeks to address and how might it be tackled? Seeking theory in a primary health prevention programme

<b>Background</b> Preventive approaches to health are disproportionately accessed by the more affluent and recent health improvement policy advocates the use of targeted preventive primary care to reduce risk factors in poorer individuals and communities. Outreach has become part of the health service response. Outreach has a long history of engaging those who do not otherwise access services. It has, however, been described as eclectic in its purpose, clientele and mode of practice; its effectiveness is unproven. Using a primary prevention programme in the UK as a case, this paper addresses two research questions: what are the perceived problems of non-engagement that outreach aims to address; and, what specific mechanisms of outreach are hypothesised to tackle these.<p></p> <b>Methods</b> Drawing on a wider programme evaluation, the study undertook qualitative interviews with strategically selected health-care professionals. The analysis was thematically guided by the concept of 'candidacy' which theorises the dynamic process through which services and individuals negotiate appropriate service use.<p></p> <b>Results</b> The study identified seven types of engagement 'problem' and corresponding solutions. These 'problems' lie on a continuum of complexity in terms of the challenges they present to primary care. Reasons for non-engagement are congruent with the concept of 'candidacy' but point to ways in which it can be expanded.<p></p> <b>Conclusions</b> The paper draws conclusions about the role of outreach in contributing to the implementation of inequalities focused primary prevention and identifies further research needed in the theoretical development of both outreach as an approach and candidacy as a conceptual framework

Modifiable predictors of depression following childhood maltreatment: a systematic review and meta-analysis

Although maltreatment experiences in childhood increase the risk for depression, not all maltreated children become depressed. This review aims to systematically examine the existing literature to identify modifiable factors that increase vulnerability to, or act as a buffer against, depression, and could therefore inform the development of targeted interventions. Thirteen databases (including Medline, PsychINFO, SCOPUS) were searched (between 1984 and 2014) for prospective, longitudinal studies published in English that included at least 300 participants and assessed associations between childhood maltreatment and later depression. The study quality was assessed using an adapted Newcastle-Ottawa Scale checklist. Meta-analyses (random effects models) were performed on combined data to estimate the effect size of the association between maltreatment and depression. Meta-regressions were used to explore effects of study size and quality. We identified 22 eligible articles (N=12 210 participants), of which 6 examined potential modifiable predictors of depression following maltreatment. No more than two studies examined the same modifiable predictor; therefore, it was not possible to examine combined effects of modifiable predictors with meta-regression. It is thus difficult to draw firm conclusions from this study, but initial findings indicate that interpersonal relationships, cognitive vulnerabilities and behavioral difficulties may be modifiable predictors of depression following maltreatment. There is a lack of well-designed, prospective studies on modifiable predictors of depression following maltreatment. A small amount of initial research suggests that modifiable predictors of depression may be specific to maltreatment subtypes and gender. Corroboration and further investigation of causal mechanisms is required to identify novel targets for intervention, and to inform guidelines for the effective treatment of maltreated children

Revisiting in vivo staining with alizarin red S - a valuable approach to analyse zebrafish skeletal mineralization during development and regeneration

Background The correct evaluation of mineralization is fundamental for the study of skeletal development, maintenance, and regeneration. Current methods to visualize mineralized tissue in zebrafish rely on: 1) fixed specimens; 2) radiographic and μCT techniques, that are ultimately limited in resolution; or 3) vital stains with fluorochromes that are indistinguishable from the signal of green fluorescent protein (GFP)-labelled cells. Alizarin compounds, either in the form of alizarin red S (ARS) or alizarin complexone (ALC), have long been used to stain the mineralized skeleton in fixed specimens from all vertebrate groups. Recent works have used ARS vital staining in zebrafish and medaka, yet not based on consistent protocols. There is a fundamental concern on whether ARS vital staining, achieved by adding ARS to the water, can affect bone formation in juvenile and adult zebrafish, as ARS has been shown to inhibit skeletal growth and mineralization in mammals. Results Here we present a protocol for vital staining of mineralized structures in zebrafish with a low ARS concentration that does not affect bone mineralization, even after repetitive ARS staining events, as confirmed by careful imaging under fluorescent light. Early and late stages of bone development are equally unaffected by this vital staining protocol. From all tested concentrations, 0.01 % ARS yielded correct detection of bone calcium deposits without inducing additional stress to fish. Conclusions The proposed ARS vital staining protocol can be combined with GFP fluorescence associated with skeletal tissues and thus represents a powerful tool for in vivo monitoring of mineralized structures. We provide examples from wild type and transgenic GFP-expressing zebrafish, for endoskeletal development and dermal fin ray regeneration

Nano-mechanical properties of Fe-Mn-Al-C lightweight steels

High Al Low-density steels could have a transformative effect on the light-weighting of steel structures for transportation and achieving the desired properties with the minimum amount of Ni is of great interest from an economic perspective. In this study, the mechanical properties of two duplex low-density steels, Fe-15Mn-10Al-0.8C-5Ni and Fe-15Mn-10Al-0.8C (wt.%) were investigated through nano-indentation and simulation through utilization of ab initio formalisms in Density Functional Theory (DFT) in order to establish the hardness resulting from two critical structural features (ߢ-carbides and B2 intermetallic) as a function of annealing temperature (500 − 1050 ℃) and the addition of Ni. In the Ni-free sample, the calculated elastic properties of kappa-carbides were compared with those of the B2 intermetallic Fe3Al − L12, and the role of Mn in the kappa structure and its elastic properties were studied. The Ni-containing samples were found to have a higher hardness due to the B2 phase composition being NiAl rather than FeAl, with Ni-Al bonds reported to be stronger than the Fe-Al bonds. In both samples, at temperatures of 900 ℃ and above, the ferrite phase contained nano-sized discs of B2 phase, wherein the Ni-containing samples exhibited higher hardness, attributed again to the stronger Ni-Al bonds in the B2 phase. At 700 ℃ and below, the nano-sized B2 discs were replaced by micrometre sized needles of kappa in the Ni-free sample resulting in a lowering of the hardness. In the Ni-containing sample, the entire alpha phase was replaced by B2 stringers, which had a lower hardness than the Ni-Al nano-discs due to a lower Ni content in B2 stringer bands formed at 700 ℃ and below. In addition, the hardness of needle-like kappa-carbides formed in alpha phase was found to be a function of Mn content. Although it was impossible to measure the hardness of cuboid kappa particles in gamma phase because of their nano-size, the hardness value of composite phases, e.g. gamma + kappa was measured and reported. All the hardness values were compared and rationalized by bonding energy between different atoms

Sea ice dynamics across the Mid-Pleistocene transition in the Bering Sea.

Sea ice and associated feedback mechanisms play an important role for both long- and short-term climate change. Our ability to predict future sea ice extent, however, hinges on a greater understanding of past sea ice dynamics. Here we investigate sea ice changes in the eastern Bering Sea prior to, across, and after the Mid-Pleistocene transition (MPT). The sea ice record, based on the Arctic sea ice biomarker IP25 and related open water proxies from the International Ocean Discovery Program Site U1343, shows a substantial increase in sea ice extent across the MPT. The occurrence of late-glacial/deglacial sea ice maxima are consistent with sea ice/land ice hysteresis and land-glacier retreat via the temperature-precipitation feedback. We also identify interactions of sea ice with phytoplankton growth and ocean circulation patterns, which have important implications for glacial North Pacific Intermediate Water formation and potentially North Pacific abyssal carbon storage

Probiotic Microbes Sustain Youthful Serum Testosterone Levels and Testicular Size in Aging Mice

The decline of circulating testosterone levels in aging men is associated with adverse health effects. During studies of probiotic bacteria and obesity, we discovered that male mice routinely consuming purified lactic acid bacteria originally isolated from human milk had larger testicles and increased serum testosterone levels compared to their age-matched controls. Further investigation using microscopy-assisted histomorphometry of testicular tissue showed that mice consuming Lactobacillus reuteri in their drinking water had significantly increased seminiferous tubule cross-sectional profiles and increased spermatogenesis and Leydig cell numbers per testis when compared with matched diet counterparts This showed that criteria of gonadal aging were reduced after routinely consuming a purified microbe such as L. reuteri. We tested whether these features typical of sustained reproductive fitness may be due to anti-inflammatory properties of L. reuteri, and found that testicular mass and other indicators typical of old age were similarly restored to youthful levels using systemic administration of antibodies blocking pro-inflammatory cytokine interleukin-17A. This indicated that uncontrolled host inflammatory responses contributed to the testicular atrophy phenotype in aged mice. Reduced circulating testosterone levels have been implicated in many adverse effects; dietary L. reuteri or other probiotic supplementation may provide a viable natural approach to prevention of male hypogonadism, absent the controversy and side-effects of traditional therapies, and yield practical options for management of disorders typically associated with normal aging. These novel findings suggest a potential high impact for microbe therapy in public health by imparting hormonal and gonad features of reproductive fitness typical of much younger healthy individuals.National Institutes of Health (U.S.) (Grant P30-ES002109)National Institutes of Health (U.S.) (Grant U01 CA164337)National Institutes of Health (U.S.) (Grant RO1CA108854

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012