Delta infection without increase in severity of hepatitis.

The findings of increased morbidity of HbsAG positive hepatitis with delta infection in a study by Dr. Smedile et al were contrary to those of studies performed by the authors. A group of 27 and a group of 41 drug abusers were examined serologically and had liver biopsies performed. There was no significant difference in histological findings between delta positive and delta negative patients in the 27 member group. None of the 41 member group showed any increase in severity of illness. Ethnic origin may be an important factor in the pathogenicity of the delta agent

Astrocytic gap junctional communication is reduced in amyloid-β-treated cultured astrocytes, but not in Alzheimer's disease transgenic mice

Alzheimer's disease is characterized by accumulation of amyloid deposits in brain, progressive cognitive deficits and reduced glucose utilization. Many consequences of the disease are attributed to neuronal dysfunction, but roles of astrocytes in its pathogenesis are not well understood. Astrocytes are extensively coupled via gap junctions, and abnormal trafficking of metabolites and signalling molecules within astrocytic syncytia could alter functional interactions among cells comprising the neurovascular unit. To evaluate the influence of amyloid-β on astrocyte gap junctional communication, cultured astrocytes were treated with monomerized amyloid-β1–40 (1 μmol/l) for intervals ranging from 2 h to 5 days, and the areas labelled by test compounds were determined by impaling a single astrocyte with a micropipette and diffusion of material into coupled cells. Amyloid-β-treated astrocytes had rapid, sustained 50–70% reductions in the area labelled by Lucifer Yellow, anionic Alexa Fluor® dyes and energy-related compounds, 6-NBDG (a fluorescent glucose analogue), NADH and NADPH. Amyloid-β treatment also caused a transient increase in oxidative stress. In striking contrast with these results, spreading of Lucifer Yellow within astrocytic networks in brain slices from three regions of 8.5–14-month-old control and transgenic Alzheimer's model mice was variable, labelling 10–2000 cells; there were no statistically significant differences in the number of dye-labelled cells among the groups or with age. Thus amyloid-induced dysfunction of gap junctional communication in cultured astrocytes does not reflect the maintenance of dye transfer through astrocytic syncytial networks in transgenic mice; the pathophysiology of Alzheimer's disease is not appropriately represented by the cell culture system

Combining computational effects: commutativity and sum

We begin to develop a unified account of modularity for computational effects. We use the notion of enriched Lawvere theory, together with its relationship with strong monads, to reformulate Moggi’s paradigm for modelling computational effects; we emphasise the importance here of the operations that induce computational effects. Effects qua theories are then combined by appropriate bifunctors (on the category of theories). We give a theory of the commutative combination of effects, which in particular yields Moggi’s side-effects monad transformer (an application is the combination of side-effects with nondeterminism). And we give a theory for the sum of computational effects, which in particular yields Moggi’s exceptions monad transformer (an application is the combination of exceptions with other effects)

Multiscale correlative tomography: an investigation of creep cavitation in 316 stainless steel

Creep cavitation in an ex-service nuclear steam header Type 316 stainless steel sample is investigated through a multiscale tomography workflow spanning eight orders of magnitude, combining X-ray computed tomography (CT), plasma focused ion beam (FIB) scanning electron microscope (SEM) imaging and scanning transmission electron microscope (STEM) tomography. Guided by microscale X-ray CT, nanoscale X-ray CT is used to investigate the size and morphology of cavities at a triple point of grain boundaries. In order to understand the factors affecting the extent of cavitation, the orientation and crystallographic misorientation of each boundary is characterised using electron backscatter diffraction (EBSD). Additionally, in order to better understand boundary phase growth, the chemistry of a single boundary and its associated secondary phase precipitates is probed through STEM energy dispersive X-ray (EDX) tomography. The difference in cavitation of the three grain boundaries investigated suggests that the orientation of grain boundaries with respect to the direction of principal stress is important in the promotion of cavity formation

New constraints on the free-streaming of warm dark matter from intermediate and small scale Lyman-α forest data

We present new measurements of the free-streaming of warm dark matter (WDM) from Lyman-α flux-power spectra. We use data from the medium resolution, intermediate redshift XQ-100 sample observed with the X-shooter spectrograph (z=3–4.2) and the high-resolution, high-redshift sample used in Viel et al. (2013) obtained with the HIRES/MIKE spectrographs (z=4.2 – 5.4 ). Based on further improved modelling of the dependence of the Lyman- α flux-power spectrum on the free-streaming of dark matter, cosmological parameters, as well as the thermal history of the intergalactic medium (IGM) with hydrodynamical simulations, we obtain the following limits, expressed as the equivalent mass of thermal relic WDM particles. The XQ-100 flux power spectrum alone gives a lower limit of 1.4 keV, the re-analysis of the HIRES/MIKE sample gives 4.1 keV while the combined analysis gives our best and significantly strengthened lower limit of 5.3 keV (all 2 σ C.L.). The further improvement in the joint analysis is partly due to the fact that the two data sets have different degeneracies between astrophysical and cosmological parameters that are broken when the data sets are combined, and more importantly on chosen priors on the thermal evolution. These results all assume that the temperature evolution of the IGM can be modeled as a power law in redshift. Allowing for a nonsmooth evolution of the temperature of the IGM with sudden temperature changes of up to 5000 K reduces the lower limit for the combined analysis to 3.5 keV. A WDM with smaller thermal relic masses would require, however, a sudden temperature jump of 5000 K or more in the narrow redshift interval z = 4.6 – 4.8 , in disagreement with observations of the thermal history based on high-resolution resolution Lyman- α forest data and expectations for photo-heating and cooling in the low density IGM at these redshifts.V. I. is supported by U.S. NSF Grant No. AST-1514734. V. I. also thanks M. McQuinn for useful discussions, and IAS, Princeton, for hospitality during his stay where part of this work was completed. M. V. and T. S. K. are supported by ERC-StG “cosmoIGM”. S. L. has been supported by FONDECYT grant number 1140838 and partially by PFB-06 CATA. V. D., M. V., S. C. acknowledge support from the PRIN INAF 2012 “The X-Shooter sample of 100 quasar spectra at z ∼ 3.5 : Digging into cosmology and galaxy evolution with quasar absorption lines. G. B. is supported by the NSF under award AST-1615814. S. L. E. acknowledges the receipt of an NSERC Discovery Grant. M. H. acknowledges support by ERC ADVANCED GRANT 320596 “The Emergence of Structure during the epoch of Reionization”. L. C. is supported by YDUN DFF 4090-00079. K. D. D. is supported by an NSF AAPF fellowship awarded under NSF grant AST-1302093. J. S. B. acknowledges the support of a Royal Society University Research Fellowship. Based on observations collected at the European Organisation for Astronomical Research in the Southern Hemisphere under ESO programme 189.A-0424. This work made use of the DiRAC High Performance Computing System (HPCS) and the COSMOS shared memory service at the University of Cambridge. These are operated on behalf of the STFC DiRAC HPC facility. This equipment is funded by BIS National E-infrastructure capital grant ST/J005673/1 and STFC grants ST/H008586/1, ST/K00333X/1

Molecular Structure and Dimeric Organization of the Notch Extracellular Domain as Revealed by Electron Microscopy

Background: The Notch receptor links cell fate decisions of one cell to that of the immediate cellular neighbor. In humans, malfunction of Notch signaling results in diseases and congenital disorders. Structural information is essential for gaining insight into the mechanism of the receptor as well as for potentially interfering with its function for therapeutic purposes. Methodology/Principal Findings: We used the Affinity Grid approach to prepare specimens of the Notch extracellular domain (NECD) of the Drosophila Notch and human Notch1 receptors suitable for analysis by electron microscopy and three-dimensional (3D) image reconstruction. The resulting 3D density maps reveal that the NECD structure is conserved across species. We show that the NECD forms a dimer and adopts different yet defined conformations, and we identify the membrane-proximal region of the receptor and its ligand-binding site. Conclusions/Significance: Our results provide direct and unambiguous evidence that the NECD forms a dimer. Our studies further show that the NECD adopts at least three distinct conformations that are likely related to different functional states of the receptor. These findings open the way to now correlate mutations in the NECD with its oligomeric state and conformation

Lactate signalling regulates fungal β-glucan masking and immune evasion

AJPB: This work was supported by the European Research Council (STRIFE, ERC- 2009-AdG-249793), The UK Medical Research Council (MR/M026663/1), the UK Biotechnology and Biological Research Council (BB/K017365/1), the Wellcome Trust (080088; 097377). ERB: This work was supported by the UK Biotechnology and Biological Research Council (BB/M014525/1). GMA: Supported by the CNPq-Brazil (Science without Borders fellowship 202976/2014-9). GDB: Wellcome Trust (102705). CAM: This work was supported by the UK Medical Research Council (G0400284). DMM: This work was supported by UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/K000306/1). NARG/JW: Wellcome Trust (086827, 075470,101873) and Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology (097377). ALL: This work was supported by the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1).Peer reviewedPostprin

Human α2β1HI CD133+VE epithelial prostate stem cells express low levels of active androgen receptor

Stem cells are thought to be the cell of origin in malignant transformation in many tissues, but their role in human prostate carcinogenesis continues to be debated. One of the conflicts with this model is that cancer stem cells have been described to lack androgen receptor (AR) expression, which is of established importance in prostate cancer initiation and progression. We re-examined the expression patterns of AR within adult prostate epithelial differentiation using an optimised sensitive and specific approach examining transcript, protein and AR regulated gene expression. Highly enriched populations were isolated consisting of stem (α(2)β(1)(HI) CD133(+VE)), transiently amplifying (α(2)β(1)(HI) CD133(-VE)) and terminally differentiated (α(2)β(1)(LOW) CD133(-VE)) cells. AR transcript and protein expression was confirmed in α(2)β(1)(HI) CD133(+VE) and CD133(-VE) progenitor cells. Flow cytometry confirmed that median (±SD) fraction of cells expressing AR were 77% (±6%) in α(2)β(1)(HI) CD133(+VE) stem cells and 68% (±12%) in α(2)β(1)(HI) CD133(-VE) transiently amplifying cells. However, 3-fold lower levels of total AR protein expression (peak and median immunofluorescence) were present in α(2)β(1)(HI) CD133(+VE) stem cells compared with differentiated cells. This finding was confirmed with dual immunostaining of prostate sections for AR and CD133, which again demonstrated low levels of AR within basal CD133(+VE) cells. Activity of the AR was confirmed in prostate progenitor cells by the expression of low levels of the AR regulated genes PSA, KLK2 and TMPRSS2. The confirmation of AR expression in prostate progenitor cells allows integration of the cancer stem cell theory with the established models of prostate cancer initiation based on a functional AR. Further study of specific AR functions in prostate stem and differentiated cells may highlight novel mechanisms of prostate homeostasis and insights into tumourigenesis

Elevated hemostasis markers after pneumonia increases one-year risk of all-cause and cardiovascular deaths

Background: Acceleration of chronic diseases, particularly cardiovascular disease, may increase long-term mortality after community-acquired pneumonia (CAP), but underlying mechanisms are unknown. Persistence of the prothrombotic state that occurs during an acute infection may increase risk of subsequent atherothrombosis in patients with pre-existing cardiovascular disease and increase subsequent risk of death. We hypothesized that circulating hemostasis markers activated during CAP persist at hospital discharge, when patients appear to have recovered clinically, and are associated with higher mortality, particularly due to cardiovascular causes. Methods: In a cohort of survivors of CAP hospitalization from 28 US sites, we measured D-Dimer, thrombin-antithrombin complexes [TAT], Factor IX, antithrombin, and plasminogen activator inhibitor-1 at hospital discharge, and determined 1-year all-cause and cardiovascular mortality. Results: Of 893 subjects, most did not have severe pneumonia (70.6% never developed severe sepsis) and only 13.4% required intensive care unit admission. At discharge, 88.4% of subjects had normal vital signs and appeared to have clinically recovered. D-dimer and TAT levels were elevated at discharge in 78.8% and 30.1% of all subjects, and in 51.3% and 25.3% of those without severe sepsis. Higher D-dimer and TAT levels were associated with higher risk of all-cause mortality (range of hazard ratios were 1.66-1.17, p = 0.0001 and 1.46-1.04, p = 0.001 after adjusting for demographics and comorbid illnesses) and cardiovascular mortality (p = 0.009 and 0.003 in competing risk analyses). Conclusions: Elevations of TAT and D-dimer levels are common at hospital discharge in patients who appeared to have recovered clinically from pneumonia and are associated with higher risk of subsequent deaths, particularly due to cardiovascular disease. © 2011 Yende et al

Stable isotope analysis provides new information on winter habitat use of declining avian migrants that is relevant to their conservation

Winter habitat use and the magnitude of migratory connectivity are important parameters when assessing drivers of the marked declines in avian migrants. Such information is unavailable for most species. We use a stable isotope approach to assess these factors for three declining African-Eurasian migrants whose winter ecology is poorly known: wood warbler Phylloscopus sibilatrix, house martin Delichon urbicum and common swift Apus apus. Spatially segregated breeding wood warbler populations (sampled across a 800 km transect), house martins and common swifts (sampled across a 3,500 km transect) exhibited statistically identical intra-specific carbon and nitrogen isotope ratios in winter grown feathers. Such patterns are compatible with a high degree of migratory connectivity, but could arise if species use isotopically similar resources at different locations. Wood warbler carbon isotope ratios are more depleted than typical for African-Eurasian migrants and are compatible with use of moist lowland forest. The very limited variance in these ratios indicates specialisation on isotopically restricted resources, which may drive the similarity in wood warbler populations' stable isotope ratios and increase susceptibility to environmental change within its wintering grounds. House martins were previously considered to primarily use moist montane forest during the winter, but this seems unlikely given the enriched nature of their carbon isotope ratios. House martins use a narrower isotopic range of resources than the common swift, indicative of increased specialisation or a relatively limited wintering range; both factors could increase house martins' vulnerability to environmental change. The marked variance in isotope ratios within each common swift population contributes to the lack of population specific signatures and indicates that the species is less vulnerable to environmental change in sub-Saharan Africa than our other focal species. Our findings demonstrate how stable isotope research can contribute to understanding avian migrants' winter ecology and conservation status