Prior chemotherapy does not prevent effective mobilisation by G-CSF of peripheral blood progenitor cells.

In this study we demonstrate that the hemopoietic growth factor, G-CSF successfully mobilised progenitor cell populations into the peripheral blood in a population of patients despite intensive pretreatment with chemotherapy. Administration of G-CSF increased the numbers of peripheral blood progenitor cells (PBPC) by a median of 76-fold above basal levels. Maximal levels of PBPC were observed on days 5 and 6 after G-CSF treatment. In two patients a second cycle of G-CSF mobilised PBPC to levels comparable with those seen after the first cycle of G-CSF treatment. An earlier hemopoietic cell population (pre-CFC's) was also mobilised with levels increased up to 50-fold above basal levels. Using a standard mononuclear cell leukapheresis technique the PBPC were collected extremely efficiently (essentially 100%) and could be further successfully enriched by separation using a Ficoll gradient. For patients who underwent the optimal collection protocol (i.e. leukapheresis on days 5, 6 and 7) a total of 32 +/- 6 x 10(4) GM-CFC kg-1 were collected. The ability to mobilise PBPC using G-CSF alone and to successfully and efficiently harvest these cells has important implications for the future of transplantation and high dose chemotherapy procedures

Meanings of epilepsy in its sociocultural context and implications for stigma: Findings from ethnographic studies in local communities in China and Vietnam

We investigated beliefs about the causes, course, and treatment of epilepsy and its impact on quality of life (QOL) in key target groups, using “mini-ethnographies” involving 141 in-depth interviews and 12 focus groups in China, and 84 in-depth interviews and 16 focus groups in Vietnam. Data were analyzed thematically, using a qualitative data analysis package. In both countries, beliefs about causes and triggers of epilepsy and seizures were a complex interweaving of Western, traditional, and folk medicine concepts. Epilepsy was understood to be chronic, not curable, but controllable, and was seen as enormously socially disruptive, with wide-ranging impact on QOL. Our findings suggest a more “embodied” and benign set of theories about epilepsy than in some other cultural contexts; nonetheless, people with epilepsy are still seen as having low social value and face social rejection. By exploring meanings attached to epilepsy in these two cultural contexts, we have clarified reasons behind previously documented negative attitudes and foci for future intervention studies

Thermal Conversion of Guanylurea Dicyanamide into Graphitic Carbon Nitride via Prototype CNx Precursors

Guanylurea dicyanamide, [(H2N)C(-O)NHC(NH2)2][N(CN)2], has been synthesized by ion exchange reaction in aqueous solution and structurally characterized by single-crystal X-ray diffraction (C2/c, a = 2249.0(5) pm, b = 483.9(1) pm, c = 1382.4(3) pm, β = 99.49(3)°, V = 1483.8(5) × 106 pm3, T = 130 K). The thermal behavior of the molecular salt has been studied by thermal analysis, temperature-programmed X-ray powder diffraction, FTIR spectroscopy, and mass spectrometry between room temperature and 823 K. The results were interpreted on a molecular level in terms of a sequence of thermally induced addition, cyclization, and elimination reactions. As a consequence, melamine (2,4,6-triamino-1,3,5-triazine) is formed with concomitant loss of HNCO. Further condensation of melamine yields the prototypic CNx precursor melem (2,6,10-triamino-s-heptazine, C6N7(NH2)3), which alongside varying amounts of directly formed CNxHy material transforms into layered CNxHy phases without significant integration of oxygen into the core framework owing to the evaporation of HNCO. Thus, further evidence can be added to melamine and its condensation product melem acting as “key intermediates” in the synthetic pathway toward graphitic CNxHy materials, whose exact constitution is still a point at issue. Due to the characteristic formation process and hydrogen content a close relationship with the polymer melon is evident. In particular, the thermal transformation of guanylurea dicyanamide clearly demonstrates that the formation of volatile compounds such as HNCO during thermal decomposition may render a large variety of previously not considered molecular compounds suitable CNx precursors despite the presence of oxygen in the starting material

Human neutrophil clearance of bacterial pathogens triggers anti-microbial gamma delta T cell responses in early infection

Human blood Vc9/Vd2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vc9/Vd2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vc9/Vd2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-c and tumor necrosis factor (TNF)-a. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vc9/Vd2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-a dependent proliferation of Vc9/Vd2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting cd T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis – characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity – show a selective activation of local Vc9/Vd2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The cd T celldriven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of cd T cells and TNF-a and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive cd T cells in early infection and suggest novel diagnostic and therapeutic approaches.Martin S. Davey, Chan-Yu Lin, Gareth W. Roberts, Sinéad Heuston, Amanda C. Brown, James A. Chess, Mark A. Toleman, Cormac G.M. Gahan, Colin Hill, Tanya Parish, John D. Williams, Simon J. Davies, David W. Johnson, Nicholas Topley, Bernhard Moser and Matthias Eber

A combined VANDELS and LEGA-C study: the evolution of quiescent galaxy size, stellar mass, and age from z = 0.6 to z = 1.3

We study the relationships between stellar mass, size, and age within the quiescent population, using two mass-complete spectroscopic samples with log10(M⊙/M⊙) > 10.3, taken from VANDELS at 1.0 < z < 1.3, and LEGA-C at 0.6 < z < 0.8. Using robust Dn4000 values, we demonstrate that the well-known 'downsizing' signature is already in place by z 1.1, with Dn4000 increasing by 0.1 across a 1 dex mass interval for both VANDELS and LEGA-C. We then proceed to investigate the evolution of the quiescent galaxy stellar mass-size relation from z -1.1 to z -0.7. We find the median size increases by a factor of 1.9 ± 0.1 at log10(M⊙/M⊙) = 10.5, and see tentative evidence for flattening of the relation, finding slopes of α = 0.72 ± 0.06 and α =\0.56\pm 0.04 for VANDELS and LEGA-C, respectively. We finally split our sample into galaxies above and below our fitted mass-size relations, to investigate how size and Dn4000 correlate. For LEGA-C, we see a clear difference, with larger galaxies found to have smaller Dn4000 at fixed stellar mass. Due to the faintness and smaller numbers of the VANDELS sample, we cannot confirm whether a similar relation exists at z -1.1. We consider whether differences in stellar age or metallicity are most likely to drive this size-Dn4000 relation, finding that any metallicity differences are unlikely to fully explain the observed offset, meaning smaller galaxies must be older than their larger counterparts. We find the observed evolution in size, mass, and Dn4000 across the -2 Gyr from z ∼1.1 to z ∼0.7 can be explained by a simple toy model in which VANDELS galaxies evolve passively whilst experiencing a series of minor mergers

A combined VANDELS and LEGA-C study: the evolution of quiescent galaxy size, stellar mass, and age from z = 0.6 to z = 1.3

We study the relationships between stellar mass, size and age within the quiescent population, using two mass-complete spectroscopic samples with $\mathrm{log_{10}}(M_{\star}/\mathrm{M_{\odot}})>10.3$, taken from VANDELS at $1.0<z<1.3$, and LEGA-C at $0.6<z<0.8$. Using robust D$_{n}$4000 values, we demonstrate that the well-known 'downsizing' signature is already in place by $z\simeq1.1$, with D$_{n}$4000 increasing by $\simeq0.1$ across a $\simeq$ 1 dex mass interval for both VANDELS and LEGA-C. We then proceed to investigate the evolution of the quiescent galaxy stellar mass-size relation from $z\simeq1.1$ to $z\simeq0.7$. We find the median size increases by a factor of $1.9\pm{0.1}$ at $\mathrm{log_{10}}(M_{\star}/\mathrm{M_{\odot}})=10.5$, and see tentative evidence for flattening of the relation, finding slopes of $\alpha=0.72\pm0.06$ and $\alpha=$ $0.56\pm0.04$ for VANDELS and LEGA-C respectively. We finally split our sample into galaxies above and below our fitted mass-size relations, to investigate how size and D$_{n}$4000 correlate. For LEGA-C, we see a clear difference, with larger galaxies found to have smaller D$_{n}$4000 at fixed stellar mass. Due to the faintness and smaller numbers of the VANDELS sample, we cannot confirm whether a similar relation exists at $z\simeq1.1$. We consider whether differences in stellar age or metallicity are most likely to drive this size-D$_{n}$4000 relation, finding that any metallicity differences are unlikely to fully explain the observed offset, meaning smaller galaxies must be older than their larger counterparts. We find the observed evolution in size, mass and D$_{n}$4000 across the $\simeq2$ Gyr from $z\sim1.1$ to $z\sim0.7$ can be explained by a simple toy model in which VANDELS galaxies evolve passively, whilst experiencing a series of minor mergers.Comment: 14 pages, 9 figures, submitted to MNRA

Insights into the Regulatory Characteristics of the Mycobacterial Dephosphocoenzyme A Kinase: Implications for the Universal CoA Biosynthesis Pathway

Being vastly different from the human counterpart, we suggest that the last enzyme of the Mycobacterium tuberculosis Coenzyme A biosynthetic pathway, dephosphocoenzyme A kinase (CoaE) could be a good anti-tubercular target. Here we describe detailed investigations into the regulatory features of the enzyme, affected via two mechanisms. Enzymatic activity is regulated by CTP which strongly binds the enzyme at a site overlapping that of the leading substrate, dephosphocoenzyme A (DCoA), thereby obscuring the binding site and limiting catalysis. The organism has evolved a second layer of regulation by employing a dynamic equilibrium between the trimeric and monomeric forms of CoaE as a means of regulating the effective concentration of active enzyme. We show that the monomer is the active form of the enzyme and the interplay between the regulator, CTP and the substrate, DCoA, affects enzymatic activity. Detailed kinetic data have been corroborated by size exclusion chromatography, dynamic light scattering, glutaraldehyde crosslinking, limited proteolysis and fluorescence investigations on the enzyme all of which corroborate the effects of the ligands on the enzyme oligomeric status and activity. Cysteine mutagenesis and the effects of reducing agents on mycobacterial CoaE oligomerization further validate that the latter is not cysteine-mediated or reduction-sensitive. These studies thus shed light on the novel regulatory features employed to regulate metabolite flow through the last step of a critical biosynthetic pathway by keeping the latter catalytically dormant till the need arises, the transition to the active form affected by a delicate crosstalk between an essential cellular metabolite (CTP) and the precursor to the pathway end-product (DCoA)