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Functional Cellular Anti-Tumor Mechanisms are Augmented by Genetic Proteoglycan Targeting.
While recent research points to the importance of glycans in cancer immunity, knowledge on functional mechanisms is lacking. In lung carcinoma among other tumors, anti-tumor immunity is suppressed; and while some recent therapies boost T-cell mediated immunity by targeting immune-checkpoint pathways, robust responses are uncommon. Augmenting tumor antigen-specific immune responses by endogenous dendritic cells (DCs) is appealing from a specificity standpoint, but challenging. Here, we show that restricting a heparan sulfate (HS) loss-of-function mutation in the HS sulfating enzyme Ndst1 to predominantly conventional DCs (Ndst1f/f CD11cCre+ mutation) results in marked inhibition of Lewis lung carcinoma growth along with increased tumor-associated CD8+ T cells. In mice deficient in a major DC HS proteoglycan (syndecan-4), splenic CD8+ T cells showed increased anti-tumor cytotoxic responses relative to controls. Studies examining Ndst1f/f CD11cCre + mutants revealed that mutation was associated with an increase in anti-tumor cytolysis using either splenic CD8+ T cells or tumor-infiltrating (TIL) CD8+ T cells purified ex-vivo, and tested in pooled effector-to-target cytolytic assays against tumor cells from respective animals. On glycan compositional analysis, HS purified from Ndst1f/f CD11cCre + mutant DCs had reduced overall sulfation, including reduced sulfation of a tri-sulfated disaccharide species that was intriguingly abundant on wildtype DC HS. Interestingly, antigen presentation in the context of major histocompatibility complex class-I (MHC-I) was enhanced in mutant DCs, with more striking effects in the setting of HS under-sulfation, pointing to a likely regulatory role by sulfated glycans at the antigen/MHC-I - T-cell interface; and possibly future opportunities to improve antigen-specific T cell responses by immunologic targeting of HS proteoglycans in cancer
How metal films de-wet substrates - identifying the kinetic pathways and energetic driving forces
We study how single-crystal chromium films of uniform thickness on W(110)
substrates are converted to arrays of three-dimensional (3D) Cr islands during
annealing. We use low-energy electron microscopy (LEEM) to directly observe a
kinetic pathway that produces trenches that expose the wetting layer. Adjacent
film steps move simultaneously uphill and downhill relative to the staircase of
atomic steps on the substrate. This step motion thickens the film regions where
steps advance. Where film steps retract, the film thins, eventually exposing
the stable wetting layer. Since our analysis shows that thick Cr films have a
lattice constant close to bulk Cr, we propose that surface and interface stress
provide a possible driving force for the observed morphological instability.
Atomistic simulations and analytic elastic models show that surface and
interface stress can cause a dependence of film energy on thickness that leads
to an instability to simultaneous thinning and thickening. We observe that
de-wetting is also initiated at bunches of substrate steps in two other
systems, Ag/W(110) and Ag/Ru(0001). We additionally describe how Cr films are
converted into patterns of unidirectional stripes as the trenches that expose
the wetting layer lengthen along the W[001] direction. Finally, we observe how
3D Cr islands form directly during film growth at elevated temperature. The Cr
mesas (wedges) form as Cr film steps advance down the staircase of substrate
steps, another example of the critical role that substrate steps play in 3D
island formation
The Physics of the Colloidal Glass Transition
As one increases the concentration of a colloidal suspension, the system
exhibits a dramatic increase in viscosity. Structurally, the system resembles a
liquid, yet motions within the suspension are slow enough that it can be
considered essentially frozen. This kinetic arrest is the colloidal glass
transition. For several decades, colloids have served as a valuable model
system for understanding the glass transition in molecular systems. The spatial
and temporal scales involved allow these systems to be studied by a wide
variety of experimental techniques. The focus of this review is the current
state of understanding of the colloidal glass transition. A brief introduction
is given to important experimental techniques used to study the glass
transition in colloids. We describe features of colloidal systems near and in
glassy states, including tremendous increases in viscosity and relaxation
times, dynamical heterogeneity, and ageing, among others. We also compare and
contrast the glass transition in colloids to that in molecular liquids. Other
glassy systems are briefly discussed, as well as recently developed synthesis
techniques that will keep these systems rich with interesting physics for years
to come.Comment: 56 pages, 18 figures, Revie
Pain assessment for people with dementia: a systematic review of systematic reviews of pain assessment tools.
BACKGROUND: There is evidence of under-detection and poor management of pain in patients with dementia, in both long-term and acute care. Accurate assessment of pain in people with dementia is challenging and pain assessment tools have received considerable attention over the years, with an increasing number of tools made available. Systematic reviews on the evidence of their validity and utility mostly compare different sets of tools. This review of systematic reviews analyses and summarises evidence concerning the psychometric properties and clinical utility of pain assessment tools in adults with dementia or cognitive impairment. METHODS: We searched for systematic reviews of pain assessment tools providing evidence of reliability, validity and clinical utility. Two reviewers independently assessed each review and extracted data from them, with a third reviewer mediating when consensus was not reached. Analysis of the data was carried out collaboratively. The reviews were synthesised using a narrative synthesis approach. RESULTS: We retrieved 441 potentially eligible reviews, 23 met the criteria for inclusion and 8 provided data for extraction. Each review evaluated between 8 and 13 tools, in aggregate providing evidence on a total of 28 tools. The quality of the reviews varied and the reporting often lacked sufficient methodological detail for quality assessment. The 28 tools appear to have been studied in a variety of settings and with varied types of patients. The reviews identified several methodological limitations across the original studies. The lack of a 'gold standard' significantly hinders the evaluation of tools' validity. Most importantly, the samples were small providing limited evidence for use of any of the tools across settings or populations. CONCLUSIONS: There are a considerable number of pain assessment tools available for use with the elderly cognitive impaired population. However there is limited evidence about their reliability, validity and clinical utility. On the basis of this review no one tool can be recommended given the existing evidence
Event-by-Event Fluctuations in Particle Multiplicities and Transverse Energy Produced in 158.A GeV Pb+Pb collisions
Event-by-event fluctuations in the multiplicities of charged particles and
photons, and the total transverse energy in 158 GeV Pb+Pb collisions
are studied for a wide range of centralities. For narrow centrality bins the
multiplicity and transverse energy distributions are found to be near perfect
Gaussians. The effect of detector acceptance on the multiplicity fluctuations
has been studied and demonstrated to follow statistical considerations. The
centrality dependence of the charged particle multiplicity fluctuations in the
measured data has been found to agree reasonably well with those obtained from
a participant model. However for photons the multiplicity fluctuations has been
found to be lower compared to those obtained from a participant model. The
multiplicity and transverse energy fluctuations have also been compared to
those obtained from the VENUS event generator.Comment: To appear in Physical Review C; changes : more detailed discussion on
errors and few figures modifie
Interferometry of Direct Photons in Central 280Pb+208Pb Collisions at 158A GeV
Two-particle correlations of direct photons were measured in central
208Pb+208Pb collisions at 158 AGeV. The invariant interferometric radii were
extracted for 100<K_T<300 MeV/c and compared to radii extracted from charged
pion correlations. The yield of soft direct photons, K_T<300 MeV/c, was
extracted from the correlation strength and compared to theoretical
calculations.Comment: 5 pages, 4 figure
Thermal Dileptons at LHC
We predict dilepton invariant-mass spectra for central 5.5 ATeV Pb-Pb
collisions at LHC. Hadronic emission in the low-mass region is calculated using
in-medium spectral functions of light vector mesons within hadronic many-body
theory. In the intermediate-mass region thermal radiation from the Quark-Gluon
Plasma, evaluated perturbatively with hard-thermal loop corrections, takes
over. An important source over the entire mass range are decays of correlated
open-charm hadrons, rendering the nuclear modification of charm and bottom
spectra a critical ingredient.Comment: 2 pages, 2 figures, contributed to Workshop on Heavy Ion Collisions
at the LHC: Last Call for Predictions, Geneva, Switzerland, 14 May - 8 Jun
2007 v2: acknowledgment include
A Pair of Dopamine Neurons Target the D1-Like Dopamine Receptor DopR in the Central Complex to Promote Ethanol-Stimulated Locomotion in Drosophila
Dopamine is a mediator of the stimulant properties of drugs of abuse, including ethanol, in mammals and in the fruit fly Drosophila. The neural substrates for the stimulant actions of ethanol in flies are not known. We show that a subset of dopamine neurons and their targets, through the action of the D1-like dopamine receptor DopR, promote locomotor activation in response to acute ethanol exposure. A bilateral pair of dopaminergic neurons in the fly brain mediates the enhanced locomotor activity induced by ethanol exposure, and promotes locomotion when directly activated. These neurons project to the central complex ellipsoid body, a structure implicated in regulating motor behaviors. Ellipsoid body neurons are required for ethanol-induced locomotor activity and they express DopR. Elimination of DopR blunts the locomotor activating effects of ethanol, and this behavior can be restored by selective expression of DopR in the ellipsoid body. These data tie the activity of defined dopamine neurons to D1-like DopR-expressing neurons to form a neural circuit that governs acute responding to ethanol
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