It has been proposed that the local segregation of kinases and the tyrosine phosphatase CD45 underpins T cell antigen receptor (TCR) triggering, but how such segregation occurs and whether it can ...initiate signaling is unclear. Using structural and biophysical analysis, we show that the extracellular region of CD45 is rigid and extends beyond the distance spanned by TCR-ligand complexes, implying that sites of TCR-ligand engagement would sterically exclude CD45. We also show that the formation of 'close contacts', new structures characterized by spontaneous CD45 and kinase segregation at the submicron-scale, initiates signaling even when TCR ligands are absent. Our work reveals the structural basis for, and the potent signaling effects of, local CD45 and kinase segregation. TCR ligands have the potential to heighten signaling simply by holding receptors in close contacts.
In sheep, administration of a combination of zolazepam and tiletamine hydrochloride resulted in a dose dependent reduction in the duration of epileptic activity induced by an electric stun applied to ...the head. The compound also lengthened the normal period of reflex suppression that occurs after a stun. Excitatory amino acid receptor antagonists (2-amino-7-phosphonoheptanoic and 2-amino-5-phosphonovaleric acids) also reduced the duration of epileptic activity following an electric stun. These drugs did not alter the time of pedal and ear pinch reflex suppression. Administration of bicuculline (a gamma amino-4-butyric acid GABA receptor antagonist) reduced the period of stun induced reflex suppression and increased seizure duration. Administration of a GABA receptor agonist, baclofen, increased the duration of reflex suppression. The results suggest that the development of epileptiform-like activity following application of an electric current to the head is dependent upon excitatory amino acid receptors. The reflex suppression that also arises following an electric stun is contributed to by the activation of GABA receptor mechanisms.
Interest in targeting drugs into the peritoneal cavity for intra-abdominal cancers or infections is undergoing a revival as recent clinical trials have demonstrated, not only a regional advantage in ...concentration of the active agent, but also improved long-term outcomes. Solutions currently used for intraperitoneal (IP) drug delivery have short residence times, however, which can limit the exposure of all areas of the peritoneum to the active agent. Icodextrin 4% solution was compared with saline and a glucose-based peritoneal dialysis solution in a clinical study of IP residence time. The study was carried out during the fortnightly rest phase in 9 patients undergoing 5-fluorouracil (5-Fu) IP treatment for colorectal cancer. The volume remaining in the peritoneal cavity was measured at 0, 12, 24, 48, 72, and 96 hr after an instillation of 2 liters of each fluid. Saline (n = 3 dwells) and glucose (n = 3 dwells) peritoneal dialysis solutions were almost fully absorbed by 24 hr, and the patients experienced discomfort when using these solutions. In contrast, icodextrin 4% solution (n = 188 dwells) maintained its instilled volume for up to 48 hr, and half the instilled volume remained after 72 and 96 hr. This result would allow extensive and prolonged coverage of the peritoneal surface. Icodextrin 4% solution may be an effective vehicle to deliver therapeutic agents into the peritoneal cavity.
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Defining functional DNA elements in the human genome Kellis, Manolis; Wold, Barbara; Snyderd, Michael P. ...
Proceedings of the National Academy of Sciences - PNAS,
04/2014, Volume:
111, Issue:
17
Journal Article
Peer reviewed
Open access
With the completion of the human genome sequence, attention turned to identifying and annotating its functional DNA elements. As a complement to genetic and comparative genomics approaches, the ...Encyclopedia of DNA Elements Project was launched to contribute maps of RNA transcripts, transcriptional regulator binding sites, and chromatin states in many cell types. The resulting genome-wide data reveal sites of biochemical activity with high positional resolution and cell type specificity that facilitate studies of gene regulation and interpretation of noncoding variants associated with human disease. However, the biochemically active regions cover a much larger fraction of the genome than do evolutionarily conserved regions, raising the question of whether nonconserved but biochemically active regions are truly functional. Here, we review the strengths and limitations of biochemical, evolutionary, and genetic approaches for defining functional DNA segments, potential sources for the observed differences in estimated genomic coverage, and the biological implications of these discrepancies. We also analyze the relationship between signal intensity, genomic coverage, and evolutionary conservation. Our results reinforce the principle that each approach provides complementary information and that we need to use combinations of all three to elucidate genome function in human biology and disease.
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Blends of the normal alkane C
28
H
58
with either protonated or deuterated C
36
alkane,
x
C
28
H
58
.(1 −
x
)C
36
H/D
74
, have been rapidly cooled from the melt and aged under ambient conditions for ...at least seven months. For compositions 0.94 ≥
x
≥ 0.65, both Bragg peaks and associated satellite peaks appear in the small-angle X-ray scattering. The Bragg peaks may be indexed to multiple order reflections from the average spacing of the chain lengths of the two components. The offset in
q
between these peaks is constant for each composition, but dependent on molar composition, and indicates that a superstructure phase forms on prolonged annealing. This new phase appears to be a solid solution and is found for both the protonated and deuterated samples, with a larger cell in the former system. For the remaining compositions, additional peaks indicate formation of a C
36
-rich phase.
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The mRNA-1273 vaccine was approved for emergency use in December 2020; trial participants who received placebo were informed of the results and offered vaccination. At the close of the blinded phase ...of the trial, the vaccine efficacy in preventing Covid-19 illness was 93.2%, and the efficacy against severe disease was 98.2%. No new safety issues were identified.
As part of a study of men's responses to a videotape decision aid Rovner DR, Wills CE, Bonham V, Williams G, Lillie J, Kelly-Blake K, Williams MV, Holmes-Rovner M. Decision aids for benign prostatic ...hyperplasia: applicability across race and education. Med Decis Making 2004;24:359–66, preferences for BPH treatment options were assessed.
One hundred and sixty men stratified by race and education completed a semi-structured interview that included assessments of treatment preferences.
Most men initially and ultimately favored watchful waiting over other options, and 56.6% never changed their preference rank orders while viewing the videotape. BPH severity in context of treatment risk avoidance, efficacy, and expert opinion factors were frequently cited reasons for preference orders. Lesser education was associated with higher likelihood of changing preferences (
r
=
−.30,
p
<
.001), and percent increase in BPH knowledge pre- to post-videotape was weakly associated with fewer non-dominant preference shifts (
r
=
−.19,
p
<
.05).
Conservatism regarding BPH treatment is moderated by context-specific factors, including new information.
Counseling in a provider–patient partnership model should address both sources of variance in men's treatment preferences.
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500.
The Structure of Human 5-Lipoxygenase Gilbert, Nathaniel C.; Bartlett, Sue G.; Waight, Maria T. ...
Science (American Association for the Advancement of Science),
01/2011, Volume:
331, Issue:
6014
Journal Article
Peer reviewed
Open access
The synthesis of both proinflammatory leukotrienes and anti-inflammatory lipoxins requires the enzyme 5-lipoxygenase (5-LOX). 5-LOX activity is short-lived, apparently in part because of an intrinsic ...instability of the enzyme. We identified a 5-LOX-specific destabilizing sequence that is involved in orienting the carboxyl terminus, which binds the catalytic iron. Here, we report the crystal structure at 2.4 angstrom resolution of human 5-LOX stabilized by replacement of this sequence.
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