2,295 research outputs found
Fitting Parton Distribution Data with Multiplicative Normalization Uncertainties
We consider the generic problem of performing a global fit to many
independent data sets each with a different overall multiplicative
normalization uncertainty. We show that the methods in common use to treat
multiplicative uncertainties lead to systematic biases. We develop a method
which is unbiased, based on a self--consistent iterative procedure. We
demonstrate the use of this method by applying it to the determination of
parton distribution functions with the NNPDF methodology, which uses a Monte
Carlo method for uncertainty estimation.Comment: 33 pages, 5 figures: published versio
Deciphering interplay between Salmonella invasion effectors
Bacterial pathogens have evolved a specialized type III secretion system (T3SS) to translocate virulence effector proteins directly into eukaryotic target cells. Salmonellae deploy effectors that trigger localized actin reorganization to force their own entry into non-phagocytic host cells. Six effectors (SipC, SipA, SopE/2, SopB, SptP) can individually manipulate actin dynamics at the plasma membrane, which acts as a ‘signaling hub’ during Salmonella invasion. The extent of crosstalk between these spatially coincident effectors remains unknown. Here we describe trans and cis binary entry effector interplay (BENEFIT) screens that systematically examine functional associations between effectors following their delivery into the host cell. The results reveal extensive ordered synergistic and antagonistic relationships and their relative potency, and illuminate an unexpectedly sophisticated signaling network evolved through longstanding pathogen–host interaction
The inevitable QSAR renaissance
QSAR approaches, including recent advances in 3D-QSAR, are advantageous during the lead optimization phase of drug discovery and complementary with bioinformatics and growing data accessibility. Hints for future QSAR practitioners are also offered
Spatial Regulation of Membrane Fusion Controlled by Modification of Phosphoinositides
Membrane fusion plays a central role in many cell processes from vesicular
transport to nuclear envelope reconstitution at mitosis but the mechanisms that
underlie fusion of natural membranes are not well understood. Studies with
synthetic membranes and theoretical considerations indicate that accumulation of
lipids characterised by negative curvature such as diacylglycerol (DAG)
facilitate fusion. However, the specific role of lipids in membrane fusion of
natural membranes is not well established. Nuclear envelope (NE) assembly was
used as a model for membrane fusion. A natural membrane population highly
enriched in the enzyme and substrate needed to produce DAG has been isolated and
is required for fusions leading to nuclear envelope formation, although it
contributes only a small amount of the membrane eventually incorporated into the
NE. It was postulated to initiate and regulate membrane fusion. Here we use a
multidisciplinary approach including subcellular membrane purification,
fluorescence spectroscopy and Förster resonance energy transfer
(FRET)/two-photon fluorescence lifetime imaging microscopy (FLIM) to demonstrate
that initiation of vesicle fusion arises from two unique sites where these
vesicles bind to chromatin. Fusion is subsequently propagated to the endoplasmic
reticulum-derived membranes that make up the bulk of the NE to ultimately
enclose the chromatin. We show how initiation of multiple vesicle fusions can be
controlled by localised production of DAG and propagated bidirectionally.
Phospholipase C (PLCγ), GTP hydrolysis and
(phosphatidylinsositol-(4,5)-bisphosphate (PtdIns(4,5)P2) are
required for the latter process. We discuss the general implications of membrane
fusion regulation and spatial control utilising such a mechanism
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Stops making sense: translational trade-offs and stop codon reassignment
Background
Efficient gene expression involves a trade-off between (i) premature termination of protein synthesis; and (ii) readthrough, where the ribosome fails to dissociate at the terminal stop. Sense codons that are similar in sequence to stop codons are more susceptible to nonsense mutation, and are also likely to be more susceptible to transcriptional or translational errors causing premature termination. We therefore expect this trade-off to be influenced by the number of stop codons in the genetic code. Although genetic codes are highly constrained, stop codon number appears to be their most volatile feature.
Results
In the human genome, codons readily mutable to stops are underrepresented in coding sequences. We construct a simple mathematical model based on the relative likelihoods of premature termination and readthrough. When readthrough occurs, the resultant protein has a tail of amino acid residues incorrectly added to the C-terminus. Our results depend strongly on the number of stop codons in the genetic code. When the code has more stop codons, premature termination is relatively more likely, particularly for longer genes. When the code has fewer stop codons, the length of the tail added by readthrough will, on average, be longer, and thus more deleterious. Comparative analysis of taxa with a range of stop codon numbers suggests that genomes whose code includes more stop codons have shorter coding sequences.
Conclusions
We suggest that the differing trade-offs presented by alternative genetic codes may result in differences in genome structure. More speculatively, multiple stop codons may mitigate readthrough, counteracting the disadvantage of a higher rate of nonsense mutation. This could help explain the puzzling overrepresentation of stop codons in the canonical genetic code and most variants
The liver transplant waiting list—a single-center analysis
At this transplant center 1340 patients were entered on the liver transplant waiting list during the first 25 months (October 1987 to November 1989) after the initiation of the UNOS allocation system for liver grafts. Of these 972 (72.5%) of the patients received a graft, 120 (9.0%) died waiting for a graft, 109 (8.1%) remained on the active list as of the study endpoint of December 15, 1989, 123 (9.2%) were withdrawn from candidacy, and 16 (1.2%) received a transplant at another center. A total of 1201 patients were candidates for a first graft. Of the 812 primary candidates who received a graft, 64.8% received their graft within one month of entry on the waiting list. Of the 109 primary candidates who died before a graft could be found, 79.0% died within a month of entry onto the waiting list. At time of transplantation, 135 (16.6%) primary recipients of a graft were UNOS class 1, 326 (40.1%) were UNOS class 2, 190 (23.4%) were UNOS class 3, and 161 (19.8%) were UNOS class 4. Actuarial survival rates (percentage) at 6 months for recipients in UNOS class 1, class 2, class 3, and class 4 were 88.7±2.9, 82.6+2.1, 78.4±3.2, and 68.4±3.9, respectively (P<0.001). At the time of death of recipients who failed to get a graft, 6 (5.5%) were UNOS class 1, 14 (12.8%) were UNOS class 2, 23 (21.1%) were UNOS class 3, and 66 (60.6%) were UNOS class 4. These results indicate that a high proportion of liver transplant candidates are in urgent need of a graft and that the UNOS system succeeds in giving these patients high priority. However patient mortality on the waiting list and after transplantation would lessen significantly if more patients with end-stage liver disease were referred to the transplant center in a timely manner before their condition reaches the point where the probability of survival is diminished. © 1991 by Williams & Wilkins
Reasons for and consequences of missed appointments in general practice in the UK: questionnaire survey and prospective review of medical records
Background
Missed appointments are a common occurrence in primary care in the UK, yet little is known about the reasons for them, or the consequences of missing an appointment. This paper aims to determine the reasons for missed appointments and whether patients who miss an appointment subsequently consult their general practitioner (GP). Secondary aims are to compare psychological morbidity, and the previous appointments with GPs between subjects and a comparison group.
Methods
Postal questionnaire survey and prospective medical notes review of adult patients missing an appointment and the comparison group who attended appointments over a three week period in seven general practices in West Yorkshire.
Results
Of the 386 who missed appointments 122 (32%) responded. Of the 386 in the comparison group 223 (58%) responded, resulting in 23 case-control matched pairs with complete data collection. Over 40% of individuals who missed an appointment and participated said that they forgot the appointment and a quarter said that they tried very hard to cancel the appointment or that it was at an inconvenient time. A fifth reported family commitments or being too ill to attend. Over 90% of the patients who missed an appointment subsequently consulted within three months and of these nearly 60% consulted for the stated problem that was going to be presented in the missed consultation. The odds of missing an appointment decreased with increasing age and were greater among those who had missed at least one appointment in the previous 12 months. However, estimates for comparisons between those who missed appointments and the comparison group were imprecise due to the low response rate.
Conclusion
Patients who miss appointments tend to cite practice factors and their own forgetfulness as the main reasons for doing so, and most attend within three months of a missed appointment. This study highlights a number of implications for future research. More work needs to be done to engage people who miss appointments into research in a meaningful way
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