569 research outputs found
dRail: a novel physical layout methodology for power gated circuits
In this paper we present a physical layout methodology, called dRail, to allow power gated and non-power gated cells to be placed next to each other. This is unlike traditional voltage area layout which separates cells to prevent shorting of power supplies leading to impact on area, routing and power. To implement dRail, a modified standard cell architecture and physical layout is proposed. The methodology is validated by implementing power gating on the data engine in an ARM Cortex-A5 processor using a 65nm library, and shows up to 38% reduction in area cost when compared to traditional voltage area layou
Point defect dynamics in bcc metals
We present an analysis of the time evolution of self-interstitial atom and
vacancy (point defect) populations in pure bcc metals under constant
irradiation flux conditions. Mean-field rate equations are developed in
parallel to a kinetic Monte Carlo (kMC) model. When only considering the
elementary processes of defect production, defect migration, recombination and
absorption at sinks, the kMC model and rate equations are shown to be
equivalent and the time evolution of the point defect populations is analyzed
using simple scaling arguments. We show that the typically large mismatch of
the rates of interstitial and vacancy migration in bcc metals can lead to a
vacancy population that grows as the square root of time. The vacancy cluster
size distribution under both irreversible and reversible attachment can be
described by a simple exponential function. We also consider the effect of
highly mobile interstitial clusters and apply the model with parameters
appropriate for vanadium and iron.Comment: to appear in Phys. Rev.
The Adaptive Potential of the Middle Domain of Yeast Hsp90
The distribution of fitness effects (DFEs) of new mutations across different environments quantifies the potential for adaptation in a given environment and its cost in others. So far, results regarding the cost of adaptation across environments have been mixed, and most studies have sampled random mutations across different genes. Here, we quantify systematically how costs of adaptation vary along a large stretch of protein sequence by studying the distribution of fitness effects of the same approximately 2,300 amino-acid changing mutations obtained from deep mutational scanning of 119 amino acids in the middle domain of the heat shock protein Hsp90 in five environments. This region is known to be important for client binding, stabilization of the Hsp90 dimer, stabilization of the N-terminal-Middle and Middle-C-terminal interdomains, and regulation of ATPase-chaperone activity. Interestingly, we find that fitness correlates well across diverse stressful environments, with the exception of one environment, diamide. Consistent with this result, we find little cost of adaptation; on average only one in seven beneficial mutations is deleterious in another environment. We identify a hotspot of beneficial mutations in a region of the protein that is located within an allosteric center. The identified protein regions that are enriched in beneficial, deleterious, and costly mutations coincide with residues that are involved in the stabilization of Hsp90 interdomains and stabilization of client-binding interfaces, or residues that are involved in ATPase-chaperone activity of Hsp90. Thus, our study yields information regarding the role and adaptive potential of a protein sequence that complements and extends known structural information
Investigating the influence of environment on the evolution of Hsp90 using comprehensive fitness maps [preprint]
Gene-environment interactions have long been theorized to influence molecular evolution. However, the environmental dependence of most mutations remains unknown. Using deep mutational scanning, we engineered budding yeast with all 44,604 single codon changes encoding 14,160 amino acid variants in Hsp90 and quantified growth effects under standard laboratory conditions and under five stress conditions (elevated temperature, nitrogen starvation, elevated salinity, high ethanol concentration, and oxidative stress caused by diamide). To our knowledge these are the largest comprehensive fitness maps of point mutant growth effects that have been determined. The growth effects of many variants differed between each of the conditions, indicating that environmental conditions can have a large impact on the evolution of Hsp90. Multiple variants provided growth advantages relative to wildtype Hsp90 under individual conditions, however these variants tended to exhibit growth defects in other environments. The diversity of Hsp90 sequences observed in extant eukaryotes preferentially contain amino acid variants that supported robust growth under all tested conditions. Thus, rather than favoring substitutions in individual conditions, the long-term selective pressure on Hsp90 may have been that of fluctuating environments, leading to robustness under a variety of conditions
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A combinatorial extracellular matrix platform identifies cell-extracellular matrix interactions that correlate with metastasis
Extracellular matrix interactions play essential roles in normal physiology and many pathological processes. While the importance of ECM interactions in metastasis is well documented, systematic approaches to identify their roles in distinct stages of tumorigenesis have not been described. Here we report a novel screening platform capable of measuring phenotypic responses to combinations of ECM molecules. Using a genetic mouse model of lung adenocarcinoma, we measure the ECM-dependent adhesion of tumor-derived cells. Hierarchical clustering of the adhesion profiles differentiates metastatic cell lines from primary tumor lines. Furthermore, we uncovered that metastatic cells selectively associate with fibronectin when in combination with galectin-3, galectin-8, or laminin. We show that these molecules correlate with human disease and that their interactions are mediated in part by Ī±3Ī²1 integrin. Thus, our platform allowed us to interrogate interactions between metastatic cells and their microenvironments, and identified ECM and integrin interactions that could serve as therapeutic targets
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Fully Differentiated HIV-1 Specific CD8+ T Effector Cells are More Frequently Detectable in Controlled than in Progressive HIV-1 Infection
Background: CD8+ T cells impact control of viral infections by direct elimination of infected cells and secretion of a number of soluble factors. In HIV-1 infection, persistent HIV-1 specific IFN-Ī³+ CD8+ T cell responses are detected in the setting of disease progression, consistent with functional impairment in vivo. Recent data suggest that impaired maturation, as defined by the lineage markers CD45RA and CCR7, may contribute to a lack of immune control by these responses. Methodology/Principal Findings: We investigated the maturation phenotype of epitope-specific CD8+ T cell responses directed against HIV-1 in 42 chronically infected, untreated individuals, 22 of whom were āControllersā (median 1140 RNA copies/ml plasma, range less than 50 to 2520), and 20 āprogressorsā of whom had advanced disease and high viral loads (median 135,500 RNA copies/ml plasma, range 12100 to greater than 750000). Evaluation of a mean of 5 epitopes per person revealed that terminally differentiated CD8+ T cells directed against HIV-1 are more often seen in HIV-1 Controllers (16/22; 73%) compared to HIV-1 progressors (7/20; 35%)(pā=ā0.015), but the maturation state of epitope-specific responses within a given individual was quite variable. Maturation phenotype was independent of the HLA restriction or the specificity of a given CD8+ T cell response and individual epitopes associated with slow disease progression were not more likely to be terminally differentiated. Conclusions/Significance: These data indicate that although full maturation of epitope-specific CD8+ T cell responses is associated with viral control, the maturation status of HIV-1 specific CD8+ T cell responses within a given individual are quite heterogeneous, suggesting epitope-specific influences on CD8+ T cell function
Accommodating 'others'?: housing dispersed, forced migrants in the UK
Utilising insights from a qualitative study in the city of Leeds (UK), this paper considers issues related to the housing of dispersed forced migrants. The term 'dispersed forced migrants' is used here as a general label to include four groups of international migrants (i.e. refugees, asylum seekers, those with humanitarian protection status and failed asylum seekers) who have previously been dispersed, on a no choice basis, to a variety of locations across the UK under the requirements of the Immigration and Asylum Act (1999). The tiering of housing entitlement that exists within the generic population of dispersed forced migrants (a consequence of the particular socio-legal status assigned to individuals), and its role in rendering migrants susceptible to homelessness is outlined. The adequacy/standard of accommodation made available to forced migrants is also discussed. It is concluded that current arrangements fail to meet the basic housing needs of many forced migrants. Any future improvement in this situation will require a significant shift in government policy
Variants in linkage disequilibrium with the late cornified envelope gene cluster deletion are associated with susceptibility to psoriatic arthritis
Confirmation of TNIP1 and IL23A as susceptibility loci for psoriatic arthritis
Objectives:
To investigate a shared genetic aetiology for
skin involvement in psoriasis and psoriatic arthritis (PsA)
by genotyping single-nucleotide polymorphisms (SNPs),
reported to be associated in genome-wide association
studies of psoriasis, in patients with PsA.
Methods:
SNPs with reported evidence for association
with psoriasis were genotyped in a PsA case and control
collection from the UK and Ireland. Genotype and allele
frequencies were compared between PsA cases and
controls using the Armitage test for trend.
Results:
Seven SNPs mapping to the
IL1RN, TNIP1,
TNFAIP3, TSC1, IL23A, SMARCA4
and
RNF114
genes
were successfully genotyped. The
IL23A
and
TNIP1
genes showed convincing evidence for association
(rs2066808, p = 9.1 x 10
?7
; rs17728338, p = 3.5 x
10
?5
, respectively) whilst SNPs mapping to the
TNFAIP3,
TSC1
and
RNF114
genes showed nominal evidence for
association (rs610604, p = 0.03; rs1076160, p = 0.03;
rs495337, p = 0.0025). No evidence for association
with
IL1RN
or
SMARCA4
was found but the power to
detect association was low.
Conclusions:
SNPs mapping to previously reported
psoriasis loci show evidence for association to PSA,
thus supporting the hypothesis that the genetic
aetiology of skin involvement is the same in both PsA
and psoriasi
Galois sections for abelianized fundamental groups
Given a smooth projective curve of genus at least 2 over a number field
, Grothendieck's Section Conjecture predicts that the canonical projection
from the \'etale fundamental group of onto the absolute Galois group of
has a section if and only if the curve has a rational point. We show that there
exist curves where the above map has a section over each completion of but
not over . In the appendix Victor Flynn gives explicit examples in genus 2.
Our result is a consequence of a more general investigation of the existence
of sections for the projection of the \'etale fundamental group `with
abelianized geometric part' onto the Galois group. We give a criterion for the
existence of sections in arbitrary dimension and over arbitrary perfect fields,
and then study the case of curves over local and global fields more closely. We
also point out the relation to the elementary obstruction of
Colliot-Th\'el\`ene and Sansuc.Comment: This is the published version, except for a characteristic 0
assumption added in Section 5 which was unfortunately omitted there. Thanks
to O. Wittenberg for noticing i
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