Presentation of an Immunodominant Immediate-Early CD8+ T Cell Epitope Resists Human Cytomegalovirus Immunoevasion.

Control of human cytomegalovirus (HCMV) depends on CD8+ T cell responses that are shaped by an individual's repertoire of MHC molecules. MHC class I presentation is modulated by a set of HCMV-encoded proteins. Here we show that HCMV immunoevasins differentially impair T cell recognition of epitopes from the same viral antigen, immediate-early 1 (IE-1), that are presented by different MHC class I allotypes. In the presence of immunoevasins, HLA-A- and HLA-B-restricted T cell clones were ineffective, but HLA-C*0702-restricted T cell clones recognized and killed infected cells. Resistance of HLA-C*0702 to viral immunoevasins US2 and US11 was mediated by the alpha3 domain and C-terminal region of the HLA heavy chain. In healthy donors, HLA-C*0702-restricted T cells dominated the T cell response to IE-1. The same HLA-C allotype specifically protected infected cells from attack by NK cells that expressed a corresponding HLA-C-specific KIR. Thus, allotype-specific viral immunoevasion allows HCMV to escape control by NK cells and HLA-A- and HLA-B-restricted T cells, while the virus becomes selectively vulnerable to an immunodominant population of HLA-C-restricted T cells. Our work identifies a T cell population that may be of particular efficiency in HCMV-specific immunotherapy

Space-based geoengineering: challenges and requirements

The prospect of engineering the Earth's climate (geoengineering) raises a multitude of issues associated with climatology, engineering on macroscopic scales, and indeed the ethics of such ventures. Depending on personal views, such large-scale engineering is either an obvious necessity for the deep future, or yet another example of human conceit. In this article a simple climate model will be used to estimate requirements for engineering the Earth's climate, principally using space-based geoengineering. Active cooling of the climate to mitigate anthropogenic climate change due to a doubling of the carbon dioxide concentration in the Earth's atmosphere is considered. This representative scenario will allow the scale of the engineering challenge to be determined. It will be argued that simple occulting discs at the interior Lagrange point may represent a less complex solution than concepts for highly engineered refracting discs proposed recently. While engineering on macroscopic scales can appear formidable, emerging capabilities may allow such ventures to be seriously considered in the long term. This article is not an exhaustive review of geoengineering, but aims to provide a foretaste of the future opportunities, challenges, and requirements for space-based geoengineering ventures

Muscle action potential scans and ultrasound imaging in neurofibromatosis type 2

INTRODUCTION: The neuropathy in patients with neurofibromatosis type 2 (NF2) is difficult to quantify and follow up. In this study we compared 3 methods that may help assess motor axon pathology in NF2 patients. METHODS: Nerve conduction studies in median nerves were supplemented by deriving motor unit number estimates (MUNEs) from compound muscle action potential (CMAP) scans and by high-resolution ultrasound (US) peripheral nerve imaging. RESULTS: CMAP amplitudes and nerve conduction velocity were normal in the vast majority of affected individuals, but CMAP scan MUNE revealed denervation and reinnervation in many peripheral nerves. In addition, nerve US imaging enabled monitoring of the size and number of schwannoma-like fascicular enlargements in median nerve trunks. CONCLUSION: In contrast to conventional nerve conduction studies, CMAP scan MUNE in combination with US nerve imaging can quantify the NF2-associated neuropathy and may help to monitor disease progression and drug treatments

Trajectories and predictors of women's health-related quality of life during pregnancy

The objective of this study was to identify distinct trajectories and their predictors of healthrelated quali

Socio economic crisis and mortality. Epidemiological testimony of the financial collapse of Argentina

BACKGROUND: Natural disasters, war, and terrorist attacks, have been linked to cardiac mortality. We sought to investigate whether a major financial crisis may impact on the medical management and outcomes of acute coronary syndromes. METHODS: We analyzed the Argentine cohort of the international multicenter Global Registry of Acute Coronary Events (GRACE). The primary objective was to estimate if there was an association between the financial crisis period (April 1999 to December 2002) and in- hospital cardiovascular mortality, with the post-crisis period (January 2003 to September 2004) as the referent. Each period was defined according to the evolution of the Gross Domestic Product. We investigated the demographic characteristics, diagnostic and therapeutic procedures, morbidity and mortality. RESULTS: We analyzed data from 3220 patients, 2246 (69.8%) patients in the crisis period and 974 (30.2%) in the post-crisis frame. The distribution of demographic and clinical baseline characteristics were not significantly different between both periods. During the crisis period the incidence of in-hospital myocardial infarction was higher (6.9% Vs 2.9%; p value \u3c 0.0001), as well as congestive heart failure (16% Vs 11%; p value \u3c 0.0001). Time to intervention with angioplasty was longer during the crisis, especially among public sites (median 190 min Vs 27 min). The incidence proportion of mortality during hospitalization was 6.2% Vs 5.1% after crisis. The crude OR for mortality was 1.2 (95% C.I. 0.87, 1.7). The odds for mortality were higher among private institutions {1.9 (95% C.I. 0.9, 3.8)} than for public centers {1.2 (95% C.I. 0.83, 1.79)}. We did not observe a significant interaction between type of hospital and crisis. CONCLUSION: Our findings suggest that the financial crisis may have had a negative impact on cardiovascular mortality during hospitalization, and higher incidence of medical complications

Chaotic Coupling Constants

We examine some novel physical consequences of the general structure of moduli spaces of string vacua. These include (1) finiteness of the volume of the moduli space and (2) chaotic motion of the moduli in the early universe. To fix ideas we examine in detail the example of the (conjectural) dilaton-axion ``$S$-duality'' of four-dimensional string compactifications. The facts (1) and (2) together might help to solve some problems with the standard scenarios for supersymmetry breaking and vacuum selection in string theory.Comment: 18 pages (4 figs), YCTP-P2-94, RU-94-2

Associations between Maternal Health-Related Quality of Life during Pregnancy and Birth Outcomes: The Generation R Study

The objective of this study was to assess associations between maternal health-related quality of life (HRQoL) in early, mid-, and late pregnancy and birth outcomes and to assess the differences in birth outcomes between subgroups of mothers reporting relatively "low" and relatively "high" HRQoL. HRQoL was measured by the 12-item Short Form Health Survey in early (n = 6334), mid- (n = 6204), and late pregnancy (n = 6048) in a population-based mother and child cohort; Physical and Mental Component Summary (PCS/MCS) scores were calculated. Birth outcomes included pregnancy duration, preterm birth, birth weight, low birth weight, and small for gestational age. We defined very high PCS/MCS scores as the >90th percentile and very low score as the <10th percentile. The lower PCS score in late pregnancy was significantly associated with a higher chance of having small-for-gestational-age birth (per 10 points: OR = 1.20, 95% CI: 1.08, 1.33, p value = 0.0006). In early, mid-, and late pregnancy, the subgroup mothers with a low MCS score had infants with a lower average birth weight than those with very high scores (p < 0.05). The association between higher physical HRQoL in late pregnancy and a higher chance of having small-for-gestational-age birth needs further research. The role of mother's mental HRQoL during pregnancy and the potential consequences for the child require further study

Representing the Windrush generation: metaphor in discourses then and now

This paper examines the ways in which the group of people now known as the Windrush generation, who moved to the UK in the period 1948–1971, have been represented in public discourse. This group has been adversely affected by the current ‘hostile environment’ policy in the UK regarding immigration. As I show, in the ensuing and highly critical debate, the government repeatedly positioned them as ‘good’ migrants and placed them in a binary opposition with ‘undesirable’ migrants, who they cite as the intended target of their policy. Using diachronic corpora of parliamentary debates and national media, I compare this contemporary rhetoric with (a) Windrush representations in the 1940s and 1950s, and (b) contemporary representation of those the government constructs as unwanted migrants. Taking metaphor as a key for the comparison I show that there is very little continuity or overlap in how the Windrush migrants were discussed at the time of their arrival and in the current period. Instead, there is a much greater proximity in the past representations of the Windrush migrants and the current representations of ‘undesirable’ migrants. This mismatch in actual and perceived representation at the time of arrival indicates how nostalgia functions in migration discourses, even facilitating anti-immigration arguments

Macdonald Polynomials from Sklyanin Algebras: A Conceptual Basis for the pp-Adics-Quantum Group Connection

We establish a previously conjectured connection between $p$-adics and quantum groups. We find in Sklyanin's two parameter elliptic quantum algebra and its generalizations, the conceptual basis for the Macdonald polynomials, which ``interpolate'' between the zonal spherical functions of related real and $p$\--adic symmetric spaces. The elliptic quantum algebras underlie the $Z_n$\--Baxter models. We show that in the n \air \infty limit, the Jost function for the scattering of {\em first} level excitations in the $Z_n$\--Baxter model coincides with the Harish\--Chandra\--like $c$\--function constructed from the Macdonald polynomials associated to the root system $A_1$. The partition function of the $Z_2$\--Baxter model itself is also expressed in terms of this Macdonald\--Harish\--Chandra\ $c$\--function, albeit in a less simple way. We relate the two parameters $q$ and $t$ of the Macdonald polynomials to the anisotropy and modular parameters of the Baxter model. In particular the $p$\--adic ``regimes'' in the Macdonald polynomials correspond to a discrete sequence of XXZ models. We also discuss the possibility of ``$q$\--deforming'' Euler products.Comment: 25 page

Lovastatin improves impaired synaptic plasticity and phasic alertness in patients with neurofibromatosis type 1

Background: Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders causing learning disabilities by mutations in the neurofibromin gene, an important inhibitor of the RAS pathway. In a mouse model of NF1, a loss of function mutation of the neurofibromin gene resulted in increased gamma aminobutyric acid (GABA)-mediated inhibition which led to decreased synaptic plasticity and deficits in attentional performance. Most importantly, these defictis were normalized by lovastatin. This placebo-controlled, double blind, randomized study aimed to investigate synaptic plasticity and cognition in humans with NF1 and tried to answer the question whether potential deficits may be rescued by lovastatin. Methods: In NF1 patients (n = 11; 19-44 years) and healthy controls (HC; n = 11; 19-31 years) paired pulse transcranial magnetic stimulation (TMS) was used to study intracortical inhibition (paired pulse) and synaptic plasticity (paired associative stimulation). On behavioural level the Test of Attentional Performance (TAP) was used. To study the effect of 200 mg lovastatin for 4 days on all these parameters, a placebo-controlled, double blind, randomized trial was performed. Results: In patients with NF1, lovastatin revealed significant decrease of intracortical inhibition, significant increase of synaptic plasticity as well as significant increase of phasic alertness. Compared to HC, patients with NF1 exposed increased intracortical inhibition, impaired synaptic plasticity and deficits in phasic alertness. Conclusions: This study demonstrates, for the first time, a link between a pathological RAS pathway activity, intracortical inhibition and impaired synaptic plasticity and its rescue by lovastatin in humans. Our findings revealed mechanisms of attention disorders in humans with NF1 and support the idea of a potential clinical benefit of lovastatin as a therapeutic option