Oesophageal cancer: an overview of a deadly disease

Oesophageal cancer (OC) is one of the deadliest cancers in the world. Although it affects many people throughout East Africa, relatively little work has been done to fully understand this disease. This review addresses recent changes in the understanding of OC from a global perspective, with special attention given to OC in Kenya

Higher levels of B-cell mutation in the early germinal centres of an inefficient secondary antibody response to a variant Influenza Haemagglutinin

This is the final version. Available from the publisher via the DOI in this record.Designing improved vaccines against mutable viruses such as Dengue and Influenza would be helped by a better understanding of how the B-cell memory compartment responds to variant antigens. Towards this we have recently shown after secondary immunization of mice with a widely variant Dengue envelope protein, with only 63% amino-acid identity, that IgM+ memory B-cells with few mutations supported an efficient secondary germinal centre (GC) and serum response, superior to a primary response to the same protein. Here, further investigation of memory responses to variant proteins, using more closely related Influenza haemagglutinins (HA), that were 82% identical, produced a variant-induced boost response in the GC dominated by highly mutated B-cells that failed, not efficiently improving serum avidity even in the presence of extra adjuvant, and that was worse than a primary response. This supports a hypothesis that over certain antigenic differences, cross-reactive memory B-cell populations have reduced competency for affinity maturation. Combined with our previous observations these findings also provide new parameters of success and failure in antibody memory responses. This article is protected by copyright. All rights reserved.Wellcome TrustBiotechnology and Biological Sciences Research Council (BBSRC

The 'Goldilocks Zone': getting the measure of manual asymmetries

Some studies have shown that manual asymmetries decrease in older age. These results have often been explained with reference to models of reduced hemispheric specialisation. An alternative explanation, however, is that hand differences are subtle, and capturing them requires tasks that yield optimal performance with both hands. Whereas the hemispheric specialisation account implies that reduced manual asymmetries should be reliably observed in older adults, the ‘measurement difficulty’ account suggests that manual asymmetries will be hard to detect unless a task has just the right level of difficulty – i.e. within the ‘Goldilocks Zone’, where it is not too easy or too hard, but just right. Experiment One tested this hypothesis and found that manual asymmetries were only detected when participants performed in this zone; specifically, performance on a tracing task was only superior in the preferred hand when task constraints were high (i.e. fast speed tracing). Experiment Two used three different tasks to examine age differences in manual asymmetries; one task produced no asymmetries, whilst two tasks revealed asymmetries in both younger and older groups (with poorer overall performance in the old group across all tasks). Experiment Three revealed task-dependent asymmetries in both age groups, but highlighted further detection difficulties linked with the metric of performance and compensatory strategies used by participants. Results are discussed with reference to structural learning theory, whereby we suggest that the processes of inter-manual transfer lead to relatively small performance differences between the hands (despite a strong phenomenological sense of performance disparities)

Variant proteins stimulate more IgM+ GC B-cells revealing a mechanism of cross-reactive recognition by antibody memory

This is the final version. Available from eLife Sciences Publications via the DOI in this recordVaccines induce memory B-cells that provide high affinity secondary antibody responses to identical antigens. Memory B-cells can also re-instigate affinity maturation, but how this happens against antigenic variants is poorly understood despite its potential impact on driving broadly protective immunity against pathogens such as Influenza and Dengue. We immunised mice sequentially with identical or variant Dengue-virus envelope proteins and analysed antibody and germinal-centre (GC) responses. Variant protein boosts induced GCs with a higher proportion of IgM+ B cells. The most variant protein re-stimulated GCs with the highest proportion of IgM+ cells with the most diverse, least mutated V-genes and with a slower but efficient serum antibody response. Recombinant antibodies from GC B-cells showed a higher affinity for the variant antigen than antibodies from a primary response, confirming a memory origin. This reveals a new process of antibody memory, that IgM memory cells with fewer mutations participate in secondary responses to variant antigens, demonstrating how the hierarchical structure of B-cell memory is used and indicating the potential and limits of cross-reactive antibody based immunity.Funder: Wellcome Trust; Grant reference number 100115/Z/12/

A simple scheme for allocating capital in a foreign exchange proprietary trading firm

We present a model of capital allocation in a foreign exchange proprietary trading firm. The owner allocates capital to individual traders, who operate within strict risk limits. Traders specialize in individual currencies, but are given discretion over their choice of trading rule. The owner provides the simple formula that determines position sizes – a formula that does not require estimation of the firm-level covariance matrix. We provide supporting empirical evidence of excess risk-adjusted returns to the firm-level portfolio, and we discuss a modification of the model in which the owner dictates the choice of trading rule

Does monitor position influence visual-motor performance during minimally invasive surgery?

Background: In minimally invasive surgery (MIS), the natural relationship between hand and eye is disrupted, i.e. surgeons typically control tools inserted through the patient’s abdomen while viewing the workspace on a remote monitor, which can be located in a variety of positions. This separates the location of visual feedback from the area in which a motor action is executed. Previous studies suggest that the visual display should be placed directly ahead of the surgeon (i.e. to preserve visual-motor mapping). However, the extent of the impact of this rotation on surgical performance is unknown. Methods: Eighteen participants completed an aiming task on a tablet PC within a surgical box trainer using a laparoscopic tool in a controlled simulated environment. Visual feedback was presented on a remote monitor located at 0°, ±45° and ±90°, with order randomised using the Latin Square method. Results: Movements were significantly slower when the monitor was 90° relative to midline, but spatial accuracy was unaffected by monitor position. Interestingly, the effect of reduced speed in the 90° condition was transient, decreasing over time, suggesting rapid adaptation to the rotation. Conclusions: We conclude that the angle of the visual display in the context of MIS may require a surgeon to adapt to a changed mapping between visual inputs and motor outputs. While this adaptation occurs relatively quickly, it may interfere with skilled actions (e.g. intracorporeal suturing) in complex surgical procedures

Speech rhythm: a metaphor?

Is speech rhythmic? In the absence of evidence for a traditional view that languages strive to coordinate either syllables or stress-feet with regular time intervals, we consider the alternative that languages exhibit contrastive rhythm subsisting merely in the alternation of stronger and weaker elements. This is initially plausible, particularly for languages with a steep ‘prominence gradient’, i.e. a large disparity between stronger and weaker elements; but we point out that alternation is poorly achieved even by a ‘stress-timed’ language such as English, and, historically, languages have conspicuously failed to adopt simple phonological remedies that would ensure alternation. Languages seem more concerned to allow ‘syntagmatic contrast’ between successive units and to use durational effects to support linguistic functions than to facilitate rhythm. Furthermore, some languages (e.g. Tamil, Korean) lack the lexical prominence which would most straightforwardly underpin prominence alternation. We conclude that speech is not incontestibly rhythmic, and may even be antirhythmic. However, its linguistic structure and patterning allow the metaphorical extension of rhythm in varying degrees and in different ways depending on the language, and that it is this analogical process which allows speech to be matched to external rhythms

Nutritional supplements and infection in the elderly: why do the findings conflict?

BACKGROUND: Most of the randomized placebo-controlled trials that have examined the clinical effects of multivitamin-mineral supplements on infection in the elderly have shown no significant effect. The exceptions are three such trials, all using a supplement with the same composition, and all claiming dramatic benefits: a frequently cited study published in 1992, which reported a 50% reduction in the number of days of infection (NDI), and two 2002 replication studies. Questions have been raised about the 1992 report; a second report in 2001 based on the same trial, but describing effects of the supplement on cognitive functions, has been retracted by Nutrition. The primary purpose of the present paper is to evaluate the claims about the effects of supplements on NDI in the two replication reports. METHODS: Examination of internal consistency (outcomes of statistical tests versus reported data); comparison of variability of NDI across individuals in these two reports with variability in other trials; estimation of the probability of achieving the reported close agreement with the original finding. RESULTS: The standard deviations of NDI and levels of statistical significance reported are profoundly inconsistent. The reported standard deviations of NDI are consistently below what other studies have found. The reported percent reductions in NDI agree too closely with the original study. CONCLUSION: The claims of reduced NDI in the two replication reports should be questioned, which also adds to concerns about the 1992 study. It follows that there is currently no trustworthy evidence from randomized placebo-controlled clinical trials that favors the use of vitamin-mineral supplements to reduce infection in the elderly

Dwarf Galaxy Formation Was Suppressed By Cosmic Reionization

A large number of faint galaxies, born less than a billion years after the big bang, have recently been discovered. The fluctuations in the distribution of these galaxies contributed to a scatter in the ionization fraction of cosmic hydrogen on scales of tens of Mpc, as observed along the lines of sight to the earliest known quasars. Theoretical simulations predict that the formation of dwarf galaxies should have been suppressed after cosmic hydrogen was reionized, leading to a drop in the cosmic star formation rate. Here we present evidence for this suppression. We show that the post-reionization galaxies which produced most of the ionizing radiation at a redshift z~5.5, must have had a mass in excess of ~10^{10.6+/-0.4} solar masses or else the aforementioned scatter would have been smaller than observed. This limiting mass is two orders of magnitude larger than the galaxy mass that is thought to have dominated the reionization of cosmic hydrogen (~10^8 solar masses). We predict that future surveys with space-based infrared telescopes will detect a population of smaller galaxies that reionized the Universe at an earlier time, prior to the epoch of dwarf galaxy suppression.Comment: 19 pages, 3 figures. Accepted for publication in Nature; press embargo until publishe