Flexible, actin-based ridges colocalise with the β1 integrin on the surface of melanoma cells

Using a combination of laser-scanning confocal microscopy and atomic force microscopy, we have identified flexible, actin-based structures on the surface of cells derived from the vertical growth phase of melanoma progression. These flexible structures, lacking on the surface of mature melanocytes, were observed on the surface of all four melanoma cell lines tested. Further investigation revealed that the β1 integrin colocalises with these actin-based ridges on the cell surface, whereas β1 integrin distribution in melanocytes did not correlate with actin-based structures. Fibronectin staining on the surface of melanoma cells was partially codistributed with the ridges. The combination of structural information derived from atomic force microscopy images and fluorescent imaging of the distribution of labelled proteins involved in invasion and metastasis has allowed us to identify a common feature that may be involved in disease progression, at the surface of vertical growth phase melanoma cells, despite the known variation in genetic composition of melanoma

Mapping the genetic architecture of gene expression in human liver

Genetic variants that are associated with common human diseases do not lead directly to disease, but instead act on intermediate, molecular phenotypes that in turn induce changes in higher-order disease traits. Therefore, identifying the molecular phenotypes that vary in response to changes in DNA and that also associate with changes in disease traits has the potential to provide the functional information required to not only identify and validate the susceptibility genes that are directly affected by changes in DNA, but also to understand the molecular networks in which such genes operate and how changes in these networks lead to changes in disease traits. Toward that end, we profiled more than 39,000 transcripts and we genotyped 782,476 unique single nucleotide polymorphisms (SNPs) in more than 400 human liver samples to characterize the genetic architecture of gene expression in the human liver, a metabolically active tissue that is important in a number of common human diseases, including obesity, diabetes, and atherosclerosis. This genome-wide association study of gene expression resulted in the detection of more than 6,000 associations between SNP genotypes and liver gene expression traits, where many of the corresponding genes identified have already been implicated in a number of human diseases. The utility of these data for elucidating the causes of common human diseases is demonstrated by integrating them with genotypic and expression data from other human and mouse populations. This provides much-needed functional support for the candidate susceptibility genes being identified at a growing number of genetic loci that have been identified as key drivers of disease from genome-wide association studies of disease. By using an integrative genomics approach, we highlight how the gene RPS26 and not ERBB3 is supported by our data as the most likely susceptibility gene for a novel type 1 diabetes locus recently identified in a large-scale, genome-wide association study. We also identify SORT1 and CELSR2 as candidate susceptibility genes for a locus recently associated with coronary artery disease and plasma low-density lipoprotein cholesterol levels in the process. © 2008 Schadt et al

Elevated CO₂ does not increase eucalypt forest productivity on a low-phosphorus soil

Rising atmospheric CO2 stimulates photosynthesis and productivity of forests, offsetting CO2 emissions. Elevated CO2 experiments in temperate planted forests yielded ~23% increases in productivity over the initial years. Whether similar CO2 stimulation occurs in mature evergreen broadleaved forests on low-phosphorus (P) soils is unknown, largely due to lack of experimental evidence. This knowledge gap creates major uncertainties in future climate projections as a large part of the tropics is P-limited. Here,we increased atmospheric CO2 concentration in a mature broadleaved evergreen eucalypt forest for three years, in the first large-scale experiment on a P-limited site. We show that tree growth and other aboveground productivity components did not significantly increase in response to elevated CO2 in three years, despite a sustained 19% increase in leaf photosynthesis. Moreover, tree growth in ambient CO2 was strongly P-limited and increased by ~35% with added phosphorus. The findings suggest that P availability may potentially constrain CO2-enhanced productivity in P-limited forests; hence, future atmospheric CO2 trajectories may be higher than predicted by some models. As a result, coupled climate-carbon models should incorporate both nitrogen and phosphorus limitations to vegetation productivity in estimating future carbon sinks

Societal Learning in Epidemics: Intervention Effectiveness during the 2003 SARS Outbreak in Singapore

BACKGROUND: Rapid response to outbreaks of emerging infectious diseases is impeded by uncertain diagnoses and delayed communication. Understanding the effect of inefficient response is a potentially important contribution of epidemic theory. To develop this understanding we studied societal learning during emerging outbreaks wherein patient removal accelerates as information is gathered and disseminated. METHODS AND FINDINGS: We developed an extension of a standard outbreak model, the simple stochastic epidemic, which accounts for societal learning. We obtained expressions for the expected outbreak size and the distribution of epidemic duration. We found that rapid learning noticeably affects the final outbreak size even when learning exhibits diminishing returns (relaxation). As an example, we estimated the learning rate for the 2003 outbreak of severe acute respiratory syndrome (SARS) in Singapore. Evidence for relaxation during the first eight weeks of the outbreak was inconclusive. We estimated that if societal learning had occurred at half the actual rate, the expected final size of the outbreak would have reached nearly 800 cases, more than three times the observed number of infections. By contrast, the expected outbreak size for societal learning twice as effective was 116 cases. CONCLUSION: These results show that the rate of societal learning can greatly affect the final size of disease outbreaks, justifying investment in early warning systems and attentiveness to disease outbreak by both government authorities and the public. We submit that the burden of emerging infections, including the risk of a global pandemic, could be efficiently reduced by improving procedures for rapid detection of outbreaks, alerting public health officials, and aggressively educating the public at the start of an outbreak

Prioritising surveillance for alien organisms transported as stowaways on ships travelling to South Africa

The global shipping network facilitates the transportation and introduction of marine and terrestrial organisms to regions where they are not native, and some of these organisms become invasive. South Africa was used as a case study to evaluate the potential for shipping to contribute to the introduction and establishment of marine and terrestrial alien species (i.e. establishment debt) and to assess how this varies across shipping routes and seasons. As a proxy for the number of species introduced (i.e. 'colonisation pressure') shipping movement data were used to determine, for each season, the number of ships that visited South African ports from foreign ports and the number of days travelled between ports. Seasonal marine and terrestrial environmental similarity between South African and foreign ports was then used to estimate the likelihood that introduced species would establish. These data were used to determine the seasonal relative contribution of shipping routes to South Africa's marine and terrestrial establishment debt. Additionally, distribution data were used to identify marine and terrestrial species that are known to be invasive elsewhere and which might be introduced to each South African port through shipping routes that have a high relative contribution to establishment debt. Shipping routes from Asian ports, especially Singapore, have a particularly high relative contribution to South Africa's establishment debt, while among South African ports, Durban has the highest risk of being invaded. There was seasonal variation in the shipping routes that have a high relative contribution to the establishment debt of the South African ports. The presented method provides a simple way to prioritise surveillance effort and our results indicate that, for South Africa, port-specific prevention strategies should be developed, a large portion of the available resources should be allocated to Durban, and seasonal variations and their consequences for prevention strategies should be explored further. (Résumé d'auteur

Recent acquisition of Helicobacter pylori by Baka Pygmies

Both anatomically modern humans and the gastric pathogen Helicobacter pylori originated in Africa, and both species have been associated for at least 100,000 years. Seven geographically distinct H. pylori populations exist, three of which are indigenous to Africa: hpAfrica1, hpAfrica2, and hpNEAfrica. The oldest and most divergent population, hpAfrica2, evolved within San hunter-gatherers, who represent one of the deepest branches of the human population tree. Anticipating the presence of ancient H. pylori lineages within all hunter-gatherer populations, we investigated the prevalence and population structure of H. pylori within Baka Pygmies in Cameroon. Gastric biopsies were obtained by esophagogastroduodenoscopy from 77 Baka from two geographically separated populations, and from 101 non-Baka individuals from neighboring agriculturalist populations, and subsequently cultured for H. pylori. Unexpectedly, Baka Pygmies showed a significantly lower H. pylori infection rate (20.8%) than non-Baka (80.2%). We generated multilocus haplotypes for each H. pylori isolate by DNA sequencing, but were not able to identify Baka-specific lineages, and most isolates in our sample were assigned to hpNEAfrica or hpAfrica1. The population hpNEAfrica, a marker for the expansion of the Nilo-Saharan language family, was divided into East African and Central West African subpopulations. Similarly, a new hpAfrica1 subpopulation, identified mainly among Cameroonians, supports eastern and western expansions of Bantu languages. An age-structured transmission model shows that the low H. pylori prevalence among Baka Pygmies is achievable within the timeframe of a few hundred years and suggests that demographic factors such as small population size and unusually low life expectancy can lead to the eradication of H. pylori from individual human populations. The Baka were thus either H. pylori-free or lost their ancient lineages during past demographic fluctuations. Using coalescent simulations and phylogenetic inference, we show that Baka almost certainly acquired their extant H. pylori through secondary contact with their agriculturalist neighbors

Severe Hindrance of Viral Infection Propagation in Spatially Extended Hosts

The production of large progeny numbers affected by high mutation rates is a ubiquitous strategy of viruses, as it promotes quick adaptation and survival to changing environments. However, this situation often ushers in an arms race between the virus and the host cells. In this paper we investigate in depth a model for the dynamics of a phenotypically heterogeneous population of viruses whose propagation is limited to two-dimensional geometries, and where host cells are able to develop defenses against infection. Our analytical and numerical analyses are developed in close connection to directed percolation models. In fact, we show that making the space explicit in the model, which in turn amounts to reducing viral mobility and hindering the infective ability of the virus, connects our work with similar dynamical models that lie in the universality class of directed percolation. In addition, we use the fact that our model is a multicomponent generalization of the Domany-Kinzel probabilistic cellular automaton to employ several techniques developed in the past in that context, such as the two-site approximation to the extinction transition line. Our aim is to better understand propagation of viral infections with mobility restrictions, e.g., in crops or in plant leaves, in order to inspire new strategies for effective viral control

Neurogenic lower urinary tract dysfunction: Clinical management recommendations of the Neurologic Incontinence committee of the fifth International Consultation on Incontinence 2013

BACKGROUND: Evidence-based guidelines for the management of neurological disease and lower urinary tract dysfunction have been produced by the International Consultations on Incontinence (ICI). These are comprehensive guidelines, and were developed to have world-wide relevance. AIMS: To update clinical management of neurogenic bladder dysfunction from the recommendations of the fourth ICI, 2009. MATERIALS AND METHODS: A series of evidence reviews and updates were performed by members of the working group. The resulting guidelines were presented at the 2012 meeting of the European Association of Urology for consultation, and consequently amended to deliver evidence-based conclusions and recommendations in 2013. RESULTS: The current review is a synthesis of the conclusions and recommendations, including the algorithms for initial and specialized management of neurogenic lower urinary tract dysfunction. The pathophysiology is categorized according to the nature of onset of neurological disease and the part(s) of the nervous system affected. Assessment requires clinical evaluation, general investigations, and specialized testing. Treatment primarily focuses on ensuring safety of the patient and optimizing quality of life. Symptom management covers conservative and interventional measures to aid urine storage and bladder emptying, along with containment of incontinence. A multidisciplinary approach to management is essential. DISCUSSION: The review offers a pragmatic review of management in the context of complex pathophysiology and varied evidence base. Neurourol. Urodynam. 35:657-665, 2016. © 2016 Wiley Periodicals, Inc

Don't Fall Off the Adaptation Cliff: When Asymmetrical Fitness Selects for Suboptimal Traits

The cliff-edge hypothesis introduces the counterintuitive idea that the trait value associated with the maximum of an asymmetrical fitness function is not necessarily the value that is selected for if the trait shows variability in its phenotypic expression. We develop a model of population dynamics to show that, in such a system, the evolutionary stable strategy depends on both the shape of the fitness function around its maximum and the amount of phenotypic variance. The model provides quantitative predictions of the expected trait value distribution and provides an alternative quantity that should be maximized (“genotype fitness”) instead of the classical fitness function (“phenotype fitness”). We test the model's predictions on three examples: (1) litter size in guinea pigs, (2) sexual selection in damselflies, and (3) the geometry of the human lung. In all three cases, the model's predictions give a closer match to empirical data than traditional optimization theory models. Our model can be extended to most ecological situations, and the evolutionary conditions for its application are expected to be common in nature

Pathways to Care: Duration of Untreated Psychosis from Karachi, Pakistan

Background: Substantial amount of time is lost before initiation of treatment in Schizophrenia. The delay in treatment is labelled as Duration of Untreated Psychosis (DUP). Most of these estimates come from western countries, where health systems are relatively better developed. There is dearth of information on pathway to care from developing countries. Methods And Results: Patients with ICD-10 based diagnosis of Schizophrenia were enrolled by convenient method of sampling. The pathway to care was explored through a semi-structured questionnaire. Onset, course and symptoms of psychosis were assessed using Interview for the Retrospective Assessment of the Onset of Schizophrenia (IRAOS). Ethical approval of the project was taken from The Aga Khan University, Ethics Review Committee. Of the enrolled 93 subjects, 55 (59%) were males and 38 (41%) were females. In our sample, 1.56 mean (median, 2) attempts were made prior to successful help seeking. The duration of untreated psychosis was 14.8 months (St. Deviation, 29.4). DUP was 16.8 months (St. Deviation, 34.9) for males and 11.8 months (St. Deviation, 18.9) for females. In the pathway to care, psychiatrists featured prominently as initial care providers. In the first attempt at help-seeking, 43% Patients were initially taken to psychiatrists. After the initial consultation, 45% were prescribed psychotropic medication while 7% were hospitalized. Only 9% subjects were given the diagnosis of schizophrenia initially. When participants were inquired about the reasons for delay, 29% reported financial difficulties as the barrier to care. Positive symptoms of psychosis were present in 57% subjects while negative symptoms were present in 30% subjects. There was a statistically significant difference (Chi-square, 7.928, df: 1, Sig 0.005) between DUP and the positive and negative symptoms category. Conclusion: In the absence of well developed primary care health system in Pakistan, majority of Patients present to psychiatrists as a first contact. DUP, as a measurement of help seeking behaviour, tends to be shorter with positive symptoms of Schizophrenia. Substantial amount of time is lost due to non recognition of disease and subsequently, inadequate treatment. Secondary prevention strategies should focus on families, which play an important role in the treatment-seeking process of psychotic Patients