Epidemic space

The aim of this article is to highlight the importance of 'spatiality' in understanding the materialization of risk society and cultivation of risk sensibilities. More specifically it provides a cultural analysis of pathogen virulence (as a social phenomenon) by means of tracing and mapping the spatial flows that operate in the uncharted zones between the microphysics of infection and the macrophysics of epidemics. It will be argued that epidemic space consists of three types of forces: the vector, the index and the vortex. It will draw on Latour's Actor Network Theory to argue that epidemic space is geared towards instability when the vortex (of expanding associations and concerns) displaces the index (of finding a single cause)

Social sciences research in neglected tropical diseases 2: A bibliographic analysis

The official published version of the article can be found at the link below.Background There are strong arguments for social science and interdisciplinary research in the neglected tropical diseases. These diseases represent a rich and dynamic interplay between vector, host, and pathogen which occurs within social, physical and biological contexts. The overwhelming sense, however, is that neglected tropical diseases research is a biomedical endeavour largely excluding the social sciences. The purpose of this review is to provide a baseline for discussing the quantum and nature of the science that is being conducted, and the extent to which the social sciences are a part of that. Methods A bibliographic analysis was conducted of neglected tropical diseases related research papers published over the past 10 years in biomedical and social sciences. The analysis had textual and bibliometric facets, and focussed on chikungunya, dengue, visceral leishmaniasis, and onchocerciasis. Results There is substantial variation in the number of publications associated with each disease. The proportion of the research that is social science based appears remarkably consistent (<4%). A textual analysis, however, reveals a degree of misclassification by the abstracting service where a surprising proportion of the "social sciences" research was pure clinical research. Much of the social sciences research also tends to be "hand maiden" research focused on the implementation of biomedical solutions. Conclusion There is little evidence that scientists pay any attention to the complex social, cultural, biological, and environmental dynamic involved in human pathogenesis. There is little investigator driven social science and a poor presence of interdisciplinary science. The research needs more sophisticated funders and priority setters who are not beguiled by uncritical biomedical promises

Plant-symbiotic fungi as chemical engineers: multi-genome analysis of the Clavicipitaceae reveals dynamics of alkaloid Loci

The fungal family Clavicipitaceae includes plant symbionts and parasites that produce several psychoactive and bioprotective alkaloids. The family includes grass symbionts in the epichloae clade (Epichloë and Neotyphodium species), which are extraordinarily diverse both in their host interactions and in their alkaloid profiles. Epichloae produce alkaloids of four distinct classes, all of which deter insects, and some—including the infamous ergot alkaloids—have potent effects on mammals. The exceptional chemotypic diversity of the epichloae may relate to their broad range of host interactions, whereby some are pathogenic and contagious, others are mutualistic and vertically transmitted (seed-borne), and still others vary in pathogenic or mutualistic behavior. We profiled the alkaloids and sequenced the genomes of 10 epichloae, three ergot fungi (Claviceps species), a morning-glory symbiont (Periglandula ipomoeae), and a bamboo pathogen (Aciculosporium take), and compared the gene clusters for four classes of alkaloids. Results indicated a strong tendency for alkaloid loci to have conserved cores that specify the skeleton structures and peripheral genes that determine chemical variations that are known to affect their pharmacological specificities. Generally, gene locations in cluster peripheries positioned them near to transposon-derived, AT-rich repeat blocks, which were probably involved in gene losses, duplications, and neofunctionalizations. The alkaloid loci in the epichloae had unusual structures riddled with large, complex, and dynamic repeat blocks. This feature was not reflective of overall differences in repeat contents in the genomes, nor was it characteristic of most other specialized metabolism loci. The organization and dynamics of alkaloid loci and abundant repeat blocks in the epichloae suggested that these fungi are under selection for alkaloid diversification. We suggest that such selection is related to the variable life histories of the epichloae, their protective roles as symbionts, and their associations with the highly speciose and ecologically diverse cool-season grasses

Inside and out: the activities of senescence in cancer.

The core aspect of the senescent phenotype is a stable state of cell cycle arrest. However, this is a disguise that conceals a highly active metabolic cell state with diverse functionality. Both the cell-autonomous and the non-cell-autonomous activities of senescent cells create spatiotemporally dynamic and context-dependent tissue reactions. For example, the senescence-associated secretory phenotype (SASP) provokes not only tumour-suppressive but also tumour-promoting responses. Senescence is now increasingly considered to be an integrated and widespread component that is potentially important for tumour development, tumour suppression and the response to therapy.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/nrc377

An EMT-Driven Alternative Splicing Program Occurs in Human Breast Cancer and Modulates Cellular Phenotype

Epithelial-mesenchymal transition (EMT), a mechanism important for embryonic development, plays a critical role during malignant transformation. While much is known about transcriptional regulation of EMT, alternative splicing of several genes has also been correlated with EMT progression, but the extent of splicing changes and their contributions to the morphological conversion accompanying EMT have not been investigated comprehensively. Using an established cell culture model and RNA–Seq analyses, we determined an alternative splicing signature for EMT. Genes encoding key drivers of EMT–dependent changes in cell phenotype, such as actin cytoskeleton remodeling, regulation of cell–cell junction formation, and regulation of cell migration, were enriched among EMT–associated alternatively splicing events. Our analysis suggested that most EMT–associated alternative splicing events are regulated by one or more members of the RBFOX, MBNL, CELF, hnRNP, or ESRP classes of splicing factors. The EMT alternative splicing signature was confirmed in human breast cancer cell lines, which could be classified into basal and luminal subtypes based exclusively on their EMT–associated splicing pattern. Expression of EMT–associated alternative mRNA transcripts was also observed in primary breast cancer samples, indicating that EMT–dependent splicing changes occur commonly in human tumors. The functional significance of EMT–associated alternative splicing was tested by expression of the epithelial-specific splicing factor ESRP1 or by depletion of RBFOX2 in mesenchymal cells, both of which elicited significant changes in cell morphology and motility towards an epithelial phenotype, suggesting that splicing regulation alone can drive critical aspects of EMT–associated phenotypic changes. The molecular description obtained here may aid in the development of new diagnostic and prognostic markers for analysis of breast cancer progression.National Institutes of Health (U.S.) (R01-HG002439)National Science Foundation (U.S.) (equipment grant)National Institutes of Health (U.S.) (Integrative Cancer Biology Program Grant U54-CA112967)David H. Koch Institute for Integrative Cancer Research at MIT (Ludwig Center for Metastasis Research)David H. Koch Institute for Integrative Cancer Research at MITMassachusetts Institute of Technology (Croucher Scholarship)Massachusetts Institute of Technology (Ludwig Fund postdoctoral fellowship)National Institutes of Health (U.S.) (NIH CA100324)National Institutes of Health (U.S.) (AECC9526-5267

Similar TKA designs with differences in clinical outcome: A randomized, controlled trial of 77 knees with a mean follow-up of 6 years

Contains fulltext : 96347.pdf (publisher's version ) (Open Access)Background and purpose To try to improve the outcome of our TKAs, we started to use the CKS prosthesis. However, in a retrospective analysis this design tended to give worse results. We therefore conducted a randomized, controlled trial comparing this CKS prosthesis and our standard PFC prosthesis. Because many randomized studies between different TKA concepts generally fail to show superiority of a particular design, we hypothesized that these seemingly similar designs would not lead to any difference in clinical outcome. Patients and methods 82 patients (90 knees) were randomly allocated to one or other prosthesis, and 39 CKS prostheses and 38 PFC prostheses could be followed for mean 5.6 years. No patients were lost to follow-up. At each follow-up, patients were evaluated clinically and radiographically, and the KSS, WOMAC, VAS patient satisfaction scores and VAS for pain were recorded. Results With total Knee Society score (KSS) as primary endpoint, there was a difference in favor of the PFC group at final follow-up (p = 0.04). Whereas there was one revision in the PFC group, there were 6 revisions in the CKS group (p = 0.1). The survival analysis with any reoperation as endpoint showed better survival in the PFC group (97% (95% CI: 92-100) for the PFC group vs. 79% (95% CI: 66-92) for the CKS group) (p = 0.02). Interpretation Our hypothesis that there would be no difference in clinical outcome was rejected in this study. The PFC system showed excellent results that were comparable to those in previous reports. The CKS design had differences that had considerable negative consequences clinically. The relatively poor results have discouraged us from using this design

HIV-1 infected monozygotic twins: a tale of two outcomes

<p>Abstract</p> <p>Background</p> <p>Replicate experiments are often difficult to find in evolutionary biology, as this field is inherently an historical science. However, viruses, bacteria and phages provide opportunities to study evolution in both natural and experimental contexts, due to their accelerated rates of evolution and short generation times. Here we investigate HIV-1 evolution by using a natural model represented by monozygotic twins infected synchronically at birth with an HIV-1 population from a shared blood transfusion source. We explore the evolutionary processes and population dynamics that shape viral diversity of HIV in these monozygotic twins.</p> <p>Results</p> <p>Despite the identical host genetic backdrop of monozygotic twins and the identical source and timing of the HIV-1 inoculation, the resulting HIV populations differed in genetic diversity, growth rate, recombination rate, and selection pressure between the two infected twins.</p> <p>Conclusions</p> <p>Our study shows that the outcome of evolution is strikingly different between these two "replicates" of viral evolution. Given the identical starting points at infection, our results support the impact of random epigenetic selection in early infection dynamics. Our data also emphasize the need for a better understanding of the impact of host-virus interactions in viral evolution.</p

A classification of diabetic foot infections using ICD-9-CM codes: application to a large computerized medical database

<p>Abstract</p> <p>Background</p> <p>Diabetic foot infections are common, serious, and varied. Diagnostic and treatment strategies are correspondingly diverse. It is unclear how patients are managed in actual practice and how outcomes might be improved. Clarification will require study of large numbers of patients, such as are available in medical databases. We have developed and evaluated a system for identifying and classifying diabetic foot infections that can be used for this purpose.</p> <p>Methods</p> <p>We used the (VA) Diabetes Epidemiology Cohorts (DEpiC) database to conduct a retrospective observational study of patients with diabetic foot infections. DEpiC contains computerized VA and Medicare patient-level data for patients with diabetes since 1998. We determined which ICD-9-CM codes served to identify patients with different types of diabetic foot infections and ranked them in declining order of severity: Gangrene, Osteomyelitis, Ulcer, Foot cellulitis/abscess, Toe cellulitis/abscess, Paronychia. We evaluated our classification by examining its relationship to patient characteristics, diagnostic procedures, treatments given, and medical outcomes.</p> <p>Results</p> <p>There were 61,007 patients with foot infections, of which 42,063 were classifiable into one of our predefined groups. The different types of infection were related to expected patient characteristics, diagnostic procedures, treatments, and outcomes. Our severity ranking showed a monotonic relationship to hospital length of stay, amputation rate, transition to long-term care, and mortality.</p> <p>Conclusions</p> <p>We have developed a classification system for patients with diabetic foot infections that is expressly designed for use with large, computerized, ICD-9-CM coded administrative medical databases. It provides a framework that can be used to conduct observational studies of large numbers of patients in order to examine treatment variation and patient outcomes, including the effect of new management strategies, implementation of practice guidelines, and quality improvement initiatives.</p

MDCK Cystogenesis Driven by Cell Stabilization within Computational Analogues

The study of epithelial morphogenesis is fundamental to increasing our understanding of organ function and disease. Great progress has been made through study of culture systems such as Madin-Darby canine kidney (MDCK) cells, but many aspects of even simple morphogenesis remain unclear. For example, are specific cell actions tightly coupled to the characteristics of the cell's environment or are they more often cell state dependent? How does the single lumen, single cell layer cyst consistently emerge from a variety of cell actions? To improve insight, we instantiated in silico analogues that used hypothesized cell behavior mechanisms to mimic MDCK cystogenesis. We tested them through in vitro experimentation and quantitative validation. We observed novel growth patterns, including a cell behavior shift that began around day five of growth. We created agent-oriented analogues that used the cellular Potts model along with an Iterative Refinement protocol. Following several refinements, we achieved a degree of validation for two separate mechanisms. Both survived falsification and achieved prespecified measures of similarity to cell culture properties. In silico components and mechanisms mapped to in vitro counterparts. In silico, the axis of cell division significantly affects lumen number without changing cell number or cyst size. Reducing the amount of in silico luminal cell death had limited effect on cystogenesis. Simulations provide an observable theory for cystogenesis based on hypothesized, cell-level operating principles