95 research outputs found
A Monitoring Language for Run Time and Post-Mortem Behavior Analysis and Visualization
UFO is a new implementation of FORMAN, a declarative monitoring language, in
which rules are compiled into execution monitors that run on a virtual machine
supported by the Alamo monitor architecture.Comment: In M. Ronsse, K. De Bosschere (eds), proceedings of the Fifth
International Workshop on Automated Debugging (AADEBUG 2003), September 2003,
Ghent. cs.SE/030902
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~ COMMUNICATIONSThis book originally was published by Peer-to-Peer Communications. It is out ofprint and the rights have reverted to the authors, who hereby place it in the public domain. Publisher's Cataloging-in-Publication (Provided by Quality Books, Inc.
Association of acute toxic encephalopathy with litchi consumption in an outbreak in Muzaffarpur, India, 2014: a case-control study
Background Outbreaks of unexplained illness frequently remain under-investigated. In India, outbreaks of an acute
neurological illness with high mortality among children occur annually in Muzaffarpur, the country’s largest litchi
cultivation region. In 2014, we aimed to investigate the cause and risk factors for this illness.
Methods In this hospital-based surveillance and nested age-matched case-control study, we did laboratory
investigations to assess potential infectious and non-infectious causes of this acute neurological illness. Cases were
children aged 15 years or younger who were admitted to two hospitals in Muzaffarpur with new-onset seizures or
altered sensorium. Age-matched controls were residents of Muzaffarpur who were admitted to the same two hospitals
for a non-neurologic illness within seven days of the date of admission of the case. Clinical specimens (blood,
cerebrospinal fluid, and urine) and environmental specimens (litchis) were tested for evidence of infectious
pathogens, pesticides, toxic metals, and other non-infectious causes, including presence of hypoglycin A or
methylenecyclopropylglycine (MCPG), naturally-occurring fruit-based toxins that cause hypoglycaemia and metabolic
derangement. Matched and unmatched (controlling for age) bivariate analyses were done and risk factors for illness
were expressed as matched odds ratios and odds ratios (unmatched analyses).
Findings Between May 26, and July 17, 2014, 390 patients meeting the case definition were admitted to the two referral
hospitals in Muzaffarpur, of whom 122 (31%) died. On admission, 204 (62%) of 327 had blood glucose concentration
of 70 mg/dL or less. 104 cases were compared with 104 age-matched hospital controls. Litchi consumption (matched
odds ratio [mOR] 9·6 [95% CI 3·6 – 24]) and absence of an evening meal (2·2 [1·2–4·3]) in the 24 h preceding illness
onset were associated with illness. The absence of an evening meal significantly modified the effect of eating litchis
on illness (odds ratio [OR] 7·8 [95% CI 3·3–18·8], without evening meal; OR 3·6 [1·1–11·1] with an evening meal).
Tests for infectious agents and pesticides were negative. Metabolites of hypoglycin A, MCPG, or both were detected in
48 [66%] of 73 urine specimens from case-patients and none from 15 controls; 72 (90%) of 80 case-patient specimens
had abnormal plasma acylcarnitine profiles, consistent with severe disruption of fatty acid metabolism. In 36 litchi
arils tested from Muzaffarpur, hypoglycin A concentrations ranged from 12·4 μg/g to 152·0 μg/g and MCPG ranged
from 44·9 μg/g to 220·0 μg/g.
Interpretation Our investigation suggests an outbreak of acute encephalopathy in Muzaffarpur associated with both
hypoglycin A and MCPG toxicity. To prevent illness and reduce mortality in the region, we recommended minimising
litchi consumption, ensuring receipt of an evening meal and implementing rapid glucose correction for suspected
illness. A comprehensive investigative approach in Muzaffarpur led to timely public health recommendations,
underscoring the importance of using systematic methods in other unexplained illness outbreaks
A framework for human microbiome research
A variety of microbial communities and their genes (the microbiome) exist throughout the human body, with fundamental roles in human health and disease. The National Institutes of Health (NIH)-funded Human Microbiome Project Consortium has established a population-scale framework to develop metagenomic protocols, resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomic data available to the scientific community. Here we present resources from a population of 242 healthy adults sampled at 15 or 18 body sites up to three times, which have generated 5,177 microbial taxonomic profiles from 16S ribosomal RNA genes and over 3.5 terabases of metagenomic sequence so far. In parallel, approximately 800 reference strains isolated from the human body have been sequenced. Collectively, these data represent the largest resource describing the abundance and variety of the human microbiome, while providing a framework for current and future studies
Structure, function and diversity of the healthy human microbiome
Author Posting. © The Authors, 2012. This article is posted here by permission of Nature Publishing Group. The definitive version was published in Nature 486 (2012): 207-214, doi:10.1038/nature11234.Studies of the human microbiome have revealed that even healthy individuals differ remarkably in the microbes that occupy habitats such as the gut, skin and vagina. Much of this diversity remains unexplained, although diet, environment, host genetics and early microbial exposure have all been implicated. Accordingly, to characterize the ecology of human-associated microbial communities, the Human Microbiome Project has analysed the largest cohort and set of distinct, clinically relevant body habitats so far. We found the diversity and abundance of each habitat’s signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals. The project encountered an estimated 81–99% of the genera, enzyme families and community configurations occupied by the healthy Western microbiome. Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata. These results thus delineate the range of structural and functional configurations normal in the microbial communities of a healthy population, enabling future characterization of the epidemiology, ecology and translational applications of the human microbiome.This research was supported in
part by National Institutes of Health grants U54HG004969 to B.W.B.; U54HG003273
to R.A.G.; U54HG004973 to R.A.G., S.K.H. and J.F.P.; U54HG003067 to E.S.Lander;
U54AI084844 to K.E.N.; N01AI30071 to R.L.Strausberg; U54HG004968 to G.M.W.;
U01HG004866 to O.R.W.; U54HG003079 to R.K.W.; R01HG005969 to C.H.;
R01HG004872 to R.K.; R01HG004885 to M.P.; R01HG005975 to P.D.S.;
R01HG004908 to Y.Y.; R01HG004900 to M.K.Cho and P. Sankar; R01HG005171 to
D.E.H.; R01HG004853 to A.L.M.; R01HG004856 to R.R.; R01HG004877 to R.R.S. and
R.F.; R01HG005172 to P. Spicer.; R01HG004857 to M.P.; R01HG004906 to T.M.S.;
R21HG005811 to E.A.V.; M.J.B. was supported by UH2AR057506; G.A.B. was
supported by UH2AI083263 and UH3AI083263 (G.A.B., C. N. Cornelissen, L. K. Eaves
and J. F. Strauss); S.M.H. was supported by UH3DK083993 (V. B. Young, E. B. Chang,
F. Meyer, T. M. S., M. L. Sogin, J. M. Tiedje); K.P.R. was supported by UH2DK083990 (J.
V.); J.A.S. and H.H.K. were supported by UH2AR057504 and UH3AR057504 (J.A.S.);
DP2OD001500 to K.M.A.; N01HG62088 to the Coriell Institute for Medical Research;
U01DE016937 to F.E.D.; S.K.H. was supported by RC1DE0202098 and
R01DE021574 (S.K.H. and H. Li); J.I. was supported by R21CA139193 (J.I. and
D. S. Michaud); K.P.L. was supported by P30DE020751 (D. J. Smith); Army Research
Office grant W911NF-11-1-0473 to C.H.; National Science Foundation grants NSF
DBI-1053486 to C.H. and NSF IIS-0812111 to M.P.; The Office of Science of the US
Department of Energy under Contract No. DE-AC02-05CH11231 for P.S. C.; LANL
Laboratory-Directed Research and Development grant 20100034DR and the US
Defense Threat Reduction Agency grants B104153I and B084531I to P.S.C.; Research
Foundation - Flanders (FWO) grant to K.F. and J.Raes; R.K. is an HHMI Early Career
Scientist; Gordon&BettyMoore Foundation funding and institutional funding fromthe
J. David Gladstone Institutes to K.S.P.; A.M.S. was supported by fellowships provided by
the Rackham Graduate School and the NIH Molecular Mechanisms in Microbial
Pathogenesis Training Grant T32AI007528; a Crohn’s and Colitis Foundation of
Canada Grant in Aid of Research to E.A.V.; 2010 IBM Faculty Award to K.C.W.; analysis
of the HMPdata was performed using National Energy Research Scientific Computing
resources, the BluBioU Computational Resource at Rice University
Eclipse in the Dark Years: Pick-up Flights, Routes of Resistance and the Free French
This article charts the importance of clandestine flights from Britain into occupied France during the Second World War as a route of resistance. These pick-up flights were coordinated from London and were an example of the inter-allied cooperation and Franco-British negotiation that took place between the BCRA, SIS, and SOE. The flights allowed General Charles de Gaulle to hold court with the leaders of resistance networks, smoothing problems on the route to a unified resistance council. Likewise, they allowed him to build bridges between vying factions in France and in London, drawing together the movements under his command and personalising the narrative of resistance. From busy London restaurants and family homes via secret flights to darkened fields in Occupied France, the route of these transfers shaped the character of resistance. This article draws out the personal interactions and connections that underpinned these networks and describes the enduring connections of this route of resistance, starting with the commemoration of Jean Moulin's crash landing at RAF Tangmere, the forward station for many of these flights
31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two
Background
The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd.
Methods
We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background.
Results
First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001).
Conclusions
In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival
Some axioms and issues in the UFO dynamic analysis framework
In the Proceedings of Workshop on Dynamic Analysis, ICSE'03, 25th International Conference on Software Engineering, Portland, Oregon, May 3-11, 2003, pp.45-48.UFO is a framework for constructing dynamic analysis tools that require varying degrees of access and control over program executions. UFO combines run time and post-mortem techniques to perform required analyses. Declarative and imperative notations are provided for constructing monitors at appropriate semantic levels. Multiple analyses can be bundled into a given monitor, and multiple monitors can be applied to a given target program execution. This paper presents the central tenets of UFO, along with our current set of research challenges
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