454 research outputs found
Antigen targeting to endosomal pathway in dendritic cell vaccination activates regulatory T cells and attenuates tumor immunity
Lymphoma cells are malignant cells of the T- or B-cell lineage that often express many surface markers inappropriately, yet are not recognized as abnormal by the immune system. We modeled this situation by inoculating ovalbumin-expressing E.G7-OVA lymphoma cells into mice that expressed ovalbumin as a self antigen in pancreatic islets, and investigated the efficacy of dendritic cell (DC) vaccination in these mice. Although vaccination with DC-expressing ovalbumin induced strong cytotoxic T-cell immunity, which led to clearance of E.G7-OVA lymphoma cells in naive C57BL/6 mice, DC vaccination was ineffective in mice expressing ovalbumin as a self antigen. Antigen modification to increase its processing via the endosomal processing pathway dramatically increased CD4 T-cell activation but paradoxically, impaired the protective effect of DC vaccination even in naive mice. Depletion of CD25(+) T cells (regulatory T cells [Tregs]) prior to vaccination restored the efficacy of DC vaccination and allowed eradication of lymphoma also in mice expressing ovalbumin as a self antigen. We conclude that lymphoma cells may be eradicated using DC vaccination if activation of CD25(+) Tregs is simultaneously inhibited, and that intentionally enhanced endosomal antigen processing in DC vaccines may shift the balance from CD4 T-cell help toward stimulation of Tregs.</p
Genetic Annotation of Bacteriophages MScarn, Knocker, and Neos5
We annotated the genomes of three recently discovered bacteriophages to learn more about their genetic composition. MScarn is a lytic bacteriophage that infects Gordonia terrae 3612. It was discovered and purified from soil collected in Iroquois, SD. MScarn is a cluster CT phage, one of only 37 discovered to date. Its genome is 45,677 base pairs long and has 10-nucleotide 3â sticky overhanging ends. Its GC content is 60.3% which is typical of CT cluster members. Knocker is a cluster B9 phage that was isolated on the host Mycobacterium smegmatis mcÂČ155 from soil collected in Watertown, SD. Its circularly permuted genome contains 71,459 base pairs, and it has a high GC content of 69.7%. Similar to the other three members of the B9 cluster, it exhibits a lytic life cycle. Neos5, a lytic bacteriophage, was also isolated on Mycobacterium smegmatis mcÂČ155 from soil collected in Baltimore, MD. It is a cluster B3 phage with a circularly permuted genome of 68,886 base-pairs and a 67.5% GC content, synonymous to the other 37 members of the cluster. All three phages were discovered, purified, and annotated by Northwestern College students
Prospective multicentre cohort trial on acute appendicitis and microbiota, aetiology and effects of antimicrobial treatment: study protocol for the MAPPAC (Microbiology APPendicitis ACuta) trial
Introduction Based on the epidemiological and clinical data, acute appendicitis can present either as uncomplicated or complicated. The aetiology of these different appendicitis forms remains unknown. Antibiotic therapy has been shown to be safe, efficient and cost-effective for CT-confirmed uncomplicated acute appendicitis. Despite appendicitis being one of the most common surgical emergencies, there are very few reports on appendicitis aetiology and pathophysiology focusing on the differences between uncomplicated and complicated appendicitis. Microbiology APPendicitis ACuta (MAPPAC) trial aims to evaluate these microbiological and immunological aspects including immune response in the aetiology of these different forms also assessing both antibiotics non-responders and appendicitis recurrence. In addition, MAPPAC aims to determine antibiotic and placebo effects on gut microbiota composition and antimicrobial resistance.Methods and analysis MAPPAC is a prospective clinical trial with both single-centre and multicentre arm conducted in close synergy with concurrent trials APPendicitis ACuta II (APPAC II) (per oral (p.o.) vs intravenous+p.o. antibiotics, NCT03236961) and APPAC III (double-blind trial placebo vs antibiotics, NCT03234296) randomised clinical trials. Based on the enrolment for these trials, patients with CT-confirmed uncomplicated acute appendicitis are recruited also to the MAPPAC study. In addition to these conservatively treated randomised patients with uncomplicated acute appendicitis, MAPPAC will recruit patients with uncomplicated and complicated appendicitis undergoing appendectomy. Rectal and appendiceal swabs, appendicolith, faecal and serum samples, appendiceal biopsies and clinical data are collected during the hospital stay for microbiological and immunological analyses in both study arms with the longitudinal study arm collecting faecal samples also during follow-up up to 12 months after appendicitis treatment.</p
Contribution of flow conditions and sand addition on hyporheic zone exchange in gravel beds
We conducted a series of tracer test experiments in 12 outdoor semi-natural flumes to assess the effects of variable flow conditions and sand addition on hyporheic zone conditions in gravel beds, mimicking conditions in headwater streams under sediment pressure. Two tracer methods were applied in each experiment: 2â5 tracer-pulse tests were conducted in all flumes and pulses were monitored at three distances downstream of the flume inlet (0 m, 5 m and 10 m, at bed surface), and in pipes installed into the gravel bed at 5 m and 10 m distances. The tracer breakthrough curves (total of 120 tracer injections) were then analysed with a one-dimensional solute transport model (OTIS) and compared with data from the gravel pipes in point-dilution pulse tests. Sand addition had a strong negative effect on horizontal fluxes (qh), whereas the fraction of the median travel time due to transient storage (F200) was determined more by flow conditions. These results suggest that even small additions of sand can modify the hyporheic zone exchange in gravel beds, thus making headwater streams with low sediment transport capacity particularly vulnerable to sediments transported into the stream from catchment land use activities
Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies
Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosinâactin association or tropomyosin head-to-tail binding
Determinants of Multidrug-Resistant Tuberculosis Clusters, California, USA, 2004â2007
TOC summary: Type of isoniazid resistanceâconferring mutation may be a determinant of genotypic clustering
Identification, replication and characterization of epigenetic remodelling in the aging genome:A cross population analysis
Aging is a complex biological process regulated by multiple cellular pathways and molecular mechanisms including epigenetics. Using genome-wide DNA methylation data measured in a large collection of Scottish old individuals, we performed discovery association analysis to identify age-methylated CpGs and replicated them in two independent Danish cohorts. The double-replicated CpGs were characterized by distribution over gene regions and location in relation to CpG islands. The replicated CpGs were further characterized by involvement in biological pathways to study their functional implications in aging. We identified 67,604 age-associated CpG sites reaching genome-wide significance of FWE
NMR metabolomic modeling of age and lifespan: A multicohort analysis.
Metabolomic age models have been proposed for the study of biological aging, however, they have not been widely validated. We aimed to assess the performance of newly developed and existing nuclear magnetic resonance spectroscopy (NMR) metabolomic age models for prediction of chronological age (CA), mortality, and age-related disease. Ninety-eight metabolic variables were measured in blood from nine UK and Finnish cohort studies (N â31,000 individuals, age range 24-86âyears). We used nonlinear and penalized regression to model CA and time to all-cause mortality. We examined associations of four new and two previously published metabolomic age models, with aging risk factors and phenotypes. Within the UK Biobank (N â102,000), we tested prediction of CA, incident disease (cardiovascular disease (CVD), type-2 diabetes mellitus, cancer, dementia, and chronic obstructive pulmonary disease), and all-cause mortality. Seven-fold cross-validated Pearson's r between metabolomic age models and CA ranged between 0.47 and 0.65 in the training cohort set (mean absolute error: 8-9âyears). Metabolomic age models, adjusted for CA, were associated with C-reactive protein, and inversely associated with glomerular filtration rate. Positively associated risk factors included obesity, diabetes, smoking, and physical inactivity. In UK Biobank, correlations of metabolomic age with CA were modest (râ=â0.29-0.33), yet all metabolomic model scores predicted mortality (hazard ratios of 1.01 to 1.06/metabolomic age year) and CVD, after adjustment for CA. While metabolomic age models were only moderately associated with CA in an independent population, they provided additional prediction of morbidity and mortality over CA itself, suggesting their wider applicability
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