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

Digitaalinen vaaliteltta : Twitter politiikan areenana eduskuntavaaleissa 2015

Peer reviewe

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 3’ 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 mc²155 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 mc²155 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: 2–5 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 tropomyosin–actin association or tropomyosin head-to-tail binding

Determinants of Multidrug-Resistant Tuberculosis Clusters, California, USA, 2004–2007

TOC summary: Type of isoniazid resistance–conferring 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