Tumor-Derived Microvesicles Induce, Expand and Up-Regulate Biological Activities of Human Regulatory T Cells (Treg)

Background: Tumor-derived microvesicles (TMV) or exosomes are present in body fluids of patients with cancer and might be involved in tumor progression. The frequency and suppressor functions of peripheral blood CD4 + CD25 high FOXP3 + Treg are higher in patients with cancer than normal controls. The hypothesis is tested that TMV contribute to induction/ expansion/and activation of human Treg. Methodology/Principal Findings: TMV isolated from supernatants of tumor cells but not normal cells induced the generation and enhanced expansion of human Treg. TMV also mediated conversion of CD4 + CD25 neg T cells into CD4 + CD25 high FOXP3 + Treg. Upon co-incubation with TMV, Treg showed an increased FasL, IL-10, TGF-b1, CTLA-4, granzyme B and perforin expression (p,0.05) and mediated stronger suppression of responder cell (RC) proliferation (p,0.01). Purified Treg were resistant to TMV-mediated apoptosis relative to other T cells. TMV also increased phospho-SMAD2/3 and phospho-STAT3 expression in Treg. Neutralizing Abs specific for TGF-b1 and/or IL-10 significantly inhibited TMV ability to expand Treg. Conclusions/Significance: This study suggests that TMV have immunoregulatory properties. They induce Treg, promote Treg expansion, up-regulate Treg suppressor function and enhance Treg resistance to apoptosis. Interactions of TMV wit

Influenza A Virus Induces an Immediate Cytotoxic Activity in All Major Subsets of Peripheral Blood Mononuclear Cells

A replication defective influenza A vaccine virus (delNS1 virus) was developed. Its attenuation is due to potent stimulation of the innate immune system by the virus. Since the innate immune system can also target cancer cells, we reasoned that delNS1 virus induced immune-stimulation should also lead to the induction of innate cytotoxic effects towards cancer cells.Peripheral blood mononuclear cells (PBMCs), isolated CD56+, CD3+, CD14+ and CD19+ subsets and different combinations of the above subsets were stimulated by delNS1, wild type (wt) virus or heat inactivated virus and co-cultured with tumor cell lines in the presence or absence of antibodies against the interferon system. Stimulation of PBMCs by the delNS1 virus effectively induced cytotoxicity against different cancer cell lines. Surprisingly, virus induced cytotoxicity was exerted by all major subtypes of PBMCs including CD56+, CD3+, CD14+ and CD19+ cells. Virus induced cytotoxicity in CD3+, CD14+ and CD19+ cells was dependent on virus replication, whereas virus induced cytotoxicity in CD56+ cells was only dependent on the binding of the virus. Virus induced cytotoxicity of isolated cell cultures of CD14+, CD19+ or CD56+ cells could be partially blocked by antibodies against type I and type II (IFN) interferon. In contrast, virus induced cytotoxicity in the complete PBMC preparation could not be inhibited by blocking type I or type II IFN, indicating a redundant system of activation in whole blood.Our data suggest that apart from their well known specialized functions all main subsets of peripheral blood cells also initially exert a cytotoxic effect upon virus stimulation. This closely links the innate immune system to the adaptive immune response and renders delNS1 virus a potential therapeutic tool for viro-immunotherapy of cancer

Ecological Meltdown in the Firth of Clyde, Scotland: Two Centuries of Change in a Coastal Marine Ecosystem

BACKGROUND: The Firth of Clyde is a large inlet of the sea that extends over 100 km into Scotland\u27s west coast. METHODS: We compiled detailed fisheries landings data for this area and combined them with historical accounts to build a picture of change due to fishing activity over the last 200 years. FINDINGS: In the early 19th century, prior to the onset of industrial fishing, the Firth of Clyde supported diverse and productive fisheries for species such as herring (Clupea harengus, Clupeidae), cod (Gadus morhua, Gadidae), haddock (Melanogrammus aeglefinus, Gadidae), turbot (Psetta maxima, Scophthalmidae) and flounder (Platichthys flesus, Pleuronectidae). The 19th century saw increased demand for fish, which encouraged more indiscriminate methods of fishing such as bottom trawling. During the 1880s, fish landings began to decline, and upon the recommendation of local fishers and scientists, the Firth of Clyde was closed to large trawling vessels in 1889. This closure remained in place until 1962 when bottom trawling for Norway lobster (Nephrops norvegicus, Nephropidae) was approved in areas more than three nautical miles from the coast. During the 1960s and 1970s, landings of bottomfish increased as trawling intensified. The trawl closure within three nautical miles of the coast was repealed in 1984 under pressure from the industry. Thereafter, bottomfish landings went into terminal decline, with all species collapsing to zero or near zero landings by the early 21st century. Herring fisheries collapsed in the 1970s as more efficient mid-water trawls and fish finders were introduced, while a fishery for mid-water saithe (Pollachius virens, Gadidae) underwent a boom and bust shortly after discovery in the late 1960s. The only commercial fisheries that remain today are for Nephrops and scallops (Pecten maximus, Pectinidae). SIGNIFICANCE: The Firth of Clyde is a marine ecosystem nearing the endpoint of overfishing, a time when no species remain that are capable of sustaining commercial catches. The evidence suggests that trawl closures helped maintain productive fisheries through the mid-20th century, and their reopening precipitated collapse of bottomfish stocks. We argue that continued intensive bottom trawling for Nephrops with fine mesh nets will prevent the recovery of other species. This once diverse and highly productive environment will only be restored if trawl closures or other protected areas are re-introduced. The Firth of Clyde represents at a small scale a process that is occurring ocean-wide today, and its experience serves as a warning to others

Improved Upper Limit on the Neutrino Mass from a Direct Kinematic Method by KATRIN.

We report on the neutrino mass measurement result from the first four-week science run of the Karlsruhe Tritium Neutrino experiment KATRIN in spring 2019. Beta-decay electrons from a high-purity gaseous molecular tritium source are energy analyzed by a high-resolution MAC-E filter. A fit of the integrated electron spectrum over a narrow interval around the kinematic end point at 18.57 keV gives an effective neutrino mass square value of (-1.0_{-1.1}^{+0.9})  eV^{2}. From this, we derive an upper limit of 1.1 eV (90% confidence level) on the absolute mass scale of neutrinos. This value coincides with the KATRIN sensitivity. It improves upon previous mass limits from kinematic measurements by almost a factor of 2 and provides model-independent input to cosmological studies of structure formation

Expression and Localization of CLC Chloride Transport Proteins in the Avian Retina

Members of the ubiquitously expressed CLC protein family of chloride channels and transporters play important roles in regulating cellular chloride and pH. The CLCs that function as Cl−/H+ antiporters, ClCs 3–7, are essential in particular for the acidification of endosomal compartments and protein degradation. These proteins are broadly expressed in the nervous system, and mutations that disrupt their expression are responsible for several human genetic diseases. Furthermore, knock-out of ClC3 and ClC7 in the mouse result in the degeneration of the hippocampus and the retina. Despite this evidence of their importance in retinal function, the expression patterns of different CLC transporters in different retinal cell types are as yet undescribed. Previous work in our lab has shown that in chicken amacrine cells, internal Cl− can be dynamic. To determine whether CLCs have the potential to participate, we used PCR and immunohistochemical techniques to examine CLC transporter expression in the chicken retina. We observed a high level of variation in the retinal expression levels and patterns among the different CLC proteins examined. These findings, which represent the first systematic investigation of CLC transporter expression in the retina, support diverse functions for the different CLCs in this tissue

Phytophthora species and oak decline - can a weak competitor cause significant root damage in a nonsterilized acidic forest soil?

Phytophthora species in general, and P. quercina in particular, have been suggested in several studies to be a contributing factor to the problem of oak decline in Europe. Although Phytophthora species are generally regarded as weak competitors, few studies of the pathogenicity of species causing root rot on oaks have hitherto been performed in natural, nonsterilized forest soils. This study describes the effects of seven southern Swedish isolates of P. quercina and one isolate of P. cactorum on root vitality of Quercus robur seedlings grown in a natural, nonsterilized, acidic forest soil. The pathogenicity of P. quercina and P. cactorum were tested using a soil infestation test. The climatic conditions applied were an attempt to simulate summer conditions in southern Sweden. Both species of Phytophthora caused a significant dieback of fine roots, and necrotic lesions on coarser roots, of Q. robur seedlings. Total and live root lengths were significantly lower in infected seedlings than in controls. No significant effects of Phytophthora on above-ground growth or leaf nutrient concentration were found. The results demonstrate that P. quercina and P. cactorum can cause substantial root dieback of seedlings of Q. robur in natural, acidic forest soils in competition with the inhabiting soil microflora under a mesic water regime

Predictors of overweight and obesity in five to seven-year-old children in Germany: Results from cross-sectional studies

BACKGROUND: Childhood obesity is a serious public health problem and epidemiological studies are important to identify predictive factors. It is the aim of this study to analyse factors associated with overweight/obesity in samples of German children. METHODS: 35,434 five to seven year-old children (50.9% boys) participated in cross-sectional studies between 1991 and 2000 in several rural and urban areas in East and West Germany. Weight and height were measured and body mass index was calculated. International cut-off points, recommended by the International Obesity Task Force, were used to classify childhood overweight and obesity. Predictive modelling was employed to analyse independently associated factors, using logistic regression to adjust for confounding. RESULTS: 15.5% were overweight, and 4.3% were obese. Female sex, other than German nationality, smoking in the living place and increasing birth weight were found to increase the odds of overweight and obesity, while increasing educational level, living space > 75 m2 and breastfeeding for more than three months were inversely associated. CONCLUSION: The findings add to the evidence informing public health action, both through health promotion strategies (promoting breastfeeding, tackling smoking) and wider societal change management (addressing children from migrant families and families with low educational level)

The Effort of Increasing Reynolds Number in Projection-Based Reduced Order Methods: From Laminar to Turbulent Flows

We present in this double contribution two different reduced order strategies for incompressible parameterized Navier-Stokes equations characterized by varying Reynolds numbers. The first strategy deals with low Reynolds number (laminar flow) and is based on a stabilized finite element method during the offline stage followed by a Galerkin projection on reduced basis spaces generated by a greedy algorithm. The second methodology is based on a full order finite volume discretization. The latter methodology will be used for flows with moderate to high Reynolds number characterized by turbulent patterns. For the treatment of the mentioned turbulent flows at the reduced order level, a new POD-Galerkin approach is proposed. The new approach takes into consideration the contribution of the eddy viscosity also during the online stage and is based on the use of interpolation. The two methodologies are tested on classic benchmark test cases