Interleukins 7 and 15 Maintain Human T Cell Proliferative Capacity through STAT5 Signaling

T lymphocytes require signals from self-peptides and cytokines, most notably interleukins 7 and 15 (IL-7, IL-15), for survival. While mouse T cells die rapidly if IL-7 or IL-15 is withdrawn, human T cells can survive prolonged withdrawal of IL-7 and IL-15. Here we show that IL-7 and IL-15 are required to maintain human T cell proliferative capacity through the STAT5 signaling pathway. T cells from humanized mice proliferate better if stimulated in the presence of human IL-7 or IL-15 or if T cells are exposed to human IL-7 or IL-15 in mice. Freshly isolated T cells from human peripheral blood lose proliferative capacity if cultured for 24 hours in the absence of IL-7 or IL-15. We further show that phosphorylation of STAT5 correlates with proliferation and inhibition of STAT5 reduces proliferation. These results reveal a novel role of IL-7 and IL-15 in maintaining human T cell function, provide an explanation for T cell dysfunction in humanized mice, and have significant implications for in vitro studies with human T cells

A large sample analysis of European rivers on seasonal river flow correlation and its physical drivers

The geophysical and hydrological processes governing river flow formation exhibit persistence at several timescales, which may manifest itself with the presence of positive seasonal correlation of streamflow at several different time lags. We investigate here how persistence propagates along subsequent seasons and affects low and high flows. We define the high-flow season (HFS) and the low-flow season (LFS) as the 3-month and the 1-month periods which usually exhibit the higher and lower river flows, respectively. A dataset of 224 rivers from six European countries spanning more than 50 years of daily flow data is exploited. We compute the lagged seasonal correlation between selected river flow signatures, in HFS and LFS, and the average river flow in the antecedent months. Signatures are peak and average river flow for HFS and LFS, respectively. We investigate the links between seasonal streamflow correlation and various physiographic catchment characteristics and hydro-climatic properties. We find persistence to be more intense for LFS signatures than HFS. To exploit the seasonal correlation in the frequency estimation of high and low flows, we fit a bi-variate meta-Gaussian probability distribution to the selected flow signatures and average flow in the antecedent months in order to condition the distribution of high and low flows in the HFS and LFS, respectively, upon river flow observations in the previous months. The benefit of the suggested methodology is demonstrated by updating the frequency distribution of high and low flows one season in advance in a real-world case. Our findings suggest that there is a traceable physical basis for river memory which, in turn, can be statistically assimilated into high- and low-flow frequency estimation to reduce uncertainty and improve predictions for technical purposes

A stochastic model for the hourly solar radiation process for application in renewable resources management

Since the beginning of the 21st century, the scientific community has made huge leaps to exploit renewable energy sources, with solar radiation being one of the most important. However, the variability of solar radiation has a significant impact on solar energy conversion systems, such as in photovoltaic systems, characterized by a fast and non-linear response to incident solar radiation. The performance prediction of these systems is typically based on hourly or daily data because those are usually available at these time scales. The aim of this work is to investigate the stochastic nature and time evolution of the solar radiation process for daily and hourly scale, with the ultimate goal of creating a new cyclostationary stochastic model capable of reproducing the dependence structure and the marginal distribution of hourly solar radiation via the clearness index KT.</p

Thermal decomposition and gasification of biomass pyrolysis gases using a hot bed of waste derived pyrolysis char

Chars produced from the pyrolysis of different waste materials have been investigated in terms of their use as a catalyst for the catalytic cracking of biomass pyrolysis gases during the two-stage pyrolysis-gasification of biomass. The chars were produced from the pyrolysis of waste tyres, refused derived fuel and biomass in the form of date stones. The results showed that the hydrocarbon tar yields decreased significantly with all the char materials used in comparison to the non-char catalytic experiments. For example, at a cracking temperature of 800 °C, the total product hydrocarbon tar yield decreased by 70% with tyre char, 50% with RDF char and 9% with biomass date stones char compared to that without char. There was a consequent increase in total gas yield. Analysis of the tar composition showed that the content of phenolic compounds decreased and polycyclic aromatic hydrocarbons increased in the product tar at higher char temperatures

Rapid generation of human B-cell lymphomas via combined expression of Myc and Bcl2 and their use as a preclinical model for biological therapies

Although numerous mouse models of B-cell malignancy have been developed via the enforced expression of defined oncogenic lesions, the feasibility of generating lineage-defined human B-cell malignancies using mice reconstituted with modified human hematopoietic stem cells (HSCs) remains unclear. In fact, whether human cells can be transformed as readily as murine cells by simple oncogene combinations is a subject of considerable debate. Here, we describe the development of humanized mouse model of MYC/BCL2-driven ‘double-hit’ lymphoma. By engrafting human HSCs transduced with the oncogene combination into immunodeficient mice, we generate a fatal B malignancy with complete penetrance. This humanized-MYC/BCL2-model (hMB) accurately recapitulates the histopathological and clinical aspects of steroid-, chemotherapy- and rituximab-resistant human ‘double-hit’ lymphomas that involve the MYC and BCL2 loci. Notably, this model can serve as a platform for the evaluation of antibody-based therapeutics. As a proof of principle, we used this model to show that the anti-CD52 antibody alemtuzumab effectively eliminates lymphoma cells from the spleen, liver and peripheral blood, but not from the brain. The hMB humanized mouse model underscores the synergy of MYC and BCL2 in ‘double-hit’ lymphomas in human patients. Additionally, our findings highlight the utility of humanized mouse models in interrogating therapeutic approaches, particularly human-specific monoclonal antibodies.Kathy and Curt Marble Cancer Research FundSingapore-MIT Alliance for Research and TechnologyNational Institutes of Health (U.S.) (Grant R01-CA128803)Virginia and Daniel K. Ludwig Graduate FellowshipNational Institute of General Medical Sciences (U.S.) (Medical Scientist Training Program Grant T32GM007753)MIT School of Science (Cancer Research Fellowship

Membrane-Bound IL-21 Promotes Sustained Ex Vivo Proliferation of Human Natural Killer Cells

NK cells have therapeutic potential for a wide variety of human malignancies. However, because NK cells expand poorly in vitro, have limited life spans in vivo, and represent a small fraction of peripheral white blood cells, obtaining sufficient cell numbers is the major obstacle for NK-cell immunotherapy. Genetically-engineered artificial antigen-presenting cells (aAPCs) expressing membrane-bound IL-15 (mbIL15) have been used to propagate clinical-grade NK cells for human trials of adoptive immunotherapy, but ex vivo proliferation has been limited by telomere shortening. We developed K562-based aAPCs with membrane-bound IL-21 (mbIL21) and assessed their ability to support human NK-cell proliferation. In contrast to mbIL15, mbIL21-expressing aAPCs promoted log-phase NK cell expansion without evidence of senescence for up to 6 weeks of culture. By day 21, parallel expansion of NK cells from 22 donors demonstrated a mean 47,967-fold expansion (median 31,747) when co-cultured with aAPCs expressing mbIL21 compared to 825-fold expansion (median 325) with mbIL15. Despite the significant increase in proliferation, mbIL21-expanded NK cells also showed a significant increase in telomere length compared to freshly obtained NK cells, suggesting a possible mechanism for their sustained proliferation. NK cells expanded with mbIL21 were similar in phenotype and cytotoxicity to those expanded with mbIL15, with retained donor KIR repertoires and high expression of NCRs, CD16, and NKG2D, but had superior cytokine secretion. The mbIL21-expanded NK cells showed increased transcription of the activating receptor CD160, but otherwise had remarkably similar mRNA expression profiles of the 96 genes assessed. mbIL21-expanded NK cells had significant cytotoxicity against all tumor cell lines tested, retained responsiveness to inhibitory KIR ligands, and demonstrated enhanced killing via antibody-dependent cell cytotoxicity. Thus, aAPCs expressing mbIL21 promote improved proliferation of human NK cells with longer telomeres and less senescence, supporting their clinical use in propagating NK cells for adoptive immunotherapy

Nonhalogenated organic molecules from Laurencia algae

The marine red algae of the genus Laurencia have produced more 700 secondary metabolites and exhibited high molecular diversity and intriguing bioactivity. Since the halogenated structures have been comprehensively reviewed previously, this review, covering up to the end of 2012, mainly focuses on the source, structure elucidation, and bioactivity of nonhalogenated organic molecules from Laurencia spp. as well as the relationship between nonhalogenated and halogenated products. Overall, 173 new or new naturally occurring compounds with 58 skeletons, mainly including sesquiterpenes, diterpenes, triterpenes, and C15-acetogenins, are described.The marine red algae of the genus Laurencia have produced more 700 secondary metabolites and exhibited high molecular diversity and intriguing bioactivity. Since the halogenated structures have been comprehensively reviewed previously, this review, covering up to the end of 2012, mainly focuses on the source, structure elucidation, and bioactivity of nonhalogenated organic molecules from Laurencia spp. as well as the relationship between nonhalogenated and halogenated products. Overall, 173 new or new naturally occurring compounds with 58 skeletons, mainly including sesquiterpenes, diterpenes, triterpenes, and C-15-acetogenins, are described