Site-directed mutagenesis reveals a unique requirement for tyrosine residues in IL-7Rα and TSLPR cytoplasmic domains in TSLP-dependent cell proliferation

<p>Abstract</p> <p>Background</p> <p>Thymic stromal lymphopoietin (TSLP) is an interleukin-7 (IL-7) like cytokine, which plays an important role in the regulation of immune responses to allergens. TSLP binds to a heterodimeric receptor complex composed of the IL-7 receptor α chain (IL-7Rα) and the TSLP receptor (TSLPR, also known as CRLF2). It has previously been suggested that the lone tyrosine residue in the mouse TSLPR cytoplasmic domain is required for cell proliferation using chimeric receptor systems. Also the role of tyrosine residues in the IL-7Rα cytoplasmic domain in TSLP signaling has not yet been investigated. We undertook a systematic analysis to test the role of tyrosine residues of both the IL-7Rα and the TSLPR in inducing cell proliferation in a growth factor dependent cell line, Ba/F3.</p> <p>Results</p> <p>A multiple sequence alignment of the IL-7Rα and TSLPR cytoplasmic domains revealed conservation of most, but not all, cytoplasmic tyrosine residues across several species. Our site-directed mutagenesis experiments revealed that the single tyrosine residue in human TSLPR was not required for TSLP-dependent cell proliferation. It has previously been reported that Y449 of human IL-7Rα is required for IL-7 dependent proliferation. Interestingly, in contrast to IL-7 signaling, none of tyrosine residues in the human IL-7Rα cytoplasmic domain were required for TSLP-dependent cell proliferation in the presence of a wild type TSLPR. However, the mutation of all cytoplasmic four tyrosine residues of human IL-7Rα and human TSLPR to phenylalanine residues abolished the proliferative ability of the TSLP receptor complex in response to TSLP.</p> <p>Conclusion</p> <p>These results suggest that TSLP requires at least one cytoplasmic tyrosine residue to transmit proliferative signals. Unlike other members of IL-2 cytokine family, tyrosine residues in IL-7Rα and TSLPR cytoplasmic domains play a redundant role in TSLP-mediated cell growth.</p

Microbial fuel cells: a green and alternative source for bioenergy production

Microbial fuel cell (MFC) represents one of the green technologies for the production of bioenergy. MFCs using microalgae produce bioenergy by converting solar energy into electrical energy as a function of metabolic and anabolic pathways of the cells. In the MFCs with bacteria, bioenergy is generated as a result of the organic substrate oxidation. MFCs have received high attention from researchers in the last years due to the simplicity of the process, the absence in toxic by-products, and low requirements for the algae growth. Many studies have been conducted on MFC and investigated the factors affecting the MFC performance. In the current chapter, the performance of MFC in producing bioenergy as well as the factors which influence the efficacy of MFCs is discussed. It appears that the main factors affecting MFC’s performance include bacterial and algae species, pH, temperature, salinity, substrate, mechanism of electron transfer in an anodic chamber, electrodes materials, surface area, and electron acceptor in a cathodic chamber. These factors are becoming more influential and might lead to overproduction of bioenergy when they are optimized using response surface methodology (RSM)

Antigen-specific influence of GM/KM allotypes on IgG isotypes and association of GM allotypes with susceptibility to Plasmodium falciparum malaria

<p>Abstract</p> <p>Background</p> <p><it>Plasmodium falciparum </it>malaria is a complex disease in which genetic and environmental factors influence susceptibility. IgG isotypes are in part genetically controlled, and GM/KM allotypes are believed to be involved in this control.</p> <p>Methods</p> <p>In this study, 216 individuals from Daraweesh, an area of seasonal malaria transmission in Sudan, were followed for nine years for malaria infection. Total IgG and IgG isotypes against four malaria antigens, MSP2-3D7, MSP2-FC27, AMA1, and Pf332-C231 were measured in plasma obtained from the cohort at the end of the study, during the dry malaria-free period. The GM/KM allotypes of the donors were determined.</p> <p>Results</p> <p>The GM 1,17 5,13,14,6 phenotype was associated with a higher incidence of malaria compared with the non-1,17 5,13,14,6 phenotypes (P = 0.037). Paradoxically, the carriers of the GM 1,17 5,13,14,6 phenotype had significantly higher baseline levels of total IgG and non-cytophilic IgG isotypes as compared to non-carriers. The KM allotypes influence on IgG isotypes level was limited. Finally, the differences in the baseline concentrations of total IgG and IgG isotypes between the different GK/KM phenotype carriers were antigen-dependent.</p> <p>Discussion</p> <p>The results show that GM but not KM allotypes appeared to influence host susceptibility to uncomplicated malaria as well as the antibody profile of the donors, and the carriers of the GM 1,17 5,13,14,6 phenotype were the most susceptible</p> <p>Conclusions</p> <p>The GM allotypes have significant influence on susceptibility to uncomplicated <it>P. falciparum </it>malaria and antigen-dependent influence on total IgG and IgG subclasses.</p

Successfully treated synchronous double malignancy of the breast and esophagus: a case report

<p>Abstract</p> <p>Introduction</p> <p>The incidence of multiple primary cancers is reported to be between 0.3% and 4.3%. The second primary lesion is identified either simultaneously with the primary lesion (synchronous) or after a period of time (metachronous). Few cases of metastasis of breast carcinoma to the esophagus and vice versa have been reported in the past.</p> <p>Case presentation</p> <p>We report an extremely rare case of a 55-year-old Indian woman who had carcinomas in both the esophagus and the breast simultaneously. She was treated successfully using combined modalities of surgery, chemotherapy and radiation therapy.</p> <p>Conclusion</p> <p>Cases of synchronous double malignancies can be treated by dealing with the malignancy in the two sites as independent carcinomas. We have to take into consideration the total dose of radiation to a critical organ as well as the effect of the total dose of toxic chemotherapeutic drugs on our patient.</p

Characterizing genomic alterations in cancer by complementary functional associations.

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes

Living in the hinterland: Survey and excavations at Lohari Ragho 2015–2017

Living in the hinterland: Survey and excavations at Lohari Ragho 2015–201

MicroRNA-22 Regulates Hypoxia Signaling in Colon Cancer Cells

MicroRNAs (MiRNAs) are short, non-coding RNA that regulate a variety of cellular functions by suppressing target protein expression. We hypothesized that a set of microRNA regulate tumor responses to hypoxia by inhibiting components of the hypoxia signaling pathway. We found that miR-22 expression in human colon cancer is lower than in normal colon tissue. We also found that miR-22 controls hypoxia inducible factor 1α (HIF-1α) expression in the HCT116 colon cancer cell line. Over-expression of miR-22 inhibits HIF-1α expression, repressing vascular endothelial growth factor (VEGF) production during hypoxia. Conversely, knockdown of endogenous miR-22 enhances hypoxia induced expression of HIF-1α and VEGF. The conditioned media from cells over-expressing miR-22 contain less VEGF protein than control cells, and also induce less endothelial cell growth and invasion, suggesting miR-22 in adjacent cells influences endothelial cell function. Taken together, our data suggest that miR-22 might have an anti-angiogenic effect in colon cancer

Agronomic Management of Indigenous Mycorrhizas

Many of the advantages conferred to plants by arbuscular mycorrhiza (AM) are associated to the ability of AM plants to explore a greater volume of soil through the extraradical mycelium. Sieverding (1991) estimates that for each centimetre of colonized root there is an increase of 15 cm3 on the volume of soil explored, this value can increase to 200 cm3 depending on the circumstances. Due to the enhancement of the volume of soil explored and the ability of the extraradical mycelium to absorb and translocate nutrients to the plant, one of the most obvious and important advantages resulting from mycorrhization is the uptake of nutrients. Among of which the ones that have immobilized forms in soil, such as P, assume particular significance. Besides this, many other benefits are recognized for AM plants (Gupta et al, 2000): water stress alleviation (Augé, 2004; Cho et al, 2006), protection from root pathogens (Graham, 2001), tolerance to toxic heavy metals and phytoremediation (Audet and Charest, 2006; Göhre and Paszkowski, 2006), tolerance to adverse conditions such as very high or low temperature, high salinity (Sannazzaro et al, 2006), high or low pH (Yano and Takaki, 2005) or better performance during transplantation shock (Subhan et al, 1998). The extraradical hyphae also stabilize soil aggregates by both enmeshing soil particles (Miller e Jastrow, 1992) and producing a glycoprotein, golmalin, which may act as a glue-like substance to adhere soil particles together (Wright and Upadhyaya, 1998). Despite the ubiquous distribution of mycorrhizal fungi (Smith and Read, 2000) and only a relative specificity between host plants and fungal isolates (McGonigle and Fitter, 1990), the obligate nature of the symbiosis implies the establishment of a plant propagation system, either under greenhouse conditions or in vitro laboratory propagation. These techniques result in high inoculum production costs, which still remains a serious problem since they are not competitive with production costs of phosphorus fertilizer. Even if farmers understand the significance of sustainable agricultural systems, the reduction of phosphorus inputs by using AM fungal inocula alone cannot be justified except, perhaps, in the case of high value crops (Saioto and Marumoto, 2002). Nurseries, high income horticulture farmers and no-agricultural application such as rehabilitation of degraded or devegetated landscapes are examples of areas where the use of commercial inoculum is current. Another serious problem is quality of commercial available products concerning guarantee of phatogene free content, storage conditions, most effective application methods and what types to use. Besides the information provided by suppliers about its inoculum can be deceiving, as from the usually referred total counts, only a fraction may be effective for a particular plant or in specific soil conditions. Gianinazzi and Vosátka (2004) assume that progress should be made towards registration procedures that stimulate the development of the mycorrhizal industry. Some on-farm inoculum production and application methods have been studied, allowing farmers to produce locally adapted isolates and generate a taxonomically diverse inoculum (Mohandas et al, 2004; Douds et al, 2005). However the inocula produced this way are not readily processed for mechanical application to the fields, being an obstacle to the utilization in large scale agriculture, especially row crops, moreover it would represent an additional mechanical operation with the corresponding economic and soil compaction costs. It is well recognized that inoculation of AM fungi has a potential significance in not only sustainable crop production, but also environmental conservation. However, the status quo of inoculation is far from practical technology that can be widely used in the field. Together a further basic understanding of the biology and diversity of AM fungi is needed (Abbott at al, 1995; Saito and Marumoto, 2002). Advances in ecology during the past decade have led to a much more detailed understanding of the potential negative consequences of species introductions and the potential for negative ecological consequences of invasions by mycorrhizal fungi is poorly understood. Schwartz et al, (2006) recommend that a careful assessment documenting the need for inoculation, and the likelihood of success, should be conducted prior to inoculation because inoculations are not universally beneficial. Agricultural practices such as crop rotation, tillage, weed control and fertilizer apllication all produce changes in the chemical, physical and biological soil variables and affect the ecological niches available for occupancy by the soil biota, influencing in different ways the symbiosis performance and consequently the inoculum development, shaping changes and upset balance of native populations. The molecular biology tools developed in the latest years have been very important for our perception of these changes, ensuing awareness of management choice implications in AM development. In this context, for extensive farming systems and regarding environmental and economic costs, the identification of agronomic management practices that allow controlled manipulation of the fungal community and capitalization of AM mutualistic effect making use of local inoculum, seem to be a wise option for mycorrhiza promotion and development of sustainable crop production

Adaptation to Variable Environments, Resilience to Climate Change: Investigating land, water and settlement in Indus northwest India

This paper explores the nature and dynamics of adaptation and resilience in the face of a diverse and varied environmental and ecological context using the case study of South Asia’s Indus Civilization (ca. 3000–1300 BC). Most early complex societies developed in regions where the climatic parameters faced by ancient subsistence farmers were varied but rain falls primarily in one season. In contrast, the Indus Civilization developed in a specific environmental context that spanned a very distinct environmental threshold, where winter and summer rainfall systems overlap. There is now evidence to show that this region was directly subject to climate change during the period when the Indus Civilization was at its height (ca. 2500–1900 BC). The Indus Civilization, therefore, provides a unique opportunity to understand how an ancient society coped with diverse and varied ecologies and change in the fundamental environmental parameters. This paper integrates research carried out as part of the Land, Water and Settlement project in northwest India between 2007 and 2014. Although coming from only one of the regions occupied by Indus populations, these data necessitate the reconsideration of several prevailing views about the Indus Civilization as a whole and invigorate discussion about human-environment interactions and their relationship to processes of cultural transformation.UKIERI, NERC, AHRC, British Academy, McDonald Institut

miR-22 Forms a Regulatory Loop in PTEN/AKT Pathway and Modulates Signaling Kinetics

Background: The tumor suppressor PTEN (phosphatase and tensin homolog) is a lipid phosphatase that converts PIP3 into PIP2 and downregulates the kinase AKT and its proliferative and anti-apoptotic activities. The FoxO transcription factors are PTEN downstream effectors whose activity is negatively regulated by AKT-mediated phosphorylation. PTEN activity is frequently lost in many types of cancer, leading to increased cell survival and cell cycle progression. Principal Findings: Here we characterize the widely expressed miR-22 and report that miR-22 is a novel regulatory molecule in the PTEN/AKT pathway. miR-22 downregulates PTEN levels acting directly through a specific site on PTEN 39UTR. Interestingly, miR-22 itself is upregulated by AKT, suggesting that miR-22 forms a feed-forward circuit in this pathway. Timeresolved live imaging of AKT-dependent FoxO1 phosphorylation revealed that miR-22 accelerated AKT activity upon growth factor stimulation, and attenuated its down regulation by serum withdrawal. Conclusions: Our results suggest that miR-22 acts to fine-tune the dynamics of PTEN/AKT/FoxO1 pathway