Targeting co-stimulatory molecules in autoimmune disease

Therapeutic targeting of immune checkpoints has garnered significant attention in the area of cancer immunotherapy, in which efforts have focused in particular on cytotoxic T lymphocyte antigen 4 (CTLA4) and PD1, both of which are members of the CD28 family. In autoimmunity, these same pathways can be targeted to opposite effect: to curb the over-exuberant immune response. The CTLA4 checkpoint serves as an exemplar, whereby CTLA4 activity is blocked by antibodies in cancer immunotherapy and augmented by the provision of soluble CTLA4 in autoimmunity. Here, we review the targeting of co-stimulatory molecules in autoimmune diseases, focusing in particular on agents directed at members of the CD28 or tumour necrosis factor receptor families. We present the state of the art in co-stimulatory blockade approaches, including rational combinations of immune inhibitory agents, and discuss the future opportunities and challenges in this field

Modelling economic impacts of deficit irrigated maize in Brazil with consideration of different rainfall regimes

Deficit irrigation is often required to cope with droughts and limited water availability. However, to select an appropriate irrigation management, it is necessary to assess when economic impacts of deficit irrigation are acceptable. Thus, the main goal of this study was to evaluate economic water productivity for maize submitted to various levels of water deficits and different irrigation systems. The study was based on two different experiments conducted in Southern Brazil, one using sprinkler irrigation to supplement rainfall and the other using drip irrigation with precipitation excluded by a rainfall shelter to simulate cultivation under dry conditions. Water productivity indicators were calculated referring to: a) actual field collected data, including yields, commodity prices and production costs; and b) a sensitivity analysis to commodity prices and production costs. Alternative centrepivot irrigation scenarios were also developed to assess their feasibility in terms of water use and productivity when irrigation is used to supplement rainfall or when rainfall is scarce. Results show that the feasibility of deficit irrigation is highly influenced by commodity prices and by the irrigation (and water) costs when the irrigation costs are a large part of the production costs. Results also show that deficit irrigation applied when rainfall is abundant is easier to implement than deficit irrigation where rainfall is very scarce, when only a mild stress is economically viable. For well-designed and managed centrepivot systems, results confirm that adopting deficit irrigation when rainfall is scarce is less attractive than under conditions of irrigation to supplement rainfall. It could be concluded that farmers are unlikely to choose a deficit irrigation strategy unless they are facing reduced water availability for irrigatio

Modelling soil water dynamics of full and deficit drip irrigated maize cultivated under a rain shelter

Research PaperThe model HYDRUS-1D was used to simulate soil water dynamics of full and deficit irrigated maize grown under a rainout shelter during two crop seasons. Four irrigation treatments were established based on the amount of water applied to fulfil crop water requirements. Treatment D1 was irrigated to fully satisfy crop water requirements, while treatments D2 (mild deficit), D3 (moderate deficit), and D4 (severe deficit) were for increased controlled water stress conditions. The computation and partitioning of evapotranspiration data into soil evaporation and crop transpiration was carried out with the SIMDualKc model, and then used with HYDRUS-1D. The soil hydraulic properties were determined from numerical inversion of field water content data. The compensated root water uptake mechanism was used to describe water removal by plants. TheHYDRUS-1D model successfully simulated the temporal variability of soil water dynamics in treatments irrigated with full and deficit irrigation, producing RMSE values that varied between 0.014 and 0.025 cm3 cm 3 when comparing model simulations with field measurements. Actual transpiration varied between 224 and 483 mm. Potential transpiration reductions varied from 0.4 to 48.8% due to water stress, but plants were able to compensate for the water deficits in the surface layers by removing more water from the deeper, less stressed layers. HYDRUS-1D water balance estimates were also comparable with the corresponding ones determined with the SIMDualKc water balance model. Both modelling approaches should contribute to improve the webbased IRRIGA system, used to support farm irrigation scheduling in Brazilinfo:eu-repo/semantics/publishedVersio

Combined effect of bumetanide, bromide, and GABAergic agonists: An alternative treatment for intractable seizures

Univ Fed Sao Joao del Rei, Lab Neurociencia Expt & Computac, Programa Inst Bioengn, Sao Joao Del Rei, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Expt Neurol, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Fisiol, São Paulo, BrazilPontificia Univ Catolica Rio Grande do Su, Inst Cerebro, Porto Alegre, RS, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Expt Neurol, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Fisiol, São Paulo, BrazilWeb of Scienc

Bidirectional Notch signaling and osteocyte-derived factors in the bone marrow microenvironment promote tumor cell proliferation and bone destruction in multiple myeloma

In multiple myeloma, an overabundance of monoclonal plasma cells in the bone marrow induces localized osteolytic lesions that rarely heal due to increased bone resorption and suppressed bone formation. Matrix-embedded osteocytes comprise more than 95% of bone cells and are major regulators of osteoclast and osteoblast activity, but their contribution to multiple myeloma growth and bone disease is unknown. Here, we report that osteocytes in a mouse model of human MM physically interact with multiple myeloma cells in vivo, undergo caspase-3-dependent apoptosis, and express higher RANKL (TNFSF11) and sclerostin levels than osteocytes in control mice. Mechanistic studies revealed that osteocyte apoptosis was initiated by multiple myeloma cell-mediated activation of Notch signaling and was further amplified by multiple myeloma cell-secreted TNF. The induction of apoptosis increased osteocytic Rankl expression, the osteocytic Rankl/Opg (TNFRSF11B) ratio, and the ability of osteocytes to attract osteoclast precursors to induce local bone resorption. Furthermore, osteocytes in contact with multiple myeloma cells expressed high levels of Sost/sclerostin, leading to a reduction in Wnt signaling and subsequent inhibition of osteoblast differentiation. Importantly, direct contact between osteocytes and multiple myeloma cells reciprocally activated Notch signaling and increased Notch receptor expression, particularly Notch3 and 4, stimulating multiple myeloma cell growth. These studies reveal a previously unknown role for bidirectional Notch signaling that enhances MM growth and bone disease, suggesting that targeting osteocyte-multiple myeloma cell interactions through specific Notch receptor blockade may represent a promising treatment strategy in multiple myeloma