Potent immunosuppressive mechanisms within the tumor microenvironment contribute to the resistance of aggressive human cancers to immune checkpoint blockade (ICB) therapy. One of the main mechanisms for myeloid-derived suppressor cells (MDSCs) to induce T cell tolerance is through secretion of reactive nitrogen species (RNS), which nitrates tyrosine residues in proteins involved in T cell function. However, so far very few nitrated proteins have been identified. Here, using a transgenic mouse model of prostate cancer and a syngeneic cell line model of lung cancer, we applied a nitroproteomic approach based on chemical derivation of 3-nitrotyrosine and identified that lymphocyte-specific protein tyrosine kinase (LCK), an initiating tyrosine kinase in the T cell receptor signaling cascade, is nitrated at Tyr394 by MDSCs. LCK nitration inhibits T cell activation, leading to reduced interleukin 2 (IL2) production and proliferation. In human T cells with defective endogenous LCK, wild type, but not nitrated LCK, rescues IL2 production. In the mouse model of castration-resistant prostate cancer (CRPC) by prostate-specific deletion of ,, and , CRPC is resistant to an ICB therapy composed of antiprogrammed cell death 1 (PD1) and anticytotoxic-T lymphocyte-associated protein 4 (CTLA4) antibodies. However, we showed that ICB elicits strong anti-CRPC efficacy when combined with an RNS neutralizing agent. Together, these data identify a previously unknown mechanism of T cell inactivation by MDSC-induced protein nitration and illuminate a clinical path hypothesis for combining ICB with RNS-reducing agents in the treatment of CRPC.

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The existence of sympatric populations within Anopheles albimanus Wiedemann with specific host preferences and the question of whether host selection has a genetic basis or is a learned characteristic were investigated. Progeny of wild females collected from corrals or human bait were reared in an insectary. F1 females were fed on a cow or on a human host, allowed to oviposit, and then were released in an experimental hut divided into three compartments. The side rooms occupied by two human or one calf baits were connected by a "funnel-like" cone with the central room in which mosquitoes were released. Females were released at 2000 hours and recaptured the next morning at 0600 hours. A fixed proportion of mosquitoes selected either host (approximately 65% cow and 35% human), irrespective of their parental origin or source of the first blood meal. The data indicate that the existence of cryptic populations with anthropophilic habits is unlikely and that a "learned" host selection also may be ruled out.

The length of the gonotrophic cycle of Anopheles albimanus was estimated by 12 mark-release-recapture studies conducted in corrals in southern Mexico from 1987 to 1990. The initial set of three mark-release studies indicated that the gonotrophic cycle takes at least 4 d based on the day when gravid mosquitoes were first recaptured. However, in later experiments, mosquitoes recaptured seeking hosts at 48 h after release were in Sella's and Christophers' stages I and II, but parity rates had nearly doubled, indicating that eggs may have developed in less than 48 h and that mosquitoes returned to refeed immediately following oviposition. Two gonotrophic cycles probably exist, one of 48 h dominated by parous mosquitoes and one of 4 d comprised of nulliparous, pregravid mosquitoes. Daily survivorship was estimated by regression from the decrease in the daily recapture rate (0.46-0.68) was less than that estimated by the parity rates (0.67-0.69), with no important differences found between wet and dry seasons. Estimates of the probability of a mosquito living long enough to transmit malaria were 2% (range, 1.8-2.5%).

The Tesla Roadster hit the streets in 2008 as the first and only fully electric production supercar. Since 2008, over 1,800 Roadsters have been accumulating zero emission miles in more than 31 countries. In this paper we provide insights and lessons learned from supporting the Roadster's field performance and reliability with over 15 million all-electric miles driven by Roadster owners. This discussion is presented through elements of Tesla's reliability program, field service strategy and continuous improvement efforts.