Concept: Target Corporation
When a plaid object is presented, the visual system decomposes it into its constituting orientation primitives and integrates them at later processing stages. The present study reveals the time course of this process by applying meta- and paracontrast masking to both simple oriented and plaid gratings. With various stimulus onset asynchronies (SOA) between target gratings and surrounding mask annuli, subjects were asked to identify whether targets were simple gratings collinear to the masks, orthogonal to the masks, plaid, or whether no target was presented. The resulting time courses for each type of stimulus confusion showed that metacontrast peaked when orientation primitives had already begun to be integrated into one object, indicated by a dominance of “no target” responses given to plaid stimuli at SOAs around 70 ms. At SOAs around 10 to 30 ms masking also had a significant impact but acted on separable components, indicated by a dominance of “orthogonal” responses given plaid stimuli. Probability summation of “no target” responses given simple gratings revealed that only at shorter SOAs performance for plaid stimuli could be predicted assuming independent features but not at SOAs of at 50-70 ms. We discuss in how far these results could also be explained by the dynamics of cross-orientation suppression (COS) and how they might relate to the process of feature integration in plaids.
BACKGROUND: We would like to investigate the if IMRT produced better target coverage and dose sparing to adjacent normal structures as compared with 3DCRT and LOF for patients with Graves' ophthalmopathy treated with retro-orbital irradiation. METHODS: Ten consecutive patients diagnosed with Graves' ophthalmopathy were prospectively recruited into this study. An individual IMRT, 3DCRT and LOF plan was created for each patient. Conformity index (CI), homogeneity index (HI) and other dosimetric parameters of the targets and organs-at-risk (OAR) generated by IMRT were compared with the other two techniques. RESULTS: Mann–Whitney U test demonstrated that CI generated by IMRT was superior to that produced by 3DCRT and LOF (p=0.005 for both respectively). Similarly HI with IMRT was proven better than 3DCRT (p=0.007) and LOF (p=0.005). IMRT gave rise to better dose sparing to some OARs including globes, lenses and optic nerves as compared with 3DCRT but not with LOF. CONCLUSIONS: IMRT, as compared with 3DCRT and LOF, was found to have a better target coverage, conformity and homogeneity and dose sparing to some surrounding structures, despite a slight increase but clinically negligible dose to other structures. Dosimetrically it might be a preferred treatment technique and a longer follow up is warranted to establish its role in routine clinical use.
Phosphatidylinositol 4-kinase type IIIα (PI4KA) is a host factor essential for Hepatitis C virus (HCV) replication and hence is a target for drug development. PI4KA has also been linked to ER-exit sites and generation of plasma membrane phosphoinositides. Here we developed highly specific and potent inhibitors of PI4KA and conditional knockout mice to study the importance of this enzyme in vitro and in vivo. Our studies showed that PI4KA is essential for the maintenance of plasma membrane PtdIns(4,5)P2 pools but only during strong stimulation of receptors coupled to PLC activation. Pharmacological blockade of PI4KA in adult animals leads to sudden death closely correlating with the drugs ability to induce PtdIns(4,5)P2 depletion after agonist stimulation. Genetic inactivation of PI4KA also leads to death, however, the cause in this case is due to severe intestinal necrosis. These studies highlight the risks of targeting PI4KA as an anti HCV strategy and also point to important distinctions between genetic and pharmacological studies when selecting host factors as putative therapeutic targets.
The unique chemical and functional properties of nanoparticles can be harnessed for the delivery of large quantities of various therapeutic biomolecules. Active targeting of nanoparticles by conjugating ligands that bind to target cells strongly facilitates accumulation, internalization into target cells and longer retention at the target site, with consequent enhanced therapeutic effects. Recombinant antibodies with high selectivity and availability for a vast range of targets will dominate the future. In this review, we systematically outline the tremendous progress in the conjugation of antibodies to nanoparticles and the clear advantages that recombinant antibodies offer in the therapeutic targeting of nanoparticles. The demonstrated flexibility of recombinant antibody coupling to nanoparticles highlights the bright future of this technology for modern therapeutic nanomedicine.
Cyclic peptide natural products have evolved to exploit diverse protein targets, many of which control essential cellular processes. Inspired by a series of cyclic peptides with partially elucidated structures, we designed synthetic variants of ternatin, a cytotoxic and anti-adipogenic natural product whose molecular mode of action was unknown. The new ternatin variants are cytotoxic toward cancer cells, with up to 500-fold greater potency than ternatin itself. Using a ternatin photo-affinity probe, we identify the translation elongation factor-1A ternary complex (eEF1A∙GTP∙aminoacyl-tRNA) as a specific target and demonstrate competitive binding by the unrelated natural products, didemnin and cytotrienin. Mutations in domain III of eEF1A prevent ternatin binding and confer resistance to its cytotoxic effects, implicating the adjacent hydrophobic surface as a functional hot spot for eEF1A modulation. We conclude that the eukaryotic elongation factor-1A and its ternary complex with GTP and aminoacyl-tRNA are common targets for the evolution of cytotoxic natural products.
Connectivity of protected areas (PAs) is crucial for meeting their conservation goals. We provide the first global evaluation of countries' progress towards Aichi Target 11 of the Convention on Biological Diversity that is to have at least 17% of the land covered by well-connected PA systems by 2020. We quantify how well the terrestrial PA systems of countries are designed to promote connectivity, using the Protected Connected (ProtConn) indicator. We refine ProtConn to focus on the part of PA connectivity that is in the power of a country to influence, i.e. not penalizing countries for PA isolation due to the sea and to foreign lands. We found that globally only 7.5% of the area of the countries is covered by protected connected lands, which is about half of the global PA coverage of 14.7%, and that only 30% of the countries currently meet the Aichi Target 11 connectivity element. These findings suggest the need for considerable efforts to improve PA connectivity globally. We further identify the main priorities for improving or sustaining PA connectivity in each country: general increase of PA coverage, targeted designation of PAs in strategic locations for connectivity, ensuring permeability of the unprotected landscapes between PAs, coordinated management of neighbouring PAs within the country, and/or transnational coordination with PAs in other countries. Our assessment provides a key contribution to evaluate progress towards global PA connectivity targets and to highlight important strengths and weaknesses of the design of PA systems for connectivity in the world’s countries and regions.
In 2016, the World Health Organization (WHO) adopted a new Global Health Sector Strategy on HIV for 2016-2021. It establishes 15 ambitious targets, including the ‘90-90-90’ target calling on health systems to reduce under-diagnosis of HIV, treat a greater number of those diagnosed, and ensure that those being treated achieve viral suppression.
Classic evolutionary and social exchange perspectives suggest that some people have more mate value than others because they possess desirable traits (e.g., attractiveness, status) that are intrinsic to the individual. This article broadens mate value in 2 ways to incorporate relational perspectives. First, close relationships research suggests an alternative measure of mate value: whether someone can provide a high quality relationship. Second, person perception research suggests that both trait-based and relationship quality measures of mate value should contain a mixture of target variance (i.e., consensus about targets, the classic conceptualization) and relationship variance (i.e., unique ratings of targets). In Study 1, participants described their personal conceptions of mate value and revealed themes consistent with classic and relational approaches. Study 2 used a social relations model blocked design to assess target and relationship variances in participants' romantic evaluations of opposite-sex classmates at the beginning and end of the semester. In Study 3, a one-with-many design documented target and relationship variances among long-term opposite-sex acquaintances. Results generally revealed more relationship variance than target variance; participants' romantic evaluations were more likely to be unique to a particular person rather than consensual. Furthermore, the relative dominance of relationship to target variance was stronger for relational measures of mate value (i.e., relationship quality projections) than classic trait-based measures (i.e., attractiveness, resources). Finally, consensus decreased as participants got to know one another better, and long-term acquaintances in Study 3 revealed enormous amounts of relationship variance. Implications for the evolutionary, close relationships, and person-perception literatures are discussed. (PsycINFO Database Record © 2014 APA, all rights reserved).
Effective clinical cancer immunotherapies, such as administration of the cytokine IL-2, adoptive cell transfer (ACT) and the recent success of blockade of the checkpoint modulators CTLA-4 and PD-1, have been developed without clear identification of the immunogenic targets expressed by human cancers in vivo. Immunotherapy of patients with cancer through the use of ACT with autologous lymphocytes has provided an opportunity to directly investigate the antigen recognition of lymphocytes that mediate cancer regression in humans. High-throughput immunological testing of such lymphocytes in combination with improvements in deep sequencing of the autologous cancer have provided new insight into the molecular characterization and incidence of anti-tumor lymphocytes present in patients with cancer. Here we highlight evidence suggesting that T cells that target tumor neoantigens arising from cancer mutations are the main mediators of many effective cancer immunotherapies in humans.
Diffuse axonal injury (DAI) remains a prominent feature of human traumatic brain injury (TBI) and a major player in its subsequent morbidity. The importance of this widespread axonal damage has been confirmed by multiple approaches including postmortem neuropathology and advanced imaging capable of detecting the signatures of DAI across a spectrum of TBI in humans. Despite the increased interest in DAI and its implications for TBI patients, many questions remain about its pathogenesis and its therapeutic targeting. To address these deficiencies and to identify future directions needed to fill critical gaps in our understanding of DAI, the NINDS hosted a workshop in May 2011. This workshop sought to determine what is known regarding the pathogenesis of DAI in animal models of injury as well as in humnas. The workshop also addressed new tools to aid in the identification of DAI while also identifying therapeutic targets linked to DAI for continued preclinical investigation and ultimately, clinical translation. This report encapsulates the oral and written components of this workshop, addressing the key features regarding DAI, the biomechanics implicated in its initiating pathology, and those experimental animal modeling considerations that bear relevance to the biomechanical features of human TBI. Parallel considerations of alternate forms of DAI detection including advanced neuroimaging, electrophysiological, biomarker, and neurobehavioral evaluations are included, together with recommendations for how these technologies can be better integrated for a more comprehensive appreciation of the pathobiology of DAI and its overall structural and functional implications. Lastly, the document closes with a thorough review of the targets linked to the pathogenesis of DAI, while also presenting a detailed report of those target based therapies that have been utilized to date, with a consideration of their overall implications for future preclinical discovery and subsequent translation to the clinic.