Qualitative design and implementation of human-robot spatial interactions

Despite the large number of navigation algorithms available for mobile robots, in many social contexts they often exhibit inopportune motion behaviours in proximity of people, often with very "unnatural" movements due to the execution of segmented trajectories or the sudden activation of safety mechanisms (e.g., for obstacle avoidance). We argue that the reason of the problem is not only the difficulty of modelling human behaviours and generating opportune robot control policies, but also the way human-robot spatial interactions are represented and implemented. In this paper we propose a new methodology based on a qualitative representation of spatial interactions, which is both flexible and compact, adopting the well-defined and coherent formalization of Qualitative Trajectory Calculus (QTC). We show the potential of a QTC-based approach to abstract and design complex robot behaviours, where the desired robot's behaviour is represented together with its actual performance in one coherent approach, focusing on spatial interactions rather than pure navigation problems

Physical and Functional Association of LFA-1 with DNAM-1 Adhesion Molecule

Whereas ligation of the DNAM-1 adhesion molecule triggers cytotoxicity mediated by normal NK and T cells this function was defective in NK cell clones from leukocyte adhesion deficiency syndrome. However genetic reconstitution of cell surface expression of LFA-1 restored the ability of DNAM-1 to initiate anti-DNAM-1 mAb-induced cytotoxicity indicating a functional relationship between DNAM-1 and LFA-1. Further studies demonstrated that LFA-1 physically associates with DNAM-1 in NK cells and anti-CD3 mAb stimulated T cells for which serine phosphorylation of DNAM-1 plays a critical role. In addition crosslinking of LFA-1 induces tyrosine phosphorylation of DNAM-1 for which the Fyn protein tyrosine kinase is responsible. These results indicate that DNAM-1 is involved in the LFA-1-mediated intracellular signals.journal articl

Molecular Mechanisms Associated with Nicotine Pharmacology and Dependence.

Tobacco dependence is a leading cause of preventable disease and death worldwide. Nicotine, the main psychoactive component in tobacco cigarettes, has also been garnering increased popularity in its vaporized form, as derived from e-cigarette devices. Thus, an understanding of the molecular mechanisms underlying nicotine pharmacology and dependence is required to ascertain novel approaches to treat drug dependence. In this chapter, we review the field's current understanding of nicotine's actions in the brain, the neurocircuitry underlying drug dependence, factors that modulate the function of nicotinic acetylcholine receptors, and the role of specific genes in mitigating the vulnerability to develop nicotine dependence. In addition to nicotine's direct actions in the brain, other constituents in nicotine and tobacco products have also been found to alter drug use, and thus, evidence is provided to highlight this issue. Finally, currently available pharmacotherapeutic strategies are discussed, along with an outlook for future therapeutic directions to achieve to the goal of long-term nicotine cessation

The potential for detecting gamma-ray burst afterglows from population III stars with the next generation of infrared telescopes

We investigate the detectability of a proposed population of gamma-ray bursts (GRBs) from the collapse of Population III (Pop III) stars. The James Webb Space Telescope (JWST) and Space Infrared Telescope for Cosmology and Astrophysics (SPICA) will be able to observe the late time infrared afterglows. We have developed a new method to calculate their detectability, which takes into account the fundamental initial mass function and formation rates of Pop III stars, from which we find the temporal variability of the afterglows and ultimately the length of time JWST and SPICA can detect them. In the range of plausible Pop III GRB parameters, the afterglows are always detectable by these instruments during the isotropic emission, for a minimum of 55 days and a maximum of 3.7 yr. The average number of detectable afterglows will be 2.96× 10–5 per SPICA field of view (FOV) and 2.78× 10–6 per JWST FOV. These are lower limits, using a pessimistic estimate of Pop III star formation. An optimal observing strategy with SPICA could identify a candidate orphan afterglow in ~1.3 yr, with a 90% probability of confirmation with further detailed observations. A beamed GRB will align with the FOV of the planned GRB detector Energetic X-ray Imaging Survey Telescope once every 9 yr. Pop III GRBs will be more easily detected by their isotropic emissions (i.e., orphan afterglows) rather than by their prompt emissions

RESULTS OF IDENTIFICATION OF INFECTIOUS AGENTS OF INFLUENZA AND OTHER ACUTE RESPIRATORY INFECTIONS WITH THE METHOD OF RT-LAMP

Currently, the detection and identification of viruses that cause respiratory and influenza-like illness (ILI) is one of the main tasks of  public healthcare. In 2016-2017, nasopharyngeal swabs were  collected from 200 sick children with ILI aged 0 to 5 years. Detection  of pathogens in ILI patients was carried out by RT-LAMP  amplification method. In 43 % of patients ILI viruses were detected.  Among all confirmed cases of viral infection, a respiratory-syncytial  virus was detected in 49 %, rhinoviruses in 16 %, coronaviruses in 9 %,  parainfluenza viruses in 6 %, and human metapneumoviruses in 2 % of  samples. Influenza A viruses were found in 6 % of infected specimens.  The results obtained demonstrate the effectiveness of using RT-LAMP amplification in differential laboratory diagnostics of the ILI of viral etiology

Targeted hematopoietic stem cell depletion through SCF-blockade

Background: Hematopoietic stem cell transplantation (HSCT) is a curative treatment for many diverse blood and immune diseases. However, HSCT regimens currently commonly utilize genotoxic chemotherapy and/or total body irradiation (TBI) conditioning which causes significant morbidity and mortality through inducing broad tissue damage triggering infections, graft vs. host disease, infertility, and secondary cancers. We previously demonstrated that targeted monoclonal antibody (mAb)-based HSC depletion with anti(α)-CD117 mAbs could be an effective alternative conditioning approach for HSCT without toxicity in severe combined immunodeficiency (SCID) mouse models, which has prompted parallel clinical αCD117 mAbs to be developed and tested as conditioning agents in clinical trials starting with treatment of patients with SCID. Subsequent efforts have built upon this work to develop various combination approaches, though none are optimal and how any of these mAbs fully function is unknown. Methods: To improve efficacy of mAb-based conditioning as a stand-alone conditioning approach for all HSCT settings, it is critical to understand the mechanistic action of αCD117 mAbs on HSCs. Here, we compare the antagonistic properties of αCD117 mAb clones including ACK2, 2B8, and 3C11 as well as ACK2 fragments in vitro and in vivo in both SCID and wildtype (WT) mouse models. Further, to augment efficacy, combination regimens were also explored. Results: We confirm that only ACK2 inhibits SCF binding fully and prevents HSC proliferation in vitro. Further, we verify that this corresponds to HSC depletion in vivo and donor engraftment post HSCT in SCID mice. We also show that SCF-blocking αCD117 mAb fragment derivatives retain similar HSC depletion capacity with enhanced engraftment post HSCT in SCID settings, but only full αCD117 mAb ACK2 in combination with αCD47 mAb enables enhanced donor HSC engraftment in WT settings, highlighting that the Fc region is not required for single-agent efficacy in SCID settings but is required in immunocompetent settings. This combination was the only non-genotoxic conditioning approach that enabled robust donor engraftment post HSCT in WT mice. Conclusion: These findings shed new insights into the mechanism of αCD117 mAb-mediated HSC depletion. Further, they highlight multiple approaches for efficacy in SCID settings and optimal combinations for WT settings. This work is likely to aid in the development of clinical non-genotoxic HSCT conditioning approaches that could benefit millions of people world-wide

Diamond Blackfan anemia is mediated by hyperactive Nemo-like kinase

Diamond Blackfan Anemia (DBA) is a congenital bone marrow failure syndrome associated with ribosomal gene mutations that lead to ribosomal insufficiency. DBA is characterized by anemia, congenital anomalies, and cancer predisposition. Treatment for DBA is associated with significant morbidity. Here, we report the identification of Nemo-like kinase (NLK) as a potential target for DBA therapy. To identify new DBA targets, we screen for small molecules that increase erythroid expansion in mouse models of DBA. This screen identified a compound that inhibits NLK. Chemical and genetic inhibition of NLK increases erythroid expansion in mouse and human progenitors, including bone marrow cells from DBA patients. In DBA models and patient samples, aberrant NLK activation is initiated at the Megakaryocyte/Erythroid Progenitor (MEP) stage of differentiation and is not observed in non-erythroid hematopoietic lineages or healthy erythroblasts. We propose that NLK mediates aberrant erythropoiesis in DBA and is a potential target for therapy

Dysregulated lipid synthesis by oncogenic IDH1 mutation is a targetable synthetic lethal vulnerability

Isocitrate dehydrogenase 1 and 2 (IDH) are mutated in multiple cancers and drive production of (R)-2-hydroxyglutarate (2HG). We identified a lipid synthesis enzyme (acetyl CoA carboxylase 1, ACC1) as a synthetic lethal target in mutant IDH1 (mIDH1), but not mIDH2, cancers. Here, we analyzed the metabolome of primary acute myeloid leukemia (AML) blasts and identified a mIDH1-specific reduction in fatty acids. mIDH1 also induced a switch to beta-oxidation indicating reprogramming of metabolism towards a reliance on fatty acids. Compared to mIDH2, mIDH1 AML displayed depletion of NADPH with defective reductive carboxylation that was not rescued by the mIDH1-specific inhibitor ivosidenib. In xenograft models, a lipid-free diet markedly slowed the growth of mIDH1 AML, but not healthy CD34+ HSPCs or mIDH2 AML. Genetic and pharmacologic targeting of ACC1 resulted in growth inhibition of mIDH1 cancers, not reversible by ivosidenib. Critically, pharmacologic targeting of ACC1 improved sensitivity of mIDH1 AML to venetoclax.Daniel Thomas, Manhong Wu, Yusuke Nakauchi, Ming Zheng, Chloe A.L. Thompson-Peach, Kelly Lim, Niklas Landberg, Thomas Köhnke, Nirmal Robinson, Satinder Kaur, Monika Kutyna, Melissa Stafford, Devendra Hiwase, Andreas Reinisch, Gary Peltz, Ravindra Majet