Mechanisms of Hemolysis-Associated Platelet Activation

Background Intravascular hemolysis occurs after blood transfusion, in hemolytic anemias, and in other conditions, and is associated with hypercoagulable states. Hemolysis has been shown to potently activate platelets in vitro and in vivo, and several mechanisms have been suggested to account for this, including: (i) direct activation by hemoglobin (Hb); (ii) increase in reactive oxygen species (ROS); (iii) scavenging of nitric oxide (NO) by released Hb; and (iv) release of intraerythrocytic ADP. Objective To elucidate the mechanism of hemolysis-mediated platelet activation. Methods We used flow cytometry to detect PAC-1 binding to activated platelets for in vitro experiments, and a Siemens\u27 Advia 120 hematology system to assess platelet aggregation by using platelet counts from in vivo experiments in a rodent model. Results We found that Hb did not directly activate platelets. However, ADP bound to Hb could cause platelet activation. Furthermore, platelet activation caused by shearing of red blood cells (RBCs) was reduced in the presence of apyrase, which metabolizes ADP to AMP. The use of ROS scavengers did not affect platelet activation. We also found that cell-free Hb enhanced platelet activation by abrogating the inhibitory effect of NO on platelet activation. In vivo infusions of ADP and purified (ADP-free) Hb, as well as hemolysate, resulted in platelet aggregation, as shown by decreased platelet counts. Conclusion Two primary mechanisms account for RBC hemolysis-associated platelet activation: ADP release, which activates platelets; and cell-free Hb release, which enhances platelet activation by lowering NO bioavailability

Circumstellar molecular composition of the oxygen-rich AGB star IK Tau: I. Observations and LTE chemical abundance analysis

The aim of this paper is to study the molecular composition in the circumstellar envelope around the oxygen-rich star IK Tau. We observed IK Tau in several (sub)millimeter bands using the APEX telescope during three observing periods. To determine the spatial distribution of the $\mathrm{^{12}CO(3-2)}$ emission, mapping observations were performed. To constrain the physical conditions in the circumstellar envelope, multiple rotational CO emission lines were modeled using a non local thermodynamic equilibrium radiative transfer code. The rotational temperatures and the abundances of the other molecules were obtained assuming local thermodynamic equilibrium. An oxygen-rich Asymptotic Giant Branch star has been surveyed in the submillimeter wavelength range. Thirty four transitions of twelve molecular species, including maser lines, were detected. The kinetic temperature of the envelope was determined and the molecular abundance fractions of the molecules were estimated. The deduced molecular abundances were compared with observations and modeling from the literature and agree within a factor of 10, except for SO$_2$, which is found to be almost a factor 100 stronger than predicted by chemical models. From this study, we found that IK Tau is a good laboratory to study the conditions in circumstellar envelopes around oxygen-rich stars with (sub)millimeter-wavelength molecular lines. We could also expect from this study that the molecules in the circumstellar envelope can be explained more faithful by non-LTE analysis with lower and higher transition lines than by simple LTE analysis with only lower transition lines. In particular, the observed CO line profiles could be well reproduced by a simple expanding envelope model with a power law structure.Comment: 13 pages, 14 figures, 8 tables *Accepted for publication in Astronomy and Astrophysic

Integration of first-principles methods and crystallographic database searches for new ferroelectrics: Strategies and explorations

In this concept paper, the development of strategies for the integration of first-principles methods with crystallographic database mining for the discovery and design of novel ferroelectric materials is discussed, drawing on the results and experience derived from exploratory investigations on three different systems: (1) the double perovskite Sr(Sb$_{1/2}$Mn$_{1/2}$)O$_3$ as a candidate semiconducting ferroelectric; (2) polar derivatives of schafarzikite $M$Sb$_2$O$_4$; and (3) ferroelectric semiconductors with formula $M_2$P$_2$(S,Se)$_6$. A variety of avenues for further research and investigation are suggested, including automated structure type classification, low-symmetry improper ferroelectrics, and high-throughput first-principles searches for additional representatives of structural families with desirable functional properties.Comment: 13 pages, 5 figures, 4 table

Circumstellar molecular composition of the oxygen-rich AGB star IK~Tau: II. In-depth non-LTE chemical abundance analysis

Aims: Little information exists on the circumstellar molecular abundance stratifications of many molecules. The aim is to study the circumstellar chemical abundance pattern of 11 molecules and isotopologs ($^{12}$CO, $^{13}$CO, SiS, $^{28}$SiO, $^{29}$SiO, $^{30}$SiO, HCN, CN, CS, SO, SO$_2$) in the oxygen-rich evolved star IK~Tau. Methods: We have performed an in-depth analysis of a large number of molecular emission lines excited in the circumstellar envelope around IK~Tau. The analysis is done based on a non-local thermodynamic equilibrium (non-LTE) radiative transfer analysis, which calculates the temperature and velocity structure in a self-consistent way. The chemical abundance pattern is coupled to theoretical outer wind model predictions including photodestruction and cosmic ray ionization. Not only the integrated line intensities, but also the line shapes, are used as diagnostic tool to study the envelope structure. Results: The deduced wind acceleration is much slower than predicted from classical theories. SiO and SiS are depleted in the envelope, possibly due to the adsorption onto dust grains. For HCN and CS a clear difference with respect to inner wind non-equilibrium predictions is found, either indicating uncertainties in the inner wind theoretical modeling or the possibility that HCN and CS (or the radical CN) participate in the dust formation. The low signal-to-noise profiles of SO and CN prohibit an accurate abundance determination; the modeling of high-excitation SO$_2$ lines is cumbersome, possibly related to line misidentifications or problems with the collisional rates. The SiO isotopic ratios ($^{29}$SiO/$^{28}$SiO and $^{30}$SiO/$^{28}$SiO) point toward an enhancement in $^{28}$SiO compared to results of classical stellar evolution codes. Predictions for H$_2$O lines in the spectral range of the Herschel/HIFI mission are performed. [abbreviated]Comment: 24 pagees, accepted for publication in Astronomy & Astrophysic

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Five areas to advance branding theory and practice

The paper suggests five areas to advance branding theory and practice based on the authors’ recent work in brand management. In this commentary, we aim to put forward suggestions and ideas for further research in brand management; ideas, which we believe will have an impact on the way branding is researched and practiced by both academics and practitioners alike. We will focus on the future of branding in the following areas, inspired by our own work in the field: (1) branding in higher education, (2) branding in Asia Pacific, (3) brand ambidexterity, (4) brand innovation on social media, and (5) brand likeability

Phenotypic and transcriptomic characterization of canine myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSCs) are key players in immune evasion, tumor progression and metastasis. MDSCs accumulate under various pathological states and fall into two functionally and phenotypically distinct subsets that have been identified in humans and mice: polymorphonuclear (PMN)-MDSCs and monocytic (M)-MDSCs. As dogs are an excellent model for human tumor development and progression, we set out to identify PMN-MDSCs and M-MDSCs in clinical canine oncology patients. Canine hypodense MHC class II-CD5-CD21-CD11b+ cells can be subdivided into polymorphonuclear (CADO48A+CD14-) and monocytic (CADO48A-CD14+) MDSC subsets. The transcriptomic signatures of PMN-MDSCs and M-MDSCs are distinct, and moreover reveal a statistically significant similarity between canine and previously published human PMN-MDSC gene expression patterns. As in humans, peripheral blood frequencies of canine PMN-MDSCs and M-MDSCs are significantly higher in dogs with cancer compared to healthy control dogs (PMN-MDSCs: p < 0.001; M-MDSCs: p < 0.01). By leveraging the power of evolution, we also identified additional conserved genes in PMN-MDSCs of multiple species that may play a role in MDSC function. Our findings therefore validate the dog as a model for studying MDSCs in the context of cancer

Consensus Paper: Cerebellum and Social Cognition.

The traditional view on the cerebellum is that it controls motor behavior. Although recent work has revealed that the cerebellum supports also nonmotor functions such as cognition and affect, only during the last 5 years it has become evident that the cerebellum also plays an important social role. This role is evident in social cognition based on interpreting goal-directed actions through the movements of individuals (social "mirroring") which is very close to its original role in motor learning, as well as in social understanding of other individuals' mental state, such as their intentions, beliefs, past behaviors, future aspirations, and personality traits (social "mentalizing"). Most of this mentalizing role is supported by the posterior cerebellum (e.g., Crus I and II). The most dominant hypothesis is that the cerebellum assists in learning and understanding social action sequences, and so facilitates social cognition by supporting optimal predictions about imminent or future social interaction and cooperation. This consensus paper brings together experts from different fields to discuss recent efforts in understanding the role of the cerebellum in social cognition, and the understanding of social behaviors and mental states by others, its effect on clinical impairments such as cerebellar ataxia and autism spectrum disorder, and how the cerebellum can become a potential target for noninvasive brain stimulation as a therapeutic intervention. We report on the most recent empirical findings and techniques for understanding and manipulating cerebellar circuits in humans. Cerebellar circuitry appears now as a key structure to elucidate social interactions