Continuous input nonlocal games

We present a family of nonlocal games in which the inputs the players receive are continuous. We study three representative members of the family. For the first two a team sharing quantum correlations (entanglement) has an advantage over any team restricted to classical correlations. We conjecture that this is true for the third member of the family as well.     

Characterization of GPVI- or GPVI-CD39-Coated Nanoparticles and Their Impact on In Vitro Thrombus Formation

Traditional antithrombotic agents commonly share a therapy-limiting side effect, as they increase the overall systemic bleeding risk. A novel approach for targeted antithrombotic therapy is nanoparticles. In other therapeutic fields, nanoparticles have enabled site-specific delivery with low levels of toxicity and side effects. Here, we paired nanotechnology with an established dimeric glycoprotein VI-Fc (GPVI-Fc) and a GPVI-CD39 fusion protein, thereby combining site-specific delivery and new antithrombotic drugs. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles, NP-BSA, NP-GPVI and NP-GPVI-CD39 were characterized through electron microscopy, atomic force measurements and flow cytometry. Light transmission aggregometry enabled analysis of platelet aggregation. Thrombus formation was observed through flow chamber experiments. NP-GPVI and NP-GPVI-CD39 displayed a characteristic surface coating pattern. Fluorescence properties were identical amongst all samples. NP-GPVI and NP-GPVI-CD39 significantly impaired platelet aggregation. Thrombus formation was significantly impaired by NP-GPVI and was particularly impaired by NP-GPVI-CD39. The receptor-coated nanoparticles NP-GPVI and the bifunctional molecule NP-GPVI-CD39 demonstrated significant inhibition of in vitro thrombus formation. Consequently, the nanoparticle-mediated antithrombotic effect of GPVI-Fc, as well as GPVI-CD39, and an additive impact of CD39 was confirmed. In conclusion, NP-GPVI and NP-GPVI-CD39 may serve as a promising foundation for a novel therapeutic approach regarding targeted antithrombotic therapy.     

Analysis of daily body weight of high-producing dairy cows in the first one hundred twenty days of lactation and associations with ovarian inactivity

The objective of this study was to investigate, describe, and quantify daily body weight (BW) changes in the first 120 d of lactation in high-producing dairy cows. Data included 255,287 daily BW measurements from 2,167 Israeli Holstein dairy cows originating from 7 commercial dairy farms. Individual series of measurements were first smoothed using cubic splines for generating variables representing BW changes in early lactation and further analysis of the data. To construct standard BW curves stratified by parity and adjusted for farm, mixed models for repeated measurements were fit to the smoothed data, and least squares means for day in lactation were plotted. Time-series analysis techniques using polynomial functions of day in lactation and pairs of sine and cosine functions representing 7- and 21-d cycles were performed separately on each individual series of measurements. Additionally, generalized estimating equations were used to perform similar analysis on the data set as a whole. Mean days from calving to nadir BW increased significantly from first to later parities, as did mean BW loss from calving to nadir. The first-parity cow lost 6.5% of her BW from calving to d 29 in lactation, and second-parity and greater-parity cows lost 8.5 and 8.4% of their BW to d 34 and 38 in lactation, respectively. After nadir BW was reached, first-parity cows regained relative BW at a greater rate than did older parity cows. The trend in BW was nonlinear. A 7-d cycle was present in 247 cows (11.4%) and a 21-d cycle was present in 715 cows (33.0%). Presence of a 21-d cycle was associated with a 33% reduction in the risk of being diagnosed with inactive ovaries. Fewer days from calving to nadir BW and smaller BW loss from calving to nadir, coupled with a faster post-nadir increase in relative BW in first-parity cows compared with older cows indicated a smaller energy deficit in early lactation. Association between 21-d cycles in BW and ovarian activity suggest that these cycles were physiological and related to the estrous cycle. Therefore, monitoring them could be useful for indirectly assessing ovarian activity in a herd.     

Heparin and Arginine Based Plasmin Nanoformulation for Ischemic Stroke Therapy

Ischemic stroke is the most common type of stroke and thrombolytic therapy is the only approved treatment. However, current thrombolytic therapy with tissue plasminogen activator (tPA) is often hampered by the increased risk of hemorrhage. Plasmin, a direct fibrinolytic, has a significantly superior hemostatic safety profile; however, if injected intravenously it becomes rapidly inactivated by anti-plasmin. Nanoformulations have been shown to increase drug stability and half-life and hence could be applied to increase the plasmin therapeutic efficacy. Here in this paper, we report a novel heparin and arginine-based plasmin nanoformulation that exhibits increased plasmin stability and efficacy. In vitro studies revealed significant plasmin stability in the presence of anti-plasmin and efficient fibrinolytic activity. In addition, these particles showed no significant toxicity or oxidative stress effects in human brain microvascular endothelial cells, and no significant blood brain barrier permeability. Further, in a mouse photothrombotic stroke model, plasmin nanoparticles exhibited significant efficacy in reducing stroke volume without overt intracerebral hemorrhage (ICH) compared to free plasmin treatment. The study shows the potential of a plasmin nanoformulation in ischemic stroke therapy.     

Inhibition of mammary tumor growth using lysyl oxidase-targeting nanoparticles to modify extracellular matrix

A cancer nanotherapeutic has been developed that targets the extracellular matrix (ECM)-modifying enzyme lysyl oxidase (LOX) and alters the ECM structure. Poly(d,l-lactide-co-glycolide) nanoparticles (～220 nm) coated with a LOX inhibitory antibody bind to ECM and suppress mammary cancer cell growth and invasion in vitro as well as tumor expansion in vivo, with greater efficiency than soluble anti-LOX antibody. This nanomaterials approach opens a new path for treating cancer with higher efficacy and decreased side effects.     

In vitro antimicrobial susceptibility of Escherichia coli isolates from clinical bovine mastitis in Finland and Israel

Minimal inhibition concentration (MIC) values of 100 Finnish and 100 Israeli Escherichia coli isolated from clinical bovine mastitis were determined for ampicillin, cephalexin, ceftazidime, dihydrostreptomycin, gentamicin, tetracycline, trimethoprim-sulfadiazine, and ciprofloxacin by an agar dilution method. The in vitro antimicrobial susceptibility of the E. coli isolates was high; only 27% showed resistance to one or more tested antimicrobial agents. Fifteen percent of the Israeli isolates and 14% of the Finnish isolates were resistant to tetracycline, 3 and 16% to cephalexin, 10 and 7% to ampicillin, 13 and 9% to dihydrostreptomycin, and 4 and 2% to trimethoprim-sulfadiazine. No gentamicin-, ceftazidime-, or ciprofloxacin-resistant isolates were detected. Eleven percent of all the isolates were resistant to two or more antimicrobial agents. Tetracycline was most often associated with multiresistant patterns. Most of the multiresistant isolates had very high MIC values, whereas most of those that were resistant to only one tested antibiotic had MIC values close to the susceptibility breakpoint. Antimicrobial resistance appeared to pose no problem in E. coli isolated from mastitic milk of both countries. This is probably due to the controlled use of antimicrobial agents in the treatment of dairy herds. Some differences were present in the resistance patterns, which may reflect the different use of antimicrobial agents in these two countries.     

Associations among patterns in daily body weight, body condition scoring, and reproductive performance in high-producing dairy cows

The objective was to investigate the associations between body condition scores (BCS) and daily body weight (BW) in the first 150 d of lactation (DIM) and reproductive performance in high-producing dairy cows. Data included automated daily BW measurements and BCS of 2,020 Israeli Holstein cows from 7 commercial farms. Individual BW series were smoothed using penalized cubic splines, and variables representing BW patterns were generated. The presence of 7- and 21-d cycles in BW was determined using time-series analysis. Associations between BW and BCS and conception at first artificial insemination (AI) were analyzed using generalized estimating equations. Multivariate survival analysis was used for associations between BW and BCS and the calving-to-first AI interval, first AI-to-conception interval, and calving-to-conception interval. First-parity cows that lost ≥12% and second-parity cows that lost ≥15% of their BW from calving to nadir BW were less likely to conceive at first AI. Cows without 7-d cycles in BW were 1.48 times more likely to conceive at first AI relative to cows with 7-d cycles. The odds of conceiving at first AI increased by 53% for each additional unit in BCS from 40 to 60 DIM. In the multivariate survival analysis, a BCS of ≤2.5 between 40 and 60 DIM, the percentage of BW lost from calving to nadir BW, and a BW loss of ≥7% from calving to 10 DIM were associated with reduced reproductive performance. The presence of 21-d cycles in BW was associated with high reproductive performance in first-parity [odds ratio (OR) = 1.18] and second-parity cows (OR = 1.22). The presence of 7-d cycles in BW was associated with low reproductive performance in first-parity cows (OR = 0.77), but not in older cows. Based on previous findings and on the associations found in this study, we postulate that 21-d cycles are probably related to the sexual cycle and could be used as a proxy for assessing ovarian activity. Variables representing relative BW loss (%) were better predictors for impaired reproductive performance than those representing absolute BW loss (kg) and may be more suitable for estimating individual adaptation to negative energy balance in herds for which automated daily BW is available.     

Horizons for Modern Electrochemistry Related to Energy Storage and Conversion,a Review

The purpose of this paper is to suggest frontier inter‐disciplinary research directions that can be considered as important horizons of modern electrochemistry in the field of energy storage and conversion. We selected several topics that call for advancements in solid‐state, interfacial, analytical and energy‐related electrochemical science. A dramatic improvement in the performance of energy storage and conversion devices is needed to meet the urgent demands of our society. Significantly more efficient devices are needed to meet two major challenges: electro‐mobility, namely electrochemical propulsion of electric vehicles, and the ability to store and convert large quantities of energy generated from sustainable sources such as sun and wind. We suggest promotion of breakthroughs in several important directions. The examples chosen include: Development of novel in‐situ methodologies for design and testing composite electrodes for advanced energy storage devices; Improving the electrochemical performance of high specific capacity, but hard to control, LiNiO₂ cathodes for advanced lithium ion batteries designed for electric vehicles, with a quantitative goal of stable specific capacity >230 mAh/g with a charging potential lower than 4.3 V; Advancing aqueous electrochemical systems for large energy storage based on sodium electrochemistry; Promoting development of batteries based on multivalent active metals with magnesium as the most advanced example. There is a strong incentive to promote fundamental and practical progress in the field of rechargeable Mg batteries using new electrodes’ configurations and advanced electroanalytical methods. All these directions require deep efforts in basic, fundamental studies, in order to reach important practical goals.     

Nanoscale Mechanosensing of Natural Killer Cells is Revealed by Antigen‐Functionalized Nanowires

Cells sense their environment by transducing mechanical stimuli into biochemical signals. Commonly used tools to study cell mechanosensing provide limited spatial and force resolution. Here, a novel nanowire‐based platform for monitoring cell forces is reported. Nanowires are functionalized with ligands for cell immunoreceptors, and they are used to explore the mechanosensitivity of natural killer (NK) cells. In particular, it is found that NK cells apply centripetal forces to nanowires, and that the nanowires stimulate cell contraction. Based on the nanowire deformation, it is calculated that cells apply forces of down to 10 pN, which is the smallest value demonstrated so far by microstructured platforms for cell spreading. Furthermore, the roles of: i) nanowire topography and ii) activating ligands in the cell immune function are studied and it is found that only their combination produces enhanced population of activated NK cells. Thus, a mechanosensing mechanism of NK cells is proposed, by which they integrate biochemical and mechanical stimuli into a decision‐making machinery analogous to the AND logic gate, whose output is the immune activation. This work reveals unprecedented mechanical aspects of NK cell immune function and introduces an innovative nanomaterial for studying cellular mechanics with unparalleled spatial and mechanical resolution.