Multiphysics Modelling and Simulation of Thrombolysis via Activated Platelet-Targeted Nanomedicine

PURPOSE: This study establishes a multiphysics simulation platform for both conventional and targeted thrombolysis using tissue plasminogen activator (tPA). Based on our computational results, the effects of therapeutic parameters on the dynamics of thrombolysis and the risk of side effects are investigated. METHODS: The model extends our previously developed one-dimensional(1D) mathematical models for fibrinolysis by incorporating targeted thrombolysis. It consists of two parts: (i) a coupled mathematical model of systemic pharmacokinetics (PK) and pharmacodynamics (PD) and local PD in a 1D occluded artery, and (ii) a mechanistic model for a targeted thrombolytic system via activated platelet-targeted tPA-loaded nanovesicles (tPA-NV), with model parameters derived from our in vitro experiments. A total of 16 therapeutic scenarios are simulated by varying the clot location and composition as well as the dosing regimen with free tPA or tPA-NV. RESULTS: Our simulation results indicate that tPA-NV offers several advantages over free tPA for thrombolysis. It reduces systemic exposure of tPA, thereby minimising the risk of bleeding complications. Simulations with different tPA-NV doses reveal that tPA-NV at 10% of the recommended dose can be as effective as the standard regimen with the full recommended dose of free tPA, demonstrating the potential of our tPA-NV as a new thrombolytic strategy with a reduced tPA dose. Moreover, faster recanalisation can be achieved with tPA-NV, especially for platelet-rich(or fibrin-poor) clots. CONCLUSIONS: Our simulation platform for thrombolysis with well-tuned model parameters can be used to evaluate and optimise treatment regimens of existing and new thrombolytic therapies via benefit/risk assessment under various therapeutic scenarios

Quantum walks-based simple authenticated quantum cryptography protocols for secure wireless sensor networks

Wireless sensor networks play a crucial role in various applications, ranging from environmental monitoring to industrial automation that require high levels of security. With the development of quantum technologies, many security mechanisms maybe hacked due to the promising capabilities of quantum computation. To address this challenge, quantum protocols have emerged as a promising solution for enhancing the security of wireless sensor communications. One of the common types of quantum protocols is quantum key distribution (QKD) protocols, which are investigated to allow two participants with fully quantum capabilities to share a random secret key, while semi-quantum key distribution (SQKD) protocols are designed to perform the same task using fewer quantum resources to make quantum communications more realizable and practical. Quantum walk plays an essential role in quantum computing, which is a universal quantum computational paradigm. In this work, we utilize the advantages of quantum walk to design three authenticated quantum cryptographic protocols to establish secure channels for data transmission between sensor nodes: the first one is authenticated quantum key distribution (AQKD), the second one is authenticated semi quantum key distribution (ASQKD) with one of the two participants having limited quantum capabilities, and the last one is authenticated semi-quantum key distribution but both legitimate users possess limited quantum resources. The advantages of the proposed protocols are that the partners can exchange several different keys with the same exchanged qubits, and the presented protocols depend on a one-way quantum communication channel. In contrast, all previously designed SQKD protocols rely on two-way quantum communication. Security analyses prove that the presented protocols are secure against various well known attacks and highly efficient. The utilization of the presented protocols in wireless sensor communications opens up new avenues for secure and trustworthy data transmission, enabling the deployment of resilient wireless sensor networks in critical applications. This work also paves the way for future exploration of quantum-based security protocols and their integration into wireless sensor networks for enhanced data protection

Voids in the Large-Scale Structure

Voids are the most prominent feature of the LSS of the universe. Still, they have been generally ignored in quantitative analysis of it, essentially due to the lack of an objective tool to identify and quantify the voids. To overcome this, we present the Void-Finder algorithm, a novel tool for objectively quantifying galaxy voids. The algorithm classifies galaxies as either wall- or field-galaxies. Then it identifies voids in the wall-galaxy distribution. Voids are defined as continuous volumes that do not contain any wall-galaxies. The voids must be thicker than an adjustable limit, which is refined in successive iterations. We test the algorithm using Voronoi tessellations. By appropriate scaling of the parameters we apply it to the SSRS2 survey and to the IRAS 1.2 Jy. Both surveys show similar properties: ~50% of the volume is filled by the voids, which have a scale of at least 40 Mpc, and a -0.9 under-density. Faint galaxies populate the voids more than bright ones. These results suggest that both optically and IRAS selected galaxies delineate the same LSS. Comparison with the recovered mass distribution further suggests that the observed voids in the galaxy distribution correspond well to under-dense regions in the mass distribution. This confirms the gravitational origin of the voids.Comment: Submitted to ApJ; 33 pages, aaspp4 LaTeX file, using epsfig and natbib, 1 table, 12 PS figures. Complete gzipped version is available at http://shemesh.fiz.huji.ac.il/hagai/; uuencoded file is available at http://shemesh.fiz.huji.ac.il/papers/ep3.uu or ftp://shemesh.fiz.huji.ac.i

DRAM-3 modulates autophagy and promotes cell survival in the absence of glucose

Macroautophagy is a membrane-trafficking process that delivers cytoplasmic constituents to lysosomes for degradation. The process operates under basal conditions as a mechanism to turnover damaged or misfolded proteins and organelles. As a result, it has a major role in preserving cellular integrity and viability. In addition to this basal function, macroautophagy can also be modulated in response to various forms of cellular stress, and the rate and cargoes of macroautophagy can be tailored to facilitate appropriate cellular responses in particular situations. The macroautophagy machinery is regulated by a group of evolutionarily conserved autophagy-related (ATG) proteins and by several other autophagy regulators, which either have tissue-restricted expression or operate in specific contexts. We report here the characterization of a novel autophagy regulator that we have termed DRAM-3 due to its significant homology to damage-regulated autophagy modulator (DRAM-1). DRAM-3 is expressed in a broad spectrum of normal tissues and tumor cells, but different from DRAM-1, DRAM-3 is not induced by p53 or DNA-damaging agents. Immunofluorescence studies revealed that DRAM-3 localizes to lysosomes/autolysosomes, endosomes and the plasma membrane, but not the endoplasmic reticulum, phagophores, autophagosomes or Golgi, indicating significant overlap with DRAM-1 localization and with organelles associated with macroautophagy. In this regard, we further proceed to show that DRAM-3 expression causes accumulation of autophagosomes under basal conditions and enhances autophagic flux. Reciprocally, CRISPR/Cas9-mediated disruption of DRAM-3 impairs autophagic flux confirming that DRAM-3 is a modulator of macroautophagy. As macroautophagy can be cytoprotective under starvation conditions, we also tested whether DRAM-3 could promote survival on nutrient deprivation. This revealed that DRAM-3 can repress cell death and promote long-term clonogenic survival of cells grown in the absence of glucose. Interestingly, however, this effect is macroautophagy-independent. In summary, these findings constitute the primary characterization of DRAM-3 as a modulator of both macroautophagy and cell survival under starvation conditions

Segond's fracture: a biomechanical cadaveric study using navigation

Background Segond’s fracture is a well-recognised radiological sign of an anterior cruciate ligament (ACL) tear. While previous studies evaluated the role of the anterolateral ligament (ALL) and complex injuries on rotational stability of the knee, there are no studies on the biomechanical effect of Segond’s fracture in an ACL deficient knee. The aim of this study was to evaluate the effect of a Segond’s fracture on knee rotation stability as evaluated by a navigation system in an ACL deficient knee. Materials and methods Three different conditions were tested on seven knee specimens: intact knee, ACL deficient knee and ACL deficient knee with Segond’s fracture. Static and dynamic measurements of anterior tibial translation (ATT) and axial tibial rotation (ATR) were recorded by the navigation system (2.2 OrthoPilot ACL navigation system B. Braun Aesculap, Tuttlingen, Germany). Results Static measurements at 30 showed that the mean ATT at 30 of knee flexion was 5.1 ± 2.7 mm in the ACL intact condition, 14.3 ± 3.1 mm after ACL cut (P = 0.005), and 15.2 ± 3.6 mm after Segond’s fracture (P = 0.08). The mean ATR at 30 of knee flexion was 20.7 ± 4.8 in the ACL intact condition, 26.9 ± 4.1 in the ACL deficient knee (P[0.05) and 30.9 ± 3.8 after Segond’s fracture (P = 0.005). Dynamic measurements during the pivot-shift showed that the mean ATT was 7.2 ± 2.7 mm in the intact knee, 9.1 ± 3.3 mm in the ACL deficient knee(P = 0.04) and 9.7 ± 4.3 mm in the ACL deficient knee with Segond’s fracture (P = 0.07). The mean ATR was 9.6 ± 1.8 in the intact knee, 12.3 ± 2.3 in the ACL deficient knee (P[0.05) and 19.1 ± 3.1 in the ACL deficient knee with Segond’s lesion (P = 0.016). Conclusion An isolated lesion of the ACL only affects ATT during static and dynamic measurements, while the addition of Segond’s fracture has a significant effect on ATR in both static and dynamic execution of the pivot-shift test, as evaluated with the aid of navigation

The DEEP2 Galaxy Redshift Survey: The Evolution of Void Statistics from z~1 to z~0

We present measurements of the void probability function (VPF) at z~1 using data from the DEEP2 Redshift Survey and its evolution to z~0 using data from the Sloan Digital Sky Survey (SDSS). We measure the VPF as a function of galaxy color and luminosity in both surveys and find that it mimics trends displayed in the two-point correlation function, $\xi$; namely that samples of brighter, red galaxies have larger voids (i.e. are more strongly clustered) than fainter, blue galaxies. We also clearly detect evolution in the VPF with cosmic time, with voids being larger in comoving units at z~0. We find that the reduced VPF matches the predictions of a `negative binomial' model for galaxies of all colors, luminosities, and redshifts studied. This model lacks a physical motivation, but produces a simple analytic prediction for sources of any number density and integrated two-point correlation function, \bar{\xi}. This implies that differences in the VPF across different galaxy populations are consistent with being due entirely to differences in the population number density and \bar{\xi}. The robust result that all galaxy populations follow the negative binomial model appears to be due to primarily to the clustering of dark matter halos. The reduced VPF is insensitive to changes in the parameters of the halo occupation distribution, in the sense that halo models with the same \bar{\xi} will produce the same VPF. For the wide range of galaxies studied, the VPF therefore does not appear to provide useful constraints on galaxy evolution models that cannot be gleaned from studies of \bar{\xi} alone. (abridged)Comment: 17 pages, 15 figures, ApJ accepte

Voids in the PSCz Survey and the Updated Zwicky Catalog

We describe an algorithm to detect voids in galaxy redshift surveys. The method is based on the void finder algorithm of El-Ad & Piran. We apply a series of tests to determine how accurately we are able to recover the volumes of voids using our detection method. We simulate voids of different ellipticity and find that if voids are approximately spherical, our algorithm will recover 100% of the volume of the void. The more elliptical the void, the smaller the fraction of the volume we can recover. We insist that voids lie completely within the survey. Voids close to the edge of the survey will therefore be underestimated in volume. By considering a deeper sample, we estimate the maximal sphere diameters are correct to within 30%. We apply the algorithm to the Point Source Catalogue Survey (PSCz) and the Updated Zwicky Catalog (UZC). The PSCz survey is an almost all-sky survey with objects selected from the IRAS catalog. The UZC covers a smaller area of sky but is optically selected and samples the structures more densely. We detect 35 voids in the PSCz and 19 voids in the UZC with diameter larger than 20h^{-1}Mpc. Using this minimum size threshold, voids have an average effective diameter of 29.8+-3.5 h^{-1}Mpc (PSCz) and 29.2+-2.7 h^{-1}Mpc (UZC) and that they are underdense regions with delta rho /rho values of -0.92+-0.03 (PSCz) and -0.96+-0.01(UZC) respectively. Using this quite stringent threshold for void definition, voids fill up to 40% of the volume of the universe.Comment: Accepted by ApJ to appear in the Feb 20th, 2002 issue. For a version with better resolution of Figures 4 and 5 see http://star-www.dur.ac.uk/~fhoyle/papers.htm

Next-to-leading order QCD corrections to Higgs boson production in association with a photon via weak-boson fusion at the LHC

Higgs boson production in association with a hard central photon and two forward tagging jets is expected to provide valuable information on Higgs boson couplings in a range where it is difficult to disentangle weak-boson fusion processes from large QCD backgrounds. We present next-to-leading order QCD corrections to Higgs production in association with a photon via weak-boson fusion at a hadron collider in the form of a flexible parton-level Monte Carlo program. The QCD corrections to integrated cross sections are found to be small for experimentally relevant selection cuts, while the shape of kinematic distributions can be distorted by up to 20% in some regions of phase space. Residual scale uncertainties at next-to-leading order are at the few-percent level.Comment: 17 pages, 7 figures, 1 tabl

Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study

AIMS/HYPOTHESIS: Vasopressin plays a role in osmoregulation, glucose homeostasis and inflammation. Therefore, plasma copeptin, the stable C-terminal portion of the precursor of vasopressin, has strong potential as a biomarker for the cardiometabolic syndrome and diabetes. Previous results were contradictory, which may be explained by differences between men and women in responsiveness of the vasopressin system. The aim of this study was to evaluate the usefulness of copeptin for prediction of future type 2 diabetes in men and women separately. METHODS: From the Prevention of Renal and Vascular Endstage Disease (PREVEND) study, 4,063 women and 3,909 men without diabetes at baseline were included. A total of 208 women and 288 men developed diabetes during a median follow-up of 7.7 years. RESULTS: In multivariable-adjusted models, we observed a stronger association of copeptin with risk of future diabetes in women (OR 1.49 [95% CI 1.24, 1.79]) than in men (OR 1.01 [95% CI 0.85, 1.19]) (p (interaction) < 0.01). The addition of copeptin to the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) clinical model improved the discriminative value (C-statistic,+0.007, p = 0.02) and reclassification (integrated discrimination improvement [IDI] = 0.004, p < 0.01) in women. However, we observed no improvement in men. The additive value of copeptin in women was maintained when other independent predictors, such as glucose, high sensitivity C-reactive protein (hs-CRP) and 24 h urinary albumin excretion (UAE), were included in the model. CONCLUSIONS/INTERPRETATION: The association of plasma copeptin with the risk of developing diabetes was stronger in women than in men. Plasma copeptin alone, and along with existing biomarkers (glucose, hs-CRP and UAE), significantly improved the risk prediction for diabetes in women