Time and Force Dependence of the Rupture of Glycoprotein IIb-IIIa-Fibrinogen Bonds between Latex Spheres

AbstractWe studied the shear-induced breakup of doublets of aldehyde/sulfate (A/S) latex spheres covalently linked with purified platelet GPIIb-IIIa receptor, and cross-linked by fibrinogen. Flow cytometry with fluorescein isothiocyanate-fibrinogen showed than an average of 22,500 molecules of active GPIIb-IIIa were captured per sphere, with a mean Kd=56nM for fibrinogen binding. The spheres, suspended in buffered 19% Ficoll 400 containing 120 or 240pM fibrinogen, were subjected to Couette flow in a counter-rotating cone-plate rheoscope. Doublets, formed by two-body collisions at low shear rate (G=8s−1) for ≤15min, were subjected to shear stress from 0.6 to 2.9 Nm−2, their rotations recorded until they broke up or were lost to view. Although breakup was time dependent, occurring mostly in the first 2 rotations after the onset of shear, the percentage of doublets broken up after 10 rotations were almost independent of normal hydrodynamic force, Fn: at 240 pN, 15.6, 16.0, and 17.0% broke up in the force range 70–150 pN, 150–230 pN, and 230–310 pN. Unexpectedly, at both [fibrinogen], the initial rate of breakup was highest in the lowest force range, and computer simulation using a stochastic model of breakup was unable to simulate the time course of breakup. When pre-sheared at low G for >15min, no doublets broke up within 10 rotations at 70<Fn<310 pN; it required >3min shear (>1110 rotations) at Fn=210 pN for significant breakup to occur. Other published work has shown that binding of fibrinogen to GPIIb-IIIa immobilized on plane surfaces exhibits an initial fast reversible process with relative low affinity succeeded by transformation of GPIIb-IIIa to a stable high-affinity complex. We postulate that most doublet breakups observed within 10 rotations were from a population of young doublets having low numbers of bonds, by dissociation of the initial receptor complex relatively unresponsive to force. The remaining, older doublets with GPIIb-IIIa in the high-affinity complex were not broken up in the time or range of forces studied

Towards a Conceptual Model and Reasoning Structure for Insider Threat Detection

The insider threat faced by corporations and governments today is a real and significant problem, and one that has become increasingly difficult to combat as the years have progressed. From a technology standpoint, traditional protective measures such as intrusion detection systems are largely inadequate given the nature of the ‘insider’ and their legitimate access to prized organisational data and assets. As a result, it is necessary to research and develop more sophisticated approaches for the accurate recognition, detection and response to insider threats. One way in which this may be achieved is by understanding the complete picture of why an insider may initiate an attack, and the indicative elements along the attack chain. This includes the use of behavioural and psychological observations about a potential malicious insider in addition to technological monitoring and profiling techniques. In this paper, we propose a framework for modelling the insider-threat problem that goes beyond traditional technological observations and incorporates a more complete view of insider threats, common precursors, and human actions and behaviours. We present a conceptual model for insider threat and a reasoning structure that allows an analyst to make or draw hypotheses regarding a potential insider threat based on measurable states from real-world observations

Understanding Insider Threat: A Framework for Characterising Attacks

The threat that insiders pose to businesses, institutions and governmental organisations continues to be of serious concern. Recent industry surveys and academic literature provide unequivocal evidence to support the significance of this threat and its prevalence. Despite this, however, there is still no unifying framework to fully characterise insider attacks and to facilitate an understanding of the problem, its many components and how they all fit together. In this paper, we focus on this challenge and put forward a grounded framework for understanding and reflecting on the threat that insiders pose. Specifically, we propose a novel conceptualisation that is heavily grounded in insider-threat case studies, existing literature and relevant psychological theory. The framework identifies several key elements within the problem space, concentrating not only on noteworthy events and indicators- technical and behavioural- of potential attacks, but also on attackers (e.g., the motivation behind malicious threats and the human factors related to unintentional ones), and on the range of attacks being witnessed. The real value of our framework is in its emphasis on bringing together and defining clearly the various aspects of insider threat, all based on real-world cases and pertinent literature. This can therefore act as a platform for general understanding of the threat, and also for reflection, modelling past attacks and looking for useful patterns

A critical reflection on the threat from human insiders--its nature, industry perceptions, and detection approaches

Organisations today operate in a world fraught with threats, including “script kiddies”, hackers, hacktivists and advanced persistent threats. Although these threats can be harmful to an enterprise, a potentially more devastating and anecdotally more likely threat is that of the malicious insider. These trusted individuals have access to valuable company systems and data, and are well placed to undermine security measures and to attack their employers. In this paper, we engage in a critical reflection on the insider threat in order to better understand the nature of attacks, associated human factors, perceptions of threats, and detection approaches. We differentiate our work from other contributions by moving away from a purely academic perspective, and instead focus on distilling industrial reports (i.e., those that capture practitioners’ experiences and feedback) and case studies in order to truly appreciate how insider attacks occur in practice and how viable preventative solutions may be developed

An ammonia spectral map of the L1495-B218 filaments in the Taurus molecular cloud. I. Physical properties of filaments and dense cores

We present deep NH3 observations of the L1495-B218 filaments in the Taurus molecular cloud covering over a 3° angular range using the K-band focal plane array on the 100 m Green Bank Telescope. The L1495-B218 filaments form an interconnected, nearby, large complex extending over 8 pc. We observed NH3 (1, 1) and (2, 2) with a spectral resolution of 0.038 km s−1 and a spatial resolution of 31''. Most of the ammonia peaks coincide with intensity peaks in dust continuum maps at 350 and 500 μm. We deduced physical properties by fitting a model to the observed spectra. We find gas kinetic temperatures of 8–15 K, velocity dispersions of 0.05–0.25 km s−1, and NH3 column densities of 5 × 1012 to 1 × 1014 cm−2. The CSAR algorithm, which is a hybrid of seeded-watershed and binary dendrogram algorithms, identifies a total of 55 NH3 structures, including 39 leaves and 16 branches. The masses of the NH3 sources range from 0.05 to 9.5 ${{M}_{\odot }}$. The masses of NH3 leaves are mostly smaller than their corresponding virial mass estimated from their internal and gravitational energies, which suggests that these leaves are gravitationally unbound structures. Nine out of 39 NH3 leaves are gravitationally bound, and seven out of nine gravitationally bound NH3 leaves are associated with star formation. We also found that 12 out of 30 gravitationally unbound leaves are pressure confined. Our data suggest that a dense core may form as a pressure-confined structure, evolve to a gravitationally bound core, and undergo collapse to form a protostar

Beyond Shielding: The Roles of Glycans in the SARS-CoV‑2 Spike Protein

The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 28,000,000 infections and 900,000 deaths worldwide to date. Antibody development efforts mainly revolve around the extensively glycosylated SARS-CoV-2 spike (S) protein, which mediates host cell entry by binding to the angiotensin-converting enzyme 2 (ACE2). Similar to many other viral fusion proteins, the SARS-CoV-2 spike utilizes a glycan shield to thwart the host immune response. Here, we built a full-length model of the glycosylated SARS-CoV-2 S protein, both in the open and closed states, augmenting the available structural and biological data. Multiple microsecond-long, all-atom molecular dynamics simulations were used to provide an atomistic perspective on the roles of glycans and on the protein structure and dynamics. We reveal an essential structural role of N-glycans at sites N165 and N234 in modulating the conformational dynamics of the spike’s receptor binding domain (RBD), which is responsible for ACE2 recognition. This finding is corroborated by biolayer interferometry experiments, which show that deletion of these glycans through N165A and N234A mutations significantly reduces binding to ACE2 as a result of the RBD conformational shift toward the “down” state. Additionally, end-to-end accessibility analyses outline a complete overview of the vulnerabilities of the glycan shield of the SARS-CoV-2 S protein, which may be exploited in the therapeutic efforts targeting this molecular machine. Overall, this work presents hitherto unseen functional and structural insights into the SARS-CoV-2 S protein and its glycan coat, providing a strategy to control the conformational plasticity of the RBD that could be harnessed for vaccine development

Ophthalmologist–Patient Communication, Self-efficacy, and Glaucoma Medication Adherence

The objective of the study was to examine the association between provider-patient communication, glaucoma medication adherence self-efficacy, outcome expectations, and glaucoma medication adherence

Review: Far-infrared instrumentation and technological development for the next decade

This work is licensed under a Creative Commons Attribution 4.0 Unported License.Far-infrared astronomy has advanced rapidly since its inception in the late 1950s, driven by a maturing technology base and an expanding community of researchers. This advancement has shown that observations at far-infrared wavelengths are important in nearly all areas of astrophysics, from the search for habitable planets and the origin of life to the earliest stages of galaxy assembly in the first few hundred million years of cosmic history. The combination of a still-developing portfolio of technologies, particularly in the field of detectors, and a widening ensemble of platforms within which these technologies can be deployed, means that far-infrared astronomy holds the potential for paradigm-shifting advances over the next decade. We examine the current and future far-infrared observing platforms, including ground-based, suborbital, and space-based facilities, and discuss the technology development pathways that will enable and enhance these platforms to best address the challenges facing far-infrared astronomy in the 21st century

Baseline Features and Reasons for Nonparticipation in the Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) Study, a Colorectal Cancer Screening Trial.

IMPORTANCE: The Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) randomized clinical trial sought to recruit 50 000 adults into a study comparing colorectal cancer (CRC) mortality outcomes after randomization to either an annual fecal immunochemical test (FIT) or colonoscopy. OBJECTIVE: To (1) describe study participant characteristics and (2) examine who declined participation because of a preference for colonoscopy or stool testing (ie, fecal occult blood test [FOBT]/FIT) and assess that preference\u27s association with geographic and temporal factors. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study within CONFIRM, which completed enrollment through 46 Department of Veterans Affairs medical centers between May 22, 2012, and December 1, 2017, with follow-up planned through 2028, comprised veterans aged 50 to 75 years with an average CRC risk and due for screening. Data were analyzed between March 7 and December 5, 2022. EXPOSURE: Case report forms were used to capture enrolled participant data and reasons for declining participation among otherwise eligible individuals. MAIN OUTCOMES AND MEASURES: Descriptive statistics were used to characterize the cohort overall and by intervention. Among individuals declining participation, logistic regression was used to compare preference for FOBT/FIT or colonoscopy by recruitment region and year. RESULTS: A total of 50 126 participants were recruited (mean [SD] age, 59.1 [6.9] years; 46 618 [93.0%] male and 3508 [7.0%] female). The cohort was racially and ethnically diverse, with 748 (1.5%) identifying as Asian, 12 021 (24.0%) as Black, 415 (0.8%) as Native American or Alaska Native, 34 629 (69.1%) as White, and 1877 (3.7%) as other race, including multiracial; and 5734 (11.4%) as having Hispanic ethnicity. Of the 11 109 eligible individuals who declined participation (18.0%), 4824 (43.4%) declined due to a stated preference for a specific screening test, with FOBT/FIT being the most preferred method (2820 [58.5%]) vs colonoscopy (1958 [40.6%]; P \u3c .001) or other screening tests (46 [1.0%] P \u3c .001). Preference for FOBT/FIT was strongest in the West (963 of 1472 [65.4%]) and modest elsewhere, ranging from 199 of 371 (53.6%) in the Northeast to 884 of 1543 (57.3%) in the Midwest (P = .001). Adjusting for region, the preference for FOBT/FIT increased by 19% per recruitment year (odds ratio, 1.19; 95% CI, 1.14-1.25). CONCLUSIONS AND RELEVANCE: In this cross-sectional analysis of veterans choosing nonenrollment in the CONFIRM study, those who declined participation more often preferred FOBT or FIT over colonoscopy. This preference increased over time and was strongest in the western US and may provide insight into trends in CRC screening preferences