Right ventricular (RV) dysfunction is a complication of pulmonary hypertension and portends a poor prognosis. Pharmacological therapies targeting RV function in pulmonary hypertension may reduce ...symptoms, improve hemodynamics, and potentially increase survival. We hypothesize that recombinant human angiotensin-converting enzyme 2 (rhACE2) will improve RV function in a pressure overload model.
rhACE2 administered at 1.8 mg/kg/day improved RV systolic and diastolic function in pulmonary artery banded mice as measured by in vivo hemodynamics. Specifically, rhACE2 increased RV ejection fraction and decreased RV end diastolic pressure and diastolic time constant (p<0.05). In addition, rhACE2 decreased RV hypertrophy as measured by RV/LV+S ratio (p<0.05). There were no significant negative effects of rhACE2 administration on LV function. rhACE2 had no significant effect on fibrosis as measured by trichrome staining and collagen1α1 expression. In pulmonary artery banded mice, rhACE2 increased Mas receptor expression and normalized connexin 37 expression.
In a mouse RV load-stress model of early heart failure, rhACE2 diminished RV hypertrophy and improved RV systolic and diastolic function in association with a marker of intercellular communication. rhACE2 may be a novel treatment for RV failure.
•Myosuppressin N-terminal amino acids play a role in its effect on cardiac contractility.•Myosuppressin N-terminal amino acids influence its ligand-receptor interactions.•Biased agonism at a ...myosuppressin G-protein coupled receptor increases heart rate.•The myosuppressin N-terminal amino acids play a role in functional selectivity.
The structural conservation and activity of the myosuppressin cardioinhibitory peptide across species suggests it plays an important role in physiology, yet much remains unknown regarding its signaling. We previously reported Drosophila melanogaster myosuppressin (dromyosuppressin, DMS; TDVDHVFLRF-NH2) decreases cardiac contractility through a G protein-coupled receptor, DMS-R2. Our study showed the DMS N-terminus amino acids influence its structure-activity relationship (SAR), yet how they act is not established. We predicted myosuppressin N-terminal amino acids played a role in signaling. Here, we tested our hypothesis in the beetle, Zophobas atratus, using a semi-isolated heart bioassay to explore SAR in a different Order and focus on cardiac signaling. We generated a series of myosuppressin truncated analogs by removing the N-terminal residue and measuring the activity of each structure on cardiac contractility. While DVDHVFLRF-NH2 decreased cardiac contractility, we found VDHVFLRF-NH2, DHVFLRF-NH2, and HVFLRF-NH2 increased activity. In contrast, VFLRF- NH2 decreased activity and FLRF-NH2 was inactive. Next, we analyzed molecular docking data and found the active truncated analogs interacted with the 3–6 lock in DMS-R2, the myosuppressin cardiac receptor, disrupting the salt bridge between H114 and E369, and K289 and Q372. Further, the docking results showed the inhibitory effect on contractility may be associated with contact to Y78, while the analogs that increased contractility lacked this interaction. The data from our study demonstrated N-terminal amino acids played a role in myosuppressin activity and signaling suggesting the cardiac receptor can be targeted by biased agonists. Our myosuppressin cardiac contractility data and predicted receptor interactions describe the presence of functional selectivity in a ligand-directed signaling pathway in heart.
Little is known about how organizations leverage business analytics (BA) to develop, process, and exploit analytical information in cybersecurity incident response (CSIR). Drawing on information ...processing theory (IPT), we conducted a field study using a multiple case study design to answer the following research question: How do organizations exploit analytical information in the process of cybersecurity incident response by using business analytics? We developed a theoretical framework that explains how organizations respond to the dynamic cyber threat environment by exploiting analytical information processing capability in the CSIR process. This, in turn, leads to positive outcomes in enterprise security performance, delivering both strategic and financial benefits. Our findings contribute to the BA and cybersecurity literature by providing useful insights into BA applications and the facilitation of analytics-driven decision making in CSIR. Further, they contribute to IPT by providing new insights about analytical information needs, mechanisms to seek analytical information, and analytical information use in the process of CSIR.
•Organizations exploit analytical information processing capability to generate analytical insights.•Organizations develop specific mechanisms to seek analytical information.•Organizations use analytical information to enhance their cybersecurity awareness.•Analytical information processing capability enables organizations to deal with dynamic cyber threat environment proactively.
Digital assets of organizations are under constant threat from a wide assortment of nefarious actors. When threats materialize, the consequences can be significant. Most large organizations invest in ...a dedicated information security management (ISM) function to ensure that digital assets are protected. The ISM function conducts risk assessments, develops strategy, provides policies and training to define roles and guide behavior, and implements technological controls such as firewalls, antivirus, and encryption to restrict unauthorized access. Despite these protective measures, incidents (security breaches) will occur. Alongside the security management function, many organizations also retain an incident response (IR) function to mitigate damage from an attack and promptly restore digital services. However, few organizations integrate and learn from experiences of these functions in an optimal manner that enables them to not only respond to security incidents, but also proactively maneuver the threat environment. In this article we draw on organizational learning theory to develop a conceptual framework that explains how the ISM and IR functions can be better integrated. The strong integration of ISM and IR functions, in turn, creates learning opportunities that lead to organizational security benefits including: increased awareness of security risks, compilation of threat intelligence, removal of flaws in security defenses, evaluation of security defensive logic, and enhanced security response.
There considerable advice in both research and practice oriented literature on the topic of information security. Most of the discussion in literature focuses on how to prevent security attacks using ...technical countermeasures even though there are a number of other viable strategies such as deterrence, deception, detection and response. This paper reports on a qualitative study, conducted in Korea, to determine how organizations implement security strategies to protect their information systems. The findings reveal a deeply entrenched preventive mindset, driven by the desire to ensure availability of technology and services, and a comparative ignorance of exposure to business security risks. Whilst there was some evidence of usage of other strategies, they were also deployed in a preventive capacity. The paper presents a research agenda that calls for research on enterprise-wide multiple strategy deployment with a focus on how to combine, balance and optimize strategies.
Our case analysis presents and identifies significant and systemic shortcomings of the incident response practices of an Australian financial organization. Organizational Incident Response Teams ...accumulate considerable experience in addressing information security failures and attacks. Their first-hand experiences provide organizations with a unique opportunity to draw security lessons and insights towards improving enterprise-wide security management processes. However, previous research shows a distinct lack of communication and collaboration between the functions of incident response and security management, suggesting organizations are not learning from their incident experiences. We subsequently propose a number of lessons learned and a novel security-learning model.
This study examined the relationship between susceptibility to drug-related online peer influence on Facebook and offline alcohol, tobacco, and marijuana use among emerging adults (18-24 years) ...enrolled at the university level in Barbados and England. A cross-national comparative, explanatory sequential mixed-methods design was employed with samples of students of African-Caribbean descent and European descent in Barbados and England, respectively. Quantitative data were collected using surveys from 241 students in Barbados and 186 in England. Qualitative focus groups were conducted with 23 Barbadian students and 16 English students. Spearman’s rank-order correlations were conducted to analyze quantitative data and a three-tiered categorization system was used to analyze the qualitative data. Significant positive relationships between students’ susceptibility to online peer influence (SOPI) and alcohol, tobacco, and marijuana use were found. Six qualitative themes emerged representing cross-national similarities, while three themes emerged highlighting some differences between the two contexts. We propose that the relationship between SOPI and offline drug use may be mediated by the interrelated factors of emerging-adult developmental characteristics and the online and offline social environments. We represent these findings diagrammatically to convey that developmental and environmental factors together can provide a holistic understanding of the interplay between online interactions and offline risk behaviors.
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