TACE/ADAM17 substrates associate with ACS (Ep-CAM, HB-EGF) and follow-up MACE (TNFR1 and TNFR2)

BACKGROUND AND AIMS: TACE/ADAM17 is a membrane bound metalloprotease, which cleaves substrates involved in immune and inflammatory responses and plays a role in coronary artery disease (CAD). We measured TACE and its substrates in CAD patients to identify potential biomarkers within this molecular pathway with potential for acute coronary syndrome (ACS) and major adverse cardiovascular events (MACE) prediction. METHODS: Blood samples were obtained from consecutive patients (n = 229) with coronary angiographic evidence of CAD admitted with ACS or electively. MACE were recorded after a median 3-year follow-up. Controls (n = 115) had a <10% CAD risk as per the HeartSCORE. TACE and TIMP3 protein and mRNA levels were measured by ELISA and RT-qPCR respectively. TACE substrates were measured using a multiplex proximity extension assay. RESULTS: TACE mRNA and cell protein levels (p < 0.01) and TACE substrates LDLR (p = 0.006), TRANCE (p = 0.045), LAG-3 (p < 0.001) and ACE2 (p < 0.001) plasma levels were significantly higher in CAD patients versus controls. TACE inhibitor TIMP3 mRNA levels were significantly lower in CAD patients and tended to be lower in the ACS population (p < 0.05). TACE substrates TNFR1 (OR:3.237,CI:1.514–6.923,p = 0.002), HB-EGF (OR:0.484,CI:0.288–0.813,p = 0.006) and Ep-CAM (OR:0.555,CI:0.327–0.829,p = 0.004) accurately classified ACS patients with HB-EGF and Ep-CAM levels being lower compared to electively admitted patients. TNFR1 (OR:2.317,CI:1.377–3.898,p = 0.002) and TNFR2 (OR:1.902,CI:1.072–3.373,p = 0.028) were significantly higher on admission in those patients who developed MACE within 3 years. CONCLUSIONS: We demonstrate a possible role of TACE substrates LAG-3, HB-EGF and Ep-CAM in atherosclerotic plaque development and stability. We also underline the importance of measuring TNFR1 and TNFR2 earlier than previously appreciated for MACE prediction. We report an important role of TIMP3 in regulating TACE levels

Joint ACCESS: high-speed assault connector (HSAC) for joint expeditionary logistics

Includes suppmentary materialThe current notion of seabasing requires that three Battalion Landing Teams (BLT) of a 2025 Joint Expeditionary Brigade (JEB) need to be able to transit from the Sea Base to the objective within a 10 hour period. Of the three BLTs, two of them must be transported by surface craft a distance of no more than 200nm in sea state 4 or less. The two surface bound BLTs need to be loaded onto the transporting craft and delivered to shore, whether it is a port facility or austere beachhead. There is no current or future system of connectors to meet all the time-distance, sea state, and interface flexibility requirements for this aspect of seabasing. To meet these requirements a High Speed Assault Connector (HSAC) is needed which either augments current or replaces existing connector platforms to deliver and support the required forces ashore. The Joint ACCESS is a HSAC that brings the necessary speed, payload capacity, interface capability, and mission flexibility needed to fill the Sea Base to shore transportation gap. With a maximum speed of 43kts and payload capacity of 800LT, 12 Joint ACCESS trimarans can transit 200nm and fully offload in 7 hours. Its beachable design uses a floating bow ramp to reach out to austere beaches, while its combat system suite provides self defense in addition to robust offensive capabilities.http://web.archive.org/web/20050218202650/http://www.nps.navy.mil/tsse/files/2004.htmApproved for public release; distribution is unlimited

Seabasing and joint expeditionary logistics

Student Integrated ProjectIncludes supplementary material. Executive Summary and Presentation.Recent conflicts such as Operation Desert Shield/Storm and Operation Iraqi Freedom highlight the logistics difficulties the United States faces by relying on foreign access and infrastructure and large supply stockpiles ashore to support expeditionary operations. The Navy's transformational vision for the future, Sea Power 21, involves Seabasing as a way to address these difficulties by projecting and sustaining joint forces globally from the sea. This study analyzes logistics flow to, within and from a Sea Base to an objective, and the architectures and systems needed to rapidly deploy and sustain a brigade-size force. Utilizing the Joint Capabilities Integration and Development System (JCIDS), this study incorporates a systems engineering framework to examine current systems, programs of record and proposed systems out to the year 2025. Several capability gaps that hamper a brigade-size force from seizing the initiative anywhere in the world within a 10-day period point to a need for dedicated lift assets, such as high-speed surface ships or lighter-than-air ships, to facilitate the rapid formation of the Sea Base. Additionally, the study identifies the need for large-payload/high-speed or load-once/direct-to- objective connector capabilities to minimize the number of at-sea transfers required to employ such a force from the Sea Base in 10 hrs. With these gaps addressed, the Joint Expeditionary Brigade is supportable from the Sea Base.http://archive.org/details/seabasingndjoint109456918N

The Interdependency and Co-Regulation of the Vitamin D and Cholesterol Metabolism

From MDPI via Jisc Publications RouterHistory: accepted 2021-07-28, pub-electronic 2021-08-06Publication status: PublishedFunder: Harold Hyam Wingate Foundation; Grant(s): 16412Vitamin D and cholesterol metabolism overlap significantly in the pathways that contribute to their biosynthesis. However, our understanding of their independent and co-regulation is limited. Cardiovascular disease is the leading cause of death globally and atherosclerosis, the pathology associated with elevated cholesterol, is the leading cause of cardiovascular disease. It is therefore important to understand vitamin D metabolism as a contributory factor. From the literature, we compile evidence of how these systems interact, relating the understanding of the molecular mechanisms involved to the results from observational studies. We also present the first systems biology pathway map of the joint cholesterol and vitamin D metabolisms made available using the Systems Biology Graphical Notation (SBGN) Markup Language (SBGNML). It is shown that the relationship between vitamin D supplementation, total cholesterol, and LDL-C status, and between latitude, vitamin D, and cholesterol status are consistent with our knowledge of molecular mechanisms. We also highlight the results that cannot be explained with our current knowledge of molecular mechanisms: (i) vitamin D supplementation mitigates the side-effects of statin therapy; (ii) statin therapy does not impact upon vitamin D status; and critically (iii) vitamin D supplementation does not improve cardiovascular outcomes, despite improving cardiovascular risk factors. For (iii), we present a hypothesis, based on observations in the literature, that describes how vitamin D regulates the balance between cellular and plasma cholesterol. Answering these questions will create significant opportunities for advancement in our understanding of cardiovascular health

Why do people file share unlawfully? A systematic review, meta-analysis and panel study

Unlawful digital media sharing is common and believed to be extremely damaging to business. Understanding unlawful file sharers’ motivations offers the opportunity to develop business models and behavioral interventions to maximize consumers’ and businesses’ benefit. This paper uses a systematic review of unlawful file sharing research, and the Theory of Planned Behavior, to motivate a large-scale panel study in which initial determinants were used to predict subsequent behavior. A meta-analysis found Attitudes, Subjective Norms and Perceived Behavioral Control were all associated with unlawful file sharing. Media type and demographic differences in the importance of Perceived Behavioral Control were found and attributed to more accurate evaluation of familiar activities, i.e., greater experience increases the influence of Perceived Behavioral Control but age does not. The panel study confirmed that greater past experience was associated with Perceived Behavioral Control and Intention. We conclude that past experience increases the efficacy of the Theory of Planned Behavior and specifically Perceived Behavioral control in predicting behavior, contrary to some widely held beliefs about the role of experience. The role of experience is therefore crucial to understanding people’s choices. Practically, improving social approval, positive evaluation and access to lawful media should reduce unlawful behavior

Genome Sequences of Mycobacteriophages Amgine, Amohnition, Bella96, Cain, DarthP, Hammy, Krueger, LastHope, Peanam, PhelpsODU, Phrank, SirPhilip, Slimphazie, and Unicorn

We report the genome sequences of 14 cluster K mycobacteriophages isolated using Mycobacterium smegmatis mc2155 as host. Four are closely related to subcluster K1 phages, and 10 are members of subcluster K6. The phage genomes span considerable sequence diversity, including multiple types of integrases and integration sites

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival