Traumatic peripheral nerve injuries tend to be more common in younger, working age populations and can lead to long-lasting disability. Peripheral nerves have an impressive capacity to regenerate; however, successful recovery after injury depends on a number of factors including the mechanism and severity of the trauma, the distance from injury to the reinnervation target, connective tissue sheath integrity, and delay between injury and treatment. Even though modern surgical procedures have greatly improved the success rate, many peripheral nerve injuries still culminate in persistent neuropathic pain and incomplete functional recovery. Recent studies in animals suggest that botulinum neurotoxin A (BoNT/A) can accelerate nerve regeneration and improve functional recovery after injury to peripheral nerves. Possible mechanisms of BoNT/A action include activation or proliferation of support cells (Schwann cells, mast cells, and macrophages), increased angiogenesis, and improvement of blood flow to regenerating nerves.

Introduction: A systems perspective was used to describe U.S. Department of Defense (DoD) Global Health Engagement (GHE). This description was based on DoD instructions and higher-level documents related to DoD GHE. A complex system of systems such as health care can benefit from using modeling approaches to help understand the interactions among major components. Models (conceptual, computer-based programs, realistic simulations, or training exercises) can be used to help stakeholders prioritize options and to identify important components and gaps for making performance improvements. Based on the cited documents, we identified major DoD GHE components to create a conceptual model. Materials and methods: Components were selected from DoDI 2000.30 for DoD GHE. Definitions of these interacting components are given and assigned to our network model that consists of three levels: strategic, operational, and tactical. These levels are linked by critical nodes (decision points) that allow feedback to previous levels for modifying appropriate components. A network that is reminiscent of this structure is Boyd’s observe-orient-decision-act diagram. Acceptable strategic and operational plans are linked to the tactical level. Acceptable tactical components lead to the desired outcome of accomplishing the DoD GHE goals. Complex systems also have feedback loops to allow for component evaluations and modifications. Accomplishing DoD GHE goals need to have adaptable components in dynamic permissive environments. Results: The network that we considered is multicomponent and interdisciplinary. The network uses DoD GHE goals as the input (observing in the observe-orient-decide-act loop) to provide relevant information. It consists of three levels of adaptable, interacting (orienting) components that are linked by critical nodes (decision points) involving the evaluation of plans and desired outcomes. Strategic components (eg, sharing, personal interactions, agreements, planning, readiness, etc.) are required to develop strategic plans, the first critical node. If these plans are acceptable, the information is passed on (feed forward, action) to the operational components (define problems, understand strategic direction and guidance, understand the operational environment, etc.). At the second critical node, the decision is made about moving the operational plans to the tactical components (eg, evaluation, data, training, etc.). Tactical components are essential to provide further information to the third critical node, desired outcomes, in accomplishing DoD GHE goals. Feedback from all critical nodes is essential to allow modifications of various components and to attain health-related interoperability in supporting security policies and military strategies. Conclusions: Examining the composition of DoD GHE and creating a defined model can help identify interacting features of this complex system. All of the identified components have been associated with gaps, such as the need for monitoring and measuring tools, and standards. The current state of this system is dynamic and is evolving when confronting gaps. DoD GHE represents an intersection of global health and security in supporting U.S. national security objectives by establishing access and influence with partner nations and among health care-related government and non-government organizations, and as a result, improves the readiness, health, and safety of our military personnel.

Botulism is an example of true food poisoning. Several of the immunologically distinct neurotoxins (BoNT/A-G) from Clostridium botulinum and two other clostridial species have over the years been identified in inadequately stored or processed food. After their ingestion, peripheral cholinergic neurotransmission is blocked, causing flaccid paralysis that can lead to respiratory failure and death. To understand better foodborne botulism, a perspective is given as viewed through the prism of systems biology in which diverse data are integrated into predictive models. Computational models describing C. botulinum spore activation, bacterial growth, and neurotoxin production in food could be linked to risk assessments that help improve food safety procedures and public health policies. Combining experimental and clinical data is also critical in developing models designed to simulate illness onset times and durations. Subsystems, such as gene expression may also account for secondary phenomenon of botulism, for example, neurite sprouting. Expected benefits of a systems approach, among others, will be to help gauge the effectiveness of therapies and reduce the costs of hospitalizations.

Introduction:This position paper summarizes the development and the present status of Department of Defense (DoD) and other government policies and guidances regarding cloud computing services. Due to the heterogeneous and growing biomedical big datasets, cloud computing services offer an opportunity to mitigate the associated storage and analysis requirements. Having on-demand network access to a shared pool of flexible computing resources creates a consolidated system that should reduce potential duplications of effort in military biomedical research.Methods:Interactive, online literature searches were performed with Google, at the Defense Technical Information Center, and at two National Institutes of Health research portfolio information sites. References cited within some of the collected documents also served as literature resources.Results:We gathered, selected, and reviewed DoD and other government cloud computing policies and guidances published from 2009 to 2017. These policies were intended to consolidate computer resources within the government and reduce costs by decreasing the number of federal data centers and by migrating electronic data to cloud systems. Initial White House Office of Management and Budget information technology guidelines were developed for cloud usage, followed by policies and other documents from the DoD, the Defense Health Agency, and the Armed Services. Security standards from the National Institute of Standards and Technology, the Government Services Administration, the DoD, and the Army were also developed. Government Services Administration and DoD Inspectors General monitored cloud usage by the DoD. A 2016 Government Accountability Office report characterized cloud computing as being economical, flexible and fast. A congressionally mandated independent study reported that the DoD was active in offering a wide selection of commercial cloud services in addition to its milCloud system. Our findings from the Department of Health and Human Services indicated that the security infrastructure in cloud services may be more compliant with the Health Insurance Portability and Accountability Act of 1996 regulations than traditional methods. To gauge the DoD's adoption of cloud technologies proposed metrics included cost factors, ease of use, automation, availability, accessibility, security, and policy compliance.Conclusions:Since 2009, plans and policies were developed for the use of cloud technology to help consolidate and reduce the number of data centers which were expected to reduce costs, improve environmental factors, enhance information technology security, and maintain mission support for service members. Cloud technologies were also expected to improve employee efficiency and productivity. Federal cloud computing policies within the last decade also offered increased opportunities to advance military healthcare. It was assumed that these opportunities would benefit consumers of healthcare and health science data by allowing more access to centralized cloud computer facilities to store, analyze, search and share relevant data, to enhance standardization, and to reduce potential duplications of effort. We recommend that cloud computing be considered by DoD biomedical researchers for increasing connectivity, presumably by facilitating communications and data sharing, among the various intra- and extramural laboratories. We also recommend that policies and other guidances be updated to include developing additional metrics that will help stakeholders evaluate the above mentioned assumptions and expectations.

Introduction:This review summarizes the research conducted on botulinum toxin (BoTx) from 1943 to 1956 by a small group of Camp Detrick investigators and their staff. A systematic, cross-disciplinary approach was used to develop effective vaccines against this biological warfare threat agent. In response to the potential need for medical countermeasures against BoTx during World War II, the refinement of isolation and purification techniques for BoTx successfully led to the large-scale production of botulinum toxoid vaccines. In addition, the work at Camp Detrick provided the foundation for the subsequent use of BoTx as a tool for studying the trophic regulation of skeletal muscle within motor neuron terminals and, more recently, for elucidation of the intricate details of neurotransmitter release at the molecular level. Indirectly, Camp Detrick investigators also played a significant role in studies that culminated in the use of BoTx as a pharmaceutical product that has been approved by the U.S. Food and Drug Administration for treating movement disorders, autonomic dysfunctions, and other conditions.Methods:Online literature searches were performed with Google, Google Scholar, PubMed, the bibliography from the Camp Detrick technical library, and at the Defense Technical Information Center. Reference lists in some of the primary research publications and reviews also provided source material. Search terms included botulinum, botulinus, and Camp Detrick. References related to the subsequent impacts of the Camp Detrick results were selected and cited from reviews and primary references in the more recent literature. Notes on toxin nomenclature and potential sources of error in this study are presented.Results:The literature searches returned 27 citations of Camp Detrick authors, 24 of which were articles in peer-reviewed journals. The publications by these investigators included several disciplines such as biochemistry, immunology, pharmacology, physiology, and toxicology. A fundamental finding was the identification of critical nutritional components for improved growth of Clostridium botulinum and the increased production of BoTx serotype A. The purification processes that were developed at Camp Detrick allowed for the production of crystalline material to be scaled up for the manufacture of toxoid vaccine. Based on the research by Camp Detrick scientists, a toxoid supply of over 1 million units was available to vaccinate ~300,000 troops before the large-scale operations of D-Day.Conclusions:BoTx research during the period 1943 to 1956 resulted in refinements in the techniques for isolating and purifying the crystalline BoTx type A. These results led to the development and manufacture of a toxoid vaccine that was available in a sufficient quantity to protect ~300,000 warfighters in a large-scale military operation. One of the most important long-term consequences derived from the knowledge gained by the efforts at Camp Detrick was the development in the 1980s of safe and effective therapeutic uses for BoTx type A, the most lethal biological substance known.

INTRODUCTION:This pilot study was conducted to examine, for the first time, the ongoing systems biology research and development projects within the laboratories and centers of the U.S. Army Medical Research and Materiel Command (USAMRMC). The analysis has provided an understanding of the breadth of systems biology activities, resources, and collaborations across all USAMRMC subordinate laboratories.METHODS:The Systems Biology Collaboration Center at USAMRMC issued a survey regarding systems biology research projects to the eight U.S.-based USAMRMC laboratories and centers in August 2016. This survey included a data call worksheet to gather self-identified project and programmatic information. The general topics focused on the investigators and their projects, on the project's research areas, on omics and other large data types being collected and stored, on the analytical or computational tools being used, and on identifying intramural (i.e., USAMRMC) and extramural collaborations.RESULTS:Among seven of the eight laboratories, 62 unique systems biology studies were funded and active during the final quarter of fiscal year 2016. Of 29 preselected medical Research Task Areas, 20 were associated with these studies, some of which were applicable to two or more Research Task Areas. Overall, studies were categorized among six general types of objectives: biological mechanisms of disease, risk of/susceptibility to injury or disease, innate mechanisms of healing, diagnostic and prognostic biomarkers, and host/patient responses to vaccines, and therapeutic strategies including host responses to therapies. We identified eight types of omics studies and four types of study subjects. Studies were categorized on a scale of increasing complexity from single study subject/single omics technology studies (23/62) to studies integrating results across two study subject types and two or more omics technologies (13/62). Investigators at seven USAMRMC laboratories had collaborations with systems biology experts from 18 extramural organizations and three other USAMRMC laboratories. Collaborators from six USAMRMC laboratories and 58 extramural organizations were identified who provided additional research expertise to these systems biology studies.CONCLUSIONS:At the end of fiscal year 2016, USAMRMC laboratories self-reported 66 systems biology/computational biology studies (62 of which were unique) with 25 intramural and 81 extramural collaborators. Nearly two-thirds were led by or in collaboration with the U.S. Army Telemedicine and Advanced Technology Research Center/Department of Defense Biotechnology High-Performance Computing Software Applications Institute and U.S. Army Center for Environmental Health Research. The most common study objective addressed biological mechanisms of disease. The most common types of Research Task Areas addressed infectious diseases (viral and bacterial) and chemical agents (environmental toxicant exposures, and traditional and emerging chemical threats). More than 40% of the studies (27/62) involved collaborations between the reporting USAMRMC laboratory and one other organization. Nearly half of the studies (30/62) involved collaborations between the reporting USAMRMC laboratory and at least two other organizations. These survey results indicate that USAMRMC laboratories are compliant with data-centric policy and guidance documents whose goals are to prevent redundancy and promote collaborations by sharing data and leveraging capabilities. These results also serve as a foundation to make recommendations for future systems biology research efforts.

β-Glucans possess broad immunomodulatory properties, including activation of innate immune functions such as oxidative burst activity. The differential roles of complement receptor type 3 (CR3) and Dectin-1, the known β-glucan receptors, and their associated signaling pathways in the generation of oxidative burst induced by different physical forms of Saccharomyces cerevisiae-derived β-glucan were examined in human peripheral blood mononuclear cells (PBMC). In this study whole glucan particle (WGP) or immobilized soluble β-glucan (ISG) was used to represent the phagocytizable or the nonphagocytizable form of a fungus, respectively. Oxidative burst as measured by the formation of superoxide (SO) was detected in PBMC in response to WGP and ISG. SO induction with WGP was concluded to be Dectin-1-mediated and required Src family kinases, phosphatidylinositol-3 kinase and protein kinase B/Akt. In contrast, the SO induction generated by ISG was CR3-mediated and required focal adhesion kinase, spleen tyrosine kinase, phosphatidylinositol-3 kinase, Akt, p38 mitogen activated protein kinase, phospholipase C and protein kinase C. The study results support the hypothesis that human PBMC, specifically monocytes, utilize distinct receptors and overlapping, but distinct, signaling pathways for the oxidative burst in response to challenge by different physical forms of β-glucan.

A relatively new approach in the treatment of specific wounds in animal models and in patients with type A botulinum toxin is the focus of this paper. The indications or conditions include traumatic wounds (experimental and clinical), surgical (incision) wounds, and wounds such as fissures and ulcers that are signs/symptoms of disease or other processes. An objective was to conduct systematic literature searches and take note of the reactions involved in the healing process and identify corresponding pharmacokinetic data. From several case reports, we developed a qualitative model of how botulinum toxin disrupts the vicious cycle of muscle spasm, pain, inflammation, decreased blood flow, and ischemia. We transformed this model into a minimal kinetic scheme for healing chronic wounds. The model helped us to estimate the rate of decline of this toxin's therapeutic effect by calculating the rate of recurrence of clinical symptoms after a wound-healing treatment with this neurotoxin.

Force health protection (FHP) defines the medical defense approaches to maintain the health of the men and women who serve in the U.S. Armed Forces, to minimize or eliminate casualties, and to provide superior casualty care. Medical defense against biological warfare (BW) agents, whether encountered on a battlefield or as a result of bioterrorism, forms an important part of this strategy. Today, FHP related to biodefense primarily involves developing effective countermeasures against BW agents, performing appropriate surveillance, performing occupational and environmental health risk assessments, and providing medical training. These and other aspects of FHP are discussed. Keywords: biological warfare; bioterrorism; civilian public health; Department of Defense; endemic disease; environmental risk assessment; force health protection; infectious disease; medical defense; medical training; military health system; vaccine

We have used Small-Angle Neutron Scattering to investigate the structure of bilayer lipid membranes in aqueous solution. The lipids consist of equimolar concentrations of two molecules DMPG and DMPC (see text). The structures consist of solvent filled cores surrounded by shells composed of the lipid bilayers. In particular the radii of the core and shell thickness are measured as a function of lipid concentration and temperature. Other features which reveal themselves are vesicle forming ability of the lipids, additional larger structures and inter-vesicle interactions at large vesicle concentrations. The study is motivated by the possible use of these systems as delivery vehicles for various beneficial therapeutic compounds.

The times-to-maximum effect of type A botulinum neurotoxin (BoNT/A) depend to some extent on biophysical and biochemical variables. These times range from <3 h (isolated nerve-muscle preparations) to 1-3 weeks (healthy human volunteers). Hydrodynamic equations were solved for different models, some of which produced values of the diffusion coefficient (D) that are comparable to those of other proteins. Other results differed by up to five orders of magnitude. Because the in vivo findings were not related to an unusually small value for D, we propose that there is a protective reservoir for BoNT/A in vivo and possibly for other serotypes.

Of the seven immunologically distinct forms of the bacterial protein botulinum neurotoxin, serotypes A and B are currently the most widely used in the pharmaceutical treatment of the dystonias. In this study, we have outlined our approach in finding time-related clinical data, (e.g., onset times, durations of effect) from systematically mining the biomedical literature. These values are being integrated into mathematical frameworks to further our understanding of the therapeutic effects of the neurotoxin at the molecular and cellular levels. Potentially, these models could be of use in personalized medicine by making accurate predictions of individual patient responses to small doses of administered toxin.

Botulinum neurotoxin is a pharmaceutical treatment used for an increasing number of neurological and non-neurological indications, symptoms and diseases. Despite the wealth of clinical reports that involve the timing of the therapeutic effects of this toxin, few studies have attempted to integrate these data into unified models. Secondary reactions have also been examined including the development of adverse events, resistance to repeated applications, and nerve terminal sprouting. Our primary intent for conducting this review was to gather relevant pharmacodynamic data from suitable biomedical literature regarding botulinum neurotoxins via the use of automated data-mining techniques. We envision that mathematical models will ultimately be of value to those who are healthcare decision makers and providers, as well as clinical and basic researchers. Furthermore, we hypothesize that the combination of this computer-intensive approach with mathematical modeling will predict the percentage of patients who will favorably or adversely respond to this treatment and thus will eventually assist in developing the increasingly important area of personalized medicine.

The botulinum neurotoxins (BoNT, serotypes A-G) are some of the most toxic proteins known and are the causative agents of botulism. Following exposure, the neurotoxin binds and enters peripheral cholinergic nerve endings and specifically and selectively cleaves one or more SNARE proteins to produce flaccid paralysis. This review centers on the kinetics of the Zn-dependent proteolytic activities of these neurotoxins, and briefly describes inhibitors, activators and factors underlying persistence of toxin action. Some of the structural, enzymatic and inhibitor data that are discussed here are available at the botulinum neurotoxin resource, BotDB (http://botdb.abcc.ncifcrf.gov).

CRATKML-derived peptides (Cp) prevent Botulinum neurotoxin A (BoNT/A) cleavage of purified SNAP25. We tested the effects of four cell membrane permeable Cp analogs on BoNT/A poisoned neuromuscular junctions. In vitro pretreatment with these Cps did not prevent BoNT/A inhibition of neuromuscular transmission (NMT). In vivo pretreatment with these Cps did not protect NMT against BoNT/A. The lack of prophylactic effect paralleled a lack of therapeutic effect on BoNT/A intoxicated mice. These data demonstrate that although Cps are effective BoNT/A antagonists in cell free systems, they are not effective against in vitro or in vivo BoNT/A actions of motor nerve endings.

The literature search section (botXminer) in the botulinum resource database (BotDB; http://botdb.abcc.ncifcrf.gov) contains a new query tool – 'Batch Search'. In basic mode, a user can submit a list of words or phrases that are used to conduct a sequential search of the titles, abstracts and MEDLINE contents of clostridial neurotoxin citations. A table of results is returned that contains the numbers of citations found for each query term that are, in turn, linked to information from PubMed and MEDLINE for each citation. In matrix mode, a user can join two lists of user-defined terms in which all of the results from the combinatorial pairs are returned in a matrix. Each matrix element is linked to a citation list. In both modes, searches can be refined by selecting a range of publication years. Examples of 'Batch Search' matrices are statistically analysed for their quality by calculating their recall and precision values.

Virus particle 24 (VP24) is the smallest protein of the Ebola and Marburg virus genomes. Recent experiments show that Ebola VP24 blocks binding of tyrosine-phosphorylated STAT-1 homodimer (PY-STAT1) to the NPI-1 subfamily of importin alpha, thereby preventing nuclear accumulation of this interferon-promoting transcription factor which, in turn, reduces the innate immune response of the host target. Lacking an experimental structure for VP24, we applied de novo protein structure prediction using the fragment assembly-based Rosetta method to classify its fold topology and better understand its biological function. Filtering and ranking of models were performed with the DFIRE all-atom statistical potential and the CHARMM22 force field with a generalized Born solvent model. From 40,000 Rosetta-generated structures and selective comparisons with the SCOP database, a structural match to two of our top 10-ranking models was the Armadillo repeat fold topology. Specific members of this fold family include importin alpha, importin beta, and exportin. We propose that, unlike the nuclear import of host cargo, VP24 lacks a classical nuclear localization signal (NLS) and targets importin alpha in a similar manner to the observed heterodimeric complex with exportin, thereby interfering with the auto-inhibitory NLS on importin alpha and blocking peripheral docking sites for PY-STAT1 assembly.