An alternative approach to combination vaccines: intradermal administration of isolated components for control of anthrax, botulism, plague and staphylococcal toxic shock

BACKGROUND: Combination vaccines reduce the total number of injections required for each component administered separately and generally provide the same level of disease protection. Yet, physical, chemical, and biological interactions between vaccine components are often detrimental to vaccine safety or efficacy. METHODS: As a possible alternative to combination vaccines, we used specially designed microneedles to inject rhesus macaques with four separate recombinant protein vaccines for anthrax, botulism, plague and staphylococcal toxic shock next to each other just below the surface of the skin, thus avoiding potentially incompatible vaccine mixtures. RESULTS: The intradermally-administered vaccines retained potent antibody responses and were well- tolerated by rhesus macaques. Based on tracking of the adjuvant, the vaccines were transported from the dermis to draining lymph nodes by antigen-presenting cells. Vaccinated primates were completely protected from an otherwise lethal aerosol challenge by Bacillus anthracis spores, botulinum neurotoxin A, or staphylococcal enterotoxin B. CONCLUSION: Our results demonstrated that the physical separation of vaccines both in the syringe and at the site of administration did not adversely affect the biological activity of each component. The vaccination method we describe may be scalable to include a greater number of antigens, while avoiding the physical and chemical incompatibilities encountered by combining multiple vaccines together in one product

Using hydrologic landscape classification and climatic time series to assess hydrologic vulnerability of the western U.S. to climate

We apply the hydrologic landscape (HL) concept to assess the hydrologic vulnerability of the western United States (U.S.) to projected climate conditions. Our goal is to understand the potential impacts of hydrologic vulnerability for stakeholder-defined interests across large geographic areas. The basic assumption of the HL approach is that catchments that share similar physical and climatic characteristics are expected to have similar hydrologic characteristics. We use the hydrologic landscape vulnerability approach (HLVA) to map the HLVA index (an assessment of climate vulnerability) by integrating hydrologic landscapes into a retrospective analysis of historical data to assess variability in future climate projections and hydrology, which includes temperature, precipitation, potential evapotranspiration, snow accumulation, climatic moisture, surplus water, and seasonality of water surplus. Projections that are beyond 2 standard deviations of the historical decadal average contribute to the HLVA index for each metric. Separating vulnerability into these seven separate metrics allows stakeholders and/or water resource managers to have a more specific understanding of the potential impacts of future conditions. We also apply this approach to examine case studies. The case studies (Mt. Hood, Willamette Valley, and Napa–Sonoma Valley) are important to the ski and wine industries and illustrate how our approach might be used by specific stakeholders. The resulting vulnerability maps show that temperature and potential evapotranspiration are consistently projected to have high vulnerability indices for the western U.S. Precipitation vulnerability is not as spatially uniform as temperature. The highest-elevation areas with snow are projected to experience significant changes in snow accumulation. The seasonality vulnerability map shows that specific mountainous areas in the west are most prone to changes in seasonality, whereas many transitional terrains are moderately susceptible. This paper illustrates how HL and the HLVA can help assess climatic and hydrologic vulnerability across large spatial scales. By combining the HL concept and HLVA, resource managers could consider future climate conditions in their decisions about managing important economic and conservation resources.</p

Vaccine antigens modulate the innate response of monocytes to Al(OH)3.

Aluminum-based adjuvants have widely been used in human vaccines since 1926. In the absence of antigens, aluminum-based adjuvants can initiate the inflammatory preparedness of innate cells, yet the impact of antigens on this response has not been investigated so far. In this study, we address the modulating effect of vaccine antigens on the monocyte-derived innate response by comparing processes initiated by Al(OH)3 and by Infanrix, an Al(OH)3-adjuvanted trivalent combination vaccine (DTaP), containing diphtheria toxoid (D), tetanus toxoid (T) and acellular pertussis (aP) vaccine antigens. A systems-wide analysis of stimulated monocytes was performed in which full proteome analysis was combined with targeted transcriptome analysis and cytokine analysis. This comprehensive study revealed four major differences in the monocyte response, between plain Al(OH)3 and DTaP stimulation conditions: (I) DTaP increased the anti-inflammatory cytokine IL-10, whereas Al(OH)3 did not; (II) Al(OH)3 increased the gene expression of IFNγ, IL-2 and IL-17a in contrast to the limited induction or even downregulation by DTaP; (III) increased expression of type I interferons-induced proteins was not observed upon DTaP stimulation, but was observed upon Al(OH)3 stimulation; (IV) opposing regulation of protein localization pathways was observed for Al(OH)3 and DTaP stimulation, related to the induction of exocytosis by Al(OH)3 alone. This study highlights that vaccine antigens can antagonize Al(OH)3-induced programming of the innate immune responses at the monocyte level

Synthetic Nanoparticles for Vaccines and Immunotherapy

The immune system plays a critical role in our health. No other component of human physiology plays a decisive role in as diverse an array of maladies, from deadly diseases with which we are all familiar to equally terrible esoteric conditions: HIV, malaria, pneumococcal and influenza infections; cancer; atherosclerosis; autoimmune diseases such as lupus, diabetes, and multiple sclerosis. The importance of understanding the function of the immune system and learning how to modulate immunity to protect against or treat disease thus cannot be overstated. Fortunately, we are entering an exciting era where the science of immunology is defining pathways for the rational manipulation of the immune system at the cellular and molecular level, and this understanding is leading to dramatic advances in the clinic that are transforming the future of medicine.1,2 These initial advances are being made primarily through biologic drugs– recombinant proteins (especially antibodies) or patient-derived cell therapies– but exciting data from preclinical studies suggest that a marriage of approaches based in biotechnology with the materials science and chemistry of nanomaterials, especially nanoparticles, could enable more effective and safer immune engineering strategies. This review will examine these nanoparticle-based strategies to immune modulation in detail, and discuss the promise and outstanding challenges facing the field of immune engineering from a chemical biology/materials engineering perspectiveNational Institutes of Health (U.S.) (Grants AI111860, CA174795, CA172164, AI091693, and AI095109)United States. Department of Defense (W911NF-13-D-0001 and Awards W911NF-07-D-0004

Systematic Review of Potential Health Risks Posed by Pharmaceutical, Occupational and Consumer Exposures to Metallic and Nanoscale Aluminum, Aluminum Oxides, Aluminum Hydroxide and Its Soluble Salts

Aluminum (Al) is a ubiquitous substance encountered both naturally (as the third most abundant element) and intentionally (used in water, foods, pharmaceuticals, and vaccines); it is also present in ambient and occupational airborne particulates. Existing data underscore the importance of Al physical and chemical forms in relation to its uptake, accumulation, and systemic bioavailability. The present review represents a systematic examination of the peer-reviewed literature on the adverse health effects of Al materials published since a previous critical evaluation compiled by Krewski et al. (2007). Challenges encountered in carrying out the present review reflected the experimental use of different physical and chemical Al forms, different routes of administration, and different target organs in relation to the magnitude, frequency, and duration of exposure. Wide variations in diet can result in Al intakes that are often higher than the World Health Organization provisional tolerable weekly intake (PTWI), which is based on studies with Al citrate. Comparing daily dietary Al exposures on the basis of “total Al”assumes that gastrointestinal bioavailability for all dietary Al forms is equivalent to that for Al citrate, an approach that requires validation. Current occupational exposure limits (OELs) for identical Al substances vary as much as 15-fold. The toxicity of different Al forms depends in large measure on their physical behavior and relative solubility in water. The toxicity of soluble Al forms depends upon the delivered dose of Al+ 3 to target tissues. Trivalent Al reacts with water to produce bidentate superoxide coordination spheres [Al(O2)(H2O4)+ 2 and Al(H2O)6 + 3] that after complexation with O2•−, generate Al superoxides [Al(O2•)](H2O5)]+ 2. Semireduced AlO2• radicals deplete mitochondrial Fe and promote generation of H2O2, O2 • − and OH•. Thus, it is the Al+ 3-induced formation of oxygen radicals that accounts for the oxidative damage that leads to intrinsic apoptosis. In contrast, the toxicity of the insoluble Al oxides depends primarily on their behavior as particulates. Aluminum has been held responsible for human morbidity and mortality, but there is no consistent and convincing evidence to associate the Al found in food and drinking water at the doses and chemical forms presently consumed by people living in North America and Western Europe with increased risk for Alzheimer\u27s disease (AD). Neither is there clear evidence to show use of Al-containing underarm antiperspirants or cosmetics increases the risk of AD or breast cancer. Metallic Al, its oxides, and common Al salts have not been shown to be either genotoxic or carcinogenic. Aluminum exposures during neonatal and pediatric parenteral nutrition (PN) can impair bone mineralization and delay neurological development. Adverse effects to vaccines with Al adjuvants have occurred; however, recent controlled trials found that the immunologic response to certain vaccines with Al adjuvants was no greater, and in some cases less than, that after identical vaccination without Al adjuvants. The scientific literature on the adverse health effects of Al is extensive. Health risk assessments for Al must take into account individual co-factors (e.g., age, renal function, diet, gastric pH). Conclusions from the current review point to the need for refinement of the PTWI, reduction of Al contamination in PN solutions, justification for routine addition of Al to vaccines, and harmonization of OELs for Al substances

Antioxidants l-carnitine and d-methionine modulate neuronal activity through GABAergic inhibition

Article on antioxidants L-carnitine and D-methionine modulate neuronal activity through GABAergic inhibition

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Volume: 32Start Page: 121End Page: 12

Spatiotemporal Prediction of Fine Particulate Matter During the 2008 Northern California Wildfires Using Machine Learning

Estimating population exposure to particulate matter during wildfires can be difficult because of insufficient monitoring data to capture the spatiotemporal variability of smoke plumes. Chemical transport models (CTMs) and satellite retrievals provide spatiotemporal data that may be useful in predicting PM_2.5 during wildfires. We estimated PM_2.5 concentrations during the 2008 northern California wildfires using 10-fold cross-validation (CV) to select an optimal prediction model from a set of 11 statistical algorithms and 29 predictor variables. The variables included CTM output, three measures of satellite aerosol optical depth, distance to the nearest fires, meteorological data, and land use, traffic, spatial location, and temporal characteristics. The generalized boosting model (GBM) with 29 predictor variables had the lowest CV root mean squared error and a CV-R² of 0.803. The most important predictor variable was the Geostationary Operational Environmental Satellite Aerosol/Smoke Product (GASP) Aerosol Optical Depth (AOD), followed by the CTM output and distance to the nearest fire cluster. Parsimonious models with various combinations of fewer variables also predicted PM_2.5 well. Using machine learning algorithms to combine spatiotemporal data from satellites and CTMs can reliably predict PM_2.5 concentrations during a major wildfire event

A revised subtribal classification of Gnaphalieae (Asteraceae)

Gnaphalieae are one of the larger tribes of the daisy family Asteraceae (Compositae) with c. 2100 species in 178 genera, occurring globally across a wide range of temperate habitats. Recent years have seen considerable advances in our understanding of their phylogenetics and evolution, but there is no widely accepted, stable subtribal classification. The present paper summarises the taxonomic history and presents the various major clades that have been named informally in phylogenetic studies. We also provide the most comprehensive phylogenetic analysis of DNA sequence data to date, including over 1000 species. Based on published studies and our new phylogenetic analyses, we suggest a subdivision of the tribe into two subtribes. These are a largely African-endemic Relhaniinae (124 species in 11 genera) and a much enlarged Gnaphaliinae, the latter accounting for more than 90% of the species diversity (c. 2000 species in 167 genera). Although a finer division of Gnaphaliinae sensu amplo may be desirable, there are at present several obstacles to such a classification, in particular contradictory or ambiguous inferences of relationships.Fil: Smissen, Rob D.. Manaaki Whenua Landcare Research; Nueva ZelandaFil: Bayer, Randall J.. University of Memphis; Estados UnidosFil: Bergh, Nicola G.. University of Cape Town; Sudáfrica. Kirstenbosch National Botanical Gardens; SudáfricaFil: Breitwieser, Ilse. Manaaki Whenua Landcare Research; Nueva ZelandaFil: Freire, Susana Edith. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Botánica Darwinion. Academia Nacional de Ciencias Exactas, Físicas y Naturales. Instituto de Botánica Darwinion; ArgentinaFil: Galbany Casals, Mercè. Universitat Autònoma de Barcelona; EspañaFil: Schmidt Lebuhn, Alexander N.. Commonwealth Scientific and Industrial Research Organisation; AustraliaFil: Ward, Josephine M.. University of Canterbury; Nueva Zeland