Pertussis is a highly contagious respiratory illness caused by the bacterial pathogen Bordetella pertussis . Pertussis rates in the United States have been rising and reached a 50-y high of 42,000 ...cases in 2012. Although pertussis resurgence is not completely understood, we hypothesize that current acellular pertussis (aP) vaccines fail to prevent colonization and transmission. To test our hypothesis, infant baboons were vaccinated at 2, 4, and 6 mo of age with aP or whole-cell pertussis (wP) vaccines and challenged with B. pertussis at 7 mo. Infection was followed by quantifying colonization in nasopharyngeal washes and monitoring leukocytosis and symptoms. Baboons vaccinated with aP were protected from severe pertussis-associated symptoms but not from colonization, did not clear the infection faster than naïve animals, and readily transmitted B. pertussis to unvaccinated contacts. Vaccination with wP induced a more rapid clearance compared with naïve and aP-vaccinated animals. By comparison, previously infected animals were not colonized upon secondary infection. Although all vaccinated and previously infected animals had robust serum antibody responses, we found key differences in T-cell immunity. Previously infected animals and wP-vaccinated animals possess strong B. pertussis -specific T helper 17 (Th17) memory and Th1 memory, whereas aP vaccination induced a Th1/Th2 response instead. The observation that aP, which induces an immune response mismatched to that induced by natural infection, fails to prevent colonization or transmission provides a plausible explanation for the resurgence of pertussis and suggests that optimal control of pertussis will require the development of improved vaccines.
A look at how effective nanoparticle probes are in the diagnosis of cancer biomarkers, cells and tissues through fluorescence is offered. Topics addressed include nanoparticles for fluorescent ...detection, the detection of extracellular cancer biomarkers and the detection of tumor tissue in vivo.
Pertussis is a contagious, acute respiratory illness caused by the bacterial pathogen Bordetella pertussis. Although it is widely believed that transmission of B. pertussis occurs via aerosolized ...respiratory droplets, no controlled study has ever documented airborne transmission of pertussis. We set out to determine if airborne transmission occurs between infected and naive animals, utilizing the baboon model of pertussis. Our results showed that 100% of exposed naive animals became infected even when physical contact was prevented, demonstrating that pertussis transmission occurs via aerosolized respiratory droplets.
The present article gives a summary of recent technological and scientific developments in the field of polycrystalline silicon (poly-Si) thin-film solar cells on foreign substrates. Cost-effective ...fabrication methods and cheap substrate materials make poly-Si thin-film solar cells promising candidates for photovoltaics. However, it is still the challenge for research and development to achieve the necessary high electrical material quality known from crystalline Si wafers on glass as a prerequisite to harvest the advantages of thin-film technologies. A wide variety of poly-Si thin-film solar cell approaches has been investigated in the past years, such as thermal solid phase crystallization – the only technology that had already been matured to industrial production so far – the seed layer concept where a large-grained seed layer is epitaxially thickened, direct growth of fine grained material, and liquid phase crystallization methods by laser or electron beam. In the first part of this paper, the status of these four different poly-Si thin-film solar cell concepts is summarized, by comparing the technological fabrication methods, as well as the structural and electrical properties and solar cell performances of the respective materials. In the second part, three promising technologies are described in more detail due to their highly auspicious properties regarding material quality and throughput aspects during fabrication: (1) High-rate electron–beam evaporation of silicon for the low-cost deposition of high-quality material, (2) large-area periodic nano- and micro-structuring of poly-Si by the use of imprinted substrates providing a large absorption enhancement by a factor of six at a wavelength of 900nm, (3) liquid-phase crystallization of silicon thin-film solar cells by electron–beam, yielding an excellent poly-Si material quality reflected by an open-circuit voltage of 582mV which has been achieved only very recently. A successful combination of these three complementary technologies is envisaged to be the basis for a prospective low-cost and highly efficient poly-Si solar cell device.
•Various poly-Si thin-film solar cell technologies are reviewed and compared.•Liquid phase crystallized Si has largest grains and best electrical material quality.•Nanophotonic poly-Si light trapping structures yield large absorption enhancement.•Poly-Si thin-film solar cells with 580mV open circuit voltage are realized.
Glioblastoma multiforme (GBM) is a neurologically debilitating disease that culminates in death 14 to 16 months after diagnosis. An incomplete understanding of how cataloged genetic aberrations ...promote therapy resistance, combined with ineffective drug delivery to the central nervous system, has rendered GBM incurable. Functional genomics efforts have implicated several oncogenes in GBM pathogenesis but have rarely led to the implementation of targeted therapies. This is partly because many "undruggable" oncogenes cannot be targeted by small molecules or antibodies. We preclinically evaluate an RNA interference (RNAi)-based nanomedicine platform, based on spherical nucleic acid (SNA) nanoparticle conjugates, to neutralize oncogene expression in GBM. SNAs consist of gold nanoparticles covalently functionalized with densely packed, highly oriented small interfering RNA duplexes. In the absence of auxiliary transfection strategies or chemical modifications, SNAs efficiently entered primary and transformed glial cells in vitro. In vivo, the SNAs penetrated the blood-brain barrier and blood-tumor barrier to disseminate throughout xenogeneic glioma explants. SNAs targeting the oncoprotein Bcl2Like12 (Bcl2L12)--an effector caspase and p53 inhibitor overexpressed in GBM relative to normal brain and low-grade astrocytomas--were effective in knocking down endogenous Bcl2L12 mRNA and protein levels, and sensitized glioma cells toward therapy-induced apoptosis by enhancing effector caspase and p53 activity. Further, systemically delivered SNAs reduced Bcl2L12 expression in intracerebral GBM, increased intratumoral apoptosis, and reduced tumor burden and progression in xenografted mice, without adverse side effects. Thus, silencing antiapoptotic signaling using SNAs represents a new approach for systemic RNAi therapy for GBM and possibly other lethal malignancies.
•The lack of standardized laboratory measurement of serum total 25-hydroxyvitamin D 25-OHD in vitamin D research impedes development of consensus 25-OHD values to define stages of vitamin D ...status.•Some 60,000 vitamin D papers have been published since the discovery of 25-OHD with nearly all the values from non-standardized assays. We cannot just ignore this old data and focus on standardizing 25-OHD in current and future research.•Vitamin D Standardization Program (VDSP) has developed “retrospective standardization” protocols to address this problem.•VDSP retrospective standardization of 25-OHD values to gold standard reference measurements values has been shown to be accurate.•Retrospective standardization results can vary widely depending on if initial 25-OHD measurements were determined using an assay that was positively or negatively biased and the level of bias in the old assay.•An International effort is needed to identify key prior studies with stored samples for re-analysis and standardization, initially, to define the 25-OHD level associated with vitamin D deficiency (rickets/osteomalacia). Subsequent work could focus on defining inadequacy.•Finally, levels of assay variation and lack of standardized research data highlight the importance of suspending publication of meta-analyses based on unstandardized 25(OH)D results.
Substantial variability is associated with laboratory measurement of serum total 25-hydroxyvitamin D 25(OH)D. The resulting chaos impedes development of consensus 25(OH)D values to define stages of vitamin D status. As resolving this situation requires standardized measurement of 25(OH)D, the Vitamin D Standardization Program (VDSP) developed methodology to standardize 25(OH)D measurement to the gold standard reference measurement procedures of NIST, Ghent University and CDC. Importantly, VDSP developed protocols for standardizing 25(OH)D values from prior research based on availability of stored serum samples. The effect of such retrospective standardization on prevalence of “low” vitamin D status in national studies reported here for The Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994) and the German Health Interview and Examination Survey for Children and Adolescents (KIGGS, 2003–2006) was such that in NHANES III 25(OH)D values were lower than original values while higher in KIGGS. In NHANES III the percentage with values below 30, 50 and 75 nmol/L increased from 4% to 6%, 22% to 31% and 55% to 71%, respectively. Whereas in KIGGS after standardization the percentage below 30, 50, and 70 nmol/L decreased from 28% to 13%, 64% to 47% and 87% to 85% respectively. Moreover, in a hypothetical example, depending on whether the 25(OH)D assay was positively or negatively biased by 12%, the 25(OH)D concentration which maximally suppressed PTH could vary from 20 to 35ng/mL. These examples underscore the challenges (perhaps impossibility) of developing vitamin D guidelines using unstandardized 25(OH)D data. Retrospective 25(OH)D standardization can be applied to old studies where stored serum samples exist. As a way forward, we suggest an international effort to identify key prior studies with stored samples for re-analysis and standardization initially to define the 25(OH)D level associated with vitamin D deficiency (rickets/osteomalacia). Subsequent work could focus on defining inadequacy. Finally, examples reported here highlight the importance of suspending publication of meta-analyses based on unstandardized 25(OH)D results.
Immunomodulatory spherical nucleic acids Radovic-Moreno, Aleksandar F.; Chernyak, Natalia; Mader, Christopher C. ...
Proceedings of the National Academy of Sciences - PNAS,
03/2015, Volume:
112, Issue:
13
Journal Article
Peer reviewed
Open access
Immunomodulatory nucleic acids have extraordinary promise for treating disease, yet clinical progress has been limited by a lack of tools to safely increase activity in patients. Immunomodulatory ...nucleic acids act by agonizing or antagonizing endosomal toll-like receptors (TLR3, TLR7/8, and TLR9), proteins involved in innate immune signaling. Immunomodulatory spherical nucleic acids (SNAs) that stimulate (immunostimulatory, IS-SNA) or regulate (immunoregulatory, IR-SNA) immunity by engaging TLRs have been designed, synthesized, and characterized. Compared with free oligonucleotides, IS-SNAs exhibit up to 80-fold increases in potency, 700-fold higher antibody titers, 400-fold higher cellular responses to a model antigen, and improved treatment of mice with lymphomas. IR-SNAs exhibit up to eightfold increases in potency and 30% greater reduction in fibrosis score in mice with nonalcoholic steatohepatitis (NASH). Given the clinical potential of SNAs due to their potency, defined chemical nature, and good tolerability, SNAs are attractive new modalities for developing immunotherapies.
Significance We show that by organizing immunomodulatory nucleic acids into spherical nucleic acid (SNA) form, significant increases in activity are observed. Treatment of mice with cancer using immunostimulatory SNAs and nonalcoholic steatohepatitis (NASH) using immunoregulatory SNAs leads to improved disease outcomes vs. their unstructured counterparts. These improvements derive from several key SNA properties, including rapid cellular uptake, endosomal delivery, and multivalent binding. Overall, this work underscores the importance of the spatial orientation and presentation of oligonucleotides in the design of novel immunomodulators.
It has long been hypothesized that elastic modulus governs the biodistribution and circulation times of particles and cells in blood; however, this notion has never been rigorously tested. We ...synthesized hydrogel microparticles with tunable elasticity in the physiological range, which resemble red blood cells in size and shape, and tested their behavior in vivo. Decreasing the modulus of these particles altered their biodistribution properties, allowing them to bypass several organs, such as the lung, that entrapped their more rigid counterparts, resulting in increasingly longer circulation times well past those of conventional microparticles. An 8-fold decrease in hydrogel modulus correlated to a greater than 30-fold increase in the elimination phase half-life for these particles. These results demonstrate a critical design parameter for hydrogel microparticles.
Batch experiments were conducted to study the sorption of uranium on selected clay minerals (KGa-1b and KGa-2 reference kaolinite, SWy-2 and STx-1b reference montmorillonite, and IBECO natural ...bentonite) as a function of pH (4–9) and 0.001, 0.01, and 0.025 M NaCl in equilibrium with the CO
2
partial pressure of the atmosphere. Uranium concentrations were kept below 100 μg L
−1
to avoid precipitation of amorphous Uranium-hydroxides. Solely PTFE containers and materials were used, because experiments showed significant sorption at higher pH on glass ware. All batch experiments were performed over a period of 24 h, since kinetic experiments proved that the common 10 or 15 min are in many cases by far not sufficient to reach equilibrium. Kaolinite showed much greater uranium sorption than the other clay minerals due to the more aluminol sites available. Sorption on the poorly crystallized KGa-2 was higher than on the well-crystallized KGa-1b. Uranium sorption on STx-1b and IBECO exhibited parabolic behavior with a sorption maximum around pH 6.5. Sorption of uranium on montmorillonites showed a distinct dependency on sodium concentrations because of the effective competition between uranyl and sodium ions, whereas less significant differences in sorption were found for kaolinite. The presence of anatase as impurity in kaolinite enhanced the binding of uranyl-carbonate complexes with surface sites. The kinetic of uranium sorption behavior was primarily dependent on the clay minerals and pH. A multisite surface complexation model without assuming exchange is based on the binding of the most dominant uranium species to aluminol and silanol edge sites of montmorillonite, respectively to aluminol and titanol surface sites of kaolinite. For eight surface species, the log_k was determined from the experimental data using the parameter estimation code PEST together with PHREEQC.
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