Abstract Background Pneumococcal disease burden is difficult to quantify due to limited data regarding non-bacteremic disease. We assessed serotype-specific differences in pneumococcal disease ...presentations in adults in Toronto, Canada. Methods From 2003 to 2011, population-based surveillance for invasive pneumococcal disease was conducted and respiratory pneumococcal isolates collected in Metropolitan Toronto/Peel Region, Canada. Episodes of care were classified into disease categories. Results Of 3105 eligible cases of IPD, 2060 cases were bacteremic pneumonia, and 1045 bacteremia without pneumonia. Of 2751 eligible respiratory cases, 1542 (56.0%) were non-bacteremic pneumonia (NBPP), 467 (17.0%) were other acute respiratory infection (oARI), and 742 (27.0%) were isolates representing colonization. Serotypes 3 (11.3%), 19A (8.4%) and 22F (6.2%) were the most common; serotypes 1,5, and 8 were rare. Serotypes 4, 14, 7F, 9V, 12F, 14, 19A and 6C were over-represented in bacteremic disease, and serotypes 3, 6A, 11A, 19F, 23A, 23F, 35B, 35F were more common in NBPP. The proportion of cases due to PCV7 serotypes declined from 48.7% to 8.7% in bacteremic pneumonia, from 35.3% to 10.9% in NBPP, from 34.2% to 7.5% in oARI, and from 38.7% to 12.2% in colonizing isolates. In 2010–2011, PCV13 serotypes accounted for 62.6% of isolates associated with bacteremic pneumonia, 42.0% of bacteremia without pneumonia, 41.1% of NBPP, 25.7% of oARI, and 32.9% of colonizing isolates. Conclusions Serotype distributions differ significantly in different presentations of pneumococcal disease. Herd protection due to PCV7 has changed serotype distribution, but PCV13 serotypes remain important in all categories of disease.
The limb-specific effects of aging upon vessel structure and function are not well understood. Consequently, in 12 young (26 +/- 2 yr) and 12 old (72 +/- 1 yr) healthy subjects, we utilized ...ultrasound Doppler to evaluate intima-media thickness (IMT), ischemic reperfusion, and flow-mediated dilation (FMD) following (5 min) suprasystolic cuff occlusion in both the arm brachial artery (BA) and the leg popliteal artery (PA). Structural measurements, whether normalized for vessel size or not, revealed a greater IMT in both the BA and PA with age (young: BA 0.028 +/- 0.001 and PA 0.046 +/- 0.003 cm, old: BA 0.039 +/- 0.002 and PA 0.073 +/- 0.005 cm; P < 0.05). Ischemic reperfusion revealed a similar pattern as IMT in terms of limb and age-related differences. There was an age-related attenuation in both BA FMD (old: 38% smaller BA FMD compared with young) and PA FMD (old: 71% smaller PA FMD compared with young). However, when this percent change was normalized for shear rate, only the PA FMD of the old group was still significantly attenuated (old: 41% smaller PA FMD/shear rate compared with young). Together, the finding of differential structural and functional parameters in the arms and legs of healthy young people, and the somewhat negative findings that are specific to the legs of otherwise healthy older people (greater IMT and attenuated FMD), support and may help to better understand the increased propensity to develop a vascular pathology in the legs with age.
It is now generally accepted that alpha-adrenoreceptor-mediated vasoconstriction is attenuated during exercise, but the efficacy of nonadrenergic vasoconstrictor pathways during exercise remains ...unclear. Thus, in eight young (23 +/- 1 yr), healthy volunteers, we contrasted changes in leg blood flow (ultrasound Doppler) before and during intra-arterial infusion of the alpha(1)-adrenoreceptor agonist phenylephrine (PE) with that of the nonadrenergic endothelin A (ET(A))/ET(B) receptor agonist ET-1. Heart rate, arterial blood pressure, common femoral artery diameter, and mean blood velocity were measured at rest and during knee-extensor exercise at 20%, 40%, and 60% of maximal work rate (WR(max)). Drug infusion rates were adjusted for blood flow to maintain comparable doses across all subjects and conditions. At rest, PE infusion (8 ng x ml(-1) x min(-1)) provoked a rapid and significant decrease in leg blood flow (-51 +/- 3%) within 2.5 min. Resting ET-1 infusion (40 pg x ml(-1) x min(-1)) significantly decreased leg blood flow within 5 min, reaching a maximal vasoconstriction (-34 +/- 3%) after 25-30 min of continuous infusion. Compared with rest, an exercise intensity-dependent attenuation to PE-mediated vasoconstriction was observed (-18 +/- 5%, -7 +/- 2%, and -1 +/- 3% change in leg blood flow at 20%, 40%, and 60% of WR(max), respectively). Vasoconstriction in response to ET-1 was also blunted in an exercise intensity-dependent manner (-13 +/- 3%, -7 +/- 4%, and 2 +/- 3% change in leg blood flow at 20%, 40%, and 60% of WR(max), respectively). These findings support a significant contribution of ET-1 and alpha-adrenergic receptors in the regulation of skeletal muscle blood flow in the human leg at rest and suggest a similar, intensity-dependent "lysis" of peripheral ET and alpha-adrenergic vasoconstriction during dynamic exercise.
This paper compares the use of first- and second-order Sobolev gradients to solve differential equations using the method of least-squares steepest descent. The use of high-order Sobolev gradients ...offers a very effective preconditioning strategy for the linear part of a nonlinear differential equation.
This paper reviews solving differential equations using the least-squares steepest descent method with Sobolev gradients. The method's superiority over standard steepest descent with a Euclidean ...gradient is explained in terms of stability and the classical Courant–Freiderichs–Lewy condition for the path of steepest descent. The spectra for several of the operators arising from a cononical example are also computed. Kantorovich's inequality then gives explicit estimates on the rate of convergence for the two processes. In this way, use of the Sobolev gradient is viewed as a very effective preconditioning strategy for the linear part of the differential equation.
A mathematical framework has been developed for numerical analysis and simulation of applications in superconducting microelectronics. The approach is similar to those used successfully in ...semiconductor modeling. Here we investigate semidiscrete simulation of the time dependent Ginzburg-Landau equations. Several interesting numerical and modeling issues regarding the structure of the solutions and their sensitivity to the data and mesh resolution are described using results from a representative problem.
Snakes are limbless predators, and many species use venom to help overpower relatively large, agile prey. Snake venoms are complex protein mixtures encoded by several multilocus gene families that ...function synergistically to cause incapacitation. To examine venom evolution, we sequenced and interrogated the genome of a venomous snake, the king cobra (Ophiophagus hannah), and compared it, together with our unique transcriptome, microRNA, and proteome datasets from this species, with data from other vertebrates. In contrast to the platypus, the only other venomous vertebrate with a sequenced genome, we find that snake toxin genes evolve through several distinct co-option mechanisms and exhibit surprisingly variable levels of gene duplication and directional selection that correlate with their functional importance in prey capture. The enigmatic accessory venom gland shows a very different pattern of toxin gene expression from the main venom gland and seems to have recruited toxin-like lectin genes repeatedly for new nontoxic functions. In addition, tissue-specific microRNA analyses suggested the co-option of core genetic regulatory components of the venom secretory system from a pancreatic origin. Although the king cobra is limbless, we recovered coding sequences for all Hox genes involved in amniote limb development, with the exception of Hoxd12 . Our results provide a unique view of the origin and evolution of snake venom and reveal multiple genome-level adaptive responses to natural selection in this complex biological weapon system. More generally, they provide insight into mechanisms of protein evolution under strong selection.
Global genetic diversity of Aedes aegypti Gloria-Soria, Andrea; Ayala, Diego; Bheecarry, Ambicadutt ...
Molecular ecology,
November 2016, Volume:
25, Issue:
21
Journal Article
Peer reviewed
Open access
Mosquitoes, especially Aedes aegypti, are becoming important models for studying invasion biology. We characterized genetic variation at 12 microsatellite loci in 79 populations of Ae. aegypti from ...30 countries in six continents, and used them to infer historical and modern patterns of invasion. Our results support the two subspecies Ae. aegypti formosus and Ae. aegypti aegypti as genetically distinct units. Ae. aegypti aegypti populations outside Africa are derived from ancestral African populations and are monophyletic. The two subspecies co‐occur in both East Africa (Kenya) and West Africa (Senegal). In rural/forest settings (Rabai District of Kenya), the two subspecies remain genetically distinct, whereas in urban settings, they introgress freely. Populations outside Africa are highly genetically structured likely due to a combination of recent founder effects, discrete discontinuous habitats and low migration rates. Ancestral populations in sub‐Saharan Africa are less genetically structured, as are the populations in Asia. Introduction of Ae. aegypti to the New World coinciding with trans‐Atlantic shipping in the 16th to 18th centuries was followed by its introduction to Asia in the late 19th century from the New World or from now extinct populations in the Mediterranean Basin. Aedes mascarensis is a genetically distinct sister species to Ae. aegypti s.l. This study provides a reference database of genetic diversity that can be used to determine the likely origin of new introductions that occur regularly for this invasive species. The genetic uniqueness of many populations and regions has important implications for attempts to control Ae. aegypti, especially for the methods using genetic modification of populations.
Cas9 is a prokaryotic RNA-guided DNA endonuclease that binds substrates tightly in vitro but turns over rapidly when used to manipulate genomes in eukaryotic cells. Little is known about the factors ...responsible for dislodging Cas9 or how they influence genome engineering. Unbiased detection through proximity labeling of transient protein interactions in cell-free Xenopus laevis egg extract identified the dimeric histone chaperone facilitates chromatin transcription (FACT) as an interactor of substrate-bound Cas9. FACT is both necessary and sufficient to displace dCas9, and FACT immunodepletion converts Cas9’s activity from multi-turnover to single turnover. In human cells, FACT depletion extends dCas9 residence times, delays genome editing, and alters the balance between indel formation and homology-directed repair. FACT knockdown also increases epigenetic marking by dCas9-based transcriptional effectors with a concomitant enhancement of transcriptional modulation. FACT thus shapes the intrinsic cellular response to Cas9-based genome manipulation most likely by determining Cas9 residence times.
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•Histone chaperone FACT is necessary and sufficient to remove Cas9 from DNA in vitro•FACT turns Cas9 from single turnover to multi-turnover•FACT depletion in human cells delays Cas9 DSB repair and alters editing outcomes•FACT depletion increases dCas9 residence to increase epigenetic marking and CRISPRi
S. pyogenes Cas9 binds very tightly to DNA. It has been unclear how cells remove Cas9 from the genome. Wang et al. determine that the histone chaperone complex FACT displaces Cas9 from its substrate in eukaryotic systems. FACT knockdown potentiates CRISPR-based tools and alters Cas9 gene editing outcomes.
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