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pestis fulminans [keywords]
- The economics, financing and implementation of HIV treatment as prevention: What will it take to get there? [Journal Article]
- Afr J AIDS Res 2014 Jun; 13(2):109-19.
The 2013 Lancet Commission Report, Global Health 2035, rightly pointed out that we are at a unique place in history where a "grand convergence" of health initiatives to reduce both infectious diseases, and child and maternal mortality - diseases that still plague low income countries - would yield good returns in terms of development and health outcomes. This would also be a good economic investment. Such investments would support achieving health goals of reducing under-five (U5) mortality to 16 per 1 000 live births, reducing deaths due to HIV/AIDS to 8 per 100 000 population, and reducing annual TB deaths to 4 per 100 000 population. Treatment as prevention (TasP) holds enormous potential in reducing HIV transmission, and morbidity and mortality associated with HIV/AIDS - and therefore contributing to Global Health 2035 goals. However, TasP requires large financial investments and poses significant implementation challenges. In this review, we discuss the potential effectiveness, financing and implementation of TasP. Overall, we conclude that TasP shows great promise as a cost-effective intervention to address the dual aims of reducing new HIV infections and reducing the global burden of HIV-related disease. Successful implementation will be no easy feat, though. The dramatic increases in the numbers of persons who need antiretroviral therapy (ART) under a TasP approach will pose enormous challenges at all stages of the HIV treatment cascade: HIV diagnosis, antiretroviral (ARV) initiation, ARV adherence and retention, and increased drug resistance with long-term enrolment on ART. Overcoming these implementation challenges will require targeted implementation, not focusing exclusively on TasP, most-at-risk population (MARP)-friendly services for key populations, integrating services, task shifting, more efficient programme management, balancing supply and demand, integration into universal health coverage efforts, demand creation, improved ART retention and adherence strategies, the use of incentives to improve HIV treatment outcomes and reduce unit costs, continued operational research and tapping into technological innovations.
- Stochastic many-body perturbation theory for anharmonic molecular vibrations. [JOURNAL ARTICLE]
- J Chem Phys 2014 Aug 28; 141(8):084105.
A new quantum Monte Carlo (QMC) method for anharmonic vibrational zero-point energies and transition frequencies is developed, which combines the diagrammatic vibrational many-body perturbation theory based on the Dyson equation with Monte Carlo integration. The infinite sums of the diagrammatic and thus size-consistent first- and second-order anharmonic corrections to the energy and self-energy are expressed as sums of a few m- or 2m-dimensional integrals of wave functions and a potential energy surface (PES) (m is the vibrational degrees of freedom). Each of these integrals is computed as the integrand (including the value of the PES) divided by the value of a judiciously chosen weight function evaluated on demand at geometries distributed randomly but according to the weight function via the Metropolis algorithm. In this way, the method completely avoids cumbersome evaluation and storage of high-order force constants necessary in the original formulation of the vibrational perturbation theory; it furthermore allows even higher-order force constants essentially up to an infinite order to be taken into account in a scalable, memory-efficient algorithm. The diagrammatic contributions to the frequency-dependent self-energies that are stochastically evaluated at discrete frequencies can be reliably interpolated, allowing the self-consistent solutions to the Dyson equation to be obtained. This method, therefore, can compute directly and stochastically the transition frequencies of fundamentals and overtones as well as their relative intensities as pole strengths, without fixed-node errors that plague some QMC. It is shown that, for an identical PES, the new method reproduces the correct deterministic values of the energies and frequencies within a few cm(-1) and pole strengths within a few thousandths. With the values of a PES evaluated on the fly at random geometries, the new method captures a noticeably greater proportion of anharmonic effects.
- Clinical signs and symptoms of tinnitus in temporomandibular joint disorders: a pilot study comparing patients and non-patients. [Journal Article]
- S Afr J Commun Disord 2013 Dec.:16-20.
Tinnitus is one of the otologic symptoms commonly reported to be associated with temporomandibular disorder (TMD), and questions regarding its nature and cause continue to plague the clinical and research community.The current pilot study aimed to investigate the clinical signs and symptoms of presenting tinnitus in a group of individuals with TMD (group A), and compare them with a group with tinnitus but without TMD (group B). Twenty participants were included in the study, 10 from each group.All participants underwent basic audiological as well as ear, nose and throat (ENT) evaluations to establish group A and group B. For tinnitus assessment, all participants completed a tinnitus survey questionnaire, and their tinnitus was evaluated using tinnitus matching procedures.Findings revealed clinically relevant differences in attributes of tinnitus in patients with and without TMD. Most of the participants in group A matched their tinnitus to a 6 000 Hz tone or noise, at lower intensity levels than participants in group B, although these results were not statistically significant. Participants in group A associated their tinnitus with a single sound whereas some participants in group B associated it with more than one sound. More participants in group B reported the duration of their tinnitus as constant.Tinnitus may occur in patients with TMD, and be of high frequency. This highlights the importance of thorough assessment for patients with tinnitus as this might have implications for diagnosis and management.
- Embryonic diapause in the australian plague locust relative to parental experience of cumulative photophase decline. [JOURNAL ARTICLE]
- J Insect Physiol 2014 Aug 22.
The Australian plague locust Chortoicetes terminifera (Walker) exhibits facultative embryonic diapause during autumn. To approximate natural photoperiod changes during late summer and autumn, locust nymphs were reared under different total declines in laboratory photophase (-0.5, -0.75, -1.0, -1.25, -1.5, -1.75, -2 h each lowered in 15 min steps) in a 24 h photoperiod to quantify any effect on the subsequent production of diapause eggs. Induction of diapause eggs was significantly affected by accumulated photoperiod decline experienced by the parental generation throughout all development stages from mid-instar nymph to fledgling adult. The incidence of embryonic diapause ranged from nil at -0.5 h to 86.6% diapause at -2 h. Continued declines in photoperiod for post-teneral locusts (transitioned from -1 h until fledging to -1.75 h) produced a further increase in the proportion of diapause eggs. The results were unaffected by time spent at any given photoperiod, despite a previously indicated maximal inductive photoperiod of 13.5 h being used as the mid-point of all treatments. Implications for the seasonal timing processes of photoperiodism in C. terminifera, which has a high migratory capacity and a latitudinal cline in the timing of diapause egg production across a broad geographic range, are discussed.
- Reply: methodologic concerns in reliability of noncalcified coronary artery plague burden quantification. [Journal Article]
- AJR Am J Roentgenol 2014 Sep; 203(3):W344.
- Genome-Wide Mutant Fitness Profiling Identifies Nutritional Requirements for Optimal Growth of Yersinia pestis in Deep Tissue. [Journal Article]
- MBio 2014; 5(4)
Rapid growth in deep tissue is essential to the high virulence of Yersinia pestis, causative agent of plague. To better understand the mechanisms underlying this unusual ability, we used transposon mutagenesis and high-throughput sequencing (Tn-seq) to systematically probe the Y. pestis genome for elements contributing to fitness during infection. More than a million independent insertion mutants representing nearly 200,000 unique genotypes were generated in fully virulent Y. pestis. Each mutant in the library was assayed for its ability to proliferate in vitro on rich medium and in mice following intravenous injection. Virtually all genes previously established to contribute to virulence following intravenous infection showed significant fitness defects, with the exception of genes for yersiniabactin biosynthesis, which were masked by strong intercellular complementation effects. We also identified more than 30 genes with roles in nutrient acquisition and metabolism as experiencing strong selection during infection. Many of these genes had not previously been implicated in Y. pestis virulence. We further examined the fitness defects of strains carrying mutations in two such genes-encoding a branched-chain amino acid importer (brnQ) and a glucose importer (ptsG)-both in vivo and in a novel defined synthetic growth medium with nutrient concentrations matching those in serum. Our findings suggest that diverse nutrient limitations in deep tissue play a more important role in controlling bacterial infection than has heretofore been appreciated. Because much is known about Y. pestis pathogenesis, this study also serves as a test case that assesses the ability of Tn-seq to detect virulence genes.Our understanding of the functions required by bacteria to grow in deep tissues is limited, in part because most growth studies of pathogenic bacteria are conducted on laboratory media that do not reflect conditions prevailing in infected animal tissues. Improving our knowledge of this aspect of bacterial biology is important as a potential pathway to the development of novel therapeutics. Yersinia pestis, the plague bacterium, is highly virulent due to its rapid dissemination and growth in deep tissues, making it a good model for discovering bacterial adaptations that promote rapid growth during infection. Using Tn-seq, a genome-wide fitness profiling technique, we identified several functions required for fitness of Y. pestis in vivo that were not previously known to be important. Most of these functions are needed to acquire or synthesize nutrients. Interference with these critical nutrient acquisition pathways may be an effective strategy for designing novel antibiotics and vaccines.
- Molecular detection and genotyping of Aphanomyces astaci directly from preserved crayfish samples uncovers the Norwegian crayfish plague disease history. [JOURNAL ARTICLE]
- Vet Microbiol 2014 Jul 18.
Aphanomyces astaci causes crayfish plague in European freshwater crayfish, but most historical epizootics lack agent isolation and identification. Although declared as crayfish plague outbreaks by the Norwegian Competent Authorities, only presumptive diagnoses without agent isolation exist from Norwegian epizootics until 2005. Molecular methods now allow both A. astaci detection and genotype determination from preserved samples. We therefore aimed to (1) investigate molecularly if A. astaci was involved in a selection of mass-mortality events in Norwegian noble crayfish populations from 1971 to 2004, and (2) determine the eventually involved A. astaci genotype groups both from these historical and also more recent mass-mortality events. DNA was extracted directly from presumptively infected crayfish tissues, and screened by A. astaci specific qPCR. A representative selection of positive samples was confirmed by ITS-sequencing. Finally, genotype determination was performed with microsatellite markers that distinguish all known A. astaci genotype groups. The molecular examination detected A. astaci in crayfish materials from all examined mass-mortality events. The first event in 1971-1974 was caused by the A. astaci genotype group A, presumably the first genotype group that entered Europe more than 150 years ago. All later outbreaks were caused by the A. astaci genotype group B which was introduced to Europe by importation of signal crayfish in the 1960s. The results suggest that molecular methods can verify the involvement of A. astaci in the vast majority of observed crayfish mass mortalities in Europe whenever preserved materials exist. Moreover, microsatellite genotyping can reveal at least parts of the underlying epidemiology.
- LcrV delivered via Type III secretion system of live attenuated Yersinia pseudotuberculosis enhances immunogenicity against pneumonic plague. [JOURNAL ARTICLE]
- Infect Immun 2014 Aug 11.
Here, we constructed a Y. pseudotuberculosis mutant strain with arabinose-dependent regulated delayed-shutoff of crp expression (araC PBAD crp) and replacement of the msbB gene with the E. coli msbB gene to attenuate it. Then, we inserted the asd mutation into this construction to form χ10057 (Δasd-206 ΔmsbB868::PmsbB msbB (EC) ΔPcrp21::TT araC PBAD crp) for use with a balanced-lethal Asd(+) plasmid to facilitate antigen synthesis. A hybrid protein composed of YopE (1-138aa) fused with full-length LcrV (YopENt138-LcrV) was synthesized in χ10057 harboring an Asd(+) plasmid (pYA5199, yopENt138-lcrV) and could be secreted through a type III secretion system (T3SS) in vitro and vivo. Animal studies indicated that mice orally immunized with χ10057(pYA5199) developed similar titers of IgG response to whole cell lysates of Y. pestis (YpL) and subunit LcrV as χ10057(pYA3332, empty plasmid). However, only immunization of mice with χ10057(pYA5199) developed a significant secretory IgA response to LcrV. The χ10057(pYA5199) induced a higher level of protection (80% survival) against intranasal (i.n.) challenge with ∼240 LD50 (2.4 x 10(4) CFU) of Y. pestis KIM6+ (pCD1Ap) than induced by χ10057(pYA3332) (40% survival). Splenocytes from mice vaccinated with χ10057(pYA5199) produced significant levels of IFN-γ, TNF-α, and IL-17 after restimulation with LcrV and YpL antigens. Our results suggest it is possible to use an attenuated Y. pseudotuberculosis strain delivering the LcrV antigen via T3SS as a potential vaccine candidate against pneumonic plague.
- Chromosomal Rearrangement Features of Yersinia pestis Strains from Natural Plague Foci in China. [JOURNAL ARTICLE]
- Am J Trop Med Hyg 2014 Aug 11.
The Yersinia pestis chromosome contains a large variety and number of insert sequences that have resulted in frequent chromosome rearrangement events. To identify the chromosomal rearrangement features of Y. pestis strains from five typical plague foci in China and study spontaneous DNA rearrangements potentially stabilized in certain lineages of Y. pestis genomes, we examined the linking mode of locally collinear blocks (LCBs) in 30 Y. pestis strains by a polymerase chain reaction-based method. Our results suggest most strains have relatively stable chromosomal arrangement patterns, and these rearrangement characteristics also have a very close relationship with the geographical origin. In addition, some LCB linking modes are only present in specific strains. We conclude Y. pestis chromosome rearrangement patterns may reflect the genetic features of specific geographical areas and can be applied to distinguish Y. pestis isolates; furthermore, most of the rearrangement events are stable in certain lineages of Y. pestis genomes.
- Functional and structural analysis of HicA3-HicB3, a novel toxin-antitoxin system of Yersinia pestis. [JOURNAL ARTICLE]
- J Bacteriol 2014 Aug 11.
The mechanisms involved in the virulence of Y. pestis, the plague pathogen, are not fully understood. In previous research, we found that a Yersinia pestis mutant lacking the HicB3 (YPO3369) putative orphan antitoxin was attenuated for virulence in a murine model of bubonic plague. Toxin-antitoxin systems (TASs) are widespread in prokaryotes. Most bacterial species possess many TASs of several types. In type II TASs, the toxin protein is bound and neutralized by its cognate antitoxin protein in the cytoplasm. Here, we identify the hicA3 gene encoding the toxin neutralized by HicB3, and show that HicA3-HicB3 constitutes a new functional type II TAS in Y. pestis. Using biochemical and mutagenesis-based approaches, we demonstrate that the HicA3 toxin is an RNase with a catalytic histidine residue. HicB3 has two functions: it sequesters and neutralizes HicA3 by blocking its active site and it represses transcription of the hicA3B3 operon. Gel-shift assays and reporter fusion experiments indicate that the HicB3 antitoxin binds to two operators in the hicA3B3 promoter region. We solved the X-ray structures of HicB3 and the HicA3HicB3 complex, thus we present the first crystal structure of a TA complex from the HicAB-family. HicB3 forms a tetramer that can bind two HicA3 toxin molecules. HicA3 is monomeric and folds as a double-stranded-RNA-binding domain. HicB3 N-terminal domain occludes the HicA3 active site, whereas its C-terminal domain folds as a ribbon-helix-helix DNA binding motif.