HIV Transmission and Injection Drug Use: Lessons From the Indiana Outbreak

A recent outbreak of HIV infection centered in the rural town of Austin in Scott County, Indiana, was associated with widespread injection drug use and a socio-economically depressed population. Control of the outbreak required coordinated efforts by state, federal, local, and academic institutions to implement and maintain on-site programs and services that included contact tracing, HIV and hepatitis C virus testing, insurance enrollment, syringe exchange, rehabilitation services, care coordination, preexposure prophylaxis, and HIV treatment. This article summarizes a presentation by Diane M. Janowicz, MD, at the IAS-USA continuing education program, Improving the Management of HIV Disease, held in Los Angeles, California, in April 2016

Determination of an Interaction Network between an Extracellular Bacterial Pathogen and the Human Host

A major gap in understanding infectious diseases is the lack of information about molecular interaction networks between pathogens and the human host. Haemophilus ducreyi causes the genital ulcer disease chancroid in adults and is a leading cause of cutaneous ulcers in children in the tropics. We developed a model in which human volunteers are infected on the upper arm with H. ducreyi until they develop pustules. To define the H. ducreyi and human interactome, we determined bacterial and host transcriptomic and host metabolomic changes in pustules. We found that in vivo H. ducreyi transcripts were distinct from those in the inocula, as were host transcripts in pustule and wounded control sites. Many of the upregulated H. ducreyi genes were found to be involved in ascorbic acid and anaerobic metabolism and inorganic ion/nutrient transport. The top 20 significantly expressed human pathways showed that all were involved in immune responses. We generated a bipartite network for interactions between host and bacterial gene transcription; multiple positively correlated networks contained H. ducreyi genes involved in anaerobic metabolism and host genes involved with the immune response. Metabolomic studies showed that pustule and wounded samples had different metabolite compositions; the top ion pathway involved ascorbate and aldarate metabolism, which correlated with the H. ducreyi transcriptional response and upregulation of host genes involved in ascorbic acid recycling. These data show that an interactome exists between H. ducreyi and the human host and suggest that H. ducreyi exploits the metabolic niche created by the host immune response.IMPORTANCE Dual RNA sequencing (RNA-seq) offers the promise of determining an interactome at a transcriptional level between a bacterium and the host but has yet to be done on any bacterial infection in human tissue. We performed dual RNA-seq and metabolomics analyses on wounded and infected sites following experimental infection of the arm with H. ducreyi Our results suggest that H. ducreyi survives in an abscess by utilizing l-ascorbate as an alternative carbon source, possibly taking advantage of host ascorbic acid recycling, and that H. ducreyi also adapts by upregulating genes involved in anaerobic metabolism and inorganic ion and nutrient transport. To our knowledge, this is the first description of an interaction network between a bacterium and the human host at a site of infection

Control of atomic decay rates via manipulation of reservoir mode frequencies

We analyse the problem of a two-level atom interacting with a time-dependent dissipative environment modelled by a bath of reservoir modes. In the model of this paper the principal features of the reservoir structure remain constant in time, but the microscopic structure does not. In the context of an atom in a leaky cavity this corresponds to a fixed cavity and a time-dependent external bath. In this situation we show that by chirping the reservoir modes sufficiently fast it is possible to inhibit, or dramatically enhance the decay of the atomic system, even though the gross reservoir structure is fixed. Thus it is possible to extract energy from a cavity-atom system faster than the empty cavity rate. Similar, but less dramatic effects are possible for moderate chirps where partial trapping of atomic population is also possible.Comment: 12 pages, 9 figure

Mutations in the Schmallenberg virus Gc glycoprotein facilitate cellular protein synthesis shutoff and restore pathogenicity of NSs deletion mutants in mice

Serial passage of viruses in cell culture has been traditionally used to attenuate virulence and identify determinants of viral pathogenesis. In a previous study, we found that a strain of Schmallenberg virus (SBV) serially passaged in tissue culture (termed SBVp32) unexpectedly displayed increased pathogenicity in suckling mice compared to wild type SBV. In this study, we mapped the determinants of SBVp32 virulence to the viral genome M segment. SBVp32 virulence is associated with the capacity of this virus to reach higher titers in the brains of experimentally infected suckling mice. We also found that the Gc glycoprotein, encoded by the M segment of SBVp32, facilitates host cell protein shutoff in vitro. Interestingly, while the M segment of SBVp32 is a virulence factor, we found that the S segment of the same virus confers by itself an attenuated phenotype to wild type SBV as has lost the ability to block the innate immune system of the host. Single mutations present in the Gc glycoprotein of SBVp32 are sufficient to compensate both the attenuated phenotype of the SBVp32 S segment and the attenuated phenotype of NSs deletion mutants. Our data also indicate that the SBVp32 M segment does not act as an IFN antagonist. Therefore SBV mutants can retain pathogenicity even when they are unable to fully control the production of IFN by the infected cells. Overall, this study suggests that the viral glycoprotein of orthobunyaviruses can compensate, at least in part, the function of NSs. In addition, we also provide evidence that the induction of total cellular protein shutoff by SBV is determined by multiple viral proteins while the ability to control the production of IFN maps to the NSs protein. Importance The identification of viral determinants of pathogenesis is key to the development of prophylactic and interventions measures. In this study we found that the bunyavirus Gc glycoprotein is a virulence factor. Importantly, we show that mutations in the Gc glycoprotein can restore pathogenicity of attenuated mutants resulting from deletions or mutations in the non-structural protein NSs. Our findings highlight the fact that careful consideration should be taken when designing live attenuated vaccines based on deletions of non-structural proteins since single mutations in the viral glycoproteins appear to revert attenuated mutants to virulent phenotypes

Thermal radiation and near-field energy density of thin metallic films

We study the properties of thermal radiation emitted by a thin dielectric slab, employing the framework of macroscopic fluctuational electrodynamics. Particular emphasis is given to the analytical construction of the required dyadic Green's functions. Based on these, general expressions are derived for both the system's Poynting vector, describing the intensity of propagating radiation, and its energy density, containing contributions from non-propagating modes which dominate the near-field regime. An extensive discussion is then given for thin metal films. It is shown that the radiative intensity is maximized for a certain film thickness, due to Fabry-Perot-like multiple reflections inside the film. The dependence of the near-field energy density on the distance from the film's surface is governed by an interplay of several length scales, and characterized by different exponents in different regimes. In particular, this energy density remains finite even for arbitrarily thin films. This unexpected feature is associated with the film's low-frequency surface plasmon polariton. Our results also serve as reference for current near-field experiments which search for deviations from the macroscopic approach

Epidermal growth factor receptor (EGFR) inhibition on non-small-cell lung cancer treatment

Niedrobnokomórkowy rak płuca (NDRP) nadal stanowi istotny problem kliniczny i społeczny. W ostatnim okresie notuje się stały wzrost zachorowań w populacji kobiet i mężczyzn. Wyniki leczenia chirurgicznego, radioterapii i chemioterapii osiągnęły plateau. Perspektywy farmakologicznego leczenia NDRP warunkuje poznanie mechanizmów molekularnych odpowiedzialnych za rozwój nowotworu oraz powstawanie oporności. Wprowadzenie leków ukierunkowanych molekularnie stanowi istotny postęp w leczeniu NDRP. Leczenie ukierunkowane obejmuje obecnie zastosowanie leków antyangiogennych oraz monoklonalnych przeciwciał i drobnocząsteczkowych inhibitorów kinazy tyrozynowej. Ogromną rolę odgrywa identyfikacja predykcyjnych czynników pozwalająca na optymalizację leczenia. Onkol. Prak. Klin. 2011; 7, 4: 177–182Non small cell lung cancer (NSCLC) remains a significant clinical and social problem. In the last period there has been a steady increase a incidence in women and men. Results of surgical treatment, radiotherapy and chemotherapy have reached a plateau. Perspectives for pharmacological treatment of NSCLC determines understanding the molecular mechanisms responsible for tumor growth and resistance. The introduction of molecularly targeted drugs is an important step in the treatment of NSCLC. Targeted treatment includes the use of monoclonal antibodys, anti-angiogenic treatment and small molecule tyrosine kinase inhibitors. Identity of predictive factors plays a huge role for targeting treatment optimization. Onkol. Prak. Klin. 2011; 7, 4: 177–18

A (p)ppGpp-Null Mutant of Haemophilus ducreyi Is Partially Attenuated in Humans Due to Multiple Conflicting Phenotypes

(p)ppGpp responds to nutrient limitation through a global change in gene regulation patterns to increase survival. The stringent response has been implicated in the virulence of several pathogenic bacterial species. Haemophilus ducreyi, the causative agent of chancroid, has homologs of both relA and spoT, which primarily synthesize and hydrolyze (p)ppGpp in Escherichia coli. We constructed relA and relA spoT deletion mutants to assess the contribution of (p)ppGpp to H. ducreyi pathogenesis. Both the relA single mutant and the relA spoT double mutant failed to synthesize (p)ppGpp, suggesting that relA is the primary synthetase of (p)ppGpp in H. ducreyi. Compared to the parent strain, the double mutant was partially attenuated for pustule formation in human volunteers. The double mutant had several phenotypes that favored attenuation, including increased sensitivity to oxidative stress. The increased sensitivity to oxidative stress could be complemented in trans. However, the double mutant also exhibited phenotypes that favored virulence. When grown to the mid-log phase, the double mutant was significantly more resistant than its parent to being taken up by human macrophages and exhibited increased transcription of lspB, which is involved in resistance to phagocytosis. Additionally, compared to the parent, the double mutant also exhibited prolonged survival in the stationary phase. In E. coli, overexpression of DksA compensates for the loss of (p)ppGpp; the H. ducreyi double mutant expressed higher transcript levels of dksA than the parent strain. These data suggest that the partial attenuation of the double mutant is likely the net result of multiple conflicting phenotypes

An evaluative baseline for geo-semantic relatedness and similarity

In geographic information science and semantics, the computation of semantic similarity is widely recognised as key to supporting a vast number of tasks in information integration and retrieval. By contrast, the role of geo-semantic relatedness has been largely ignored. In natural language processing, semantic relatedness is often confused with the more specific semantic similarity. In this article, we discuss a notion of geo-semantic relatedness based on Lehrer’s semantic fields, and we compare it with geo-semantic similarity. We then describe and validate the Geo Relatedness and Similarity Dataset (GeReSiD), a new open dataset designed to evaluate computational measures of geo-semantic relatedness and similarity. This dataset is larger than existing datasets of this kind, and includes 97 geographic terms combined into 50 term pairs rated by 203 human subjects. GeReSiD is available online and can be used as an evaluation baseline to determine empirically to what degree a given computational model approximates geo-semantic relatedness and similarity

A Survey of Volunteered Open Geo-Knowledge Bases in the Semantic Web

Over the past decade, rapid advances in web technologies, coupled with innovative models of spatial data collection and consumption, have generated a robust growth in geo-referenced information, resulting in spatial information overload. Increasing 'geographic intelligence' in traditional text-based information retrieval has become a prominent approach to respond to this issue and to fulfill users' spatial information needs. Numerous efforts in the Semantic Geospatial Web, Volunteered Geographic Information (VGI), and the Linking Open Data initiative have converged in a constellation of open knowledge bases, freely available online. In this article, we survey these open knowledge bases, focusing on their geospatial dimension. Particular attention is devoted to the crucial issue of the quality of geo-knowledge bases, as well as of crowdsourced data. A new knowledge base, the OpenStreetMap Semantic Network, is outlined as our contribution to this area. Research directions in information integration and Geographic Information Retrieval (GIR) are then reviewed, with a critical discussion of their current limitations and future prospects