Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection

published_or_final_versio

A Model for the Ultrastructure of Bone Based on Electron Microscopy of Ion-Milled Sections

The relationship between the mineral component of bone and associated collagen has been a matter of continued dispute. We use transmission electron microscopy (TEM) of cryogenically ion milled sections of fully-mineralized cortical bone to study the spatial and topological relationship between mineral and collagen. We observe that hydroxyapatite (HA) occurs largely as elongated plate-like structures which are external to and oriented parallel to the collagen fibrils. Dark field images suggest that the structures (“mineral structures”) are polycrystalline. They are approximately 5 nm thick, 70 nm wide and several hundred nm long. Using energy-dispersive X-ray analysis we show that approximately 70% of the HA occurs as mineral structures external to the fibrils. The remainder is found constrained to the gap zones. Comparative studies of other species suggest that this structural motif is ubiquitous in all vertebrates

Surveillance of febrile patients in a district and evaluation of their spatiotemporal associations: a pilot study

<p>Abstract</p> <p>Background</p> <p>Fever is an undifferentiated clinical feature that may enhance the sensitivity of syndromic surveillance systems. By studying the spatiotemporal associations of febrile patients, it may allow early detection of case clustering that indicates imminent threat of infectious disease outbreaks in the community.</p> <p>Methods</p> <p>We captured consecutive emergency department visits that led to hospitalization in a district hospital in Hong Kong during the period of 12 Sep 2005 to 14 Oct 2005. We recorded demographic data, provisional diagnoses, temperature on presentation and residential location for each patient-episode, and geocoded the residential addresses. We applied Geographical Information System technology to study the geographical distribution these cases, and their associations within a 50-m buffer zone spatially. A case cluster was defined by three or more spatially associated febrile patients within each three consecutive days.</p> <p>Results</p> <p>One thousand and sixty six patient-episodes were eligible for analysis; 42% of them had fever (>37°C; oral temperature) on presentation. Two hundred and four patient-episodes (19.1%) came from residential care homes for elderly (RCHE). We detected a total of 40 case clusters during the study period. Clustered cases were of older age; 57 (33.3%) were residents of RCHE. We found a median of 3 patients (range: 3 - 8) and time span of 3 days (range: 2 - 8 days) in each cluster. Twenty five clusters had 2 or more patients living in the same building block; 18 of them were from RCHE.</p> <p>Conclusions</p> <p>It is technically feasible to perform surveillance on febrile patients and studying their spatiotemporal associations. The information is potentially useful for early detection of impending infectious disease threats.</p

Tumor Growth Decreases NK and B Cells as well as Common Lymphoid Progenitor

Background: It is well established that chronic tumor growth results in functional inactivation of T cells and NK cells. It is less clear, however, whether lymphopoeisis is affected by tumor growth. Principal Findings: In our efforts of analyzing the impact of tumor growth on NK cell development, we observed a major reduction of NK cell numbers in mice bearing multiple lineages of tumor cells. The decrease in NK cell numbers was not due to increased apoptosis or decreased proliferation in the NK compartment. In addition, transgenic expression of IL-15 also failed to rescue the defective production of NK cells. Our systematic characterization of lymphopoeisis in tumor-bearing mice indicated that the number of the common lymphoid progenitor was significantly reduced in tumor-bearing mice. The number of B cells also decreased substantially in tumor bearing mice. Conclusions and Significance: Our data reveal a novel mechanism for tumor evasion of host immunity and suggest a new interpretation for the altered myeloid and lymphoid ratio in tumor bearing hosts

Intermolecular channels direct crystal orientation in mineralized collagen

The mineralized collagen fibril is the basic building block of bone, and is commonly pictured as a parallel array of ultrathin carbonated hydroxyapatite (HAp) platelets distributed throughout the collagen. This orientation is often attributed to an epitaxial relationship between the HAp and collagen molecules inside 2D voids within the fibril. Although recent studies have questioned this model, the structural relationship between the collagen matrix and HAp, and the mechanisms by which collagen directs mineralization remain unclear. Here, we use XRD to reveal that the voids in the collagen are in fact cylindrical pores with diameters of ~2 nm, while electron microscopy shows that the HAp crystals in bone are only uniaxially oriented with respect to the collagen. From in vitro mineralization studies with HAp, CaCO3 and γ-FeOOH we conclude that confinement within these pores, together with the anisotropic growth of HAp, dictates the orientation of HAp crystals within the collagen fibril

On the spontaneous stochastic dynamics of a single gene: complexity of the molecular interplay at the promoter

International audienceBACKGROUND: Gene promoters can be in various epigenetic states and undergo interactions with many molecules in a highly transient, probabilistic and combinatorial way, resulting in a complex global dynamics as observed experimentally. However, models of stochastic gene expression commonly consider promoter activity as a two-state on/off system. We consider here a model of single-gene stochastic expression that can represent arbitrary prokaryotic or eukaryotic promoters, based on the combinatorial interplay between molecules and epigenetic factors, including energy-dependent remodeling and enzymatic activities. RESULTS: We show that, considering the mere molecular interplay at the promoter, a single-gene can demonstrate an elaborate spontaneous stochastic activity (eg. multi-periodic multi-relaxation dynamics), similar to what is known to occur at the gene-network level. Characterizing this generic model with indicators of dynamic and steady-state properties (including power spectra and distributions), we reveal the potential activity of any promoter and its influence on gene expression. In particular, we can reproduce, based on biologically relevant mechanisms, the strongly periodic patterns of promoter occupancy by transcription factors (TF) and chromatin remodeling as observed experimentally on eukaryotic promoters. Moreover, we link several of its characteristics to properties of the underlying biochemical system. The model can also be used to identify behaviors of interest (eg. stochasticity induced by high TF concentration) on minimal systems and to test their relevance in larger and more realistic systems. We finally show that TF concentrations can regulate many aspects of the stochastic activity with a considerable flexibility and complexity. CONCLUSIONS: This tight promoter-mediated control of stochasticity may constitute a powerful asset for the cell. Remarkably, a strongly periodic activity that demonstrates a complex TF concentration-dependent control is obtained when molecular interactions have typical characteristics observed on eukaryotic promoters (high mobility, functional redundancy, many alternate states/pathways). We also show that this regime results in a direct and indirect energetic cost. Finally, this model can constitute a framework for unifying various experimental approaches. Collectively, our results show that a gene - the basic building block of complex regulatory networks - can itself demonstrate a significantly complex behavior

Fracture-Related Infection: a consensus on definition from an international expert group

Fracture-related infection (FRI) is a common and serious complication in trauma surgery. Accurately estimating the impact of this complication has been hampered by the lack of a clear definition. The absence of a working definition of FRI renders existing studies difficult to evaluate or compare. In order to address this issue, an expert group comprised of a number of scientific and medical organizations has been convened, with the support of the AO Foundation, in order to develop a consensus definition. The process that led to this proposed definition started with a systematic literature review, which revealed that the majority of randomized controlled trials in fracture care do not use a standardized definition of FRI. In response to this conclusion, an international survey on the need for and key components of a definition of FRI was distributed amongst all registered AOTrauma users. Approximately 90% of the more than 2,000 surgeons who responded suggested that a definition of FRI is required. As a final step, a consensus meeting was held with an expert panel. The outcome of this process led to a consensus definition of FRI. Two levels of certainty around diagnostic features were defined. Criteria could be confirmatory (infection definitely present) or suggestive. Four confirmatory criteria were defined: Fistula, sinus or wound breakdown; Purulent drainage from the wound or presence of pus during surgery; Phenotypically indistinguishable pathogens identified by culture from at least two separate deep tissue/implant specimens; Presence of microorganisms in deep tissue taken during an operative intervention, as confirmed by histopathological examination. Furthermore, a list of suggestive criteria was defined. These require further investigations in order to look for confirmatory criteria. In the current paper, an overview is provided of the proposed definition and a rationale for each component and decision. The intention of establishing this definition of FRI was to offer clinicians the opportunity to standardize clinical reports and improve the quality of published literature. It is important to note that the proposed definition was not designed to guide treatment of FRI and should be validated by prospective data collection in the future