The Effects Of Previous Amenorrhea On Vascular Function

Purpose: Young premenopausal women are susceptible to amenorrhea, which contributes to negative vascular remodeling and endothelial dysfunction. It is unknown whether these vascular changes are permanent or reversable with the restoration of estrogen levels and the regaining of a consistent menstrual cycle. Methods: This study examined subclinical cardiovascular disease risk factors and the vascular function of 10 eumenorrheic women, and 6 previously amenorrhoeic women. Anthropometric measurements, radial pulse wave analysis, carotid-femoral pulse wave velocity, carotid intima media thickness, beta stiffness, bone mineral density, brachial flow mediated dilation, and handgrip exercise blood flow measurements were taken and analyzed. Results: Previously amenorrhoeic women had significantly (p<0.05) lower systolic blood pressure, mean arterial pressure, aortic systolic blood pressure, aortic diastolic blood pressure, and aortic mean arterial pressure, and a higher amount of physical activity during the week than eumenorrheic women. There were no differences between groups in average flow velocity, forearm blood flow, brachial diameter, and forearm vascular conductance for flow mediated dilation and dynamic handgrip exercise. Conclusion: There were no significant vascular structure remodeling differences between groups, and the amenorrhoeic group displayed lower peripheral and central blood pressure, thus suggesting that there are no long term detrimental cardiovascular effects of previous amenorrhea

Intrinsic point defects and volume swelling in ZrSiO4 under irradiation

The effects of high concentration of point defects in crystalline ZrSiO4 as originated by exposure to radiation, have been simulated using first principles density functional calculations. Structural relaxation and vibrational studies were performed for a catalogue of intrinsic point defects, with different charge states and concentrations. The experimental evidence of a large anisotropic volume swelling in natural and artificially irradiated samples is used to select the subset of defects that give similar lattice swelling for the concentrations studied, namely interstitials of O and Si, and the anti-site Zr(Si), Calculated vibrational spectra for the interstitials show additional evidence for the presence of high concentrations of some of these defects in irradiated zircon.Comment: 9 pages, 7 (color) figure

Evolutionary pathways to NS5A inhibitor resistance in genotype 1 hepatitis C virus

Direct-acting antivirals (DAAs) targeting NS5A are broadly effective against hepatitis C virus (HCV) infections, but sustained virological response rates are generally lower in patients infected with genotype (gt)-1a than gt-1b viruses. The explanation for this remains uncertain. Here, we adopted a highly accurate, ultra-deep primer ID sequencing approach to intensively study serial changes in the NS5A-coding region of HCV in gt-1a- and gt-1b-infected subjects receiving a short course of monotherapy with the NS5A inhibitor, elbasvir. Low or undetectable levels of viremia precluded on-treatment analysis in gt-1b-infected subjects, but variants with the resistance-associated substitution (RAS) Y93H in NS5A dominated rebounding virus populations following cessation of treatment. These variants persisted until the end of the study, two months later. In contrast, while Y93H emerged in multiple lineages and became dominant in subjects with gt-1a virus, these haplotypes rapidly decreased in frequency off therapy. Substitutions at Q30 and L31 emerged in distinctly independent lineages at later time points, ultimately coming to dominate the virus population off therapy. Consistent with this, cell culture studies with gt-1a and gt-1b reporter viruses and replicons demonstrated that Y93H confers a much greater loss of replicative fitness in gt-1a than gt-1b virus, and that L31M/V both compensates for the loss of fitness associated with Q30R (but not Y93H) and also boosts drug resistance. These observations show how differences in the impact of RASs on drug resistance and replicative fitness influence the evolution of gt-1a and gt-1b viruses during monotherapy with an antiviral targeting NS5A. © 2018 Elsevier B.V

Kinetic analyses reveal potent and early blockade of hepatitis C virus assembly by NS5A inhibitors

Background & Aims All-oral regimens combining different classes of direct-acting antivirals (DAA) are highly effective for treatment of patients with chronic hepatitis C. NS5A inhibitors will likely form a component of future interferon-sparing treatment regimens. However, despite their potential, the detailed mechanism of action of NS5A inhibitors is unclear. To study their mechanisms, we compared their kinetics of antiviral suppression with those of other classes of DAA, using the hepatitis C virus genotype 1a cell culture-infectious virus H77S.3. Methods We performed detailed kinetic analyses of specific steps in the hepatitis C virus life cycle using cell cultures incubated with protease inhibitors, polymerase inhibitors, or NS5A inhibitors. Assays were designed to measure active viral RNA synthesis and steady-state RNA abundance, polyprotein synthesis, virion assembly, and infectious virus production. Results Despite their high potency, NS5A inhibitors were slow to inhibit viral RNA synthesis compared with protease or polymerase inhibitors. By 24 hours after addition of an NS5A inhibitor, polyprotein synthesis was reduced <50%, even at micromolar concentrations. In contrast, inhibition of virus release by NS5A inhibitors was potent and rapid, with onset of inhibition as early as 2 hours. Cells incubated with NS5A inhibitors were rapidly depleted of intracellular infectious virus and RNA-containing hepatitis C virus particles, indicating a block in virus assembly. Conclusions DAAs that target NS5A rapidly inhibit intracellular assembly of genotype 1a virions. They also inhibit formation of functional replicase complexes, but have no activity against preformed replicase, thereby resulting in slow shut-off of viral RNA synthesis

The Xpc gene markedly affects cell survival in mouse bone marrow

The XPC protein (encoded by the xeroderma pigmentosum Xpc gene) is a key DNA damage recognition factor that is required for global genomic nucleotide excision repair (G-NER). In contrast to transcription-coupled nucleotide excision repair (TC-NER), XPC and G-NER have been reported to contribute only modestly to cell survival after DNA damage. Previous studies were conducted using fibroblasts of human or mouse origin. Since the advent of Xpc−/− mice, no study has focused on the bone marrow of these mice. We used carboplatin to induce DNA damage in Xpc−/− and strain-matched wild-type mice. Using several independent methods, Xpc−/− bone marrow was ∼10-fold more sensitive to carboplatin than the wild type. Importantly, 12/20 Xpc−/− mice died while 0/20 wild-type mice died. We conclude that G-NER, and XPC specifically, can contribute substantially to cell survival. The data are important in the context of cancer chemotherapy, where Xpc gene status and G-NER may be determinants of response to DNA-damaging agents including carboplatin. Additionally, altered cell cycles and altered DNA damage signalling may contribute to the cell survival end point

The use of a vortex insertion technique to simulate the extratropical transition of Hurricane Michael (2000)

On 19 October 2000, Hurricane Michael merged with an approaching baroclinic trough over the western North Atlantic Ocean south of Nova Scotia. As the hurricane moved over cooler sea surface temperatures (SSTs; less than 25°C), it intensified to category-2 intensity on the Saffir–Simpson hurricane scale [maximum sustained wind speeds of 44 m s−1 (85 kt)] while tapping energy from the baroclinic environment. The large “hybrid” storm made landfall on the south coast of Newfoundland with maximum sustained winds of 39 m s−1 (75 kt) causing moderate damage to coastal communities east of landfall. Hurricane Michael presented significant challenges to weather forecasters. The fundamental issue was determining which of two cyclones (a newly formed baroclinic low south of Nova Scotia or the hurricane) would become the dominant circulation center during the early stages of the extratropical transition (ET) process. Second, it was difficult to predict the intensity of the storm at landfall owing to competing factors: 1) decreasing SSTs conducive to weakening and 2) the approaching negatively tilted upper-level trough, favoring intensification. Numerical hindcast simulations using the limited-area Mesoscale Compressible Community model with synthetic vortex insertion (cyclone bogus) prior to the ET of Hurricane Michael led to a more realistic evolution of wind and pressure compared to running the model without vortex insertion. Specifically, the mesoscale model correctly simulates the hurricane as the dominant circulation center early in the transition process, versus the baroclinic low to its north, which was the favored development in the runs not employing vortex insertion. A suite of experiments is conducted to establish the sensitivity of the ET to various initial conditions, lateral driving fields, domain sizes, and model parameters. The resulting storm tracks and intensities fall within the range of the operational guidance, lending support to the possibility of improving numerical forecasts using synthetic vortex insertion prior to ET in such a model

The imprint of atmospheric evolution in the D/H of Hesperian clay minerals on Mars

The deuterium to hydrogen (D/H) ratio in strongly bound water or hydroxyl groups in ancient martian clays retains the imprint of the water of formation of these minerals. Curiosity’s Sample Analysis at Mars (SAM) experiment measured thermally evolved water and hydrogen gas released between 550°C and 950°C from samples of Hesperian era Gale crater smectite to determine this isotope ratio. The D/H value is 3.0 (±0.2) times the ratio in Standard Mean Ocean Water (SMOW). The D/H ratio in this ~3 billion year old mudstone that is half that of the present martian atmosphere but substantially higher than that expected in very early Mars indicates an extended history of hydrogen escape and desiccation of the planet

A Normalization Model of Attentional Modulation of Single Unit Responses

Although many studies have shown that attention to a stimulus can enhance the responses of individual cortical sensory neurons, little is known about how attention accomplishes this change in response. Here, we propose that attention-based changes in neuronal responses depend on the same response normalization mechanism that adjusts sensory responses whenever multiple stimuli are present. We have implemented a model of attention that assumes that attention works only through this normalization mechanism, and show that it can replicate key effects of attention. The model successfully explains how attention changes the gain of responses to individual stimuli and also why modulation by attention is more robust and not a simple gain change when multiple stimuli are present inside a neuron's receptive field. Additionally, the model accounts well for physiological data that measure separately attentional modulation and sensory normalization of the responses of individual neurons in area MT in visual cortex. The proposal that attention works through a normalization mechanism sheds new light a broad range of observations on how attention alters the representation of sensory information in cerebral cortex