Summary Cryptosporidium spp are well recognised as causes of diarrhoeal disease during waterborne epidemics and in immunocompromised hosts. Studies have also drawn attention to an underestimated ...global burden and suggest major gaps in optimum diagnosis, treatment, and immunisation. Cryptosporidiosis is increasingly identified as an important cause of morbidity and mortality worldwide. Studies in low-resource settings and high-income countries have confirmed the importance of cryptosporidium as a cause of diarrhoea and childhood malnutrition. Diagnostic tests for cryptosporidium infection are suboptimum, necessitating specialised tests that are often insensitive. Antigen-detection and PCR improve sensitivity, and multiplexed antigen detection and molecular assays are underused. Therapy has some effect in healthy hosts and no proven efficacy in patients with AIDS. Use of cryptosporidium genomes has helped to identify promising therapeutic targets, and drugs are in development, but methods to assess the efficacy in vitro and in animals are not well standardised. Partial immunity after exposure suggests the potential for successful vaccines, and several are in development; however, surrogates of protection are not well defined. Improved methods for propagation and genetic manipulation of the organism would be significant advances.
Abstract
Radar-based convective modes were assigned to a sample of tornadoes and significant severe thunderstorms reported in the contiguous United States (CONUS) during 2003–11. The significant hail ...(≥2-in. diameter), significant wind (≥65-kt thunderstorm gusts), and tornadoes were filtered by the maximum event magnitude per hour on a 40-km Rapid Update Cycle model horizontal grid. The filtering process produced 22 901 tornado and significant severe thunderstorm events, representing 78.5% of all such reports in the CONUS during the sample period. The convective mode scheme presented herein begins with three radar-based storm categories: 1) discrete cells, 2) clusters of cells, and 3) quasi-linear convective systems (QLCSs). Volumetric radar data were examined for right-moving supercell (RM) and left-moving supercell characteristics within the three radar reflectivity designations. Additional categories included storms with marginal supercell characteristics and linear hybrids with a mix of supercell and QLCS structures. Smoothed kernel density estimates of events per decade revealed clear geographic and seasonal patterns of convective modes with tornadoes. Discrete and cluster RMs are the favored convective mode with southern Great Plains tornadoes during the spring, while the Deep South displayed the greatest variability in tornadic convective modes in the fall, winter, and spring. The Ohio Valley favored a higher frequency of QLCS tornadoes and a lower frequency of RM compared to the Deep South and the Great Plains. Tornadoes with nonsupercellular/non-QLCS storms were more common across Florida and the high plains in the summer. Significant hail events were dominated by Great Plains supercells, while variations in convective modes were largest for significant wind events.
A fundamental question in herpes simplex virus (HSV) pathogenesis is the consequence of viral reactivation to the neuron. Evidence supporting both post-reactivation survival and demise is published. ...The exceedingly rare nature of this event at the neuronal level in the sensory ganglion has limited direct examination of this important question. In this study, an in-depth in vivo analysis of the resolution of reactivation was undertaken. Latently infected C57BL/6 mice were induced to reactivate in vivo by hyperthermic stress. Infectious virus was detected in a high percentage (60-80%) of the trigeminal ganglia from these mice at 20 hours post-reactivation stimulus, but declined by 48 hours post-stimulus (0-13%). With increasing time post-reactivation stimulus, the percentage of reactivating neurons surrounded by a cellular cuff increased, which correlated with a decrease in detectable infectious virus and number of viral protein positive neurons. Importantly, in addition to intact viral protein positive neurons, fragmented viral protein positive neurons morphologically consistent with apoptotic bodies and containing cleaved caspase-3 were detected. The frequency of this phenotype increased through time post-reactivation. These fragmented neurons were surrounded by Iba1+ cells, consistent with phagocytic removal of dead neurons. Evidence of neuronal destruction post-reactivation prompted re-examination of the previously reported non-cytolytic role of T cells in controlling reactivation. Latently infected mice were treated with anti-CD4/CD8 antibodies prior to induced reactivation. Neither infectious virus titers nor neuronal fragmentation were altered. In contrast, when viral DNA replication was blocked during reactivation, fragmentation was not observed even though viral proteins were expressed. Our data demonstrate that at least a portion of reactivating neurons are destroyed. Although no evidence for direct T cell mediated antigen recognition in this process was apparent, inhibition of viral DNA replication blocked neuronal fragmentation. These unexpected findings raise new questions about the resolution of HSV reactivation in the host nervous system.
Abstract
This study examines the possibility that supercell tornado forecasts could be improved by utilizing the storm-relative helicity (SRH) in the lowest few hundred meters of the atmosphere ...(instead of much deeper layers). This hypothesis emerges from a growing body of literature linking the near-ground wind profile to the organization of the low-level mesocyclone and thus the probability of tornadogenesis. This study further addresses the ramifications of near-ground SRH to the skill of the significant tornado parameter (STP), which is probably the most commonly used environmental indicator for tornadic thunderstorms. Using a sample of 20 194 severe, right-moving supercells spanning a 13-yr period, sounding-derived parameters were compared using forecast verification metrics, emphasizing a high probability of detection for tornadic supercells while minimizing false alarms. This climatology reveals that the kinematic components of environmental profiles are more skillful at discriminating significantly tornadic supercells from severe, nontornadic supercells than the thermodynamic components. The effective-layer SRH has by far the greatest forecast skill among the components of the STP, as it is currently defined. However, using progressively shallower layers for the SRH calculation leads to increasing forecast skill. Replacing the effective-layer SRH with the 0–500 m AGL SRH in the formulation of STP increases the number of correctly predicted events by 8% and decreases the number of missed events and false alarms by 18%. These results provide promising evidence that forecast parameters can still be improved through increased understanding of the environmental controls on the processes that govern tornado formation.
A cross-correlative precession electron diffraction - atom probe tomography investigation of Cr segregation in a Fe(Cr) nanocrystalline alloy was undertaken. Solute segregation was found to be ...dependent on grain boundary type. The results of which were compared to a hybrid Molecular Dynamics and Monte Carlo simulation that predicted the segregation for special character, low angle, and high angle grain boundaries, as well as the angle of inclination of the grain boundary. It was found that the highest segregation concentration was for the high angle grain boundaries and is explained in terms of clustering driven by the onset of phase separation. For special character boundaries, the highest Gibbsain interfacial excess was predicted at the incoherent ∑3 followed by ∑9 and ∑11 boundaries with negligible segregation to the twin and ∑5 boundaries. In addition, the low angle grain boundaries predicted negligible segregation. All of these trends matched well with the experiment. This solute-boundary segregation dependency for the special character grain boundaries is explained in terms of excess volume and the energetic distribution of the solute in the boundary.
The life long relationship between herpes simplex virus and its host hinges on the ability of the virus to aggressively replicate in epithelial cells at the site of infection and transport into the ...nervous system through axons innervating the infection site. Interaction between the virus and the sensory neuron represents a pivot point where largely unknown mechanisms lead to a latent or a lytic infection in the neuron. Regulation at this pivot point is critical for balancing two objectives, efficient widespread seeding of the nervous system and host survival. By combining genetic and in vivo in approaches, our studies reveal that the balance between latent and lytic programs is a process occurring early in the trigeminal ganglion. Unexpectedly, activation of the latent program precedes entry into the lytic program by 12 -14hrs. Importantly, at the individual neuronal level, the lytic program begins as a transition out of this acute stage latent program and this escape from the default latent program is regulated by de novo VP16 expression. Our findings support a model in which regulated de novo VP16 expression in the neuron mediates entry into the lytic cycle during the earliest stages of virus infection in vivo. These findings support the hypothesis that the loose association of VP16 with the viral tegument combined with sensory axon length and transport mechanisms serve to limit arrival of virion associated VP16 into neuronal nuclei favoring latency. Further, our findings point to specialized features of the VP16 promoter that control the de novo expression of VP16 in neurons and this regulation is a key component in setting the balance between lytic and latent infections in the nervous system.
Singlet exciton fission is a process that occurs in select organic semiconductors and entails the splitting of a singlet excited state into two lower triplet excitons located on adjacent ...chromophores. Research examining this phenomenon has recently seen a renaissance due to the potential to exploit singlet fission within the context of organic photovoltaics to prepare devices with the ability to circumvent the Shockley–Queisser limit. To date, high singlet fission yields have only been reported for crystalline or polycrystalline materials, suggesting that molecular disorder inhibits singlet fission. Here, we report the results of ultrafast transient absorption and time-resolved emission experiments performed on 5,12-diphenyl tetracene (DPT). Unlike tetracene, which tends to form polycrystalline films when vapor deposited, DPT’s pendant phenyl groups frustrate crystal growth, yielding amorphous films. Despite the high level of disorder in these films, we find that DPT exhibits a surprisingly high singlet fission yield, with 1.22 triplets being created per excited singlet. This triplet production occurs over two principal time scales, with ∼50% of the triplets appearing within 1 ps after photoexcitation followed by a slower phase of triplet growth over a few hundred picoseconds. To fit these kinetics, we have developed a model that assumes that due to molecular disorder, only a subset of DPT dimer pairs adopt configurations that promote fission. Singlet excitons directly excited at these sites can undergo fission rapidly, while singlet excitons created elsewhere in the film must diffuse to these sites to fission.
Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. In a cross-sectional study of asthmatics of varying severity (n = 51), endobronchial ...tissue gene expression analysis revealed three major patient clusters: TH2-high, TH17-high, and TH2/17-low. TH2-high and TH17-high patterns were mutually exclusive in individual patient samples, and their gene signatures were inversely correlated and differentially regulated by interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (TH2) and TH17 signatures, we investigated the potential of type 2 cytokine suppression in promoting TH17 responses in a preclinical model of allergen-induced asthma. Neutralization of IL-4 and/or IL-13 resulted in increased TH17 cells and neutrophilic inflammation in the lung. However, neutralization of IL-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and airway hyperreactivity and abolished the neutrophilic inflammation, suggesting that combination therapies targeting both pathways may maximize therapeutic efficacy across a patient population comprising both TH2 and TH17 endotypes.
Modern approaches to discovering molecular mechanisms and validating treatments for age-related neuromusculoskeletal dysfunction typically rely on high-throughput transcriptome analysis. Previously ...harvested and fixed tissues offer an incredible reservoir of untapped molecular information. However, obtaining RNA from such formaldehyde-fixed neuromusculoskeletal tissues, especially fibrotic aged tissues, is technically challenging and often results in RNA degradation, chemical modification and yield reduction, prohibiting further analysis. Therefore, we developed a protocol to extract high-quality RNA from formaldehyde-fixed brain, cartilage, muscle and peripheral nerve isolated from naturally aged mice. Isolated RNA produced reliable gene expression data comparable to fresh and flash-frozen tissues and was sensitive enough to detect age-related changes, making our protocol valuable to researchers in the field of aging.
This study describes an RNA extraction protocol that successfully produces high-quality RNA from formaldehyde-fixed naturally aged neuromusculoskeletal tissues. Yield, purity and integrity of the RNA were comparable to fresh and flash-frozen tissues isolated from adult and naturally aged mice. This protocol is applicable to a range of tissues, including brain, articular cartilage, skeletal muscle and peripheral nerve, and was validated with subsequent transcriptome analysis.
Nanocrystals of phase-pure tin(II) selenide (SnSe) were synthesized via a solution-phase route employing stoichiometric amounts of di-tert-butyl diselenide as a novel and facile selenium source. The ...direct band gap of the resulting nanocrystals (E g = 1.71 eV) is significantly blue-shifted relative to the bulk value (E g = 1.30 eV), a likely consequence of quantum confinement resulting from the relatively small average diameter of the nanocrystals (μD < 20 nm). Preliminary solar cell devices incorporating SnSe nanocrystals into a poly2-methoxy-5-(3′,7′-dimethyloctyloxy)-1,4-phenylenevinylene matrix demonstrate a significant enhancement in quantum efficiency and short-circuit current density, suggesting that this earth-abundant material could be a valuable component in future photovoltaic devices.
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