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The haunted cabin mystery
\"Henry, Jesse, Violet, and Benny Alden take a trip down the Mississippi River and stay in a haunted cabin! At least it seems haunted--there are spooky phone calls, flickering lights, and strange shadows. Is there a ghost in the cabin? Join the Boxcar Children in their graphic novel adventure as they solve the mystery of the haunted cabin!\"--Page 4 of cover.
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Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology
Zika virus (ZIKV) infection during pregnancy leads to an increased risk of fetal growth restriction and fetal central nervous system malformations, which are outcomes broadly referred to as the Congenital Zika Syndrome (CZS). Here we infect pregnant rhesus macaques and investigate the impact of persistent ZIKV infection on uteroplacental pathology, blood flow, and fetal growth and development. Despite seemingly normal fetal growth and persistent fetal-placenta-maternal infection, advanced non-invasive in vivo imaging studies reveal dramatic effects on placental oxygen reserve accompanied by significantly decreased oxygen permeability of the placental villi. The observation of abnormal oxygen transport within the placenta appears to be a consequence of uterine vasculitis and placental villous damage in ZIKV cases. In addition, we demonstrate a robust maternal-placental-fetal inflammatory response following ZIKV infection. This animal model reveals a potential relationship between ZIKV infection and uteroplacental pathology that appears to affect oxygen delivery to the fetus during development.
Zika virus infection during pregnancy can result in birth defects, but underlying pathogenesis at the maternal-fetal interface is unclear. Here, the authors use non-invasive in vivo imaging of Zika-infected rhesus macaques and show that infection results in abnormal oxygen transport across the placenta.
Journal Article
Zika Virus infection of rhesus macaques leads to viral persistence in multiple tissues
Zika virus (ZIKV), an emerging flavivirus, has recently spread explosively through the Western hemisphere. In addition to symptoms including fever, rash, arthralgia, and conjunctivitis, ZIKV infection of pregnant women can cause microcephaly and other developmental abnormalities in the fetus. We report herein the results of ZIKV infection of adult rhesus macaques. Following subcutaneous infection, animals developed transient plasma viremia and viruria from 1-7 days post infection (dpi) that was accompanied by the development of a rash, fever and conjunctivitis. Animals produced a robust adaptive immune response to ZIKV, although systemic cytokine response was minimal. At 7 dpi, virus was detected in peripheral nervous tissue, multiple lymphoid tissues, joints, and the uterus of the necropsied animals. Notably, viral RNA persisted in neuronal, lymphoid and joint/muscle tissues and the male and female reproductive tissues through 28 to 35 dpi. The tropism and persistence of ZIKV in the peripheral nerves and reproductive tract may provide a mechanism of subsequent neuropathogenesis and sexual transmission.
Journal Article
Wavelength- and irradiance-dependent changes in intracellular nitric oxide level
Significance: Photobiomodulation (PBM) refers to the beneficial effects of low-energy light absorption. Although there is a large body of literature describing downstream physiological benefits of PBM, there is a limited understanding of the molecular mechanisms underlying these effects. At present, the most popular hypothesis is that light absorption induces release of nitric oxide (NO) from the active site of cytochrome c oxidase (COX), allowing it to bind O2 instead. This is believed to increase mitochondrial respiration, and result in greater overall health of the cell due to increased adenosine triphosphate production.
Aim: Although NO itself is a powerful signaling molecule involved in a host of biological responses, less attention has been devoted to NO mechanisms in the context of PBM. The purpose of our work is to investigate wavelength-specific effects on intracellular NO release in living cells.
Approach: We have conducted in-depth dosimetry analyses of NO production and function in an in vitro retinal model in response to low-energy exposure to one or more wavelengths of laser light.
Results: We found statistically significant wavelength-dependent elevations (10% to 30%) in intracellular NO levels following laser exposures at 447, 532, 635, or 808 nm. Sequential or simultaneous exposures to light at two different wavelengths enhanced the NO modulation up to 50% of unexposed controls. Additionally, the immediate increases in cellular NO levels were independent of the function of NO synthase, depended greatly on the substrate source of electrons entering the electron transport chain, and did not result in increased levels of cyclic guanosine monophosphate.
Conclusions: Our study concludes the simple model of light-mediated release of NO from COX is unlikely to explain the wide variety of PBM effects reported in the literature. Our multiwavelength method provides a novel tool for studying immediate and early mechanisms of PBM as well as exploring intracellular NO signaling networks.
Journal Article
Infection with chikungunya virus confers heterotypic cross-neutralizing antibodies and memory B-cells against other arthritogenic alphaviruses predominantly through the B domain of the E2 glycoprotein
Infections with Chikungunya virus, a mosquito-borne alphavirus, cause an acute febrile syndrome often followed by chronic arthritis that persists for months to years post-infection. Neutralizing antibodies are the primary immune correlate of protection elicited by infection, and the major goal of vaccinations in development. Using convalescent blood samples collected from both endemic and non-endemic human subjects at multiple timepoints following suspected or confirmed chikungunya infection, we identified antibodies with broad neutralizing properties against other alphaviruses within the Semliki Forest complex. Cross-neutralization generally did not extend to the Venezuelan Equine Encephalitis virus (VEEV) complex, although some subjects had low levels of VEEV-neutralizing antibodies. This suggests that broadly neutralizing antibodies elicited following natural infection are largely complex restricted. In addition to serology, we also performed memory B-cell analysis, finding chikungunya-specific memory B-cells in all subjects in this study as remotely as 24 years post-infection. We functionally assessed the ability of memory B-cell derived antibodies to bind to chikungunya virus, and related Mayaro virus, as well as the highly conserved B domain of the E2 glycoprotein thought to contribute to cross-reactivity between related Old-World alphaviruses. To specifically assess the role of the E2 B domain in cross-neutralization, we depleted Mayaro and Chikungunya virus E2 B domain specific antibodies from convalescent sera, finding E2B depletion significantly decreases Mayaro virus specific cross-neutralizing antibody titers with no significant effect on chikungunya virus neutralization, indicating that the E2 B domain is a key target of cross-neutralizing and potentially cross-protective neutralizing antibodies.
Journal Article
Solar wind turbulence and shear: A superposed-epoch analysis of corotating interaction regions at 1 AU
A superposed‐epoch analysis of ACE and OMNI2 measurements is performed on 27 corotating interaction regions (CIRs) in 2003–2008, with the zero epoch taken to be the stream interface as determined by the maximum of the plasma vorticity. When the measurements are rotated into the local‐Parker‐spiral coordinate system, the shear is seen to be abrupt. Converging flows are seen; about half of the CIRs show a layer of divergent rebound flow away from the stream interface. Analysis of the turbulence across the CIRs is performed. When possible, the effects of discontinuities are removed. Fluctuation amplitudes, the Alfvenicity, and the level of Alfvenic correlations all vary smoothly across the CIR. The Alfven ratio exhibits a decrease at the shear zone of the stream interface. Fourier analysis of subintervals is performed, and the results are superposed averaged as an ensemble of realizations. The spectral slopes of the velocity, magnetic field, and total energy vary smoothly across the CIR. The total‐energy spectral index is ∼3/2 in the slow and fast wind and in the CIRs. Fourier analysis of Elsasser fluctuations shows a smooth transition across the CIR from an inward‐outward balance in the slow wind to an outward dominance in the fast wind. Spreading of turbulence away from the region where it is produced is limited to ∼106 km. A number of signatures of turbulence driving at the shear zone are sought (entropy change, turbulence amplitude, Alfvenicity, spectral slopes, and in‐out nature): none show evidence of driving of turbulence by shear.
Journal Article
Damage integral and other predictive formulas for nonisothermal heating during laser exposure
Significance: Physics-based models supply simulated temperature rises to photothermal damage rate models and provide comprehensive risk assessments for laser-induced damage. As the physics-based models continue to be refined, the damage rate models have not advanced. This peculiar lack of improvement is counterintuitive considering the damage integral (Ω), originally derived for isothermal heating events, and fails to accurately represent the nonisothermal heating from short laser exposures.
Aim: Derive a nonisothermal form of the damage integral and predict more accurately the damage induced by short laser exposures, as well as identify the role of heating rate in laser damage.
Approach: From first principles, we derived a version of the damage integral specific to the shape of thermal profiles rather than the square function provided by Arrhenius plots. We used previously published threshold thermal profiles, where all nonisothermal frequency factors (Anon) solved all Ωnon values to unity. Nonisothermal correction factors correct isothermal Aiso values.
Results: The Ea values were identical for both the isothermal and nonisothermal conventions. Correction factor values for Ωiso ranged from 0.0 (20-s exposures at thermal steady state) to −0.93 (0.05-s exposures). Based on empirical results, we have derived a two-dimensional empirical formula that predicts the heating rate as a function of exposure duration and ambient temperature. Threshold peak temperatures (Tpthr) and threshold critical temperatures are mathematically determined without thermal profiles when appropriate Ea and Anon values are established.
Conclusions: We have identified a modified damage integral that does not rely on the Arrhenius plot and provides a value for the frequency factor (A) that accounts for the nonisothermal nature of short laser exposures. The method, validated in our in vitro retinal model, requires thermal profiles recorded under threshold conditions, such as at minimum visible lesions or the boundary of cell death. The method is a new option for laser damage modelers.
Journal Article
Relativistic-electron dropouts and recovery: A superposed epoch study of the magnetosphere and the solar wind
During 124 high‐speed‐stream‐driven storms from two solar cycles, a multispacecraft average of the 1.1–1.5 MeV electron flux measured at geosynchronous orbit is examined to study global dropouts of the flux. Solar wind and magnetospheric measurements are analyzed with a superposed epoch technique, with the superpositions triggered by storm‐convection onset, by onset of the relativistic‐electron dropouts, and by recovery of the dropouts. It is found that the onset of dropout occurs after the passage of the IMF sector reversal prior to the passage of the corotating interaction region (CIR) stream interface. The recovery from dropout commences during the passage of the compressed fast wind. Relativistic‐electron‐dropout onset is temporally associated with the onset of the superdense ion and electron plasma sheet, with the onset of the extra‐hot ion and electron plasma sheet and with the formation of the plasmaspheric drainage plume. Dropout recovery is associated with the termination of the superdense plasma sheet and with a decay of the plasmaspheric drainage plume. When there is appreciable spatial overlap of the superdense ion plasma sheet with the drainage plume, dropouts occur, and when that overlap ends, dropouts recover. This points to pitch‐angle scattering by electromagnetic ion‐cyclotron (EMIC) waves as the primary cause of the relativistic‐electron dropouts, with the waves residing in the lumpy drainage plumes driven by the superdense ion plasma sheet. The drainage plume is caused by enhanced magnetospheric convection associated with southward (GSM) magnetic field after the IMF sector reversal. The superdense plasma sheet has its origin in the compressed slow wind of the CIR.
Journal Article
Energetic electron precipitation during high-speed solar wind stream driven storms
Electron precipitation from the Earth's inner magnetosphere transmits solar variability to the Earth's upper atmosphere and may affect surface level climate. Here we conduct a superposed epoch analysis of energetic electrons observed by the NOAA POES spacecraft during 42 high‐speed solar wind stream (HSS) driven geomagnetic storms to determine the temporal evolution and global distribution of the precipitating flux. The flux of trapped and precipitating E > 30 keV electrons increases immediately following storm onset and remains elevated during the passage of the HSS. In contrast, the trapped and precipitating relativistic electrons (E > 1 MeV) drop out following storm onset and subsequently increase during the recovery phase to levels which eventually exceed the prestorm levels. There is no evidence for enhanced precipitation of relativistic electrons during the MeV flux drop out, suggesting that flux drop outs during the main phase of HSS‐driven storms are not due to precipitation to the atmosphere. On average, the flux of precipitating E > 30 keV electrons is enhanced by a factor of ∼10 during the passage of the high‐speed stream at all geographic longitudes. In contrast, the precipitating relativistic electron count rate is observed to peak in the region poleward of the South Atlantic Anomaly. During the passage of the high‐speed stream, the flux of precipitating E > 30 keV electrons peaks in the region from 2100 to 1200 magnetic local time at low L (4 < L < 7) and in the prenoon sector at high L (7 < L < 9), suggesting that chorus waves are responsible for the precipitation of E > 30 keV electrons in both regions. Key Points MeV flux drop outs during HSS‐driven storms not due to precipitation E > 30 keV electron precipitation during HSS‐driven storms caused by chorus Plasmaspheric hiss cause of relativistic electron precipitation at L equals 4
Journal Article
Proximity-dependent mapping of the HCMV US28 interactome identifies RhoGEF signaling as a requirement for efficient viral reactivation
Human cytomegalovirus (HCMV) encodes multiple putative G protein-coupled receptors (GPCRs). US28 functions as a viral chemokine receptor and is expressed during both latent and lytic phases of virus infection. US28 actively promotes cellular migration, transformation, and plays a major role in mediating viral latency and reactivation; however, knowledge about the interaction partners involved in these processes is still incomplete. Herein, we utilized a proximity-dependent biotinylating enzyme (TurboID) to characterize the US28 interactome when expressed in isolation, and during both latent (CD34 + hematopoietic progenitor cells) and lytic (fibroblasts) HCMV infection. Our analyses indicate that the US28 signalosome converges with RhoA and EGFR signal transduction pathways, sharing multiple mediators that are major actors in processes such as cellular proliferation and differentiation. Integral members of the US28 signaling complex were validated in functional assays by immunoblot and small-molecule inhibitors. Importantly, we identified RhoGEFs as key US28 signaling intermediaries. In vitro latency and reactivation assays utilizing primary CD34 + hematopoietic progenitor cells (HPCs) treated with the small-molecule inhibitors Rhosin or Y16 indicated that US28 –RhoGEF interactions are required for efficient viral reactivation. These findings were recapitulated in vivo using a humanized mouse model where inhibition of RhoGEFs resulted in a failure of the virus to reactivate. Together, our data identifies multiple new proteins in the US28 interactome that play major roles in viral latency and reactivation, highlights the utility of proximity-sensor labeling to characterize protein interactomes, and provides insight into targets for the development of novel anti-HCMV therapeutics.
Journal Article