Comparison of proton channel, phagocyte oxidase, and respiratory burst levels between human eosinophil and neutrophil granulocytes.

Robust production of reactive oxygen species (ROS) by phagocyte NADPH oxidase (phox) during the respiratory burst (RB) is a characteristic feature of eosinophil and neutrophil granulocytes. In these cells the voltage-gated proton channel (Hv1) is now considered as an ancillary subunit of the phox needed for intense ROS production. Multiple sources reported that the expression of phox subunits and RB is more intensive in eosinophils than in neutrophils. In most of these studies the eosinophils were not isolated from healthy individuals, and a comparative analysis of Hv1 expression had never been carried out. We performed a systematic comparison of the levels of essential phox subunits, Hv1 expression and ROS producing capacity between eosinophils and neutrophils of healthy individuals. The expression of phox components was similar, whereas the amount of Hv1 was approximately 10-fold greater in eosinophils. Furthermore, Hv1 expression correlated with Nox2 expression only in eosinophils. Additionally, in confocal microscopy experiments co-accumulation of Hv1 and Nox2 at the cell periphery was observed in resting eosinophils but not in neutrophils. While phorbol-12-myristate-13-acetate-induced peak extracellular ROS release was approximately 1.7-fold greater in eosinophils, oxygen consumption studies indicated that the maximal intensity of the RB is only approximately 1.4-fold greater in eosinophils. Our data reinforce that eosinophils, unlike neutrophils, generate ROS predominantly extracellularly. In contrast to previous works we have found that the two granulocyte types display very similar phox subunit expression and RB capacity. The large difference in Hv1 expression suggests that its support to intense ROS production is more important at the cell surface

The UV Continuum Slopes of Early Star-Forming Galaxies in JADES

The power-law slope of the rest-UV continuum ($f_{\lambda}\propto\lambda^{\beta}$) is a key metric of early star forming galaxies, providing one of our only windows into the stellar populations and physical conditions of $z>10$ galaxies. Expanding upon previous studies with limited sample sizes, we leverage deep imaging from JADES to investigate the UV slopes of 179 $z>9$ galaxies with apparent magnitudes of $m_{\rm F200W}=26-31$, which display a median UV slope of $\beta=-2.4$. We compare to a statistical sample of $z=5-9$ galaxies, finding a shift toward bluer rest-UV colors at all $\rm~M_{UV}$. The most UV-luminous $z>9$ galaxies are significantly bluer than their lower-redshift counterparts, representing a dearth of moderately-red galaxies in the first $500~$Myr. At yet earlier times, the $z>11$ galaxy population exhibits very blue UV slopes, implying very low attenuation from dust. We identify a robust sample of 44 galaxies with $\beta<-2.8$, which have SEDs requiring models of density-bounded HII regions and median ionizing photon escape fractions of $0.51$ to reproduce. Their rest-optical colors imply that this sample has weaker emission lines (median $m_{\rm F356W}-m_{\rm F444W}=0.19$ mag) than typical galaxies (median $m_{\rm F356W}-m_{\rm F444W}=0.39$ mag), consistent with the inferred escape fractions. This sample has relatively low stellar masses (median $\log(M/M_{\odot})=7.5$), and specific star-formation rates (median$=79\rm/Gyr$) nearly twice that of our full sample (median$=44\rm/Gyr$), suggesting they are more common among systems experiencing a recent upturn in star formation. We demonstrate that the shutoff of star formation provides an alternative solution for modelling of extremely blue UV colors, making distinct predictions for the rest-optical emission of these galaxies. Future spectroscopy will be required to distinguish between these physical pictures.Comment: 17 pages, 13 figures; submitted to MNRA

The UV continuum slopes of early star-forming galaxies in JADES

© 2024 The Author(s). Published by Oxford University Press on behalf of Royal Astronomical Society. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/The power-law slope of the rest-ultraviolet (UV) continuum (fλ ∝ λβ) is a key metric of early star-forming galaxies, providing one of our only windows into the stellar populations and physical conditions of z ≳ 10 galaxies. Expanding upon previous studies with limited sample sizes, we leverage deep imaging from the JWST Advanced Deep Extragalactic Survey (JADES) to investigate the UV slopes of 179 z ≳ 9 galaxies with apparent magnitudes of mF200W ≃ 26–31, which display a median UV slope of β = −2.4. We compare to a statistical sample of z ≃ 5–9 galaxies, finding a shift towards bluer rest-UV colours at all $M_{\rm UV}$. The most UV-luminous z ≳ 9 galaxies are significantly bluer than their lower redshift counterparts, representing a dearth of moderately red galaxies within the first 500 Myr. At yet earlier times, the z ≳ 11 galaxy population exhibits very blue UV slopes, implying very low impact from dust attenuation. We identify a robust sample of 44 galaxies with β ≲ −2.8, which have spectral energy distributions requiring models of density-bounded H ii regions and median ionizing photon escape fractions of 0.51 to reproduce. Their rest-optical colours imply that this sample has weaker emission lines (median mF356W − mF444W = 0.19 mag) than typical galaxies (median mF356W − mF444W = 0.39 mag), consistent with the inferred escape fractions. This sample consists of relatively low stellar masses (median $\log (M/{\rm M}_{\odot })=7.5\pm 0.2$), and specific star formation rates (sSFRs; median $=79 \, \rm Gyr^{-1}$) nearly twice that of our full galaxy sample (median sSFRs $=44 \, \rm Gyr^{-1}$), suggesting these objects are more common among systems experiencing a recent upturn in star formation. We demonstrate that the shutoff of star formation provides an alternative solution for modelling of extremely blue UV colours, making distinct predictions for the rest-optical emission of these galaxies. Future spectroscopy will be required to distinguish between these physical pictures.Peer reviewe

JADES Initial Data Release for the Hubble Ultra Deep Field: Revealing the Faint Infrared Sky with Deep JWST NIRCam Imaging

© 2023. The Author(s). Published by the American Astronomical Society. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/JWST has revolutionized the field of extragalactic astronomy with its sensitive and high-resolution infrared view of the distant Universe. Adding to the new legacy of JWST observations, we present the first NIRCam imaging data release from the JWST Advanced Deep Extragalactic Survey (JADES), providing nine filters of infrared imaging of ∼25 arcmin2 covering the Hubble Ultra Deep Field and portions of Great Observatories Origins Deep Survey South. Utilizing 87 on-sky dual-filter hours of exposure time, these images reveal the deepest ever near-infrared view of this iconic field. We supply carefully constructed nine-band mosaics of the JADES bands, as well as matching reductions of five additional bands from the JWST Extragalactic Medium-band Survey. Combining with existing Hubble Space Telescope imaging, we provide 23-band space-based photometric catalogs and photometric redshifts for ≈47,500 sources. To promote broad engagement with JADES, we have created an interactive FitsMap website to provide an interface for professional researchers and the public to experience these JWST data sets. Combined with the first JADES NIRSpec data release, these public JADES imaging and spectroscopic data sets provide a new foundation for discoveries of the infrared Universe by the worldwide scientific community.Peer reviewe

Field and Laboratory Studies Provide Insights into the Meaning of Day-Time Activity in a Subterranean Rodent (Ctenomys aff. knighti), the Tuco-Tuco

South American subterranean rodents (Ctenomys aff. knighti), commonly known as tuco-tucos, display nocturnal, wheel-running behavior under light-dark (LD) conditions, and free-running periods >24 h in constant darkness (DD). However, several reports in the field suggested that a substantial amount of activity occurs during daylight hours, leading us to question whether circadian entrainment in the laboratory accurately reflects behavior in natural conditions. We compared circadian patterns of locomotor activity in DD of animals previously entrained to full laboratory LD cycles (LD12∶12) with those of animals that were trapped directly from the field. In both cases, activity onsets in DD immediately reflected the previous dark onset or sundown. Furthermore, freerunning periods upon release into DD were close to 24 h indicating aftereffects of prior entrainment, similarly in both conditions. No difference was detected in the phase of activity measured with and without access to a running wheel. However, when individuals were observed continuously during daylight hours in a semi-natural enclosure, they emerged above-ground on a daily basis. These day-time activities consisted of foraging and burrow maintenance, suggesting that the designation of this species as nocturnal might be inaccurate in the field. Our study of a solitary subterranean species suggests that the circadian clock is entrained similarly under field and laboratory conditions and that day-time activity expressed only in the field is required for foraging and may not be time-dictated by the circadian pacemaker

Plasticity of the Intrinsic Period of the Human Circadian Timing System

Human expeditions to Mars will require adaptation to the 24.65-h Martian solar day-night cycle (sol), which is outside the range of entrainment of the human circadian pacemaker under lighting intensities to which astronauts are typically exposed. Failure to entrain the circadian time-keeping system to the desired rest-activity cycle disturbs sleep and impairs cognitive function. Furthermore, differences between the intrinsic circadian period and Earth's 24-h light-dark cycle underlie human circadian rhythm sleep disorders, such as advanced sleep phase disorder and non-24-hour sleep-wake disorders. Therefore, first, we tested whether exposure to a model-based lighting regimen would entrain the human circadian pacemaker at a normal phase angle to the 24.65-h Martian sol and to the 23.5-h day length often required of astronauts during short duration space exploration. Second, we tested here whether such prior entrainment to non-24-h light-dark cycles would lead to subsequent modification of the intrinsic period of the human circadian timing system. Here we show that exposure to moderately bright light (∼450 lux; ∼1.2 W/m2) for the second or first half of the scheduled wake episode is effective for entraining individuals to the 24.65-h Martian sol and a 23.5-h day length, respectively. Estimations of the circadian periods of plasma melatonin, plasma cortisol, and core body temperature rhythms collected under forced desynchrony protocols revealed that the intrinsic circadian period of the human circadian pacemaker was significantly longer following entrainment to the Martian sol as compared to following entrainment to the 23.5-h day. The latter finding of after-effects of entrainment reveals for the first time plasticity of the period of the human circadian timing system. Both findings have important implications for the treatment of circadian rhythm sleep disorders and human space exploration

Enhancement of Cell Membrane Invaginations, Vesiculation and Uptake of Macromolecules by Protonation of the Cell Surface

The different pathways of endocytosis share an initial step involving local inward curvature of the cell’s lipid bilayer. It has been shown that to generate membrane curvature, proteins or lipids enforce transversal asymmetry of the plasma membrane. Thus it emerges as a general phenomenon that transversal membrane asymmetry is the common required element for the formation of membrane curvature. The present study demonstrates that elevating proton concentration at the cell surface stimulates the formation of membrane invaginations and vesiculation accompanied by efficient uptake of macromolecules (Dextran-FITC, 70 kD), relative to the constitutive one. The insensitivity of proton induced uptake to inhibiting treatments and agents of the known endocytic pathways suggests the entry of macromolecules to proceeds via a yet undefined route. This is in line with the fact that neither ATP depletion, nor the lowering of temperature, abolishes the uptake process. In addition, fusion mechanism such as associated with low pH uptake of toxins and viral proteins can be disregarded by employing the polysaccharide dextran as the uptake molecule. The proton induced uptake increases linearly in the extracellular pH range of 6.5 to 4.5, and possesses a steep increase at the range of 4> pH>3, reaching a plateau at pH≤3. The kinetics of the uptake implies that the induced vesicles release their content to the cytosol and undergo rapid recycling to the plasma membrane. We suggest that protonation of the cell’s surface induces local charge asymmetries across the cell membrane bilayer, inducing inward curvature of the cell membrane and consequent vesiculation and uptake

Clofazimine Inhibits Human Kv1.3 Potassium Channel by Perturbing Calcium Oscillation in T Lymphocytes

The Kv1.3 potassium channel plays an essential role in effector memory T cells and has been implicated in several important autoimmune diseases including multiple sclerosis, psoriasis and type 1 diabetes. A number of potent small molecule inhibitors of Kv1.3 channel have been reported, some of which were found to be effective in various animal models of autoimmune diseases. We report herein the identification of clofazimine, a known anti-mycobacterial drug, as a novel inhibitor of human Kv1.3. Clofazimine was initially identified as an inhibitor of intracellular T cell receptor-mediated signaling leading to the transcriptional activation of human interleukin-2 gene in T cells from a screen of the Johns Hopkins Drug Library. A systematic mechanistic deconvolution revealed that clofazimine selectively blocked the Kv1.3 channel activity, perturbing the oscillation frequency of the calcium-release activated calcium channel, which in turn led to the inhibition of the calcineurin-NFAT signaling pathway. These effects of clofazimine provide the first line of experimental evidence in support of a causal relationship between Kv1.3 and calcium oscillation in human T cells. Furthermore, clofazimine was found to be effective in blocking human T cell-mediated skin graft rejection in an animal model in vivo. Together, these results suggest that clofazimine is a promising immunomodulatory drug candidate for treating a variety of autoimmune disorders

JADES Initial Data Release for the Hubble Ultra Deep Field: Revealing the Faint Infrared Sky with Deep JWST NIRCam Imaging

JWST has revolutionized the field of extragalactic astronomy with its sensitive and high-resolution infrared view of the distant universe. Adding to the new legacy of JWST observations, we present the first NIRCam imaging data release from the JWST Advanced Deep Extragalactic Survey (JADES) providing 9 filters of infrared imaging of $\sim$25 arcmin$^2$ covering the Hubble Ultra Deep Field and portions of Great Observatories Origins Deep Survey (GOODS) South. Utilizing 87 on-sky dual-filter hours of exposure time, these images reveal the deepest ever near-infrared view of this iconic field. We supply carefully constructed 9-band mosaics of the JADES bands, as well as matching reductions of 5 additional bands from the JWST Extragalactic Medium-band Survey (JEMS). Combining with existing HST imaging, we provide 23-band space-based photometric catalogs and photometric redshifts for $\approx47,500$ sources. To promote broad engagement with the JADES survey, we have created an interactive {\tt FitsMap} website to provide an interface for professional researchers and the public to experience these JWST datasets. Combined with the first JADES NIRSpec data release, these public JADES imaging and spectroscopic datasets provide a new foundation for discoveries of the infrared universe by the worldwide scientific community.Comment: Several figures were modified to use better line styles. A brief comparison to IRAC Channel 1 photometry was added along with a few other clarifications. Paper has been accepted for publication in ApJ

Inhibition of HERG1 K+ channel protein expression decreases cell proliferation of human small cell lung cancer cells

HERG (human ether-à-go-go-related gene) K+ currents fulfill important ionic functions in cardiac and other excitable cells. In addition, HERG channels influence cell growth and migration in various types of tumor cells. The mechanisms underlying these functions are still not resolved. Here, we investigated the role of HERG channels for cell growth in a cell line (SW2) derived from small cell lung cancer (SCLC), a malignant variant of lung cancer. The two HERG1 isoforms (HERG1a, HERG1b) as well as HERG2 and HERG3 are expressed in SW2 cells. Inhibition of HERG currents by acute or sustained application of E-4031, a specific ERG channel blocker, depolarized SW2 cells by 10–15 mV. This result indicated that HERG K+ conductance contributes considerably to the maintenance of the resting potential of about −45 mV. Blockage of HERG channels by E-4031 for up to 72 h did not affect cell proliferation. In contrast, siRNA-induced inhibition of HERG1 protein expression decreased cell proliferation by about 50%. Reduction of HERG1 protein expression was confirmed by Western blots. HERG current was almost absent in SW2 cells transfected with siRNA against HERG1. Qualitatively similar results were obtained in three other SCLC cell lines (OH1, OH3, H82), suggesting that the HERG1 channel protein is involved in SCLC cell growth, whereas the ion-conducting function of HERG1 seems not to be important for cell growth