Sex-biased immunological processes drive hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that can manifest with abscesses, sinus tracts, and scarring in the intertriginous areas of the body. HS is characterized by immune dysregulation, featuring elevated levels of myeloid cells, T helper (Th) cells, and pro-inflammatory cytokines, particularly those involved in Th1- and Th17-mediated immunity. In most epidemiological studies, HS shows a strong female sex bias, with reported female-to-male ratios estimated at roughly 3:1, suggesting that sex-related factors contribute to HS pathophysiology. In this article, we review the role of intrinsic and extrinsic factors that contribute to immunological differences between the sexes and postulate their role in the female sex bias observed in HS. We discuss the effects of hormones, X chromosome dosage, genetics, the microbiome, and smoking on sex-related differences in immunity to postulate potential immunological mechanisms in HS pathophysiology. Future studies are required to better characterize sex-biased factors that contribute to HS disease presentations

Latent NOTCH3 epitopes unmasked in CADASIL and regulated by protein redox state

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy CADASIL is caused by more than a hundred NOTCH3 mutations. Virtually all encoded mutant proteins contain an odd number of cysteines. As such, structural changes in NOTCH3 may be the primary molecular abnormality in CADASIL. Thus, we sought evidence for structurally altered NOTCH3 protein in CADASIL tissue. Four antibodies were raised in rabbits against two non-overlapping N-terminal NOTCH3 sequences. These reagents were used in immunohistochemical experiments to detect epitopes in post-mortem CADASIL brains (n=8), control brains, and cells overexpressing NOTCH3. To determine the biochemical nature of NOTCH3 epitopes, we used these antibodies to probe pure NOTCH3-Fc fusion proteins treated with acid, urea, guanidinium, ionic detergents, acrylamide, and thiol- and phosphorus-based reductants. All antibodies avidly stained arteries in 8 of 8 CADASIL brain samples. The most prominent staining was in degenerating media of leptomeningeal arteries and sclerotic penetrating vessels. Normal appearing vessels from control brains were not reactive. Antibodies did not react with cultured cells overexpressing NOTCH3 or with purified NOTCH3-Fc protein. Furthermore, treatment of pure protein with acid, chaotropic denaturants, alkylators, and detergents failed to unmask N-terminal NOTCH3 epitopes. Antibodies, however, recognized novel N-terminal epitopes in purified NOTCH3-Fc protein treated with three different reductants (DTT, beta-mercaptoethanol, and TCEP). We conclude that CADASIL arteries feature latent N-terminal NOTCH3 epitopes, suggesting the first evidence in vivo of NOTCH3 structural alterations

Sex-biased immunological processes drive hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that can manifest with abscesses, sinus tracts, and scarring in the intertriginous areas of the body. HS is characterized by immune dysregulation, featuring elevated levels of myeloid cells, T helper (Th) cells, and pro-inflammatory cytokines, particularly those involved in Th1- and Th17-mediated immunity. In most epidemiological studies, HS shows a strong female sex bias, with reported female-to-male ratios estimated at roughly 3:1, suggesting that sex-related factors contribute to HS pathophysiology. In this article, we review the role of intrinsic and extrinsic factors that contribute to immunological differences between the sexes and postulate their role in the female sex bias observed in HS. We discuss the effects of hormones, X chromosome dosage, genetics, the microbiome, and smoking on sex-related differences in immunity to postulate potential immunological mechanisms in HS pathophysiology. Future studies are required to better characterize sex-biased factors that contribute to HS disease presentations

Accretion Rate and the Physical Nature of Unobscured Active Galaxies

We show how accretion rate governs the physical properties of a sample of unobscured broad-line, narrow-line, and lineless active galactic nuclei (AGNs). We avoid the systematic errors plaguing previous studies of AGN accretion rate by using accurate accretion luminosities (L_int) from well-sampled multiwavelength SEDs from the Cosmic Evolution Survey (COSMOS), and accurate black hole masses derived from virial scaling relations (for broad-line AGNs) or host-AGN relations (for narrow-line and lineless AGNs). In general, broad emission lines are present only at the highest accretion rates (L_int/L_Edd > 0.01), and these rapidly accreting AGNs are observed as broad-line AGNs or possibly as obscured narrow-line AGNs. Narrow-line and lineless AGNs at lower specific accretion rates (L_int/L_Edd < 0.01) are unobscured and yet lack a broad line region. The disappearance of the broad emission lines is caused by an expanding radiatively inefficient accretion flow (RIAF) at the inner radius of the accretion disk. The presence of the RIAF also drives L_int/L_Edd < 10^-2 narrow-line and lineless AGNs to 10 times higher ratios of radio to optical/UV emission than L_int/L_Edd > 0.01 broad-line AGNs, since the unbound nature of the RIAF means it is easier to form a radio outflow. The IR torus signature also tends to become weaker or disappear from L_int/L_Edd < 0.01 AGNs, although there may be additional mid-IR synchrotron emission associated with the RIAF. Together these results suggest that specific accretion rate is an important physical "axis" of AGN unification, described by a simple model.Comment: Accepted for publication in the Astrophysical Journal. 15 pages, 9 figure

The low level of debris disk activity at the time of the Late Heavy Bombardment: a Spitzer study of Praesepe

We present 24 micron photometry of the intermediate-age open cluster Praesepe. We assemble a catalog of 193 probable cluster members that are detected in optical databases, the Two Micron All Sky Survey (2MASS), and at 24 micron, within an area of ~ 2.47 square degrees. Mid-IR excesses indicating debris disks are found for one early-type and for three solar-type stars. Corrections for sampling statistics yield a 24 micron excess fraction (debris disk fraction) of 6.5 +- 4.1% for luminous and 1.9 +- 1.2% for solar-type stars. The incidence of excesses is in agreement with the decay trend of debris disks as a function of age observed for other cluster and field stars. The values also agree with those for older stars, indicating that debris generation in the zones that emit at 24 micron falls to the older 1-10 Gyr field star sample value by roughly 750 Myr. We discuss our results in the context of previous observations of excess fractions for early- and solar-type stars. We show that solar-type stars lose their debris disk 24 micron excesses on a shorter timescale than early-type stars. Simplistic Monte Carlo models suggest that, during the first Gyr of their evolution, up to 15-30% of solar-type stars might undergo an orbital realignment of giant planets such as the one thought to have led to the Late Heavy Bombardment, if the length of the bombardment episode is similar to the one thought to have happened in our Solar System. In the Appendix, we determine the cluster's parameters via boostrap Monte Carlo isochrone fitting, yielding an age of 757 Myr (+- 36 Myr at 1 sigma confidence) and a distance of 179 pc (+- 2 pc at 1 sigma confidence), not allowing for systematic errors.Comment: 22 pages, 14 figures, 9 tables, emulateapj format; Accepted for publication in The Astrophysical Journa

Psg22 null mouse embryos develop normally under normoxic and hypoxic conditions of pregnancy

Pregnancy-specific glycoproteins are secreted immunoglobulin superfamily members encoded by multigene families in eutherian mammals with haemochorial placentation. They are expressed predominantly in placental trophoblast and exhibits immunomodulatory, anti-platelet and pro-angiogenic functions. An inversion of Psg22 in the mouse locus is associated with relatively high Psg22 expression in the first half of the pregnancy. Bioinformatic analysis of seventeen mouse strains indicated that the Psg22 inversion arose at least 1.7 MYA. We used CRISPR-Cas9 mutagenesis to generate Psg22 null mutants, two of which were analysed in detail (Psg22Δ10 and Psg22Δ16). Both mutants contain frame-shifting deletions in exon 2, resulting in premature stop codons, and Psg22 mRNA was virtually undetectable. Both mutants are fertile and there was no distortion of Mendelian ratios in heterozygous crosses. Housing of pregnant females in a hypoxic (11% O2) environment for five (E5 - E10) or ten (E5 - E15) days did not induce differential growth or survival of Psg22 wildtype and null mutant genotypes. Our results indicate that Psg22 is dispensable for embryonic development and reproduction under laboratory conditions. As PSGs are secreted into maternal blood, future work will focus on whether Psg22 deficiency alters maternal physiology

The Chandra COSMOS Survey: III. Optical and Infrared Identification of X-ray Point Sources

The Chandra COSMOS Survey (C-COSMOS) is a large, 1.8 Ms, Chandra program that has imaged the central 0.9 deg^2 of the COSMOS field down to limiting depths of 1.9 10^-16 erg cm^-2 s-1 in the 0.5-2 keV band, 7.3 10^-16 erg cm^-2 s^-1 in the 2-10 keV band, and 5.7 10^-16 erg cm^-2 s-1 in the 0.5-10 keV band. In this paper we report the i, K and 3.6micron identifications of the 1761 X-ray point sources. We use the likelihood ratio technique to derive the association of optical/infrared counterparts for 97% of the X-ray sources. For most of the remaining 3%, the presence of multiple counterparts or the faintness of the possible counterpart prevented a unique association. For only 10 X-ray sources we were not able to associate a counterpart, mostly due to the presence of a very bright field source close by. Only 2 sources are truly empty fields. Making use of the large number of X-ray sources, we update the "classic locus" of AGN and define a new locus containing 90% of the AGN in the survey with full band luminosity >10^42 erg/s. We present the linear fit between the total i band magnitude and the X-ray flux in the soft and hard band, drawn over 2 orders of magnitude in X-ray flux, obtained using the combined C-COSMOS and XMM-COSMOS samples. We focus on the X-ray to optical flux ratio (X/O) and we test its known correlation with redshift and luminosity, and a recently introduced anti-correlation with the concentration index (C). We find a strong anti-correlation (though the dispersion is of the order of 0.5 dex) between C and X/O, computed in the hard band, and that 90% of the obscured AGN in the sample with morphological information live in galaxies with regular morphology (bulgy and disky/spiral), suggesting that secular processes govern a significant fraction of the BH growth at X-ray luminosities of 10^43- 10^44.5 erg/s.Comment: 21 pages, 17 figures, 4 tables; accepted for publication in ApJS. The catalog is available at the urls listed in the pape

Centrality Dependence of the High p_T Charged Hadron Suppression in Au+Au collisions at sqrt(s_NN) = 130 GeV

PHENIX has measured the centrality dependence of charged hadron p_T spectra from central Au+Au collisions at sqrt(s_NN)=130 GeV. The truncated mean p_T decreases with centrality for p_T > 2 GeV/c, indicating an apparent reduction of the contribution from hard scattering to high p_T hadron production. For central collisions the yield at high p_T is shown to be suppressed compared to binary nucleon-nucleon collision scaling of p+p data. This suppression is monotonically increasing with centrality, but most of the change occurs below 30% centrality, i.e. for collisions with less than about 140 participating nucleons. The observed p_T and centrality dependence is consistent with the particle production predicted by models including hard scattering and subsequent energy loss of the scattered partons in the dense matter created in the collisions.Comment: 7 pages text, LaTeX, 6 figures, 2 tables, 307 authors, resubmitted to Phys. Lett. B. Revised to address referee concerns. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are publicly available at http://www.phenix.bnl.gov/phenix/WWW/run/phenix/papers.htm

A Scalable System for Production of Functional Pancreatic Progenitors from Human Embryonic Stem Cells

Development of a human embryonic stem cell (hESC)-based therapy for type 1 diabetes will require the translation of proof-of-principle concepts into a scalable, controlled, and regulated cell manufacturing process. We have previously demonstrated that hESC can be directed to differentiate into pancreatic progenitors that mature into functional glucose-responsive, insulin-secreting cells in vivo. In this study we describe hESC expansion and banking methods and a suspension-based differentiation system, which together underpin an integrated scalable manufacturing process for producing pancreatic progenitors. This system has been optimized for the CyT49 cell line. Accordingly, qualified large-scale single-cell master and working cGMP cell banks of CyT49 have been generated to provide a virtually unlimited starting resource for manufacturing. Upon thaw from these banks, we expanded CyT49 for two weeks in an adherent culture format that achieves 50–100 fold expansion per week. Undifferentiated CyT49 were then aggregated into clusters in dynamic rotational suspension culture, followed by differentiation en masse for two weeks with a four-stage protocol. Numerous scaled differentiation runs generated reproducible and defined population compositions highly enriched for pancreatic cell lineages, as shown by examining mRNA expression at each stage of differentiation and flow cytometry of the final population. Islet-like tissue containing glucose-responsive, insulin-secreting cells was generated upon implantation into mice. By four- to five-months post-engraftment, mature neo-pancreatic tissue was sufficient to protect against streptozotocin (STZ)-induced hyperglycemia. In summary, we have developed a tractable manufacturing process for the generation of functional pancreatic progenitors from hESC on a scale amenable to clinical entry