Direct Autocrine Action of Insulin on β-Cells: Does It Make Physiological Sense?

In recent years there has been a growing interest in the possibility of a direct autocrine effect of insulin on the pancreatic β-cell. Indeed, there have been numerous intriguing articles and several eloquent reviews written on the subject (1–3); however, the concept is still controversial. Although many in vitro experiments, a few transgenic mouse studies, and some human investigations would be supportive of the notion, there exist different insights, other studies, and circumstantial evidence that question the concept. Therefore, the idea of autocrine action of insulin remains a conundrum. Here we outline a series of thoughts, insights, and alternative interpretations of the available experimental evidence. We ask, how convincing are these, and what are the confusing issues? We agree that there is a clear contribution of certain downstream elements in the insulin signaling pathway for β-cell function and survival, but the question of whether insulin itself is actually the physiologically relevant ligand that triggers this signal transduction remains unsettled

Migratory Flyways May Affect Population Structure in Double‐Crested Cormorants

Double‐crested cormorants (Phalacrocorax auritus) recovered from a demographic bottleneck so well that they are now considered a nuisance species at breeding and wintering grounds across the United States and Canada. Management of this species could be improved by refining genetic population boundaries and assigning individuals to their natal population. Further, recent radio‐telemetry data suggest the existence of Interior and Atlantic migratory flyways, which could reduce gene flow and result in substantial genetic isolation. In this study, we used 1,784 individuals collected across the eastern United States, a large panel of microsatellite markers developed for this species, and individuals banded as chicks and recaptured as adults to explore the effects of migratory flyways on population structure, quantify the genetic effects of demographic bottlenecks, and determine whether individuals could be assigned to their natal population based on genotype. We found evidence for genetic population division only along migratory flyways, no evidence of genetic bottlenecks, and mixed effectiveness of assignment tests. Our population structure findings suggest that gene flow is high across large scales; for example, individuals from New York, Minnesota, and Alabama are all in panmixia. We also found that traditional subspecies ranges may not be valid because \u3e1 subspecies was present in single genetic populations. The lack of evidence for genetic bottlenecks also likely underscores the vagility of this species, suggesting that even during demographic bottlenecks, populations were not isolated from allelic exchange. Finally, the failure of assignment tests to consistently perform is likely due in part to imperfect a priori sampling of Atlantic and Interior chicks and the high vagility of adults. We conclude that the demographic bottleneck is not likely to have reduced genetic diversity, and that assignment tests remain unreliable for this species. We recommend double-crested cormorants be managed by flyway. Further development of genomic resources in this species could improve population subdivision resolution, improve assignment tests, and reveal further information on demographic histories

A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential

Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin

The bone microenvironment is composed of niches that house cells across variable oxygen tensions. However, the contribution of oxygen gradients in regulating bone and blood homeostasis remains unknown. Here, we generated mice with either single or combined genetic inactivation of the critical oxygen-sensing prolyl hydroxylase (PHD) enzymes (PHD1–3) in osteoprogenitors. Hypoxia-inducible factor (HIF) activation associated with Phd2 and Phd3 inactivation drove bone accumulation by modulating osteoblastic/osteoclastic cross-talk through the direct regulation of osteoprotegerin (OPG). In contrast, combined inactivation of Phd1, Phd2, and Phd3 resulted in extreme HIF signaling, leading to polycythemia and excessive bone accumulation by overstimulating angiogenic–osteogenic coupling. Wealso demonstrate that genetic ablation of Phd2 and Phd3 was sufficient to protect ovariectomized mice against bone loss without disrupting hematopoietic homeostasis. Importantly,we identify OPG as a HIF target gene capable of directing osteoblast-mediated osteoclastogenesis to regulate bone homeostasis. Here, we show that coordinated activation of specific PHD isoforms fine-tunes the osteoblastic response to hypoxia, thereby directing two important aspects of bone physiology: cross-talk between osteoblasts and osteoclasts and angiogenic–osteogenic coupling

COSMOS-Web: Intrinsically Luminous z≳\gtrsim10 Galaxy Candidates Test Early Stellar Mass Assembly

We report the discovery of 15 exceptionally luminous $10\lesssim z\lesssim14$ candidate galaxies discovered in the first 0.28 deg$^2$ of JWST/NIRCam imaging from the COSMOS-Web Survey. These sources span rest-frame UV magnitudes of $-20.5>M_{\rm UV}>-22$, and thus constitute the most intrinsically luminous $z\gtrsim10$ candidates identified by JWST to-date. Selected via NIRCam imaging with Hubble ACS/F814W, deep ground-based observations corroborate their detection and help significantly constrain their photometric redshifts. We analyze their spectral energy distributions using multiple open-source codes and evaluate the probability of low-redshift solutions; we conclude that 12/15 (80%) are likely genuine $z\gtrsim10$ sources and 3/15 (20%) likely low-redshift contaminants. Three of our $z\sim12$ candidates push the limits of early stellar mass assembly: they have estimated stellar masses $\sim5\times10^{9}\,M_\odot$, implying an effective stellar baryon fraction of $\epsilon_{\star}\sim0.2-0.5$, where $\epsilon_{\star}\equiv M_{\star}/(f_{b}M_{halo})$. The assembly of such stellar reservoirs is made possible due to rapid, burst-driven star formation on timescales $<$100\,Myr where the star-formation rate may far outpace the growth of the underlying dark matter halos. This is supported by the similar volume densities inferred for $M_\star\sim10^{10}\,M_\odot$ galaxies relative to $M_\star\sim10^{9}\,M_\odot$ -- both about $10^{-6}$ Mpc$^{-3}$ -- implying they live in halos of comparable mass. At such high redshifts, the duty cycle for starbursts would be of order unity, which could cause the observed change in the shape of the UVLF from a double powerlaw to Schechter at $z\approx8$. Spectroscopic redshift confirmation and ensuing constraints of their masses will be critical to understanding how, and if, such early massive galaxies push the limits of galaxy formation in $\Lambda$CDM.Comment: 30 pages, 9 figures; ApJ submitte

Genetic Variation and Reproductive Timing: African American Women from the Population Architecture Using Genomics and Epidemiology (PAGE) Study

Age at menarche (AM) and age at natural menopause (ANM) define the boundaries of the reproductive lifespan in women. Their timing is associated with various diseases, including cancer and cardiovascular disease. Genome-wide association studies have identified several genetic variants associated with either AM or ANM in populations of largely European or Asian descent women. The extent to which these associations generalize to diverse populations remains unknown. Therefore, we sought to replicate previously reported AM and ANM findings and to identify novel AM and ANM variants using the Metabochip (n = 161,098 SNPs) in 4,159 and 1,860 African American women, respectively, in the Women's Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) studies, as part of the Population Architecture using Genomics and Epidemiology (PAGE) Study. We replicated or generalized one previously identified variant for AM, rs1361108/CENPW, and two variants for ANM, rs897798/BRSK1 and rs769450/APOE, to our African American cohort. Overall, generalization of the majority of previously-identified variants for AM and ANM, including LIN28B and MCM8, was not observed in this African American sample. We identified three novel loci associated with ANM that reached significance after multiple testing correction (LDLR rs189596789, p = 5×10-08; KCNQ1 rs79972789, p = 1.9×10-07; COL4A3BP rs181686584, p = 2.9×10-07). Our most significant AM association was upstream of RSF1, a gene implicated in ovarian and breast cancers (rs11604207, p = 1.6×10-06). While most associations were identified in either AM or ANM, we did identify genes suggestively associated with both: PHACTR1 and ARHGAP42. The lack of generalization coupled with the potentially novel associations identified here emphasize the need for additional genetic discovery efforts for AM and ANM in diverse populations. © 2013 Spencer et al

JWST and ALMA discern the assembly of structural and obscured components in a high-redshift starburst galaxy

We present observations and analysis of the starburst, PACS-819, at z=1.45 ($M_*=10^{10.7}$ M$_{ \odot}$), using high-resolution ($0^{\prime \prime}.1$; 0.8 kpc) ALMA and multi-wavelength JWST images from the COSMOS-Web program. Dissimilar to HST/ACS images in the rest-frame UV, the redder NIRCam and MIRI images reveal a smooth central mass concentration and spiral-like features, atypical for such an intense starburst. Through dynamical modeling of the CO J=5--4 emission with ALMA, PACS-819 is rotation-dominated thus has a disk-like nature. However, kinematic anomalies in CO and asymmetric features in the bluer JWST bands (e.g., F150W) support a more disturbed nature likely due to interactions. The JWST imaging further enables us to map the distribution of stellar mass and dust attenuation, thus clarifying the relationships between different structural components, not discernable in the previous HST images. The CO J = 5 -- 4 and FIR dust continuum emission are co-spatial with a heavily-obscured starbursting core (<1 kpc) which is partially surrounded by much less obscured star-forming structures including a prominent arc, possibly a tidally-distorted dwarf galaxy, and a clump, either a sign of an ongoing violent disk instability or a recently accreted low-mass satellite. With spatially-resolved maps, we find a high molecular gas fraction in the central area reaching $\sim3$ ($M_{\text{gas}}$/$M_*$) and short depletion times ($M_{\text{gas}}/SFR\sim$ 120 Myrs) across the entire system. These observations provide insights into the complex nature of starbursts in the distant universe and underscore the wealth of complementary information from high-resolution observations with both ALMA and JWST.Comment: 18 pages, 12 figures, Submitted to Ap

Unveiling the distant Universe: Characterizing z≥9z\ge9 Galaxies in the first epoch of COSMOS-Web

We report the identification of 15 galaxy candidates at $z\ge9$ using the initial COSMOS-Web JWST observations over 77 arcmin$^2$ through four NIRCam filters (F115W, F150W, F277W, F444W) with an overlap with MIRI (F770W) of 8.7 arcmin$^2$. We fit the sample using several publicly-available SED fitting and photometric redshift codes and determine their redshifts between $z=9.3$ and $z=10.9$ ($\langle z\rangle=10.0$), UV-magnitudes between M$_{\rm UV}$ = $-$21.2 and $-$19.5 (with $\langle$M$_{\rm UV}\rangle=-20.2$) and rest-frame UV slopes ($\langle \beta\rangle=-2.4$). These galaxies are, on average, more luminous than most $z\ge9$ candidates discovered by JWST so far in the literature, while exhibiting similar blue colors in their rest-frame UV. The rest-frame UV slopes derived from SED-fitting are blue ($\beta\sim$[$-$2.0, $-$2.7]) without reaching extremely blue values as reported in other recent studies at these redshifts. The blue color is consistent with models that suggest the underlying stellar population is not yet fully enriched in metals like similarly luminous galaxies in the lower redshift Universe. The derived stellar masses with $\langle \log_{\rm 10} ($M$_\star/$M$_\odot)\rangle\approx8-9$ are not in tension with the standard $\Lambda$CDM model and our measurement of the volume density of such UV luminous galaxies aligns well with previously measured values presented in the literature at $z\sim9-10$. Our sample of galaxies, although compact, are significantly resolved.Comment: Submitted to Ap