Triply mixed coverings of arbitrary base curves : quasimodularity, quantum curves and a mysterious topological recursions

Simple Hurwitz numbers are classical invariants in enumerative geometry counting branched morphisms between Riemann surfaces with fixed ramification data. In recent years, several modifications of this notion for genus 0 base curves have appeared in the literature. Among them are so-called monotone Hurwitz numbers, which are related to the Harish–Chandra–Itzykson–Zuber integral in random matrix theory and strictly monotone Hurwitz numbers which enumerate certain Grothendieck dessins d’enfants. We generalise the notion of Hurwitz numbers to interpolations between simple, monotone and strictly monotone Hurwitz numbers for arbitrary genera and any number of arbitrary but fixed ramification profiles. This yields generalisations of several results known for Hurwitz numbers. When the target surface is of genus one, we show that the generating series of these interpolated Hurwitz numbers are quasimodular forms. In the case that all ramification is simple, we refine this result by writing this series as a sum of quasimodular forms corresponding to tropical covers weighted by Gromov–Witten invariants. Moreover, we derive a quantum curve for monotone and Grothendieck dessins d’enfants Hurwitz numbers for arbitrary genera and one arbitrary but fixed ramification profile. Thus, we obtain spectral curves via the semi-classical limit as input data for the Chekhov–Eynard–Orantin (CEO) topological recursion. Astonishingly, we find that the CEO topological recursion for the genus 1 spectral curve of the strictly monotone Hurwitz numbers computes the monotone Hurwitz numbers in genus 0. Thus, we give a new proof that monotone Hurwitz numbers satisfy CEO topological recursion. This points to an unknown relation between those enumerative invariants. Finally, specializing to target surface ℙ1, we find recursions for monotone and Grothendieck dessins d’enfants double Hurwitz numbers, which enables the computation of the respective Hurwitz numbers for any genera with one arbitrary but fixed ramification profile

Color/magnitude calibration for National Aeronautics and Space Administration (NASA) standard Fixed-Head Star Trackers (FHST)

This paper characterizes and analyzes the spectral response of Ball Aerospace fixed-head star trackers, (FHST's) currently in use on some three-axis stabilized spacecraft. The FHST output is a function of the frequency and intensity of the incident light and the position of the star image in the field of view. The FHST's on board the Extreme Ultraviolet Explorer (EUVE) have had occasional problems identifying stars with a high B-V value. These problems are characterized by inaccurate intensity counts observed by the tracker. The inaccuracies are due to errors in the observed star magnitude values. These errors are unique to each individual FHST. For this reason, data were also collected and analyzed from the Upper Atmosphere Research Satellite (UARS). As a consequence of this work, the Goddard Space Flight Center (GSFC) Flight Dynamics Division (FDD) hopes to improve the attitude accuracy on these missions and to adopt better star selection procedures for catalogs

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

Nonalcoholic fatty liver disease (NAFLD) spectrum disorders affect approximately 1 billion individuals worldwide. However, the drivers of progressive steatohepatitis remain incompletely defined. Ketogenesis can dispose of much of the fat that enters the liver, and dysfunction in this pathway could promote the development of NAFLD. Here, we evaluated mice lacking mitochondrial 3-hydroxymethylglutaryl CoA synthase (HMGCS2) to determine the role of ketogenesis in preventing diet-induced steatohepatitis. Antisense oligonucleotide–induced loss of HMGCS2 in chow-fed adult mice caused mild hyperglycemia, increased hepatic gluconeogenesis from pyruvate, and augmented production of hundreds of hepatic metabolites, a suite of which indicated activation of the de novo lipogenesis pathway. High-fat diet feeding of mice with insufficient ketogenesis resulted in extensive hepatocyte injury and inflammation, decreased glycemia, deranged hepatic TCA cycle intermediate concentrations, and impaired hepatic gluconeogenesis due to sequestration of free coenzyme A (CoASH). Supplementation of the CoASH precursors pantothenic acid and cysteine normalized TCA intermediates and gluconeogenesis in the livers of ketogenesis-insufficient animals. Together, these findings indicate that ketogenesis is a critical regulator of hepatic acyl-CoA metabolism, glucose metabolism, and TCA cycle function in the absorptive state and suggest that ketogenesis may modulate fatty liver disease

CTIP2 Expression in Human Head and Neck Squamous Cell Carcinoma Is Linked to Poorly Differentiated Tumor Status

We have demonstrated earlier that CTIP2 is highly expressed in mouse skin during embryogenesis and in adulthood. CTIP2 mutant mice die at birth with epidermal differentiation defects and a compromised epidermal permeability barrier suggesting its role in skin development and/or homeostasis. CTIP2 has also been suggested to function as tumor suppressor in cells, and several reports have described a link between chromosomal rearrangements of CTIP2 and human T cell acute lymphoblast leukemia (T-ALL). The aim of the present study was to look into the pattern of CTIP2 expression in Head and Neck Squamous Cell Carcinoma (HNSCC).In the present study, we analyzed CTIP2 expression in human HNSCC cell lines by western blotting, in paraffin embedded archival specimens by immunohistochemistry (IHC), and in cDNA samples of human HNSCC by qRT-PCR. Elevated levels of CTIP2 protein was detected in several HNSCC cell lines. CTIP2 staining was mainly detected in the basal layer of the head and neck normal epithelium. CTIP2 expression was found to be significantly elevated in HNSCC (p<0.01), and increase in CTIP2 expression was associated with poorly differentiated tumor status. Nuclear co-localization of CTIP2 protein and cancer stem cell (CSC) marker BMI1 was observed in most, if not all of the cells expressing BMI1 in moderately and poorly differentiated tumors.We report for the first time expression of transcriptional regulator CTIP2 in normal human head and neck epithelia. A statistically significant increase in the expression of CTIP2 was detected in the poorly differentiated samples of the human head and neck tumors. Actual CTIP2, rather than the long form of CTIP2 (CTIP2(L)) was found to be more relevant to the differentiation state of the tumors. Results demonstrated existence of distinct subsets of cancer cells, which express CTIP2 and underscores the use of CTIP2 and BMI1 co-labeling to distinguish tumor initiating cells or cancer stem cells (CSCs) from surrounding cancer cells

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

yesThyroid hormone (TH) is essential for adult brain function and its actions include several key roles in the hypothalamus. Although TH controls gene expression via specific TH receptors of the nuclear receptor class, surprisingly few genes have been demonstrated to be directly regulated by TH in the hypothalamus, or the adult brain as a whole. This study explored the rapid induction by TH of retinaldehyde dehydrogenase 1 (Raldh1), encoding a retinoic acid (RA)-synthesizing enzyme, as a gene specifically expressed in hypothalamic tanycytes, cells that mediate a number of actions of TH in the hypothalamus. The resulting increase in RA may then regulate gene expression via the RA receptors, also of the nuclear receptor class. In vivo exposure of the rat to TH led to a significant and rapid increase in hypothalamic Raldh1 within 4 hours. That this may lead to an in vivo increase in RA is suggested by the later induction by TH of the RA-responsive gene Cyp26b1. To explore the actions of RA in the hypothalamus as a potential mediator of TH control of gene regulation, an ex vivo hypothalamic rat slice culture method was developed in which the Raldh1-expressing tanycytes were maintained. These slice cultures confirmed that TH did not act on genes regulating energy balance but could induce Raldh1. RA has the potential to upregulate expression of genes involved in growth and appetite, Ghrh and Agrp. This regulation is acutely sensitive to epigenetic changes, as has been shown for TH action in vivo. These results indicate that sequential triggering of two nuclear receptor signalling systems has the capability to mediate some of the functions of TH in the hypothalamus

A de novo substitution in BCL11B leads to loss of interaction with transcriptional complexes and craniosynostosis

Craniosynostosis, the premature ossification of cranial sutures, is a developmental disorder of the skull vault, occurring in approximately 1 in 2250 births. The causes are heterogeneous, with a monogenic basis identified in ~25% of patients. Using whole-genome sequencing, we identified a novel, de novo variant in BCL11B, c.7C>A, encoding an R3S substitution (p.R3S), in a male patient with coronal suture synostosis. BCL11B is a transcription factor that interacts directly with the nucleosome remodelling and deacetylation complex (NuRD) and polycomb-related complex 2 (PRC2) through the invariant proteins RBBP4 and RBBP7. The p.R3S substitution occurs within a conserved amino-terminal motif (RRKQxxP) of BCL11B and reduces interaction with both transcriptional complexes. Equilibrium binding studies and molecular dynamics simulations show that the p.R3S substitution disrupts ionic coordination between BCL11B and the RBBP4-MTA1 complex, a subassembly of the NuRD complex, and increases the conformational flexibility of Arg-4, Lys-5 and Gln-6 of BCL11B. These alterations collectively reduce the affinity of BCL11B p.R3S for the RBBP4-MTA1 complex by nearly an order of magnitude. We generated a mouse model of the BCL11B p.R3S substitution using a CRISPR-Cas9-based approach, and we report herein that these mice exhibit craniosynostosis of the coronal suture, as well as other cranial sutures. This finding provides strong evidence that the BCL11B p.R3S substitution is causally associated with craniosynostosis and confirms an important role for BCL11B in the maintenance of cranial suture patency

ATP7A is a novel target of retinoic acid receptor β2 in neuroblastoma cells

Increased retinoic acid receptor β (RARβ2) gene expression is a hallmark of cancer cell responsiveness to retinoid anticancer effects. Moreover, low basal or induced RARβ2 expression is a common feature of many human cancers, suggesting that RARβ2 may act as a tumour suppressor gene in the absence of supplemented retinoid. We have previously shown that low RARβ2 expression is a feature of advanced neuroblastoma. Here, we demonstrate that the ABC domain of the RARβ2 protein alone was sufficient for the growth inhibitory effects of RARβ2 on neuroblastoma cells. ATP7A, the copper efflux pump, is a retinoid-responsive gene, was upregulated by ectopic overexpression of RARβ2. The ectopic overexpression of the RARβ2 ABC domain was sufficient to induce ATP7A expression, whereas, RARβ2 siRNA blocked the induction of ATP7A expression in retinoid-treated neuroblastoma cells. Forced downregulation of ATP7A reduced copper efflux and increased viability of retinoid-treated neuroblastoma cells. Copper supplementation enhanced cell growth and reduced retinoid-responsiveness, whereas copper chelation reduced the viability and proliferative capacity. Taken together, our data demonstrates ATP7A expression is regulated by retinoic acid receptor β and it has effects on intracellular copper levels, revealing a link between the anticancer action of retinoids and copper metabolism

The Oncoprotein BCL11A Binds to Orphan Nuclear Receptor TLX and Potentiates its Transrepressive Function

Nuclear orphan receptor TLX (NR2E1) functions primarily as a transcriptional repressor and its pivotal role in brain development, glioblastoma, mental retardation and retinopathologies make it an attractive drug target. TLX is expressed in the neural stem cells (NSCs) of the subventricular zone and the hippocampus subgranular zone, regions with persistent neurogenesis in the adult brain, and functions as an essential regulator of NSCs maintenance and self-renewal. Little is known about the TLX social network of interactors and only few TLX coregulators are described. To identify and characterize novel TLX-binders and possible coregulators, we performed yeast-two-hybrid (Y2H) screens of a human adult brain cDNA library using different TLX constructs as baits. Our screens identified multiple clones of Atrophin-1 (ATN1), a previously described TLX interactor. In addition, we identified an interaction with the oncoprotein and zinc finger transcription factor BCL11A (CTIP1/Evi9), a key player in the hematopoietic system and in major blood-related malignancies. This interaction was validated by expression and coimmunoprecipitation in human cells. BCL11A potentiated the transrepressive function of TLX in an in vitro reporter gene assay. Our work suggests that BCL11A is a novel TLX coregulator that might be involved in TLX-dependent gene regulation in the brain

Role of retinoic receptors in lung carcinogenesis

Several in vitro and in vivo studies have examined the positive and negative effects of retinoids (vitamin A analogs) in premalignant and malignant lesions. Retinoids have been used as chemopreventive and anticancer agents because of their pleiotropic regulator function in cell differentiation, growth, proliferation and apoptosis through interaction with two types of nuclear receptors: retinoic acid receptors and retinoid X receptors. Recent investigations have gradually elucidated the function of retinoids and their signaling pathways and may explain the failure of earlier chemopreventive studies

BCL11B Regulates Epithelial Proliferation and Asymmetric Development of the Mouse Mandibular Incisor

Mouse incisors grow continuously throughout life with enamel deposition uniquely on the outer, or labial, side of the tooth. Asymmetric enamel deposition is due to the presence of enamel-secreting ameloblasts exclusively within the labial epithelium of the incisor. We have previously shown that mice lacking the transcription factor BCL11B/CTIP2 (BCL11B hereafter) exhibit severely disrupted ameloblast formation in the developing incisor. We now report that BCL11B is a key factor controlling epithelial proliferation and overall developmental asymmetry of the mouse incisor: BCL11B is necessary for proliferation of the labial epithelium and development of the epithelial stem cell niche, which gives rise to ameloblasts; conversely, BCL11B suppresses epithelial proliferation, and development of stem cells and ameloblasts on the inner, or lingual, side of the incisor. This bidirectional action of BCL11B in the incisor epithelia appears responsible for the asymmetry of ameloblast localization in developing incisor. Underlying these spatio-specific functions of BCL11B in incisor development is the regulation of a large gene network comprised of genes encoding several members of the FGF and TGFβ superfamilies, Sprouty proteins, and Sonic hedgehog. Our data integrate BCL11B into these pathways during incisor development and reveal the molecular mechanisms that underlie phenotypes of both Bcl11b−/− and Sprouty mutant mice