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

Simple Hurwitz numbers enumerate branched morphisms between Riemann surfaces with fixed ramification data. In recent years, several variants 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 HCIZ integral in random matrix theory and strictly monotone Hurwitz numbers which count certain Grothendieck dessins d'enfants. We generalise the notion of Hurwitz numbers to interpolations between simple, monotone and strictly monotone Hurwitz numbers to any genus 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 corresonding 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 semiclassical limit as input data for the CEO topological recursion. Astonishingly, we find that the CEO topological recursion for the genus $1$ spectral curve of the strictly monotone Hurwitz numbers compute 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 enumerants. Finally, specializing to target surface $\mathbb{P}^1$, 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.Comment: 41 page

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

In-flight estimation of gyro noise on the Upper Atmosphere Research Satellite (UARS) and Extreme Ultraviolet Explorer (EUVE) missions

This paper characterizes the low-frequency noise response of the Teledyne dry rotor inertial reference unit (DRIRU) gyroscopes on the Upper Atmosphere Research Satellite (UARS) and the Extreme Ultraviolet Explorer (EUVE). The accuracy of spacecraft attitude estimation algorithms that use gyro data for propagating the spacecraft attitude is sensitive to gyro noise. EUVE gyro data were processed to validate a single-axis gyro noise model, which is used onboard various spacecraft. The paper addresses the potential impact of temperature effects on the gyro noise model and the overall impact on attitude determination accuracy. The power spectral density (PSD) of the gyro noise is estimated from UARS in-flight data by Fast Fourier Transform (FFT). The role of actuator dynamics on the PSD function is also discussed

Regulation of transcription factor activity by interconnected, post-translational modifications

Transcription factors comprise just over 7% of the human proteome and serve as gatekeepers of cellular function, integrating external signal information into gene expression programs that reconfigure cellular physiology at the most basic levels. Surface-initiated cell signaling pathways converge on transcription factors, decorating these proteins with an array of post-translational modifications (PTMs) that are often interdependent, being linked in time, space, and combinatorial function. These PTMs orchestrate every activity of a transcription factor over its entire lifespan—from subcellular localization to protein–protein interactions, sequence-specific DNA binding, transcriptional regulatory activity, and protein stability—and play key roles in the epigenetic regulation of gene expression. The multitude of PTMs of transcription factors also offers numerous potential points of intervention for development of therapeutic agents to treat a wide spectrum of diseases. We review PTMs most commonly targeting transcription factors, focusing on recent reports of sequential and linked PTMs of individual factors

Kinetic Analysis of BCL11B Multisite Phosphorylation–Dephosphorylation and Coupled Sumoylation in Primary Thymocytes by Multiple Reaction Monitoring Mass Spectroscopy

Transcription factors with multiple post-translational modifications (PTMs) are not uncommon, but comprehensive information on site-specific dynamics and interdependence is comparatively rare. Assessing dynamic changes in the extent of PTMs has the potential to link multiple sites both to each other and to biological effects observable on the same time scale. The transcription factor and tumor suppressor BCL11B is critical to three checkpoints in T-cell development and is a target of a T-cell receptor (TCR)-mediated MAP kinase signaling. Multiple reaction monitoring (MRM) mass spectroscopy was used to assess changes in relative phosphorylation on 18 of 23 serine and threonine residues and sumoylation on one of two lysine resides in BCL11B. We have resolved the composite phosphorylation–dephosphorylation and sumoylation changes of BCL11B in response to MAP kinase activation into a complex pattern of site-specific PTM changes in primary mouse thymocytes. The site-specific resolution afforded by MRM analyses revealed four kinetic patterns of phosphorylation and one of sumoylation, including both rapid simultaneous site-specific increases and decreases at putative MAP kinase proline-directed phosphorylation sites, following stimulation. These data additionally revealed a novel spatiotemporal bisphosphorylation motif consisting of two kinetically divergent proline-directed phosphorylation sites spaced five resides apart.Keywords: SRM, T-cell receptor, Post-translational modification, Signal transduction, Sumoylation, MRM, BCL11

Regulation of virulence gene expression resulting from Streptococcus pneumoniae and nontypeable Haemophilus influenzae interactions in chronic disease

Chronic rhinosinusitis (CRS) is a common inflammatory disease of the sinonasal cavity mediated, in part, by polymicrobial communities of bacteria. Recent molecular studies have confirmed the importance of Streptococcus pneumoniae and nontypeable Haemophilus influenzae (NTHi) in CRS. Here, we hypothesize that interaction between S. pneumoniae and NTHi mixed-species communities cause a change in bacterial virulence gene expression. We examined CRS as a model human disease to validate these polymicrobial interactions. Clinical strains of S. pneumoniae and NTHi were grown in mono- and coculture in a standard biofilm assay. Reverse transcriptase real-time PCR (RTqPCR) was used to measure gene expression of key virulence factors. To validate these results, we investigated the presence of the bacterial RNA transcripts in excised human tissue from patients with CRS. Consequences of physical or chemical interactions between microbes were also investigated. Transcription of NTHi type IV pili was only expressed in co-culture in vitro, and expression could be detected ex vivo in diseased tissue. S. pneumoniae pyruvate oxidase was up-regulated in co-culture, while pneumolysin and pneumococcal adherence factor A were down-regulated. These results were confirmed in excised human CRS tissue. Gene expression was differentially regulated by physical contact and secreted factors. Overall, these data suggest that interactions between H. influenzae and S. pneumoniae involve physical and chemical mechanisms that influence virulence gene expression of mixed-species biofilm communities present in chronically diseased human tissue. These results extend previous studies of population-level virulence and provide novel insight into the importance of S. pneumoniae and NTHi in CRS

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

Microbial interactions and differential protein expression in Staphylococcus aureus –Candida albicans dual-species biofilms

The fungal species Candida albicans and the bacterial species Staphylococcus aureus are responsible for a majority of hospital-acquired infections and often coinfect critically ill patients as complicating polymicrobial biofilms. To investigate biofilm structure during polymicrobial growth, dual-species biofilms were imaged with confocal scanning laser microscopy. Analyses revealed a unique biofilm architecture where S. aureus commonly associated with the hyphal elements of C. albicans. This physical interaction may provide staphylococci with an invasion strategy because candidal hyphae can penetrate through epithelial layers. To further understand the molecular mechanisms possibly responsible for previously demonstrated amplified virulence during coinfection, protein expression studies were undertaken. Differential in-gel electrophoresis identified a total of 27 proteins to be significantly differentially produced by these organisms during coculture biofilm growth. Among the upregulated staphylococcal proteins was l-lactate dehydrogenase 1, which confers resistance to host-derived oxidative stressors. Among the downregulated proteins was the global transcriptional repressor of virulence factors, CodY. These findings demonstrate that the hyphae-mediated enhanced pathogenesis of S. aureus may not only be due to physical interactions but can also be attributed to the differential regulation of specific virulence factors induced during polymicrobial growth. Further characterization of the intricate interaction between these pathogens at the molecular level is warranted, as it may aid in the design of novel therapeutic strategies aimed at combating fungal–bacterial polymicrobial infection

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