The SLIT-ROBO pathway: a regulator of cell function with implications for the reproductive system

The secreted SLIT glycoproteins and their Roundabout (ROBO) receptors were originally identified as important axon guidance molecules. They function as a repulsive cue with an evolutionarily conserved role in preventing axons from migrating to inappropriate locations during the assembly of the nervous system. In addition the SLIT-ROBO interaction is involved in the regulation of cell migration, cell death and angiogenesis and, as such, has a pivotal role during the development of other tissues such as the lung, kidney, liver and breast. The cellular functions that the SLIT/ROBO pathway controls during tissue morphogenesis are processes that are dysregulated during cancer development. Therefore inactivation of certain SLITs and ROBOs is associated with advanced tumour formation and progression in disparate tissues. Recent research has indicated that the SLIT/ROBO pathway could also have important functions in the reproductive system. The fetal ovary expresses most members of the SLIT and ROBO families. The SLITs and ROBOs also appear to be regulated by steroid hormones and regulate physiological cell functions in adult reproductive tissues such as the ovary and endometrium. Furthermore several SLITs and ROBOs are aberrantly expressed during the development of ovarian, endometrial, cervical and prostate cancer. This review will examine the roles this pathway could have in the development, physiology and pathology of the reproductive system and highlight areas for future research that could further dissect the influence of the SLIT/ROBO pathway in reproduction

Bond operator theory of doped antiferromagnets: from Mott insulators with bond-centered charge order, to superconductors with nodal fermions

The ground states and excitations of two-dimensional insulating and doped Mott insulators are described by a bond operator formalism. While the method represents the degrees of freedom of an arbitrary antiferromagnet exactly, it is especially suited to systems in which there is a natural pairing of sites into bonds, as in states with spontaneous or explicit spin-Peierls order (or bond-centered charge order). In the undoped insulator, as discussed previously, we obtain both paramagnetic and magnetically-ordered states. We describe the evolution of superconducting order in the ground state with increasing doping--at low doping, the superconductivity is weak, can co-exist with magnetic order, and there are no gapless spin 1/2 fermionic excitations; at high doping, the magnetic order is absent and we obtain a BCS d-wave superconductor with gapless spin 1/2, nodal fermions. We present the critical theory describing the onset of these nodal fermionic excitations. We discuss the evolution of the spin spectrum, and obtain regimes where a spin 1 exciton contributes a sharp resonance in the dynamic spin susceptiblity. We also discuss the experimental consequences of low-energy, dynamically fluctuating, spin-Peierls order in an isotropic CuO_2 plane--we compute consequences for the damping and dispersion of an optical phonon involving primarily the O ions, and compare the results with recent neutron scattering measurements of phonon spectra.Comment: 16 pages + 14 pages of appendices, 18 figures; (v3) expanded discussion of theory and experimental implications; (v4) Removed some introductory review discussion and moved it to cond-mat/010823

Current challenges in software solutions for mass spectrometry-based quantitative proteomics

This work was in part supported by the PRIME-XS project, grant agreement number 262067, funded by the European Union seventh Framework Programme; The Netherlands Proteomics Centre, embedded in The Netherlands Genomics Initiative; The Netherlands Bioinformatics Centre; and the Centre for Biomedical Genetics (to S.C., B.B. and A.J.R.H); by NIH grants NCRR RR001614 and RR019934 (to the UCSF Mass Spectrometry Facility, director: A.L. Burlingame, P.B.); and by grants from the MRC, CR-UK, BBSRC and Barts and the London Charity (to P.C.

A chemical biology toolbox to study protein methyltransferases and epigenetic signaling

© 2019, The Author(s). Protein methyltransferases (PMTs) comprise a major class of epigenetic regulatory enzymes with therapeutic relevance. Here we present a collection of chemical probes and associated reagents and data to elucidate the function of human and murine PMTs in cellular studies. Our collection provides inhibitors and antagonists that together modulate most of the key regulatory methylation marks on histones H3 and H4, providing an important resource for modulating cellular epigenomes. We describe a comprehensive and comparative characterization of the probe collection with respect to their potency, selectivity, and mode of inhibition. We demonstrate the utility of this collection in CD4 + T cell differentiation assays revealing the potential of individual probes to alter multiple T cell subpopulations which may have implications for T cell-mediated processes such as inflammation and immuno-oncology. In particular, we demonstrate a role for DOT1L in limiting Th1 cell differentiation and maintaining lineage integrity. This chemical probe collection and associated data form a resource for the study of methylation-mediated signaling in epigenetics, inflammation and beyond

The sub-arcsecond dusty environment of Eta Carinae

The core of the nebula surrounding Eta Carinae has been observed with the VLT Adaptive Optics system NACO and with the interferometer VLTI/MIDI to constrain spatially and spectrally the warm dusty environment and the central object. In particular, narrow-band images at 3.74 and 4.05 micron reveal the butterfly shaped dusty environment close to the central star with unprecedented spatial resolution. A void whose radius corresponds to the expected sublimation radius has been discovered around the central source. Fringes have been obtained in the Mid-IR which reveal a correlated flux of about 100Jy situated 0.3" south-east of the photocenter of the nebula at 8.7 micron, which corresponds with the location of the star as seen in other wavelengths. This correlated flux is partly attributed to the central object, and these observations provide an upper limit for the SED of the central source from 2.2 to 13.5 micron. Moreover, we have been able to spectrally disperse the signal from the nebula itself at PA=318 degree, i.e. in the direction of the bipolar nebula 310 degree) within the MIDI field of view of 3". A large amount of corundum (Al2O3) is discovered, peaking at 0.6-1.2" south-east from the star, whereas the dust content of the Weigelt blobs is dominated b silicates. We discuss the mechanisms of dust formation which are closely related to the geometry of this Butterfly nebulae

Formation of Interstellar Clouds: Parker Instability with Phase Transitions

We follow numerically the nonlinear evolution of the Parker instability in the presence of phase transitions from a warm to a cold HI interstellar medium in two spatial dimensions. The nonlinear evolution of the system favors modes that allow the magnetic field lines to cross the galactic plane. Cold HI clouds form with typical masses ~= 10^5 M_sun, mean densities ~= 20 cm^-3, mean magnetic field strengths ~= 4.3 muG (rms field strengths ~= 6.4 muG), mass-to-flux ratios ~= 0.1 - 0.3 relative to critical, temperatures ~= 50 K, (two-dimensional) turbulent velocity dispersions ~= 1.6 km s^-1, and separations ~= 500 pc, in agreement with observations. The maximum density and magnetic field strength are ~= 10^3 cm^-3 and ~= 20 muG, respectively. Approximately 60% of all HI mass is in the warm neutral medium. The cold neutral medium is arranged into sheet-like structures both perpendicular and parallel to the galactic plane, but it is also found almost everywhere in the galactic plane, with the density being highest in valleys of the magnetic field lines. `Cloudlets' also form whose physical properties are in quantitative agreement with those observed for such objects by Heiles (1967). The nonlinear phase of the evolution takes ~< 30 Myr, so that, if the instability is triggered by a nonlinear perturbation such as a spiral density shock wave, interstellar clouds can form within a time suggested by observations.Comment: 11 pages, 7 figures, accepted for publication in MNRAS; high-resolution color figures may be found at https://netfiles.uiuc.edu/mkunz/MKC08

VLDL Hydrolysis by Hepatic Lipase Regulates PPARδ Transcriptional Responses

PPARs (α,γ,δ) are a family of ligand-activated transcription factors that regulate energy balance, including lipid metabolism. Despite these critical functions, the integration between specific pathways of lipid metabolism and distinct PPAR responses remains obscure. Previous work has revealed that lipolytic pathways can activate PPARs. Whether hepatic lipase (HL), an enzyme that regulates VLDL and HDL catabolism, participates in PPAR responses is unknown.Using PPAR ligand binding domain transactivation assays, we found that HL interacted with triglyceride-rich VLDL (>HDL≫LDL, IDL) to activate PPARδ preferentially over PPARα or PPARγ, an effect dependent on HL catalytic activity. In cell free ligand displacement assays, VLDL hydrolysis by HL activated PPARδ in a VLDL-concentration dependent manner. Extended further, VLDL stimulation of HL-expressing HUVECs and FAO hepatoma cells increased mRNA expression of canonical PPARδ target genes, including adipocyte differentiation related protein (ADRP), angiopoietin like protein 4 and pyruvate dehydrogenase kinase-4. HL/VLDL regulated ADRP through a PPRE in the promoter region of this gene. In vivo, adenoviral-mediated hepatic HL expression in C57BL/6 mice increased hepatic ADRP mRNA levels by 30%. In ob/ob mice, a model with higher triglycerides than C57BL/6 mice, HL overexpression increased ADRP expression by 70%, demonstrating the importance of triglyceride substrate for HL-mediated PPARδ activation. Global metabolite profiling identified HL/VLDL released fatty acids including oleic acid and palmitoleic acid that were capable of recapitulating PPARδ activation and ADRP gene regulation in vitro.These data define a novel pathway involving HL hydrolysis of VLDL that activates PPARδ through generation of specific monounsaturated fatty acids. These data also demonstrate how integrating cell biology with metabolomic approaches provides insight into specific lipid mediators and pathways of lipid metabolism that regulate transcription

Effects of low-magnitude, high-frequency mechanical stimulation in the rat osteopenia model

In this study, short-term, whole-body vertical vibration at 90 Hz improved trabecular bone quality. There was an improvement of bone quality and density in both osteoporotic and control rats. This treatment may therefore be an attractive option for the treatment of osteoporosis. Aside from pharmacological treatment options, physical exercise is known to augment bone mass. In this study, the effects of whole-body vertical vibration (WBVV) on bone quality and density were evaluated using an osteoporotic rat model. Sixty female Sprague Dawley rats were ovariectomized (C) or sham (SHAM) operated at the age of 3 months. After 3 months, both groups were divided into two subgroups that received either WBVV at 90 Hz for 35 days or no treatment. After sacrificing the rats, we evaluated vertebral bone strength, histomorphometric parameters, and bone mineral density (BMD). Treatment with WBVV resulted in improved biomechanical properties. The yield load after WBVV was significantly enhanced. According to yield load and Young's modulus, the treated OVX rats reached the level of the untreated SHAM animals. In all measured histomorphometric parameters, WBVV significantly improved bone density. Treatment with WBVV demonstrated greater effects on the trabecular bone compared to the cortical bone. The ash-BMD index showed significant differences between treated and untreated rats. Using WBVV as a non-pharmacological supportive treatment option for osteoporosis demonstrated an enhancement of bone strength and bone mass. This procedure may be an attractive option for the treatment of osteoporosis

A Novel Peptide Enhances Therapeutic Efficacy of Liposomal Anti-Cancer Drugs in Mice Models of Human Lung Cancer

Lung cancer is the leading cause of cancer-related mortality worldwide. The lack of tumor specificity remains a major drawback for effective chemotherapies and results in dose-limiting toxicities. However, a ligand-mediated drug delivery system should be able to render chemotherapy more specific to tumor cells and less toxic to normal tissues. In this study, we isolated a novel peptide ligand from a phage-displayed peptide library that bound to non-small cell lung cancer (NSCLC) cell lines. The targeting phage bound to several NSCLC cell lines but not to normal cells. Both the targeting phage and the synthetic peptide recognized the surgical specimens of NSCLC with a positive rate of 75% (27 of 36 specimens). In severe combined immunodeficiency (SCID) mice bearing NSCLC xenografts, the targeting phage specifically bound to tumor masses. The tumor homing ability of the targeting phage was inhibited by the cognate synthetic peptide, but not by a control or a WTY-mutated peptide. When the targeting peptide was coupled to liposomes carrying doxorubicin or vinorelbine, the therapeutic index of the chemotherapeutic agents and the survival rates of mice with human lung cancer xenografts markedly increased. Furthermore, the targeting liposomes increased drug accumulation in tumor tissues by 5.7-fold compared with free drugs and enhanced cancer cell apoptosis resulting from a higher concentration of bioavailable doxorubicin. The current study suggests that this tumor-specific peptide may be used to create chemotherapies specifically targeting tumor cells in the treatment of NSCLC and to design targeted gene transfer vectors or it may be used one in the diagnosis of this malignancy