The vision of multivalency as a strategy limited to achieve affinity enhancements between a protein receptor and its putative sugar ligand (glycotope) has proven too simplistic. On the one hand, ...binding of a glycotope in a dense glycocalix‐like construct to a lectin partner has been shown to be sensitive to the presence of a third sugar entity (heterocluster effect). On the other hand, several carbohydrate processing enzymes (glycosidases and glycosyltransferases) have been found to be also responsive to multivalent presentations of binding partners (multivalent enzyme inhibition), a phenomenon first discovered for iminosugar‐type inhibitory species (inhitopes) and recently demonstrated for multivalent carbohydrate constructs. By assessing a series of homo‐ and heteroclusters combining α‐d‐glucopyranosyl‐related glycotopes and inhitopes, it was shown that multivalency and heteromultivalency govern both kinds of events, allowing for activation, deactivation or enhancement of specific recognition phenomena towards a spectrum of lectin and glycosidase partners in a multimodal manner. This unified scenario originates from the ability of (hetero)multivalent architectures to trigger glycosidase binding modes that are reminiscent of those harnessed by lectins, which should be considered when profiling the biological activity of multivalent architectures.
Different selectivity patterns towards enzymes and lectins can be elicited by (hetero)multivalent displays of sugar and glycomimetic motifs. The binding modes at play reveal analogies between the (hetero)cluster effect and (hetero)multivalent enzyme inhibition that underline the need of a reformulation of the multivalent effect.
Summary
Background
Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer‐prone genodermatoses whose causal ...genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders.
Objectives
To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC.
Methods
We conducted RNA‐Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies.
Results
Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in situ analyses validated the RNA‐Seq data. In addition, enzyme‐linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB.
Conclusions
Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury‐sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS.
What's already known about this topic?
Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three genodermatoses with high predisposition to cancer development.
Although their causal genetic mutations mainly affect epithelia, the dermal microenvironment likely contributes to the physiopathology of these disorders.
What does this study add?
We disclose a large overlapping transcription profile between XPC, KS and RDEB fibroblasts that points towards an activated phenotype with high matrix‐synthetic capacity.
This common signature seems to be independent of the primary causal deficiency, but reflects an underlying derangement of the extracellular matrix via transforming growth factor‐β signalling activation and oxidative state imbalance.
What is the translational message?
This study broadens the current knowledge about the pathology of these diseases and highlights new targets and biomarkers for effective therapeutic intervention.
It is suggested that high levels of circulating periostin could represent a potential biomarker in RDEB.
Linked Comment: Has. Br J Dermatol 2019; 181:440–441.
Plain language summary available online
Abstract
We present a detailed prompt emission and early optical afterglow analysis of the two very-high-energy (VHE) detected bursts GRB 201015A and GRB 201216C, and their comparison with a subset ...of similar bursts. Time-resolved spectral analysis of multistructured GRB 201216C using the Bayesian binning algorithm revealed that during the entire duration of the burst, the low-energy spectral index (
α
pt
) remained below the limit of the synchrotron line of death. However, statistically some of the bins supported the additional thermal component. Additionally, the evolution of spectral parameters showed that both the peak energy (
E
p
) and
α
pt
tracked the flux. These results were further strengthened using the values of the physical parameters obtained by synchrotron modeling of the data. Our earliest optical observations of both bursts using the F/Photometric Robotic Atmospheric Monitor Observatorio del Roque de los Muchachos and Burst Observer and Optical Transient Exploring System robotic telescopes displayed a smooth bump in their early optical light curves, consistent with the onset of the afterglow due to synchrotron emission from an external forward shock. Using the observed optical peak, we constrained the initial bulk Lorentz factors of GRB 201015A and GRB 201216C to Γ
0
= 204 and Γ
0
= 310, respectively. The present early optical observations are the earliest known observations constraining outflow parameters and our analysis indicate that VHE detected bursts could have a diverse range of observed luminosity within the detectable redshift range of present VHE facilities.
Several active galactic nuclei show correlated variations in the UV/optical range, with time delays increasing at longer wavelengths. Thermal reprocessing of the X-rays illuminating the accretion ...disk has been proposed as a viable explanation. In this scenario, the variable X-ray flux irradiating the accretion disk is partially reflected in X-rays and partially absorbed, thermalized, and reemitted with some delay by the accretion disk at longer wavelengths. We investigate this scenario assuming an X-ray pointlike source illuminating a standard Novikov-Thorne accretion disk around a rotating black hole. We consider all special and general relativistic effects to determine the incident X-ray flux on the disk and in propagating light from the source to the disk and to the observer. We also compute the disk reflection flux, taking into consideration the disk ionization. We investigate the dependence of the disk response function and time lags on various physical parameters, such as the black hole mass and spin; X-ray corona height, luminosity, and photon index; accretion rate; inclination; and inner/outer disk radii. We find it is important to consider relativistic effects and the disk ionization in estimating the disk response. We also find a strong nonlinearity between the X-ray luminosity and the disk response. We present an analytic function for the time-lag dependence on wavelength, which can be used to fit observed time-lag spectra. We also estimate the fraction of the reverberation signal with respect to the total flux, and we suggest possible explanations for the lack of X-ray-UV/optical correlated variations in a few sources.
Aims.
Gamma-ray burst (GRB) 190829A (
z
= 0.0785) was detected by
Fermi
and
Swift
and also at very high energy (VHE) by the High-Energy Stereoscopic System (H.E.S.S.) telescopes. The prompt emission ...displayed two emission episodes separated by a quiescent gap of ∼40 s. We present the 10.4 m Gran Telescopio Canarias (GTC) observations of the afterglow of GRB 190829A and its underlying supernova. We also compare GRB 190829A to GRB 180728A, a GRB with similar behaviour, and discuss the implications on underlying physical mechanisms producing these two GRBs.
Methods.
We present multi-band photometric data along with spectroscopic follow-up observations taken with the 10.4 m GTC telescope. Together with the data from the prompt emission, the 10.4 m GTC data are used to understand the emission mechanisms and possible progenitor.
Results.
A detailed analysis of the multi-band observations of the afterglow requires the cooling frequency to pass between the optical and X-ray bands at early epochs. The afterglow then transitions to the underlying supernova (SN) 2019oyw, which dominates later on.
Conclusions.
Although the prompt emission temporal properties of GRB 190829A and GRB 180728A are similar, the two pulses are different in the spectral domain. We find that SN 2019oyw associated with GRB 190829A is powered by Ni decay and is a Type Ic-BL SN. The spectroscopic and photometric properties of this SN are consistent with those observed for SN 1998bw, but evolved earlier.
We apply a reflection-based model to the best available XMM–Newton spectra of X-ray bright ultraluminous X-ray sources (NGC 1313 X–1, NGC 1313 X–2, M 81 X–6, Holmberg IX X–1, NGC 5408 X–1 and ...Holmberg II X–1). A spectral drop is apparent in the data of all the sources at energies 6–7 keV. The drop is interpreted here in terms of relativistically blurred ionized reflection from the accretion disc. A soft excess is also detected from these sources as usually found in the spectra of active galactic nuclei (AGN), with emission from O K and Fe L, in the case of NGC 5408 X–1 and Holmberg II X–1, which can be understood as features arising from reflection of the disc. Remarkably, ionized disc reflection and the associated power-law continuum provide a good description of the broad-band spectrum, including the soft excess. There is no requirement for thermal emission from the inner disc in the description of the spectra. The black holes of these systems must then be highly spinning, with a spin close to the maximum rate of a maximal spinning black hole. The results require the action of strong light bending in these sources. We suggest that they could be strongly accreting black holes in which most of the energy is extracted from the flow magnetically and released above the disc thereby avoiding the conventional Eddington limit.
This consensus statement revises and updates the recommendations for biomarkers use in the diagnosis and treatment of breast cancer, and is a joint initiative of the Spanish Society of Medical ...Oncology and the Spanish Society of Pathology. This expert group recommends determining in all cases of breast cancer the histologic grade and the alpha-estrogen receptor (ER), progesterone receptor, Ki-67 and HER2 status, in order to assist prognosis and establish therapeutic options, including hormone therapy, chemotherapy and anti-HER2 therapy. One of the four available genetic prognostic platforms (MammaPrint
®
, Oncotype DX
®
, Prosigna
®
or EndoPredict
®
) may be used in node-negative ER-positive patients to establish a prognostic category and decide with the patient whether adjuvant treatment may be limited to hormonal therapy. Newer technologies including next-generation sequencing, liquid biopsy, tumour-infiltrating lymphocytes or PD-1 determination are at this point investigational.
Background and Purpose
Lymphangiogenesis is an important biological process associated with the pathogenesis of several diseases, including metastatic dissemination, graft rejection, lymphoedema and ...other inflammatory disorders. The development of new drugs that block lymphangiogenesis has become a promising therapeutic strategy. In this study, we investigated the ability of toluquinol, a 2‐methyl‐hydroquinone isolated from the culture broth of the marine fungus Penicillium sp. HL‐85‐ALS5‐R004, to inhibit lymphangiogenesis in vitro, ex vivo and in vivo.
Experimental Approach
We used human lymphatic endothelial cells (LECs) to analyse the effect of toluquinol in 2D and 3D in vitro cultures and in the ex vivo mouse lymphatic ring assay. For in vivo approaches, the transgenic Fli1:eGFPy1 zebrafish, mouse ear sponges and cornea models were used. Western blotting and apoptosis analyses were carried out to search for drug targets.
Key Results
Toluquinol inhibited LEC proliferation, migration, tubulogenesis and sprouting of new lymphatic vessels. Furthermore, toluquinol induced apoptosis of LECs after 14 h of treatment in vitro, blocked the development of the thoracic duct in zebrafish and reduced the VEGF‐C‐induced lymphatic vessel formation and corneal neovascularization in mice. Mechanistically, we demonstrated that this drug attenuates VEGF‐C‐induced VEGFR‐3 phosphorylation in a dose‐dependent manner and suppresses the phosphorylation of Akt and ERK1/2.
Conclusions and Implications
Based on these findings, we propose toluquinol as a new candidate with pharmacological potential for the treatment of lymphangiogenesis‐related pathologies. Notably, its ability to suppress corneal neovascularization paves the way for applications in vascular ocular pathologies.
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