Ligand-based drug repurposing strategy identified SARS-CoV-2 RNA G-quadruplex binders

The single-stranded RNA genome of SARS-CoV-2 contains some G-quadruplex-forming G-rich elements which are putative drug targets. Here, we performed a ligand-based pharmacophore virtual screening of FDA approved drugs to find candidates targeting such RNA structures. Further in silico and in vitro assays identified three drugs as emerging SARS-CoV-2 RNA G-quadruplex binders

Polymer-based photocathodes with a solution-processable cuprous iodide anode layer and a polyethyleneimine protective coating

Organic semiconductors are proven to efficiently drive photoelectrochemical water splitting

Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation

Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in the GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging from mild hematological and visceral involvement to severe neurological disease. Neuronopathic patients display dramatic neuronal loss and increased neuroinflammation, whose molecular basis are still unclear. Using a combination of Drosophila dGBA1b loss-of-function models and GD patient-derived iPSCs differentiated towards neuronal precursors and mature neurons we showed that different GD- tissues and neuronal cells display an impairment of growth mechanisms with an increased cell death and reduced proliferation. These phenotypes are coupled with the downregulation of several Hippo transcriptional targets, mainly involved in cells and tissue growth, and YAP exclusion from nuclei. Interestingly, Hippo knock-down in the GBA-KO flies rescues the proliferative defect, suggesting that targeting the Hippo pathway can be a promising therapeutic approach to neuronopathic GD.A combination of Drosophila dGBA1b loss-of-function models and Gaucher Disease (GD) patient-derived iPSCs reveals an impairment in GD neuronal cell growth and that Hippo pathway hyperactivation contributes to the impairment

Cytosine epigenetic modifications and conformational changes in G-quadruplex DNA: An ultraviolet resonance Raman spectroscopy study

Epigenetic modifications of DNA are known to play important regulatory roles in biological systems, especially in regulation of gene expression, and are associated with many types of human diseases, including cancer. Alternative DNA secondary structures, such as G-quadruplexes, can also influence gene transcription, thus suggesting that such structures may represent a distinctive layer of epigenetic information. G-quadruplex structures and DNA epigenetic modifications often go side by side, and recent evidence reveals that cytosine modifications within loops of G-quadruplexes can play a role in modulating their stability and structural polymorphism. Therefore, the development and validation of experimental techniques that can easily and reliably analyse G-quadruplex structures are highly desirable. In the present study, we propose to exploit the advantages of UV resonance Raman (UVRR) spectroscopy to investigate cytosine epigenetic modifications along with conformational changes in G-quadruplex-forming DNA. Our findings show that clear and specific spectral changes occur when there is a change in a G-quadruplex structure. Moreover, UVRR spectral analysis can indirectly distinguish the spectral variations occurring because of modifications in the guanine glycosidic conformations, as well as detect changes in the loops induced by H-bond formation or hydration of nitrogenous bases. The results further underscore the utility of UVRR spectroscopy for G-quadruplex structure elucidation under biologically relevant solution conditions

Progressive Encephalomyelitis with Rigidity and Myoclonus Associated With Anti-GlyR Antibodies and Hodgkin’s Lymphoma: A Case Report

IntroductionA 60-year-old man presented with a 6-month history of low back pain and progressive rigidity of the trunk and lower limbs, followed by pruritus, dysphonia, hyperhydrosis, and urinary retention. Brain and spinal imaging were normal. EMG showed involuntary motor unit hyperactivity. Onconeural, antiglutamic acid decarboxylase (anti-GAD), voltage-gated potassium channel, and dipeptidyl peptidase-like protein 6 (DPPX) autoantibodies were negative. CSF was negative. Symptoms were partially responsive to baclofen, gabapentin, and clonazepam, but he eventually developed severe dysphagia. Antiglycine receptor (anti-GlyR) antibodies turned out positive on both serum and CSF. A plasmapheresis cycle was completed with good clinical response. A PET scan highlighted an isolated metabolically active axillary lymphnode that turned out to be a classic type Hodgkin lymphoma (HL), in the absence of bone marrow infiltration nor B symptoms. Polychemotherapy with ABVD protocol was completed with good clinical response and at 1-year follow-up the neurological examination is normal.BackgroundProgressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare and severe neurological syndrome characterized by muscular rigidity and spasms as well as brain stem and autonomic dysfunction. It can be associated with anti-GAD, GlyR, and DPPX antibodies. All of these autoantibodies may be variably associated with malignant tumors and their response to immunotherapy, as well as to tumor removal, is not easily predictable.ConclusionProgressive encephalomyelitis with rigidity and myoclonus has already been described in association with HL, but this is the first case report of a HL manifesting as anti-GlyR antibodies related PERM. Our report highlights the importance of malignancy screening in autoimmune syndromes of suspected paraneoplastic origin

Conformational plasticity of DNA secondary structures: probing the conversion between i-motif and hairpin species by circular dichroism and ultraviolet resonance Raman spectroscopies

The promoter regions of important oncogenes such as BCL2 and KRAS contain GC-rich sequences that can form distinctive noncanonical DNA structures involved in the regulation of transcription: G-quadruplexes on the G-rich strand and i-motifs on the C-rich strand. Interestingly, BCL2 and KRAS promoter i-motifs are highly dynamic in nature and exist in a pH-dependent equilibrium with hairpin and even with hybrid i-motif/hairpin species. Herein, the effect of pH and presence of cell-mimicking molecular crowding conditions on conformational equilibria of the BCL2 and KRAS i-motif-forming sequences were investigated by ultraviolet resonance Raman (UVRR) and circular dichroism (CD) spectroscopies. Multivariate analysis of CD data was essential to model the presence and identity of the species involved. Analysis of UVRR spectra measured as a function of pH, performed also by the two-dimensional correlation spectroscopy (2D-COS) technique, showed the role of several functional groups in the DNA conformational transitions, and provided structural and dynamic information. Thus, the UVRR investigation of intramolecular interactions and of local and environmental dynamics in promoting the different species induced by the solution conditions provided valuable insights into i-motif conformational transitions. The combined use of the two spectroscopic tools is emphasized by the relevant possibility to work in the same DNA concentration range and by the heterospectral UVRR/CD 2D-COS analysis. The results of this study shed light on the factors that can influence at molecular level the equilibrium between the different conformational species putatively involved in the oncogene expression

Thermal properties of iopamidol: Crystalline anhydrous, hydrated and amorphous forms

Three crystal forms of iopamidol, an iodinated contrast media used in radiology, have been so far elucidated: an anhydrous, a monohydrate and a pentahydrate form (labeled hereafter as W0, W1 and W5, respectively), which showed the occurrence of different conformations, atropisomeric in nature. Specifically, the anhydrous and monohydrate forms contain iopamidol with a \ue2\u80\u9csyn\ue2\u80\u9d conformation of the two symmetric sidearms, while an \ue2\u80\u9canti\ue2\u80\u9d conformation was found in the pentahydrate, making it a conformational (pseudo)-polymorph of the first two. The three crystal forms have been here investigated by means of DSC, variable temperature X-ray powder diffraction and Raman spectroscopy. This study enabled us to highlight the thermal-induced transformations, leading to the discovery of new crystal forms, for a total of four hydrated and four distinct anhydrous phases. In particular, the DSC curve of W0 revealed only a reversible solid\ue2\u80\u93solid transition at around 180 \uc2\ub0C before melting, with subsequent degradation above 300 \uc2\ub0C. W1, after the loss of lattice water around 100 \uc2\ub0C, shows a characteristic split peak at about 250 \uc2\ub0C, which is attributed to melting. Below 150 \uc2\ub0C, powder diffraction of W1 suffers of minor changes, with a smooth variation of the lattice parameters, in agreement with a progressive loss of water in a reversible event, monitored also by DSC. At variance, W5 evidenced an irreversible loss of water in three distinct steps, for three, one and one H2O molecules each, respectively; subsequent transitions occur at 140 and 180 \uc2\ub0C, before melting at 240 \uc2\ub0C. Three clearly visible transformations were also detected by variable temperature powder diffraction measurements, where the loss of three molecules of water in a single step, generating a bis-hydrated species (W2), is followed by a second dehydration process leading, above 75 \uc2\ub0C, to a new monohydrate phase W1\ue2\u80\ub2, different from the known W1 form. The Raman spectra of the three crystal forms, measured upon heating up to 160 \uc2\ub0C, evidenced changes in spectral regions of amides that, according to our simulations of the vibrational properties, can be attributed to changes of the hydration properties and, more significantly, in terms of the \ue2\u80\u9csyn\ue2\u80\u9d and \ue2\u80\u9canti\ue2\u80\u9d conformations

Crowding and conformation interplay on human DNA G-quadruplex by ultraviolet resonant Raman scattering

The G-quadruplex-forming telomeric sequence (TTAGGG)4TT was investigated by polarized Ultraviolet Resonance Raman Scattering (UVRR) at 266 nm. The presence of 40% poly(ethylene glycol) and the so-called \u2018\u2018self-crowding\u2019\u2019 condition were used to induce the hybrid-to-parallel topology transition. Analysis of frequency shifts with temperature showed the role of several functional groups in the topological transitions and provides structural dynamical information. Circular dichroism under similar conditions was used as a reference. UVRR shed light on the effect of intramolecular interactions and of local and environmental dynamics in promoting different G-quadruplex topologies, induced by solution conditions or by temperature changes. Overall, these findings showed the enormous potential of this spectroscopy for G-quadruplex conformational studies

TiO2 Nanotubes: Interdependence of Substrate Grain Orientation and Growth Rate

International audienceHighly ordered arrays of TiO2 nanotubes can be produced by self-organized anodic growth. It is desirable to identify key parameters playing a role in the maximization of the surface area, growth rate, and nanotube lengths. In this work, the role of the crystallographic orientation of the underlying Ti substrate on the growth rate of anodic self-organized TiO2 nanotubes in viscous organic electrolytes in the presence of small amounts of fluorides is studied. A systematic analysis of cross sections of the nanotubular oxide films on differently oriented substrate grains was conducted by a combination of electron backscatter diffraction and scanning electron microscopy. The characterization allows for a correlation between TiO2 nanotube lengths and diameters and crystallographic parameters of the underlying Ti metal substrate, such as planar surface densities. It is found that the growth rate of TiO2 nanotubes gradually increases with the decreasing planar atomic density of the titanium substrate. Anodic TiO2 nanotubes with the highest aspect ratio form on Ti(-151) [which is close to Ti(010)], whereas nanotube formation is completely inhibited on Ti(001). In the thin compact oxide on Ti(001), the electron donor concentration and electronic conductivity are higher, which leads to a competition between oxide growth and other electrochemical oxidation reactions, such as the oxygen evolution reaction, upon anodic polarization. At grain boundaries between oxide films on Ti(hk0), where nanotubes grow, and Ti(001), where thin compact oxide films are formed, the length of nanotubes decreases most likely because of lateral electron migration from TiO2 on Ti(001) to TiO2 on Ti(hk0)