A structural modeling approach for the understanding of initiation and elongation of ALS-linked superoxide dismutase fibrils

Familial amyotrophic lateral sclerosis caused by mutations in copper-zinc superoxide dismutase (SOD1) is characterized by the presence of SOD1-rich inclusions in spinal cords. It has been shown that a reduced intra-subunit disulfide bridge apo-SOD1 can rapidly initiate fibrillation forming an inter-subunits disulfide under mild, physiologically accessible conditions. Once initiated, elongation can proceed via recruitment of either apo or partially metallated disulfide-intact SOD1 and the presence of copper, but not zinc, ions inhibit fibrillation. We propose a structural model, refined through molecular dynamics simulations, that, taking into account these experimental findings, provides a molecular explanation for the initiation and the elongation of SOD1 fibrils in physiological conditions. The model indicates the occurrence of a new dimeric unit, prone to interact one with the other due to the presence of a wide hydrophobic surface and specific electrostatic interactions. The model has dimensions consistent with the SOD1 fibril size observed through electron microscopy and provides a structural basis for the understanding of SOD1 fibrillation

Natural compounds as therapeutic agents: The case of human topoisomerase ib

Natural products are widely used as source for drugs development. An interesting example is represented by natural drugs developed against human topoisomerase IB, a ubiquitous enzyme involved in many cellular processes where several topological problems occur due the formation of supercoiled DNA. Human topoisomerase IB, involved in the solution of such problems relaxing the DNA cleaving and religating a single DNA strand, represents an important target in anticancer therapy. Several natural compounds inhibiting or poisoning this enzyme are under investigation as possible new drugs. This review summarizes the natural products that target human topoisomerase IB that may be used as the lead compounds to develop new anticancer drugs. Moreover, the natural compounds and their derivatives that are in clinical trial are also commented on

Localized prostate cancer genotyping: Another step towards personalized therapy

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Recent advances in searching c-Myc transcriptional cofactors during tumorigenesis

Background: The mechanism by which c-Myc exerts its oncogenic functions is not completely clear and different hypotheses are still under investigation. The knowledge of the capacity of c-Myc to bind exclusively E-box sequences determined the discrepancy between, on the one hand, genomic studies showing the binding of c-Myc to all active promoters and, on the other hand, the evidence that only 60% or less of the binding sites have E-box sequences. Main body: In this review, we provide support to the hypothesis that the cooperation of c-Myc with transcriptional cofactors mediates c-Myc-induced cellular functions. We produce evidence that recently identified cofactors are involved in c-Myc control of survival mechanisms of cancer cells. Conclusion: The identification of new c-Myc cofactors could favor the development of therapeutic strategies able to compensate the difficulty of targeting c-Myc

Searching for Primordial Black Holes with the Einstein Telescope: impact of design and systematics

Primordial Black Holes (PBHs) have recently attracted much attention as they may explain some of the LIGO/Virgo/KAGRA observations and significantly contribute to the dark matter in our universe. The next generation of Gravitational Wave (GW) detectors will have the unique opportunity to set stringent bounds on this putative population of objects. Focusing on the Einstein Telescope (ET), in this paper we analyse in detail the impact of systematics and different detector designs on our future capability of observing key quantities that would allow us to discover and/or constrain a population of PBH mergers. We also perform a population analysis, with a mass and redshift distribution compatible with the current observational bounds. Our results indicate that ET alone can reach an exquisite level of accuracy on the key observables considered, as well as detect up to tens of thousands of PBH binaries per year, but for some key signatures (in particular high--redshift sources) the cryogenic instrument optimised for low frequencies turns out to be crucial, both for the number of observations and the error on the parameters reconstruction. As far as the detector geometry is concerned, we find that a network consisting of two separated L--shaped interferometers of 15 (20)~km arm length, oriented at $45^{\circ}$ with respect to each other performs better than a single triangular shaped instrument of 10 (15)~km arm length, for all the metrics considered.Comment: 24 pages, 13 figure

Profile and potential bioactivity of the miRNome and metabolome expressed in Malva sylvestris L. leaf and flower

Malva sylvestris L. (common mallow) is a plant species widely used in phytotherapy and ethnobotanical practices since time immemorial. Characterizing the components of this herb might promote a better comprehension of its biological effects on the human body but also favour the identification of the molecular processes that occur in the plant tissues. Thus, in the present contribution, the scientific knowledge about the metabolomic profile of the common mallow was expanded. In particular, the phytocomplex of leaves and flowers from this botanical species and the extraction capacity of different concentrations of ethanol (i.e., 95%, 70%, 50%, and 0%; v/v in ddH2O) for it were investigated by spectrophotometric and chromatographic approaches. In detail, 95% ethanol extracts showed the worst capacity in isolating total phenols and flavonoids, while all the hydroalcoholic samples revealed a specific ability in purifying the anthocyanins. HPLC–DAD system detected and quantified 20 phenolic secondary metabolites, whose concentration in the several extracts depended on their own chemical nature and the percentage of ethanol used in the preparation. In addition, the stability of the purified phytochemicals after resuspension in pure ddH2O was also proved, considering a potential employment of them in biological/medical studies which include in vitro and in vivo experiments on mammalian models. Here, for the first time, the expressed miRNome in M. sylvestris was also defined by Next Generation Sequencing, revealing the presence of 33 microRNAs (miRNAs), 10 typical for leaves and 2 for flowers. Then, both plant and human putative mRNA targets for the detected miRNAs were predicted by bioinformatics analyses, with the aim to clarify the possible role of these small nucleic acids in the common mallow plant tissues and to try to understand if they could exert a potential cross-kingdom regulatory activity on the human health. Surprisingly, our investigations revealed that 19 miRNAs out of 33 were putatively able to modulate, in the plant cells, the expression of various chromosome scaffold proteins. In parallel, we found, in the human transcriptome, a total of 383 mRNAs involved in 5 fundamental mammalian cellular processes (i.e., apoptosis, senescence, cell-cycle, oxidative stress, and invasiveness) that theoretically could be bound and regulated by M. sylvestris miRNAs. The evidence collected in this work would suggest that the beneficial properties of the use of M. sylvestris, documented by the folk medicine, are probably linked to their content of miRNAs and not only to the action of phytochemicals (e.g., anthocyanins). This would open new perspectives about the possibility to develop gene therapies based on miRNAs isolated from medicinal plants, including M. sylvestris

False-negative RT-PCR in SARS-CoV-2 disease: experience from an Italian COVID-19 unit

False-negative cases of COVID19 are being increasingly reported. Laboratory diagnosis through RT-PCR testing alone lacks adequate sensitivity to be recommended as the only valid criterion to confirm COVID-19 diagnosis

3-T MRI and clinical validation of ultrasound-guided transperineal laser ablation of benign prostatic hyperplasia

Background: Transperineal laser ablation (TPLA) of the prostate is a novel, mini-invasive option for men with lower urinary tract symptoms (LUTS) due to benign prostate hyperplasia (BPH). Our aim was to assess the impact of ultrasound-guided TPLA regarding urodynamic improvement and sexual function, monitoring clinical data, postprocedural complications and imaging findings at 3-T multiparametric magnetic resonance imaging. Methods: Forty-four patients aged ≥ 50 affected with moderate to severe LUTS (International Prostate Symptoms score ≥ 12) due to benign prostatic obstruction and refractoriness, intolerance or poor compliance to medical therapies underwent US-guided TPLA between May 2018 and February 2020. Clinical measurements included PSA, uroflowmetry, sexual function assessment (using the International Index of Erectile Function and Male Sexual Health Questionnaire-Ejaculatory Dysfunction short form) and quality of life questionnaire. Adverse events were evaluated using the Clavien-Dindo scale. Volume changes were measured by MRI and automatic segmentation software during 1-year follow-up. Registration: NCT04044573 – May 5th, 2018, https://www.clinicaltrials.gov Results: MRI assessed the changes over time with a 53% mean reduction of adenoma volume and 71% of the ablated area, associated with clinical and functional improvement and resolution of LUTS in all cases. Five of 44 patients (11.3%) had urinary blockage due to clots and required re-catheterisation for 2 weeks. The overall adverse event rate was 7%. Conclusion: US-guided TPLA performed as a safe, manageable and effective treatment for LUTS. It could be considered an alternative effective mini-invasive procedure to standard treatments for BPH in the outpatient setting