217 research outputs found

    Computational investigations of polymerase enzymes: Structure, function, inhibition, and biotechnology

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    AbstractDNA and RNA polymerases (Pols) are central to life, health, and biotechnology because they allow the flow of genetic information in biological systems. Importantly, Pol function and (de)regulation are linked to human diseases, notably cancer (DNA Pols) and viral infections (RNA Pols) such as COVID‐19. In addition, Pols are used in various applications such as synthesis of artificial genetic polymers and DNA amplification in molecular biology, medicine, and forensic analysis. Because of all of this, the field of Pols is an intense research area, in which computational studies contribute to elucidating experimentally inaccessible atomistic details of Pol function. In detail, Pols catalyze the replication, transcription, and repair of nucleic acids through the addition, via a nucleotidyl transfer reaction, of a nucleotide to the 3′‐end of the growing nucleic acid strand. Here, we analyze how computational methods, including force‐field‐based molecular dynamics, quantum mechanics/molecular mechanics, and free energy simulations, have advanced our understanding of Pols. We examine the complex interaction of chemical and physical events during Pol catalysis, like metal‐aided enzymatic reactions for nucleotide addition and large conformational rearrangements for substrate selection and binding. We also discuss the role of computational approaches in understanding the origin of Pol fidelity—the ability of Pols to incorporate the correct nucleotide that forms a Watson–Crick base pair with the base of the template nucleic acid strand. Finally, we explore how computations can accelerate the discovery of Pol‐targeting drugs and engineering of artificial Pols for synthetic and biotechnological applications.This article is categorized under: Structure and Mechanism > Reaction Mechanisms and Catalysis Structure and Mechanism > Computational Biochemistry and Biophysics Software > Molecular Modelin

    Perinatal mental health around the world: priorities for research and service development in Italy

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    In Italy, most studies on perinatal mental health and initiatives aimed at improving the early detection and management of perinatal mental disorders have been carried out at the local level. National population-based studies are lacking. A study of pregnant women, recruited and diagnosed by a university hospital, found a 12.4% prevalence of minor and major depression during pregnancy, and a prevalence of 9.6% in the postpartum period. In a population-based surveillance system, covering 77% of national births, suicide was identified to be one of the main causes of maternal death within the first year after birth, yet half of those who were known to have a high suicide risk during the postpartum period had not been referred to a mental health service. The value of recognising depressive or anxiety symptoms early, during pregnancy, has been emphasised by recent research and should be linked to multi-professional psychosocial interventions. Since 2017, the Italian public primary care services that are dedicated to pregnancy assistance (Family Care Centres) have been tasked to provide free psychological assessment to pregnant and postpartum women. Action is now needed in order to improve access to Italian Family Care Centres for pregnant women and to develop an integrated care model involving obstetric and mental health services

    Another point of view about the expression of p16 and Ki67 in melanocytic and non-melanocytic cutaneous lesions

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    The new analysis on the expression of cell cycle regulators, (used in various neoplasms) and the nominal immunohistological essays, still  represent valid and feasible diagnostic methods in most pathology practice. We examined 114 paraffin-embedded histological specimens of melanocytic cutaneous lesions. The primary objective of this study was to explore the potential diagnostic of  two important cell cycle regulators (p16 and Ki67) evaluating also the variations of expression using a semi quantitative graded scale. While, another aim  was to study an hypothetical correlation between p16 expression (in melanocytic and non-melanocytic lesions) and two independent variables, such as the age of the patients and the  anatomical sites ( if sun exposed or not sun exposed) of the lesions analyzed. Cell population was considered positive for antibody-specific p16 and Ki67 when at least 33 % of the cells showed well defined nuclear and/or cytoplasmic staining. A special p16 and Ki67 trend was found only in Spitz nevus (SN), atypical Spitz nevus (ASN) and invasive malignant melanoma (MM) . While, regarding the other lesions ( junctional melanocytic nevus, in situ MM, superficial spreading MM, non-melanoma cancers) discriminative values were not found. P16  was over expressed on sun exposed sites and was hypo expressed on non-sun-exposed areas , founding a statistical significance correlation ( p &lt; 0.03); while,  p16 expression was over expressed in patients  ≥ 61 while it was hypo expressed in patients ≤ 60 ( p = 0.09). </p

    Another point of view about the expression of p16 and Ki67 in melanocytic and non-melanocytic cutaneous lesions

    Get PDF
    The new analysis on the expression of cell cycle regulators, (used in various neoplasms) and the nominal immunohistological essays, still  represent valid and feasible diagnostic methods in most pathology practice. We examined 114 paraffin-embedded histological specimens of melanocytic cutaneous lesions. The primary objective of this study was to explore the potential diagnostic of  two important cell cycle regulators (p16 and Ki67) evaluating also the variations of expression using a semi quantitative graded scale. While, another aim  was to study an hypothetical correlation between p16 expression (in melanocytic and non-melanocytic lesions) and two independent variables, such as the age of the patients and the  anatomical sites ( if sun exposed or not sun exposed) of the lesions analyzed. Cell population was considered positive for antibody-specific p16 and Ki67 when at least 33 % of the cells showed well defined nuclear and/or cytoplasmic staining. A special p16 and Ki67 trend was found only in Spitz nevus (SN), atypical Spitz nevus (ASN) and invasive malignant melanoma (MM) . While, regarding the other lesions ( junctional melanocytic nevus, in situ MM, superficial spreading MM, non-melanoma cancers) discriminative values were not found. P16  was over expressed on sun exposed sites and was hypo expressed on non-sun-exposed areas , founding a statistical significance correlation ( p &lt; 0.03); while,  p16 expression was over expressed in patients  ≥ 61 while it was hypo expressed in patients ≤ 60 ( p = 0.09). </p

    MiRNAs as Potential Prognostic Biomarkers for Metastasis in Thin and Thick Primary Cutaneous Melanomas.

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    Background/Aim: The identification of novel prognostic biomarkers for melanoma metastasis is essential to improve patient outcomes. To this aim, we characterized miRNA expression profiles in relation to metastasis in melanoma and correlated miRNAs expression with clinicalpathological factors. Materials and Methods: MiR-145-5p, miR-150-5p, miR-182-5p, miR-203-3p, miR-205-5p and miR211-5p expression levels were analyzed in primary cutaneous melanomas, including thin and thick melanomas, and in melanoma metastases by quantitative Real-Time PCR. Results: A significantly lower miR-205-5p expression was found in metastases compared to primary melanomas. Furthermore, a progressive down-regulation of miR-205-5p expression was observed from loco-regional to distant metastasis. Significantly lower miR-145-5p and miR-203-3p expression levels were found in cases with Breslow thickness &gt;1 mm, high Clark level, ulceration and mitotic rate ≥1/mm2. Conclusion: Our findings point to miR-205-5p as potential biomarker of distant metastases and to miR-145-5p and miR-203-3p as markers of aggressiveness in melanoma
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