Publications by authors named "Francesca Fanelli"

131 Publications

Frontiers in Multiscale Modeling of Photoreceptor Proteins.

Photochem Photobiol 2020 Dec 28. Epub 2020 Dec 28.

Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.

This perspective article highlights the challenges in the theoretical description of photoreceptor proteins using multiscale modeling, as discussed at the CECAM workshop in Tel Aviv, Israel. The participants have identified grand challenges and discussed the development of new tools to address them. Recent progress in understanding representative proteins such as green fluorescent protein, photoactive yellow protein, phytochrome, and rhodopsin is presented, along with methodological developments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/php.13372DOI Listing
December 2020

Microbial quality and safety of milk and milk products in the 21st century.

Compr Rev Food Sci Food Saf 2020 07 23;19(4):2013-2049. Epub 2020 May 23.

Department of Microbiology and Biotechnology, Max-Rubner Institut, Kiel, Germany.

Milk and milk products have been utilized by humans for many thousands of years. With the advent of metagenomic studies, our knowledge on the microbiota of milk and milk products, especially as affected by the environment, production, and storage parameters, has increased. Milk quality depends on chemical parameters (fat and protein content and absence of inhibitory substances), as well as microbial and somatic cells counts, and affects the price of milk. The effects of hygiene and effective cooling on the spoilage microbiota have shown that proteolytic and lipolytic bacteria such as Pseudomonas or Acinetobacter spp. predominate the spoilage bacterial populations. These bacteria can produce heat-stable proteases and lipases, which remain active after pasteurization and thus can spoil the milk during prolonged storage. Additionally, milk can become contaminated after pasteurization and therefore there is still a high demand on developing better cleaning and sanitation regimes and equipment, as well as test systems to (quantitatively) detect relevant pathogenic or spoilage microorganisms. Raw milk and raw milk cheese consumption is also increasing worldwide with the growing demand of minimally processed, sustainable, healthy, and local foods. In this context, emerging and re-emerging pathogens once again represent a major food safety challenge. As a result of global warming, it is conceivable that not only microbiological risks but also chemical risks relating to presence of mycotoxins or plant toxins in milk will increase. Herein, we provide an overview of the major microbial hazards occurring in the 21st century.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1541-4337.12568DOI Listing
July 2020

Arcobacter butzleri: Up-to-date taxonomy, ecology, and pathogenicity of an emerging pathogen.

Compr Rev Food Sci Food Saf 2020 07 11;19(4):2071-2109. Epub 2020 Jun 11.

Institute of Sciences of Food Production, National Research Council of Italy (CNR-ISPA), Bari, Italy.

Arcobacter butzleri, recently emended to the Aliarcobacter butzleri comb. nov., is an emerging pathogen causing enteritis, severe diarrhea, septicaemia, and bacteraemia in humans and enteritis, stillbirth, and abortion in animals. Since its recognition as emerging pathogen on 2002, advancements have been made in elucidating its pathogenicity and epidemiology, also thanks to advent of genomics, which, moreover, contributed in emending its taxonomy. In this review, we provide an overview of the up-to-date taxonomy, ecology, and pathogenicity of this emerging pathogen. Moreover, the implication of A. butzleri in the safety of foods is pinpointed, and culture-dependent and independent detection, identification, and typing methods as well as strategies to control and prevent the survival and growth of this pathogen are provided.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1541-4337.12577DOI Listing
July 2020

Membrane Estrogen Receptor (GPER) and Follicle-Stimulating Hormone Receptor (FSHR) Heteromeric Complexes Promote Human Ovarian Follicle Survival.

iScience 2020 Dec 18;23(12):101812. Epub 2020 Nov 18.

Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Ospedale Civile Sant'Agostino-Estense, Via P. Giardini 1355, 41126 Modena, Italy.

Classically, follicle-stimulating hormone receptor (FSHR)-driven cAMP-mediated signaling boosts human ovarian follicle growth and oocyte maturation. However, contradicting data suggest a different view on physiological significance of FSHR-mediated cAMP signaling. We found that the G-protein-coupled estrogen receptor (GPER) heteromerizes with FSHR, reprogramming cAMP/death signals into proliferative stimuli fundamental for sustaining oocyte survival. In human granulosa cells, survival signals are missing at high FSHR:GPER ratio, which negatively impacts follicle maturation and strongly correlates with preferential Gαs protein/cAMP-pathway coupling and FSH responsiveness of patients undergoing controlled ovarian stimulation. In contrast, FSHR/GPER heteromers triggered anti-apoptotic/proliferative FSH signaling delivered via the Gβγ dimer, whereas impairment of heteromer formation or GPER knockdown enhanced the FSH-dependent cell death and steroidogenesis. Therefore, our findings indicate how oocyte maturation depends on the capability of GPER to shape FSHR selective signals, indicating hormone receptor heteromers may be a marker of cell proliferation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2020.101812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702187PMC
December 2020

ETNK1 mutations induce a mutator phenotype that can be reverted with phosphoethanolamine.

Nat Commun 2020 11 23;11(1):5938. Epub 2020 Nov 23.

Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy.

Recurrent somatic mutations in ETNK1 (Ethanolamine-Kinase-1) were identified in several myeloid malignancies and are responsible for a reduced enzymatic activity. Here, we demonstrate in primary leukemic cells and in cell lines that mutated ETNK1 causes a significant increase in mitochondrial activity, ROS production, and Histone H2AX phosphorylation, ultimately driving the increased accumulation of new mutations. We also show that phosphoethanolamine, the metabolic product of ETNK1, negatively controls mitochondrial activity through a direct competition with succinate at mitochondrial complex II. Hence, reduced intracellular phosphoethanolamine causes mitochondria hyperactivation, ROS production, and DNA damage. Treatment with phosphoethanolamine is able to counteract complex II hyperactivation and to restore a normal phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-19721-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684297PMC
November 2020

Atopic dermatitis in schoolchildren and adolescents: a critical review of Italian epidemiological data and systemic treatments.

G Ital Dermatol Venereol 2020 Oct 16. Epub 2020 Oct 16.

Outcome Research Unit, Statinfo Srl, Renate, Monza-Brianza, Italy -

Introduction: The epidemiology of atopic dermatitis (AD) is largely different in preschool and schoolchildren. We summarized the available epidemiological data on schoolchildren (6-11 years) and adolescents (12-17 years) in Italy and reviewed information on systemic treatments for moderate-to-severe AD in adolescents.

Evidence Acquisition: In January 2019, we searched for data on prevalence and/or incidence of AD and on the efficacy, effectiveness and safety of systemic AD therapies. Papers were evaluated and selected, and relevant information was extracted. Twenty papers from 17 studies reported original epidemiological information on AD in Italy.

Evidence Synthesis: Most studies were conducted before 2005. Though variations emerged between studies, the lifetime prevalence of AD was estimated between 15%-17% in schoolchildren and between 8%-13% in adolescents. The (12-months) period prevalence of AD was estimated between 8%-10% in children and between 8%-11% in adolescents. Up-to-date information on the prevalence of severe AD is not available. Cyclosporine A may be used in pediatric age patients (children and adolescents) with persistent or severe AD refractory to topical treatments, but its use has several limitations, and is not recommended in patients younger than 16 years. The treatment paradigm of AD is still far from being satisfactory.

Conclusions: We provided a quantitative synthesis of AD epidemiology in Italian schoolchildren and adolescents. Recent data are needed, as most information dates back to the 1990s or early 2000s, and data on the incidence of AD, the proportion of severe cases, and treatment of severe cases in the Real-World are scanty.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.23736/S0392-0488.20.06669-9DOI Listing
October 2020

Using 2nd generation basal insulins in type 2 diabetes: Costs and savings in a comparative economic analysis in Italy, based on the BRIGHT study.

Nutr Metab Cardiovasc Dis 2020 10 8;30(11):1937-1944. Epub 2020 Jul 8.

EBMA Consulting, Melegnano, Milan, Italy. Electronic address:

Background And Aims: To evaluate the economic impact of using 2nd generation basal insulin analogs, Glargine 300 Units/ml (Gla-300) vs Degludec 100 Units/ml (IDeg-100), in patients with type 2 diabetes (T2D).

Methods And Results: An economic analysis was conducted using findings from the BRIGHT study (the first controlled, head-to-head study comparing Gla-300 vs IDeg-100), and costs for the Italian National Healthcare Service (NHS). A cost-minimization analysis (CMA) and a budget impact analysis (BIA) were conducted. Only pharmacological costs were included in the analysis. The CMA estimated patient treatment costs at 24 weeks and 1 year; the BIA assessed the economic impact of treating the overall Italian population of T2D insulin-naïve patients, who initiated insulin treatment during the period September 2017-August 2018 (N = 55 318). In the BIA, four different scenarios were compared: i) all patients receive IDeg-100 (Scenario A); ii) 61% of patients receive Gla-300, 39% IDeg-100 (Scenario B); iii) 80% of patients receive Gla-300, 20% IDeg-100 (Scenario C); iv) all patients treated with Gla-300 (Scenario D). The average treatment costs per patient were lower with Gla-300 vs IDeg-100 (at 24 weeks: €129 vs €161; at 1 year: €324 vs €409, respectively). Results of the BIA showed that comparing Scenario D vs Scenario A, total savings would amount to €1.76 million at 24 weeks, €4.73 million at 1 year, €5.53 million at 2 years.

Conclusion: A larger use of Gla-300 vs IDeg-100 for the treatment of T2D patients would lead to a relevant reduction of therapy costs in Italy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.numecd.2020.07.005DOI Listing
October 2020

Genomic Analysis of Three Cheese-Borne with Biofilm and Spoilage-Associated Behavior.

Microorganisms 2020 Aug 8;8(8). Epub 2020 Aug 8.

Institute of Sciences of Food Production, National Research Council of Italy, Via G. Amendola 122/O, 70126 Bari, Italy.

Psychrotrophic pseudomonads cause spoilage of cold fresh cheeses and their shelf-life reduction. Three cheese-borne sp., ITEM 17295, ITEM 17298, and ITEM 17299 strains, previously isolated from mozzarella cheese, revealed distinctive spoilage traits based on molecular determinants requiring further investigations. Genomic indexes (ANI, DDH), MLST-based phylogeny of four housekeeping genes (16S rRNA, B, B and D) and genome-based phylogeny reclassified them as . Each strain showed distinctive phenotypic traits at 15 and 30 °C: ITEM 17298 was the highest biofilm producer at both temperatures, whilst ITEM 17295 and ITEM 17299 showed the strongest proteolytic activity at 30 °C. A wider pattern of pigments was found for ITEM 17298, while ITEM 17295 colonies were not pigmented. Although the high genomic similarity, some relevant molecular differences supported this phenotypic diversity: ITEM 17295, producing low biofilm amount, missed the operon involved in EPS synthesis and the biofilm-related Toxin-Antitoxin systems (RA, BS); S, required for the pyoverdine synthesis, was a truncated gene in ITEM 17295, harboring, instead, a second A involved in milk proteolysis. This work provided new insight into the food spoiler microbiota by identifying these mozzarella cheese spoilers as ; molecular targets to be exploited in the development of novel preservative strategies were also revealed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/microorganisms8081208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464908PMC
August 2020

Biofilm and Pathogenesis-Related Proteins in the Foodborne ITEM 17298 With Distinctive Phenotypes During Cold Storage.

Front Microbiol 2020 28;11:991. Epub 2020 May 28.

Institute of Microbiology, University of Greifswald, Greifswald, Germany.

In food chain, spp. cause spoilage by reducing shelf life of fresh products, especially during cold storage, with a high economic burden for industries. However, recent studies have shed new light on health risks occurring when they colonize immunocompromised patient tissues. Likewise to , they exhibit antibiotic resistance and biofilm formation, responsible for their spread and persistence in the environment. Biofilm formation might be induced by environmental stresses, such as temperature fluctuations causing physiological and metabolic changes exacerbating food spoilage (by protease and pigment synthesis), and the production of adhesion molecules, chemotactic or underestimated virulence factors. In order to provide a new insight into phenotypic biodiversity of spoilers isolated from cold stored cheese, in this work 19 spp. were investigated for biofilm, pigments, exopolysaccharide production and motility at low temperature. Only nine strains showed these phenotypic traits and the blue pigmenting cheese strain ITEM 17298 was the most distinctive. In addition, this strain decreased the survival probability of infected larvae, showing, for the first time, a pathogenic potential. Genomic and proteomic analyses performed on the ITEM 17298 planktonic cells treated or not with lactoferrin derived antibiofilm peptides allowed to reveal specific biofilm related-pathways as well as proteins involved in pathogenesis. Indeed, several genes were found related to signaling system by cGMP-dependent protein kinases, cellulose, rhamnolipid and alginate synthesis, antibiotic resistance, adhesion and virulence factors. The proteome of the untreated ITEM 17298, growing at low temperature, showed that most of the proteins associated with biofilm regulation, pigmentation motility, antibiotic resistance and pathogenecity were repressed, or decreased their levels in comparison to that of the untreated cultures. Thus, the results of this work shed light on the complex pathways network allowing psychrotrophic pseudomonads to adapt themselves to food-refrigerated conditions and enhance their spoilage. In addition, the discovery of virulence factors and antibiotic resistance determinants raises some questions about the need to deeper investigate these underestimated bacteria in order to increase awareness and provide input to update legislation on their detection limits in foods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmicb.2020.00991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326052PMC
May 2020

webPSN v2.0: a webserver to infer fingerprints of structural communication in biomacromolecules.

Nucleic Acids Res 2020 07;48(W1):W94-W103

Department of Life Sciences, University of Modena and Reggio Emilia, Modena 41125, Italy.

A mixed Protein Structure Network (PSN) and Elastic Network Model-Normal Mode Analysis (ENM-NMA)-based strategy (i.e. PSN-ENM) was developed to investigate structural communication in bio-macromolecules. Protein Structure Graphs (PSGs) are computed on a single structure, whereas information on system dynamics is supplied by ENM-NMA. The approach was implemented in a webserver (webPSN), which was significantly updated herein. The webserver now handles both proteins and nucleic acids and relies on an internal upgradable database of network parameters for ions and small molecules in all PDB structures. Apart from the radical restyle of the server and some changes in the calculation setup, other major novelties concern the possibility to: a) compute the differences in nodes, links, and communication pathways between two structures (i.e. network difference) and b) infer links, hubs, communities, and metapaths from consensus networks computed on a number of structures. These new features are useful to identify commonalties and differences between two different functional states of the same system or structural-communication signatures in homologous or analogous systems. The output analysis relies on 3D-representations, interactive tables and graphs, also available for download. Speed and accuracy make this server suitable to comparatively investigate structural communication in large sets of bio-macromolecular systems. URL: http://webpsn.hpc.unimore.it.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gkaa397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319592PMC
July 2020

Dynamics and structural communication in the ternary complex of fully phosphorylated V2 vasopressin receptor, vasopressin, and β-arrestin 1.

Biochim Biophys Acta Biomembr 2020 09 12;1862(9):183355. Epub 2020 May 12.

Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy; Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, via Campi 287, 41125 Modena, Italy. Electronic address:

G protein-coupled receptors (GPCRs) are critically regulated by arrestins, which not only desensitize G-protein signaling but also initiate a G protein-independent wave of signaling. The information from structure determination was herein exploited to build a structural model of the ternary complex, comprising fully phosphorylated V2 vasopressin receptor (V2R), the agonist arginine vasopressin (AVP), and β-arrestin 1 (β-arr1). Molecular simulations served to explore dynamics and structural communication in the ternary complex. Flexibility and mechanical profiles reflect fold of V2R and β-arr1. Highly conserved amino acids tend to behave as hubs in the structure network and contribute the most to the mechanical rigidity of V2R seven-helix bundle and of β-arr1. Two structurally and dynamically distinct receptor-arrestin interfaces assist the twist of the N- and C-terminal domains (ND and CD, respectively) of β-arr1 with respect to each other, which is linked to arrestin activation. While motion of the ND is essentially assisted by the fully phosphorylated C-tail of V2R (V2RCt), that of CD is assisted by the second and third intracellular loops and the cytosolic extensions of helices 5 and 6. In the presence of the receptor, the β-arr1 inter-domain twist angle correlates with the modes describing the essential subspace of the ternary complex. β-arr1 motions are also influenced by the anchoring to the membrane of the C-edge-loops in the β-arr1-CD. Overall fluctuations reveal a coupling between motions of the agonist binding site and of β-arr1-ND, which are in allosteric communication between each other. Mechanical rigidity points, often acting as hubs in the structure network and distributed along the main axis of the receptor helix bundle, contribute to establish a preferential communication pathway between agonist ligand and the ND of arrestin. Such communication, mediated by highly conserved amino acids, involves also the first amino acid in the arrestin C-tail, which is highly dynamic and is involved in clathrin-mediated GPCR internalization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbamem.2020.183355DOI Listing
September 2020

Novel insights into the enterotoxigenic potential and genomic background of Staphylococcus aureus isolated from raw milk.

Food Microbiol 2020 Sep 6;90:103482. Epub 2020 Mar 6.

National Research Council of Italy, Institute of Sciences of Food Production (CNR-ISPA), Bari, Italy. Electronic address:

In this study, 53 Staphylococcus (S.) aureus strains were typed by 16S-23S rDNA intergenic spacer region (ISR) typing and staphylococcal enterotoxin gene (SEg) typing for all the staphylococcal enterotoxin (se) and staphylococcal enterotoxin-like toxin (sel) genes known to date, revealing a higher discriminatory power than that of multi locus sequence typing. Six strains, one of each ISR- and SEg-type, were genome sequenced and the ability to produce some classical and new SEs when growing in milk was investigated. The manual analysis of the six genomes allowed us to confirm, correct and expand the results of common available genomic data pipelines such as VirulenceFinder. Moreover, it enabled us to (i) investigate the actual location of se and sel genes, even for genes such as selY, whose location (in the core genome) was so far unknown, (ii) find novel allelic variants of se and sel genes and pseudogenes, (iii) correctly annotate se and sel genes and pseudogenes, and (iv) discover a novel type of enterotoxin gene cluster (egc), i.e. the egc type 5 in strains 356P and 364P, while S. argenteus MSHR1132 harbored the egc type 6. Four of the six S. aureus strains produced sufficient amounts of SEA, SEC, SED and SEH in milk to cause staphylococcal food poisoning (SFP), with S. aureus 372 P being the highest producer of SED in milk found to date, producing as much as ca. 47,300 ng/mL and 49,200 ng/mL of SED, after 24 and 48 h of incubation in milk at 37 °C, respectively. S. aureus 372 P released a low amount of SER in milk, most likely because the seR gene was present as a pseudogene, putatively encoding only 51 amino acids. These findings confirm that not only the classical SEs, but also the new ones can represent a potential hazard for the consumers' health if produced in foods in sufficient amounts. Therefore, the detection of SEs in foods, especially if involved in SFP cases, should focus not only on classical, but also on all the new SEs and SEls known to date. Where reference methods are unavailable, the presence of the relevant genes, by using the conventional and real time PCR protocols we exhaustively provided herein, and their nucleotide sequences, should be investigated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fm.2020.103482DOI Listing
September 2020

CRB1-Related Cystic Maculopathy in Twins Conceived Through Heterologous Fertilization With Variant-Carrying Oocytes.

J Pediatr Ophthalmol Strabismus 2020 Mar 12;57:e19-e24. Epub 2020 Mar 12.

Cystic maculopathy has been associated with genetic disorders such as retinitis pigmentosa, X-linked retinoschisis, cone dystrophy, and foveal retinoschisis. Familial foveal retinoschisis was recently described as a rare disease caused by CRB1 variants. The authors report the phenotype-genotype pattern of a pair of dizygotic twins with early-onset cystic maculopathy due to CRB1 pathogenic variants. The twins were conceived by heterologous fertilization with variant-carrying oocytes. The probands were monitored for a period of 4 years. Next generation sequencing of a panel of genes responsible for retinal dystrophies was performed. Both children carried three pathogenic variants in CRB1: a novel heterozygous truncating variant p.(Val855*) inherited from the father and two known heterozygous missense variants, p.[(Phe144Val; Thr745Met)], inherited from the oocyte donor. The findings confirm that CRB1 variants can be responsible for foveal retinoschisis with variable clinical expressivity ranging from schitic macular alteration to early-onset forms of cystic maculopathy. The authors highlight the importance of exome analysis of gamete donors to assess the likelihood of recessively inherited disorders by means of a prediction algorithm able to combine parent and donor exome data. [J Pediatr Ophthalmol Strabismus. 2020;57:e19-e24.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3928/01913913-20200204-02DOI Listing
March 2020

Phenotype and genomic background of Arcobacter butzleri strains and taxogenomic assessment of the species.

Food Microbiol 2020 Aug 10;89:103416. Epub 2020 Jan 10.

Institute of Sciences of Food Production of the National Research Council of Italy (CNR-ISPA), Bari, 70126, Italy. Electronic address:

In this study the phenotypic and genomic characterization of two Arcobacter butzleri (Ab) strains (Ab 34_O and Ab 39_O) isolated from pre-cut ready-to-eat vegetables were performed. Results provided useful data about their taxonomy and their overall virulence potential with particular reference to the antibiotic and heavy metal susceptibility. These features were moreover compared with those of two Ab strains isolated from shellfish and a genotaxonomic assessment of the Ab species was performed. The two Ab isolated from vegetables were confirmed to belong to the Aliarcobacter butzleri species by 16S rRNA gene sequence analysis, MLST and genomic analyses. The genome-based taxonomic assessment of the Ab species brought to the light the possibility to define different subspecies reflecting the source of isolation, even though further genomes from different sources should be available to support this hypothesis. The strains isolated from vegetables in the same geographic area shared the same distribution of COGs with a prevalence of the cluster "inorganic ion transport and metabolism", consistent with the lithotrophic nature of Arcobacter spp. None of the Ab strains (from shellfish and from vegetables) metabolized carbohydrates but utilized organic acids and amino acids as carbon sources. The metabolic fingerprinting of Ab resulted less discriminatory than the genome-based approach. The Ab strains isolated from vegetables and those isolated from shellfish endowed multiple resistance to several antibiotics and heavy metals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fm.2020.103416DOI Listing
August 2020

Insulin Glargine U100 Utilization in Patients with Type 2 Diabetes in an Italian Real-World Setting: A Retrospective Study.

J Diabetes Res 2019 30;2019:3174654. Epub 2019 Dec 30.

Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.

Background: This study is aimed at estimating the proportion of type 2 diabetes mellitus (T2DM) patients treated with basal insulin (insulin glargine U100) and at evaluating daily insulin dose, treatment pattern, and adherence to treatment of these patients.

Methods: Data from administrative and laboratory databases of 3 Italian Local Health Units were retrospectively collected and analyzed. All patients with a diagnosis of T2DM between 01/01/2012 and 31/12/2012 were considered, and those with at least a prescription of insulin glargine between 01/01/2013 and 31/12/2014 were included and followed up for one year. For each patient, we evaluated HbA1c levels both at baseline and during the follow-up period and the daily average dose of insulin. Medication adherence was defined by using medication possession ratio (MPR) and reported as proportion of patients with MPR ≥ 80%.

Results: 7,422 T2DM patients were available for the study. According to the antidiabetic medication prescribed, patients were categorized into four groups: insulin glargine only, insulin glargine plus oral glucose-lowering drugs, insulin glargine plus rapid-acting insulin, and insulin glargine plus DPP-4 inhibitors. Median daily dose of insulin among insulin glargine only patients was higher than in other groups (35 IU vs. 20 IU, < 0.05), and a higher percentage of them achieved a target HbA1c value of less than 7.0% (53.8% vs. 30%, < 0.001). Adherence to insulin treatment was lowest (41%) in the insulin glargine only group compared to other groups (ranging from 58.4% to 64.4%), < 0.001.

Conclusions: A large proportion of T2DM patients treated with insulin fail in achieving the glycemic target of HbA1c level < 7%, irrespective of treatment regimen; however, basal insulin only is associated with lower therapeutic unsuccess. Adherence to antidiabetes medications is also suboptimal in these patients and should be addressed to improve long-term outcomes of reducing and preventing microvascular and macrovascular complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/3174654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955113PMC
June 2020

Integrated structural modeling and super-resolution imaging resolve GPCR oligomers.

Prog Mol Biol Transl Sci 2020 6;169:151-179. Epub 2019 Dec 6.

King's College, Department of Women & Children's Health Great Maze Pond, London, United Kingdom.

Formation of G protein-coupled receptors (GPCRs) dimers and higher order oligomers represents a key mechanism in pleiotropic signaling, yet how individual protomers function within oligomers remains poorly understood. For the Class A/rhodopsin subfamily of glycoprotein hormone receptors (GpHRs), di/oligomerization has been demonstrated to play a significant role in regulating its signaling activity at a cellular and physiological level and even pathophysiologically. Here we will describe and discuss the developments in our understanding of GPCR oligomerization, in both health and disease, from the study of this unique and complex subfamily of GPCRs with light on the luteinizing hormone receptor (LHR). Focus will be put on the results of an approach relying on the combination of atomistic modeling by protein-protein docking with super-resolution imaging. The latter could resolve single LHR molecules to ~8nm resolution in functional asymmetric dimers and oligomers, using dual-color photoactivatable dyes and localization microscopy (PD-PALM). Structural modeling of functionally asymmetric LHR trimers and tetramers strongly aligned with PD-PALM-imaged spatial arrangements, identifying multiple possible helix interfaces mediating inter-protomer associations. Diverse spatial and structural assemblies mediating GPCR oligomerization may acutely fine-tune the cellular signaling profile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/bs.pmbts.2019.11.005DOI Listing
December 2020

Atrial septal defects, supravalvular aortic stenosis and syndromes predisposing to aneurysm of large vessels.

Acta Biomed 2019 09 30;90(10-S):53-57. Epub 2019 Sep 30.

MAGI Euregio, Bolzano, Italy.

Atrial septal defect is a persistent interatrial communication. It is the second most common congenital heart defect and is detected in 1:1500 live births. Clinical course is variable and depends on the size of the malformation. Clinical diagnosis is based on patient history, physical and instrumental examination. Atrial septal defect is frequently sporadic, but familial cases have been reported. The disease has autosomal dominant inheritance with reduced penetrance, variable expressivity and genetic heterogeneity. Supravalvular aortic stenosis is a congenital narrowing of the lumen of the ascending aorta. It has an incidence of 1:20000 newborns and a prevalence of 1:7500. Clinical diagnosis is based on patient history, physical and instrumental examination. Supravalvular aortic stenosis is either sporadic or familial and has autosomal dominant inheritance with reduced penetrance and variable expressivity. It is associated with mutations in the ELN gene. Syndromes predisposing to aneurysm of large vessels is a group of inherited disorders that may affect different segments of the aorta. They may occur in isolation or associated with other genetic syndromes. Clinical symptoms are highly variable. Familial thoracic aortic aneurysm and dissection accounts for ~20% of all cases of aneurysms. The exact prevalence is unknown. Clinical diagnosis is based on medical history, physical and instrumental examination. Genetic testing is useful for confirming diagnosis of these syndromes and for differential diagnosis, recurrence risk evaluation and prenatal diagnosis in families with a known mutation. Most syndromes predisposing to aneurysm of large vessels have autosomal dominant inheritance with reduced penetrance and variable expressivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.23750/abm.v90i10-S.8760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233642PMC
September 2019

Interconnecting Flexibility, Structural Communication, and Function in RhoGEF Oncoproteins.

J Chem Inf Model 2019 10 25;59(10):4300-4313. Epub 2019 Sep 25.

Department of Life Sciences , University of Modena and Reggio Emilia , via Campi 103 , 41125 Modena , Italy.

Dbl family Rho guanine nucleotide exchange factors (RhoGEFs) play a central role in cell biology by catalyzing the exchange of guanosine 5'-triphosphate for guanosine 5'-diphosphate (GDP) on RhoA. Insights into the oncogenic constitutive activity of the Lbc RhoGEF were gained by analyzing the structure and dynamics of the protein in different functional states and in comparison with a close homologue, leukemia-associated RhoGEF. Higher intrinsic flexibility, less dense and extended structure network, and less stable allosteric communication pathways in Lbc, compared to the nonconstitutively active homologue, emerged as major determinants of the constitutive activity. Independent of the state, the essential dynamics of the two RhoGEFs is contributed by the last 10 amino acids of Dbl homology (DH) and the whole pleckstrin homology (PH) domains and tends to be equalized by the presence of RhoA. The catalytic activity of the RhoGEF relies on the scaffolding action of the DH domain that primarily turns the switch I (SWI) of RhoA on itself through highly conserved amino acids participating in the stability core and essential for function. Changes in the conformation of SWI and disorganization of the RhoA regions deputed to nucleotide binding are among the major RhoGEF effects leading to GDP release. Binding of RhoA reorganizes the allosteric communication on RhoGEF, strengthening the communication among the canonical RhoA binding site on DH, a secondary RhoA binding site on PH, and the binding site for heterotrimeric G proteins, suggesting dual roles for RhoA as a catalysis substrate and as a regulatory protein. The structure network-based analysis tool employed in this study proved to be useful for predicting potentially druggable regulatory sites in protein structures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jcim.9b00271DOI Listing
October 2019

Antibiotic Resistant Spp. Spoilers in Fresh Dairy Products: An Underestimated Risk and the Control Strategies.

Foods 2019 Sep 1;8(9). Epub 2019 Sep 1.

Institute of Sciences of Food Production, National Research Council of Italy, Via G. Amendola 122/O, 70126 Bari, Italy.

Microbial multidrug resistance (MDR) is a growing threat to public health mostly because it makes the fight against microorganisms that cause lethal infections ever less effective. Thus, the surveillance on MDR microorganisms has recently been strengthened, taking into account the control of antibiotic abuse as well as the mechanisms underlying the transfer of antibiotic genes (ARGs) among microbiota naturally occurring in the environment. Indeed, ARGs are not only confined to pathogenic bacteria, whose diffusion in the clinical field has aroused serious concerns, but are widespread in saprophytic bacterial communities such as those dominating the food industry. In particular, fresh dairy products can be considered a reservoir of spp. resistome, potentially transmittable to consumers. Milk and fresh dairy cheeses products represent one of a few "hubs" where commensal or opportunistic pseudomonads frequently cohabit together with food microbiota and hazard pathogens even across their manufacturing processes. spp., widely studied for food spoilage effects, are instead underestimated for their possible impact on human health. Recent evidences have highlighted that non-pathogenic pseudomonads strains () are associated with some human diseases, but are still poorly considered in comparison to the pathogen In addition, the presence of ARGs, that can be acquired and transmitted by horizontal genetic transfer, further increases their risk and the need to be deeper investigated. Therefore, this review, starting from the general aspects related to the physiological traits of these spoilage microorganisms from fresh dairy products, aims to shed light on the resistome of cheese-related pseudomonads and their genomic background, current methods and advances in the prediction tools for MDR detection based on genomic sequences, possible implications for human health, and the affordable strategies to counteract MDR spread.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/foods8090372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769999PMC
September 2019

Frontal Variant of Alzheimer's Disease: A Report of a Novel PSEN1 Mutation.

J Alzheimers Dis 2019 ;70(1):11-15

Ospedale Policlinico San Martino, I.R.C.C.S. Per l'Oncologia, Genoa, Italy.

Alzheimer's disease may mimic frontotemporal dementia. We describe a case of presenile dementia who presented with peudo-psychotic symptoms carrying a PSEN1 mutation (P355 S), which was not known to be pathogenic. PET-FDG showed bilateral frontotemporal hypometabolism, but at MRI, multiple microbleeds were detected, suggestive of amyloid angiopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-190363DOI Listing
September 2020

Genomic Characterization of Isolated From Shellfish: Novel Insight Into Antibiotic Resistance and Virulence Determinants.

Front Microbiol 2019 16;10:670. Epub 2019 Apr 16.

Institute of Sciences of Food Production (CNR-ISPA), National Research Council of Italy, Bari, Italy.

is an emerging pathogenic microorganism, whose taxonomy has been recently suggested to be emended to the comb. nov. Despite extensive taxonomic analysis, only few fragmented studies have investigated the occurrence and the prevalence of virulence and antibiotic resistance determinants of this species in strains isolated from shellfish. Herein we report for the first time the whole genome sequencing and genomic characterization of two strains isolated from shellfish, with particular reference to the antibiotic, heavy metals and virulence determinants. This study supported the taxonomic assignment of these strains to the species, and allowed us to identify antibiotic and metal resistance along with virulence determinants, also additional to those previously reported for the only two strains from different environments genomically characterized. Moreover, both strains showed resistance to β-lactams, vanocomycin, tetracycline and erythromycin and susceptibility to aminoglycosides and ciprofloxacin. Beside enlarging the availability of genomic data to perform comparative studies aimed at correlating phenotypic differences associated with ecological niche and geographic distribution with the genetic diversity of spp., this study reports the endowment of antibiotic and heavy metal resistance and virulence determinants of these shellfish-isolated strains. This leads to hypothesize a relatively high virulence of isolated from shellfish and prompt the need for a wider genomic analysis and for and studies of more strains isolated from this and other ecological niches, to unravel the mechanism of pathogenicity of this species, and the potential risk associated to their consumption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmicb.2019.00670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477937PMC
April 2019

Proteomic analysis of the food spoiler Pseudomonas fluorescens ITEM 17298 reveals the antibiofilm activity of the pepsin-digested bovine lactoferrin.

Food Microbiol 2019 Sep 8;82:177-193. Epub 2019 Feb 8.

Institute of Microbiology, University of Greifswald, Greifswald, D-17487, Germany.

Pseudomonas fluorescens is implicated in food spoilage especially under cold storage. Due to its ability to form biofilm P. fluorescens resists to common disinfection strategies increasing its persistance especially across fresh food chain. Biofilm formation is promoted by several environmental stimuli, but gene expression and protein changes involved in this lifestyle are poorly investigated in this species. In this work a comparative proteomic analysis was performed to investigate metabolic pathways of underlying biofilm formation of the blue cheese pigmenting P. fluorescens ITEM 17298 after incubation at 15 and 30 °C; the same methodology was also applied to reveal the effects of the bovine lactoferrin hydrolysate (HLF) used as antibiofilm agent. At 15 °C biofilm biomass and motility increased, putatively sustained by the induction of regulators (PleD, AlgB, CsrA/RsmA) involved in these phenotypic traits. In addition, for the first time, TycC and GbrS, correlated to indigoidine synthesis (blue pigment), were detected and identified. An increase of virulence factors amounts (leukotoxin and PROKKA_04561) were instead found at 30 °C. HLF caused a significant reduction in biofilm biomass; indeed, at 15 °C HLF repressed PleD, TycC and GbrS and induced the negative regulators of alginate biosynthesis; at both temperatures induced the cyclic-di-GMP-binding biofilm dispersal mediator (PROKKA_02061). In conclusion, in this work protein determinats of biofilm formation were revelead in ITEM 17298 under the low temperature; the synthesis of these latter were inhibited by HLF confirming its possible exploitation as antibiofilm agent for biotechnological applications in cold stored foods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fm.2019.02.003DOI Listing
September 2019

a-ARM: Automatic Rhodopsin Modeling with Chromophore Cavity Generation, Ionization State Selection, and External Counterion Placement.

J Chem Theory Comput 2019 May 12;15(5):3134-3152. Epub 2019 Apr 12.

Department of Biotechnologies, Chemistry and Pharmacy , Università degli Studi di Siena , via A. Moro 2 , I-53100 Siena , Italy.

The Automatic Rhodopsin Modeling (ARM) protocol has recently been proposed as a tool for the fast and parallel generation of basic hybrid quantum mechanics/molecular mechanics (QM/MM) models of wild type and mutant rhodopsins. However, in its present version, input preparation requires a few hours long user's manipulation of the template protein structure, which also impairs the reproducibility of the generated models. This limitation, which makes model building semiautomatic rather than fully automatic, comprises four tasks: definition of the retinal chromophore cavity, assignment of protonation states of the ionizable residues, neutralization of the protein with external counterions, and finally congruous generation of single or multiple mutations. In this work, we show that the automation of the original ARM protocol can be extended to a level suitable for performing the above tasks without user's manipulation and with an input preparation time of minutes. The new protocol, called a-ARM, delivers fully reproducible (i.e., user independent) rhodopsin QM/MM models as well as an improved model quality. More specifically, we show that the trend in vertical excitation energies observed for a set of 25 wild type and 14 mutant rhodopsins is predicted by the new protocol better than when using the original. Such an agreement is reflected by an estimated (relative to the probed set) trend deviation of 0.7 ± 0.5 kcal mol (0.03 ± 0.02 eV) and mean absolute error of 1.0 kcal mol (0.04 eV).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jctc.9b00061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141608PMC
May 2019

Auto-regulation of Secretory Flux by Sensing and Responding to the Folded Cargo Protein Load in the Endoplasmic Reticulum.

Cell 2019 03;176(6):1461-1476.e23

Institute of Protein Biochemistry (IBP), Italian National Research Council (CNR), Napoli, Italy. Electronic address:

Maintaining the optimal performance of cell processes and organelles is the task of auto-regulatory systems. Here we describe an auto-regulatory device that helps to maintain homeostasis of the endoplasmic reticulum (ER) by adjusting the secretory flux to the cargo load. The cargo-recruiting subunit of the coatomer protein II (COPII) coat, Sec24, doubles as a sensor of folded cargo and, upon cargo binding, acts as a guanine nucleotide exchange factor to activate the signaling protein Gα12 at the ER exit sites (ERESs). This step, in turn, activates a complex signaling network that activates and coordinates the ER export machinery and attenuates proteins synthesis, thus preventing large fluctuations of folded and potentially active cargo that could be harmful to the cell or the organism. We call this mechanism AREX (autoregulation of ER export) and expect that its identification will aid our understanding of human physiology and diseases that develop from secretory dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2019.01.035DOI Listing
March 2019

Effect of different light-emitting diode (LED) irradiation on the shelf life and phytonutrient content of broccoli (Brassica oleracea L. var. italica).

Food Chem 2019 Jun 14;283:206-214. Epub 2019 Jan 14.

Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, CNR, via G. Amendola 165/A, 70126 Bari, Italy.

Broccoli (Brassica oleracea L. var. italica) is largely cultivated in southern Italy. It is an important source of phytonutrients, which are partially lost during postharvest storage. The aim of this work was to evaluate the overall effect of five different low-intensity light-emitting diodes (LEDs) on the quality parameters of broccoli florets over 20 d of cold storage. The level of ascorbic acid, chlorophylls, carotenoids, phenolic compounds and soluble proteins, as well as colour analysis, were evaluated. Green LED increased the chlorophyll and ascorbic acid content; white, red and yellow LEDs had a positive effect on the redox status of broccoli. Globally, only green LED had a statistically significant positive effect when considering all analysed parameters and could be proposed to prolong the shelf life of broccoli during cold storage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.foodchem.2019.01.021DOI Listing
June 2019

First bloom event of the small dinoflagellate Prorocentrum shikokuense in the Mediterranean Sea: cryptogenic or introduced?

Mar Pollut Bull 2019 Feb 28;139:197-204. Epub 2018 Dec 28.

CNR-IRSA National Research Council-Water Research Institute, Unit of Taranto Via Roma, 3, 74121 Taranto, Italy.

A bloom of putatively non-indigenous species (NIS) Prorocentrum shikokuense was detected for the first time in the Mediterranean Sea at the Brindisi harbor (Southern Adriatic Sea) on September 2016, in the context of EU Marine Strategy Framework Directive monitoring in the ports. This species is usually observed in the East China Sea and Japanese and Korean waters. In the Brindisi harbor this dinoflagellate reached the concentration 10 cell/L and represented from 30 to 50% of the total phytoplankton population. Besides this event, Prorocentrum shikokuense has not been found blooming until today in Mediterranean waters. This study suggests the necessity to improve the monitoring surveys in areas that are known vulnerable systems to alien and invasive species, such as ports.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.marpolbul.2018.12.034DOI Listing
February 2019

A Small Chaperone Improves Folding and Routing of Rhodopsin Mutants Linked to Inherited Blindness.

iScience 2018 Jun 5;4:1-19. Epub 2018 May 5.

Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy; Center for Neuroscience and Neurotechnology, via Campi 287, 41125 Modena, Italy. Electronic address:

The autosomal dominant form of retinitis pigmentosa (adRP) is a blindness-causing conformational disease largely linked to mutations of rhodopsin. Molecular simulations coupled to the graph-based protein structure network (PSN) analysis and in vitro experiments were conducted to determine the effects of 33 adRP rhodopsin mutations on the structure and routing of the opsin protein. The integration of atomic and subcellular levels of analysis was accomplished by the linear correlation between indices of mutational impairment in structure network and in routing. The graph-based index of structural perturbation served also to divide the mutants in four clusters, consistent with their differences in subcellular localization and responses to 9-cis retinal. The stability core of opsin inferred from PSN analysis was targeted by virtual screening of over 300,000 anionic compounds leading to the discovery of a reversible orthosteric inhibitor of retinal binding more effective than retinal in improving routing of three adRP mutants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2018.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147235PMC
June 2018

Genomic characterization of Trichoderma atrobrunneum (T. harzianum species complex) ITEM 908: insight into the genetic endowment of a multi-target biocontrol strain.

BMC Genomics 2018 Sep 11;19(1):662. Epub 2018 Sep 11.

Institute of Sciences of Food Production, National Research Council, Bari, Italy.

Background: So far, biocontrol agent selection has been performed mainly by time consuming in vitro confrontation tests followed by extensive trials in greenhouse and field. An alternative approach is offered by application of high-throughput techniques, which allow extensive screening and comparison among strains for desired genetic traits. In the genus Trichoderma, the past assignments of particular features or strains to one species need to be reconsidered according to the recent taxonomic revisions. Here we present the genome of a biocontrol strain formerly known as Trichoderma harzianum ITEM 908, which exhibits both growth promoting capabilities and antagonism against different fungal pathogens, including Fusarium graminearum, Rhizoctonia solani, and the root-knot nematode Meloidogyne incognita. By genomic analysis of ITEM 908 we investigated the occurrence and the relevance of genes associated to biocontrol and stress tolerance, providing a basis for future investigation aiming to unravel the complex relationships between genomic endowment and exhibited activities of this strain.

Results: The MLST analysis of ITS-TEF1 concatenated datasets reclassified ITEM 908 as T. atrobrunneum, a species recently described within the T. harzianum species complex and phylogenetically close to T. afroharzianum and T. guizhouense. Genomic analysis revealed the presence of a broad range of genes encoding for carbohydrate active enzymes (CAZYmes), proteins involved in secondary metabolites production, peptaboils, epidithiodioxopiperazines and siderophores potentially involved in parasitism, saprophytic degradation as well as in biocontrol and antagonistic activities. This abundance is comparable to other Trichoderma spp. in the T. harzianum species complex, but broader than in other biocontrol species and in the species T. reesei, known for its industrial application in cellulase production. Comparative analysis also demonstrated similar genomic organization of major secondary metabolites clusters, as in other Trichoderma species.

Conclusions: Reported data provide a contribution to a deeper understanding of the mode of action and identification of activity-specific genetic markers useful for selection and improvement of biocontrol strains. This work will also enlarge the availability of genomic data to perform comparative studies with the aim to correlate phenotypic differences with genetic diversity of Trichoderma species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12864-018-5049-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131884PMC
September 2018

Gut Dysbiosis and Muscle Aging: Searching for Novel Targets against Sarcopenia.

Mediators Inflamm 2018 30;2018:7026198. Epub 2018 Jan 30.

Department of Geriatrics, Neurosciences and Orthopedics, Catholic University of the Sacred Heart, Rome, Italy.

Advanced age is characterized by several changes, one of which is the impairment of the homeostasis of intestinal microbiota. These alterations critically influence host health and have been associated with morbidity and mortality in older adults. "Inflammaging," an age-related chronic inflammatory process, is a common trait of several conditions, including sarcopenia. Interestingly, imbalanced intestinal microbial community has been suggested to contribute to inflammaging. Changes in gut microbiota accompanying sarcopenia may be attenuated by supplementation with pre- and probiotics. Although muscle aging has been increasingly recognized as a biomarker of aging, the pathophysiology of sarcopenia is to date only partially appreciated. Due to its development in the context of the age-related inflammatory milieu, several studies favor the hypothesis of a tight connection between sarcopenia and inflammaging. However, conclusive evidence describing the signaling pathways involved has not yet been produced. Here, we review the current knowledge of the changes in intestinal microbiota that occur in advanced age with a special emphasis on findings supporting the idea of a modulation of muscle physiology through alterations in gut microbial composition and activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2018/7026198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893006PMC
September 2018

Computational modeling approaches to quantitative structure-binding kinetics relationships in drug discovery.

Drug Discov Today 2018 07 21;23(7):1396-1406. Epub 2018 Mar 21.

Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy; Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy.

Simple comparative correlation analyses and quantitative structure-kinetics relationship (QSKR) models highlight the interplay of kinetic rates and binding affinity as an essential feature in drug design and discovery. The choice of the molecular series, and their structural variations, used in QSKR modeling is fundamental to understanding the mechanistic implications of ligand and/or drug-target binding and/or unbinding processes. Here, we discuss the implications of linear correlations between kinetic rates and binding affinity constants and the relevance of the computational approaches to QSKR modeling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.drudis.2018.03.010DOI Listing
July 2018