Publications by authors named "Luigi Russo"

119 Publications

Design, Optimization, and Structural Characterization of an Apoptosis-Inducing Factor Peptide Targeting Human Cyclophilin A to Inhibit Apoptosis Inducing Factor-Mediated Cell Death.

J Med Chem 2021 Aug 2;64(15):11445-11459. Epub 2021 Aug 2.

Institute of Biostructures and Bioimaging (IBB)-CNR, Via Mezzocannone, 16, 80134 Napoli, Italy.

Blocking the interaction between the apoptosis-inducing factor (AIF) and cyclophilin A (CypA) by the AIF fragment AIF(370-394) is protective against glutamate-induced neuronal cell death and brain injury in mice. Starting from AIF(370-394), we report the generation of the disulfide-bridged and shorter variant AIF(381-389) and its structural characterization by nuclear magnetic resonance (NMR) in the free and CypA-bound state. AIF(381-389) in both the free and bound states assumes a β-hairpin conformation similar to that of the fragment in the AIF protein and shows a highly reduced conformational flexibility. This peptide displays a similar affinity for CypA, an improved antiapoptotic activity in cells and an enhanced proteolytic stability compared to the parent peptide. The NMR-based 3D model of the AIF(381-389)/CypA complex provides a better understanding of the binding hot spots on both the peptide and the protein and can be exploited to design AIF/CypA inhibitors with improved pharmacokinetic and pharmacodynamics features.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00777DOI Listing
August 2021

Lanthionine, a Novel Uremic Toxin, in the Vascular Calcification of Chronic Kidney Disease: The Role of Proinflammatory Cytokines.

Int J Mol Sci 2021 Jun 26;22(13). Epub 2021 Jun 26.

Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy.

Vascular calcification (VC) is a risk factor for cardiovascular events and mortality in chronic kidney disease (CKD). Several components influence the occurrence of VC, among which inflammation. A novel uremic toxin, lanthionine, was shown to increase intracellular calcium in endothelial cells and may have a role in VC. A group of CKD patients was selected and divided into patients with a glomerular filtration rate (GFR) of <45 mL/min/1.73 m and ≥45 mL/min/1.73 m. Total Calcium Score (TCS), based on the Agatston score, was assessed as circulating lanthionine and a panel of different cytokines. A hemodialysis patient group was also considered. Lanthionine was elevated in CKD patients, and levels increased significantly in hemodialysis patients with respect to the two CKD groups; in addition, lanthionine increased along with the increase in TCS, starting from one up to three. Interleukin IL-6, IL-8, and Eotaxin were significantly increased in patients with GFR < 45 mL/min/1.73 m with respect to those with GFR ≥ 45 mL/min/1.73 m. IL-1b, IL-7, IL-8, IL-12, Eotaxin, and VEGF increased in calcified patients with respect to the non-calcified. IL-8 and Eotaxin were elevated both in the low GFR group and in the calcified group. We propose that lanthionine, but also IL-8 and Eotaxin, in particular, are a key feature of VC of CKD, with possible marker significance.
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http://dx.doi.org/10.3390/ijms22136875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269354PMC
June 2021

A novel approach for studying receptor-ligand interactions on living cells surface by using NUS/T1ρ-NMR methodologies combined with computational techniques: The RGDechi15D-αβ integrin complex.

Comput Struct Biotechnol J 2021 29;19:3303-3318. Epub 2021 May 29.

Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania - Luigi Vanvitelli, via Vivaldi 43, 81100 Caserta, Italy.

Structural investigations of receptor-ligand interactions on living cells surface by high-resolution Nuclear Magnetic Resonance (NMR) are problematic due to their short lifetime, which often prevents the acquisition of experiments longer than few hours. To overcome these limitations, we developed an on-cell NMR-based approach for exploring the molecular determinants driving the receptor-ligand recognition mechanism under native conditions. Our method relies on the combination of high-resolution structural and dynamics NMR data with Molecular Dynamics simulations and Molecular Docking studies. The key point of our strategy is the use of Non Uniform Sampling (NUS) and T1ρ-NMR techniques to collect atomic-resolution structural and dynamics information on the receptor-ligand interactions with living cells, that can be used as conformational constraints in computational studies. In fact, the application of these two NMR methodologies allows to record spectra with high S/N ratio and resolution within the lifetime of cells. In particular, 2D NUS [H-H] trNOESY spectra are used to explore the ligand conformational changes induced by receptor binding; whereas T1ρ-based experiments are applied to characterize the ligand binding epitope by defining two parameters: T1ρ Attenuation factor and T1ρ Binding Effect. This approach has been tested to characterize the molecular determinants regulating the recognition mechanism of αβ-integrin by a selective cyclic binder peptide named RGDechi15D. Our data demonstrate that the developed strategy represents an alternative in-cell NMR tool for studying, at atomic resolution, receptor-ligand recognition mechanism on living cells surface. Additionally, our application may be extremely useful for screening of the interaction profiling of drugs with their therapeutic targets in their native cellular environment.
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http://dx.doi.org/10.1016/j.csbj.2021.05.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207173PMC
May 2021

Risks and Protective Factors Associated With Mental Health Symptoms During COVID-19 Home Confinement in Italian Children and Adolescents: The #Understandingkids Study.

Front Pediatr 2021 11;9:664702. Epub 2021 Jun 11.

Department of Human Neuroscience, Sapienza - University of Rome, Rome, Italy.

To identify risk and protective factors for mental health symptoms associated with lifestyle changes caused by home confinement in pediatric subjects and in children and adolescents with a neuropsychiatric disorder. This was a prospective, cross-sectional study conducted from May 10 to May 31, 2020. Two online anonymous surveys were developed: population-based and clinical-based (children with neuropsychiatric disorders). Outcomes included emotional and behavioral symptoms, as assessed by psychometric scales (BPSC, PPSC, PSC, CES-DC and SCARED, respectively), and lifestyle changes during home confinement (i.e., physical activity, screen time, home schooling, reading). The sample included 9,688 pediatric subjects, and 289 children and adolescents with a neuropsychiatric disorder. The presence of siblings was a protective factor in all ages. In pre- and school children: male sex, a diagnosis of autism, residency in highly affected areas, high parental educational level or job loss, and screen time (>2 h/day) were risk factors. Physical activity, home-schooling, reading, talking with other people were protective factors. Residency in highly affected areas, a diagnosis of mood disorder, parental job loss, and screen time, were associated with a worsening of the depressive symptoms, whereas physical activity, talking with other people, playing with parents were protective activities. Screen time was also a risk factor for anxiety symptoms, while physical activity, reading and talking with other people were protective factors. This study identified risk and protective factors for mental health symptoms associated with lifestyle changes caused by COVID-19 home confinement to promote mental well-being in pediatrics during pandemic times.
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http://dx.doi.org/10.3389/fped.2021.664702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225997PMC
June 2021

Ca as activator of pseudoperoxidase activity of pigeon, Eurasian woodcock and chicken myoglobins: New features for meat preservation studies.

Food Chem 2021 Nov 28;363:130234. Epub 2021 May 28.

Department of Environmental, Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), University of Campania 'Luigi Vanvitelli', Via Vivaldi 43, 81100-Caserta, Italy. Electronic address:

Myoglobin (Mb), hemeprotein that binds dioxygen in muscle, affects meat colour. Moreover, in presence of peroxides, metMb is a potent oxidant involved in oxidative rancidity in meat. Here, following pigeon Mb purification and primary structure mass spectroscopy characterization, we determined its autoxidation rate and pseudoperoxidase activity with respect to chicken and E. woodcock Mbs. The three Mbs exhibit different autoxidation rates (0.153-h pigeon, 0.194-h chicken and 0.220-h E. woodcock Mbs) and similar specificity constant (9.86x10 Ms pigeon, 8.81x10 Ms chicken and 9.90x10 Ms E. woodcock Mbs), considering their pseudoperoxidase activity. Moreover, for the first time, we detected an increase in pseudoperoxidase activity in presence of Ca, particularly at pH 5.8. NMR and CD data indicate that the nonspecific Ca binding induces small local structural rearrangements that in turn slightly reduce pigeon Mb thermal stability. However, considering Ca concentration variations before and post-mortem, this finding must be considered for meat preservation.
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http://dx.doi.org/10.1016/j.foodchem.2021.130234DOI Listing
November 2021

Vaccination strategy and anti - SARS-CoV-2 S titers in healthcare workers of the INT - IRCCS "Fondazione Pascale" Cancer Center (Naples, Italy).

Infect Agent Cancer 2021 May 12;16(1):32. Epub 2021 May 12.

Istituto Nazionale Tumori - IRCCS Fondazione Pascale, Napoli, Italy.

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and the resulting disease, coronavirus disease 2019 (COVID-19), have spread to millions of people globally, requiring the development of billions of different vaccine doses. The SARS-CoV-2 spike mRNA vaccine (named BNT162b2/Pfizer), authorized by the FDA, has shown high efficacy in preventing SARS-CoV-2 infection after administration of two doses in individuals 16 years of age and older. In the present study, we retrospectively evaluated the differences in the SARS-CoV-2 humoral immune response after vaccine administration in the two different cohorts of workers at the INT - IRCCS "Fondazione Pascale" Cancer Center (Naples, Italy): previously infected to SARS-CoV-2 subjects and not infected to SARS-CoV-2 subjects.

Methods: We determined specific anti-RBD (receptor-binding domain) titers against trimeric spike glycoprotein (S) of SARS-CoV-2 by Roche Elecsys Anti-SARS-CoV-2 S immunoassay in serum samples of 35 healthcare workers with a previous documented history of SARS-CoV-2 infection and 158 healthcare workers without, after 1 and 2 doses of vaccine, respectively. Moreover, geometric mean titers and relative fold changes (FC) were calculated.

Results: Both previously infected and not infected to SARS-CoV-2 subjects developed significant immune responses to SARS-CoV-2 after the administration of 1 and 2 doses of vaccine, respectively. Anti-S antibody responses to the first dose of vaccine were significantly higher in previously SARS-CoV-2-infected subjects in comparison to titers of not infected subjects after the first as well as the second dose of vaccine. Fold changes for subjects previously infected to SARS-CoV-2 was very modest, given the high basal antibody titer, as well as the upper limit of 2500.0 BAU/mL imposed by the Roche methods. Conversely, for naïve subjects, mean fold change following the first dose was low ([Formula: see text] =1.6), reaching 3.8 FC in 72 subjects (45.6%) following the second dose.

Conclusions: The results showed that, as early as the first dose, SARS-CoV-2-infected individuals developed a remarkable and statistically significant immune response in comparison to those who did not contract the virus previously, suggesting the possibility of administering only one dose in previously SARS-CoV-2-infected subjects. FC for previously infected subjects should not be taken into account for the generally high pre-vaccination values. Conversely, FC for not infected subjects, after the second dose, were = 3.8 in > 45.0% of vaccinees, and ≤ 3.1 in 19.0%, the latter showing a potential susceptibility to further SARS-CoV-2 infection.
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http://dx.doi.org/10.1186/s13027-021-00375-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114024PMC
May 2021

Characterization of Autism Spectrum Disorder (ASD) subtypes based on the relationship between motor skills and social communication abilities.

Hum Mov Sci 2021 Jun 21;77:102802. Epub 2021 Apr 21.

Unit for Severe Disabilities in Developmental Age and Young Adults, Scientific Institute, IRCCS E. Medea, Brindisi, Italy.

Motor abnormalities are generally observed in autism spectrum disorder (ASD), and motor difficulties are certainly evident during the early years of life and may thus precede social-communication impairments. The main aim of the present study was to examine ASD subtypes based on the relationship between motor skills and social communication abilities. Motor skills and social communication abilities were evaluated through the Movement Assessment Battery for Children-Second Edition, the Autism Diagnostic Observation Schedule-Second Version and the Psychoeducational Profile-Third Edition. In addition, social communication abilities were classified according to the Autism Classification System of Functioning: Social Communication-ACSF:SC criteria. We found that children with ASD presented poorer motor skills than their TD peers, and motor impairments correlated with poorer social communication abilities in children with ASD. In addition, children with lower social and communication functioning showed a more prominent impairment in manual dexterity and fine motor skills than children with better social and communication functioning. In conclusion, we suggest that stratifying children with ASD based on motor and social endophenotypes may be useful to understand the neurobiological mechanisms of ASD and lead to new types of treatment.
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http://dx.doi.org/10.1016/j.humov.2021.102802DOI Listing
June 2021

Immunotherapy may protect cancer patients from SARS-CoV-2 infection: a single-center retrospective analysis.

J Transl Med 2021 03 31;19(1):132. Epub 2021 Mar 31.

Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Naples, Italy.

Coronavirus disease 2019 (COVID-19) global pandemic has created unique challenges to healthcare systems throughout the world. Ensuring subjects' safety is mandatory especially in oncology, in consideration of cancer patients' particular frailty. We examined the proportion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgM and/or IgG positive subjects in three different groups from Istituto Nazionale Tumori - IRCCS "Fondazione G. Pascale" in Naples (Campania region, Italy): cancer patients treated with Innovative Immunotherapy (Immune Checkpoint Inhibitors, ICIs), cancer patients undergoing standard Chemotherapies (CHTs) and healthcare providers. 9 out of 287 (3.1%) ICIs patients resulted positive, with a significant lower percentage in respect to CHTs patients (39 positive subjects out of 598, 6.5%) (p = 0.04). There was no statistically significant difference between ICIs cohort and healthcare providers, 48 out of 1050 resulting positive (4.6%). Performing a Propensity Score Matching based on gender and tumor stage, the effect of treatment on seropositivity was analyzed through a regression logistic model and the ICIs treatment resulted to be the only protective factor significantly (p = 0.03) associated with positivity (odds ratio-OR: 0.41; 95% confidence interval-CI 0.18-0.91). According to these preliminary data, ICIs would appear to be a protective factor against the onset of COVID-19 infection.
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http://dx.doi.org/10.1186/s12967-021-02798-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010485PMC
March 2021

Characterization of the Mycobacterial MSMEG-3762/63 Efflux Pump in Drug Efflux.

Front Microbiol 2020 3;11:575828. Epub 2020 Dec 3.

Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, Università degli Studi della Campania Luigi Vanvitelli, Caserta, Italy.

Multi-drug resistant tuberculosis (MDR-TB) represents a major health problem worldwide. Drug efflux and the activity of efflux transporters likely play important roles in the development of drug-tolerant and drug-resistant mycobacterial phenotypes. This study is focused on the action of a mycobacterial efflux pump as a mechanism of drug resistance. Previous studies demonstrated up-regulation of the TetR-like transcriptional regulator in and its ortholog in () in acid-nitrosative stress conditions. MSMEG-3765 regulates the expression of the operon, and of the orthologous region in (). MSMEG-3762 and Rv1687c are annotated as ATP-binding proteins, while MSMEG-3763 and Rv1686c are annotated as trans-membrane polypeptides, defining an ABC efflux pump in both and . The two putative efflux systems share a high percentage of identity. To examine the role of the putative efflux system MSMEG-3762/63, we constructed and characterized a deletion mutant in (∆). By comparative analysis of wild type, knockout, and complemented strains, together with structural modeling and molecular docking bioinformatics analyses of the MSMEG-3763 trans-membrane protein, we define the protein complex MSMEG-3762/63 as an efflux pump. Moreover, we demonstrate involvement of this pump in biofilm development and in the extrusion of rifampicin and ciprofloxacin (CIP), antimicrobial drugs used in first- and second-line anti-TB therapies.
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http://dx.doi.org/10.3389/fmicb.2020.575828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744416PMC
December 2020

The change of conditions does not affect Ros87 downhill folding mechanism.

Sci Rep 2020 12 3;10(1):21067. Epub 2020 Dec 3.

Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Via Vivaldi 43, 81100, Caserta, Italy.

Downhill folding has been defined as a unique thermodynamic process involving a conformations ensemble that progressively loses structure with the decrease of protein stability. Downhill folders are estimated to be rather rare in nature as they miss an energetically substantial folding barrier that can protect against aggregation and proteolysis. We have previously demonstrated that the prokaryotic zinc finger protein Ros87 shows a bipartite folding/unfolding process in which a metal binding intermediate converts to the native structure through a delicate barrier-less downhill transition. Significant variation in folding scenarios can be detected within protein families with high sequence identity and very similar folds and for the same sequence by varying conditions. For this reason, we here show, by means of DSC, CD and NMR, that also in different pH and ionic strength conditions Ros87 retains its partly downhill folding scenario demonstrating that, at least in metallo-proteins, the downhill mechanism can be found under a much wider range of conditions and coupled to other different transitions. We also show that mutations of Ros87 zinc coordination sphere produces a different folding scenario demonstrating that the organization of the metal ion core is determinant in the folding process of this family of proteins.
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http://dx.doi.org/10.1038/s41598-020-78008-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713307PMC
December 2020

Cell Surface Mechanics Gate Embryonic Stem Cell Differentiation.

Cell Stem Cell 2021 02 17;28(2):209-216.e4. Epub 2020 Nov 17.

Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany. Electronic address:

Cell differentiation typically occurs with concomitant shape transitions to enable specialized functions. To adopt a different shape, cells need to change the mechanical properties of their surface. However, whether cell surface mechanics control the process of differentiation has been relatively unexplored. Here we show that membrane mechanics gate exit from naive pluripotency of mouse embryonic stem cells. By measuring membrane tension during early differentiation, we find that naive stem cells release their plasma membrane from the underlying actin cortex when transitioning to a primed state. By mechanically tethering the plasma membrane to the cortex by enhancing Ezrin activity or expressing a synthetic signaling-inert linker, we demonstrate that preventing this detachment forces stem cells to retain their naive pluripotent identity. We thus identify a decrease in membrane-to-cortex attachment as a new cell-intrinsic mechanism that is essential for stem cells to exit pluripotency.
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http://dx.doi.org/10.1016/j.stem.2020.10.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875094PMC
February 2021

Substitution of the Native Zn(II) with Cd(II), Co(II) and Ni(II) Changes the Downhill Unfolding Mechanism of Ros87 to a Completely Different Scenario.

Int J Mol Sci 2020 Nov 5;21(21). Epub 2020 Nov 5.

Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania-Luigi Vanvitelli, Via Vivaldi 43, 81100 Caserta, Italy.

The structural effects of zinc replacement by xenobiotic metal ions have been widely studied in several eukaryotic and prokaryotic zinc-finger-containing proteins. The prokaryotic zinc finger, that presents a bigger βββαα domain with a larger hydrophobic core with respect to its eukaryotic counterpart, represents a valuable model protein to study metal ion interaction with metallo-proteins. Several studies have been conducted on Ros87, the DNA binding domain of the prokaryotic zinc finger Ros, and have demonstrated that the domain appears to structurally tolerate Ni(II), albeit with important structural perturbations, but not Pb(II) and Hg(II), and it is in vitro functional when the zinc ion is replaced by Cd(II). We have previously shown that Ros87 unfolding is a two-step process in which a zinc binding intermediate converts to the native structure thorough a delicate downhill folding transition. Here, we explore the folding/unfolding behaviour of Ros87 coordinated to Co(II), Ni(II) or Cd(II), by UV-Vis, CD, DSC and NMR techniques. Interestingly, we show how the substitution of the native metal ion results in complete different folding scenarios. We found a two-state unfolding mechanism for Cd-Ros87 whose metal affinity is comparable to the one obtained for the native Zn-Ros87, and a more complex mechanism for Co-Ros87 and Ni-Ros87, that show higher values. Our data outline the complex cross-correlation between the protein-metal ion equilibrium and the folding mechanism proposing such an interplay as a key factor in the proper metal ion selection by a specific metallo-protein.
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http://dx.doi.org/10.3390/ijms21218285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663847PMC
November 2020

Selective Targeting of αvβ5 Integrin in HepG2 Cell Line by RGDechi15D Peptide.

Molecules 2020 Sep 19;25(18). Epub 2020 Sep 19.

CIRPeB, University of Naples "Federico II", 80134 Naples, Italy.

Recently, the research community has become increasingly concerned with the receptor αvβ5, a member of the well-known integrin family. Different ongoing studies have evidenced that αvβ5 integrin regulates not only physiological processes but also a wide array of pathological events, suggesting the receptor as a valuable biomarker to specifically target for therapeutic/diagnostic purposes. Remarkably, in some tumors the involvement of the receptor in cell proliferation, tumor dissemination and angiogenesis is well-documented. In this scenario, the availability of a selective αvβ5 antagonist without 'off-target' protein effects may improve survival rate in patients with highly aggressive tumors, such as hepatocellular carcinoma. We recently reported a cyclic peptide, RGDechi15D, obtained by structure-activity studies. To our knowledge it represents the first peptide-based molecule reported in the literature able to specifically bind αvβ5 integrin and not cross react with αvβ3. Here we demonstrated the ability of the peptide to diminish both adhesion and invasion of HepG2 cells, an in vitro model system for hepatocellular carcinoma, to reduce the cell proliferation through an apoptotic process, and to interfere with the PI3K pathway. The peptide, also decreases the formation of new vessels in endothelial cells. Taken together these results indicate that the peptide can be considered a promising molecule with properties suited to be assessed in the future for its validation as a selective therapeutic/diagnostic weapon in hepatocarcinoma.
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http://dx.doi.org/10.3390/molecules25184298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570809PMC
September 2020

The Ethic of Care, Disability, and Rehabilitation During the Coronavirus Disease 2019 Pandemic.

Pediatr Neurol 2020 10 16;111:39. Epub 2020 Jun 16.

Unit for Severe Disabilities in Developmental Age and Young Adults (Developmental Neurology and Neurorehabilitation), Scientific Institute IRCCS "E. Medea", Brindisi, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.pediatrneurol.2020.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297163PMC
October 2020

Zinc Fingers.

Met Ions Life Sci 2020 Mar;20

Zinc finger (ZF) domains, that represent the majority of the DNA-binding motifs in eukaryotes, are involved in several processes ranging from RNA packaging to transcriptional activation, regulation of apoptosis, protein folding and assembly, and lipid binding. While their amino acid composition varies from one domain to the other, a shared feature is the coordination of a zinc ion, with a structural role, by a different combination of cysteines and histidines. The classical zinc finger domain (also called Cys2His2) that represents the most common class, uses two cysteines and two histidines to coordinate the metal ion, and forms a compact ββα architecture consisting in a β-sheet and an α-helix. GAG-knuckle resembles the classical ZF, treble clef and zinc ribbon are also well represented in the human genome. Zinc fingers are also present in prokaryotes. The first prokaryotic ZF domain found in the transcriptional regulator Ros protein was identified in Agrobacterium tumefaciens. It shows a Cys2His2 metal ion coordination sphere and folds in a domain significantly larger than its eukaryotic counterpart arranged in a βββαα topology. Interestingly, this domain does not strictly require the metal ion coordination to achieve the functional fold. Here, we report what is known on the main classes of eukaryotic and prokarotic ZFs, focusing our attention to the role of the metal ion, the folding mechanism, and the DNA binding. The hypothesis of a horizontal gene transfer from prokaryotes to eukaryotes is also discussed.
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http://dx.doi.org/10.1515/9783110589757-018DOI Listing
March 2020

A potential prognostic marker in primitive lung neuroendocrine tumor: A case report.

Int J Biol Markers 2020 Sep 20;35(3):102-106. Epub 2020 Aug 20.

Division of Laboratory Medicine, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italy.

Background: The diagnosis and monitoring of primitive lung neuroendocrine tumors (lung pNETs) are usually performed by the measurement of serum chromogranin A (CgA) and urinary 5-hydroxyindolacetic acid (5-HIAA) levels. However, imaging techniques are necessary due to the poor diagnostic efficiency of the laboratory tests.

Methods: A total-body computed tomography and bone scintigraphy scans showed multiple hepatic and bone metastases of a 55-year-old man affected by well-differentiated lung pNETs without severe initial symptoms. After diagnosis, he started therapy and was monitored with serum, urinary markers, and imaging techniques.

Results: During follow-up, the urinary 5-HIAA levels did not significantly increase, while serum CgA and urinary para-hydroxyphenylacetic acid (pHPAA) levels (urinary organic acid physiologically present in the urines of healthy subjects) showed significant increases related to worsening clinical condition.

Conclusions: The early increase in urinary pHPAA levels-usually not dosed in pNET patient monitoring-could be a promising prognostic marker.
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http://dx.doi.org/10.1177/1724600820947107DOI Listing
September 2020

Short- and Long-Term Evaluation of Renal Function after Radical Cystectomy and Cutaneous Ureterostomy in High-Risk Patients.

J Clin Med 2020 Jul 11;9(7). Epub 2020 Jul 11.

Urologic Section, Department of Neurosciences, Sciences of Reproduction, and Odontostomatology, University of Naples Federico II, 80131 Naples, Italy.

Deterioration of renal function has been reported after radical cystectomy (RC) with urinary diversion. We investigated renal function changes in elderly bladder cancer (BCa) patients who underwent RC with cutaneous ureterostomy (CU) urinary diversion. We performed a retrospective, observational study. BCa patients aged ≥75 with an American Society of Anesthesiologists (ASA) class greater than II were included. Glomerular filtration rate (GFR) was the main outcome measure. GFR values were recorded preoperatively, at discharge, at 6-month follow-up, and yearly up to 60 months. A total of 70 patients with a median age of 78.0 years were identified. Median preoperative GFR was 74.3 mL/min/1.73 m and declined significantly to 54.6 mL/min/1.73 m after 6 months ( < 0.001). A gradual GFR decline was observed thereafter, reaching a median value of 46.2 after 60 months. Preoperative GFR and acute kidney injury were significant predictors of fast deterioration of GFR and of 25% deterioration of GFR after 12 months. Elderly BCa patients with high comorbidity rates undergoing RC with CU should be carefully informed about the risk of GFR deterioration and the need for adequate monitoring.
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http://dx.doi.org/10.3390/jcm9072191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408808PMC
July 2020

Structural Insight of the Full-Length Ros Protein: A Prototype of the Prokaryotic Zinc-Finger Family.

Sci Rep 2020 06 9;10(1):9283. Epub 2020 Jun 9.

Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", via Vivaldi, 43, 81100, Caserta, Italy.

Ros/MucR is a widespread family of bacterial zinc-finger (ZF) containing proteins that integrate multiple functions such as virulence, symbiosis and/or cell cycle transcription. NMR solution structure of Ros DNA-binding domain (region 56-142, i.e. Ros87) has been solved by our group and shows that the prokaryotic ZF domain shows interesting structural and functional features that differentiate it from its eukaryotic counterpart as it folds in a significantly larger zinc-binding globular domain. We have recently proposed a novel functional model for this family of proteins suggesting that they may act as H-NS-'like' gene silencers. Indeed, the N-terminal region of this family of proteins appears to be responsible for the formation of functional oligomers. No structural characterization of the Ros N-terminal domain (region 1-55) is available to date, mainly because of serious solubility problems of the full-length protein. Here we report the first structural characterization of the N-terminal domain of the prokaryotic ZF family examining by means of MD and NMR the structural preferences of the full-length Ros protein from Agrobacterium tumefaciens.
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http://dx.doi.org/10.1038/s41598-020-66204-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283297PMC
June 2020

COVID-19 and child disabilities: whom to protect and how.

Eur J Phys Rehabil Med 2020 Jun 24;56(3):372-373. Epub 2020 Apr 24.

Unit for Severe Disabilities in Developmental Age and Young Adults (Developmental Neurology and Neurorehabilitation), Scientific Institute IRCCS E. Medea, Brindisi, Italy.

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http://dx.doi.org/10.23736/S1973-9087.20.06309-1DOI Listing
June 2020

Evaluation of Hypertension, Proteinuria, and Abnormalities of Body Weight in Italian Adolescents Participating in the World Kidney Days.

Kidney Blood Press Res 2020 7;45(2):286-296. Epub 2020 Feb 7.

Department of Public Health, Nephrology Unit, University Federico II, Naples, Italy.

Introduction: World Kidney Day (WKD) was promoted by the Italian Kidney Foundation and the Italian Society of Nephrology for raising awareness, detection, prevention, and treatment of kidney diseases. The Italian WKD focused on the "School Project" by screening students attending the fifth year of high school. The main goal of the "School Project" was to assess in healthy adolescents the presence of hypertension (HTN) and proteinuria; as well as to evaluate potential interrelations between overweight, obesity (both measured with different anthropometric methods), blood pressure (BP) levels, and proteinuria. The ancillary goal was to have an estimate of awareness on some nephrology topics.

Methods: The study population consisted of 17- to 19-year-old students. HTN was defined as systolic BP (SBP) ≥140 mm Hg and/or diastolic BP (DBP) ≥90 mm Hg. Isolated systolic hypertension (ISH) was defined as SBP ≥140 mm Hg and DBP <90 mm Hg; isolated diastolic hypertension as SBP <140 mm Hg and DBP ≥90 mm Hg; systolic and diastolic hypertension as SBP ≥140 mm Hg and DBP ≥90 mm Hg; pre-hypertension as SBP >120 mm Hg but <140 mm Hg or DBP >80 mm Hg but <90 mm Hg; and optimal BP as SBP ≤120 mm Hg and DBP ≤80 mm Hg. Urine tests were performed with a dipstick; the subjects were regarded as proteinuric when the urine dipstick was positive (proteinuria ≥30 mg/dL). Body weight, height, and waist circumference (WC) were measured; body mass index (BMI), waist-to-height ratio (WHtR), and conicity index (Ci) were calculated. According to the BMI, the following classifications were adopted: underweight (<18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), class-I obesity (30-34.9 kg/m2), class-II obesity (35-39.9 kg/m2), class-III obesity (≥40 kg/m2).

Results: Data from 12,125 students (45.6% males) were evaluated. HTN was found in 1,349 participants (11.1%; 61.1% male), and ISH was present in 7.4%. Overweight (24.1%) and class-I (6%), -II (3.6%), and -III (1%) obesity were present in hypertensive participants. Compared to participants with normal BP, hypertensive participants had a higher BMI (p < 0.001), WC (p < 0.001), and WHtR (p < 0.001); whereas the Ci was not different (p = 0.527). Multivariate linear regression analysis showed that both WC and BMI were predictors of abnormal SBP and DBP (p < 0.001) both in males and females. Proteinuria was present in 14.8, 13.8, 14.7, and 14.7% of all normal weight, overweight, obese, and all subjects, respectively. In addition, no association was found between body weight, proteinuria, and BP.

Conclusion: This study shows that overweight and obesity were significantly associated to HTN in Italian adolescents. BMI and WC were predictors of SBP and DBP. The occurrence of proteinuria was quite similar to that of HTN, but it was not associated with anthropometric indicators or HTN.
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http://dx.doi.org/10.1159/000502547DOI Listing
November 2020

Correlation of structure, function and protein dynamics in myoglobins from Eurasian woodcock, chicken and ostrich.

J Biomol Struct Dyn 2021 Feb 31;39(3):851-866. Epub 2020 Jan 31.

Department of Environmental, Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), University of Campania 'Luigi Vanvitelli', Caserta, Italy.

Myoglobin (Mb), oxygen-binding heme-protein retrieved primarily in muscles, is a local oxygen reservoir providing to oxygen when oxygen delivery is insufficient during catabolism. Furthermore, Mb structure is studied as example of molecular evolution for its ability to respond to environmental pressures and adapt to it through few amino acid substitutions. Here, in order to explore the structure-function-dynamics relationships of Eurasian woodcock chicken and ostrich Mbs we have applied an integrated approach in which spectroscopic and biochemical data have been coupled to computational techniques as structural modelling and molecular dynamics simulations. The primary structure of E. woodcock Mb, reveals the presence of 3 (i.e. Q34H, E44D and V66A) and 10 (i.e. A19T, E27A, V28I, K50T, D53E, G57A, D60E, N81K, S84A and A120S) amino acid substitutions respect to chicken and ostrich Mbs, respectively. Although the high amino acid sequence identity, E. woodcock Mb displays a higher autoxidation rate than chicken and ostrich Mb, despite of a similar melting temperature ( ∼ 358 K). Yet, the 3D structural models validated by using experimental data indicate that the three Mbs adopt an almost identical three-dimensional structure conserving the typical secondary and tertiary structural organization. Interestingly, dynamics data reveal that the E. woodcock Mb exhibits greater internal motions than either chicken or ostrich Mbs. Overall, our study demonstrates that in Mbs the functional properties are significantly driven by the protein dynamic peculiarities, which in turn depend on the amino acid composition of the region located in proximity of the pathways for the gas ligands. [Formula: see text] Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1719201DOI Listing
February 2021

A systematic review of coping strategies in parents of children with attention deficit hyperactivity disorder (ADHD).

Res Dev Disabil 2020 Mar 13;98:103571. Epub 2020 Jan 13.

Scientific Institute, IRCCS E. Medea, Unit for Severe Disabilities in Developmental Age and Young Adults, Brindisi, Italy. Electronic address:

Background: Parents of children with attention deficit hyperactivity disorder (ADHD) use several coping strategies to deal with ADHD symptoms impacting family life.

Aim: The aim of this systematic review was to summarize the coping strategies used by parents of children with ADHD, identify which tools are most frequently used to measure coping strategies, and examine factors influencing parental coping.

Method: According to PRISMA guidelines, we searched for articles indexed in PubMed, EBSCOhost, Scopus, and Web of Science using a combination of expressions including "coping" AND "ADHD" OR "attention-deficit/hyperactivity disorder" AND "parent" OR "parenting" OR "caregiver".

Results: Fourteen empirical studies were identified as relevant to our research. Many different types of tools are used to assess coping strategies. We found that parents of ADHD children used more avoidant-focused coping strategies than parents of typical children. Mothers of ADHD children sought significantly more support and used more indirect means than mothers of typically developing (TD) children.

Conclusions: This review underlines the importance of further exploring coping mechanisms of parents of children with ADHD in order to promote positive coping strategies for parents of children with ADHD, and to help such parents to identify people who can support them.
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http://dx.doi.org/10.1016/j.ridd.2020.103571DOI Listing
March 2020

Nissen fundoplication and dyspeptic symptoms: is the water load test useful?

Minerva Gastroenterol Dietol 2020 Mar 20;66(1):11-16. Epub 2019 Nov 20.

Unit of Gastroenterology and Endoscopy, Cardinal Massaja Hospital, Asti, Italy.

Background: The water load test is a simple, cheap and standardized method to evaluate gastric distension and gastric motility responses. We have previously shown that in patients with mild erosive or non-erosive esophagitis this test is frequently abnormal, suggesting an altered gastric function. The aim was to evaluate the water load test score before and after Nissen fundoplication in reflux patients.

Methods: Thirty-one patients (16 men, 15 women, mean age 46.5 y) were studied before and 3 months after Nissen fundoplication by stationary esophageal manometry, wireless Bravo pH system monitoring (48 hours), and water load test. A dyspepsia symptom questionnaire was also completed before and after surgery. Data were compared with those of 35 controls.

Results: All patients had pH-monitoring positive for pathological acid exposure and/or related-reflux symptoms in the absence of motility disorders. Basal symptoms scores were higher in patients compared to controls and improved after surgery, except than postprandial fullness, early satiation, and bloating, that were significantly increased. At baseline, all patients ingested significantly lower water volumes than controls, with a tendency to early onset of fullness and nausea, respectively. After surgery, the water volumes were significantly lower than presurgery.

Conclusions: In patients with reflux-related symptoms, with or without esophagitis, the water load test is frequently abnormal, suggesting an altered gastric function. Nissen fundoplication is associated with a relatively higher incidence of bloating, epigastric pain and fullness. These preliminary data could explain the incomplete resolution of symptoms after surgery in some patients, and suggest the use of additional studies to explore the gastric function in presurgical evaluation.
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http://dx.doi.org/10.23736/S1121-421X.19.02632-1DOI Listing
March 2020

Vitamin D in kidney transplant recipients
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Clin Nephrol 2020 Feb;93(2):57-64

Kidney transplant recipients (KTRs) are susceptible to low levels of vitamin D, which may be responsible for mineral and bone metabolism disorders and play some role in the occurrence of cardiovascular, metabolic, immunologic, neoplastic, and infectious complications after kidney transplant. Kidney Disease Improving Global Outcomes (KDIGO) guidelines of the year 2017 recommended vitamin D supplementation in the first 12 months after transplant using the same treatment strategies for the general population. However, no recommendations are provided after the first 12 months due to a lack of sufficient data. This review analyses some studies that assessed the vitamin D status of KTRs and the effects of nutritional and active vitamin D supplementation on bone mineral density, cardiovascular disease, proteinuria, and graft function in KTRs.
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http://dx.doi.org/10.5414/CN109735DOI Listing
February 2020

Coping, stress and negative psychological outcomes in parents of children admitted to a pediatric neurorehabilitation care unit.

Eur J Phys Rehabil Med 2019 Dec 9;55(6):772-782. Epub 2019 Jul 9.

Unit for Severe Disabilities in Developmental Age and Young Adults, Scientific Institute, IRCCS E. Medea, Brindisi, Italy -

Background: Parents' attitudes and psychological adjustment during their child's hospitalization in a pediatric neurorehabilitation care unit are key aspects for the child's adherence to care and the impact of the disease.

Aim: The aim of this study was to examine the relationship between parenting stress, coping style, and negative psychological outcomes in families of children admitted for the first time to a pediatric neurorehabilitation care unit.

Design: This is an observational study.

Setting: Pediatric neurorehabilitation care unit.

Population: One hundred twenty-four parents of children diagnosed with neurodevelopmental or neurological conditions.

Methods: Parents completed standardized questionnaires assessing parenting stress, coping style, anxiety and depressive symptoms.

Results: We found that parents of children with neurodevelopmental conditions showed more emotion-focused coping strategies (P=0.016) and depressive symptoms (P=0.01) compared with parents of children with neurological conditions. Hierarchical regression analyses showed that emotion- and avoidance-oriented coping style and socioeconomic status are crucial factors in the adjustment process of parents of children with neurodevelopmental conditions. By contrast, parenting stress and child difficulties were the most significant predictors of negative psychological outcomes in parents with neurological conditions.

Conclusions: This study sought to develop more understanding of the relationship among parenting stress, coping, and anxiety or depressive symptoms in parent of children hospitalized in a pediatric neurorehabilitation care unit. We suggest that examining parents may increase our understanding of the interplay between child and parent functioning in families with children admitted for the first time to a pediatric neurorehabilitation care unit.

Clinical Rehabilitation Impact: Identify these predictors might help professionals to develop screening procedures to identify parent at high risk for anxiety or depression, and to conduct early interventions to reduce uncertainty and maladaptive coping strategies that may influences rehabilitation process.
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http://dx.doi.org/10.23736/S1973-9087.19.05695-8DOI Listing
December 2019

The Empathizing-Systemizing Theory and 'Extreme Male Brain' (EMB) Theory in Parents of Children with Autism Spectrum Disorders (ASD): An Explorative, Cross-Sectional Study.

J Autism Dev Disord 2019 Oct;49(10):4067-4078

Unit for Severe Disabilities in Developmental Age and Young Adults, Scientific Institute, IRCCS, E. Medea, Piazza "A. Di Summa", 72100, Brindisi, Italy.

The aim of this study was to evaluate whether empathizing and systemizing are part of the parental broad autism phenotype (BAP). Parents (N = 76) of preschool children with a diagnosis of ASD and parents (N = 48) of typically developing (TD) children completed the Empathy Quotient (EQ) and Systemizing Quotient-Revised (SQ-R) questionnaires. The E-S discrepancy (D score) was used to test for sex differences in five "brain types". Our results suggest that the E-S theory do not seem to be part of the BAP. However, a stronger drive to systemize than empathize (Type S brain) could be a highly inheritable cognitive endophenotype of mothers of children with ASD. This study should be repeated with a larger sample size.
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http://dx.doi.org/10.1007/s10803-019-04114-wDOI Listing
October 2019

Conformational studies of RGDechi peptide by natural-abundance NMR spectroscopy.

J Pept Sci 2019 May 18;25(5):e3166. Epub 2019 Mar 18.

Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania Luigi Vanvitelli, Caserta, Italy.

Integrins are heterodimeric cell-surface proteins that play important roles during developmental and pathological processes. Diverse human pathologies involve integrin adhesion including thrombotic diseases, inflammation, tumour progression, fibrosis, and infectious diseases. Although in the past decade, novel integrin-inhibitor drugs have been developed for integrin-based medical applications, the structural determinants modulating integrin-ligands recognition mechanisms are still poorly understood, reducing the number of integrin subtype exclusive antagonists. In this scenario, we have very recently showed, by means of chemical and biological assays, that a chimeric peptide (named RGDechi), containing a cyclic RGD motif linked to an echistatin C-terminal fragment, is able to interact with the components of integrin family with variable affinities, the highest for α β3. Here, in order to understand the mechanistic details driving the molecular recognition mechanism of α β by RGDechi, we have performed a detailed structural and dynamics characterization of the free peptide by natural abundance nuclear magnetic resonance (NMR) spectroscopy. Our data indicate that RGDechi presents in solution an heterogeneous conformational ensemble characterized by a more constrained and rigid pentacyclic ring and a largely unstructured acyclic region. Moreover, we propose that the molecular recognition of α β integrin by RGDechi occurs by a combination of conformational selection and induced fit mechanisms. Finally, our study indicates that a detailed NMR characterization, by means of natural abundance N and C, of a mostly unstructured bioactive peptide may provide the molecular basis to get essential structural insights into the binding mechanism to the biological partner.
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http://dx.doi.org/10.1002/psc.3166DOI Listing
May 2019

Ni(II), Hg(II), and Pb(II) Coordination in the Prokaryotic Zinc-Finger Ros87.

Inorg Chem 2019 Jan 31;58(2):1067-1080. Epub 2018 Dec 31.

Department of Environmental, Biological and Pharmaceutical Science and Technology , University of Campania "L. Vanvitelli" , via Vivaldi 43 , 81100 Caserta , Italy.

Zinc ion binding is a principal event in the achievement of the correct fold in classical zinc finger domains since the motif is largely unfolded in the absence of metal. In the case of a prokaryotic zinc finger, the larger βββαα domain contributes to the folding mechanism with a larger hydrophobic core. For these reasons, following the great amount of attention devoted to unveiling the effect of xenobiotic metal ion replacement in zinc fingers and in zinc-containing proteins in general, the prokaryotic zinc finger domain appears to be an interesting model for studying metal ion interaction with metalloproteins. Here, we explore the binding of Ni(II), Hg(II), and Pb(II) to Ros87, the DNA binding domain of the prokaryotic zinc finger protein Ros. We measured Ros87-metal ion dissociation constants and monitored the effects on the structure and function of the domain. Interestingly, we found that the protein folds in the presence of Ni(II) with important structural perturbations, while in the presence of Pb(II) and Hg(II) it does not appear to be significantly folded. Accordingly, an overall strong reduction in the DNA binding capability is observed for all of the examined proteins. Our data integrate and complement the information collected in the past few years concerning the functional and structural effects of metal ion substitution in classical zinc fingers in order to contribute to a better comprehension of the toxicity of these metals in biological systems.
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http://dx.doi.org/10.1021/acs.inorgchem.8b02201DOI Listing
January 2019

Exploring Visual Perspective Taking and body awareness in children with Autism Spectrum Disorder.

Cogn Neuropsychiatry 2018 07 21;23(4):254-265. Epub 2018 Jun 21.

a Scientific Institute I.R.C.C.S. "Eugenio Medea", "La Nostra Famiglia", Unit for Severe disabilities in developmental age and young adults (Developmental Neurology and Neurorehabilitation) , Brindisi Research Centre , Brindisi , Italy.

Introduction: Recent evidence suggests that impairments in social cognition are associated to the cognitive abilities needed to take several viewpoints in perceptual situations and body awareness. The aim of the current study was to investigate Visual Perspective Taking (VPT) and Body awareness performance in a group of children with Autism Spectrum Disorders (ASD) compared with a group of children with Intellectual Disability (ID) and typically developing (TD) children.

Methods: Our groups were administered an IQ test and a VPT task, and body awareness tests.

Results: Children with ASD or ID were more impaired in body awareness development compared to TD (p < .001) children. The ASD group differentiates largely from the other two groups in the mean VPT (p < .001) scores.

Conclusions: The current study provides a framework for considering social impairments in autism on a broader scale, including visuoperceptual and body awareness difficulties as a core contributor to social interaction difficulties.
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http://dx.doi.org/10.1080/13546805.2018.1486182DOI Listing
July 2018

Folding mechanisms steer the amyloid fibril formation propensity of highly homologous proteins.

Chem Sci 2018 Apr 1;9(13):3290-3298. Epub 2018 Mar 1.

Department of Environmental, Biological and Pharmaceutical Sciences and Technologies , University of Campania "Luigi Vanvitelli" , Via Vivaldi 43 , 81100 Caserta , Italy . Email:

Significant advances in the understanding of the molecular determinants of fibrillogenesis can be expected from comparative studies of the aggregation propensities of proteins with highly homologous structures but different folding pathways. Here, we fully characterize, by means of stopped-flow, T-jump, CD and DSC experiments, the unfolding mechanisms of three highly homologous proteins, zinc binding Ros87 and Ml1 and zinc-lacking Ml4. The results indicate that the three proteins significantly differ in terms of stability and (un)folding mechanisms. Particularly, Ros87 and Ml1 appear to be much more stable to guanidine denaturation and are characterized by folding mechanisms including the presence of an intermediate. On the other hand, metal lacking Ml4 folds according to a classic two-state model. Successively, we have monitored the capabilities of Ros87, Ml4 and Ml1 to form amyloid fibrils under native conditions. Particularly, we show, by CD, fluorescence, DLS, TEM and SEM experiments, that after 168 hours, amyloid formation of Ros87 has started, while Ml1 has formed only amorphous aggregates and Ml4 is still monomeric in solution. This study shows how metal binding can influence protein folding pathways and thereby control conformational accessibility to aggregation-prone states, which in turn changes aggregation kinetics, shedding light on the role of metal ions in the development of protein deposition diseases.
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http://dx.doi.org/10.1039/c8sc00166aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933289PMC
April 2018
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