Publications by authors named "M Ferrari"

3,981 Publications

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Headache in people with epilepsy.

Nat Rev Neurol 2021 Jul 26. Epub 2021 Jul 26.

Stichting Epilepsie Instellingen Nederland, Heemstede, The Netherlands.

Epidemiological estimates indicate that individuals with epilepsy are more likely to experience headaches, including migraine, than individuals without epilepsy. Headaches can be temporally unrelated to seizures, or can occur before, during or after an episode; seizures and migraine attacks are mostly not temporally linked. The pathophysiological links between headaches (including migraine) and epilepsy are complex and have not yet been fully elucidated. Correct diagnoses and appropriate treatment of headaches in individuals with epilepsy is essential, as headaches can contribute substantially to disease burden. Here, we review the insights that have been made into the associations between headache and epilepsy over the past 5 years, including information on the pathophysiological mechanisms and genetic variants that link the two disorders. We also discuss the current best practice for the management of headaches co-occurring with epilepsy and highlight future challenges for this area of research.
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http://dx.doi.org/10.1038/s41582-021-00516-6DOI Listing
July 2021

Translational regulation in pathogenic and beneficial plant-microbe interactions.

Biochem J 2021 Jul;478(14):2775-2788

Instituto de Biotecnología y Biología Molecular, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Centro Científico y Tecnológico-La Plata, Consejo Nacional de Investigaciones Científicas y Técnicas, 1900 La Plata, Argentina.

Plants are surrounded by a vast diversity of microorganisms. Limiting pathogenic microorganisms is crucial for plant survival. On the other hand, the interaction of plants with beneficial microorganisms promotes their growth or allows them to overcome nutrient deficiencies. Balancing the number and nature of these interactions is crucial for plant growth and development, and thus, for crop productivity in agriculture. Plants use sophisticated mechanisms to recognize pathogenic and beneficial microorganisms and genetic programs related to immunity or symbiosis. Although most research has focused on characterizing changes in the transcriptome during plant-microbe interactions, the application of techniques such as Translating Ribosome Affinity Purification (TRAP) and Ribosome profiling allowed examining the dynamic association of RNAs to the translational machinery, highlighting the importance of the translational level of control of gene expression in both pathogenic and beneficial interactions. These studies revealed that the transcriptional and the translational responses are not always correlated, and that translational control operates at cell-specific level. In addition, translational control is governed by cis-elements present in the 5'mRNA leader of regulated mRNAs, e.g. upstream open reading frames (uORFs) and sequence-specific motifs. In this review, we summarize and discuss the recent advances made in the field of translational control during pathogenic and beneficial plant-microbe interactions.
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http://dx.doi.org/10.1042/BCJ20210066DOI Listing
July 2021

Lectin Pathway Mediates Complement Activation by SARS-CoV-2 Proteins.

Front Immunol 2021 5;12:714511. Epub 2021 Jul 5.

Department of Veterinary Medicine, School of Biological Sciences, University of Cambridge, Cambridge, United Kingdom.

Early and persistent activation of complement is considered to play a key role in the pathogenesis of COVID-19. Complement activation products orchestrate a proinflammatory environment that might be critical for the induction and maintenance of a severe inflammatory response to SARS-CoV-2 by recruiting cells of the cellular immune system to the sites of infection and shifting their state of activation towards an inflammatory phenotype. It precedes pathophysiological milestone events like the cytokine storm, progressive endothelial injury triggering microangiopathy, and further complement activation, and causes an acute respiratory distress syndrome (ARDS). To date, the application of antiviral drugs and corticosteroids have shown efficacy in the early stages of SARS-CoV-2 infection, but failed to ameliorate disease severity in patients who progressed to severe COVID-19 pathology. This report demonstrates that lectin pathway (LP) recognition molecules of the complement system, such as MBL, FCN-2 and CL-11, bind to SARS-CoV-2 S- and N-proteins, with subsequent activation of LP-mediated C3b and C4b deposition. In addition, our results confirm and underline that the N-protein of SARS-CoV-2 binds directly to the LP- effector enzyme MASP-2 and activates complement. Inhibition of the LP using an inhibitory monoclonal antibody against MASP-2 effectively blocks LP-mediated complement activation. FACS analyses using transfected HEK-293 cells expressing SARS-CoV-2 S protein confirm a robust LP-dependent C3b deposition on the cell surface which is inhibited by the MASP-2 inhibitory antibody. In light of our present results, and the encouraging performance of our clinical candidate MASP-2 inhibitor Narsoplimab in recently published clinical trials, we suggest that the targeting of MASP-2 provides an unsurpassed window of therapeutic efficacy for the treatment of severe COVID-19.
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http://dx.doi.org/10.3389/fimmu.2021.714511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287855PMC
July 2021

Characterisation of a novel ACE2-based therapeutic with enhanced rather than reduced activity against SARS-CoV-2 variants.

J Virol 2021 Jul 21:JVI0068521. Epub 2021 Jul 21.

Autolus Limited, The MediaWorks, 191 Wood Lane, London, W12 7FP.

The human angiotensin-converting enzyme 2 acts as the host cell receptor for SARS-CoV-2 and the other members of the family SARS-CoV-1 and HCoV-NL63. Here we report the biophysical properties of the SARS-CoV-2 spike variants D614G, B.1.1.7, B.1.351 and P.1 with affinities to the ACE2 receptor and infectivity capacity, revealing weaknesses in the developed neutralising antibody approaches. Furthermore, we report a pre-clinical characterisation package for a soluble receptor decoy engineered to be catalytically inactive and immunologically inert, with broad neutralisation capacity, that represents an attractive therapeutic alternative in light of the mutational landscape of COVID-19. This construct efficiently neutralised four SARS-CoV-2 variants of concern. The decoy also displays antibody-like biophysical properties and manufacturability, strengthening its suitability as a first-line treatment option in prophylaxis or therapeutic regimens for COVID-19 and related viral infections. Mutational drift of SARS-CoV-2 risks rendering both therapeutics and vaccines less effective. Receptor decoy strategies utilising soluble human ACE2 may overcome the risk of viral mutational escape since mutations disrupting viral interaction with the ACE2 decoy will by necessity decrease virulence thereby preventing meaningful escape. The solution described here of a soluble ACE2 receptor decoy is significant for the following reasons: While previous ACE2-based therapeutics have been described, ours has novel features including (1) mutations within ACE2 to remove catalytical activity and systemic interference with the renin/angiotensin system; (2) abrogated FcγR engagement, reduced risk of antibody-dependent enhancement of infection and reduced risk of hyperinflammation, and (3) streamlined antibody-like purification process and scale-up manufacturability indicating that this receptor decoy could be produced quickly and easily at scale. Finally, we demonstrate that ACE2-based therapeutics confer a broad-spectrum neutralisation potency for ACE2-tropic viruses, including SARS-CoV-2 variants of concern in contrast to therapeutic mAb.
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http://dx.doi.org/10.1128/JVI.00685-21DOI Listing
July 2021
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