Publications by authors named "Sebastian Esperante"

Article Synopsis
  • * Researchers discovered that the C-terminal domain (CTD) of the JUNV NP can be purified and has a stable structure similar to NP from other viruses, and it interacts with the viral matrix protein Z.
  • * The JUNV NP CTD shows metal-ion-dependent nuclease activity on DNA and RNA, suggesting a new function that could influence the immune response to this virus, especially if mutations occur in key residues.
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Article Synopsis
  • Viral factories, which have a liquid-like nature, are essential for the transcription and replication processes in most viruses, including the respiratory syncytial virus (RSV).
  • The interaction between the phosphoprotein (P) and nucleoprotein (N) is crucial, as it regulates the formation and dissolution of these viral factories through a phase separation process.
  • This phase separation of P is typically kept in check by its structure but is activated when partnered with N or when certain sequences are removed, highlighting P's role as a "solvent-protein" in the organization of viral components.
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Background: Precise determination of the causal chain that leads to community deaths in children in low- and middle-income countries is critical to estimating all causes of mortality accurately and to planning preemptive strategies for targeted allocation of resources to reduce this scourge.

Methods: An active surveillance population-based study that combined minimally invasive tissue sampling (MITS) and verbal autopsies (VA) among children under 5 was conducted in Buenos Aires, Argentina, from September 2018 to December 2020 to define the burden of all causes of community deaths.

Results: Among 90 cases enrolled (86% of parental acceptance), 81 had complete MITS, 15.

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Background: Many deaths in infants from low-middle income countries (LMICs) occur at home or upon arrival to health facilities. Although acute lower respiratory tract illness plays an important role in community mortality, the accuracy of mortality rates due to respiratory syncytial virus (RSV) remains unknown.

Methods: An active surveillance study among children aged under 5 years old (U5) was performed in Buenos Aires, Argentina, between January and December 2019, to define the burden and role of RSV in childhood community mortality.

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Hereditary transthyretin amyloidosis (ATTR) is an autosomal dominant disease characterized by the extracellular deposition of the transport protein transthyretin (TTR) as amyloid fibrils. Despite the progress achieved in recent years, understanding why different TTR residue substitutions lead to different clinical manifestations remains elusive. Here, we studied the molecular basis of disease-causing missense mutations affecting residues R34 and K35.

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Background: Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness.

Methods: We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adult patients within 72 hours after the onset of mild Covid-19 symptoms.

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Hereditary transthyretin amyloidosis (ATTR) is a disease characterized by the extracellular deposition of transthyretin (TTR) amyloid fibrils. Highly destabilizing TTR mutations cause leptomeningeal amyloidosis, a rare, but fatal, disorder in which TTR aggregates in the brain. The disease remains intractable, since liver transplantation, the reference therapy for systemic ATTR, does not stop mutant TTR production in the brain.

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Article Synopsis
  • Interferon response suppression in respiratory syncytial virus (RSV) is facilitated by nonstructural proteins NS1 and NS2, which form high-order complexes with cellular partners.
  • Proline residues P81 and P67 are crucial for the conformational changes that enable NS1 oligomerization, with P81 involved in stabilizing the structure and P67 influencing aggregation tendencies.
  • Despite their spatial distance from the C-terminal helix, both proline mutations affect the stability of oligomerization and aggregation processes, highlighting a significant connection between structural dynamics and the functionality of NS1 in multiprotein complexes.
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Amyloids have been exploited to build amazing bioactive materials. In most cases, short synthetic peptides constitute the functional components of such materials. The controlled assembly of globular proteins into active amyloid nanofibrils is still challenging, because the formation of amyloids implies a conformational conversion towards a β-sheet-rich structure, with a concomitant loss of the native fold and the inactivation of the protein.

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  • The Pneumovirus family, part of Mononegavirales, relies on the M2-1 protein for RNA polymerase processivity and viral particle assembly, which is influenced by a zinc-binding motif.
  • Respiratory syncytial virus M2-1 exhibits higher stability, while the human metapneumovirus (HMPV) M2-1 shows greater intersubunit affinity; removing zinc leads to slow oligomerization with altered structures.
  • Structural modeling indicates that the CCCH motif significantly impacts the strength of protein interactions, with HMPV-M2-1 having unique intersubunit contacts that explain differences in stability and dissociation kinetics.
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Article Synopsis
  • - RNA transcription in mononegavirales decreases from the 3' to the 5' end due to reduced polymerase efficiency, with M protein playing a key role in transcription anti-termination for viruses like respiratory syncytial virus (RSV) and metapneumovirus.
  • - RSV M protein can bind two RNA molecules of at least 13 nucleotides each, and its interaction leads to changes in RNA structure, demonstrating a cooperative binding mechanism that enhances RNA affinity through conformational changes.
  • - This research reveals how the M protein's binding affects gene transcription, providing insight into transcription regulation in pneumoviruses and related mechanisms in other viruses like Ebola.
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Article Synopsis
  • Human syncytial respiratory virus (HRSV) is a negative-strand RNA virus that primarily affects infants and has been reclassified into the Pneumoviridae family due to its unique features.
  • The virus has a transcriptional antiterminator named M, which plays a crucial role in RNA synthesis and is unusual among viruses, making its mechanism of action intriguing to researchers.
  • Recent studies provide a detailed crystal structure of the M protein, revealing important insights into its RNA-binding domain and stability, which could have implications for understanding transcription regulation and developing antiviral therapies.
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Nerita Versicolor carboxypeptidase inhibitor (NvCI) is the strongest inhibitor reported so far for the M14A subfamily of carboxypeptidases. It comprises 53 residues and a protein fold composed of a two-stranded antiparallel β sheet connected by three loops and stabilized by three disulfide bridges. Here we report the oxidative folding and reductive unfolding pathways of NvCI.

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Article Synopsis
  • * The R104H and T119M mutations are known to stabilize TTR and act as disease suppressors, while a novel mutation A108V from a Portuguese individual shows increased stability that prevents aggregation.
  • * The crystal structure analysis of A108V indicates stabilization from new contacts in the T binding site, and a designed A108I mutation further enhances stability, suggesting potential for gene and protein replacement therapies.
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Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat TTR amyloidoses.

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Article Synopsis
  • * The study investigated the disorder-order transitions of P using a domain fragmentation technique, revealing that P remains a tetramer at high temperatures but undergoes significant structural changes between 10 and 60 °C, showcasing different behaviors in its N-terminal and C-terminal modules.
  • * These findings indicate that the C-terminal module, when linked to the tetramerization component, exhibits increased structural stability and temperature sensitivity, which may serve to fine-tune protein interactions necessary for the
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Article Synopsis
  • Human respiratory syncytial virus (hRSV) predominantly affects infants and the elderly, with the M2-1 protein playing a key role in viral processes like transcription and particle budding, making it a target for antiviral drugs.
  • The M2-1 protein contains a zinc-binding motif crucial for its function; removing zinc turns it into a monomeric form while maintaining similar structural stability to its tetrameric state.
  • This zinc removal process is potentially reversible and can be influenced by natural chelators, indicating that it may modulate M2-1's role in viral assembly and release.
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Paramyxoviruses share the essential RNA polymerase complex components, namely, the polymerase (L), phosphoprotein (P), and nucleoprotein (N). Human respiratory syncytial virus (RSV) P is the smallest polypeptide among the family, sharing a coiled coil tetramerization domain, which disruption renders the virus inactive. We show that unfolding of P displays a first transition with low cooperativity but substantial loss of α-helix content and accessibility to hydrophobic sites, indicative of loose chain packing and fluctuating tertiary structure, typical of molten globules.

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The human respiratory syncytial virus M(2-1) transcription antiterminator is an essential elongation factor required by the RNA polymerase for effective transcription beyond the first two nonstructural genes. Its exclusive presence in pneumovirus among all paramyxovirus suggests a unique function within this small genus. With the aim of understanding its biochemical properties, we investigated this α-helical tetramer by making use of a biophysical approach.

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Thyroglobulin (TG) defects due to TG gene mutations have an estimated incidence of approximately 1 in 100,000 newborns. This dyshormonogenesis displays a wide phenotype variation and is characterized usually by: the presence of congenital goiter or goiter appearing shortly after birth, high (131)I uptake, negative perchlorate discharge test, low serum TG and elevated serum TSH with simultaneous low serum T(4) and low, normal or high serum T(3). Mutations in TG gene have been also reported associated with endemic and euthyroid nonendemic simple goiter.

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Context: Thyroid dysgenesis may be associated with mutations in the paired box transcription factor 8 (PAX8) gene and is characterized by congenital hypothyroidism transmitted in an autosomal dominant mode.

Objectives: The aim of this study was to identify new mutations in the PAX8 gene. Sixty congenital hypothyroidism-affected individuals with dysgenetic (agenesis, ectopia and hypoplasia) and eutopic thyroid glands were studied.

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Context: Thyroid dyshormonogenesis is associated with mutations in the thyroglobulin (TG) gene and characterized by normal organification of iodide and low serum TG. These mutations give rise to congenital goitrous hypothyroidism, transmitted in an autosomal recessive mode.

Objectives: The aim of this study was to identify new mutations in the TG gene in an attempt to increase the understanding of the molecular basis of this disorder.

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Background: Iodide organification defects are associated with mutations in the dual oxidase 2 (DUOX2) gene and are characterized by a positive perchlorate discharge test. These mutations produce a congenital goitrous hypothyroidism, usually transmitted in an autosomal recessive mode.

Methods: We studied the complete coding sequence of the human DUOX2 gene by single-strand conformational polymorphism (SSCP) analysis of DNA from 17 unrelated patients with iodide organification defects.

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