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showing 10 items of 806 documents
Human Monkeypox: A Comprehensive Narrative Review and Analysis of the Public Health Implications.
2022
Recently, numerous cases of monkeypox were reported from several non-endemic countries in Europe, North America, and Oceania, suggesting an unusual and alarming public health issue, particularly considering that the disease is not directly related to human or animal travels. Attention is currently being drawn to this phenomenon since more than 70% of the global population is no longer vaccinated against smallpox. Indeed, the smallpox vaccination also confers some indirect degree of protection against other poxviruses, including monkeypox. We performed a narrative review to describe the existing literature with regard to monkeypox using the MEDLINE, EMBASE, and Scopus databases. This review …
All-atom simulations disentangle the functional dynamics underlying gene maturation in the intron lariat spliceosome
2018
The spliceosome (SPL) is a majestic macromolecular machinery composed of five small nuclear RNAs and hundreds of proteins. SPL removes noncoding introns from precursor messenger RNAs (pre-mRNAs) and ligates coding exons, giving rise to functional mRNAs. Building on the first SPL structure solved at near–atomic-level resolution, here we elucidate the functional dynamics of the intron lariat spliceosome (ILS) complex through multi-microsecond-long molecular-dynamics simulations of ∼1,000,000 atoms models. The ILS essential dynamics unveils (i) the leading role of the Spp42 protein, which heads the gene maturation by tuning the motions of distinct SPL components, and (ii) the critical particip…
Reaction between Indazole and Pd-Bound Isocyanides-A Theoretical Mechanistic Study
2018
The mechanism of the addition of indazole (Ind)&mdash
Molecular dissection of human Argonaute proteins by DNA shuffling.
2013
A paramount task in RNA interference research is to decipher the complex biology of cellular effectors, exemplified in humans by four pleiotropic Argonaute proteins (Ago1-Ago4). Here, we exploited DNA family shuffling, a molecular evolution technology, to generate chimeric Ago protein libraries for dissection of intricate phenotypes independently of prior structural knowledge. Through shuffling of human Ago2 and Ago3, we discovered two N-terminal motifs that govern RNA cleavage in concert with the PIWI domain. Structural modeling predicts an impact on protein rigidity and/or RNA-PIWI alignment, suggesting new mechanistic explanations for Ago3's slicing deficiency. Characterization of hybrid…
Cationic Nanohydrogel Particles as Potential siRNA Carriers for Cellular Delivery
2012
Oligonucleotides such as short, double-stranded RNA (siRNA) or plasmid DNA (pDNA) promise high potential in gene therapy. For pharmaceutical application, however, adequate drug carriers are required. Among various concepts progressing in the market or final development, nanosized hydrogel particles may serve as novel transport media especially for siRNA. In this work, a new concept of synthesizing polymeric cationic nanohydrogels was developed, which offers a promising strategy to complex and transport siRNA into cells. For this purpose, amphiphilic reactive ester block copolymers were synthesized by RAFT polymerization of pentafluorophenyl methacrylate as reactive ester monomer together wi…
Crystal Structure of Human Filamin C Domain 23 and Small Angle Scattering Model for Filamin C 23–24 Dimer
2007
Filamin C is a dimeric, actin-binding protein involved in organization of cortical cytoskeleton and of the sarcomere. We performed crystallographic, small-angle X-ray scattering and analytical ultracentrifugation experiments on the constructs containing carboxy-terminal domains of the protein (domains 23-24 and 19-21). The crystal structure of domain 23 of filamin C showed that the protein adopts the expected immunoglobulin (Ig)-like fold. Small-angle X-ray scattering experiments performed on filamin C tandem Ig-like domains 23 and 24 reveal a dimer that is formed by domain 24 and that domain 23 has little interactions with itself or with domain 24, while the analytical ultracentrifugation …
Small-angle X-ray scattering reveals compact domain-domain interactions in the N-terminal region of filamin C
2014
Filamins are multi-domain, actin cross-linking, and scaffolding proteins. In addition to the actin cross-linking function, filamins have a role in mechanosensor signaling. The mechanosensor function is mediated by domain-domain interaction in the C-terminal region of filamins. Recently, we have shown that there is a three-domain interaction module in the Nterminal region of filamins, where the neighboring domains stabilize the structure of the middle domain and thereby regulate its interaction with ligands. In this study, we have used small-angle X-ray scattering as a tool to screen for potential domain-domain interactions in the N-terminal region. We found evidence of four domain-domain in…
The C-terminal rod 2 fragment of filamin A forms a compact structure that can be extended
2012
Filamins are large proteins that cross-link actin filaments and connect to other cellular components. The C-terminal rod 2 region of FLNa (filamin A) mediates dimerization and interacts with several transmembrane receptors and intracellular signalling adaptors. SAXS (small-angle X-ray scattering) experiments were used to make a model of a six immunoglobulin-like domain fragment of the FLNa rod 2 (domains 16–21). This fragment had a surprising three-branched structural arrangement, where each branch was made of a tightly packed two-domain pair. Peptides derived from transmembrane receptors and intracellular signalling proteins induced a more open structure of the six domain fragment. Mutagen…
Sequential conformational transitions and α-helical supercoiling regulate a sensor histidine kinase
2017
Sensor histidine kinases are central to sensing in bacteria and in plants. They usually contain sensor, linker, and kinase modules and the structure of many of these components is known. However, it is unclear how the kinase module is structurally regulated. Here, we use nano- to millisecond time-resolved X-ray scattering to visualize the solution structural changes that occur when the light-sensitive model histidine kinase YF1 is activated by blue light. We find that the coiled coil linker and the attached histidine kinase domains undergo a left handed rotation within microseconds. In a much slower second step, the kinase domains rearrange internally. This structural mechanism presents a t…
Mechanistic analysis and experimental verification of bicarbonate-controlled enteric coat dissolution: Potential in vivo implications
2019
Enteric coatings have shown in vivo dissolution rates that are poorly predicted by traditional in vitro tests, with the in vivo dissolution being considerably slower than in vitro. To provide a more mechanistic understanding of this, the dependence of the release properties of various enteric-coated (EC) products on bulk pH and bicarbonate molarity was investigated. It was found that, at presumably in vivo-relevant values, the bicarbonate molarity is a more significant determinant of the dissolution profile than the bulk pH. The findings also indicate that this steep relationship between the dissolution of enteric coatings and bicarbonate molarity limits those coatings' performance in vivo.…