Sven Larsen-Ledet, Aleksandra Panfilova, Amelie Stein
Advances in sequencing have revealed that each individual carries about 10,000 missense variants. For the vast majority, we do not know what the functional consequences - if any - will be. Further, mechanistic insight, such as structural details, would be immensely helpful in development of therapeutic approaches. Here we review recent developments in experimental and computational techniques aimed to assess the impact of variants on protein-protein interactions, including limitations and upcoming challenges.
Addressing Alzheimer's disease (AD) requires innovative strategies beyond current single-target drugs. This Letter to the Editor suggests that multitarget molecules, especially those targeting neuronal membrane protection, could offer a comprehensive approach to AD therapy, advocating for further research into their mechanisms and therapeutic potential.
AbstractBackgroundPatient advocacy organizations (PAOs) have an increasing influence on health policy and biomedical research, therefore, questions about the specific character of their responsibility arise: Can PAOs bear moral responsibility and, if so, to whom are they responsible, for what and on which normative basis? Although the concept of responsibility in healthcare is strongly discussed, PAOs particularly have rarely been systematically analyzed as morally responsible agents. The aim of the current paper is to analyze the character of PAOs’ responsibility to provide guidance to themselves and to other stakeholders in healthcare.MethodsResponsibility is presented as a concept with four reference points: (1) The subject, (2) the object, (3) the addressee and (4) the underlying normative standard. This four-point relationship is applied to PAOs and the dimensions of collectivity and prospectivity are analyzed in each reference point.ResultsUnderstood as collectives, PAOs are, in principle, capable of intentionality and able to act and, thus, fulfill one prerequisite for the attribution of moral responsibility. Given their common mission to represent those affected, PAOs can be seen as responsible for patients’ representation and advocacy, primarily towards a certain group but secondarily in a broader social context. Various legal and political statements and the bioethical principles of justice, beneficence and empowerment can be used as a normative basis for attributing responsibility to PAOs.ConclusionsThe understanding of responsibility as a four-point relation incorporating collective and forward-looking dimensions helps one to understand the PAOs’ roles and responsibilities better. The analysis, thus, provides a basis for the debate about PAOs’ contribution and cooperation in the healthcare sector.
The presence of metamorphism in the protein's native state is not yet fully understood. In an attempt to throw light on this issue here we present an assessment, in terms of the amide hydrogen exchange protection factor, that aims to determine the likely existence of structural fluctuations in the native-state consistent with both the upper bound marginal stability of proteins and the metamorphism presence. The preliminary results enable us to conclude that the native-state metamorphism is, indeed, more probable than thought.
Laurin Gierse, Alexander Meene, Daniel Schultz
et al.
Swine are regarded as promising biomedical models, but the dynamics of their gastrointestinal microbiome have been much less investigated than that of humans or mice. The aim of this study was to establish an integrated multi-omics protocol to investigate the fecal microbiome of healthy swine. To this end, a preparation and analysis protocol including integrated sample preparation for meta-omics analyses of deep-frozen feces was developed. Subsequent data integration linked microbiome composition with function, and metabolic activity with protein inventories, i.e., 16S rRNA data and expressed proteins, and identified proteins with corresponding metabolites. 16S rRNA gene amplicon and metaproteomics analyses revealed a fecal microbiome dominated by Prevotellaceae, Lactobacillaceae, Lachnospiraceae, Ruminococcaceae and Clostridiaceae. Similar microbiome compositions in feces and colon, but not ileum samples, were observed, showing that feces can serve as minimal-invasive proxy for porcine colon microbiomes. Longitudinal dynamics in composition, e.g., temporal decreased abundance of Lactobacillaceae and Streptococcaceae during the experiment, were not reflected in microbiome function. Instead, metaproteomics and metabolomics showed a rather stable functional state, as evident from short-chain fatty acids (SCFA) profiles and associated metaproteome functions, pointing towards functional redundancy among microbiome constituents. In conclusion, our pipeline generates congruent data from different omics approaches on the taxonomy and functionality of the intestinal microbiome of swine.
Thermodynamic profiles, based on bioinformatic hydropathicity scales and membrane-fitted sliding windows, exhibit accurately level sets of hydrophobic peaks or valleys in the constant fragment Fc of monoclonal antibodies. These sets provide a roadmap for selected short regions where a few directed amino acid mutations could produce either accelerated antibody kinetics or increased stability. These profiles may reveal dramatic differences in antibody activity
It is a common belief that metamorphic proteins challenge the Anfinsen thermodynamic hypothesis (or dogma). Here we argue against this view aims to show that metamorphic proteins not just fulfill the Anfinsen dogma but also exhibit marginal stability comparable to that seen on macromolecules and macromolecular complexes. This work contributes to our general understanding of protein classification and may spur significant progress in our effort to analyze protein evolvability.
DNA and RNA quadruplexes are extensively studied for the key roles they are suspected to play in the cellular regulation networks at both genomic and transcriptomic levels. The reliable detection of quadruplexes in cells was and remains a challenging task. Here, we describe the various strategies that have been implemented over the past years to visualize functionally relevant DNA and RNA quadruplexes in human cells, from immunodetection studies to the design and use of quadruplex-specific turn-on fluorescent probes.
Use of a combination of statistical thermodynamics and the Gershgorin theorem enable us to guess, in the thermodynamic limit, a plausible value for the upper bound free-energy difference between native-like structures of monomeric globular proteins. Support to our result in light of both the observed free-energy change between the native and denatured states and the microstability free-energy values obtained from the observed micro-unfolding tendency of nine globular proteins, will be here discussed.
A mechanism of the translation in oligomer world is proposed. The translation is carried out by a minimum cycle, which is sustained by adaptors and helicases, and the first information processing in oligomer world. We expect that such a cycle actually worked in a primitive cell and can be constructed in vitro. By computer simulation we have shown that a proofreading is achieved by the fluctuation in the cell. It is rather paradoxical that the proofreading is effective for the system consisting of molecular machines with low efficiency.
HIV integrase is a 32 kDa protein produced from the C-terminal portion of the Pol gene product, and is an attractive target for new anti-HIV drugs. Integrase is an enzyme produced by a retrovirus (such as HIV) that enables its genetic material to be integrated into the DNA of the infected cell. Raltegravir and Elvitegravir are two important drugs against integrase.
It is shown that the nucleotide sequences in DNA molecules have cluster-scaling properties (discovered for the first time in turbulent processes: Sreenivasan and Bershadskii, 2006, J. Stat. Phys., 125, 1141-1153.). These properties are relevant to both types of nucleotide pair-bases interactions: hydrogen bonds and stacking interactions. It is shown that taking into account the cluster-scaling properties can help to improve heterogeneous models of the DNA dynamics. Two human genes: BRCA2 and NRXN1, have been considered as examples.
This note represents the further progress in understanding the determination of the genetic code by Golden mean (Rakocevic, 1998). Three classes of amino acids that follow from this determination (the 7 "golden" amino acids, 7 of their complements, and 6 non-complements) are observed now together with two further possible splittings into 4 x 5 and 5 x 4 amino acids.
An $k$-noncrossing RNA structure can be identified with an $k$-noncrossing diagram over $[n]$, which in turn corresponds to a vacillating tableaux having at most $(k-1)$ rows. In this paper we derive the limit distribution of irreducible substructures via studying their corresponding vacillating tableaux. Our main result proves, that the limit distribution of the numbers of irreducible substructures in $k$-noncrossing, $σ$-canonical RNA structures is determined by the density function of a $Γ(-\lnτ_k,2)$-distribution for some $τ_k<1$.
A simple and surprisingly accurate description of spectral diffusion in deeply frozen globular proteins is constructed directly using the concept of ultrametricity of protein dynamics. Earlier the similar concept has been used for successful description of ligand-rebinding kinetics of myoglobin at temperatures about of 200 K. Hence the ultrametricity offers a universal background for the protein dynamics in a wide range of scales of protein motions.
The paper shows how the diffusive movement of ions through a channel protein can be described as a chemical reaction over an arbitrary shaped potential barrier. The result is simple and intuitive but without approximation beyond the electrodiffusion description of ion movement.
A hypothesis of the evolution of the genetic code is proposed, the leading mechanism of which is the nucleotide spontaneous damage leading to AT-enrichment of the genome. The hypothesis accounts for stability of the genetic code towards point mutations, the presence of code dialects, emergence of stop codons, emergence of the DNA double helix and the symmetry of the genetic code table. The assumption of the originally triplet structure of the genetic code has been substantiated. A hypothesis concerning the primary structure of the first gene and the first protein has been proposed.
Secondary structure elements of many protein families exhibit differential conservation on their opposing faces. Amphipathic helices and beta-sheets by definition possess this property, and play crucial functional roles. This type of evolutionary trajectory of a protein family is usually critical to the functions of the protein family, as well as in creating functions within subfamilies. That is, differential conservation maintains properties of a protein structure related to its orientation, and that are important in packing, recognition, and catalysis. Here I define and formulate a new concept, called the selection moment, that detects this evolutionary process in protein sequences. A treatment of its various applications is detailed.
Zhumur Ghosh, Smarajit Das, Jayprokas Chakrabarti
et al.
In euryarchaeal methanogen M.kandleri and in Nanoarchaea N. equitans some of the missing tRNA genes are embedded in others. We argue from bioinformatic evidence that position specific intron splicing is the key behind co-location of these tRNA genes.