It is a common belief that metamorphic proteins challenge Anfinsen's thermodynamic hypothesis (or dogma). Here we argue against this view and aim to show that metamorphic proteins not only fulfill ...Anfinsen's dogma but also exhibit marginal stability comparable to that seen on biomolecules 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.
Proteins have evolved through mutations-amino acid substitutions-since life appeared on Earth, some 109 years ago. The study of these phenomena has been of particular significance because of their ...impact on protein stability, function, and structure. This study offers a new viewpoint on how the most recent findings in these areas can be used to explore the impact of mutations on protein sequence, stability, and evolvability. Preliminary results indicate that: (1) mutations can be viewed as sensitive probes to identify 'typos' in the amino-acid sequence, and also to assess the resistance of naturally occurring proteins to unwanted sequence alterations; (2) the presence of 'typos' in the amino acid sequence, rather than being an evolutionary obstacle, could promote faster evolvability and, in turn, increase the likelihood of higher protein stability; (3) the mutation site is far more important than the substituted amino acid in terms of the marginal stability changes of the protein, and (4) the unpredictability of protein evolution at the molecular level-by mutations-exists even in the absence of epistasis effects. Finally, the Darwinian concept of evolution "descent with modification" and experimental evidence endorse one of the results of this study, which suggests that some regions of any protein sequence are susceptible to mutations while others are not. This work contributes to our general understanding of protein responses to mutations and may spur significant progress in our efforts to develop methods to accurately forecast changes in protein stability, their propensity for metamorphism, and their ability to evolve.Proteins have evolved through mutations-amino acid substitutions-since life appeared on Earth, some 109 years ago. The study of these phenomena has been of particular significance because of their impact on protein stability, function, and structure. This study offers a new viewpoint on how the most recent findings in these areas can be used to explore the impact of mutations on protein sequence, stability, and evolvability. Preliminary results indicate that: (1) mutations can be viewed as sensitive probes to identify 'typos' in the amino-acid sequence, and also to assess the resistance of naturally occurring proteins to unwanted sequence alterations; (2) the presence of 'typos' in the amino acid sequence, rather than being an evolutionary obstacle, could promote faster evolvability and, in turn, increase the likelihood of higher protein stability; (3) the mutation site is far more important than the substituted amino acid in terms of the marginal stability changes of the protein, and (4) the unpredictability of protein evolution at the molecular level-by mutations-exists even in the absence of epistasis effects. Finally, the Darwinian concept of evolution "descent with modification" and experimental evidence endorse one of the results of this study, which suggests that some regions of any protein sequence are susceptible to mutations while others are not. This work contributes to our general understanding of protein responses to mutations and may spur significant progress in our efforts to develop methods to accurately forecast changes in protein stability, their propensity for metamorphism, and their ability to evolve.
One of the main concerns of Anfinsen was to reveal the connection between the amino-acid sequence and their biologically active conformation. This search gave rise to two crucial questions in ...structural biology, namely,
why
the proteins fold and
how
a sequence encodes its folding. As to the
why
, he proposes a plausible answer, namely, the thermodynamic hypothesis. As to the
how
, this remains an unsolved challenge. Consequently, the protein folding problem is examined here from a new perspective, namely, as an ‘analytic whole’. Conceiving the protein folding in this way enabled us to (i) examine in detail why the force-field-based approaches have failed, among other purposes, in their ability to predict the three-dimensional structure of a protein accurately; (ii) propose how to redefine them to prevent these shortcomings, and (iii) conjecture on the origin of the state-of-the-art numerical-methods success to predict the tridimensional structure of proteins accurately.
Despite the spectacular success of cutting-edge protein fold prediction methods, many critical questions remain unanswered, including why proteins can reach their native state in a biologically ...reasonable time. A satisfactory answer to this simple question could shed light on the slowest folding rate of proteins as well as how mutations—amino-acid substitutions and/or post-translational modifications—might affect it. Preliminary results indicate that (i) Anfinsen’s dogma validity ensures that proteins reach their native state on a reasonable timescale regardless of their sequence or length, and (ii) it is feasible to determine the evolution of protein folding rates without accounting for epistasis effects or the mutational trajectories between the starting and target sequences. These results have direct implications for evolutionary biology because they lay the groundwork for a better understanding of why, and to what extent, mutations—a crucial element of evolution and a factor influencing it—affect protein evolvability. Furthermore, they may spur significant progress in our efforts to solve crucial structural biology problems, such as how a sequence encodes its folding.
A comparative analysis between two problems—apparently unrelated—which are solved in a period of ~400 years, viz., the accurate prediction of both the planetary orbits and the protein structures, ...leads to inferred conjectures that go far beyond the existence of a common path in their resolution, i.e., observation → pattern recognition → modeling. The preliminary results from this analysis indicate that complementary science, together with a new perspective on protein folding, may help us discover common features that could contribute to a more in-depth understanding of still-unsolved problems such as protein folding.
Intracardiac heartworm (IH) disease is a serious condition that can become life threatening if the patient develops caval syndrome. We aim to describe the management and outcome of IH in dogs ...evaluated by Medvet's New Orleans cardiology service from November 2015 to December 2021.
Records of 27 dogs with IH were examined retrospectively. Follow-up information was obtained from phone conversations with referring veterinarians and owners.
Nine of 27 dogs had a previous diagnosis of heartworm disease and were undergoing "slow kill" treatment; 12/27 dogs' heartworm disease was a new diagnosis, and 6/27 had either scheduled or started adulticide therapy. Nine dogs had heartworm extraction. No dogs died during the heartworm extraction procedure. Four of 9 dogs have died (survival time 1; 676; 1815 and 2184 days). One dog died the day after the procedure secondary to continued respiratory distress; the other three died of non-cardiac causes. Five of nine are alive (median follow-up 1062 (range 648-1831) days. Eleven dogs had IH resolution. In 7/11 this occurred while undergoing stabilization for heartworm extraction. In 4/11 heartworm extraction was not recommended because of low IH burden. All dogs with IH resolution were discharged from the hospital. Four of 11 have died (survival time 6; 22, 58 and 835 days), and 6/11 are alive (median follow-up 523 (range 268-2081) days. One was lost to follow-up after 18 days. Five dogs were medically managed. In one of five dogs, extraction was not recommended because of low IH burden. In four of five extraction was recommended but declined. One of five has died (survival 26 days), and four of five are alive (follow-up 155, 371, 935 and 947 days). Two dogs were killed at the time of diagnosis. Fifteen of 27 dogs were considered to have caval syndrome.
The results suggest that patients with IH resolution have a good long-term prognosis. Most often IH resolution occurred while the dog was undergoing stabilization for heartworm extraction. When IHs are present, heartworm extraction should still be considered the treatment of choice and recommended as first-line therapy whenever possible.
Purpose
To assess the 3‐year effectiveness and safety of the XEN gel stent implanted ab interno in open‐angle glaucoma (OAG).
Methods
This study was a multicentre, retrospective chart review of ...consecutive patients with OAG who underwent ab‐interno gel stent placement alone or combined with phacoemulsification between 1 January 2014 and 1 October 2015. Outcome measures included mean changes in intraocular pressure (IOP) and IOP‐lowering medication count from medicated baseline at 1, 2, 3 (primary outcome) and 4 years (if available) postimplantation. Intraoperative complications, adverse events of special interest (AESIs) and secondary surgical interventions (SSIs) were recorded.
Results
The safety and effectiveness populations included 212 eyes (primary and secondary) and 174 eyes (primary), respectively. Mean IOP and medication decreased from 20.7 mmHg and 2.5 at baseline (n = 163 primary/first implanted eyes) to 13.9 mmHg and 1.1 medications (n = 76) at 3 years postimplantation, respectively. Mean changes from baseline in IOP (−5.6, −6.2 and −6.6 mmHg) and IOP‐lowering medication count (−1.8, −1.6 and −1.4) were statistically significant at 1, 2 and 3 years postimplantation, respectively. Results appeared comparable when implantation was performed with (n = 76) or without (n = 98) phacoemulsification. In primary eyes with 4‐year IOP and medication count data (n = 27), mean IOP was 14.0 mmHg on 1.3 medications at 4 years postimplantation. Fifteen (7.1%) eyes had intraoperative complications, 31 (14.6%) experienced 46 postoperative AESIs, and 26 (12.3%) required SSI.
Conclusion
The gel stent effectively lowered IOP and IOP‐lowering medication count over 3 years, with a predictable and acceptable safety profile, when implanted via the traditional ab‐interno technique.
An accurate estimation of the Protein Space size, in light of the factors that govern it, is a long-standing problem and of paramount importance in evolutionary biology, since it determines the ...nature of protein evolvability. A simple analysis will enable us to, firstly, reduce an unrealistic Protein Space size of ~ 10
130
sequences, for a 100-residues polypeptide chain, to ~ 10
9
functional proteins and, secondly, estimate a robust average-mutation rate per amino acid (ξ ~ 1.23) and infer from it, in light of the protein marginal stability, that
only
a fraction of the sequence will be available at any one time for a functional protein to evolve. Although this result does not solve the Protein Space vastness problem frames it in a more rational one and illustrates the impact of the marginal stability on protein evolvability.
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