Analysis of proteins in the light of mutations.

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.

Disseminated Cutaneous Histoplasmosis and Its Recurrence in an Apparently Immunocompetent Patient.

Histoplasmosis is a fungal infection caused by the fungus Histoplasma capsulatum. It can manifest in various ways, ranging from pulmonary to disseminated presentations. Most of the disseminated cases are seen in immunocompromised patients; here, we present an unusual case of an 81-year-old Mexican male with a history of cave exposure in his childhood, with 75 years of incubation period of the disease, who developed disseminated cutaneous histoplasmosis with no evident immunocompromising conditions. We considered the hypotheses of transient immunosuppression, CD4+ T lymphocytopenia, and immune senescence as the cause of this manifestation. The present case is also notable for its recurrence following therapy. This report underscores the challenges in diagnosing histoplasmosis in immunocompetent individuals and highlights the importance of long-term treatment and follow-up.

MITRAL REGURGITATION IN SADDLE-BILLED STORKS (EPHIPPIORHYNCHUS SENEGALENSIS) IN HUMAN CARE: DIAGNOSIS, ECHOCARDIOGRAPHIC MEASUREMENTS, AND MANAGEMENT.

The asymptomatic and slow progressive nature of cardiopathies represents a risk to the welfare of avian species in human care. Diagnosis and treatment of cardiac disease in birds pose a challenge due to unique anatomic and physiologic characteristics. Comprehensive cardiac assessments with diagnostic tools such as echocardiography, color-Doppler, the biomarker cardiac troponin I (cTn1), and cholesterol serum concentrations have been utilized in different bird species with varying success. Saddle-billed storks (Ephippiorhynchus senegalensis) have been maintained in human care for over 80 yrs and several institutions have noted heart murmurs and cardiomegaly. Despite these findings, peer-reviewed literature describing cardiopathies is lacking for this species. This case series documents the identification of mitral valve regurgitation in saddle-billed storks in a breeding center. Transcoelomic echocardiography using a ventromedial approach with a two-chambered view and color Doppler was utilized. Echocardiographic measurements were taken and compared 1 yr later in most of the birds. There was left atrial enlargement and worsened mitral regurgitation in one geriatric patient, and no progression of the disease in two young birds. Serum samples showed that cTn1 had different concentrations depending on the severity of the disease, whereas cholesterol was within reference range for all birds. Treatment with digoxin and pimobendan was recommended in one bird, serum concentrations of digoxin were tested in a 6-mon span, results were within therapeutic range, and there were no overt adverse effects. There was a suspected genetic component in this population, as four of the five birds with confirmed mitral regurgitation were related.

Protein folding rate evolution upon mutations.

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.

Protein structure prediction from the complementary science perspective.

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.

Rethinking the protein folding problem from a new perspective.

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.

Management and outcome of intracardiac heartworms in dogs.

BACKGROUND: 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. METHODS: Records of 27 dogs with IH were examined retrospectively. Follow-up information was obtained from phone conversations with referring veterinarians and owners. RESULTS: 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. CONCLUSION: 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.

Micronodular Basal Cell Carcinoma Presenting as an Achromic Macule.

A 63-year-old woman with light skin and a history of chronic sun damage presented with a painless, pale macule on her nasal tip. A punch biopsy was performed due to concerns about skin conditions like vitiligo or morpheaform basal cell carcinoma (BCC). The biopsy confirmed a micronodular BCC, an unusual presentation, as these typically manifest as an erythematous macule or thin papule/plaque. This report highlights the importance of considering various factors and differential diagnoses to ensure the best patient care and the need for vigilance in diagnosing rare presentations of BCC.

Proteins' Evolution upon Point Mutations.

As the reader must be already aware, state-of-the-art protein folding prediction methods have reached a smashing success in their goal of accurately determining the three-dimensional structures of proteins. Yet, a solution to simple problems such as the effects of protein point mutations on their (i) native conformation; (ii) marginal stability; (iii) ensemble of high-energy nativelike conformations; and (iv) metamorphism propensity and, hence, their evolvability, remains as an unsolved problem. As a plausible solution to the latter, some properties of the amide hydrogen-deuterium exchange, a highly sensitive probe of the structure, stability, and folding of proteins, are assessed from a new perspective. The preliminary results indicate that the protein marginal stability change upon point mutations provides the necessary and sufficient information to estimate, through a Boltzmann factor, the evolution of the amide hydrogen exchange protection factors and, consequently, that of the ensemble of folded conformations coexisting with the native state. This work contributes to our general understanding of the effects of point mutations on proteins and may spur significant progress in our efforts to develop methods to determine the appearance of new folds and functions accurately.

Thoughts on the Protein's Native State.

The presence of metamorphism in the protein's native state is not yet fully understood. To shed light on this issue, we present an assessment, in terms of the amide hydrogen exchange protection factor, that aims to determine the possible existence of structural fluctuations in the native-state consistent with both the upper-bound marginal stability of proteins and the presence of metamorphism. The preliminary results enable us to conclude that the native-state metamorphism is, indeed, more probable than previously thought.

Exploring the quality of protein structural models from a Bayesian perspective.

We explore how ideas and practices common in Bayesian modeling can be applied to help assess the quality of 3D protein structural models. The basic premise of our approach is that the evaluation of a Bayesian statistical model's fit may reveal aspects of the quality of a structure when the fitted data is related to protein structural properties. Therefore, we fit a Bayesian hierarchical linear regression model to experimental and theoretical 13 Cα chemical shifts. Then, we propose two complementary approaches for the evaluation of such fitting: (a) in terms of the expected differences between experimental and posterior predicted values; (b) in terms of the leave-one-out cross-validation point-wise predictive accuracy. Finally, we present visualizations that can help interpret these evaluations. The analyses presented in this article are aimed to aid in detecting problematic residues in protein structures. The code developed for this work is available on: https://github.com/BIOS-IMASL/Hierarchical-Bayes-NMR-Validation.

About the Protein Space Vastness.

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 ~ 10130 sequences, for a 100-residues polypeptide chain, to ~ 109 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.

16 Sesamoid bones in the hands of healthy patient: case report

The sesamoid bones are round or oval bones that are located within tendons, and most theories consider that sesamoid bones in humans develop in response to local mechanical stress on a joint. Although their function is not well understood, it is known that they act as a pulley modifying the angle of movement and their insertion. They are mostly inconsistent, which is why they tend to be supernumerary and are located in different parts of the body at the level of the extremities, with the patella being the largest, most constant and best known. The prevalence and distribution of sesamoids in the hand varies between different populations and sex. They are rarely reported since they are only considered anatomical variants, but clinically there are several pathologies related to the sesamoid bones in the hand such as: trauma, degenerative disorders, giant cell tumors, osteochondroma, avascular necrosis, tendon ruptures, genetic disorders and attention should be paid in patients with acromegaly where their length is increased. In this article, we report a total of 16 sesamoid bones, symmetrically distributed 8 ineach hand of a healthy individual treated in the Plastic Surgery Department of the "Dr. Rubén Leñero" Hospital in Mexico City. In the literature reviewed, we did not find a report with the presence of so many sesamoid bones in both hands, which motivated us to report it

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Thermodynamics of cell penetrating peptides on lipid membranes: sequence and membrane acidity regulate surface binding.

Cell-penetrating peptides (CPPs) are molecules that traverse cell membranes and facilitate the cellular uptake of nano-sized cargoes. In this work we characterize the adsorption of amphipathic and purely cationic CPPs on membranes containing acidic lipids. We describe how the peptide primary sequence, the location of amino-acids within the sequence, the membrane composition, and the pH of the environment, determine both the surface concentration of the peptides and the molecular organization of the interface. Our results are obtained by applying a molecular theory that takes into account the size, shape, protonation state, charge distribution and conformational flexibility of the peptides, as well as the acid-base chemistry of the lipids. We find that peptide adsorption and binding free energy result from a balance between electrostatic and van der Waals interactions, and between chemical and entropic effective forces. We observe that, within a range of physiologically relevant parameters, acidic lipids respond to pH in ways that fully promote or deplete the surface accumulation of CPPs. Membrane acidity emerges thus as a crucial parameter to consider when designing CPP-based cargo-delivery vehicles.

Metamorphic Proteins in Light of Anfinsen's Dogma.

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.

The Marginal Stability of Proteins: How the Jiggling and Wiggling of Atoms is Connected to Neutral Evolution.

Here we propose that the upper bound marginal stability of proteins is a universal property that includes macro-molecular complexes and is not affected by molecular changes such as mutations and post-translational modifications. We theorize that its existence is a consequence of Afinsen's thermodynamic hypothesis rather than a result of an evolutionary process. This result enables us to conjecture that neutral evolution should also be, with respect to protein stability, a universal phenomenon.

Resolution of caval syndrome during initial hemodynamic stabilization in dogs with heartworm disease.

OBJECTIVE: To report on the spontaneous resolution of caval syndrome in 5 dogs selected for their response to medical stabilization prior to scheduled heartworm extraction. SERIES SUMMARY: Five dogs with heartworm caval syndrome were treated with sildenafil, fluid, and supplemental oxygen therapy. Moreover, 4 of 5 dogs were also administered pimobendan to achieve hemodynamic stabilization in preparation for percutaneous heartworm extraction. Spontaneous heartworm migration back into the pulmonary arteries was detected from 2 h to 5 days after treatment initiation. UNIQUE INFORMATION PROVIDED: Unanticipated spontaneous resolution of caval syndrome was documented in a low number of dogs after initiation of a patient stabilization protocol aiming at improving right ventricular hemodynamics and reducing pulmonary artery pressure prior to scheduled heartworm extraction. At this time, it is unknown if intervention to improve the hemodynamic status of the animal prior to heartworm extraction improves procedure outcome, and which factors contributed to the migration of the heartworms back into the pulmonary arteries in these selected cases. Therefore, this approach cannot be recommended in place of current recommendations for treatment of caval syndrome.

Assessing the One-Bond Cα-H Spin-Spin Coupling Constants in Proteins: Pros and Cons of Different Approaches.

In the present work, we explore three different approaches for the computation of the one-bond spin-spin coupling constants (SSCC) 1JCαH in proteins: density functional theory (DFT) calculations, a Karplus-like equation, and Gaussian process regression. The main motivation of this work is to select the best method for fast and accurate computation of the 1JCαH SSCC, for its use in everyday applications in protein structure validation, refinement, and/or determination. Our initial results showed a poor agreement between the DFT-computed and observed 1JCαH SSCC values. Further analysis leads us to the understanding that the model chosen for the DFT computations is inappropriate and that more complex models will require a higher, if not prohibitively, computational cost. Finally, we show that the Karplus-like equation and Gaussian Process regression provide faster and more accurate results than DFT-based calculations.

Classification of RNA backbone conformations into rotamers using 13C' chemical shifts: exploring how far we can go.

The conformational space of the ribose-phosphate backbone is very complex as it is defined in terms of six torsional angles. To help delimit the RNA backbone conformational preferences, 46 rotamers have been defined in terms of these torsional angles. In the present work, we use the ribose experimental and theoretical 13C' chemical shifts data and machine learning methods to classify RNA backbone conformations into rotamers and families of rotamers. We show to what extent the experimental 13C' chemical shifts can be used to identify rotamers and discuss some problem with the theoretical computations of 13C' chemical shifts.