Omicron Mutations Increase Interdomain Interactions and Reduce Epitope Exposure in the SARS-CoV-2 Spike

Omicron BA.1 is a highly infectious variant of SARS-CoV-2 that carries more than thirty mutations on the spike protein in comparison to the Wuhan wild type (WT). Some of the Omicron mutations, located on the receptor binding domain (RBD), are exposed to the surrounding solvent and are known to help evade immunity. However, the impact of buried mutations on the RBD conformations and on the mechanics of the spike opening is less evident. Here, we use all-atom molecular dynamics (MD) simulations with metadynamics to characterize the thermodynamic RBD-opening ensemble, identifying significant differences between WT and Omicron. Specifically, the Omicron mutations S371L, S373P, and S375F make more RBD interdomain contacts during the spike's opening. Moreover, Omicron takes longer to reach the transition state than WT. It stabilizes up-state conformations with fewer RBD epitopes exposed to the solvent, potentially favoring immune or antibody evasion.© 2023 The Author(s)

Takotsubo Cardiomyopathy: A Case Series and Review of the Literature

Takotsubo cardiomyopathy (TCM) is an unusual form of acute cardiomyopathy showing left ventricular apical ballooning. It is often triggered by intense physical or emotional distress. We report here four cases of TCM and a review of the literature on the topic

Hyaluronan concentration and size distribution in human knee synovial fluid: variations with age and cartilage degeneration.

BackgroundOne potential mechanism for early superficial cartilage wear in normal joints is alteration of the lubricant content and quality of synovial fluid. The purpose of this study was to determine if the concentration and quality of the lubricant, hyaluronan, in synovial fluid: (1) was similar in left and right knees; (2) exhibited similar age-associated trends, whether collected postmortem or antemortem; and (3) varied with age and grade of joint degeneration.MethodsHuman synovial fluid of donors (23-91 years) without osteoarthritis was analyzed for the concentrations of protein, hyaluronan, and hyaluronan in the molecular weight ranges of 2.5-7 MDa, 1-2.5 MDa, 0.5-1 MDa, and 0.03-0.5 MDa. Similarity of data between left and right knees was assessed by reduced major axis regression, paired t-test, and Bland-Altman analysis. The effect of antemortem versus postmortem collection on biochemical properties was assessed for age-matched samples by unpaired t-test. The relationships between age, joint grade, and each biochemical component were assessed by regression analysis.ResultsJoint grade and the concentrations of protein, hyaluronan, and hyaluronan in the molecular weight ranges of 2.5-7 MDa, 1-2.5 MDa, and 0.5-1 MDa in human synovial fluid showed good agreement between left and right knees and were similar between age-matched patient and cadaver knee joints. There was an age-associated decrease in overall joint grade (-15 %/decade) and concentrations of hyaluronan (-10.5 %/decade), and hyaluronan in the molecular weight ranges of 2.5-7 MDa (-9.4 %/decade), 1-2.5 MDa (-11.3 %/decade), 0.5-1 MDa (-12.5 %/decade), and 0.03-0.5 MDa (-13.0 %/decade). Hyaluronan concentration and quality was more strongly associated with age than with joint grade.ConclusionsThe age-related increase in cartilage wear in non-osteoarthritic joints may be related to the altered hyaluronan content and quality of synovial fluid

Optimising the Structure-Function Relationship at the Locus of Deficit in Retinal Disease

Technologies such as optical coherence tomography have facilitated the visualization of anatomical tissues such as that of the retina. The availability of in vivo retinal anatomical data has led to the hypothesis that it may be able to accurately predict visual function from anatomical information. However, accurate determination of the structure-function relationship has remained elusive in part due to contributions of non-retinal sources of variability, thus imposing potential limitations in the fidelity of the relationship. Furthermore, differences in manifestation of functional loss due to different retinal loci of change (inner retina or outer retinal elements) have also been the subject of debate. Here, we assessed the application of a novel, more objective psychophysical paradigm to better characterize the relationship between functional and structural characteristics in the eye. Using ocular diseases with known loci of anatomical change (glaucoma, inner retinal loss; and retinitis pigmentosa, outer retinal loss), we compared conventional more subjective psychophysical techniques that may be contaminated by the presence of non-retinal sources of variability with our more objective approach. We show that stronger correlations between underlying retinal structure and visual function can be achieved across a breadth of anatomical change by using a more objective psychophysical paradigm. This was independent of the locus of structural loss (at the ganglion cells for glaucoma or photoreceptors for retinitis pigmentosa), highlighting the role of downstream retinal elements to serve as anatomical limiting factors for studying the structure-function relationship. By reducing the contribution of non-retinal sources of variability in psychophysical measurements, we herein provide a structure-function model with higher fidelity. This reinforces the need to carefully consider the psychophysical protocol when examining the structure-function relationship in sensory systems

Anterior Chamber Angle Evaluation Using Gonioscopy: Consistency and Agreement between Optometrists and Ophthalmologists

SIGNIFICANCE In our intermediate-tier glaucoma care clinic, we demonstrate fair to moderate agreement in gonioscopy examination between optometrists and ophthalmologists, but excellent agreement when considering open versus closed angles. We highlight the need for increased consistency in the evaluation and recording of angle status using gonioscopy. PURPOSE The consistency of gonioscopy results obtained by different clinicians is not known but is important in moving toward practice modalities such as telemedicine and collaborative care clinics. The purpose of this study was to evaluate the description and concordance of gonioscopy results among different practitioners. METHODS The medical records of 101 patients seen within a collaborative care glaucoma clinic who had undergone gonioscopic assessment by two clinicians (one optometrist and either one general ophthalmologist [n = 50] or one glaucoma specialist [n = 51]) were reviewed. The gonioscopy records were evaluated for their descriptions of deepest structure seen, trabecular pigmentation, iris configuration, and other features. These were compared between clinicians (optometrist vs. ophthalmologist) and against the final diagnosis. RESULTS Overall, 51.9 and 59.8% of angles were graded identically in terms of deepest visible structure when comparing between optometrist versus general ophthalmologist and optometrist versus glaucoma specialist, respectively. The concordance increased when considering ±1 of the grade (67.4 and 78.5%, respectively), and agreement with the final diagnosis was high (>90%). Variations in angle grading other than naming structures were observed (2.0, 30, and 3.9% for optometrist, general ophthalmologist, and glaucoma specialist, respectively). Most of the time, trabecular pigmentation or iris configuration was not described. CONCLUSIONS Fair to moderate concordance in gonioscopy was achieved between optometrists and ophthalmologists in a collaborative care clinic in which there is consistent feedback and clinical review. To move toward unified medical records and a telemedicine model, improved consistency of record keeping and angle description is required

"Cultural additivity" and how the values and norms of Confucianism, Buddhism, and Taoism co-exist, interact, and influence Vietnamese society: A Bayesian analysis of long-standing folktales, using R and Stan

Every year, the Vietnamese people reportedly burned about 50,000 tons of joss papers, which took the form of not only bank notes, but iPhones, cars, clothes, even housekeepers, in hope of pleasing the dead. The practice was mistakenly attributed to traditional Buddhist teachings but originated in fact from China, which most Vietnamese were not aware of. In other aspects of life, there were many similar examples of Vietnamese so ready and comfortable with adding new norms, values, and beliefs, even contradictory ones, to their culture. This phenomenon, dubbed "cultural additivity", prompted us to study the co-existence, interaction, and influences among core values and norms of the Three Teachings--Confucianism, Buddhism, and Taoism--as shown through Vietnamese folktales. By applying Bayesian logistic regression, we evaluated the possibility of whether the key message of a story was dominated by a religion (dependent variables), as affected by the appearance of values and anti-values pertaining to the Three Teachings in the story (independent variables).Comment: 8 figures, 35 page

Afferent thermosensory function in relapsing-remitting multiple sclerosis following exercise-induced increases in body temperature

In multiple sclerosis (MS), increases in body temperature result in transient worsening of clinical symptoms (heat-sensitivity/Uhthoff's phenomenon). While the impact of heat-sensitivity on efferent physiological function has been investigated, the effects of heat stress on afferent sensory function in MS are unknown. Hence, we quantified afferent thermosensory function in MS following exercise-induced increases in body temperature with a novel quantitative sensory test. Eight relapsing-remitting MS patients (3M/5F; 51.4 ± 9.1 y; EDSS score: 2.8 ± 1.1) and 8 age-matched controls (CTR; 5M/3F; 47.4 ± 9.1 y) rated perceived magnitude of two cold (26; 22°C) and warm (34; 38°C) stimuli applied to the dorsum of the hand, pre and post 30-min cycling in the heat (30°C air; 30% RH). Exercise produced similar increases in mean body temperature in MS (+0.39°C [95%CI: +0.21, +0.53] P = 0.001) and CTR (+0.41°C [95%CI: +0.25, +0.58] P = 0.001). These changes were sufficient to significantly decrease thermosensitivity to all cold (26°C stimulus: -9.1% [95%CI: -17.0, -1.5], P = 0.006; 22°C stimulus: -10.6% [95%CI: -17.3, -3.7], P = 0.027), but not warm, stimuli in MS. Contrariwise, CTR showed sensitivity reductions to colder stimuli only (22°C stimulus: -9.7% [95%CI: -16.4, -3.1], P = 0.011). The observation that reductions in thermal-sensitivity in MS were confined to the myelinated cold-sensitive pathway, and extended across a wider (including milder/colder) temperature range than what is observed in CTR, provides novel evidence on the impact of rising body temperature on afferent neural function in MS. Also, our findings support the use of our novel approach to investigate afferent sensory function in MS during heat stress. This article is protected by copyright. All rights reserved

Cold water ingestion improves exercise tolerance of heat-sensitive people with MS

© 2018 Lippincott Williams and Wilkins. All rights reserved. Purpose Heat intolerance commonly affects the exercise capacity of people with multiple sclerosis (MS) during bouts of hot weather. Cold water ingestion is a simple cooling strategy, but its efficacy for prolonging exercise capacity with MS remains undetermined. We sought to identify whether cold water ingestion blunts exercise-induced rises in body temperature and improves exercise tolerance in heat-sensitive individuals with MS. Methods On two separate occasions, 20 participants (10 relapsing-remitting MS (expanded disability status scale, 2-4.5); 10 age-matched healthy controls) cycled at ∼40% VO 2max at 30°C and 30% relative humidity until volitional exhaustion (or a maximum of 60 min). Every 15 min, participants ingested 3.2 mL·kg -1 of either 1.5°C (CLD) or 37°C (NEU) water. Rectal (T re ) temperature, mean skin (T sk ) temperature, and heart rate (HR) were measured throughout. Results All 10 controls but only 3 of 10 MS participants completed 60 min of exercise in NEU trial. The remaining 7 MS participants all cycled longer (P = 0.006) in CLD (46.4 ± 14.2 min) compared with NEU (32.7 ± 11.5 min), despite a similar absolute T re (NEU: 37.32°C ± 0.34°C; CLD: 37.28°C ± 0.26°C; P = 0.44), change in T re (NEU: 0.38°C ± 0.21°C; CLD: 0.34°C ± 0.24°C), absolute T sk (NEU: 34.48°C ± 0.47°C; CLD: 34.44°C ± 0.54°C; P = 0.82), and HR (NEU: 114 ± 20 bpm; CLD: 113 ± 18 bpm; P = 0.38) for the same exercise volume. Conclusions Cold water ingestion enhanced exercise tolerance of MS participants in the heat by ∼30% despite no differences in T re , T sk or HR. These findings support the use of a simple cooling strategy for mitigating heat intolerance with MS and lend insight into the potential role of cold-afferent thermoreceptors that reside in the abdomen and oral cavity in the modulation of exercise tolerance with MS in the heat

Herbal Medicine for Cardiovascular Diseases: Efficacy, Mechanisms, and Safety

Cardiovascular diseases (CVDs) are a significant health burden with an ever-increasing prevalence. They remain the leading causes of morbidity and mortality worldwide. The use of medicinal herbs continues to be an alternative treatment approach for several diseases including CVDs. Currently, there is an unprecedented drive for the use of herbal preparations in modern medicinal systems. This drive is powered by several aspects, prime among which are their cost-effective therapeutic promise compared to standard modern therapies and the general belief that they are safe. Nonetheless, the claimed safety of herbal preparations yet remains to be properly tested. Consequently, public awareness should be raised regarding medicinal herbs safety, toxicity, potentially lifethreatening adverse effects, and possible herb–drug interactions. Over the years, laboratory data have shown that medicinal herbs may have therapeutic value in CVDs as they can interfere with several CVD risk factors. Accordingly, there have been many attempts to move studies on medicinal herbs from the bench to the bedside, in order to effectively employ herbs in CVD treatments. In this review, we introduce CVDs and their risk factors. Then we overview the use of herbs for disease treatment in general and CVDs in particular. Further, data on the ethnopharmacological therapeutic potentials and medicinal properties against CVDs of four widely used plants, namely Ginseng, Ginkgo biloba, Ganoderma lucidum, and Gynostemma pentaphyllum, are gathered and reviewed. In particular, the employment of these four plants in the context of CVDs, such as myocardial infarction, hypertension, peripheral vascular diseases, coronary heart disease, cardiomyopathies, and dyslipidemias has been reviewed, analyzed, and critically discussed. We also endeavor to document the recent studies aimed to dissect the cellular and molecular cardio-protective mechanisms of the four plants, using recently reported in vitro and in vivo studies. Finally, we reviewed and reported the results of the recent clinical trials that have been conducted using these four medicinal herbs with special emphasis on their efficacy, safety, and toxicity.This work has been made possible thanks to grants (Ager S.O.S.) and (fondo di Ateneo per la ricerca 2019) to GP and Qatar University grant (IRCC-2019-007) to GN and GP

Coordination of frontline defense mechanisms under severe oxidative stress

Inference of an environmental and gene regulatory influence network (EGRINOS) by integrating transcriptional responses to H2O2 and paraquat (PQ) has revealed a multi-tiered oxidative stress (OS)-management program to transcriptionally coordinate three peroxidase/catalase enzymes, two superoxide dismutases, production of rhodopsins, carotenoids and gas vesicles, metal trafficking, and various other aspects of metabolism.ChIP-chip, microarray, and survival assays have validated important architectural aspects of this network, identified novel defense mechanisms (including two evolutionarily distant peroxidase enxymes), and showed that general transcription factors of the transcription factor B family have an important function in coordinating the OS response (OSR) despite their inability to directly sense ROS.A comparison of transcriptional responses to sub-lethal doses of H2O2 and PQ with predictions of these responses made by an EGRIN model generated earlier from responses to other environmental factors has confirmed that a significant fraction of the OSR is made up of a generalized component that is also observed in response to other stressors.Analysis of active regulons within environment and gene regulatory influence network for OS (EGRINOS) across diverse environmental conditions has identified the specialized component of oxidative stress response (OSR) that is triggered by sub-lethal OS, but not by other stressors, including sub-inhibitory levels of redox-active metals, extreme changes in oxygen tension, and a sub-lethal dose of γ rays