Insights into the Mechanism of Tryptophan Fluorescence Quenching due to Synthetic Crowding Agents: A Combined Experimental and Computational Study.

Intrinsic tryptophan fluorescence spectroscopy is an important tool for examining the effects of molecular crowding and confinement on the structure, dynamics, and function of proteins. Synthetic crowders such as dextran, ficoll, polyethylene glycols, polyvinylpyrrolidone, and their respective monomers are used to mimic crowded intracellular environments. Interactions of these synthetic crowders with tryptophan and the subsequent impact on its fluorescence properties are therefore critically important for understanding the possible interference created by these crowders. In the present study, the effects of polymer and monomer crowders on tryptophan fluorescence were assessed by using experimental and computational approaches. The results of this study demonstrated that both polymer and monomer crowders have an impact on the tryptophan fluorescence intensity; however, the molecular mechanisms of quenching were different. Using Stern-Volmer plots and a temperature variation study, a physical basis for the quenching mechanism of commonly used synthetic crowders was established. The quenching of free tryptophan was found to involve static, dynamic, and sphere-of-action mechanisms. In parallel, computational studies employing Kohn-Sham density functional theory provided a deeper insight into the effects of intermolecular interactions and solvation, resulting in differing quenching modes for these crowders. Taken together, the study offers new physical insights into the quenching mechanisms of some commonly used monomer and polymer synthetic crowders.

Evolution of Stronger SARS-CoV-2 Variants as Revealed Through the Lens of Molecular Dynamics Simulations.

Using molecular dynamics simulations, the protein-protein interactions of the receptor-binding domain of the wild-type and seven variants of the severe acute respiratory syndrome coronavirus 2 spike protein and the peptidase domain of human angiotensin-converting enzyme 2 were investigated. These variants are alpha, beta, gamma, delta, eta, kappa, and omicron. Using 100 ns simulation data, the residue interaction networks at the protein-protein interface were identified. Also, the impact of mutations on essential protein dynamics, backbone flexibility, and interaction energy of the simulated protein-protein complexes were studied. The protein-protein interface for the wild-type, delta, and omicron variants contained several stronger interactions, while the alpha, beta, gamma, eta, and kappa variants exhibited an opposite scenario as evident from the analysis of the inter-residue interaction distances and pair-wise interaction energies. The study reveals that two distinct residue networks at the central and right contact regions forge stronger binding affinity between the protein partners. The study provides a molecular-level insight into how enhanced transmissibility and infectivity by delta and omicron variants are most likely tied to a handful of interacting residues at the binding interface, which could potentially be utilized for future antibody constructs and structure-based antiviral drug design.

Identification of western North Atlantic odontocete echolocation click types using machine learning and spatiotemporal correlates.

A combination of machine learning and expert analyst review was used to detect odontocete echolocation clicks, identify dominant click types, and classify clicks in 32 years of acoustic data collected at 11 autonomous monitoring sites in the western North Atlantic between 2016 and 2019. Previously-described click types for eight known odontocete species or genera were identified in this data set: Blainville's beaked whales (Mesoplodon densirostris), Cuvier's beaked whales (Ziphius cavirostris), Gervais' beaked whales (Mesoplodon europaeus), Sowerby's beaked whales (Mesoplodon bidens), and True's beaked whales (Mesoplodon mirus), Kogia spp., Risso's dolphin (Grampus griseus), and sperm whales (Physeter macrocephalus). Six novel delphinid echolocation click types were identified and named according to their median peak frequencies. Consideration of the spatiotemporal distribution of these unidentified click types, and comparison to historical sighting data, enabled assignment of the probable species identity to three of the six types, and group identity to a fourth type. UD36, UD26, and UD28 were attributed to Risso's dolphin (G. griseus), short-finned pilot whale (G. macrorhynchus), and short-beaked common dolphin (D. delphis), respectively, based on similar regional distributions and seasonal presence patterns. UD19 was attributed to one or more species in the subfamily Globicephalinae based on spectral content and signal timing. UD47 and UD38 represent distinct types for which no clear spatiotemporal match was apparent. This approach leveraged the power of big acoustic and big visual data to add to the catalog of known species-specific acoustic signals and yield new inferences about odontocete spatiotemporal distribution patterns. The tools and call types described here can be used for efficient analysis of other existing and future passive acoustic data sets from this region.

Ketone Bodies Impact on Hypoxic CO2 Retention Protocol During Exercise.

Exogenous ketone esters have demonstrated the capacity to increase oxygen availability during acute hypoxic exposure leading to the potential application of their use to mitigate performance declines at high altitudes. Voluntary hypoventilation (VH) with exercise reliably reduces oxygen availability and increases carbon dioxide retention without alterations to ambient pressure or gas content. Utilizing a double-blind randomized crossover design, fifteen recreational male distance runners performed submaximal exercise (4 × 5 min; 70% VO2 Max) with VH. An exogenous ketone ester (KME; 573 mg⋅kg-1) or iso-caloric flavor matched placebo (PLA) was consumed prior to exercise. Metabolites, blood gases, expired air, heart rate, oxygen saturation, cognition, and perception metrics were collected throughout. KME rapidly elevated R-ß-hydroxybutyrate and reduced blood glucose without altering lactate production. KME lowered pH, bicarbonate, and total carbon dioxide. VH with exercise significantly reduced blood (SpO2) and muscle (SmO2) oxygenation and increased cognitive mean reaction time and respiratory rate regardless of condition. KME administration significantly elevated respiratory exchange ratio (RER) at rest and throughout recovery from VH, compared to PLA. Blood carbon dioxide (PCO2) retention increased in the PLA condition while decreasing in the KME condition, leading to a significantly lower PCO2 value immediately post VH exercise (IPE; p = 0.031) and at recovery (p = 0.001), independent of respiratory rate. The KME's ability to rapidly alter metabolism, acid/base balance, CO2 retention, and respiratory exchange rate independent of respiratory rate changes at rest, during, and/or following VH exercise protocol illustrates a rapid countermeasure to CO2 retention in concert with systemic metabolic changes.

Vitamin D and COVID-19: A review on the role of vitamin D in preventing and reducing the severity of COVID-19 infection.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a pathogenic coronavirus causing COVID-19 infection. The interaction between the SARS-CoV-2 spike protein and the human receptor angiotensin-converting enzyme 2, both of which contain several cysteine residues, is impacted by the disulfide-thiol balance in the host cell. The host cell redox status is affected by oxidative stress due to the imbalance between the reactive oxygen/nitrogen species and antioxidants. Recent studies have shown that Vitamin D supplementation could reduce oxidative stress. It has also been proposed that vitamin D at physiological concentration has preventive effects on many viral infections, including COVID-19. However, the molecular-level picture of the interplay of vitamin D deficiency, oxidative stress, and the severity of COVID-19 has remained unclear. Herein, we present a thorough review focusing on the possible molecular mechanism by which vitamin D could alter host cell redox status and block viral entry, thereby preventing COVID-19 infection or reducing the severity of the disease.

Streptococcus milleri infection.

We report three cases of flexor sheath infection due to Streptococcus milleri in two patients. Soft tissue damage was extensive despite surgical debridement and appropriate antibiotic therapy. One patient had two digits amputated and the other had the affected digit amputated at the level of the proximal interphalangeal joint. These cases illustrate the potential pathogenicity of a bacterium which is often regarded as a commensal.

Open carpal tunnel release under local anaesthesia: a patient satisfaction survey.

The patient acceptability of open carpal tunnel release under local anaesthesia (LA) and tourniquet control was assessed by a postal survey. 58 releases on 44 patients over a 3-year period were surveyed, with a questionnaire response rate of 91%. Use of LA for this procedure was effective and acceptable to most patients, but the incidence of severe pain due to infiltration of LA and the tourniquet intolerance rate were unacceptably high and have been addressed by use of LA with adrenaline and bipolar diathermy to dispense with tourniquet and use of dental syringe and injecting LA from proximal to distal direction to make infiltration more comfortable.

Effectiveness of the A-V impulse hand pump.

Acute swelling of the hand is a common problem after trauma or surgery and is associated with both pain and loss of function. We describe a prospective study of 47 patients in which we assessed the effects of a pneumatic compression device (A-V impulse hand pump) on the swollen hand. The pump reduced swelling by increasing the velocity of venous return as demonstrated by Duplex scanning of the median cubital vein. Continuous use of the pump for 48 hours gave a reduction of 78.6% in swelling of the injured hand compared with the opposite, uninjured side. Even when used intermittently, with the pump on for 12 hours out of 24, a statistically significant effect was seen. There was a subjective reduction in pain and an objective improvement in function of the hand. Use of the pump resulted in a nearly normal hand by the time of discharge from hospital after, on average, 48 hours.

Closure of fasciotomy wounds. A technical modification.

The closure of fasciotomy wounds creates problems for patient and surgeon alike. Split thickness skin grafting results in unsightly and insensate wounds and often requires general anaesthesia and prolonged inpatient care. We describe an improvement of a previously reported technique which is as effective as proprietary medical devices currently available. The technique may also be applied to the delayed primary closure of traumatic wounds.

Outcomes of hand surgery. British Society for Surgery of the Hand.

The findings are presented of a conference on Outcomes of Hand Surgery organized by the audit committee of British Society for Surgery of the Hand in 1993. Measures of outcome in terms of movement, power, sensibility, pain, activities of daily living, complications and patient satisfaction are considered, and an example of a patient evaluation measure given as an appendix.

Hand surgery coding and classification.

The development of codes for hand surgery as part of the Read Code System is described. A lexicon of clinical terms and surgery has been developed, and will shortly be available from the National Health Service Centre for Coding and Classification in Loughborough, UK.

The use of injury scoring in the evaluation of the Kegworth M1 aircrash.

The Abbreviated Injury Scale (AIS) score and the Injury Severity Score (ISS) were calculated for all passengers and crew of the M1 Kegworth aircraft crash. Regional injury scores were significantly higher in nonsurvivors than survivors of the impact. Mortality and ISSs were found to correlate with the structural damage sustained by the aircraft. The use of injury scoring has highlighted variations in the severity of injuries sustained by occupants involved in an impact crash of an airliner. This information has demonstrated that other factors in addition to the force of the impact were involved in the causation of injury, such as structural integrity, attempts by occupants to protect adjoining passengers, and rear-facing seats.

Unnecessary arthroscopies.

A review of the results of arthroscopies on patients taken from an 'open access' service waiting list has been carried out. One-third of all arthroscopies proved to be negative. Accuracy of clinical diagnosis was not related to the clinical grade of the examining doctor. The excess annual cost to the Northern Ireland Orthopaedic Service of unnecessary arthroscopies may have been of the order of 89,000 pounds.

Survivors of the M1 aircrash. Outcome of injuries after 1 year. The Nottingham, Leicester, Derby and Belfast Study Group.

The 79 survivors of the M1 aircrash have been assessed at an average of great britain 1 year after the accident. Return to work, continued hospital care and recovery from injuries has been found to be related to the severity of injury. The 188 pelvic and limb fractures have been reviewed and the incidence of complications from these injuries has been low. Spinal and lower limb injuries account for the majority of the residual disability.

Subcapital fracture in a femoral prosthesis: brief report.

Stem fractures in prosthetic femoral components are a well recognized problem. More recently neck fractures have been described. An unusual case of a 'sub-capital fracture' in a femoral component is described.