G-protein-coupled receptors (GPCRs) modulate many physiological processes by transducing a variety of extracellular cues into intracellular responses. Ligand binding to an extracellular orthosteric ...pocket propagates conformational change to the receptor cytosolic region to promote binding and activation of downstream signalling effectors such as G proteins and β-arrestins. It is well known that different agonists can share the same binding pocket but evoke unique receptor conformations leading to a wide range of downstream responses (‘efficacy’). Furthermore, increasing biophysical evidence, primarily using the β2-adrenergic receptor (β2AR) as a model system, supports the existence of multiple active and inactive conformational states. However, how agonists with varying efficacy modulate these receptor states to initiate cellular responses is not well understood. Here we report stabilization of two distinct β2AR conformations using single domain camelid antibodies (nanobodies)—a previously described positive allosteric nanobody (Nb80) and a newly identified negative allosteric nanobody (Nb60). We show that Nb60 stabilizes a previously unappreciated low-affinity receptor state which corresponds to one of two inactive receptor conformations as delineated by X-ray crystallography and NMR spectroscopy. We find that the agonist isoprenaline has a 15,000-fold higher affinity for β2AR in the presence of Nb80 compared to the affinity of isoprenaline for β2AR in the presence of Nb60, highlighting the full allosteric range of a GPCR. Assessing the binding of 17 ligands of varying efficacy to the β2AR in the absence and presence of Nb60 or Nb80 reveals large ligand-specific effects that can only be explained using an allosteric model which assumes equilibrium amongst at least three receptor states. Agonists generally exert efficacy by stabilizing the active Nb80-stabilized receptor state (R80). In contrast, for a number of partial agonists, both stabilization of R80 and destabilization of the inactive, Nb60-bound state (R60) contribute to their ability to modulate receptor activation. These data demonstrate that ligands can initiate a wide range of cellular responses by differentially stabilizing multiple receptor states.
Evidence regarding the risk factors and characteristics of those with foot fragility fractures compared to non-foot fragility fractures is limited. Foot fragility fracture patients are more likely to ...be younger female with a higher BMI. A foot fragility fracture is strongly predictive of a subsequent foot fragility fracture.Evidence regarding the risk factors and characteristics of those with foot fragility fractures compared to non-foot fragility fractures is limited. Foot fragility fracture patients are more likely to be younger female with a higher BMI. A foot fragility fracture is strongly predictive of a subsequent foot fragility fracture.Osteoporosis can clinically result in fragility fractures. Evidence regarding the risk factors and characteristics of foot fragility fractures compared to non-foot fragility fractures is limited. The American Orthopaedic Association's Own the Bone (OTB) is a bone health initiative with a substantial dataset. The purpose of this study was to examine and compare characteristics of patients presenting with isolated foot fragility fracture to those with a non-foot fragility fracture.PURPOSEOsteoporosis can clinically result in fragility fractures. Evidence regarding the risk factors and characteristics of foot fragility fractures compared to non-foot fragility fractures is limited. The American Orthopaedic Association's Own the Bone (OTB) is a bone health initiative with a substantial dataset. The purpose of this study was to examine and compare characteristics of patients presenting with isolated foot fragility fracture to those with a non-foot fragility fracture.Between January 2009 and March of 2022, 58,001 fragility fractures occurred that were included in this cohort. A total of 750 patients had foot fragility fracture(s) and 57,251 patients had a non-foot fragility fracture that included shoulder, arm, elbow, forearm, wrist, spine, ribs, pelvis, hip, thigh, knee, tibia/fibula, and ankle. Demographics, fracture history, bone health factors, medication history, and medication use for each patient were reported in the OTB database. This data was utilized in our secondary cohort comparative analysis of characteristics and the risk of future fractures between foot fragility fracture and non-foot fragility fracture groups.METHODSBetween January 2009 and March of 2022, 58,001 fragility fractures occurred that were included in this cohort. A total of 750 patients had foot fragility fracture(s) and 57,251 patients had a non-foot fragility fracture that included shoulder, arm, elbow, forearm, wrist, spine, ribs, pelvis, hip, thigh, knee, tibia/fibula, and ankle. Demographics, fracture history, bone health factors, medication history, and medication use for each patient were reported in the OTB database. This data was utilized in our secondary cohort comparative analysis of characteristics and the risk of future fractures between foot fragility fracture and non-foot fragility fracture groups.Foot fragility fracture patients have a significantly higher probability to be younger (66.9 years old), female (91.5%), and have a higher BMI (28.3 kg/m2) compared to non-foot fragility fracture (p < 0.0001) patients. Patients with a foot fragility fracture are nine times (OR = 9.119, CI = 7.44-11.18, p < 0.001) more likely to have had a prior foot fragility fracture. Young, female patients with a prior foot fragility fracture are at higher risk of a future foot fragility fracture, and this risk increased as BMI increased.RESULTSFoot fragility fracture patients have a significantly higher probability to be younger (66.9 years old), female (91.5%), and have a higher BMI (28.3 kg/m2) compared to non-foot fragility fracture (p < 0.0001) patients. Patients with a foot fragility fracture are nine times (OR = 9.119, CI = 7.44-11.18, p < 0.001) more likely to have had a prior foot fragility fracture. Young, female patients with a prior foot fragility fracture are at higher risk of a future foot fragility fracture, and this risk increased as BMI increased.Foot fragility fracture patients are more likely to be female and younger compared to patients with a non-foot fragility fracture. A foot fragility fracture is a sentinel event considering that a prior foot fragility fracture is strongly predictive of a subsequent foot fragility fracture.CONCLUSIONSFoot fragility fracture patients are more likely to be female and younger compared to patients with a non-foot fragility fracture. A foot fragility fracture is a sentinel event considering that a prior foot fragility fracture is strongly predictive of a subsequent foot fragility fracture.3 (retrospective cohort).LEVEL OF EVIDENCE3 (retrospective cohort).
Research on astronaut health and model organisms have revealed six features of spaceflight biology that guide our current understanding of fundamental molecular changes that occur during space ...travel. The features include oxidative stress, DNA damage, mitochondrial dysregulation, epigenetic changes (including gene regulation), telomere length alterations, and microbiome shifts. Here we review the known hazards of human spaceflight, how spaceflight affects living systems through these six fundamental features, and the associated health risks of space exploration. We also discuss the essential issues related to the health and safety of astronauts involved in future missions, especially planned long-duration and Martian missions.
An international group of spaceflight researchers detail how spaceflight affects human biology from the molecular to physiological level and identify key challenges for making space exploration compatible with human health.
Background:
Ankle fragility fractures (AFX) continue to increase in the elderly population. There is limited knowledge of AFX characteristics compared to nonankle fragility fractures (NAFX). The ...American Orthopaedic Association’s Own the Bone (OTB) is a fragility fracture initiative. This robust data set was used to examine and compare characteristics of patients presenting with AFX to those with NAFX.
Methods:
The OTB database contained 72,617 fragility fractures between January 2009 and March of 2022 and were reviewed in our secondary cohort comparative analysis. After exclusions, AFX accounted for 3229 patients and 54,772 patients were in the NAFX cohort. Bivariate analysis and logistic regression compared the AFX and NAFX groups concerning demographics, bone health factors, medication use, and prior fragility fracture.
Results:
AFX patients were found to have a higher likelihood to be younger (67.6 years old), female (81.4%), non-Caucasian (11.7%) and have a higher BMI (30.6) compared to NAFX. Prior AFX predicted the risk of a future AFX. The probability of an AFX increased with increased age and BMI.
Conclusion:
A prior AFX is independently predictive of subsequent AFX. Therefore, these fractures should be considered a sentinel event. These patients are more likely to have higher BMI, to be of female gender, non-Caucasian race, and are younger compared to patients with NAFX.
Level of Evidence:
Level III, retrospective cohort.
Context:
Wearable performance devices and sensors are becoming more readily available to the general population and athletic teams. Advances in technology have allowed individual endurance athletes, ...sports teams, and physicians to monitor functional movements, workloads, and biometric markers to maximize performance and minimize injury. Movement sensors include pedometers, accelerometers/gyroscopes, and global positioning satellite (GPS) devices. Physiologic sensors include heart rate monitors, sleep monitors, temperature sensors, and integrated sensors. The purpose of this review is to familiarize health care professionals and team physicians with the various available types of wearable sensors, discuss their current utilization, and present future applications in sports medicine.
Evidence Acquisition:
Data were obtained from peer-reviewed literature through a search of the PubMed database. Included studies searched development, outcomes, and validation of wearable performance devices such as GPS, accelerometers, and physiologic monitors in sports.
Study Design:
Clinical review.
Level of Evidence:
Level 4.
Results:
Wearable sensors provide a method of monitoring real-time physiologic and movement parameters during training and competitive sports. These parameters can be used to detect position-specific patterns in movement, design more efficient sports-specific training programs for performance optimization, and screen for potential causes of injury. More recent advances in movement sensors have improved accuracy in detecting high-acceleration movements during competitive sports.
Conclusion:
Wearable devices are valuable instruments for the improvement of sports performance. Evidence for use of these devices in professional sports is still limited. Future developments are needed to establish training protocols using data from wearable devices.
The treatment of subchondral lesions is an area with limited focus within the foot and ankle literature. The literature has shown an association between disruption of the subchondral bone plate and ...the formation of subchondral cysts. The primary causes of subchondral lesions are acute trauma, repetitive microtrauma, as well as idiopathic means. Evaluation of these injuries should be done carefully and often requires advanced imaging including MRI and computed tomography. Treatment does vary depending on the presentation of the subchondral lesion with or without the presence of an osteochondral lesion.
Heart rate variability and implication for sport concussion Bishop, Scott A.; Dech, Ryan T.; Guzik, Przemyslaw ...
Clinical physiology and functional imaging,
September 2018, 2018-Sep, 2018-09-00, 20180901, Letnik:
38, Številka:
5
Journal Article
Recenzirano
Summary
Finding sensitive and specific markers for sports‐related concussion is both challenging and clinically important. Such biomarkers might be helpful in the management of patients with ...concussion (i.e. diagnosis, monitoring and risk prediction). Among many parameters, blood flow–pressure metrics and heart rate variability (HRV) have been used to gauge concussion outcomes. Reports on the relation between HRV and both acute and prolonged concussion recovery are conflicting. While some authors report on differences in the low‐frequency (LF) component of HRV during postural manipulations and postexercise conditions, others observe no significant differences in various HRV measures. Despite the early success of using the HRV LF for concussion recovery, the interpretation of the LF is debated. Recent research suggests the LF power is a net effect of several intrinsic modulatory factors from both sympathetic and parasympathetic branches of the autonomic nervous system, vagally mediated baroreflex and even some respiratory influences at lower respiratory rate. There are only a few well‐controlled concussion studies that specifically examine the contribution of the autonomic nervous system branches with HRV for concussion management. This study reviews the most recent HRV– concussion literature and the underlying HRV physiology. It also highlights cerebral blood flow studies related to concussion and the importance of multimodal assessment of various biological signals. It is hoped that a better understanding of the physiology behind HRV might generate cost‐effective, repeatable and reliable protocols, all of which will improve the interpretation of HRV throughout concussion recovery.
We compared the BD Phoenix automated microbiology system to the Bruker Biotyper (version 2.0) matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry (MS) system for ...identification of Gram-negative bacilli, using biochemical testing and/or genetic sequencing to resolve discordant results. The BD Phoenix correctly identified 363 (83%) and 330 (75%) isolates to the genus and species level, respectively. The Bruker Biotyper correctly identified 408 (93%) and 360 (82%) isolates to the genus and species level, respectively. The 440 isolates were grouped into common (308) and infrequent (132) isolates in the clinical laboratory. For the 308 common isolates, the BD Phoenix and Bruker Biotyper correctly identified 294 (95%) and 296 (96%) of the isolates to the genus level, respectively. For species identification, the BD Phoenix and Bruker Biotyper correctly identified 93% of the common isolates (285 and 286, respectively). In contrast, for the 132 infrequent isolates, the Bruker Biotyper correctly identified 112 (85%) and 74 (56%) isolates to the genus and species level, respectively, compared to the BD Phoenix, which identified only 69 (52%) and 45 (34%) isolates to the genus and species level, respectively. Statistically, the Bruker Biotyper overall outperformed the BD Phoenix for identification of Gram-negative bacilli to the genus (P < 0.0001) and species (P = 0.0005) level in this sample set. When isolates were categorized as common or infrequent isolates, there was statistically no difference between the instruments for identification of common Gram-negative bacilli (P > 0.05). However, the Bruker Biotyper outperformed the BD Phoenix for identification of infrequently isolated Gram-negative bacilli (P < 0.0001).
The genetic architecture of sporadic congenital heart disease (CHD) is characterized by enrichment in damaging de novo variants in chromatin-modifying genes. To test the hypothesis that gene pathways ...contributing to de novo forms of CHD are distinct from those for recessive forms, we analyze 2391 whole-exome trios from the Pediatric Cardiac Genomics Consortium. We deploy a permutation-based gene-burden analysis to identify damaging recessive and compound heterozygous genotypes and disease genes, controlling for confounding effects, such as background mutation rate and ancestry. Cilia-related genes are significantly enriched for damaging rare recessive genotypes, but comparatively depleted for de novo variants. The opposite trend is observed for chromatin-modifying genes. Other cardiac developmental gene classes have less stratification by mode of inheritance than cilia and chromatin-modifying gene classes. Our analyses reveal dominant and recessive CHD are associated with distinct gene functions, with cilia-related genes providing a reservoir of rare segregating variation leading to CHD.
We demonstrate a plasmon nanoruler using a coupled film nanoparticle (film-NP) format that is well-suited for investigating the sensitivity extremes of plasmonic coupling. Because it is relatively ...straightforward to functionalize bulk surface plasmon supporting films, such as gold, we are able to precisely control plasmonic gap dimensions by creating ultrathin molecular spacer layers on the gold films, on top of which we immobilize plasmon resonant nanoparticles (NPs). Each immobilized NP becomes coupled to the underlying film and functions as a plasmon nanoruler, exhibiting a distance-dependent resonance red shift in its peak plasmon wavelength as it approaches the film. Due to the uniformity of response from the film-NPs to separation distance, we are able to use extinction and scattering measurements from ensembles of film-NPs to characterize the coupling effect over a series of very short separation distancesranging from 5 to 20 Åand combine these measurements with similar data from larger separation distances extending out to 27 nm. We find that the film-NP plasmon nanoruler is extremely sensitive at very short film-NP separation distances, yielding spectral shifts as large as 5 nm for every 1 Å change in separation distance. The film-NP coupling at extremely small spacings is so uniform and reliable that we are able to usefully probe gap dimensions where the classical Drude model of the conducting electrons in the metals is no longer descriptive; for gap sizes smaller than a few nanometers, either quantum or semiclassical models of the carrier response must be employed to predict the observed wavelength shifts. We find that, despite the limitations, large field enhancements and extreme sensitivity persist down to even the smallest gap sizes.
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