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1.
Bone Jt Open ; 5(5): 419-425, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38767221

RESUMO

Aims: The purpose of this survey study was to examine the demographic and lifestyle factors of women currently in orthopaedic surgery. Methods: An electronic survey was conducted of practising female orthopaedic surgeons based in the USA through both the Ruth Jackson Society and the online Facebook group "Women of Orthopaedics". Results: The majority of surveyed female orthopaedic surgeons reported being married (76.4%; 285/373) and having children (67.6%; 252/373). In all, 66.5% (247/373) were collegiate athletes; 82.0% (306/373) reported having no female orthopaedic surgeon mentors in undergraduate and medical school. Their mean height is 65.8 inches and average weight is 147.3 lbs. Conclusion: The majority of female orthopaedic surgeons did not have female mentorship during their training. Additionally, biometrically, their build is similar to that of the average American woman.

2.
J Biol Chem ; 300(5): 107248, 2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38556082

RESUMO

P2X receptors are a family of ligand gated ion channels found in a range of eukaryotic species including humans but are not naturally present in the yeast Saccharomyces cerevisiae. We demonstrate the first recombinant expression and functional gating of the P2X2 receptor in baker's yeast. We leverage the yeast host for facile genetic screens of mutant P2X2 by performing site saturation mutagenesis at residues of interest, including SNPs implicated in deafness and at residues involved in native binding. Deep mutational analysis and rounds of genetic engineering yield mutant P2X2 F303Y A304W, which has altered ligand selectivity toward the ATP analog AMP-PNP. The F303Y A304W variant shows over 100-fold increased intracellular calcium amplitudes with AMP-PNP compared to the WT receptor and has a much lower desensitization rate. Since AMP-PNP does not naturally activate P2X receptors, the F303Y A304W P2X2 may be a starting point for downstream applications in chemogenetic cellular control. Interestingly, the A304W mutation selectively destabilizes the desensitized state, which may provide a mechanistic basis for receptor opening with suboptimal agonists. The yeast system represents an inexpensive, scalable platform for ion channel characterization and engineering by circumventing the more expensive and time-consuming methodologies involving mammalian hosts.

3.
Telemed Rep ; 5(1): 18-35, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38469166

RESUMO

Background: While the importance of structured rehabilitation following anterior cruciate ligament reconstruction (ACLR), particularly in the return-to-sport phase, is known, for most patients, supervised physical therapy is often completed before this time point. The recent emergence of telerehabilitation and other digital health interventions has the potential to address this "rehabilitation gap." Methods: The study was conducted as a cross-section, online survey collecting qualitative and quantitative data from open and closed questions. Inclusion criteria included local qualified physical therapists or other professionals working with ACLR patients. Results: Eighty-three percent of respondents experienced a "rehabilitation gap" with their ACLR patients. Few reported currently utilizing apps or websites (9.74%). The majority (41/58) reported experience with telerehabilitation, and 84% felt that there was a role for digital rehabilitation strategies to address the "rehabilitation gap." The vast majority (94.74%) of participants felt that standard commercial insurance did not permit sufficient rehabilitation. Discussion: While the majority of our respondents acknowledged the existence of a "rehabilitation gap," as well as familiarity with and confidence in telerehabilitation, few were using this technique at the time of our survey. This suggests an opportunity for development in this space.

4.
Int J Eat Disord ; 57(5): 1260-1267, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38213085

RESUMO

BACKGROUND: Cognitive-behavioral therapy for avoidant/restrictive food intake disorder (ARFID; CBT-AR) theoretically targets three prototypic motivations (sensory sensitivity, lack of interest/low appetite, fear of aversive consequences), aligned with three modularized interventions. As an exploratory investigation, we: (1) evaluated change in candidate mechanisms in relationship to change in ARFID severity, and (2) tested if assignment (vs. not) to a module resulted in larger improvements in the corresponding mechanism. METHOD: Males and females (N = 42; 10-55 years) participated in an open trial of CBT-AR. RESULTS: Decreases in scaled scores for each candidate mechanism had medium to large correlations with decreases in ARFID severity-sensory sensitivity: -0.7 decrease (r = .42, p = .01); lack of interest/low appetite: -0.3 decrease (r = .60, p < .0001); and fear of aversive consequences: -1.1 decrease (r = .33, p = .05). Linear mixed models revealed significant weekly improvements for each candidate mechanism across the full sample (ps < .0001). There were significant interactions for the sensory and fear of aversive consequences modules-for each, participants who received the corresponding module had significantly larger decreases in the candidate mechanism than those who did not receive the module. DISCUSSION: Sensory sensitivity and fear of aversive consequences improved more if the CBT-AR module was received, but lack of interest/low appetite may improve regardless of receipt of the corresponding module. Future research is needed to test target engagement in CBT-AR with adaptive treatment designs, and to identify valid and sensitive measures of candidate mechanisms. PUBLIC SIGNIFICANCE: The mechanisms through which components of CBT-AR work have yet to be elucidated. We conducted an exploratory investigation to test if assignment (vs. not) to a CBT-AR module resulted in larger improvements in the corresponding prototypic ARFID motivation that the module intended to target. Measures of the sensory sensitivity and the fear of aversive consequences motivations improved more in those who received the corresponding treatment module, whereas the lack of interest/low appetite measure improved regardless of if the corresponding module was received.


Assuntos
Transtorno Alimentar Restritivo Evitativo , Terapia Cognitivo-Comportamental , Humanos , Masculino , Feminino , Terapia Cognitivo-Comportamental/métodos , Adulto , Pessoa de Meia-Idade , Adolescente , Criança , Resultado do Tratamento , Adulto Jovem , Estudo de Prova de Conceito , Motivação
5.
J Strength Cond Res ; 38(1): 146-152, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37815263

RESUMO

ABSTRACT: Summer, LC, Cheng, R, Moran, JT, Lee, M, Belanger, AJ, TaylorIV, WL, and Gardner, EC. Changes in body composition and athletic performance in National Collegiate Athletic Association Division I female field hockey athletes throughout a competitive season. J Strength Cond Res 38(1): 146-152, 2024-The purposes of this study were (a) to analyze the changes in total and regional body composition measurements in a National Collegiate Athletic Association (NCAA) Division I female field hockey team throughout a 17-game competitive season using dual X-ray absorptiometry (DXA); (b) to examine improvements, if any, in athletic performance measures after a season; and (c) to report on the relationship between these body composition changes and changes in athletic performance. Preseason and postseason dual-energy DXA and performance data from the 2019-2020 season were retrospectively identified for 20 field players (forwards, midfielders, and defenders). Body composition data included total and regional fat mass, lean mass, and body fat percentage, whereas athletic performance measures included the vertical jump, 10-yard dash, and pro-agility (5-10-5) shuttle run. All variables were quantitative and analyzed using paired t -tests or its nonparametric equivalent and an alpha level of p < 0.05 was used to determine significance. After a competitive season, athletes had significant decreases in fat mass and increases in lean mass in their arms, legs, trunks, gynoids, and total body measurements. Android fat mass and body fat percentage also decreased. Athletes performed significantly better on the pro-agility shuttle run at the end of the season, but no significant differences were observed in other performance metrics. Moderate correlations were observed between changes in body composition (total fat mass and total lean mass) and changes in athletic performance. Our study provides a novel, longitudinal assessment of body composition and athletic performance for elite female field hockey athletes that will help trainers and coaches better understand how these variables change throughout a season and allow them to better prepare their players for competitive success.


Assuntos
Desempenho Atlético , Hóquei , Humanos , Feminino , Estações do Ano , Estudos Retrospectivos , Composição Corporal , Atletas
6.
Commun Biol ; 6(1): 1250, 2023 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-38082099

RESUMO

The ongoing evolution of SARS-CoV-2 into more easily transmissible and infectious variants has provided unprecedented insight into mutations enabling immune escape. Understanding how these mutations affect the dynamics of antibody-antigen interactions is crucial to the development of broadly protective antibodies and vaccines. Here we report the characterization of a potent neutralizing antibody (N3-1) identified from a COVID-19 patient during the first disease wave. Cryogenic electron microscopy revealed a quaternary binding mode that enables direct interactions with all three receptor-binding domains of the spike protein trimer, resulting in extraordinary avidity and potent neutralization of all major variants of concern until the emergence of Omicron. Structure-based rational design of N3-1 mutants improved binding to all Omicron variants but only partially restored neutralization of the conformationally distinct Omicron BA.1. This study provides new insights into immune evasion through changes in spike protein dynamics and highlights considerations for future conformationally biased multivalent vaccine designs.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Anticorpos Neutralizantes
7.
Orthop J Sports Med ; 11(9): 23259671231198208, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37736602

RESUMO

Background: Ice skating, inline skating, and roller skating are popular sports in the United States (US). Although they are similar, injuries incurred may be distinct and may have evolved over time. Purpose: To characterize injuries related to ice skating, inline skating, and roller skating and track injury patterns over a 20-year period. Study Design: Descriptive epidemiology study. Methods: The current study utilized the National Electronic Injury Surveillance System, a database reporting consumer product-related injuries seen at emergency departments in the US. All ice skating, inline skating, and roller skating injuries between 2002 and 2021 were identified, and patient demographics, types of injury, and year of injury were compared between skating types. Results: A total of 1,656,746 skating-related injuries were estimated nationally: 24% (403,791) for ice skating, 24% (400,172) for inline skating, and 52% (852,783) for roller skating. While the incidence of ice-skating- and roller-skating-related injuries decreased by 34.4% (from 22,490 in 2002-2004 to 14,758 in 2019-2021) and 29.6% (from 42,452 in 2002-2004 to 31,980 in 2019-2021), respectively, injuries related to inline skating decreased comparatively more, by 75.8% over the study period (from 48,097 in 2002-2004 to 11,662 in 2019-2021). Injuries occurred predominantly to the head/face/neck for ice skating (n = 139,501; 34.5% of injuries), whereas injuries occurred predominantly in the shoulder/arm/elbow/wrist for inline skating (n = 212,088, 53.0% of injuries) and roller skating (n = 425,216, 49.9% of injuries). Fracture was the most common injury type for all 3 skating types (n = 614,853, 37.1% of injuries), and the majority of fractures occurred in the upper extremity (shoulder/arm/elbow/wrist) for all 3 skating types (n = 59,624, 60.0% [ice skating]; n = 69,197, 41.2% [inline skating], and n = 237,099, 68.2% [roller skating]). Lower extremity (leg/knee/ankle) fractures were more common among ice skating (n = 28,019, 28.2%) and roller skating (n = 82,094, 23.6%) injuries compared with inline skating (n = 21,391, 12.7%). Conclusion: In the current study, we found that fractures were the most common type of injury regardless of skating type but that the location of the injury/fracture varied by skating type.

8.
Arthrosc Sports Med Rehabil ; 5(3): e671-e678, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37388885

RESUMO

Purpose: (1) To define the incidence of surgically treated isolated bucket-handle meniscus tears (BHMTs); (2) to investigate risk of subsequent ipsilateral anterior cruciate ligament reconstruction (ACLR) in patients who underwent previous isolated bucket handle (BH) meniscus repair; and (3) to investigate the risk of subsequent ACLR for various types of surgically treated meniscal tears. Methods: A retrospective review of a national database was conducted to identify patients, aged 10 to 40 years, who underwent primary isolated BH meniscus surgery from 2015 to 2020. Patients were stratified by operative method. A control group of 500,000 age-matched patients was randomly selected to establish a benchmark rate of ACLR. Kaplan-Meier analysis was performed to compare the timing and incidence of subsequent ipsilateral ACLR after primary isolated BH meniscus surgery to the control group within 2 and 5 years. Results: In total, 1,767 patients with isolated BHMTs treated with surgery were identified and met inclusion criteria. The incidence of isolated BHMTs among all surgically treated (repair or meniscectomy) meniscal injuries was 1.67%. Isolated BH repairs had significantly greater odds of ACLR within 5 years compared to the control group (odds ratio [OR] 6.09; 95% confidence interval [CI] 2.86-12.99; P < .001). Medial BH repairs had the greatest odds of ACLR within 5 years (OR 9.15; 95% CI 4.27-19.57; P < .001). Lateral BH repair was not associated with subsequent ipsilateral ACLR within 5 years (OR 2.63; CI 0.37-18.90; P = .340). Conclusions: Isolated BHMTs comprised 1.67% of all surgically treated meniscal injuries. Patients who underwent prior surgery for isolated BHMT were at increased risk of undergoing subsequent ipsilateral ACLR compared with the general population. Isolated medial BHMTs treated with repair had the highest risk for subsequent ACLR. Level of Evidence: Level III, retrospective cohort study.

9.
J Hand Surg Glob Online ; 5(2): 184-188, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36974296

RESUMO

Purpose: Increasing ownership and use of mobile phones has been recently linked to reports of hand and wrist pain from overuse, as well as more serious injuries related to distracted behaviors, such as falls and texting while driving. We describe the epidemiology of hand and wrist injuries presenting to US emergency departments from 2011 to 2020, which were associated with cell phone use using the Consumer Product Safety Commission's National Electronic Injury Surveillance System. Methods: The National Electronic Injury Surveillance System database was queried for treatment records from 2011 through to 2020 for all cell phone-related injuries of the lower arm, wrist, hand, and fingers. Using parameters provided by the National Electronic Injury Surveillance System database, there were 1,213 unique cases, yielding a total weighted estimate of 50,487 national cases presenting to emergency departments in the United States. Results: Between 2011 and 2020, the weighted estimate of annual cell phone-related injuries ranged from 3,389 to 7,320 cases. Falls were the most common cause of injury, accounting for 29.8% of estimated cases. The most common types of injuries were lacerations (22.3%). The national estimate of cell phone-related injury was the highest in the age range of 11-20 years (26.4%), followed by 21-30 years (22.2%). Women were affected more frequently than men (59.6% vs 40.4%). Conclusions: Upper extremity injuries related to cell phone use represent an increasing burden of disease to the US healthcare system. Raising awareness regarding cell phone-related injuries and in-home fall-prevention strategies, especially among elderly individuals, should be considered as means of decreasing the number of such injuries. Strategies for decreasing the burden of cell phone-related injuries occurring as a result of falls among teenagers and young adults should focus on minimizing distractions while using a cell phone. Limitations of the study include inaccuracies related to probability-weighted case estimation and limitations in reporting injuries. Clinical relevance: Knowledge of the burden of upper extremities injuries associated with this common handheld device can help to both raise awareness of this issue, as well as to potentially inform injury-prevention strategies.

10.
J Am Acad Orthop Surg ; 31(11): 565-573, 2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-36730692

RESUMO

INTRODUCTION: Bucket-handle meniscus tears are common knee injuries that are often treated surgically with meniscectomy or meniscal repair. Although clinical factors may influence the choice of one treatment approach over the other, the influence of patient, socioeconomic, and hospital factors remains poorly characterized. This study aimed to estimate the relative nationwide utilization of these two procedures and delineate a variety of factors that are associated with the selection of one treatment approach over the other. METHODS: Meniscal repair and meniscectomy procedures conducted for isolated bucket-handle meniscus tears in 2016 and 2017 were identified in the Nationwide Ambulatory Surgery Sample database. Cases were weighted using nationally representative discharge weights. Univariate analyses and a multivariable logistic regression model were used to compare patient, socioeconomic, and hospital factors associated with meniscal repair versus meniscectomy. RESULTS: In total, 12,239 cases were identified, which represented 17,236 cases after weighting. Of these, meniscal repair was conducted for 4,138 (24.0%). Based on the logistic regression model, meniscal repair was less likely for older and sicker patients. By contrast, several factors were associated with markedly higher odds of undergoing meniscal repair compared with meniscectomy. These included urban teaching hospitals; geographic location in the midwest, south, and west; and higher median household income. DISCUSSION: Using a large nationally representative cohort, the current data revealed that only 24.0% of surgically treated bucket-handle meniscus tears were treated using repair. Identification of patient, socioeconomic, and hospital factors differentially associated with meniscal repair suggest that other factors may systematically influence surgical decision-making for this patient population. Surgeons should be conscious of these potential healthcare disparities when determining the optimal treatment for their patients. LEVEL OF EVIDENCE: Level III.


Assuntos
Traumatismos do Joelho , Lesões do Menisco Tibial , Humanos , Meniscectomia , Meniscos Tibiais/cirurgia , Traumatismos do Joelho/cirurgia , Lesões do Menisco Tibial/cirurgia , Lesões do Menisco Tibial/complicações , Hospitais de Ensino , Fatores Socioeconômicos , Artroscopia/métodos , Estudos Retrospectivos
11.
Int J Sports Med ; 44(1): 29-37, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35672010

RESUMO

The objective of this investigation was to compare isokinetic strength, countermovement jump and drop jump variables between high-contributors and low-contributors within NCAA Division I Men's and Women's lacrosse athletes. Men's (N=36) and Women's (N=30) NCAA Division I lacrosse athletes completed strength testing of the quadriceps and hamstring across three speeds (60°·s-1, 180°·s-1, 300°·s-1), countermovement and drop jumps. To determine the discriminative ability of select lower-limb strength and power characteristics participants were categorized as high-contributors (Males N=18, age=20.3±0.4 yrs, height=183.9±5.5 cm, mass=90.8±5.8 kg; Females N=15, age=20.8±0.8 yrs, height=169.3±6.7 cm, mass=64.1±7.2 kg) or low-contributors (Males N=18, age=19.5±0.2 yrs, height=184.1±5.6 cm; mass=87.9±8.1 kg; Females N=15, age=19.7±0.2 yrs, height=169.8±7.0 cm, mass=62.9±7.7 kg ) based upon the number of games the participants competed in during the regular season. Within the male cohort, moderate significant (p<0.05) differences were observed between high-contributors and low-contributors in isokinetic hamstring strength of the left leg at 300°·s-1 (d=0.69) and peak power in countermovement jump (d=0.68). Within the women's cohort a large (d=0.87) significant difference (p<0.05) in isokinetic strength of the left hamstring was observed between high-contributors and low-contributors at 60°·s-1. Hamstring strength and lower-limb power are important strength measures for lacrosse performance and should be prioritized in training prescription for lacrosse athletes.


Assuntos
Força Muscular , Esportes com Raquete , Humanos , Masculino , Feminino , Adulto Jovem , Adulto , Extremidade Inferior , Perna (Membro) , Atletas
12.
Artigo em Inglês | MEDLINE | ID: mdl-35816646

RESUMO

INTRODUCTION: The extent to which physical therapy (PT) is used after meniscectomy is unknown. The objective of this study was to estimate the extent to which PT is implemented after meniscectomy and to identify factors associated with its utilization. METHODS: The Mariner PearlDiver database was queried to identify patients who underwent uncomplicated meniscectomy. The number of PT visits for each patient was tabulated. Logistic regressions were used to compare demographic factors associated with no use of PT and use of nine or more PT visits. RESULTS: In total, 92,291 patients met inclusion criteria. Of these patients, 72.21% did not use PT and 27.8% used 1 or more PT visits. Of the patients who used PT, 19.76% had 1 to 8 PT visits and 8.03% had 9 or more PT visits. Older age and noncommercial insurance types were associated with no PT use. Male sex, Medicaid, and Medicare were associated with markedly lower odds of increased PT utilization. CONCLUSION: PT is used in the minority of the time after meniscectomy. Among patients who do use PT, however, notable variation exists in the amount of PT visits used. Patient age, sex, insurance status, and geographic variables were independently associated with PT utilization.


Assuntos
Medicare , Meniscectomia , Idoso , Demografia , Humanos , Masculino , Modalidades de Fisioterapia , Fatores Socioeconômicos , Estados Unidos
13.
Food Chem Toxicol ; 165: 113122, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35580760

RESUMO

Arsenic is a persistent environmental contaminant that humans are exposed to primarily through contaminated water supplies. Arsenic has been shown to have numerous immunomodulatory effects, including deleterious effects on T cell function. However, the effect of arsenic on human T cell function in the context of influenza infection remains poorly characterized. The goal of this study was to determine the effects of arsenic on T cell activation and effector function in a human-relevant ex vivo model with influenza challenge. Flow cytometric analysis of T cells following the treatment of primary human peripheral blood mononuclear cells with environmentally relevant concentrations of arsenic trioxide and subsequent challenge with influenza A virus showed reduced viability, alterations in activation, a reduction in the population of memory cells, and reduced effector function evidenced by decreased IFNγ and granzyme B production. Overall, these studies suggest that arsenic impairs the human T cell response to influenza which corroborates epidemiological findings and could have further implications for antiviral immunity and vaccine efficacy.


Assuntos
Arsênio , Vírus da Influenza A , Influenza Humana , Arsênio/toxicidade , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Humanos , Leucócitos Mononucleares
14.
Orthop J Sports Med ; 10(5): 23259671221088009, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35547614

RESUMO

Background: Traumatic hip dislocations are rare injuries that most commonly occur in motor vehicle accidents. There is a paucity of literature that describes sports-related hip dislocations. Purpose: To estimate the incidence of sports-related hip dislocations and determine any sport- or sex-related epidemiological trends using the National Electronic Injury Surveillance System (NEISS) database. Study Design: Descriptive epidemiology study. Methods: Data regarding sports-related hip dislocations from 2010 to 2019 were retrieved from the NEISS, a database that catalogs injury information during emergency department visits from 100 hospitals across the United States to produce nationwide estimates of the injury burden. The estimated number of injuries was calculated using weights assigned by the NEISS database. The injuries were then stratified by sport and sex to determine any epidemiological patterns. Results: A total of 102 hip dislocation injuries were identified over the surveyed 10 years, indicating 2941 estimated injuries nationwide. Overall, 10 (9.8%) of 102 sports-related hip dislocations presented with concomitant acetabular fractures, representing an estimated 288 injuries nationally over 10 years. Male athletes sustained more sports-related hip dislocations than female athletes, with a relative incidence of 12.51 (P < .001). Adolescents aged 15 to 19 years recorded the highest number of hip dislocations. There were 17 sports identified as having caused at least 1 hip dislocation over the 10-year period. More hip dislocation injuries were sustained from contact sports (91.2%) than noncontact sports (8.8%) (P < .001). Football (estimated 164 injuries per year; 55.6%), snowboarding (28 per year; 9.5%), skiing (26 per year; 8.8%), and basketball (21 per year; 7.1%) had the highest rates of hip dislocation. Additionally, 43 (82.7%) football-related injuries were caused by tackling mechanisms, and 9 (17.3%) were caused by nontackling mechanisms (P < .001). Conclusion: The incidence of traumatic sports-related hip dislocations was extremely low in the United States during the study period. Male adolescents, aged 15 to 19 years, sustained the greatest number of injuries during football. Significantly more hip dislocations occurred in contact sports, most commonly football, snowboarding, skiing, and basketball, compared with noncontact sports. As adolescent athletes may have limited treatment options if osteonecrosis occurs, these data serve to increase the clinical awareness of these injuries.

15.
Nat Commun ; 13(1): 2882, 2022 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-35610225

RESUMO

The yeast Saccharomyces cerevisiae is powerful for studying human G protein-coupled receptors as they can be coupled to its mating pathway. However, some receptors, including the mu opioid receptor, are non-functional, which may be due to the presence of the fungal sterol ergosterol instead of cholesterol. Here we engineer yeast to produce cholesterol and introduce diverse mu, delta, and kappa opioid receptors to create sensitive opioid biosensors that recapitulate agonist binding profiles and antagonist inhibition. Additionally, human mu opioid receptor variants, including those with clinical relevance, largely display expected phenotypes. By testing mu opioid receptor-based biosensors with systematically adjusted cholesterol biosynthetic intermediates, we relate sterol profiles to biosensor sensitivity. Finally, we apply sterol-modified backgrounds to other human receptors revealing sterol influence in SSTR5, 5-HTR4, FPR1, and NPY1R signaling. This work provides a platform for generating human G protein-coupled receptor-based biosensors, facilitating receptor deorphanization and high-throughput screening of receptors and effectors.


Assuntos
Fitosteróis , Saccharomyces cerevisiae , Colesterol/metabolismo , Humanos , Fitosteróis/metabolismo , Receptores Opioides/metabolismo , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/genética , Receptores Opioides mu/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Esteróis/metabolismo
16.
Plant Methods ; 18(1): 42, 2022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35351174

RESUMO

BACKGROUND: The construction and application of synthetic genetic circuits is frequently improved if gene expression can be orthogonally controlled, relative to the host. In plants, orthogonality can be achieved via the use of CRISPR-based transcription factors that are programmed to act on natural or synthetic promoters. The construction of complex gene circuits can require multiple, orthogonal regulatory interactions, and this in turn requires that the full programmability of CRISPR elements be adapted to non-natural and non-standard promoters that have few constraints on their design. Therefore, we have developed synthetic promoter elements in which regions upstream of the minimal 35S CaMV promoter are designed from scratch to interact via programmed gRNAs with dCas9 fusions that allow activation of gene expression. RESULTS: A panel of three, mutually orthogonal promoters that can be acted on by artificial gRNAs bound by CRISPR regulators were designed. Guide RNA expression targeting these promoters was in turn controlled by either Pol III (U6) or ethylene-inducible Pol II promoters, implementing for the first time a fully artificial Orthogonal Control System (OCS). Following demonstration of the complete orthogonality of the designs, the OCS was tied to cellular metabolism by putting gRNA expression under the control of an endogenous plant signaling molecule, ethylene. The ability to form complex circuitry was demonstrated via the ethylene-driven, ratiometric expression of fluorescent proteins in single plants. CONCLUSIONS: The design of synthetic promoters is highly generalizable to large tracts of sequence space, allowing Orthogonal Control Systems of increasing complexity to potentially be generated at will. The ability to tie in several different basal features of plant molecular biology (Pol II and Pol III promoters, ethylene regulation) to the OCS demonstrates multiple opportunities for engineering at the system level. Moreover, given the fungibility of the core 35S CaMV promoter elements, the derived synthetic promoters can potentially be utilized across a variety of plant species.

17.
Clin Ther ; 44(1): 33-40, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34911642

RESUMO

Sarcopenia or muscle mass atrophy reportedly occurs in up to 50% of those aged >80 years and is a significant risk factor for functional disability and poor physical performance. Over time, the deterioration in both skeletal muscle quality and composition may compromise functional independence and has been shown to independently increase the risk for falls, fractures, and overall poor health in the elderly population. These are seen most obviously in older women. Given these serious consequences, much effort has been directed toward promoting increased activity and resistance training for muscle maintenance or even muscle regeneration in older adults. The Centers for Disease Control and Prevention states that for all adults ≥65 years of age, weekly aerobic and strength training are vital to healthy aging. Older patients who have not previously participated in strength training may be hesitant about starting a resistance training program and resort to simple and familiar aerobic exercise options such as walking, jogging, or cycling. However, the benefits of strength training are too important to miss: it can improve skeletal muscle metabolic capacity, mitigate effects of aging on functional capacity, maintain bone density, and, most importantly, help individuals maintain a higher quality of life and independence. Due to their increased risk of disability and injury, this opportunity for "exercise as medicine" is particularly important to women and must be encouraged by clinicians. As such, the purpose of this commentary was to highlight known sex-related differences in muscle metabolism and potential benefits of resistance training for elderly patients. A comprehensive understanding of the issues and prevention measures presented here may allow clinicians to better serve their patients, especially older female patients, and, ultimately, alleviate the burden placed on our society by our rapidly aging population.


Assuntos
Treinamento Resistido , Sarcopenia , Idoso , Feminino , Humanos , Força Muscular/fisiologia , Músculo Esquelético , Qualidade de Vida , Sarcopenia/prevenção & controle
18.
Clin Sports Med ; 41(1): 15-26, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34782071

RESUMO

Coronal malalignment of the patellofemoral joint may contribute to both instability as well as pain and joint overload. The use of distal realignment procedures has evolved to include uniplanar and multiplanar osteotomies, which allows patient-specific treatment. With a careful understanding of the complex pathoanatomy, including osseous, soft tissue, and dynamic muscular factors, an appropriately designed tibial tubercle osteotomy (TTO) is an invaluable tool for the orthopedic surgeon to improve joint biomechanics and off-load articular injuries. Current techniques have improved TTO surgery to limit complications and produce reliably good results.


Assuntos
Instabilidade Articular , Articulação Patelofemoral , Humanos , Instabilidade Articular/cirurgia , Osteotomia , Patela , Articulação Patelofemoral/diagnóstico por imagem , Articulação Patelofemoral/cirurgia , Tíbia/cirurgia
19.
Mol Cell ; 81(24): 5099-5111.e8, 2021 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-34919820

RESUMO

The SARS-CoV-2 spike protein is a critical component of vaccines and a target for neutralizing monoclonal antibodies (nAbs). Spike is also undergoing immunogenic selection with variants that increase infectivity and partially escape convalescent plasma. Here, we describe Spike Display, a high-throughput platform to rapidly characterize glycosylated spike ectodomains across multiple coronavirus-family proteins. We assayed ∼200 variant SARS-CoV-2 spikes for their expression, ACE2 binding, and recognition by 13 nAbs. An alanine scan of all five N-terminal domain (NTD) loops highlights a public epitope in the N1, N3, and N5 loops recognized by most NTD-binding nAbs. NTD mutations in variants of concern B.1.1.7 (alpha), B.1.351 (beta), B.1.1.28 (gamma), B.1.427/B.1.429 (epsilon), and B.1.617.2 (delta) impact spike expression and escape most NTD-targeting nAbs. Finally, B.1.351 and B.1.1.28 completely escape a potent ACE2 mimic. We anticipate that Spike Display will accelerate antigen design, deep scanning mutagenesis, and antibody epitope mapping for SARS-CoV-2 and other emerging viral threats.


Assuntos
Mamíferos/virologia , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , COVID-19/imunologia , COVID-19/virologia , Linhagem Celular , Epitopos/genética , Epitopos/imunologia , Células HEK293 , Humanos , Mamíferos/imunologia , Ligação Proteica/genética , Ligação Proteica/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia
20.
Case Rep Orthop ; 2021: 2396200, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34824874

RESUMO

CASE: We report an 11-year-old male who sustained a lesser tuberosity avulsion fracture of the proximal humerus upon making contact with a baseball during an at-bat. This injury was neglected for 14 months and was eventually detected by an axillary radiograph and subsequent MRI. He successfully underwent an open surgical repair and regained full range of motion and level of activity at 1-year follow-up. CONCLUSION: In pediatric baseball players, lesser tuberosity avulsion fractures may occur upon striking a baseball with a bat. Even after being neglected for several months, these injuries can be treated successfully with an open surgical repair.

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