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1.
Microbiol Resour Announc ; : e0004024, 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38967463

ABSTRACT

Mobile clustered regularly interspaced palindromic repeats interference (Mobile-CRISPRi) is an established method for bacterial gene expression knockdown. The deactivated Cas9 protein and guide RNA are isopropyl ß-D-1-thiogalactopyranoside inducible, and all components are integrated into the chromosome via Tn7 transposition. Here, we optimized methods specific for applying Mobile-CRISPRi in multiple Vibrio species.

2.
BMJ Open Sport Exerc Med ; 10(2): e001869, 2024.
Article in English | MEDLINE | ID: mdl-38895645

ABSTRACT

Objectives: The primary purpose of the study was to assess the one-factor and two-factor structure of the Injury Psychological Readiness to Return to Sport Scale (IPRRS) in an injured physically active population using confirmatory factor analysis (CFA) procedures and assess group (ie, sex, age, injury type, athlete status) and longitudinal differences using structural equation modelling (eg, invariance testing). Methods: The non-experimental study included a sample of 629 physically active individuals who suffered a musculoskeletal injury who sought treatment at an outpatient integrated sport medicine and rehabilitation therapy clinic. Participants filled out a questionnaire packet at three time points. Data analysis included a CFA and multigroup and longitudinal invariance. Results: Sample mean age was 26.3 years, with females comprising 49.5%. Chronic injuries represented 29.6% of the sample and 35.0% were classified as competitive athletes. A six-item, one-factor model was confirmed in the sample with factor loadings ranging from 0.67 to 0.86. Multigroup and longitudinal invariance were established. Multigroup invariance demonstrated null differences between sex and injury type, and statistical differences between age and athlete status subgroups. Longitudinal invariance demonstrated a statistically significant increase in psychological readiness over time. Conclusions: The findings support the use of the IPRRS as a tool to measure aspects of psychological readiness. Clinicians and researchers can use the IPRRS to assess interventions in future research.

3.
Healthcare (Basel) ; 12(11)2024 May 21.
Article in English | MEDLINE | ID: mdl-38891127

ABSTRACT

Limited U.S. research has been conducted examining factors affecting healthcare provider recruitment in rural settings, necessitating community-level investigations due to community differences. The aim of this study was to explore the factors involved in healthcare provider recruitment in a rural community in Northern Idaho. A retooled version of the Nursing Community Apgar Questionnaire (NCAQ) was used to collect data from 50 healthcare providers to assess items influencing provider recruitment. Items were categorized into five factors: geographic, economic, scope of practice, medical support, and facility and community support classes. Healthcare providers ranked items based on perceived importance and how advantageous or challenging it was to recruitment. A "Community Apgar" score is a composite score calculated using the advantage/challenge and importance scores. In our sample, medical support was rated as the most important class. Additionally, facility and community support was rated as the highest advantage class and had the most impactful Apgar scores, meaning it contained the most important advantage and challenge. Our findings suggest that these classes contain dominant factors related to the recruitment of providers in rural areas. Rural healthcare organizations seeking to improve the recruitment of healthcare providers should consider the potential impact of these factors on their population. Further investigations should be conducted on diverse rural samples across the U.S. to enable comparisons of research findings.

4.
Article in English | MEDLINE | ID: mdl-38853655

ABSTRACT

KEY POINTS: A convolutional neural network (CNN)-based model can accurately localize and segment turbinates in images obtained during nasal endoscopy (NE). This model represents a starting point for algorithms that comprehensively interpret NE findings.

5.
Appl Environ Microbiol ; 90(6): e0006524, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38775491

ABSTRACT

CRISPRi (Clustered Regularly Interspaced Palindromic Repeats interference) is a gene knockdown method that uses a deactivated Cas9 protein (dCas9) that binds a specific gene target locus dictated by an encoded guide RNA (sgRNA) to block transcription. Mobile-CRISPRi is a suite of modular vectors that enable CRISPRi knockdowns in diverse bacteria by integrating IPTG-inducible dcas9 and sgRNA genes into the genome using Tn7 transposition. Here, we show that the Mobile-CRISPRi system functions robustly and specifically in multiple Vibrio species: Vibrio cholerae, Vibrio fischeri, Vibrio vulnificus, Vibrio parahaemolyticus, and Vibrio campbellii. We demonstrate efficacy by targeting both essential and non-essential genes that function to produce defined, measurable phenotypes: bioluminescence, quorum sensing, cell division, and growth arrest. We anticipate that Mobile-CRISPRi will be used in Vibrio species to systematically probe gene function and essentiality in various behaviors and native environments.IMPORTANCEThe genetic manipulation of bacterial genomes is an invaluable tool in experimental microbiology. The development of CRISPRi (Clustered Regularly Interspaced Palindromic Repeats interference) tools has revolutionized genetics in many organisms, including bacteria. Here, we optimized the use of Mobile-CRISPRi in five Vibrio species, each of which has significant impacts on marine environments and organisms that include squid, shrimp, shellfish, finfish, corals, and multiple of which pose direct threats to human health. The Mobile-CRISPRi technology is easily adaptable, moveable from strain to strain, and enables researchers to selectively turn off gene expression. Our experiments demonstrate Mobile-CRISPRi is effective and robust at repressing gene expression of both essential and non-essential genes in Vibrio species.


Subject(s)
Vibrio vulnificus , Vibrio , Vibrio/genetics , Vibrio vulnificus/genetics , Vibrio parahaemolyticus/genetics , Gene Expression Regulation, Bacterial , CRISPR-Cas Systems , Vibrio cholerae/genetics , Clustered Regularly Interspaced Short Palindromic Repeats , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Gene Knockdown Techniques , Aliivibrio fischeri/genetics
6.
Healthcare (Basel) ; 12(10)2024 May 15.
Article in English | MEDLINE | ID: mdl-38786431

ABSTRACT

Patient-Reported Outcome Measures (PROMs), such as the six-item International Knee Documentation Committee Subjective Knee Form (IKDC-6), play a crucial role in assessing health conditions and guiding clinical decisions. Latent Growth Modeling (LGM) can be employed to understand recovery trajectories in patients post-operatively. Therefore, the purpose of this study was to assess LGM properties of the IKDC-6 in patients with knee pathologies that require surgical intervention and to assess differences between subgroups (i.e., sex and age). A cross-sectional study was conducted using the Surgical Outcome System (SOS) database with patients who had undergone knee arthroscopy. Our results found that preoperative scores did not influence the rate of change overtime. Perceived knee health improved over time, with varying rates among individuals. The adolescent age subgroup and male subgroup exhibited faster recovery rates compared to the older age subgroup and female subgroup. While initial hypotheses suggested IKDC-6 could serve as a prognostic tool, results did not support this. However, results indicated favorable outcomes irrespective of preoperative perceived knee impairment levels. This study provides valuable insights into recovery dynamics following knee surgery, emphasizing the need for personalized rehabilitation strategies tailored to individual patient characteristics.

8.
BMC Health Serv Res ; 24(1): 381, 2024 Mar 27.
Article in English | MEDLINE | ID: mdl-38539177

ABSTRACT

BACKGROUND: A shortage of healthcare providers, particularly in primary care and mental health, exists in the predominately rural state of Idaho. There are also barriers to retaining healthcare providers to work in rural and remote communities. Limited research using U.S. samples has explored factors that may affect the retention of healthcare providers in rural areas. Additionally, due to differences between communities, it is important to conduct community-level investigations to better understand how these factors may affect retention in rural areas. Therefore, the purpose of this study was to explore factors affecting healthcare provider retention in a rural community in Northern Idaho. METHODS: A modified version of the Nursing Community Apgar Questionnaire (NCAQ) was completed by 30 healthcare providers in a rural and frontier community in Northern Idaho to assess factors influencing healthcare provider retention. Factors were classified into classes including geographic, economic, scope of practice, medical support, and facility and community support classes. Retention factors were assessed on their perceived importance to retention as well as whether they were perceived as an advantage or challenge to retention based on Likert scales. A "Community Apgar" score was also created by combining the importance and advantage/challenge factors. RESULTS: Overall, items in the medical support group had the highest importance of any other class and included factors such as nursing workforce. Additionally, the facility and community support class, which included factors such as televideo support, was rated the highest advantage class and had the highest Apgar score, indicating it contained the factor that healthcare providers identified as the most important advantage (i.e., medical reference resources). CONCLUSION: Our study identified multiple factors that healthcare providers deemed as important advantages or disadvantages to retaining healthcare providers in rural areas. Overall, facility and community support factors were found to have the highest advantage in the retention of rural providers. Rural healthcare organizations looking to increase healthcare provider retention should target retention efforts towards these factors. Additional research should also be conducted on other rural samples across the U.S. to make comparisons of findings.


Subject(s)
Nursing Staff , Rural Health Services , Humans , Idaho , Rural Population , Health Personnel
9.
Healthcare (Basel) ; 12(4)2024 Feb 06.
Article in English | MEDLINE | ID: mdl-38391790

ABSTRACT

BACKGROUND: The Knee Injury and Osteoarthritis Outcome Score (KOOS) scale is used to assess patient perspectives on knee health. However, the structural validity of the KOOS has not been sufficiently tested; therefore, our objective was to assess the KOOS in a large, multi-site database of patient responses who were receiving care for knee pathology. METHODS: A cross-sectional study was conducted using the Surgical Outcome System (SOS) database. A confirmatory factor analysis (CFA) was conducted to assess the proposed five-factor KOOS using a priori cut-off values. Because model fit indices were not met, a subsequent exploratory factor analysis (EFA) was conducted to identify a parsimonious model. The resulting four-factor structure (i.e., KOOS SF-12) was then assessed using CFA and subjected to multigroup invariance testing. RESULTS: The original KOOS model did not meet rigorous CFA fit recommendations. The KOOS SF-12 did meet model fit recommendations and passed all invariance testing between intervention procedure, sex, and age groups. CONCLUSION: The KOOS failed to meet model fit recommendations. The KOOS SF-12 met model fit recommendations, maintained a multi-factorial structure, and was invariant across all tested groups. The KOOS did not demonstrate sound structural validity. A refined KOOS SF-12 model that met recommended model fit indices and invariance testing criteria was identified. Our findings provide initial support for a multidimensional KOOS structure (i.e., KOOS SF-12) that is a more psychometrically sound instrument for measuring patient-reported knee health.

10.
Adv Mater ; 36(21): e2311467, 2024 May.
Article in English | MEDLINE | ID: mdl-38241649

ABSTRACT

Successful and selective inhibition of the cytosolic protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associating protein 1 (Keap1) can enhance the antioxidant response, with the potential for a therapeutic effect in a range of settings including in neurodegenerative disease (ND). Small molecule inhibitors have been developed, yet many have off-target effects, or are otherwise limited by poor cellular permeability. Peptide-based strategies have also been attempted to enhance specificity, yet face challenges due to susceptibility to degradation and lack of cellular penetration. Herein, these barriers are overcome utilizing a polymer-based proteomimetics. The protein-like polymer (PLP) consists of a synthetic, lipophilic polymer backbone displaying water soluble Keap1-binding peptides on each monomer unit forming a brush polymer architecture. The PLPs are capable of engaging Keap1 and displacing the cellular protective transcription factor Nrf2, which then translocates to the nucleus, activating the antioxidant response element (ARE). PLPs exhibit increased Keap1 binding affinity by several orders of magnitude compared to free peptides, maintain serum stability, are cell-penetrant, and selectively activate the ARE pathway in cells, including in primary cortical neuronal cultures. Keap1/Nrf2-inhibitory PLPs have the potential to impact the treatment of disease states associated with dysregulation of oxidative stress, such as NDs.


Subject(s)
Kelch-Like ECH-Associated Protein 1 , NF-E2-Related Factor 2 , Polymers , Protein Binding , Kelch-Like ECH-Associated Protein 1/metabolism , Kelch-Like ECH-Associated Protein 1/chemistry , NF-E2-Related Factor 2/metabolism , Polymers/chemistry , Humans , Animals , Peptides/chemistry , Peptides/metabolism , Peptides/pharmacology , Antioxidant Response Elements , Neurons/metabolism , Neurons/drug effects
11.
Int J Sports Phys Ther ; 18(5): 1094-1105, 2023.
Article in English | MEDLINE | ID: mdl-37795315

ABSTRACT

Background: The Knee Osteoarthritis Outcome Score for Joint Replacement (KOOS-JR) is a seven-item patient reported outcome measure used to assess perceived knee health. Though commonly used, the longitudinal psychometric properties of the KOOS-JR have not been established and further characterization of its structural validity and multi-group invariance properties is warranted. Purpose: The purpose of this study was to evaluate psychometric properties of the KOOS-JR in a large sample of patients who received care for knee pathology. Study Design: Original research. Methods: Longitudinal data extracted from the Surgical Outcome System (SOS) database of 13,470 knee pathology patients who completed the KOOS-JR at baseline, three-months, six- months, and one-year. Scale structure was assessed with confirmatory factor analysis (CFA), while multi-group and longitudinal invariance properties were assessed with CFA-based procedures. Latent group means were compared with statistical significance set at α ≤ .05 and Cohen's d effect size as d = 0.2 (small), d = 0.5 (medium), and d = 0.8 (large). Results: CFA results exceeded goodness-of-fit indices at all timepoints. Multi-group invariance properties passed test requirements. Longitudinal analysis identified a biased item resulting in removal of item #1; the retained six-item model (KOOS-JR-6) passed longitudinal invariance requirements. KOOS-JR-6 scores significantly changed over time (p ≤ .001, Mdiff = 1.08, Cohen's d = 0.57): the highest scores were at baseline examination and the lowest at 12-month assessment. Conclusions: The KOOS-JR can be used to assess baseline differences between males and females, middle and older aged adults, and patients receiving total knee arthroplasty or non-operative care. Caution is warranted if the KOOS-JR is used longitudinally due to potential measurement error associated with item #1. The KOOS-JR-6 may be a more viable option to assess change over time; however, more research is warranted. Level of Evidence: 3© The Author(s).

12.
Int J Sports Phys Ther ; 18(4): 923-939, 2023.
Article in English | MEDLINE | ID: mdl-37547827

ABSTRACT

Background: The International Knee Document Committee Subjective Knee Form (IKDC-SKF) is a patient-reported outcome measure used in orthopedics and sports medicine. Further psychometric assessment is necessary to confirm measurement properties in a large, heterogenous sample. Purpose: The purpose of the study was to assess the psychometric properties of the IKDC-SKF in a large, heterogenous sample. Study Design: Cross-Sectional Study. Methods: An exploratory factor analysis (EFA) was conducted to identify a sound latent structure and to assess internal consistency in a large sample of patients who underwent knee arthroscopy. A confirmatory factor analysis (CFA) was conducted to confirm structural validity. Multi-group invariance was conducted to assess factorial stability across sex and age groups, while longitudinal invariance procedures were performed to assess stability over time. Results: A 3-factor, 9-item IKDC-SKF short form was identified with EFA procedures. The model was confirmed with CFA (CFI = 0.983; TLI = 0.975; IFI = 0.983; RMSEA = 0.057), while a sound 2-factor, 6-item model was also identified (CFI = 1.0; TLI = 0.999; IFI = 1.0; RMSEA = 0.11). The 9-item IKDC-SKF short form was invariant across groups but not time; removal of a single item (i.e., 8-item IKDC-SKF short form) resulted in longitudinal invariance. The 6-item IKDC-SKF short form was invariant across groups and time. Conclusion: The 6-item, 8-item, and 9-item short form versions of the IKDC-SKF exceed contemporary fit recommendations and present as plausible alternatives to the IKDC-SKF with improved measurement properties, reduced scale response burden, and evidence of multi-group and longitudinal invariance. Further, the 6- and 8-item IKDC-SKF short forms may be used to assess group differences or change across time.# Level of evidence hereLevel 3©The Author(s).

13.
Dermatol Surg ; 49(5): 466-472, 2023 05 01.
Article in English | MEDLINE | ID: mdl-36943756

ABSTRACT

BACKGROUND: Deep defects on the nasal ala and lateral nasal tip may result in nasal valve insufficiency or alar notching and are often repaired with a 2-stage reconstruction. Previous literature has demonstrated high failure rates of composite grafts. OBJECTIVE: Identify survival rates and cosmetic outcomes of nasal composite grafts harvested from the antihelix. METHODS: A retrospective review of 52 patients who underwent ala or lateral nasal tip composite graft repair from April 2019 through May 2022, with statistical analysis of cosmetic outcomes graded by 2 surgeons. RESULTS: Defect size ranged from 0.7 cm × 0.8 cm to 1.9 cm × 2.5 cm. 48 grafts survived (92.3% survival rate). Four patients sustained at least partial integument sloughing (epidermal necrosis), but the cartilage survived in all 52 cases. Overall, aesthetic results yielded the following: excellent (19.5%), very good (35.5%), good (11.5%), decent (16.5%), and poor (6%). In 93% of cases, there was no evidence of nasal collapse or retraction. Two patients (3.8%) required surgical revision. Donor site morbidity was low. CONCLUSION: The antihelical composite skin graft is a 1-step reliable repair option for ala and lateral nasal tip defects with an acceptable cosmetic outcome.


Subject(s)
Plastic Surgery Procedures , Rhinoplasty , Humans , Retrospective Studies , Nose/surgery , Rhinoplasty/methods , Skin Transplantation/methods
14.
J Sport Rehabil ; 32(5): 581-589, 2023 Jul 01.
Article in English | MEDLINE | ID: mdl-36963411

ABSTRACT

CONTEXT: Mental health is an important component of holistic care in athletic settings. Burnout is one of many factors associated with poor mental health, and clinicians should assess for these symptoms. The Athlete Burnout Questionnaire (ABQ) has been proposed as a measure of burnout in athletes; however, design concerns are prevalent within the scale, and psychometric analyses have resulted in inconsistent measurement properties, limiting the usefulness of the scale for accurate assessment of burnout in athletes. The objective of our study was to assess the factor structure of the Alternate Modified ABQ-15v2 using confirmatory factor analysis. If model fit was inadequate, a secondary purpose was to identify a psychometrically sound alternate ABQ model. DESIGN: Observational study. METHODS: Intercollegiate athletes and dancers pursuing a degree in dance (n = 614) were recruited from programs across the United States. Individuals had varied health statuses (eg, healthy, injured), scholarship support, and participated in a variety of intercollegiate sports. A confirmatory factor analysis was conducted on the modified 15-item ABQ (Alternate Modified ABQ-15v2). Exploratory factor analysis and covariance modeling of a proposed alternate 9-item scale (ABQ-9) was conducted and multigroup invariance analysis was assessed across athlete category, class standing, and student-athlete scholarship status to assess consistency of item interpretation across subgroups. RESULTS: The Modified ABQ did not meet recommended model fit criteria. The ABQ-9 met all recommended model fit indices but was not invariant across athlete category. CONCLUSIONS: The ABQ-9 may be a viable and efficient option for assessing burnout in the collegiate athletics setting. However, further research is needed to validate the ABQ-9 in a cross-validation study.


Subject(s)
Burnout, Professional , Sports , Humans , Psychometrics/methods , Surveys and Questionnaires , Burnout, Psychological , Burnout, Professional/diagnosis , Athletes
15.
Telemed Rep ; 4(1): 10-20, 2023.
Article in English | MEDLINE | ID: mdl-36942263

ABSTRACT

Background: Idaho, a predominately rural state, has a high prevalence of mental illness with minimal access to care. Barriers in diagnosis and treatment of pediatric behavioral health disorders could be mitigated with an accessible and effective specialty training program. Methods: A 10-session Project Extension for Community Health Outcomes (ECHO) series was designed to expand provider knowledge about pediatric behavioral health conditions and improve perceived clinical practice skills. Pre- and postseries evaluation surveys and individual session evaluations were used to assess the program. Results: A total of 148 individuals attended at least 1 of the 10 sessions. Participants reported high satisfaction with individual sessions and indicated that attendance positively impacted their knowledge and competency. Participants also reported that the knowledge and skills gained from the series would benefit more than half of their patients or clients. Conclusion: The short ECHO series appears to be a viable and valuable option to provide Idaho providers with effective specialty training that is well attended and well received.

16.
Int J Sports Phys Ther ; 18(1): 145-159, 2023.
Article in English | MEDLINE | ID: mdl-36793579

ABSTRACT

Background: Hip Disability and Osteoarthritis Outcome Score (HOOS), HOOS-Joint Replacement (JR), HOOS Physical Function (PS), and HOOS-12 item scale have been suggested as reliable and valid instruments for assessing hip disability. However, factorial validity, invariance across subgroups, and repeated measures of the scale across different populations have not been well supported in the literature. Purpose: The primary study objectives were to: (1) assess model fit and psychometric properties of the original 40-item HOOS scale, (2) assess model fit of the HOOS-JR, (3) assess model fit of the HOOS-PS, and (4) assess model fit of the HOOS-12. A secondary objective was to perform multigroup invariance testing across physical activity level and hip pathology subgroups for models that met recommended fit indices. Study Design: Cross-Sectional Study. Methods: Individual confirmatory factor analyses (CFAs) were conducted for the HOOS, HOOS-JR, HOOS-PS, and HOOS-12. Additionally, multigroup invariance testing (i.e., activity level, injury type) was conducted on the HOOS-JR and HOOS-PS. Results: Model fit indices did not meet contemporary recommendations for the HOOS and the HOOS-12. Model fit indices for the HOOS-JR and the HOOS-PS met some, but not all, contemporary recommendations. Invariance criteria was met for the HOOS-JR and HOOS-PS. Conclusion: The scale structure of the HOOS and HOOS-12 were not supported; however, preliminary evidence to support the scale structure of the HOOS-JR and HOOS-PS was found. Clinicians and researchers who utilize the scales should do so with caution due to their limitations and untested properties until further research establishes the full psychometric properties of these scales and recommendations for their continued use.

17.
J Sport Rehabil ; 32(5): 505-512, 2023 Jul 01.
Article in English | MEDLINE | ID: mdl-36791729

ABSTRACT

CONTEXT: Among numerous knee-related patient-reported outcome measures, the International Knee Documentation Committee Subjective Knee Form (IKDC-SKF) has been used across a wide variety of knee pathologies. However, traditional validation procedures (classical test theory) and existing studies (estimating item parameters) have limitations in establishing the measurement properties of the IKDC-SKF. Rasch analysis reveals a strong validation approach to improve IKDC-SKF clinical interpretation with larger samples. OBJECTIVE: To assess psychometric properties, including differential item functioning, of the IKDC-SKF as a patient-reported measure of knee function. DESIGN: Cross-sectional study. SETTING: Secondary data. Data were extracted from the cloud-based orthopedic and sports medicine global registry Surgical Outcome System (Arthrex). PATIENTS: A total of 1725 individuals who underwent an arthroscopic knee procedure and completed all items on the IKDC-SKF. MAIN OUTCOME MEASURE(S): Rasch analysis including model-data fit, rating scale's function, item-person map (distribution of item difficulty and person ability), and differential item functioning (sex and age groups) was used to evaluate the psychometric properties of the IKDC-SKF. RESULTS: Ten misfit items were found and removed. The 5-point Likert scale of the 9-item IKDC-SKF worked well. Item difficulty ranged from 0.58 to 0.81 logits, and person's knee function had ranged from -5.56 to 4.86 logits, with a wide distribution. The IKDC-SKF was found to function similarly for sex (male vs female) and age. CONCLUSIONS: Rasch analysis identified a unidimensional structure retaining 9 of the original IKDC-SKF items; however, a more comprehensive inventory is necessary to assess a wider range of knee function and improve measurement validity.


Subject(s)
Knee Injuries , Humans , Male , Female , Calibration , Cross-Sectional Studies , Knee Injuries/surgery , Surveys and Questionnaires , Documentation , Reproducibility of Results
18.
Annu Rev Phys Chem ; 74: 493-520, 2023 04 24.
Article in English | MEDLINE | ID: mdl-36791782

ABSTRACT

Photosynthetic light harvesting exhibits near-unity quantum efficiency. The high efficiency is achieved through a series of energy and charge transfer steps within a network of pigment-containing proteins. Remarkably, high efficiency is conserved across many organisms despite differences in the protein structures and organization that allow each organism to respond to its own biological niche and the stressors within. In this review, we highlight recent progress toward understanding how organisms maintain optimal light-harvesting ability by acclimating to their environment. First, we review the building blocks of photosynthetic light harvesting, energy transfer, and time-resolved spectroscopic techniques. Then, we explore how three classes of photosynthetic organisms-purple bacteria, cyanobacteria, and green plants-optimize their light-harvesting apparatuses to their particular environment. Overall, research has shown that photosynthetic energy transfer is robust to changing environmental conditions, with each organism utilizing its own strategies to optimize photon capture in its particular biological niche.


Subject(s)
Light-Harvesting Protein Complexes , Photosynthesis , Light-Harvesting Protein Complexes/chemistry , Light-Harvesting Protein Complexes/metabolism , Spectrum Analysis , Acclimatization , Light
19.
bioRxiv ; 2023 Jan 02.
Article in English | MEDLINE | ID: mdl-36711980

ABSTRACT

While specific cell signaling pathway inhibitors have yielded great success in oncology, directly triggering cancer cell death is one of the great drug discovery challenges facing biomedical research in the era of precision oncology. Attempts to eradicate cancer cells expressing unique target proteins, such as antibody-drug conjugates (ADCs), T-cell engaging therapies, and radiopharmaceuticals have been successful in the clinic, but they are limited by the number of targets given the inability to target intracellular proteins. More recently, heterobifunctional small molecules such as Proteolysis Targeting Chimera (PROTACs) have paved the way for protein proximity inducing therapeutic modalities. Here, we describe a proof-of-concept study using novel heterobifunctional small molecules called Regulated Induced Proximity Targeting Chimeras or RIPTACs, which elicit a stable ternary complex between a target protein selectively expressed in cancer tissue and a pan-expressed protein essential for cell survival. The resulting cooperative protein:protein interaction (PPI) abrogates the function of the essential protein, thus leading to cell death selectively in cells expressing the target protein. This approach not only opens new target space by leveraging differentially expressed intracellular proteins but also has the advantage of not requiring the target to be a driver of disease. Thus, RIPTACs can address non-target mechanisms of resistance given that cell killing is driven by inactivation of the essential protein. Using the HaloTag7-FKBP model system as a target protein, we describe RIPTACs that incorporate a covalent or non-covalent target ligand connected via a linker to effector ligands such as JQ1 (BRD4), BI2536 (PLK1), or multi-CDK inhibitors such as TMX3013 or dinaciclib. We show that these RIPTACs exhibit positive co-operativity, accumulate selectively in cells expressing HaloTag7-FKBP, form stable target:RIPTAC:effector trimers in cells, and induce an anti-proliferative response in target-expressing cells. We propose that RIPTACs are a novel heterobifunctional therapeutic modality to treat cancers that are known to selectively express a specific intracellular protein.

20.
Osteoarthr Cartil Open ; 4(4): 100296, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36474795

ABSTRACT

Objective: The Knee Osteoarthritis Outcome Score for Joint Replacement (KOOS-JR) scale is commonly used to assess patient progress. Scale structural validity has not been completely assessed. The purpose of this study was to assess the internal consistency, structural validity, and multi-group invariance properties of the KOOS-JR in a large sample of patients receiving knee arthroplasty or non-operative care. Methods: A cross-sectional study using the Surgical Outcome System (SOS) database. Patients receiving care for degenerative knee conditions were included in the study. Internal consistency was assessed using Cronbach's alpha and McDonald's Omega. A confirmatory factor analysis was conducted to confirm scale structure of the KOOS-JR using a priori cut-off values (Comparative Fit Index [CFI], Tucker-Lewis Index [TLI], Incremental Fit Index [IFI] â€‹≥ â€‹0.95, Root Mean Square Error of Approximation [RMSEA] â€‹≤ â€‹0.06 preferred and ≤0.08 acceptable). Multigroup invariance testing was conducted across sex, age, and intervention groups. Results: Internal consistency was acceptable (alpha â€‹= â€‹0.83; omega â€‹= â€‹0.83). The unidimensional structure of the KOOS-JR exceeded most contemporary model fit recommendations (CFI â€‹= â€‹0.976, TLI â€‹= â€‹0.964, IFI â€‹= â€‹0.976, RMSEA â€‹= â€‹0.067). The KOOS-JR was invariant across groups, allowing for comparison of variances and means between sex, age, and intervention groups. Conclusion: The KOOS-JR met or exceeded most of the recommendations for model fit. The scale can be used to assess differences between males and females, middle and older aged adults, and between baseline measures of patients who received total knee arthroplasty or non-operative care.

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