Impeding DNA Break Repair Enables Oocyte Quality Control.

Oocyte quality control culls eggs with defects in meiosis. In mouse, oocyte death can be triggered by defects in chromosome synapsis and recombination, which involve repair of DNA double-strand breaks (DSBs) between homologous chromosomes. We show that RNF212, a SUMO ligase required for crossing over, also mediates oocyte quality control. Both physiological apoptosis and wholesale oocyte elimination in meiotic mutants require RNF212. RNF212 sensitizes oocytes to DSB-induced apoptosis within a narrow window as chromosomes desynapse and cells transition into quiescence. Analysis of DNA damage during this transition implies that RNF212 impedes DSB repair. Consistently, RNF212 is required for HORMAD1, a negative regulator of inter-sister recombination, to associate with desynapsing chromosomes. We infer that oocytes impede repair of residual DSBs to retain a "memory" of meiotic defects that enables quality-control processes. These results define the logic of oocyte quality control and suggest RNF212 variants may influence transmission of defective genomes.

CHARACTERISTICS OF PARTICIPANTS IN DIABETIC RETINOPATHY CLINICAL RESEARCH CLINICAL TRIALS WHO WERE LOST TO FOLLOW-UP.

PURPOSE: Our study describes the racial/ethnic composition and the broad health status/severity of disease of the cohorts of Diabetic Retinopathy Clinical Research clinical trials and compares the rates of noncompletion of the trial with the first data report (lost to follow-up). METHODS: This study is a retrospective cohort study of participants in Diabetic Retinopathy Clinical Research Retina Network clinical trials who met our inclusion criteria. The primary outcome was the lost to follow-up rates and their associated risk factors. RESULTS: Eight clinical trials with 3,492 participants met our inclusion criteria. Participants who were lost to follow-up were more likely to be younger, Hispanic or Black, had Type 1 diabetes mellitus, had worse baseline best-corrected visual acuity, had higher hemoglobin A1c, had higher blood pressure, and had proliferative diabetic retinopathy (PDR) (Diabetic Retinopathy Severity Score >66). CONCLUSION: Participants who were lost to follow-up during Diabetic Retinopathy Clinical Research clinical trials tended to be younger, Hispanic or Black, and had worse diabetes and hypertension. This study highlights the importance of ensuring that a representative population is maintained through the end of the study period.

Refractive outcomes of immediately sequential bilateral cataract surgery in eyes with long and short axial lengths.

PURPOSE: To report the refractive outcomes of long (≥25.00 mm) and short (≤22.00 mm) axial length (AL) eyes undergoing immediately sequential bilateral cataract surgery (ISBCS). METHODS: In this retrospective cohort study, patients who underwent ISBCS were identified and eyes of patients with bilateral long and short ALs were included. Pre- and postoperative biometry, autorefraction, and ocular comorbidities or complications were recorded. The primary outcome was the mean refractive prediction error. RESULTS: Thirty-seven patients (74 eyes) with long ALs and 18 patients (36 eyes) with short ALs were included. The means ± standard deviations of the ALs were 26.40 ± 1.38 mm and 21.44 ± 0.46 mm in the long and short AL groups, respectively. In long AL eyes, the mean absolute error from the biometry-predicted refraction was - 0.16 ± 0.46 D, corresponding to 74% of eyes achieving a refraction within ±0.50 D of the predicted value. In short AL eyes, the mean absolute error was - 0.63 ± 0.73 D, corresponding to 44% of eyes achieving a refraction within ±0.50 D of the predicted value. Eight (44.4%) patients with short AL eyes had a myopic deviation greater than ±0.50 D from the predicted result in both eyes. CONCLUSIONS: Compared to patients with long AL eyes, ISBCS in patients with short ALs had a wider variance in refractive outcome and a lower rate of achieving a postoperative refraction within ±0.50 D of the predicted target.

Utilizing RNA origami scaffolds in Saccharomyces cerevisiae for dCas9-mediated transcriptional control.

Designer RNA scaffolds constitute a promising tool for synthetic biology, as they can be genetically expressed to perform specific functions in vivo such as scaffolding enzymatic cascades and regulating gene expression through CRISPR-dCas9 applications. RNA origami is a recently developed RNA design approach that allows construction of large RNA nanostructures that can position aptamer motifs to spatially organize other molecules, including proteins. However, it is still not fully understood how positioning multiple aptamers on a scaffold and the orientation of a scaffold affects functional properties. Here, we investigate fusions of single-guide RNAs and RNA origami scaffolds (termed sgRNAO) capable of recruiting activating domains for control of gene expression in yeast. Using MS2 and PP7 as orthogonal protein-binding aptamers, we observe a gradual increase in transcriptional activation for up to four aptamers. We demonstrate that different aptamer positions on a scaffold and scaffold orientation affect transcriptional activation. Finally, sgRNAOs are used to regulate expression of enzymes of the violacein biosynthesis pathway to control metabolic flux. The integration of RNA origami nanostructures at promoter sites achieved here, can in the future be expanded by the addition of functional motifs such as riboswitches, ribozymes and sensor elements to allow for complex gene regulation.

A strong nonequilibrium bound for sorting of cross-linkers on growing biopolymers.

Understanding the role of nonequilibrium driving in self-organization is crucial for developing a predictive description of biological systems, yet it is impeded by their complexity. The actin cytoskeleton serves as a paradigm for how equilibrium and nonequilibrium forces combine to give rise to self-organization. Motivated by recent experiments that show that actin filament growth rates can tune the morphology of a growing actin bundle cross-linked by two competing types of actin-binding proteins [S. L. Freedman et al., Proc. Natl. Acad. Sci. U.S.A. 116, 16192-16197 (2019)], we construct a minimal model for such a system and show that the dynamics of a growing actin bundle are subject to a set of thermodynamic constraints that relate its nonequilibrium driving, morphology, and molecular fluxes. The thermodynamic constraints reveal the importance of correlations between these molecular fluxes and offer a route to estimating microscopic driving forces from microscopy experiments.

Heart rate variability (HRV) after traumatic brain injury (TBI): a scoping review.

BACKGROUND: Heart rate variability (HRV), defined as the variability between successive heart beats, is a noninvasive measure of autonomic nervous system (ANS) function, which may be altered following traumatic brain injury (TBI). This scoping review summarizes the existing literature regarding changes in HRV after TBI as well as the association between measures of HRV and outcomes following TBI. METHODS: A literature search for articles assessing 'heart rate variability' and 'brain injury' or 'concussion' was completed. Articles were included if HRV was measured in human subjects with TBI or concussion. Review articles, protocol papers, and studies including non-traumatic injuries were excluded. RESULTS: Sixty-three articles were included in this review. Varied methods were used to measure HRV in the different studies. Forty articles included information about differences in HRV measures after TBI and/or longitudinal changes after TBI. Fifteen studies assessed HRV and symptoms following TBI, and 15 studies assessed HRV and either functional or cognitive outcomes after TBI. CONCLUSIONS: HRV has been studied in the context of mortality, clinical symptoms, and medical, functional, or cognitive outcomes following TBI. Methods used to measure HRV have varied amongst the different studies, which may impact findings, standardized protocols are needed for future research.

Internal Rotation Limitation is Prevalent Following Modern Reverse Shoulder Arthroplasty and Negatively Affects Patients' Subjective Rating of the Procedure.

BACKGROUND: While forward elevation, abduction, and external rotation are often successfully restored, internal rotation (IR) is frequently not satisfactorily recovered following reverse shoulder arthroplasty (RSA), affecting patients' ability to perform certain daily activities. This study examined the prevalence of limited IR in patients receiving modern RSA and its impact on clinical outcomes and patient satisfaction with their RSA. METHODS: A cross-sectional study was conducted on patients who had undergone primary RSA using a modern RSA prosthesis with a minimum one-year follow-up. Patients returned for a research visit where they were examined for range of motion and surveyed for patient-reported outcome measures (PROMs) and subjective rating of the success level of their RSA. Postoperative range of motion data were compared with the preoperative data. The relationship of postoperative IR with PROMs and patients' subjective rating of RSA was analyzed. Logistic regression was performed to identify factors affecting patients' subjective rating of RSA. RESULTS: A total of 78 patients met the criteria and completed the study. A significant portion (59%) reported subjective IR limitations, and 41% showed objective IR limitations. Comparison of preoperative and postoperative IR showed that 24% had worsened IR, while 33% improved. Limited IR was associated with lower patients' subjective rating of RSA and negatively impacted PROMs, especially when the dominant side was operated on. Regression analysis showed that limited IR was the only independent determining factor that was significantly associated with lower subjective rating of RSA. DISCUSSION: Despite advancements in RSA design, limited IR remains a prevalent issue, significantly affecting patients' satisfaction and clinical outcomes. This study underscores the need for setting appropriate expectations regarding IR through patient education and focused efforts to improve IR limitations in RSA patients, particularly on the dominant side.

Effect of making skin incision with electrocautery on positive Cutibacterium acnes culture rates in shoulder arthroplasty: a prospective randomized clinical trial.

BACKGROUND: Cutibacterium acnes remains the most commonly detected organism in shoulder arthroplasty. C acnes infection is thought to occur during shoulder arthroplasty through contamination of the surgical field with C acnes from the incised dermis. The purpose of this study was to examine whether using electrocautery for making skin incisions would decrease C acnes culture rates at the incised dermis compared to using scalpels during shoulder arthroplasty. METHODS: Patients undergoing primary shoulder arthroplasty were randomized into 2 groups, electrocautery vs. scalpel incision group. All patients received a standard preoperative antiseptic preparation including chlorhexidine gluconate showers, intravenous antibiotic administration, and topical application of hydrogen peroxide, povidone iodine, isopropyl alcohol, and DuraPrep. Cultures were obtained from the incised dermal edge immediately after skin incision and later from surgeon's gloves and forceps immediately prior to humeral component implantation. The primary outcome was positive C acnes culture rates compared between the groups. RESULTS: A total of 64 patients (32 in each group) were enrolled. There were 24 males in each group. Regarding dermis cultures, 10 patients (31%) in the scalpel group were positive with 8 of them positive for C acnes, whereas no patients in the electrocautery group were positive (P < .001). Regarding glove cultures, the electrocautery group had 8 patients positive C acnes, while the scalpel group had 8 (P = .777). Regarding forceps cultures, the electrocautery group had 4 patients positive for C acnes, and the scalpel group had 6 (P = .491). All positive cultures were exclusively from male patients. There were no wound complications or infection in the electrocautery group while the scalpel group had 1 acute postoperative infection. CONCLUSIONS: Making skin incisions using electrocautery resulted in 0 C acnes culture at the incised dermis, suggesting its potential effect against C acnes. However, despite this initial antibacterial effect, C acnes still appeared on surgeon's gloves and forceps during surgery of male patients. All positive cultures were from male patients, suggesting that the source of C acnes was specifically related to the male body. While the study hypothesis was supported by the results, the present study also raises new questions and calls for further research.

Mitocans induce lipid flip-flop and permeabilize the membrane to signal apoptosis.

Pancratistatin (PST) and narciclasine (NRC) are natural therapeutic agents that exhibit specificity toward the mitochondria of cancerous cells and initiate apoptosis. Unlike traditional cancer therapeutic agents, PST and NRC are effective, targeted, and have limited adverse effects on neighboring healthy, noncancerous cells. Currently, the mechanistic pathway of action for PST and NRC remains elusive, which in part inhibits PST and NRC from becoming efficacious therapeutic alternatives. Herein, we use neutron and x-ray scattering in combination with calcein leakage assays to characterize the effects of PST, NRC, and tamoxifen (TAM) on a biomimetic model membrane. We report an increase in lipid flip-flop half-times (t1/2) (≈12.0%, ≈35.1%, and a decrease of ≈45.7%) with 2 mol percent PST, NRC, and TAM respectively. An increase in bilayer thickness (≈6.3%, ≈7.8%, and ≈7.8%) with 2 mol percent PST, NRC, and TAM, respectively, was also observed. Lastly, increases in membrane leakage (≈31.7%, ≈37.0%, and ≈34.4%) with 2 mol percent PST, NRC, and TAM, respectively, were seen. Considering the maintenance of an asymmetric lipid composition across the outer mitochondrial membrane (OMM) is crucial to eukaryotic cellular homeostasis and survival, our results suggest PST and NRC may play a role in disrupting the native distribution of lipids within the OMM. A possible mechanism of action for PST- and NRC-induced mitochondrial apoptosis is proposed via the redistribution of the native OMM lipid organization and through OMM permeabilization.

Monitoring Drug Safety in Pregnancy with Scan Statistics: A Comparison of Two Study Designs.

BACKGROUND: Traditional surveillance of adverse infant outcomes following maternal medication exposures relies on pregnancy exposure registries, which are often underpowered. We characterize the statistical power of TreeScan, a data mining tool, to identify potential signals in the setting of perinatal medication exposures and infant outcomes. METHODS: We used empirical data to inform background incidence of major congenital malformations and other birth conditions. Statistical power was calculated using two probability models compatible with TreeScan, Bernoulli and Poisson, while varying the sample size, magnitude of the risk increase, and incidence of a specified outcome. We also simulated larger referent to exposure matching ratios when using the Bernoulli model in the setting of fixed N:1 propensity score matching. Finally, we assessed the impact of outcome misclassification on power. RESULTS: The Poisson model demonstrated greater power to detect signals than the Bernoulli model across all scenarios and suggested a sample size of 4,000 exposed pregnancies is needed to detect a twofold increase in risk of a common outcome (approximately 8 per 1,000) with 85% power. Increasing the fixed matching ratio with the Bernoulli model did not reliably increase power. An outcome definition with high sensitivity is expected to have somewhat greater power to detect signals than an outcome definition with high positive predictive value. CONCLUSIONS: Use of the Poisson model with an outcome definition that prioritizes sensitivity may be optimal for signal detection. TreeScan is a viable method for surveillance of adverse infant outcomes following maternal medication use.

Validation of Acute Pancreatitis Among Adults in an Integrated Healthcare System.

BACKGROUND: Acute pancreatitis is a serious gastrointestinal disease that is an important target for drug safety surveillance. Little is known about the accuracy of ICD-10 codes for acute pancreatitis in the United States, or their performance in specific clinical settings. We conducted a validation study to assess the accuracy of acute pancreatitis ICD-10 diagnosis codes in inpatient, emergency department (ED), and outpatient settings. METHODS: We reviewed electronic medical records for encounters with acute pancreatitis diagnosis codes in an integrated healthcare system from October 2015 to December 2019. Trained abstractors and physician adjudicators determined whether events met criteria for acute pancreatitis. RESULTS: Out of 1,844 eligible events, we randomly sampled 300 for review. Across all clinical settings, 182 events met validation criteria for an overall positive predictive value (PPV) of 61% (95% confidence intervals [CI] = 55, 66). The PPV was 87% (95% CI = 79, 92%) for inpatient codes, but only 45% for ED (95% CI = 35, 54%) and outpatient (95% CI = 34, 55%) codes. ED and outpatient encounters accounted for 43% of validated events. Acute pancreatitis codes from any encounter type with lipase >3 times the upper limit of normal had a PPV of 92% (95% CI = 86, 95%) and identified 85% of validated events (95% CI = 79, 89%), while codes with lipase <3 times the upper limit of normal had a PPV of only 22% (95% CI = 16, 30%). CONCLUSIONS: These results suggest that ICD-10 codes accurately identified acute pancreatitis in the inpatient setting, but not in the ED and outpatient settings. Laboratory data substantially improved algorithm performance.

Investigating the cut-off effect of n-alcohols on lipid movement: a biophysical study.

Cellular membranes are responsible for absorbing the effects of external perturbants for the cell's survival. Such perturbants include small ubiquitous molecules like n-alcohols which were observed to exhibit anesthetic capabilities, with this effect tapering off at a cut-off alcohol chain length. To explain this cut-off effect and complement prior biochemical studies, we investigated a series of n-alcohols (with carbon lengths 2-18) and their impact on several bilayer properties, including lipid flip-flop, intervesicular exchange, diffusion, membrane bending rigidity and more. To this end, we employed an array of biophysical techniques such as time-resolved small angle neutron scattering (TR-SANS), small angle X-ray scattering (SAXS), all atomistic and coarse-grained molecular dynamics (MD) simulations, and calcein leakage assays. At an alcohol concentration of 30 mol% of the overall lipid content, TR-SANS showed 1-hexanol (C6OH) increased transverse lipid diffusion, i.e. flip-flop. As alcohol chain length increased from C6 to C10 and longer, lipid flip-flop slowed by factors of 5.6 to 32.2. Intervesicular lipid exchange contrasted these results with only a slight cut-off at alcohol concentrations of 30 mol% but not 10 mol%. SAXS, MD simulations, and leakage assays revealed changes to key bilayer properties, such as bilayer thickness and fluidity, that correlate well with the effects on lipid flip-flop rates. Finally, we tie our results to a defect-mediated pathway for alcohol-induced lipid flip-flop.

Novel methods for pregnancy drug safety surveillance in the FDA Sentinel System.

PURPOSE: It is a priority of the US Food and Drug Administration (FDA) to monitor the safety of medications used during pregnancy. Pregnancy exposure registries and cohort studies utilizing electronic health record data are primary sources of information but are limited by small sample sizes and limited outcome assessment. TreeScan™, a statistical data mining tool, can be applied within the FDA Sentinel System to simultaneously identify multiple potential adverse neonatal and infant outcomes after maternal medication exposure. METHODS: We implemented TreeScan using the Sentinel analytic tools in a cohort of linked live birth deliveries and infants nested in the IBM MarketScan® Research Database. As a case study, we compared first trimester fluoroquinolone use and cephalosporin use. We used the Bernoulli and Poisson TreeScan statistics with compatible propensity score-based study designs for confounding control (matching and stratification) and used multiple propensity score models with various strategies for confounding control to inform best practices. We developed a hierarchical outcome tree including major congenital malformations and outcomes of gestational length and birth weight. RESULTS: A total of 1791 fluoroquinolone-exposed and 8739 cephalosporin-exposed mother-infant pairs were eligible for analysis. Both TreeScan analysis methods resulted in single alerts that were deemed to be due to uncontrolled confounding or otherwise not warranting follow-up. CONCLUSIONS: In this implementation of TreeScan using Sentinel analytic tools, we did not observe any new safety signals for fluoroquinolone use in the first trimester. TreeScan, with tailored or high-dimensional propensity scores for confounding control, is a valuable tool in addition to current safety surveillance methods for medications used during pregnancy.

Ankle fractures: a systematic review of patient-reported outcome measures and their measurement properties.

PURPOSE: Ankle fractures are commonly occurring fractures, especially in the aging population, where they often present as fragility fractures. The disease burden and economic costs to the patient and society are considerable. Choosing accurate outcome measures for the evaluation of the management of ankle fractures in clinical trials facilitates better decision-making. This systematic review assesses the evidence for the measurement properties of patient-reported outcome measures (PROMs) used in the evaluation of adult patients with ankle fractures. METHODS: Searches were performed in CINAHL, EMBASE, Medline and Google Scholar from the date of inception to July 2021. Studies that assessed the measurement properties of a PROM in an adult ankle fracture population were included. The included studies were assessed according to the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) methodology for systematic reviews of PROMs. RESULTS: In total, 13 different PROMs were identified in the 23 included articles. Only the Ankle Fracture Outcome of Rehabilitation Measure (A-FORM) presented some evidence on content validity. The Olerud-Molander Ankle Score (OMAS) and Self-reported Foot and Ankle Score (SEFAS) displayed good evidence of construct validity and internal consistency. The measurement properties of the OMAS, LEFS and SEFAS were most studied. CONCLUSION: The absence of validation studies covering all measurement properties of PROMs used in the adult ankle fracture population precludes the recommendation of a specific PROM to be used in the evaluation of this population. Further research should focus on validation of the content validity of the instruments used in patients with ankle fractures.

MRI findings of growth plate fractures of the knee: are there age- and fracture-dependent differences?

OBJECTIVE: To investigate MRI findings in children with physeal fractures of the knee with respect to age, location, and articular involvement. METHODS: Children with physeal fractures who underwent knee MRI between 2008 and 2021 were included. Two radiologists retrospectively reviewed all examinations to determine articular involvement, findings of physeal instability (perichondral disruption, periosteal entrapment), and internal derangement (cruciate ligament injury, meniscal tear, chondromalacia). Independent samples t, Mann-Whitney U, Pearson's chi-square, and Fisher's exact tests were used to compare findings. RESULTS: Fifty-six patients (37 boys, 19 girls; mean age: 12.2 ± 2.5 years; 32 distal femur, 24 proximal tibial fractures) included 24(43%) intraarticular fractures. Fractures were more common in the tibia than the femur (67% versus 25%, p = 0.004) and intraarticular fractures were more common in older than younger children (13.1 ± 2.0 versus 11.5 ± 2.7 years, p = 0.01), to associate with chondromalacia (46% versus 12%, p = 0.02) and undergo surgery (33% versus 10%, p = 0.04) when compared to extraarticular fractures. Perichondral disruption (n = 44, 79%) and periosteal entrapment (n = 13, 23%) did not significantly differ based on location or articular involvement (p > 0.05). At a median follow-up of 17.5 months (interquartile range: 1.25-34), 3 patients (2 intraarticular, 1 extraarticular fractures) developed osteoarthritis, osteochondral lesion, and leg-length discrepancy from growth arrest, which required additional surgery. CONCLUSION: Intraarticular physeal fractures were more common with older children, associate with chondromalacia, and underdo surgical intervention when compared to extraarticular fractures of the knee. While MRI findings of physeal instability were common, no significant differences were found between fractures based on anatomic location or fracture pattern.

Pulse Oximetry Screening: Association of State Mandates with Emergency Hospitalizations.

We evaluated the association between implementation of state-mandated pulse oximetry screening (POS) and rates of emergency hospitalizations among infants with Critical Congenital Heart Disease (CCHD) and assessed differences in that association across race/ethnicity. We hypothesized that emergency hospitalizations among infants with CCHD decreased after implementation of mandated POS and that the reduction was larger among racial and ethnic minorities compared to non-Hispanic Whites. We utilized statewide inpatient databases from Arizona, California, Kentucky, New Jersey, New York, and Washington State (2010-2014). A difference-in-differences model with negative binomial regression was used. We identified patients with CCHD whose hospitalizations between three days and three months of life were coded as "emergency" or "urgent" or occurred through the emergency department. Numbers of emergency hospitalizations aggregated by month and state were used as outcomes. The intervention variable was an implementation of state-mandated POS. Difference in association across race/ethnicity was evaluated with interaction terms between the binary variable indicating the mandatory policy period and each race/ethnicity group. The model was adjusted for state-specific variables, such as percent of female infants and percent of private insurance. We identified 9,147 CCHD emergency hospitalizations. Among non-Hispanic Whites, there was a 22% (Confidence Interval [CI] 6%-36%) decline in CCHD emergency hospitalizations after implementation of mandated POS, on average. This decline was 65% less among non-Hispanic Blacks compared to non-Hispanic Whites. Our study detected an attenuated association with decreased number of emergency hospitalizations among Black compared to White infants. Further research is needed to clarify this disparity.

Antioxidants Amelioration Is Insufficient to Prevent Acrylamide and Alpha-Solanine Synergistic Toxicity in BEAS-2B Cells.

Cells produce free radicals and antioxidants when exposed to toxic compounds during cellular metabolism. However, free radicals are deleterious to lipids, proteins, and nucleic acids. Antioxidants neutralize and eliminate free radicals from cells, preventing cell damage. Therefore, the study aims to determine whether the antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) will ameliorate the maximum dose of acrylamide and alpha (α)-solanine synergistic toxic effects in exposed BEAS-2B cells. These toxic compounds are consumed worldwide by eating potato products. BEAS-2B cells were simultaneously treated with BHA 10 µM and BHT 20 µM and incubated in a 5% CO2 humidified incubator for 24 h, followed by individual or combined treatment with acrylamide (3.5 mM) and α-solanine (44 mM) for 48 h, including the controls. Cell morphology, DNA, RNA, and protein were analyzed. The antioxidants did not prevent acrylamide and α-solanine synergistic effects in exposed BEAS-2B cells. However, cell morphology was altered; polymerase chain reaction (PCR) showed reduced RNA constituents but not DNA. In addition, the toxic compounds synergistically inhibited AKT/PKB expression and its downstream genes. The study showed BHA and BHT are not protective against the synergetic toxic effects of acrylamide and α-solanine in exposed BEAS-2B cells.

Proteoglycans and proteoglycan mimetics for tissue engineering.

Proteoglycans play a crucial role in proper tissue morphology and function throughout the body that is defined by a combination of their core protein and the attached glycosaminoglycan chains. Although they serve a myriad of roles, the functions of extracellular proteoglycans can be generally sorted into four categories: modulation of tissue mechanical properties, regulation and protection of the extracellular matrix, sequestering of proteins, and regulation of cell signaling. The loss of proteoglycans can result in significant tissue dysfunction, ranging from poor mechanical properties to uncontrolled inflammation. Because of the key roles they play in proper tissue function and due to their complex synthesis, the past two decades have seen significant research into the development of proteoglycan mimetic molecules to recapitulate the function of proteoglycans for therapeutic and tissue engineering applications. These strategies have ranged from semisynthetic graft copolymers to recombinant proteoglycan domains synthesized by genetically engineered cells. In this review, we highlight some of the important functions of extracellular proteoglycans, as well as the strategies developed to recapitulate these functions.

Vitamin E Does Not Disturb Polyunsaturated Fatty Acid Lipid Domains.

The function of vitamin E in biomembranes remains a prominent topic of discussion. As its limitations as an antioxidant persist and novel functions are discovered, our understanding of the role of vitamin E becomes increasingly enigmatic. As a group of lipophilic molecules (tocopherols and tocotrienols), vitamin E has been shown to influence the properties of its host membrane, and a wealth of research has connected vitamin E to polyunsaturated fatty acid (PUFA) lipids. Here, we use contrast-matched small-angle neutron scattering and differential scanning calorimetry to integrate these fields by examining the influence of vitamin E on lipid domain stability in PUFA-based lipid mixtures. The influence of α-tocopherol, γ-tocopherol, and α-tocopherylquinone on the lateral organization of a 1:1 lipid mixture of saturated distearoylphosphatidylcholine (DSPC) and polyunsaturated palmitoyl-linoleoylphosphatidylcholine (PLiPC) with cholesterol provides a complement to our growing understanding of the influence of tocopherol on lipid phases. Characterization of domain melting suggests a slight depression in the transition temperature and a decrease in transition cooperativity. Tocopherol concentrations that are an order of magnitude higher than anticipated physiological concentrations (2 mol percent) do not significantly perturb lipid domains; however, addition of 10 mol percent is able to destabilize domains and promote lipid mixing. In contrast to this behavior, increasing concentrations of the oxidized product of α-tocopherol (α-tocopherylquinone) induces a proportional increase in domain stabilization. We speculate how the contrasting effect of the oxidized product may supplement the antioxidant response of vitamin E.

Diffusion Tensor Imaging of the Knee to Predict Childhood Growth.

Background Accurate and precise methods to predict growth remain lacking. Diffusion tensor imaging (DTI) depicts the columnar structure of the physis and metaphyseal spongiosa and provides measures of tract volume and length that may help predict growth. Purpose To validate physeal DTI metrics as predictors of height velocity (1-year height gain from time of MRI examination) and total height gain (height gain from time of MRI examination until growth stops) and compare the prediction accuracy with bone age-based models. Materials and Methods Femoral DTI studies (b values = 0 and 600 sec/mm2; directions = 20) of healthy children who underwent MRI of the knee between February 2012 and December 2016 were retrospectively analyzed. Children with height measured at MRI and either 1 year later (height velocity) or after growth cessation (total height gain, mean = 34 months from MRI) were included. Physeal DTI tract volume and length were correlated with height velocity and total height gain. Multilinear regression was used to assess the potential of DTI metrics in the prediction of both parameters. Bland-Altman plots were used to compare root mean square error (RMSE) and bias in height prediction using DTI versus bone age methods. Results Eighty-nine children (mean age, 13 years ± 3 [SD]; 47 boys) had height velocity measured, and 70 (mean age, 14 years ± 1; 36 girls) had total height gain measured. Tract volumes correlated with height velocity (r2 = 0.49) and total height gain (r2 = 0.46) (P < .001 for both) after controlling for age and sex. Tract volume was the strongest predictor for height velocity and total height gain. An optimal multilinear model including tract volume improved prediction of height velocity (R2 = 0.63, RMSE = 1.7 cm) and total height gain (R2 = 0.59, RMSE = 1.8 cm) compared with bone age-based methods (height velocity: R2 = 0.32, RMSE = 2.9 cm; total height gain: R2 = 0.42, RMSE = 5.0 cm). Conclusion Models using tract volume derived from diffusion tensor imaging may perform better than bone age-based models in children for the prediction of height velocity and total height gain. © RSNA, 2022.