Bioaccessibility of avocado polyhydroxylated fatty alcohols.

Avocado-derived polyhydroxylated fatty alcohols (PFAs), such as avocadene and avocadyne, have been recently identified as potent modulators of mitochondrial metabolism which selectively induce leukemia cell death and reverse pathologies associated with diet-induced obesity. However, avocadene and avocadyne bioaccessibility from avocado pulp is not reported; hence, this study aims to investigate if these PFAs are bioaccessible. Dynamic (TNO dynamic intestinal model-1 (TIM-1)) and static in vitro digestion of lyophilized Hass avocado pulp powder shows lipolytic gastrointestinal enzymes led to appreciable bioaccessibility of avocadene (55%) and avocadyne (50%). Furthermore, TIM-1 digestion of a 1:1 ratio of pure avocadene and avocadyne (avocatin B or AvoB) crystals formulated in an oil-in-water microemulsion has on average 15% higher bioaccessibility than the avocado pulp powder demonstrating both dosage forms as potential dietary sources of avocado PFAs. This research provides the impetus for further research on the nutritional significance of dietary long chain fatty alcohols.

Survival trends in heart transplant patients supported on ECMO and IABP: A 10-year UNOS database analysis.

The United Network for Organ Sharing (UNOS) heart transplant allocation policy was changed in 2018. This study examines the impact of the change in UNOS heart transplant allocation policy on the use of temporary mechanical circulatory support (MCS) devices and post-transplant survival. The analysis included a total of 26,481 patients listed and transplanted between January 2013 and June 2022. The results showed a decrease in waiting time for transplant after the policy change, indicating a successful reduction in waitlist time for high-priority status patients. However, the length of hospital stays from transplant to discharge increased following the policy change. The study also found an increase in the frequency of ECMO and IABP use both at the time of listing and at the time of transplant following the policy change. Cumulative patient and graft survival at 1000 days decreased following the policy change (86.1 per cent versus 83.7 per cent at 1000 days, p = 0.002). However, the survival curves showed similar survival trends in the first 2 years, with late divergence in survival occurring after 2 years. In conclusion the latest UNOS heart transplant allocation policy change led to a decrease in waiting times and an increase in the use of temporary MCS devices. There was a decrease in cummulative survival at 1000 days following the policy change.

Pharmaceutical Pollution of the English National Parks.

England's 10 national parks are renowned for their landscapes, wildlife, and recreational value. However, surface waters in the national parks may be vulnerable to pollution from human-use chemicals, such as active pharmaceutical ingredients (APIs), because of factors like ineffective wastewater treatment, seasonal tourism, a high proportion of elderly residents, and the presence of low-flow water bodies that limit dilution. The present study determined the extent of API contamination in the English national parks by monitoring 54 APIs in 37 rivers across all national parks over two seasons. Results were compared to existing data sets for UK cities and to concentration thresholds for ecological impacts and antimicrobial resistance selection. Results revealed widespread contamination of the national parks, with APIs detected at 52 out of 54 sites and in both seasons. Thirty-one APIs were detected, with metformin, caffeine, and paracetamol showing the highest mean concentrations and cetirizine, metformin, and fexofenadine being the most frequently detected. While total API concentrations were generally lower than seen previously in UK cities, locations in the Peak District and Exmoor had higher concentrations than most city rivers. Fourteen locations had concentrations of either amitriptyline, carbamazepine, clarithromycin, diltiazem, metformin, paracetamol, or propranolol above levels of concern for fish, invertebrates, and algae or for selection for antimicrobial resistance. Therefore, API pollution of the English national parks appears to pose risks to ecological health and potentially human health through recreational water use. Given that these parks are biodiversity hotspots with protected ecosystems, there is an urgent need for improved monitoring and management of pharmaceutical pollution and pollution more generally not only in national parks in England but also in similar environments across the world. Environ Toxicol Chem 2024;00:1-14. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Targeting NGF but not VEGFR1 or BDNF signaling reduces endometriosis-associated pain in mice.

INTRODUCTION: Endometriosis is a chronic inflammatory disease that affects âˆ¼10 % of women. A significant fraction of patients experience limited or no efficacy with current therapies. Tissue adjacent to endometriosis lesions often exhibits increased neurite and vascular density, suggesting that disease pathology involves neurotrophic activity and angiogenesis. OBJECTIVES: We aim to evaluate the potential for key tyrosine-kinase-receptor-coupled neurotrophic molecules to contribute to endometriosis-associated pain in mice. METHODS: Peritoneal fluid was collected from endometriosis patients undergoing surgery and the levels of NGF and VEGFR1 regulators (VEGFA, VEGFB, PLGF, and sVEGFR1) were quantified by ELISA. VEGFR1 regulator concentrations were used to calculate VEGFR1 occupancy. We used genetic depletion, neutralizing antibodies, and pharmacological approaches to specifically block neurotrophic ligands (NGF or BDNF) or receptors (VEGFR1, TRKs) in a murine model of endometriosis-associated pain. Endometriosis-associated pain was measured using von Frey filaments, quantification of spontaneous abdominal pain-related behavior, and thermal discomfort. Disease parameters were evaluated by lesion size and prevalence. To evaluate potential toxicity, we measured the effect of entrectinib dose and schedule on body weight, liver and kidney function, and bone structure (via micro-CT). RESULTS: We found that entrectinib (pan-Trk inhibitor) or anti-NGF treatments reduced evoked pain, spontaneous pain, and thermal discomfort. In contrast, even though calculated receptor occupancy revealed that VEGFR1 agonist levels are sufficient to support signaling, blocking VEGFR1 via antibody or tamoxifen-induced knockout did not reduce pain or lesion size in mice. Targeting BDNF-TrkB with an anti-BDNF antibody also proved ineffective. Notably, changing dosing schedule to once weekly eliminated entrectinib-induced bone-loss without decreasing efficacy against pain. CONCLUSIONS: This suggests NGF-TrkA signaling, but not BDNF-TrkB or VEGF-VEGFR1, mediates endometriosis-associated pain. Moreover, entrectinib blocks endometriosis-associated pain and reduces lesion sizes. Our results also indicated that entrectinib-like molecules are promising candidates for endometriosis treatment.

Mapping deterioration in electrospun zein nonwoven nanostructures encapsulating corn oil.

Electrospun nonwovens of biopolymers are gaining popularity in filtration, coatings, encapsulation, and packaging materials. However, their applications are hindered by limited stability, particularly when loaded with lipids. This research aimed to apply a multiscale approach to gain insights into deteriorative processes, e.g., oxidation, limiting the shelf life of these complex materials, using corn oil-loaded electrospun zein nonwovens as a model system. Oil-doped zein electrospun nonwovens were stored in the dark at 23 °C and 33% relative humidity for 28 days and tested at selected intervals to monitor their morphology and mechanical properties. Lipid oxidation was assessed using the thiobarbituric acid reactive species (TBARS) assay. The photophysical properties of intrinsic, i.e., tyrosine (Tyr), and extrinsic, i.e., boron-dipyrromethene undecanoic acid 581/591 (BODIPY C11), lumiphores were also monitored to evaluate changes in local molecular rigidity, and oxidation, respectively. The protein secondary structure was determined with Fourier transform infrared spectroscopy (FTIR). Scanning electron microscopy (SEM) analysis of the oil-loaded electrospun nonwovens revealed that the diameter of the ribbon-like fiber significantly decreased during storage from 701 ± 23 nm to 620 ± 44 nm. Breakage of the electrospun fibers was observed and correlated with increased brittleness and molecular rigidity of the nonwoven material, reflected by an increase in Tyr emission intensity and phosphorescence lifetime. Changes in tensile strength, brittleness and matrix rigidity also correlated with a zein secondary structure transition from unordered to ordered ß-sheets. Raman and luminescence micrographs showed oil migration during storage, thereby increasing lipid oxidation. The correlation between local rigidity and lipid distribution/oxidation suggests that reorganizing protein structures increased material brittleness and displaced encapsulated oils within the electrospun fiber. Understanding deteriorative mechanisms aids in developing innovative strategies to improve the stability of these novel food-grade materials.

Analyzing the L4-5 Segmental Alignment Change of Two Minimally Invasive Prone-Based Interbody Fusions.

STUDY DESIGN: Retrospective Cohort Study. OBJECTIVE: Restoration of lumbar lordosis (LL) is a principal objective during spinal fusion procedures, traditionally focusing on achieving an LL within 10° of the pelvic incidence (PI). Recent studies have demonstrated a relatively constant L4-S1 alignment of 35-40° at L4-S1 and at least 15° at L4-5, regardless of PI. Based on these results, this study was created to examine the success rate of achieving a minimum of 15° at L4-5 through two differing prone-based techniques: Prone Lateral (pLLIF) and Trans Foraminal Interbody Fusion (TLIF). METHODS: One hundred patients with a primary single-level L4-5 interbody fusion (50 pLLIF and 50 TLIF) were retrospectively analyzed. Pre and post-operative radiographs were measured to examine the segmental change at each level in the lumbar spine and calculate the success rate for achieving a minimum L4-5 segmental lordosis of 15° at the final follow-up. RESULTS: The overall success rate of achieving an L4-5 segmental alignment >15° at the final follow-up was 70%. Prone LLIF was significantly more likely than TLIF to achieve this goal, achieving L4-5 > 15° 84% of the time vs TLIFs 56% (P = 0.002). Prone LLIF demonstrated an average L4-5 increase of 5.6 ± 5.9° which was larger than the mean increase for TLIF 0.4 ± 3.8° (P < 0.001). In both techniques, there was an inverse correlation between pre-operative L4-5 angle and L4-5 angle change. CONCLUSION: Prone lateral lumbar interbody fusion demonstrates a high success rate for achieving a post-operative L4-5 angle >15° and achieves this at a higher rate than TLIF.

Clinical Applications of Machine Learning.

Objective: This review introduces interpretable predictive machine learning approaches, natural language processing, image recognition, and reinforcement learning methodologies to familiarize end users. Background: As machine learning, artificial intelligence, and generative artificial intelligence become increasingly utilized in clinical medicine, it is imperative that end users understand the underlying methodologies. Methods: This review describes publicly available datasets that can be used with interpretable predictive approaches, natural language processing, image recognition, and reinforcement learning models, outlines result interpretation, and provides references for in-depth information about each analytical framework. Results: This review introduces interpretable predictive machine learning models, natural language processing, image recognition, and reinforcement learning methodologies. Conclusions: Interpretable predictive machine learning models, natural language processing, image recognition, and reinforcement learning are core machine learning methodologies that underlie many of the artificial intelligence methodologies that will drive the future of clinical medicine and surgery. End users must be well versed in the strengths and weaknesses of these tools as they are applied to patient care now and in the future.

Meta-Analysis in Surgical Research: Methodology and Statistical Application.

In evidence-based medicine, systematic review continues to carry the highest weight in terms of quality and reliability, synthesizing robust information from previously published cohort studies to provide a comprehensive overview of a topic. Meta-analysis provides further depth by allowing for comparative analysis between the studied intervention and the control group, providing the most up-to-date evidence on their characteristics and efficacy. We discuss the principles and methodology of meta-analysis, and its applicability to the field of surgical research. The clinical question is defined using PICO framework (Problem, Intervention, Comparison, Outcome). Then a systematic article search is performed across multiple medical databases using relevant search terms, which are then filtered out based on appropriate screening tools. Pertinent data from the selected articles are collected and undergo critical appraisal by at least two independent reviewers. Additional statistical tests may be performed to identify the presence of any significant bias. The data are then synthesized to perform comparative analysis between the intervention and comparison groups. In this article, we discuss specifically the usage of R software (R Foundation for Statistical Computing, Vienna, Austria) for data analysis and visualization. Meta-analysis results of the pooled data are presented using forest plots. Concerns for potential bias may be addressed through the creation of funnel plots. Meta-analysis is a powerful tool to provide highly reliable medical evidence. It may be readily performed by independent researchers with minimal need for funding or institutional approval. The ability to conduct such studies is an asset to budding medical scholars.

Survival Tree Provides Individualized Estimates of Survival After Lung Transplant.

INTRODUCTION: Identifying contributors to lung transplant survival is vital in mitigating mortality. To enhance individualized mortality estimation and determine variable interaction, we employed a survival tree algorithm utilizing recipient and donor data. METHODS: United Network Organ Sharing data (2000-2021) were queried for single and double lung transplants in adult patients. Graft survival time <7 d was excluded. Sixty preoperative and immediate postoperative factors were evaluated with stepwise logistic regression on mortality; final model variables were included in survival tree modeling. Data were split into training and testing sets and additionally validated with 10-fold cross validation. Survival tree pruning and model selection was based on Akaike information criteria and log-likelihood values. Estimated survival probabilities and log-rank pairwise comparisons between subgroups were calculated. RESULTS: A total of 27,296 lung transplant patients (8175 single; 19,121 double lung) were included. Stepwise logistic regression yielded 47 significant variables associated with mortality. Survival tree modeling returned six significant factors: recipient age, length of stay from transplant to discharge, recipient ventilator duration post-transplant, double lung transplant, recipient reintubation post-transplant, and donor cytomegalovirus status. Eight subgroups consisting of combinations of these factors were identified with distinct Kaplan-Meier survival curves. CONCLUSIONS: Survival trees provide the ability to understand the effects and interactions of covariates on survival after lung transplantation. Individualized survival probability with this technique found that preoperative and postoperative factors influence survival after lung transplantation. Thus, preoperative patient counseling should acknowledge a degree of uncertainty given the influence of postoperative factors.

Statewide Hospital Admissions for Adult Survivors of Infant Surgical Diseases Over a 10-Year Period.

INTRODUCTION: The number of patients with congenital disease living to adulthood continues to grow. Often undergoing surgical correction in infancy, they continue to require lifelong care. Their numbers are largely unknown. We sought to evaluate hospital admissions of adult patients with esophageal atresia with tracheoesophageal fistula (EA/TEF), congenital diaphragmatic hernia (CDH), and Hirschsprung disease (HD). METHODS: The Florida Agency for Healthcare Administration inpatient database was merged with the Distressed Communities Index and Centers for Medicare and Medicaid Services Hospital and Physician Compare datasets. The dataset was queried for adult patients (≥18 y, born after 1970) with EA/TEF, CDH, and HD in their problem list from 2010 to 2020. Patient demographics, hospitalization characteristics, and discharge information were obtained. RESULTS: In total, 1140 admissions were identified (266 EA/TEF, 135 CDH, 739 HD). Patients were mostly female (53%), had a mean age of 31.6 y, and often admitted to an adult internist in a general hospital under emergency. Principal diagnoses and procedures (when performed) varied with diagnosis and age at admission. EA patients were admitted with dysphagia and foregut symptoms and often underwent upper endoscopy with dilation. CDH patients were often admitted for diaphragmatic hernias and underwent adult diaphragm repair. Hirschsprung patients were often admitted for intestinal obstructive issues and frequently underwent colonoscopy but trended toward operative intervention with increasing age. CONCLUSIONS: Adults with congenital disease continue to require hospital admission and invasive procedures. As age increases, diagnoses and performed procedures for each diagnoses evolve. These data could guide the formulation of multispecialty disease-specific follow-up programs for these patients.

Single-Position Prone Lateral Lumbar Interbody Fusion Technique Guide: Surgical Tips and Tricks.

Lateral lumbar interbody fusion (LLIF) is a popular technique as it allows for the placement of a large interbody implant through a retroperitoneal, transpsoas working corridor. Historically, the interbody is placed with the patient in lateral decubitus and then repositioned to prone for the posterior instrumentation. While this has been an effective and successful technique, removing the interoperative flip would improve the efficiency of these cases. This has led to modified LLIF approaches including single-position prone LLIF (pLLIF). This modification has shown to be an efficient and powerful technique; however, learning to navigate the LLIF approach in the prone position has its own challenges. The purpose of this article is to provide a detailed description of our pLLIF technique while simultaneously introducing surgical tips to overcome the challenges of the approach and optimize the implantation of the interbody device.

Faster discharge with lactated ringers than normal saline in first 72 h of acute pancreatitis: A multicenter randomized trial.

OBJECTIVES: Data driven strategies for acute pancreatitis (AP) in pediatrics are limited; adult data suggests lactated ringers (LR) compared to normal saline (NS) resulted in favorable outcomes, but has not been studied in pediatrics. Our objective was to evaluate the efficacy of LR during the first 48 h of an AP episode compared with NS. STUDY DESIGN: A multisite randomized controlled clinical trial, from 2015 to 2020 (Clinical Trials.gov NCT03242473). Patients were randomized to exclusively LR or NS for the first 48 h. Primary outcomes were serial C-reactive protein (CRP) values. Secondary outcomes included other lab values, time to feeds, length of stay (LOS), systemic inflammatory response syndrome (SIRS) development, and progression to severe AP (SAP). RESULTS: We studied 76 patients (38 LR, 38 NS). CRP at 24 and 48 h were not significantly different between LR or NS group. Additionally, there were no differences in trends of BUN, amylase, lipase, SIRS status, or SAP development between the LR and NS group at 24 and 48 h. A higher proportion of LR patients (32%, 12/38) were discharged before 48 h compared to NS (13%, 5/38). The LR group had a significantly higher rate of discharge within the first 72 h compared to the NS group (p = 0.02). CONCLUSION: The use of LR was associated with a faster rate of discharge during the intervention period and in the first 72 h, but no other differences compared to NS. This reduction in length of hospitalization has significant implications for patients and healthcare costs.

Interfacial crystallized oleogel emulsion with improved freeze-thaw stability and tribological properties: Influence of cooling rate.

In this study, the influence of cooling rate on the freeze-thaw stability, rheological and tribological properties of interfacial crystalized oleogel emulsion was investigated. Results showed that slower cooling rate could promote formation of larger crystals and stronger network in oleogels. Additionally, oleogel emulsions showed higher freeze-thaw stability than those stabilized solely by emulsifiers. The slower cooling rate resulted in larger crystals adsorbed at the droplet surface. This led to greater steric hindrance that prevented the migration of oil droplets with higher resistance to disruption by ice crystals. The rheological and tribological measurements suggested that with appropriate amount of crystals, the tribological properties were better maintained for emulsions prepared at slow cooling rate after freeze-thaw treatment. This strategy greatly enriched oleogel emulsion formulations and provided important clues for potential applications in food products involved with freeze-thaw treatment.

Comparison of complication rates between anterior versus posterior approaches for treating unstable Hangman's fracture. A systematic review and meta-analysis.

Study design: Systematic Review and Meta-analysis. Objective: To compare the complication rates associated with anterior and posterior approaches for the surgical treatment of unstable hangman's fractures. Methods: A systematic review and meta-analysis were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in PubMed, Web of Science, and Scopus databases to identify comparative studies reporting complications of anterior versus posterior approaches for the treatment of unstable hangman's fractures. Results: The search yielded 1163 papers from which 5 studies were fully included. One hundred fifteen (115) patients were operated on using an anterior approach versus 65 through a posterior approach. The average complication rates for the anterior and posterior approaches were 26.1 % and 13.8 %, respectively. No complications following the anterior approach required pharmacological or surgical intervention (Clavien-Dindo, Grade 1), while 88.9 % of complications following the posterior approach did (Clavien-Dindo, Grade 2). Conclusion: No significant differences in the complication rates were found when comparing anterior versus posterior surgery for treating a C2 traumatic spondylolisthesis. However, most of the complications presented in the posterior surgery group were more severe.

Is nonoperative management of appendicitis inferior in the COVID-19 era?

BACKGROUND: Previous studies on nonoperative management (NOM) of acute appendicitis (AA) indicated comparable outcomes to surgery, but the effect of COVID-19 infection on appendicitis outcomes remains unknown. Thus, we evaluate appendicitis outcomes during the COVID-19 pandemic to determine the effect of COVID-19 infection status and treatment modality. We hypothesized that active COVID-19 patients would have worse outcomes than COVID-negative patients, but that outcomes would not differ between recovered COVID-19 and COVID-negative patients. Moreover, we hypothesized that outcomes would not differ between nonoperative and operative management groups, regardless of COVID-19 status. METHODS: We queried the National COVID Cohort Collaborative from 2020 to 2023 to identify adults with AA who underwent operative or NOM. COVID-19 status was denoted as follows: COVID-negative, COVID-active, or COVID-recovered. Intention to treat was used for NOM. Propensity score-balanced analysis was performed to compare outcomes within COVID groups, as well as within treatment modalities. RESULTS: A total of 37,868 patients were included: 34,866 COVID-negative, 2,540 COVID-active, and 460 COVID-recovered. COVID-active and recovered less often underwent operative management. Unadjusted, there was no difference in mortality between COVID groups for operative management. There was no difference in rate of failure of NOM between COVID groups. Adjusted analysis indicated, compared with operative, NOM carried higher odds of mortality and readmission for COVID-negative and COVID-active patients. CONCLUSION: This study demonstrates higher odds of mortality among NOM of appendicitis and near equivalent outcomes for operative management regardless of COVID-19 status. We conclude that NOM of appendicitis is associated with worse outcomes for COVID-active and COVID-negative patients. In addition, we conclude that a positive COVID test or recent COVID-19 illness alone should not preclude a patient from appendectomy for AA. Surgeon clinical judgment of a patient's physiology and surgical risk should, of course, inform the decision to proceed to the operating room. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Artificial Intelligence in Surgical Research: Accomplishments and Future Directions.

MINI-ABSTRACT: The study introduces various methods of performing conventional ML and their implementation in surgical areas, and the need to move beyond these traditional approaches given the advent of big data. OBJECTIVE: Investigate current understanding and future directions of machine learning applications, such as risk stratification, clinical data analytics, and decision support, in surgical practice. SUMMARY BACKGROUND DATA: The advent of the electronic health record, near unlimited computing, and open-source computational packages have created an environment for applying artificial intelligence, machine learning, and predictive analytic techniques to healthcare. The "hype" phase has passed, and algorithmic approaches are being developed for surgery patients through all stages of care, involving preoperative, intraoperative, and postoperative components. Surgeons must understand and critically evaluate the strengths and weaknesses of these methodologies. METHODS: The current body of AI literature was reviewed, emphasizing on contemporary approaches important in the surgical realm. RESULTS AND CONCLUSIONS: The unrealized impacts of AI on clinical surgery and its subspecialties are immense. As this technology continues to pervade surgical literature and clinical applications, knowledge of its inner workings and shortcomings is paramount in determining its appropriate implementation.

Wheat milling across history altered sugar bioaccessibility assessed using TIM-1 in vitro digestion model.

The differences in wheat flour characteristics caused by ancient (pestle and mortar), old (stone hand mill), and modern (roller and cyclone) milling techniques and their effect on in vitro starch digestibility of wheat porridge using the simulated TIM Gastrointestinal Model (TIM-1) were investigated. Ancient flour (AF) was the coarsest flour (∼70 % is >1000 µm), followed by old wholemeal flour (OWF) and old refined flour (ORF) with similar particle size distribution showing one prominent peak (at ∼1000 µm for OWF and ∼800 µm for ORF). Modern refined flour (MRF) had a monomodal distribution centered at a particle size of ∼100 µm, while modern wholemeal flour (MWF) particle size was distributed between 40 and 600 µm. MRF and MWF porridges had higher cumulative sugar bioaccessibility than OWF and AF porridges, with ORF porridge having an intermediate cumulative sugar bioaccessibility. Characterizing the cumulative sugar bioaccessibility profile with a shifted logistic model allows identifying that the maximum sugar bioaccessibility and rate of sugar release were significantly higher (p < 0.05) for MRF and MWF compared to OWF and AF porridges, while the induction times were shorter, demonstrating the importance of processing on modulating starch digestibility.

KDM5-mediated activation of genes required for mitochondrial biology is necessary for viability in Drosophila.

Histone-modifying proteins play important roles in the precise regulation of the transcriptional programs that coordinate development. KDM5 family proteins interact with chromatin through demethylation of H3K4me3 as well as demethylase-independent mechanisms that remain less understood. To gain fundamental insights into the transcriptional activities of KDM5 proteins, we examined the essential roles of the single Drosophila Kdm5 ortholog during development. KDM5 performs crucial functions in the larval neuroendocrine prothoracic gland, providing a model to study its role in regulating key gene expression programs. Integrating genome binding and transcriptomic data, we identify that KDM5 regulates the expression of genes required for the function and maintenance of mitochondria, and we find that loss of KDM5 causes morphological changes to mitochondria. This is key to the developmental functions of KDM5, as expression of the mitochondrial biogenesis transcription factor Ets97D, homolog of GABPα, is able to suppress the altered mitochondrial morphology as well as the lethality of Kdm5 null animals. Together, these data establish KDM5-mediated cellular functions that are important for normal development and could contribute to KDM5-linked disorders when dysregulated.