Growth deficiency in a mouse model of Kabuki syndrome 2 bears mechanistic similarities to Kabuki syndrome 1.

Growth deficiency is a characteristic feature of both Kabuki syndrome 1 (KS1) and Kabuki syndrome 2 (KS2), Mendelian disorders of the epigenetic machinery with similar phenotypes but distinct genetic etiologies. We previously described skeletal growth deficiency in a mouse model of KS1 and further established that a Kmt2d-/- chondrocyte model of KS1 exhibits precocious differentiation. Here we characterized growth deficiency in a mouse model of KS2, Kdm6atm1d/+. We show that Kdm6atm1d/+ mice have decreased femur and tibia length compared to controls and exhibit abnormalities in cortical and trabecular bone structure. Kdm6atm1d/+ growth plates are also shorter, due to decreases in hypertrophic chondrocyte size and hypertrophic zone height. Given these disturbances in the growth plate, we generated Kdm6a-/- chondrogenic cell lines. Similar to our prior in vitro model of KS1, we found that Kdm6a-/- cells undergo premature, enhanced differentiation towards chondrocytes compared to Kdm6a+/+ controls. RNA-seq showed that Kdm6a-/- cells have a distinct transcriptomic profile that indicates dysregulation of cartilage development. Finally, we performed RNA-seq simultaneously on Kmt2d-/-, Kdm6a-/-, and control lines at Days 7 and 14 of differentiation. This revealed surprising resemblance in gene expression between Kmt2d-/- and Kdm6a-/- at both time points and indicates that the similarity in phenotype between KS1 and KS2 also exists at the transcriptional level.

Soliciting Social Support from Migrant Domestic Workers' Connections to Storytelling Networks during a Public Health Crisis.

Guided by communication infrastructure theory and social support theory, this study scrutinizes how the storytelling networks of marginalized communities, particularly migrant domestic workers (MDWs), provided social support amid the COVID-19 pandemic. Data obtained from in-depth interviews with 32 Indonesian MDWs in Hong Kong revealed that the community storytelling networks, comprising interpersonal relationships, community organizations, and media outlets, played an essential role in assisting the coping efforts of MDWs during the pandemic. These storytelling networks offered various types of social support, including informational, emotional, and instrumental or tangible assistance. However, these connections to the storytelling networks were also sources of the spread of misinformation. Theoretical and practical implications are further discussed.

MALDI-TOF-MS for Rapid Screening and Typing of ß-Globin Variant and ß-Thalassemia through Direct Measurements of Intact Globin Chains.

BACKGROUND: Traditional phenotype-based screening for ß-globin variant and ß-thalassemia using hematological parameters is time-consuming with low-resolution detection. Development of a MALDI-TOF-MS assay using alternative markers is needed. METHODS: We constructed a MALDI-TOF-MS-based approach for identifying various ß-globin disorders and classifying thalassemia major (TM) and thalassemia intermedia (TI) patients using 901 training samples with known HBB/HBA genotypes. We then validated the accuracy of population screening and clinical classification in 2 separate cohorts consisting of 16 172 participants and 201 ß-thalassemia patients. Traditional methods were used as controls. Genetic tests were considered the gold standard for testing positive specimens. RESULTS: We established a prediction model for identifying different forms of ß-globin disorders in a single MALDI-TOF-MS test based on δ- to ß-globin, γ- to α-globin, γ- to ß-globin ratios, and/or the abnormal globin-chain patterns. Our validation study yielded comparable results of clinical specificity (99.89% vs 99.71%), and accuracy (99.78% vs 99.16%) between the new assay and traditional methods but higher clinical sensitivity for the new method (97.52% vs 88.01%). The new assay identified 22 additional abnormal hemoglobins in 69 individuals including 9 novel ones, and accurately screened for 9 carriers of deletional hereditary persistence of fetal hemoglobin or δß-thalassemia. TM and TI were well classified in 178 samples out of 201 ß-thalassemia patients. CONCLUSIONS: MALDI-TOF-MS is a highly accurate, predictive tool that could be suitable for large-scale screening and clinical classification of ß-globin disorders.

Timing of Adjuvant Radiotherapy After Keloid Excision: A Systematic Review and Meta-Analysis.

BACKGROUND: No consensus exists regarding the appropriate timing of adjuvant radiotherapy administration after surgical excision of keloids. OBJECTIVE: This study investigated the appropriate timing of adjuvant radiotherapy. MATERIALS AND METHODS: A systematic review and meta-analysis of randomized controlled trials and observational cohort studies was performed. A pooled estimate of the incidence rate was performed using a random-effects model. Subgroup analyses based on different anatomic region, biologically effective dose, keloid length, and radiotherapy regimen were also conducted. RESULTS: Sixteen observational cohort studies (1,908 keloid lesions) met the inclusion criteria. The incidence rate was significantly lower in the group treated with electron beam therapy more than 24 hours after surgery (3.80%; 95% confidence interval [CI], 1.78%-8.13%) than that in the group treated with the same therapy within 24 hours of surgery (37.16%; 95% CI, 20.80%-66.37%; p < .0001), but no significant difference was observed between the groups regarding brachytherapy and x-ray treatments. CONCLUSION: Immediate adjuvant radiotherapy did not significantly reduce the incidence rate of recurrent keloids.

Novel Toilet Paper-Based Point-Of-Care Test for the Rapid Detection of Fecal Occult Blood: Instrument Validation Study.

BACKGROUND: Colorectal cancer screening by fecal occult blood testing has been an important public health test and shown to reduce colorectal cancer-related mortality. However, the low participation rate in colorectal cancer screening by the general public remains a problematic public health issue. This fact could be attributed to the complex and unpleasant operation of the screening tool. OBJECTIVE: This study aimed to validate a novel toilet paper-based point-of-care test (ie, JustWipe) as a public health instrument to detect fecal occult blood and provide detailed results from the evaluation of the analytic characteristics in the clinical validation. METHODS: The mechanism of fecal specimen collection by the toilet-paper device was verified with repeatability and reproducibility tests. We also evaluated the analytical characteristics of the test reagents. For clinical validation, we conducted comparisons between JustWipe and other fecal occult blood tests. The first comparison was between JustWipe and typical fecal occult blood testing in a central laboratory setting with 70 fecal specimens from the hospital. For the second comparison, a total of 58 volunteers were recruited, and JustWipe was compared with the commercially available Hemoccult SENSA in a point-of-care setting. RESULTS: Adequate amounts of fecal specimens were collected using the toilet-paper device with small day-to-day and person-to-person variations. The limit of detection of the test reagent was evaluated to be 3.75 µg of hemoglobin per milliliter of reagent. Moreover, the test reagent also showed high repeatability (100%) on different days and high reproducibility (>96%) among different users. The overall agreement between JustWipe and a typical fecal occult blood test in a central laboratory setting was 82.9%. In the setting of point-of-care tests, the overall agreement between JustWipe and Hemoccult SENSA was 89.7%. Moreover, the usability questionnaire showed that the novel test tool had high scores in operation friendliness (87.3/100), ease of reading results (97.4/100), and information usefulness (96.1/100). CONCLUSIONS: We developed and validated a toilet paper-based fecal occult blood test for use as a point-of-care test for the rapid (in 60 seconds) and easy testing of fecal occult blood. These favorable characteristics render it a promising tool for colorectal cancer screening as a public health instrument.

From Moment to Movement: Empowerment and Resilience as a Framework for Collective Action in Hong Kong.

The Transconceptual Model of Empowerment and Resilience (American Journal of Community Psychology, 52, 2013, 333) suggests that a set of resilience and empowerment resources fuel both initial and sustained participation in collective action. Using the case study of a prodemocracy movement in Hong Kong, the present study focused on the subset of those resources that are relevant in ongoing collective action: efficacy, skills, and maintenance. As individuals possess varying combinations of these resources, the present study utilized latent profile analysis to test how patterns of empowerment and resilience resources influence initial and long-term collective action. Five groups were identified: (a) Uncommitted/Uninspired; (b) Committed to Status Quo; (c) Mainstream Populist; (d) Empowered; and (e) Ambivalent. ANOVA and ANCOVA analyses found that there are significant group differences in initial and long-term participation. Groups with higher level of resources reported greater levels of initial participation than their counterparts; however, high resource groups did not uniformly report greater levels of intention to participate in future collective action. Of the maintenance processes tested, collective identity emerged as a particularly important predictor differentiating initial and sustained participation. Findings from the present study raise questions about how individuals with multiple identities can come together and participate in collective action.

Trusting Social Media as a Source of Health Information: Online Surveys Comparing the United States, Korea, and Hong Kong.

BACKGROUND: The Internet has increasingly become a popular source of health information by connecting individuals with health content, experts, and support. More and more, individuals turn to social media and Internet sites to share health information and experiences. Although online health information seeking occurs worldwide, limited empirical studies exist examining cross-cultural differences in perceptions about user-generated, experience-based information compared to expertise-based information sources. OBJECTIVE: To investigate if cultural variations exist in patterns of online health information seeking, specifically in perceptions of online health information sources. It was hypothesized that Koreans and Hongkongers, compared to Americans, would be more likely to trust and use experience-based knowledge shared in social Internet sites, such as social media and online support groups. Conversely, Americans, compared to Koreans and Hongkongers, would value expertise-based knowledge prepared and approved by doctors or professional health providers more. METHODS: Survey questionnaires were developed in English first and then translated into Korean and Chinese. The back-translation method ensured the standardization of questions. Surveys were administered using a standardized recruitment strategy and data collection methods. RESULTS: A total of 826 participants living in metropolitan areas from the United States (n=301), Korea (n=179), and Hong Kong (n=337) participated in the study. We found significant cultural differences in information processing preferences for online health information. A planned contrast test revealed that Koreans and Hongkongers showed more trust in experience-based health information sources (blogs: t451.50=11.21, P<.001; online support group: t455.71=9.30, P<.001; social networking sites [SNS]: t466.75=11.36, P<.001) and also reported using blogs (t515.31=6.67, P<.001) and SNS (t529.22=4.51, P<.001) more frequently than Americans. Americans showed a stronger preference for using expertise-based information sources (eg, WebMD and CDC) compared to Koreans and Hongkongers (t360.02=3.01, P=.003). Trust in expertise-based information sources was universal, demonstrating no cultural differences (Brown-Forsythe F2,654=1.82, P=.16). Culture also contributed significantly to differences in searching information on behalf of family members (t480.38=5.99, P<.001) as well as to the goals of information searching. CONCLUSIONS: This research found significant cultural differences in information processing preferences for online health information. Further discussion is included regarding effective communication strategies in providing quality health information.

Jaypatient-induced service sabotage behavior: the issue of self-esteem of hospital nurses.

Worrying incidents exist where disgruntled nurses destroy good service quality through sabotage behavior. Previous studies report the organizational and environmental factors that might lead to service sabotage behaviors; here individual differences in proclivity to service sabotage within any given environment of managerial context are reported. The study first uses interviews to establish typologies of difficult patients. Regression analysis and ANOVA applied to survey data shows that low self-esteem in nurses leads to service sabotage behavior, and that these nurses are less mature both chronologically and emotionally, less experienced, and less educated than their more typical counterparts.

Ferroptosis in Glaucoma: A Promising Avenue for Therapy.

Glaucoma, a blind-leading disease largely since chronic pathological intraocular high pressure (ph-IOP). Hitherto, it is reckoned incurable for irreversible neural damage and challenges in managing IOP. Thus, it is significant to develop neuroprotective strategies. Ferroptosis, initially identified as an iron-dependent regulated death that triggers Fenton reactions and culminates in lipid peroxidation (LPO), has emerged as a focal point in multiple tumors and neurodegenerative diseases. Researches show that iron homeostasis play critical roles in the optic nerve (ON) and retinal ganglion cells (RGCs), suggesting targeted treatments could be effective. In glaucoma, apart from neural lesions, disrupted metal balance and increased oxidative stress in trabecular meshwork (TM) are observed. These disturbances lead to extracellular matrix excretion disorders, known as sclerotic mechanisms, resulting in refractory blockages. Importantly, oxidative stress, a significant downstream effect of ferroptosis, is also a key factor in cell senescence. It plays a crucial role in both the etiology and risk of glaucoma. Moreover, ferroptosis also induces non-infectious inflammation, which exacerbate glaucomatous injury. Therefore, the relevance of ferroptosis in glaucoma is extensive and multifaceted. In this review, the study delves into the current understanding of ferroptosis mechanisms in glaucoma, aiming to provide clues to inform clinical therapeutic practices.

Integrating Artificial Intelligence for Advancing Multiple-Cancer Early Detection via Serum Biomarkers: A Narrative Review.

The concept and policies of multicancer early detection (MCED) have gained significant attention from governments worldwide in recent years. In the era of burgeoning artificial intelligence (AI) technology, the integration of MCED with AI has become a prevailing trend, giving rise to a plethora of MCED AI products. However, due to the heterogeneity of both the detection targets and the AI technologies, the overall diversity of MCED AI products remains considerable. The types of detection targets encompass protein biomarkers, cell-free DNA, or combinations of these biomarkers. In the development of AI models, different model training approaches are employed, including datasets of case-control studies or real-world cancer screening datasets. Various validation techniques, such as cross-validation, location-wise validation, and time-wise validation, are used. All of the factors show significant impacts on the predictive efficacy of MCED AIs. After the completion of AI model development, deploying the MCED AIs in clinical practice presents numerous challenges, including presenting the predictive reports, identifying the potential locations and types of tumors, and addressing cancer-related information, such as clinical follow-up and treatment. This study reviews several mature MCED AI products currently available in the market, detecting their composing factors from serum biomarker detection, MCED AI training/validation, and the clinical application. This review illuminates the challenges encountered by existing MCED AI products across these stages, offering insights into the continued development and obstacles within the field of MCED AI.

A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition.

Weaver syndrome is a Mendelian disorder of the epigenetic machinery (MDEM) caused by germline pathogenic variants in EZH2, which encodes the predominant H3K27 methyltransferase and key enzymatic component of Polycomb repressive complex 2 (PRC2). Weaver syndrome is characterized by striking overgrowth and advanced bone age, intellectual disability, and distinctive facies. We generated a mouse model for the most common Weaver syndrome missense variant, EZH2 p.R684C. Ezh2R684C/R684C mouse embryonic fibroblasts (MEFs) showed global depletion of H3K27me3. Ezh2R684C/+ mice had abnormal bone parameters, indicative of skeletal overgrowth, and Ezh2R684C/+ osteoblasts showed increased osteogenic activity. RNA-Seq comparing osteoblasts differentiated from Ezh2R684C/+, and Ezh2+/+ BM-mesenchymal stem cells (BM-MSCs) indicated collective dysregulation of the BMP pathway and osteoblast differentiation. Inhibition of the opposing H3K27 demethylases KDM6A and KDM6B substantially reversed the excessive osteogenesis in Ezh2R684C/+ cells both at the transcriptional and phenotypic levels. This supports both the ideas that writers and erasers of histone marks exist in a fine balance to maintain epigenome state and that epigenetic modulating agents have therapeutic potential for the treatment of MDEMs.

Long-Term Outcomes of Sacubitril/Valsartan in Heart Failure with Reduced Ejection Fraction and Coexisting End-Stage Renal Disease.

Sacubitril/valsartan (Entresto) has proven therapeutic effects in heart failure (HF) patients, but its impact on those with advanced chronic kidney disease (CKD) remains unclear, particularly in HF patients with coexisting end-stage renal disease (ESRD). This study aims to assess the long-term survival of patients with heart failure with reduced ejection fraction (HFrEF) and coexisting ESRD treated with sacubitril/valsartan. A retrospective cohort study included 2,860 HFrEF and ESRD patients between January 2008 and December 2020. After propensity score matching, data from a sacubitril/valsartan group (n = 61) and a candesartan or valsartan group (n = 117) were analyzed. Patients on sacubitril/valsartan for at least 9 months had significantly lower 5-year all-cause mortality (39.3%) compared with the non-sacubitril/valsartan group (54.7%) (HR 0.46; 95% CI, 0.25-0.82; P = 0.0094). Left ventricular ejection fraction (LVEF) improvement after 3 years in the sacubitril/valsartan group (14.51 ±18.98) was significantly greater than the non-sacubitril/valsartan group (6.91 ±18.44) (P = 0.0408). Average hospitalizations in sacubitril/valsartan and non-sacubitril/valsartan groups were 1.39 and 0.97, respectively (incidence rate ratio, 1.59; 95% CI, 0.90-2.82; P = 0.1106). Sacubitril/valsartan treatment demonstrated significantly lower 5-year mortality rates and greater LVEF improvement in HFrEF patients with coexisting ESRD compared with candesartan or valsartan. These findings suggest that sacubitril/valsartan is a beneficial treatment option for this patient population.

TBK1-associated protein in endolysosomes (TAPE)/CC2D1A is a key regulator linking RIG-I-like receptors to antiviral immunity.

Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are key RNA viral sensors for triggering antiviral immunity. The underlying mechanisms for RLRs to trigger antiviral immunity have yet to be explored. Here we report the identification of TAPE (TBK1-associated protein in endolysosomes) as a novel regulator of the RLR pathways. TAPE functionally and physically interacts with RIG-I, MDA5, and IPS-1 to activate the IFN-ß promoter. TAPE knockdown impairs IFN-ß activation induced by RLRs but not IPS-1. TAPE-deficient cells are defective in cytokine production upon RLR ligand stimulation. During RNA virus infection, TAPE knockdown or deficiency diminishes cytokine production and antiviral responses. Our data demonstrate a critical role for TAPE in linking RLRs to antiviral immunity.

Ischemic preconditioning reduces neurovascular damage after hypoxia-ischemia via the cellular inhibitor of apoptosis 1 in neonatal brain.

BACKGROUND AND PURPOSE: The neurovascular unit is a major target of hypoxia-ischemia (HI) injury in the neonatal brain. Although neurons are the cellular target of ischemic preconditioning (IP), vessel tolerance also contributes greatly to protection. Nerves and vessels cross-talk and use common signals during development. Cellular inhibitor of apoptosis 1 (cIAP1) is an important regulator that inhibits apoptosis. This study hypothesized that cIAP1 is a shared molecule underlying IP-mediated neurovascular protection against HI in the neonatal brain. METHODS: In vivo IP was induced by 2-hour reversible occlusion of right carotid artery 24 hours before HI on postpartum day 7 in rat pups. In vitro oxygen-glucose deprivation (OGD) preconditioning was established in SH-SY5Y neuronal cells and in human microvascular endothelial cell-1 vascular endothelial cells. cIAP1 expression was inhibited by cIAP1 small interfering RNA in vivo or by lentivirus-mediated short hairpin RNA in vitro, or was upregulated by the lentiviral expression system. RESULTS: IP reduced apoptosis, selectively increased cIAP1 in neurons and vascular endothelial cells, and provided long-term neuroprotection against HI. Intracerebroventricular delivery of cIAP1 small interfering RNA significantly attenuated IP-mediated cIAP1 upregulation and neuroprotection in vivo. In vitro, OGD preconditioning induced cIAP1 and protected against OGD cell death in SH-SY5Y neuronal and human microvascular endothelial cells-1. Knockdown of cIAP1 by lentivirus-mediated short hairpin RNA decreased the protective effect of OGD preconditioning in SH-SY5Y and human microvascular endothelial cell-1, whereas overexpression of cIAP1 by lentivirus protected against OGD in these cells. CONCLUSIONS: cIAP1 is a shared molecule underlying IP-induced protection in neurons and vascular endothelial cells against HI in the neonatal brain.

Biomechanical study of the male lower urinary tract: Simulation of internal and external sphincters dyssynergia.

Urethral sphincter dysfunction is an important cause of stress urinary incontinence (SUI). The most effective treatment is the insertion of an artificial urethral sphincter (AUS), which relies to a large extent on the surgeon's experience. However, there is no quantitative standard for cuff tightness, resulting in frequent postoperative complications. This study aimed to investigate the effect of internal and external sphincter dyssynergia on urodynamic parameters in the lower urinary tract. A geometric model of male lower urinary tract tissue was constructed from collodion slices, accounting for the active behavior of the internal and external sphincters. Normal and dyssynergic internal and external sphincters (active sphincter behavior was individually injured by 25%, 50%, 75%, or 100%) were simulated with fluid-structure interactions and changes in urethral stress, displacement, and urine flow rate were detected. We found that when the internal sphincter was injured by 25%, 50%, 75%, and 100%, urethral stress near the internal sphincter decreased by 8.3%, 15.6%, 24.3%, and 35.7%, respectively. Additionally, when the external sphincter was injured by 25%, 50%, 75%, and 100%, urethral stress near the external sphincter was reduced by 13.3%, 24.3%, 38.6%, and 46.6%, respectively. Internal sphincter injury primarily affects positions near the internal sphincter and prostate, while external sphincter injury affects the area between the prostate and urethral outlet. These data could facilitate the standardized evaluation of internal and external sphincter dysfunction and lead to novel methods of preoperative assessment for AUS surgery.

Alternate Antimicrobial Therapies and Their Companion Tests.

New antimicrobial approaches are essential to counter antimicrobial resistance. The drug development pipeline is exhausted with the emergence of resistance, resulting in unsuccessful trials. The lack of an effective drug developed from the conventional drug portfolio has mandated the introspection into the list of potentially effective unconventional alternate antimicrobial molecules. Alternate therapies with clinically explicable forms include monoclonal antibodies, antimicrobial peptides, aptamers, and phages. Clinical diagnostics optimize the drug delivery. In the era of diagnostic-based applications, it is logical to draw diagnostic-based treatment for infectious diseases. Selection criteria of alternate therapeutics in infectious diseases include detection, monitoring of response, and resistance mechanism identification. Integrating these diagnostic applications is disruptive to the traditional therapeutic development. The challenges and mitigation methods need to be noted. Applying the goals of clinical pharmacokinetics that include enhancing efficacy and decreasing toxicity of drug therapy, this review analyses the strong correlation of alternate antimicrobial therapeutics in infectious diseases. The relationship between drug concentration and the resulting effect defined by the pharmacodynamic parameters are also analyzed. This review analyzes the perspectives of aligning diagnostic initiatives with the use of alternate therapeutics, with a particular focus on companion diagnostic applications in infectious diseases.

Antibiotic Resistance Diagnosis in ESKAPE Pathogens-A Review on Proteomic Perspective.

Antibiotic resistance has emerged as an imminent pandemic. Rapid diagnostic assays distinguish bacterial infections from other diseases and aid antimicrobial stewardship, therapy optimization, and epidemiological surveillance. Traditional methods typically have longer turn-around times for definitive results. On the other hand, proteomic studies have progressed constantly and improved both in qualitative and quantitative analysis. With a wide range of data sets made available in the public domain, the ability to interpret the data has considerably reduced the error rates. This review gives an insight on state-of-the-art proteomic techniques in diagnosing antibiotic resistance in ESKAPE pathogens with a future outlook for evading the "imminent pandemic".

Association between statin use and risk of gallstone disease and cholecystectomy: a meta-analysis of 590,086 patients.

Background: Statins have been reported to reduce the risk of gallstone disease. However, the impacts of different durations of statin use on gallstone disease have not been clarified. The aim of this study is toperform a systematic review with meta-analysis to update and to elucidate the association between statin use and the risk of gallstone disease and cholecystectomy. Methods: Medline, Embase and Cochrane Library were searched from the inception until August 2022 for relevant articles investigating the difference in the risk of gallstone disease between statin users and non-users (PROSPERO, ID: CRD42020182445). Meta-analyses were conducted using odds ratios (ORs) with corresponding 95% confidence intervals (CIs) to compare the risk of gallstone disease and cholecystectomy between statin user and nonusers. Results: Eight studies enrolling 590,086 patients were included. Overall, the use of statins was associated with a marginally significant lower risk of gallstone disease than nonusers (OR, 0.91; 95% CI [0.82-1.00]). Further subgroup analysis showed that short-term users, medium-term users, and long-term users were associated with a significantly higher risk (OR, 1.18; 95% CI [1.11-1.25]), comparable risk (OR, 0.93; 95% CI [0.83-1.04]), and significantly lower risk of gallstone diseases (OR, 0.78; 95% CI [0.68-0.90]) respectively, compared to nonusers. Conclusions: Patients with medium-term or long-term use of statins without discontinuation are at a lower risk of gallstone disease or cholecystectomy.

Novel mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition.

Weaver syndrome is a Mendelian disorder of the epigenetic machinery (MDEM) caused by germline pathogenic variants in EZH2, which encodes the predominant H3K27 methyltransferase and key enzymatic component of Polycomb repressive complex 2 (PRC2). Weaver syndrome is characterized by striking overgrowth and advanced bone age, intellectual disability, and distinctive facies. We generated a mouse model for the most common Weaver syndrome missense variant, EZH2 p.R684C. Ezh2R684C/R684C mouse embryonic fibroblasts (MEFs) showed global depletion of H3K27me3. Ezh2R684C/+ mice had abnormal bone parameters indicative of skeletal overgrowth, and Ezh2R684C/+ osteoblasts showed increased osteogenic activity. RNA-seq comparing osteoblasts differentiated from Ezh2R684C/+ and Ezh2+/+ bone marrow mesenchymal stem cells (BM-MSCs) indicated collective dysregulation of the BMP pathway and osteoblast differentiation. Inhibition of the opposing H3K27 demethylases Kdm6a/6b substantially reversed the excessive osteogenesis in Ezh2R684C/+ cells both at the transcriptional and phenotypic levels. This supports both the ideas that writers and erasers of histone marks exist in a fine balance to maintain epigenome state, and that epigenetic modulating agents have therapeutic potential for the treatment of MDEMs.