SET1 and p300 act synergistically, through coupled histone modifications, in transcriptional activation by p53.

The H3K4me3 mark in chromatin is closely correlated with actively transcribed genes, although the mechanisms involved in its generation and function are not fully understood. In vitro studies with recombinant chromatin and purified human factors demonstrate a robust SET1 complex (SET1C)-mediated H3K4 trimethylation that is dependent upon p53- and p300-mediated H3 acetylation, a corresponding SET1C-mediated enhancement of p53- and p300-dependent transcription that reflects a primary effect of SET1C through H3K4 trimethylation, and direct SET1C-p53 and SET1C-p300 interactions indicative of a targeted recruitment mechanism. Complementary cell-based assays demonstrate a DNA-damage-induced p53-SET1C interaction, a corresponding enrichment of SET1C and H3K4me3 on a p53 target gene (p21/WAF1), and a corresponding codependency of H3K4 trimethylation and transcription upon p300 and SET1C. These results establish a mechanism in which SET1C and p300 act cooperatively, through direct interactions and coupled histone modifications, to facilitate the function of p53.

Variant patterns of electrical activation and recovery in normal human hearts revealed by noninvasive electrocardiographic imaging.

AIMS: Although electrical activity of the normal human heart is well characterized by the electrocardiogram, detailed insights into within-subject and between-subject variations of ventricular activation and recovery by noninvasive electroanatomic mapping are lacking. We characterized human epicardial activation and recovery within and between normal subjects using non-invasive electrocardiographic imaging (ECGI) as a basis to better understand pathology. METHODS AND RESULTS: Epicardial activation and recovery were assessed by ECGI in 22 normal subjects, 4 subjects with bundle branch block (BBB) and 4 with long-QT syndrome (LQTS). We compared characteristics between the ventricles [left ventricle (LV) and right ventricle (RV)], sexes, and age groups (<50/≥50years). Pearson's correlation coefficient (CC) was used for within-subject and between-subject comparisons. Age of normal subjects averaged 49 ± 14 years, 6/22 were male, and no structural/electrical heart disease was present. The average activation time was longer in LV than in RV, but not different by sex or age. Electrical recovery was similar for the ventricles, but started earlier and was on average shorter in males. Median CCs of between-subject comparisons of the ECG signals, activation, and recovery patterns were 0.61, 0.32, and 0.19, respectively. Within-subject beat-to-beat comparisons yielded higher CCs (0.98, 0.89, and 0.82, respectively). Activation and/or recovery patterns of patients with BBB or LQTS contrasted significantly with those found in the normal population. CONCLUSION: Activation and recovery patterns vary profoundly between normal subjects, but are stable individually beat to beat, with a male preponderance to shorter recovery. Individual characterization by ECGI at baseline serves as reference to better understand the emergence, progression, and treatment of electrical heart disease.

Evaluation of Pm2.5 Influence on Human Lung Cancer Cells Using a Microfluidic Platform.

In this study, we developed a microfluidic device that is able to monitor cell biology under continuous PM2.5 treatment. The effects of PM2.5 on human alveolar basal epithelial cells, A549 cells, and uncovered several significant findings were investigated. The results showed that PM2.5 exposure did not lead to a notable decrease in cell viability, indicating that PM2.5 did not cause cellular injury or death. However, the study found that PM2.5 exposure increased the invasion and migration abilities of A549 cells, suggesting that PM2.5 might promote cell invasiveness. Results of RNA sequencing revealed 423 genes that displayed significant differential expression in response to PM2.5 exposure, with a particular focus on pathways associated with the generation of reactive oxygen species (ROS) and mitochondrial dysfunction. Real-time detection demonstrated an increase in ROS production in A549 cells after exposure to PM2.5. JC1 assay, which indicated a loss of mitochondrial membrane potential (ΔΨm) in A549 cells exposed to PM2.5. The disruption of mitochondrial membrane potential further supports the detrimental effects of PM2.5 on A549 cells. These findings highlight several adverse effects of PM2.5 on A549 cells, including enhanced invasion and migration capabilities, altered gene expression related to ROS pathways, increased ROS production and disruption of mitochondrial membrane potential. These findings contribute to our understanding of the potential mechanisms through which PM2.5 can impact cellular function and health.

Patient Education Materials for Immobilisation Masks in Radiation Therapy for Adult Head and Neck Cancer Patients: A Scoping Review.

Immobilisation masks (IMs) are used for people with head and neck cancer (HNC) undergoing radiation therapy (RT) treatment to ensure accuracy and reproducibility between treatments. Claustrophobia-related mask anxiety in HNC patients is common and can compromise treatment due to patient distress. This scoping review aimed to describe the content of publicly available Patient Education Materials (PEMs) for people with HNC undergoing RT. Three search engines (Bing, Yahoo, and Google) were systematically searched using standard terms. PEMs in audio-visual or written formats were eligible for inclusion if the target readership was adults with HNC and included content on IMs for RT. Content was appraised using the Patient Education Materials Assessment Tool for Printable and Audio-Visual Materials to assess understandability and actionability. In total, 304 PEMs were identified of which 20 met the inclusion criteria. Sixteen PEMs were webpages, three were PDF format, and one was a standalone video. The understandability and actionability of PEMs ranged between 47 to 100% and 0 to 80%, respectively. PEMs authored by Foundations/Organisations scored higher in understandability (80-100%) and were more likely to discuss mask anxiety coping strategies. In comparison, News sites and IM manufacturers published PEMs with the lowest understandability scores (20-80%). The significant variations in the quality of IM PEMs identified suggest that some sources may be more effective at informing patients about IMs. Although multiple aspects of the PEMs were consistent across the reviewed materials, many PEMs lacked information, and a stronger focus on understandability and actionability is required.

Metabolites from Streptomyces aureus (VTCC43181) and Their Inhibition of Mycobacterium tuberculosis ClpC1 Protein.

Tuberculosis is one of the most common infectious diseases in the world, caused by Mycobacterium tuberculosis. The outbreak of multiple drug-resistant tuberculosis has become a major challenge to prevent this disease worldwide. ClpC1 is a Clp ATPase protein of Mycobacterium tuberculosis, functioning as a chaperon when combined with the Clp complex. ClpC1 has emerged as a new target to discover anti-tuberculosis drugs. This study aimed to explore the ClpC1 inhibitors from actinomycetes, which have been known to provide abundant sources of antibiotics. Two cyclic peptides, including nocardamin (1), halolitoralin A (3), and a lactone pleurone (2), were isolated from the culture of Streptomyces aureus (VTCC43181). The structures of these compounds were determined based on the detailed analysis of their spectral data and comparison with references. This is the first time these compounds have been isolated from S. aureus. Compounds 1-3 were evaluated for their affection of ATPase activity of the recombinant ClpC1 protein. Of these compounds, halolitoralin A (1), a macrocyclic peptide, was effective for the ATPase hydrolysis of the ClpC1 protein.

LBD18 and IAA14 antagonistically interact with ARF7 via the invariant Lys and acidic residues of the OPCA motif in the PB1 domain.

MAIN CONCLUSION: LBD18 and IAA14 antagonistically interact with ARF7 through the electrostatic faces in the ARF7PB1 domain, modulating ARF7 transcriptional activity. Auxin Response Factor 7 (ARF7)/ARF19 control lateral root development by directly activating Lateral Organ Boundaries Domain 16 (LBD16)/LBD18 genes in Arabidopsis. LBD18 upregulates ARF19 expression by binding to the ARF19 promoter. It also interacts with ARF7 through the Phox and Bem1 (PB1) domain to enhance the ARF7 transcriptional activity, forming a dual mode of positive feedback loop. LBD18 competes with the repressor indole-3-acetic acid 14 (IAA14) for ARF7 binding through the PB1 domain. In this study, we examined the molecular determinant of the ARF7 PB1 domain for interacting with LBD18 and showed that the electronic faces in the ARF7 PB1 domain are critical for interacting with LBD18 and IAA14/17. We used a luminescence complementation imaging assay to determine protein-protein interactions. The results showed that mutation of the invariant lysine residue and the OPCA motif in the PB1 domain in ARF7 significantly reduces the protein interaction between ARF7 and LBD18. Transient gene expression assays with Arabidopsis protoplasts showed that IAA14 suppressed transcription-enhancing activity of LBD18 on the LUC reporter gene fused to the ARF19 promoter harboring an auxin response element, but mutation of the invariant lysine residue and OPCA motif in the PB1 domain of IAA14 reduced the repression capability of IAA14 for transcription-enhancing activity of LBD18. We further showed that the same mutation in the PB1 domain of IAA14 reduces its repression capability, thereby increasing the LUC activity induced by both ARF7 and LBD18 compared with IAA14. These results suggest that LBD18 competes with IAA14 for ARF7 binding via the electrostatic faces of the ARF7 PB1 domain to modulate ARF7 transcriptional activity.

Moderation effects of serotype on dengue severity across pregnancy status in Mexico.

BACKGROUND: Pregnancy increases a woman's risk of severe dengue. To the best of our knowledge, the moderation effect of the dengue serotype among pregnant women has not been studied in Mexico. This study explores how pregnancy interacted with the dengue serotype from 2012 to 2020 in Mexico. METHOD: Information from 2469 notifying health units in Mexican municipalities was used for this cross-sectional analysis. Multiple logistic regression with interaction effects was chosen as the final model and sensitivity analysis was done to assess potential exposure misclassification of pregnancy status. RESULTS: Pregnant women were found to have higher odds of severe dengue [1.50 (95% CI 1.41, 1.59)]. The odds of dengue severity varied for pregnant women with DENV-1 [1.45, (95% CI 1.21, 1.74)], DENV-2 [1.33, (95% CI 1.18, 1.53)] and DENV-4 [3.78, (95% CI 1.14, 12.59)]. While the odds of severe dengue were generally higher for pregnant women compared with non-pregnant women with DENV-1 and DENV-2, the odds of disease severity were much higher for those infected with the DENV-4 serotype. CONCLUSION: The effect of pregnancy on severe dengue is moderated by the dengue serotype. Future studies on genetic diversification may potentially elucidate this serotype-specific effect among pregnant women in Mexico.

ISWI chromatin remodellers sense nucleosome modifications to determine substrate preference.

ATP-dependent chromatin remodellers regulate access to genetic information by controlling nucleosome positions in vivo. However, the mechanism by which remodellers discriminate between different nucleosome substrates is poorly understood. Many chromatin remodelling proteins possess conserved protein domains that interact with nucleosomal features. Here we used a quantitative high-throughput approach, based on the use of a DNA-barcoded mononucleosome library, to profile the biochemical activity of human ISWI family remodellers in response to a diverse set of nucleosome modifications. We show that accessory (non-ATPase) subunits of ISWI remodellers can distinguish between differentially modified nucleosomes, directing remodelling activity towards specific nucleosome substrates according to their modification state. Unexpectedly, we show that the nucleosome acidic patch is necessary for maximum activity of all ISWI remodellers evaluated. This dependence also extends to CHD and SWI/SNF family remodellers, suggesting that the acidic patch may be generally required for chromatin remodelling. Critically, remodelling activity can be regulated by modifications neighbouring the acidic patch, signifying that it may act as a tunable interaction hotspot for ATP-dependent chromatin remodellers and, by extension, many other chromatin effectors that engage this region of the nucleosome surface.

Physician-level determinants of HCV screening during pregnancy in a U.S. sample.

PURPOSE: The purpose of this study was to assess the association between select determinants and HCV screening guideline adherence among physicians who provide prenatal care. RESEARCH QUESTION: What factors may act as determinants of guideline adherence to HCV screening among physicians who provide prenatal care? METHODS: We surveyed a national sample of physicians who provided prenatal care in 2021. The survey included questions from the Clinician Guideline Determinant (CGD) questionnaire, demographic characteristics, and medical practice characteristics. We estimated odds ratios and 95% confidence intervals (CIs) using semi-Bayesian logistic regression for the association between determinants and guideline adherence. RESULTS: Participants included 224 physicians in the United States who reported providing prenatal care. Most physicians practiced in private practice (65%) and the majority were members of the American College of Obstetricians and Gynecologists (ACOG; 91%). Less than half (43%; 95% CI: 36%-49%) of physicians reported regular use of the HCV screening guideline. Physicians who reported general knowledge about HCV (OR = 9.0, 95% CI 3.1-30) or endorsed agreement with ease of implementation (OR = 8.0, 95% CI 2.7-25) had higher odds of adherence to the HCV screening guideline. CONCLUSION: Our study suggests that less than half of practicing prenatal care physicians adhere to HCV screening guidelines for pregnant patients. Our results may be useful as a preliminary screening of select determinants of guideline use for further investigation.

University lecturers' conceptions of online teaching in distance education courses in Vietnamese higher education.

This study aimed to characterise academics' conceptions of teaching in fully online undergraduate distance education courses with no on-campus component. The study aimed to fill a gap in the literature, as previous research had examined conceptions of teaching in face-to-face courses, with a few studies of blended teaching via the Internet in on-campus courses. Fourteen academics from five faculties in a Vietnamese regional university were interviewed, with the study taking place shortly after the outbreak of Covid-19. Grounded theory was used for data analysis. The results revealed four categories of conceptions of online teaching, namely online teaching (1) as transmitting structured knowledge and skills, (2) as guiding students to acquire knowledge and skills, (3) as facilitating students' understanding via interaction and (4) as developing students' understanding and capabilities. The four categories of conceptions were defined and distinguished by a set of six dimensions, which included e-Learning/LMS. The set of categories had some similarities to those found for face-to-face teaching, but also some distinctions which could be explained by the nature of online teaching and learning. The study, therefore, makes a major contribution by establishing a category scheme for conceptions of teaching in online distance education, with detailed characterisation of the four categories of conceptions. The descriptors of the conceptions showed cultural influences, particularly from a Confucian heritage, which is of significance as research into face-to-face conceptions had not found cultural variations.

Use of Cold-Stored Whole Blood is Associated With Improved Mortality in Hemostatic Resuscitation of Major Bleeding: A Multicenter Study.

OBJECTIVE: The aim of this study was to identify a mortality benefit with the use of whole blood (WB) as part of the resuscitation of bleeding trauma patients. BACKGROUND: Blood component therapy (BCT) is the current standard for resuscitating trauma patients, with WB emerging as the blood product of choice. We hypothesized that the use of WB versus BCT alone would result in decreased mortality. METHODS: We performed a 14-center, prospective observational study of trauma patients who received WB versus BCT during their resuscitation. We applied a generalized linear mixed-effects model with a random effect and controlled for age, sex, mechanism of injury (MOI), and injury severity score. All patients who received blood as part of their initial resuscitation were included. Primary outcome was mortality and secondary outcomes included acute kidney injury, deep vein thrombosis/pulmonary embolism, pulmonary complications, and bleeding complications. RESULTS: A total of 1623 [WB: 1180 (74%), BCT: 443(27%)] patients who sustained penetrating (53%) or blunt (47%) injury were included. Patients who received WB had a higher shock index (0.98 vs 0.83), more comorbidities, and more blunt MOI (all P <0.05). After controlling for center, age, sex, MOI, and injury severity score, we found no differences in the rates of acute kidney injury, deep vein thrombosis/pulmonary embolism or pulmonary complications. WB patients were 9% less likely to experience bleeding complications and were 48% less likely to die than BCT patients ( P <0.0001). CONCLUSIONS: Compared with BCT, the use of WB was associated with a 48% reduction in mortality in trauma patients. Our study supports the use of WB use in the resuscitation of trauma patients.

Emergence of amoxicillin resistance and identification of novel mutations of the pbp1A gene in Helicobacter pylori in Vietnam.

BACKGROUND: Amoxicillin-resistant Helicobacter pylori (H. pylori) strains seem to have increased over time in Vietnam. This threatens the effectiveness of H. pylori eradication therapies with this antibiotic. This study aimed to investigate the prevalence of primary resistance of H. pylori to amoxicillin and to assess its association with pbp1A point mutations in Vietnamese patients. MATERIALS AND METHODS: Naive patients who presented with dyspepsia undergoing upper gastrointestinal endoscopy were recruited. Rapid urease tests and PCR assays were used to diagnose H. pylori infection. Amoxicillin susceptibility was examined by E-tests. Molecular detection of the mutant pbp1A gene conferring amoxicillin resistance was carried out by real-time PCR followed by direct sequencing of the PCR products. Phylogenetic analyses were performed using the Tamura-Nei genetic distance model and the neighbor-joining tree building method. RESULTS: There were 308 patients (46.1% men and 53.9% women, p = 0.190) with H. pylori infection. The mean age of the patients was 40.5 ± 11.4 years, ranging from 18 to 74 years old. The E-test was used to determine the susceptibility to amoxicillin (minimum inhibitory concentration (MIC) ≤ 0.125 µg/ml) in 101 isolates, among which the rate of primarily resistant strains to amoxicillin was 25.7%. Then, 270 sequences of pbp1A gene fragments were analysed. There were 77 amino acid substitution positions investigated, spanning amino acids 310-596, with the proportion varying from 0.4 to 100%. Seven amino acid changes were significantly different between amoxicillin-sensitive (AmoxS) and amoxicillin-resistant (AmoxR) samples, including Phe366 to Leu (p <  0.001), Ser414 to Arg (p <  0.001), Glu/Asn464-465 (p = 0.009), Val469 to Met (p = 0.021), Phe473 to Val (p <  0.001), Asp479 to Glu (p = 0.044), and Ser/Ala/Gly595-596 (p = 0.001). Phylogenetic analyses suggested that other molecular mechanisms might contribute to amoxicillin resistance in H. pylori in addition to the alterations in PBP1A. CONCLUSIONS: We reported the emergence of amoxicillin-resistant Helicobacter pylori strains in Vietnam and new mutations statistically associated with this antimicrobial resistance. Additional studies are necessary to identify the mechanisms contributing to this resistance in Vietnam.

Predictors of COVID-19 vaccine acceptability among health professions students in Vietnam.

BACKGROUND: The COVID-19 vaccine hesitancy or refusal has actually been a threat to global health. In the current situation, health professions students are at risk for SARS-CoV-2 infection during their internship at healthcare facilities. Furthermore, those future healthcare workers will advise people to accept the COVID-19 vaccination. Therefore, the attitude of students towards vaccine acceptance and the predicting factors needs to be elucidated. This study applied the Health Belief Model to determine predictors of COVID-19 vaccine acceptability among health professions students. METHODS: Nine hundred eleven students participated in a cross-sectional online survey in Vietnam. Data were collected from 1st April to 30th June 2021. Data analysis was performed using SPSS software version 20.0 with Chi-square and Kruskal-Wallis tests before executing multinomial logistic regression to identify predictors of the COVID-19 vaccine acceptability RESULTS: The overall vaccine acceptance, hesitancy, and refusal rates were 58% (95% CI: 54.7% - 61.3%), 40.4% (95% CI: 37.2% - 43.7%) and 1.5% (95% CI: 0.8% - 2.6%), respectively. Regarding vaccination hesitancy, a predictor such as "Receiving recent flu shots" had a negative correlation, whereas "Vaccines have little efficacy & serious adverse effects" (Perceived barriers), nationality, and majors were positive correlates. For refusal, "Unvaccinated students feasibly infected COVID-19 during hospital internship" (Perceived susceptibility) was a negative correlate. For predicting both hesitancy and refusal, "Mass media appreciating effectiveness and safety of vaccines" (Cues to action), and " Health professions students get serious complications of COVID-19 if not vaccinated" (Perceived severity) were negative predictors. In contrast, "Manufacturers do not disclose adverse effects of vaccines" (Cues to action), and "Adverse effect causes death" (Perceived barrier) were recognized as positive predictors. Strong Health Belief Model predictors of vaccine refusal were "Manufacturers do not disclose adverse effects of vaccines" (Cues to action) with OR= 5.299(95% CI: 1.687-16.641, p= 0.004), and "Adverse effect causes death" (Perceived barrier) with OR= 10.255 (95% CI = 3.528-29.814, p= 0.0005). CONCLUSION: Health professions students' acceptability of COVID-19 vaccination might be based on the perceived susceptibility to and severity of COVID-19, concerns about vaccine efficacy and safety, and the influence levels of information from various sources. Health education and measures to prevent the harmful effects of COVID-19 vaccine misinformation could potentially improve the acceptance rate of the COVID-19 vaccine.

1-year trajectories of patients undergoing primary total hip arthroplasty: Patient reported outcomes and resource needs according to education level.

BACKGROUND: Objectives were first to evaluate by education level one-year trajectories of pain, function and general health, as well as hospital resource and medication needs in patients undergoing primary total hip arthroplasty (THA); and second, to evaluate whether outcome differences are related to existing baseline differences in health and disease severity. METHODS: We included all primary THAs from a public hospital-based prospective arthroplasty registry, performed in a high-income country 2010 to 2017. Education was classified in three levels: ≤8years of schooling (low), 9-12years (medium), and ≥13years (high). Pain and function prior to and one-year after surgery were assessed with the Western Ontario McMaster Universities score (WOMAC) and general health with the 12-item short-form health survey (SF-12). RESULTS: Overall 963 patients were included, 340 (35.3%) with low, 306 (31.8%) with medium, and 317 (32.9%) with high education. With increasing educational level preoperative scores for pain, function and SF-12 mental health component increased. One year after surgery improvement was observed in all education categories for WOMAC pain and function, SF-12 mental and physical component. However, absolute postoperative scores remained lower in all four domains for the low education group. After adjustment for baseline characteristics differences were much attenuated and no longer significant. There was also greater resource need in low educated patients. CONCLUSIONS: The inferior absolute results one year after surgery in less educated patients were largely due to older age, worse preoperative health and greater symptom severity calling for greater attention to timely and equal management, for more targeted perioperative care and increased support for the lower education group.

Spatiotemporal approximation of cardiac activation and recovery isochrones.

BACKGROUND: The sequence of myocardial activation and recovery can be studied in detail by invasive catheter recordings of cardiac electrograms (EGMs), or noninvasive inverse reconstructions thereof with electrocardiographic imaging (ECGI). Local activation and recovery times are obtained from a unipolar EGM by the moment of maximum downslope of the QRS complex or maximum upslope of the T wave, respectively. However, both invasive and noninvasive recordings of intracardiac EGMs may suffer from noise and fractionation, making reliable detection of these deflections nontrivial. METHODS: Here, we introduce a novel method that benefits from the spatial coupling of these processes, and incorporate not only the temporal EGM deflection, but also the spatial gradients. We validated this approach in computer simulations, in animal data with ECGI and invasive electrode recordings, and illustrated its use in a clinical case. RESULTS: In the simulated data, the spatiotemporal approach was able to incorporate spatial information to better select the correct deflection in artificially fractionated EGMs and outperformed the traditional temporal-only method. In experimental data, the accuracy of time estimation from ECGI compared to invasive recordings significantly increased from R = 0.73 (activation) and R = 0.58 (recovery) with the temporal-only method to R = 0.79 (activation) and R = 0.72 (recovery) with the novel approach. Localization of the pacing origin of paced beats improved significantly from 36 mm mean error with the temporal-only approach to 23 mm with the spatiotemporal approach. CONCLUSION: The spatiotemporal method to compute activation and recovery times from EGMs outperformed the traditional temporal-only approach in which spatial information was not taken into account.

Graphitic Carbon with MnO/Mn7 C3 Prepared by Laser-Scribing of MOF for Versatile Supercapacitor Electrodes.

Pseudocapacitive materials encapsulated in conductive carbon matrix are of paramount importance to develop energy storage devices with high performance and long lifespan. Here, via simple laser-scribing, the Mn-based metal-organic framework [EG-MOF-74(Mn)] is transformed into pseudocapacitive hybrid MnO/Mn7 C3 encapsulated in highly conductive graphitic carbon. It is revealed that the rapid carbothermic reduction of MnO (C + MnO → C' + Mn7 C3 + CO) leads to the formation of the intermediate pseudocapacitive MnO/Mn7 C3 and the concurrent catalytic graphitization of disordered carbon. This reaction produces a new type of pseudocapacitive material in the form of MnO/Mn7 C3 fully embedded in highly conductive graphitic carbon. Thanks to the synergistic effect of the MnO/Mn7 C3 nanoparticles and the graphitic carbon, the composite exhibits a high specific capacitance of 403 F g-1 with excellent stability. Asymmetric coin-cell supercapacitors based on the composite demonstrate high energy (29.2 Wh kg-1 ) and power densities (8000 W kg-1 ) with a long lifespan. Prototypes of flexible paper-based supercapacitors made of the composite also show great potential toward applications of flexible electronics.

ASH2L regulates ubiquitylation signaling to MLL: trans-regulation of H3 K4 methylation in higher eukaryotes.

Crosstalk between H2B ubiquitylation (H2Bub) and H3 K4 methylation plays important roles in coordinating functions of diverse cofactors during transcription activation. The underlying mechanism for this trans-tail signaling pathway is poorly defined in higher eukaryotes. Here, we show the following: (1) ASH2L in the MLL complex is essential for H2Bub-dependent H3 K4 methylation. Deleting or mutating K99 of the N-terminal winged helix (WH) motif in ASH2L abrogates H2Bub-dependent regulation. (2) Crosstalk can occur in trans and does not require ubiquitin to be on nucleosomes or histones to exert regulatory effects. (3) trans-regulation by ubiquitin promotes MLL activity for all three methylation states. (4) MLL3, an MLL homolog, does not respond to H2Bub, highlighting regulatory specificity for MLL family histone methyltransferases. Altogether, our results potentially expand the classic histone crosstalk to nonhistone proteins, which broadens the scope of chromatin regulation by ubiquitylation signaling.

The n-SET domain of Set1 regulates H2B ubiquitylation-dependent H3K4 methylation.

Past studies have documented a crosstalk between H2B ubiquitylation (H2Bub) and H3K4 methylation, but little (if any) direct evidence exists explaining the mechanism underlying H2Bub-dependent H3K4 methylation on chromatin templates. Here, we took advantage of an in vitro histone methyltransferase assay employing a reconstituted yeast Set1 complex (ySet1C) and a recombinant chromatin template containing fully ubiquitylated H2B to gain valuable insights. Combined with genetic analyses, we demonstrate that the n-SET domain within Set1, but not Swd2, is essential for H2Bub-dependent H3K4 methylation. Spp1, a homolog of human CFP1, is conditionally involved in this crosstalk. Our findings extend to the human Set1 complex, underscoring the conserved nature of this disease-relevant crosstalk pathway. As not all members of the H3K4 methyltransferase family contain n-SET domains, our studies draw attention to the n-SET domain as a predictor of an H2B ubiquitylation-sensing mechanism that leads to downstream H3K4 methylation.

Risk of venous thromboembolism in knee, hip and hand osteoarthritis: a general population-based cohort study.

OBJECTIVES: Osteoarthritis is a leading cause of immobility and joint replacement, two strong risk factors for venous thromboembolism (VTE). We aimed to examine the relation of knee, hip and hand osteoarthritis to the risk of VTE and investigate joint replacement as a potential mediator. METHODS: We conducted three cohort studies using data from The Health Improvement Network. Up to five individuals without osteoarthritis were matched to each case of incident knee (n=20 696), hip (n=10 411) or hand (n=6329) osteoarthritis by age, sex, entry time and body mass index. We examined the relation of osteoarthritis to VTE (pulmonary embolism and deep vein thrombosis) using a multivariable Cox proportional hazard model. RESULTS: VTE developed in 327 individuals with knee osteoarthritis and 951 individuals without osteoarthritis (2.7 vs 2.0 per 1000 person-years), with multivariable-adjusted HR being 1.38 (95% CI 1.23 to 1.56). The indirect effect (HR) of knee osteoarthritis on VTE through knee replacement was 1.07 (95% CI 1.01 to 1.15), explaining 24.8% of its total effect on VTE. Risk of VTE was higher in hip osteoarthritis than non-osteoarthritis (3.3 vs 1.8 per 1000 person-years; multivariable-adjusted HR=1.83, 95% CI 1.56 to 2.13). The indirect effect through hip replacement yielded an HR of 1.14 (95% CI 1.04 to 1.25), explaining 28.1% of the total effect. No statistically significant difference in VTE risk was observed between hand osteoarthritis and non-osteoarthritis (1.5 vs 1.6 per 1000 person-years; multivariable-adjusted HR=0.88, 95% CI 0.67 to 1.16). CONCLUSION: Our large population-based cohort study provides the first evidence that knee or hip osteoarthritis, but not hand osteoarthritis, was associated with an increased risk of VTE, and such an association was partially mediated through knee or hip replacement.