EZH2-Mediated H3K27me3 Targets Transcriptional Circuits of Neuronal Differentiation.

The Polycomb Repressive Complex 2 (PRC2) plays important roles in the epigenetic regulation of cellular development and differentiation through H3K27me3-dependent transcriptional repression. Aberrant PRC2 activity has been associated with cancer and neurodevelopmental disorders, particularly with respect to the malfunction of sits catalytic subunit EZH2. Here, we investigated the role of the EZH2-mediated H3K27me3 apposition in neuronal differentiation. We made use of a transgenic mouse model harboring Ezh2 conditional KO alleles to derive embryonic stem cells and differentiate them into glutamatergic neurons. Time course transcriptomics and epigenomic analyses of H3K27me3 in absence of EZH2 revealed a significant dysregulation of molecular networks affecting the glutamatergic differentiation trajectory that resulted in: (i) the deregulation of transcriptional circuitries related to neuronal differentiation and synaptic plasticity, in particular LTD, as a direct effect of EZH2 loss and (ii) the appearance of a GABAergic gene expression signature during glutamatergic neuron differentiation. These results expand the knowledge about the molecular pathways targeted by Polycomb during glutamatergic neuron differentiation.

hOA-DN30: a highly effective humanized single-arm MET antibody inducing remission of 'MET-addicted' cancers.

BACKGROUND: The tyrosine kinase receptor encoded by the MET oncogene is a major player in cancer. When MET is responsible for the onset and progression of the transformed phenotype (MET-addicted cancers), an efficient block of its oncogenic activation results in potent tumor growth inhibition. METHODS: Here we describe a molecular engineered MET antibody (hOA-DN30) and validate its pharmacological activity in MET-addicted cancer models in vitro and in vivo. Pharmacokinetics and safety profile in non-human primates have also been assessed. RESULTS: hOA-DN30 efficiently impaired MET activation and the intracellular signalling cascade by dose and time dependent removal of the receptor from the cell surface (shedding). In vitro, the antibody suppressed cell growth by blocking cell proliferation and by concomitantly inducing cell death in multiple MET-addicted human tumor cell lines. In mice xenografts, hOA-DN30 induced an impressive reduction of tumor masses, with a wide therapeutic window. Moreover, the antibody showed high therapeutic efficacy against patient-derived xenografts generated from MET-addicted gastric tumors, leading to complete tumor regression and long-lasting effects after treatment discontinuation. Finally, hOA-DN30 showed a highly favorable pharmacokinetic profile and substantial tolerability in Cynomolgus monkeys. CONCLUSIONS: hOA-DN30 unique ability to simultaneously erase cell surface MET and release the 'decoy' receptor extracellular region results in a paramount MET blocking action. Its remarkable efficacy in a large number of pre-clinical models, as well as its pharmacological features and safety profile in non-human primates, strongly envisage a successful clinical application of this novel single-arm MET therapeutic antibody for the therapy of MET-addicted cancers.

Visual and auditory brain areas share a representational structure that supports emotion perception.

Emotionally expressive music and dance occur together across the world. This may be because features shared across the senses are represented the same way even in different sensory brain areas, putting music and movement in directly comparable terms. These shared representations may arise from a general need to identify environmentally relevant combinations of sensory features, particularly those that communicate emotion. To test the hypothesis that visual and auditory brain areas share a representational structure, we created music and animation stimuli with crossmodally matched features expressing a range of emotions. Participants confirmed that each emotion corresponded to a set of features shared across music and movement. A subset of participants viewed both music and animation during brain scanning, revealing that representations in auditory and visual brain areas were similar to one another. This shared representation captured not only simple stimulus features but also combinations of features associated with emotion judgments. The posterior superior temporal cortex represented both music and movement using this same structure, suggesting supramodal abstraction of sensory content. Further exploratory analysis revealed that early visual cortex used this shared representational structure even when stimuli were presented auditorily. We propose that crossmodally shared representations support mutually reinforcing dynamics across auditory and visual brain areas, facilitating crossmodal comparison. These shared representations may help explain why emotions are so readily perceived and why some dynamic emotional expressions can generalize across cultural contexts.

The fundamental ultrasonic edge wave mode: Propagation characteristics and potential for distant damage detection.

Engineering structures are often composed of thin elements containing features such as free edges, welds, ribs, and holes, which makes distant safety inspections based on guided waves difficult due to wave scattering. However, these features can themselves generate so-called 'feature-guided' waves, which can potentially be utilised for damage detection. One such example are flexural wedge waves, which have been investigated extensively both theoretically and experimentally in the past. Another example is edge waves. These waves, which are a natural analogue of Rayleigh waves propagating in a finite thickness plate, have received relatively little attention, specifically with respect to their possible use in distant damage inspections and Structural Health Monitoring systems. The current paper is aimed to address this gap, and it is focused on the investigation of the fundamental mode of edge waves (ES0), which is the most promising for practical applications. The features of the transient ES0 mode are investigated experimentally and numerically, and compared with previous theoretical studies. It was demonstrated that the ES0 mode can be effectively excited with the wedge excitation method, and distant damage detection with this wave mode at low frequency-thickness values (FTV < 5) is readily achievable. In particular, in a laboratory environment the ES0 mode propagated several meters with almost no decay. However, at higher frequency-thickness values, a wave amplitude modulation, significant energy decay and strong coupling between the ES0 and S0 wave modes were observed. These phenomena may restrict the defect resolution as well as the range of damage inspections based on the fundamental edge wave mode.

Machine learning-based prediction of adverse events following an acute coronary syndrome (PRAISE): a modelling study of pooled datasets.

BACKGROUND: The accuracy of current prediction tools for ischaemic and bleeding events after an acute coronary syndrome (ACS) remains insufficient for individualised patient management strategies. We developed a machine learning-based risk stratification model to predict all-cause death, recurrent acute myocardial infarction, and major bleeding after ACS. METHODS: Different machine learning models for the prediction of 1-year post-discharge all-cause death, myocardial infarction, and major bleeding (defined as Bleeding Academic Research Consortium type 3 or 5) were trained on a cohort of 19 826 adult patients with ACS (split into a training cohort [80%] and internal validation cohort [20%]) from the BleeMACS and RENAMI registries, which included patients across several continents. 25 clinical features routinely assessed at discharge were used to inform the models. The best-performing model for each study outcome (the PRAISE score) was tested in an external validation cohort of 3444 patients with ACS pooled from a randomised controlled trial and three prospective registries. Model performance was assessed according to a range of learning metrics including area under the receiver operating characteristic curve (AUC). FINDINGS: The PRAISE score showed an AUC of 0·82 (95% CI 0·78-0·85) in the internal validation cohort and 0·92 (0·90-0·93) in the external validation cohort for 1-year all-cause death; an AUC of 0·74 (0·70-0·78) in the internal validation cohort and 0·81 (0·76-0·85) in the external validation cohort for 1-year myocardial infarction; and an AUC of 0·70 (0·66-0·75) in the internal validation cohort and 0·86 (0·82-0·89) in the external validation cohort for 1-year major bleeding. INTERPRETATION: A machine learning-based approach for the identification of predictors of events after an ACS is feasible and effective. The PRAISE score showed accurate discriminative capabilities for the prediction of all-cause death, myocardial infarction, and major bleeding, and might be useful to guide clinical decision making. FUNDING: None.

High-throughput screening identifies histone deacetylase inhibitors that modulate GTF2I expression in 7q11.23 microduplication autism spectrum disorder patient-derived cortical neurons.

BACKGROUND: Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental condition affecting almost 1% of children, and represents a major unmet medical need with no effective drug treatment available. Duplication at 7q11.23 (7Dup), encompassing 26-28 genes, is one of the best characterized ASD-causing copy number variations and offers unique translational opportunities, because the hemideletion of the same interval causes Williams-Beuren syndrome (WBS), a condition defined by hypersociability and language strengths, thereby providing a unique reference to validate treatments for the ASD symptoms. In the above-indicated interval at 7q11.23, defined as WBS critical region, several genes, such as GTF2I, BAZ1B, CLIP2 and EIF4H, emerged as critical for their role in the pathogenesis of WBS and 7Dup both from mouse models and human studies. METHODS: We performed a high-throughput screening of 1478 compounds, including central nervous system agents, epigenetic modulators and experimental substances, on patient-derived cortical glutamatergic neurons differentiated from our cohort of induced pluripotent stem cell lines (iPSCs), monitoring the transcriptional modulation of WBS interval genes, with a special focus on GTF2I, in light of its overriding pathogenic role. The hits identified were validated by measuring gene expression by qRT-PCR and the results were confirmed by western blotting. RESULTS: We identified and selected three histone deacetylase inhibitors (HDACi) that decreased the abnormal expression level of GTF2I in 7Dup cortical glutamatergic neurons differentiated from four genetically different iPSC lines. We confirmed this effect also at the protein level. LIMITATIONS: In this study, we did not address the molecular mechanisms whereby HDAC inhibitors act on GTF2I. The lead compounds identified will now need to be advanced to further testing in additional models, including patient-derived brain organoids and mouse models recapitulating the gene imbalances of the 7q11.23 microduplication, in order to validate their efficacy in rescuing phenotypes across multiple functional layers within a translational pipeline towards clinical use. CONCLUSIONS: These results represent a unique opportunity for the development of a specific class of compounds for treating 7Dup and other forms of intellectual disability and autism.

Evaluation of Educational Interventions to Enhance Adolescent Specific Vaccination Coverage.

BACKGROUND: In this study, we assessed impact of two educational interventions designed to increase coverage of three vaccines recommended during adolescence among Georgia middle and high school students (tetanus diphtheria pertussis [Tdap], meningococcal [MenACWY], and human papillomavirus [HPV] vaccines). METHODS: We randomized 11 middle and high schools in one school district into one of three arms: (1) control; (2) educational intervention for parents only (P only); and (3) multicomponent educational intervention for parents and adolescents (P + A), which consisted of educational brochures for parents about vaccines recommended during adolescence and a vaccine-focused curriculum delivered to adolescents by science teachers. We obtained vaccination coverage data during intervention years from the state immunization registry. RESULTS: Odds of receiving at least one vaccine during the study were higher among adolescents in P + A arm compared to control (Odds Ratio [OR]: 1.4; 95% Confidence Interval [CI]: 1.1-2.0). Adolescents in P + A arm had greater odds of receiving at least one vaccine compared with those in P only arm (OR: 1.4; 95% CI: 1.1-1.7). CONCLUSIONS: A multicomponent educational intervention for adolescents and parents increased adolescent vaccination uptake. Results suggest similar interventions can increase awareness and demand for vaccines among parents and adolescents.

Prioritizing a One Health Approach in the Immediate Fight Against Antimicrobial Resistance.

Antimicrobial resistance is a major threat to global health security. While the global community has made recent advances to mitigate the threat of antimicrobial resistance, we continue to face challenges in creating solutions and concrete actions that will yield the greatest immediate impact. To examine the critical areas in human, animal and environmental health that contribute to the emergence and spread of antimicrobial resistance, the Forum on Microbial Threats of the U.S. National Academies of Sciences, Engineering and Medicine hosted a public workshop on June 20-21, 2017 in Washington, DC. This article summarizes the final synthesis discussion that took place at the workshop on suggestions for immediate actions and implementation that are feasible and cost-effective for combating antimicrobial resistance across the One Health domains. The priorities that emerged from the participants' discussions addressed the following topics: (1) Surveillance; (2) Stewardship, Infection Prevention and Behavior Modification; (3) Basic and Applied Research and Development; and (4) Global Policy and Coordination.

Influence of Sources of Information and Parental Attitudes on Human Papillomavirus Vaccine Uptake among Adolescents.

STUDY OBJECTIVE: The purpose of this study was to: 1) describe parental sources of information about human papillomavirus (HPV) vaccination for adolescents, 2) understand how parental sources of information about HPV vaccine are associated with adolescent HPV vaccine uptake, and 3) understand if the relationship between a greater number of HPV-related information sources and HPV vaccine uptake among adolescents is mediated by parental attitudes. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: We conducted a 3-arm randomized controlled trial in middle and high schools in eastern Georgia from 2011 to 2013. As part of the trial, we surveyed parents during the final year to understand their sources of information about HPV vaccine for their adolescent. Data were collected from 360 parents via phone and online surveys. MAIN OUTCOME MEASURES: Parents responded to a survey that asked them to identify demographic information, parental HPV attitudes, sources of information about HPV vaccination, and HPV vaccine uptake. RESULTS: Most of the sample was African American (74%; n = 267) and 53% of parents (n = 192) reported that their adolescent received at least 1 HPV vaccine dose. The top sources of information about HPV vaccine reported by parents were a doctor or medical professional (80%; n = 287) and television (64%; n = 232). A mediation analysis showed sources of information about HPV vaccine are associated with parental attitudes, and parental attitudes about HPV vaccine are associated with vaccine uptake among adolescents. CONCLUSION: These findings highlight the importance of HPV sources of information on parental attitudes.

Recommendations for Structure and Content for a School-Based Adolescent Immunization Curriculum.

Despite high utilization of childhood vaccinations, adolescent immunization coverage rates lag behind recommended coverage levels. The four vaccines recommended for adolescents ages 11 to 18 years are tetanus, diphtheria, and pertussis vaccine; human papillomavirus vaccine; meningococcal conjugate vaccine; and an annual influenza vaccine. The Healthy People 2020 goal is 80% coverage for each recommended immunization, but coverage rates in Georgia among adolescents fall below those goals for all but the tetanus, diphtheria, and pertussis vaccine. We developed a multicomponent intervention that included a school-based, teacher-delivered educational curriculum to increase adolescent vaccination coverage rates in Richmond County, Georgia. We facilitated focus group discussions with middle- and high school science teachers who delivered the immunization curriculum in two consecutive school years. The objective of the focus group was to understand teachers' perspectives about the curriculum impact and to synthesize recommendations for optimal dissemination of the curriculum content, structure, and packaging. Teachers provided recommendations for curriculum fit within existing classes, timing of delivery, and dosage of delivery and recommended creating a flexible tool kit, such as a downloadable online package. Teachers also recommended increasing emphasis on disease transmission and symptoms to keep students engaged. These findings can be applied to the development of an online, cost-effective tool kit geared toward teaching adolescents about the immune system and adolescent vaccinations.

Antimicrobial Resistance, Food Safety, and One Health: The Need for Convergence.

Antimicrobial resistance is a complex, multifaceted, urgent global health problem. There is increasing concern about the emergence of multidrug-resistant superbugs. These superbugs result in infections responsive to treatment with few if any currently available antimicrobial agents, reviving memories of the preantibiotic era and evoking concerns about a postantibiotic era. Use of antibiotics exerts selective pressure on pathogens as well as on commensal organisms that are part of the normal flora of humans, animals, and the environment; this favors the emergence of resistant strains and sometimes involves the food supply. Addressing this urgent threat requires implementation of a multifaceted strategy that has been articulated in the past few years; implementation will require sustained political will, investment in systems and research, and a One Health approach involving improved communication, cooperation, and collaboration among the many professional disciplines and organizations with important roles to play at the intersection of human, animal, and environmental health. Priorities include strengthened human and animal health surveillance and monitoring for resistant organisms, antimicrobial stewardship programs, infection-control programs, development and approval of new antimicrobial agents, research on innovative therapeutic approaches, development of rapid diagnostic tests and new vaccines, and educational programs that target professional groups and the public.

Communication Between Infectious Disease Physicians and US State and Local Public Health Agencies: Strengths, Challenges, and Opportunities.

Strong working relationships between infectious disease (ID) physicians and public health have resulted in the early detection of emerging infectious threats. From May 6 through June 5, 2015, we surveyed ID physicians in the Infectious Diseases Society of America's Emerging Infections Network about communications with public health. A total of 688 of 1491 (46%) members completed the survey, 624 (91%) of whom knew how to reach their health department directly for an urgent issue. Only 38 (6%) described communications with their health department as poor. Interest in newer technologies (eg, mobile smartphone applications) showed mixed results. Interest in a smartphone application differed significantly by years of ID experience, with 81 of 146 (55%) respondents with <5 years of ID experience, 172 of 359 (48%) respondents with 5 to 24 years of ID experience, and 61 of 183 (33%) respondents with ≥25 years of ID experience in favor of a smartphone application (P < .001). As more physicians adopt newer communication technologies, health departments should be prepared to incorporate these tools to communicate with ID physicians.

Preexisting Chronic Health Conditions and Health Insurance Status Associated With Vaccine Receipt Among Adolescents.

PURPOSE: Four vaccines are routinely recommended for adolescents: tetanus, diphtheria, and acellular pertussis (Tdap); human papillomavirus (HPV); meningococcal-conjugate (MCV4); and a yearly seasonal influenza vaccine. Vaccination promotion and outreach approaches may need to be tailored to certain populations, such as those with chronic health conditions or without health insurance. METHODS: In a controlled trial among middle and high school students in Georgia, 11 schools were randomized to one of three arms: no intervention, parent education brochure, or parent education brochure plus a student curriculum on the four recommended vaccines. Parents in all arms were surveyed regarding their adolescent's vaccine receipt, chronic health conditions, and health insurance status. RESULTS: Of the 686 parents, most (91%) reported their adolescent had received at least one of the four vaccines: Tdap (82%), MCV4 (59%), current influenza vaccine (53%) and HPV (48%). Twenty-three percent of parents reported that their adolescent had asthma. Most parents reported that their adolescent's insurance was Medicaid (60%) or private insurance (34%), and 6% reported no insurance. More adolescents with a chronic health condition received any adolescent vaccine than adolescents without a chronic health condition (p < .0001). Among those with no insurance, fewer had received any adolescent vaccine than those with Medicaid or private insurance (p < .0001). CONCLUSIONS: The federal Vaccines for Children program offers recommended vaccines free to eligible children (including those without health insurance). Our findings suggest that parents may not be aware of this program or eligibility for it, thus revealing a need for education or other fixes.

Assessment of Arbovirus Surveillance 13 Years after Introduction of West Nile Virus, United States.

Before 1999, the United States had no appropriated funding for arboviral surveillance, and many states conducted no such surveillance. After emergence of West Nile virus (WNV), federal funding was distributed to state and selected local health departments to build WNV surveillance systems. The Council of State and Territorial Epidemiologists conducted assessments of surveillance capacity of resulting systems in 2004 and in 2012; the assessment in 2012 was conducted after a 61% decrease in federal funding. In 2004, nearly all states and assessed local health departments had well-developed animal, mosquito, and human surveillance systems to monitor WNV activity and anticipate outbreaks. In 2012, many health departments had decreased mosquito surveillance and laboratory testing capacity and had no systematic disease-based surveillance for other arboviruses. Arboviral surveillance in many states might no longer be sufficient to rapidly detect and provide information needed to fully respond to WNV outbreaks and other arboviral threats (e.g., dengue, chikungunya).

C/EBPα-p30 protein induces expression of the oncogenic long non-coding RNA UCA1 in acute myeloid leukemia.

Accumulating evidences indicate that different long non-coding RNAs (lncRNAs) might play a relevant role in tumorigenesis, with their expression and function already associated to cancer development and progression. CCAAT/enhancer-binding protein-α (CEBPA) is a critical regulator of myeloid differentiation whose inactivation contributes to the development of acute myeloid leukemia (AML). Mutations in C/EBPα occur in around 10% of AML cases, leading to the expression of a 30-kDa dominant negative isoform (C/EBPα-p30). In this study, we identified the oncogenic urothelial carcinoma associated 1 (UCA1) lncRNA as a novel target of the C/EBPα-p30. We show that wild-type C/EBPα and C/EBPα-p30 isoform can bind the UCA1 promoter but have opposite effects on UCA1 expression. While wild-type C/EBPα represses, C/EBPα-p30 can induce UCA1 transcription. Notably, we also show that UCA1 expression increases in cytogenetically normal AML cases carrying biallelic CEBPA mutations. Furthermore, we demonstrate that UCA1 sustains proliferation of AML cells by repressing the expression of the cell cycle regulator p27kip1. Thus, we identified, for the first time, an oncogenic lncRNA functioning in concert with the dominant negative isoform of C/EBPα in AML.

Influence of sources of information about influenza vaccine on parental attitudes and adolescent vaccine receipt.

In 2011-2012, only 34% of 13-17 years olds in the United States (US) received seasonal influenza vaccine. Little is known about the link between parents' sources of health information, their vaccine-related attitudes, and vaccination of their adolescent against influenza. This study seeks to determine the relationship between number of sources of information on influenza vaccine, parental attitudes toward influenza vaccine, and influenza vaccine uptake in adolescents. We conducted a telephone and web-based survey among US parents of students enrolled in 6 middle and 5 high schools in Georgia. Bivariate and multivariable analyses were conducted to examine associations between the number of information sources about influenza vaccine and vaccine receipt and whether parent vaccine-related attitudes act as a mediator. The most commonly reported sources of information were: a physician/medical professional (95.0%), a family member or friend (80.6%), and television (77.2%). Parents who had higher attitude scores toward influenza vaccine were 5 times as likely to report their adolescent had ever received influenza vaccine compared to parents who had lower attitude scores (adjusted odds ratio (aOR) 5.1; 95% confidence intervals (CI) 3.1-8.4; P < 0.01). Parent vaccine-related attitudes were a significant mediator of the relationship between sources of information and vaccine receipt. In light of the low response rate and participation in an adolescent vaccination intervention, findings may not be generalizable to other populations. This study shows the importance of multiple sources of information in influencing parental decision-making about influenza vaccine for adolescents. Harnessing the power of mass media and family members and friends as health advocates for influenza vaccination can potentially help increase vaccination coverage of adolescents.