An SDN-based device-aware live video service for inter-domain adaptive bitrate streaming

The emerging popularity of live streaming services poses a great challenge for the rigid and static traditional Internet architecture. The rise in adaptation of Software Defined Networking (SDN) by Internet Service Providers (ISP) and Content Delivery Networks (CDN) presents an opportunity to dynamically adapt and respond in real-time to high definition (HD) mega events or dynamic short-lived broadcast events. In this paper, we present an SDN-based system design that utilizes a communication framework between ISPs and CDNs to interact and thus enable a reliable and resource efficient live streaming service. We build and deploy an optimization model that can maximize the video quality for users while minimizing the resource utilization for both ISPs and CDNs. The model considers device capabilities, network constraints and the subscription level of users with the ISP/CDN. Our system is a network-assisted, cross-layer, approach that implements multicast at the network layer and can dynamically adapt the video bitrates that are served to each client at the application layer. We build a prototype of our proposed design and evaluate real-world scenarios with up to 500 users streaming multiple videos at different bitrates. Results show that our approach can increase average user goodput by up to 70% while almost eliminating frame drops by handling network congestion

Clinical and molecular correlates in fragile X premutation females.

The prevalence of the fragile X premutation (55-200 CGG repeats) among the general population is relatively high, but there remains a lack of clear understanding of the links between molecular biomarkers and clinical outcomes. In this study we investigated the correlations between molecular measures (CGG repeat size, FMR1 mRNA, FMRP expression levels, and methylation status at the promoter region and in FREE2 site) and clinical phenotypes (anxiety, obsessive compulsive symptoms, depression and executive function deficits) in 36 adult premutation female carriers and compared to 24 normal control subjects. Premutation carriers reported higher levels of obsessive compulsive symptoms, depression, and anxiety, but demonstrated no significant deficits in global cognitive functions or executive function compared to the control group. Increased age in carriers was significantly associated with increased anxiety levels. As expected, FMR1 mRNA expression was significantly correlated with CGG repeat number. However, no significant correlations were observed between molecular (including epigenetic) measures and clinical phenotypes in this sample. Our study, albeit limited by the sample size, establishes the complexity of the mechanisms that link the FMR1 locus to the clinical phenotypes commonly observed in female carriers suggesting that other factors, including environment or additional genetic changes, may have an impact on the clinical phenotypes. However, it continues to emphasize the need for assessment and treatment of psychiatric problems in female premutation carriers

Perinatal outcomes associated with low birth weight in a historical cohort

<p>Abstract</p> <p>Objective</p> <p>To identify perinatal outcomes associated with low birth weight (LBW).</p> <p>Methods</p> <p>A retrospective cohort study in a tertiary maternity hospital. Analysis of the database on 43,499 liveborn infants delivered between 1986 and 2004 with low (n = 6,477) and normal (n = 37,467) birth weight. Outcomes associated with LBW were identified through crude and adjusted risk ratio (RR) and 95%CI with bivariate and multivariate analysis. The main outcomes were: onset of labor, mode of delivery, indication for cesarean section; amniotic fluid, fetal heart rate pattern, Apgar score, somatic gestational age, gender and congenital malformation.</p> <p>Results</p> <p>LBW infants showed more frequently signs of perinatal compromise such as abnormal amniotic fluid volume (especially olygohydramnios), nonreassuring patterns of fetal heart rate, malformation, lower Apgar scores and lower gestational age at birth. They were associated with a greater risk of labor induction and cesarean delivery, but lower risk of forceps.</p> <p>Conclusion</p> <p>There was a clear association between LBW and unfavorable perinatal outcomes.</p

Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways

UNLABELLED Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293

Molecular biomarkers predictive of sertraline treatment response in young children with fragile X syndrome

ObjectivesSeveral neurotransmitters involved in brain development are altered in fragile X syndrome (FXS), the most common monogenic cause of autism spectrum disorder (ASD). Serotonin plays a vital role in synaptogenesis and postnatal brain development. Deficits in serotonin synthesis and abnormal neurogenesis were shown in young children with autism, suggesting that treating within the first years of life with a selective serotonin reuptake inhibitor might be the most effective time. In this study we aimed to identify molecular biomarkers involved in the serotonergic pathway that could predict the response to sertraline treatment in young children with FXS.MethodsGenotypes were determined for several genes involved in serotonergic pathway in 51 children with FXS, ages 24-72months. Correlations between genotypes and deviations from baseline in primary and secondary outcome measures were modeled using linear regression models.ResultsA significant association was observed between a BDNF polymorphism and improvements for several clinical measures, including the Clinical Global Impression scale (P=0.008) and the cognitive T score (P=0.017) in those treated with sertraline compared to those in the placebo group. Additionally, polymorphisms in the MAOA, Cytochrome P450 2C19 and 2D6, and in the 5-HTTLPR gene showed a significant correlation with some of the secondary measures included in this study.ConclusionThis study shows that polymorphisms of genes involved in the serotonergic pathway could play a potential role in predicting response to sertraline treatment in young children with FXS. Larger studies are warranted to confirm these initial findings

Targeting SWI/SNF ATPases in H3.3K27M diffuse intrinsic pontine gliomas

Diffuse midline gliomas (DMGs) including diffuse intrinsic pontine gliomas (DIPGs) bearing lysine-to-methionine mutations in histone H3 at lysine 27 (H3K27M) are lethal childhood brain cancers. These tumors harbor a global reduction in the transcriptional repressive mark H3K27me3 accompanied by an increase in the transcriptional activation mark H3K27ac. We postulated that H3K27M mutations, in addition to altering H3K27 modifications, reprogram the master chromatin remodeling switch/sucrose nonfermentable (SWI/SNF) complex. The SWI/SNF complex can exist in two main forms termed BAF and PBAF that play central roles in neurodevelopment and cancer. Moreover, BAF antagonizes PRC2, the main enzyme catalyzing H3K27me3. We demonstrate that H3K27M gliomas show increased protein levels of the SWI/SNF complex ATPase subunits SMARCA4 and SMARCA2, and the PBAF component PBRM1. Additionally, knockdown of mutant H3K27M lowered SMARCA4 protein levels. The proteolysis targeting chimera (PROTAC) AU-15330 that simultaneously targets SMARCA4, SMARCA2, and PBRM1 for degradation exhibits cytotoxicity in H3.3K27M but not H3 wild-type cells. AU-15330 lowered chromatin accessibility measured by ATAC-Seq at nonpromoter regions and reduced global H3K27ac levels. Integrated analysis of gene expression, proteomics, and chromatin accessibility in AU-15330-treated cells demonstrated reduction in the levels of FOXO1, a key member of the forkhead family of transcription factors. Moreover, genetic or pharmacologic targeting of FOXO1 resulted in cell death in H3K27M cells. Overall, our results suggest that H3K27M up-regulates SMARCA4 levels and combined targeting of SWI/SNF ATPases in H3.3K27M can serve as a potent therapeutic strategy for these deadly childhood brain tumors. Copyright © 2023 the Author(s).TRU