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Dominant-negative effects of Weaver syndrome-associated EZH2 variants
Get PDFHeterozygous missense mutations in EZH2 cause Weaver syndrome (WS), a developmental disorder characterized by intellectual disability and overgrowth. EZH2 encodes the enzymatic subunit of Polycomb repressive complex 2 (PRC2), which mediates monomethylation, dimethylation, and trimethylation of histone H3 lysine 27 (H3K27me1/2/3). Most WS-associated EZH2 variants lack functional characterization but are presumed loss-of-function. However, the lack of early truncating mutations in EZH2 led us to hypothesize a dominant-negative mechanism for WS, which was supported by our structural analysis of all known WS-associated EZH2 variants. We isogenically modeled 10 representative variants in embryonic stem cells and showed that they reduce global H3K27me2/3 with concomitant increases in H3K27ac and chromatin decompaction. Notably, the pattern of H3K27me2/3 reductions indicated dominant-negative interference on PRC2 activity even when WS variants were expressed at low levels. RNA-seq identified weakly Polycomb-bound genes that lose canonical PRC1 (cPRC1) occupancy and become derepressed, including several phenotypically relevant growth control genes. Comparative analysis of a gain-of-function EZH2 variant causing growth restriction revealed reciprocal chromatin and transcriptional changes compared with WS-associated variants. Taken together, our findings support a model in which EZH2 variants associated with opposing developmental growth syndromes affect not only H3K27me3 but also intergenic H3K27me2, chromatin architecture, and cPRC1 recruitment.</p
He Kept Me Safe:A play on intimate partner violence amongst gay and bisexual men
Get PDFHe Kept Me Safe is a multi-actor theatre play shedding light on the experiences of intimate partner violence (IPV) amongst gay and bisexual men (GBM). The play is based on qualitative research conducted with 10 GBM survivors in Scotland using a narrative inquiry approach, allowing participants to authentically recount their IPV experiences. Subsequently, using narrative portraiture, the interview transcripts were transformed into a script featuring a mental health practitioner facilitating a group session with four male survivors. The play delves into various forms of abuse endured, the resulting trauma, and the journey toward healing and recovery
Zero-phase sound via giant FFT
Get PDFGiven the speedy computation of the FFT in current computer hardware, there are new possibilities for examining transformations for very long sounds. A zero-phase version of any audio signal can be obtained by zeroing the phase angle of its complex spectrum and taking the inverse FFT. This paper recommends additional processing steps, including zero-padding, transient suppression at the signal’s start and end, and gain compensation, to enhance the resulting sound quality. As a result, a sound with the same spectral characteristics as the original one, but with different temporal events, is obtained. Repeating rhythm patterns are retained, however. Zero-phase sounds are palindromic in the sense that they are symmetric in time. A comparison of the zero-phase conversion to the autocorrelation function helps to understand its properties, such as why the rhythm of the original sound is emphasized. It is also argued that the zero-phase signal has the same autocorrelation function as the original sound. One exciting variation of the method is to apply the method separately to the real and imaginary parts of the spectrum to produce a stereo effect. A frame-based technique enables the use of the zero-phase conversion in real-time audio processing. The zero-phase conversion is another member of the giant FFT toolset, allowing the modification of sampled sounds, such as drum loops or entire songs
Just verification of mutual exclusion algorithms
Get PDFWe verify the correctness of a variety of mutual exclusion algorithms through model checking. We look at algorithms where communication is via shared read/write registers, where those registers can be atomic or non-atomic. For the verification of liveness properties, it is necessary to assume a completeness criterion to eliminate spurious counterexamples. We use justness as completeness criterion. Justness depends on a concurrency relation; we consider several such relations, modelling different assumptions on the working of the shared registers. We present executions demonstrating the violation of correctness properties by several algorithms, and in some cases suggest improvements
Pathways between intimate partner violence and HIV care and treatment during pregnancy and postpartum:a qualitative study in southwestern Kenya
Get PDFIntimate partner violence (IPV) is associated with suboptimal HIV treatment behaviors and health outcomes among perinatal women. Less is known about the postpartum phase or how distinct types of perinatal IPV exposure may inhibit HIV-related care. We conducted a qualitative study nested within an ongoing trial among perinatal women in rural Kenya to explore the influence of IPV on adherence to HIV treatment during pregnancy and postpartum. In 2022, a trained researcher fluent in Dholuo and Kiswahili conducted 23 semi-structured interviews with women up to 2 years postpartum living with HIV and self-reported IPV in their current relationship. Digitally recorded interviews were translated into English, transcribed verbatim, and thematically coded using deductive and inductive techniques. Nearly all women reported psychological and financial IPV, the majority reported physical IPV, half reported male controlling behaviors, half reported reproductive coercion, and many reported sexual IPV. Many women described a link between IPV and their adherence to perinatal HIV care and treatment. An indirect pathway was exhibited when psychological IPV heightened mental distress, leading to non-adherence through symptoms of depression and anxiety. A second path occurred when financial IPV and withholding food led to HIV treatment challenges. A direct pathway occurred when male partners sabotaged HIV treatment or controlled women’s access to HIV care. In turn, women’s evasion of IPV through leaving home or strategic non-disclosure had unanticipated consequences for their HIV treatment. Despite enduring IPV, many women described adhering to HIV treatment to sustain good health for themselves and their children. IPV-exposed women living with HIV described multiple ways a violent relationship was detrimental to maintaining their HIV treatment. To meet global goals to end vertical transmission of HIV and improve maternal and infant health, preventing and addressing IPV within maternal health settings should be prioritized in HIV programming
HIV status and the risk of typhoid fever and iNTS:A systematic review and meta-analysis
No full textOBJECTIVES: The WHO recommends prioritising people living with HIV (PLHIV) for typhoid vaccination, but evidence for increased typhoid fever risk is inconsistent. We aimed to evaluate whether HIV infection alters the risk of blood culture-confirmed typhoid fever.METHODS: We systematically searched four databases from inception to 30 November 2023 for studies reporting Salmonella Typhi bacteraemia with documented HIV status. Where available, we also extracted data on invasive non-typhoidal Salmonella (iNTS) bacteraemia. We used random-effects meta-analysis to pool odds ratios (ORs) and assessed effect modification by ART era, age, and CD4 count.RESULTS: Seventeen studies met inclusion criteria, comprising 10,117 PLHIV and 53,289 HIV-negative individuals from Africa and Asia. PLHIV had lower odds of typhoid fever (OR 0.53, 95% CI 0.30-0.92), but higher odds of iNTS disease (OR 4.06, 2.23-7.39). Apparent protection against typhoid was most evident in adults with CD4 counts <200 cells/µl and was not significant after ART rollout.CONCLUSIONS: Advanced HIV infection may reduce the risk of typhoid fever. While altered clinical presentations or healthcare-seeking behaviours could contribute, the contrasting increase in iNTS risk within the same populations suggests a genuine difference in susceptibility. These findings support re-evaluating WHO guidance that prioritises PLHIV for typhoid vaccination.</p
Trastuzumab deruxtecan in HER2-low metastatic breast cancer: long-term survival analysis of the randomized, phase 3 DESTINY-Breast04 trial
No full textIn DESTINY-Breast04 (NCT03734029), trastuzumab deruxtecan (T-DXd) significantly improved overall survival (OS) and progression-free survival compared with treatment of physician’s choice of chemotherapy (TPC) for patients with human epidermal growth factor receptor 2 (HER2)-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization−) metastatic breast cancer (mBC). After an extended median follow-up of 32.0 months, median OS in the overall cohort was 22.9 months for T-DXd and 16.8 months for TPC (hazard ratio, 0.69; 95% confidence interval [CI], 0.55–0.86). For the hormone receptor (HR)+ cohort, median OS was 23.9 and 17.6 months for T-DXd and TPC, respectively (hazard ratio, 0.69; 95% CI, 0.55–0.87). Median OS also favored T-DXd in exploratory analyses of HR−, estrogen receptor IHC 1%–10%, and estrogen receptor IHC >10% cohorts. The overall safety profile of T-DXd was acceptable and generally manageable. Results confirm T-DXd as standard of care after prior chemotherapy in patients with HER2-low mBC. ClinicalTrials.gov identifier: NCT03734029
Mature students’ experiences of disability and vocational care-related degrees in college-based higher education:Recognition and redistribution
No full textThis research paper investigates how subjective experiences of disability influence mature students’ decisions about care-related vocational degrees. It offers a fresh perspective by considering the impact of disability on both disabled students and on students who have disabled relatives. The article also interrogates the application of Fraser’s two-dimensional theory of social justice to the claims of disabled people, arguing for its integration with her earlier work on the politics of needs interpretation. Ten participants from three further education colleges were interviewed, and their transcripts were thematically analysed. Findings indicated that both positive and negative life experiences of disability and/or unpaid care affected the career choices of most of the participants. They were motivated to acquire qualifications to have their experiences recognised so that they could effect change. Accessing resources that enhance the learning of disabled people and their carers was a fight. These draining battles affected some participants’ capacity to study, and some understood the need to learn new expert discourses to succeed. The research concludes that approaches to widening participation need to be less focussed on the collection of quantitative data and more inclusive of lived experiences
Patterns of adverse childhood experiences from a longitudinal South African community sample:A latent class analysis
No full textSouth African children have a high risk of experiencing multiple adverse childhood experiences (ACEs) compared to children living in high-income countries. In a low- and middle-income context with high levels of deprivation and crime, we should consider expanded ACEs (ACE-E) that are contextually sensitive, alongside conventional ACEs (ACEs-C). Latent class analysis was used to explore patterns of 14 ACEs measured in a sample of 3,401 South African adolescents (56.42% girls). Data were collected in 2010/2011 and 2011/2012. We assessed the association between class membership and demographic covariates of poverty, location (rural vs. urban), gender, age, and province. 5 classes emerged based on model fit indices and theory: “Low ACEs,” “High Parental AIDS-Affectedness and Parental Death,” “High Parental AIDS-Affectedness and Parental Sickness,” “Moderate Multi-Type Abuse,” and “Highest Multi-type ACEs.” ACEs-E played a stronger role in shaping latent classes than ACEs-C. Compared to the low ACE class, adolescents in other classes lived in greater poverty, were older, and more likely to be girls. Children in “High Parental AIDS-Affectedness and Parental Death” were more likely to be in the Mpumalanga province and children in “Moderate Multi-Type Abuse” were more likely to be in Western Cape. South African adolescents are at risk of multiple ACE exposure and contextually sensitive ACEs mattered most when characterising patterns of ACEs. Research should continue to focus on person-centred approaches to ACEs for understanding the complexity and multiplicative effects of ACEs in low-resource settings
Nanopore- and AI-empowered microbial viability inference
No full textBackgroundThe ability to differentiate between viable and dead microorganisms in metagenomic data is crucial for various microbial inferences, ranging from assessing ecosystem functions of environmental microbiomes to inferring the virulence of potential pathogens from metagenomic analysis. Established viability-resolved genomic approaches are labor-intensive as well as biased and lacking in sensitivity.ResultsWe here introduce a new fully computational framework that leverages nanopore sequencing technology to assess microbial viability directly from freely available nanopore signal data. Our approach utilizes deep neural networks to learn features from such raw nanopore signal data that can distinguish DNA from viable and dead microorganisms in a controlled experimental setting of UV-induced Escherichia cell death. The application of explainable artificial intelligence (AI) tools then allows us to pinpoint the signal patterns in the nanopore raw data that allow the model to make viability predictions at high accuracy. Using the model predictions as well as explainable AI, we show that our framework can be leveraged in a real-world application to estimate the viability of obligate intracellular Chlamydia, where traditional culture-based methods suffer from inherently high false-negative rates. This application shows that our viability model captures predictive patterns in the nanopore signal that can be utilized to predict viability across taxonomic boundaries. We finally show the limits of our model’s generalizability through antibiotic exposure of a simple mock microbial community, where a new model specific to the killing method had to be trained to obtain accurate viability predictions.ConclusionsWhile the potential of our computational framework’s generalizability and applicability to metagenomic studies needs to be assessed in more detail, we here demonstrate for the first time the analysis of freely available nanopore signal data to infer the viability of microorganisms, with many potential applications in environmental, veterinary, and clinical settings
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