Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration.

Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.

Enhancer-instructed epigenetic landscape and chromatin compartmentalization dictate a primary antibody repertoire protective against specific bacterial pathogens.

Antigen receptor loci are organized into variable (V), diversity (D) and joining (J) gene segments that rearrange to generate antigen receptor repertoires. Here, we identified an enhancer (E34) in the murine immunoglobulin kappa (Igk) locus that instructed rearrangement of Vκ genes located in a sub-topologically associating domain, including a Vκ gene encoding for antibodies targeting bacterial phosphorylcholine. We show that E34 instructs the nuclear repositioning of the E34 sub-topologically associating domain from a recombination-repressive compartment to a recombination-permissive compartment that is marked by equivalent activating histone modifications. Finally, we found that E34-instructed Vκ-Jκ rearrangement was essential to combat Streptococcus pneumoniae but not methicillin-resistant Staphylococcus aureus or influenza infections. We propose that the merging of Vκ genes with Jκ elements is instructed by one-dimensional epigenetic information imposed by enhancers across Vκ and Jκ genomic regions. The data also reveal how enhancers generate distinct antibody repertoires that provide protection against lethal bacterial infection.

Nuclear morphology is shaped by loop-extrusion programs.

It is well established that neutrophils adopt malleable polymorphonuclear shapes to migrate through narrow interstitial tissue spaces1-3. However, how polymorphonuclear structures are assembled remains unknown4. Here we show that in neutrophil progenitors, halting loop extrusion-a motor-powered process that generates DNA loops by pulling in chromatin5-leads to the assembly of polymorphonuclear genomes. Specifically, we found that in mononuclear neutrophil progenitors, acute depletion of the loop-extrusion loading factor nipped-B-like protein (NIPBL) induced the assembly of horseshoe, banded, ringed and hypersegmented nuclear structures and led to a reduction in nuclear volume, mirroring what is observed during the differentiation of neutrophils. Depletion of NIPBL also induced cell-cycle arrest, activated a neutrophil-specific gene program and conditioned a loss of interactions across topologically associating domains to generate a chromatin architecture that resembled that of differentiated neutrophils. Removing NIPBL resulted in enrichment for mega-loops and interchromosomal hubs that contain genes associated with neutrophil-specific enhancer repertoires and an inflammatory gene program. On the basis of these observations, we propose that in neutrophil progenitors, loop-extrusion programs produce lineage-specific chromatin architectures that permit the packing of chromosomes into geometrically confined lobular structures. Our data also provide a blueprint for the assembly of polymorphonuclear structures, and point to the possibility of engineering de novo nuclear shapes to facilitate the migration of effector cells in densely populated tumorigenic environments.

SnapHiC-D: a computational pipeline to identify differential chromatin contacts from single-cell Hi-C data.

Single-cell high-throughput chromatin conformation capture technologies (scHi-C) has been used to map chromatin spatial organization in complex tissues. However, computational tools to detect differential chromatin contacts (DCCs) from scHi-C datasets in development and through disease pathogenesis are still lacking. Here, we present SnapHiC-D, a computational pipeline to identify DCCs between two scHi-C datasets. Compared to methods designed for bulk Hi-C data, SnapHiC-D detects DCCs with high sensitivity and accuracy. We used SnapHiC-D to identify cell-type-specific chromatin contacts at 10 Kb resolution in mouse hippocampal and human prefrontal cortical tissues, demonstrating that DCCs detected in the hippocampal and cortical cell types are generally associated with cell-type-specific gene expression patterns and epigenomic features. SnapHiC-D is freely available at https://github.com/HuMingLab/SnapHiC-D.

SnapHiC: a computational pipeline to identify chromatin loops from single-cell Hi-C data.

Single-cell Hi-C (scHi-C) analysis has been increasingly used to map chromatin architecture in diverse tissue contexts, but computational tools to define chromatin loops at high resolution from scHi-C data are still lacking. Here, we describe Single-Nucleus Analysis Pipeline for Hi-C (SnapHiC), a method that can identify chromatin loops at high resolution and accuracy from scHi-C data. Using scHi-C data from 742 mouse embryonic stem cells, we benchmark SnapHiC against a number of computational tools developed for mapping chromatin loops and interactions from bulk Hi-C. We further demonstrate its use by analyzing single-nucleus methyl-3C-seq data from 2,869 human prefrontal cortical cells, which uncovers cell type-specific chromatin loops and predicts putative target genes for noncoding sequence variants associated with neuropsychiatric disorders. Our results indicate that SnapHiC could facilitate the analysis of cell type-specific chromatin architecture and gene regulatory programs in complex tissues.

Breast Cancer Patients' Preferred Source and Timing of Nutrition Information.

It is important that breast cancer patients know where they can access evidence-based nutrition information because misinformation may lead to confusion for patients regarding dietary requirements, as well as potentially causing harm to health. There are gaps in knowledge about where and when patients seek nutrition information. Our exploratory study used telephone interviews to investigate where patients with breast cancer obtained nutrition information pre and postdiagnosis, and their preferred sources and timing for receiving nutrition information. We interviewed 29 women diagnosed with breast cancer who had attended the Cross Cancer Institute in Edmonton, Alberta. The structured interview included 13 closed-ended questions and 1 open-ended question. Interviews revealed that motives for seeking nutrition information changed between pre and postdiagnosis, but the sources did not. The majority of participants did not access a registered dietitian (RD) postdiagnosis but did specify that meeting with a RD would be their preferred source of information. Responses varied for the preferred sources and timing of nutrition information provision. Our study suggests that further research is necessary to know how to best meet the nutrition information needs of patients diagnosed with breast cancer.

Demographic and environmental factors associated with disability in India, Laos, and Tajikistan: a population-based cross-sectional study.

BACKGROUND: The number of people experiencing functional limitations due to health conditions (capacity) is expected to increase in low and middle-income countries as populations age and rates of non-communicable disease rise. This trend could raise the prevalence and levels of disability worldwide. Understanding the demographic and environmental factors associated with disability can inform the design of policy interventions to make societies more accessible and inclusive for all. METHODS: Approximately 2,500-3,000 participants in each of India, Laos, and Tajikistan responded to the Gallup World Poll and the World Health Organization's Brief Model Disability Survey through face-to-face interviews. For each country, random forest regression was performed to explore the associations of demographic and environmental factors with disability while controlling for capacity. Using the variable importance measures generated by the random forest models, linear regression models were built in a stepwise manner for each country to predict disability level based on these contextual factors. RESULTS: Capacity was strongly associated with disability in all three countries. Most of the variance in disability was explained by minimally adjusted linear models that included only capacity, sex, and age. Inclusion of additional demographic factors and environmental factors explained slightly more of the variance in disability score. Across all three countries, the level of basic infrastructure, public services, and financial stability were moderately associated with disability. Age, sex, employment status, the use of assistive technologies, and other factors had associations with disability that were highly variable across countries. CONCLUSION: While capacity was the main determinant of disability, individual demographic and environmental factors were associated with disability in a country-specific manner while controlling for the effects of capacity.

Standardized Discharge Planning Tool Leads to Earlier Discharges and Fewer Readmissions.

BACKGROUND: In an inpatient setting, aspects of discharge planning are often left to the provider's memory, leading to errors, inefficiencies, and avoidable costs. METHODS: A multidisciplinary team of oncology practitioners used process improvement methodologies to redesign the discharge planning process. INTERVENTIONS: The primary intervention was an evidence-based discharge planning tool, called the discharge navigator, used from admission through discharge. RESULTS: Thirty-day unplanned readmission rates decreased by 29.0% from preimplementation (March 2017 through August 2017) to postimplementation (September 2017 through March 2020). The percentage of patients discharged before noon increased 76.2%. A comparable service not utilizing the intervention saw lesser or no improvement in these measures. CONCLUSION: The tool provided a systematic approach to discharge planning. Key design elements included a centralized location within the electronic health record and an electronic shortcut to populate the tool. Although developed for a specialized population, most elements are applicable to any hospitalized patient.

On the relationship between aerosol model uncertainty and radiative forcing uncertainty.

The largest uncertainty in the historical radiative forcing of climate is caused by the interaction of aerosols with clouds. Historical forcing is not a directly measurable quantity, so reliable assessments depend on the development of global models of aerosols and clouds that are well constrained by observations. However, there has been no systematic assessment of how reduction in the uncertainty of global aerosol models will feed through to the uncertainty in the predicted forcing. We use a global model perturbed parameter ensemble to show that tight observational constraint of aerosol concentrations in the model has a relatively small effect on the aerosol-related uncertainty in the calculated forcing between preindustrial and present-day periods. One factor is the low sensitivity of present-day aerosol to natural emissions that determine the preindustrial aerosol state. However, the major cause of the weak constraint is that the full uncertainty space of the model generates a large number of model variants that are equally acceptable compared to present-day aerosol observations. The narrow range of aerosol concentrations in the observationally constrained model gives the impression of low aerosol model uncertainty. However, these multiple "equifinal" models predict a wide range of forcings. To make progress, we need to develop a much deeper understanding of model uncertainty and ways to use observations to constrain it. Equifinality in the aerosol model means that tuning of a small number of model processes to achieve model-observation agreement could give a misleading impression of model robustness.

Occurrence of pristine aerosol environments on a polluted planet.

Natural aerosols define a preindustrial baseline state from which the magnitude of anthropogenic aerosol effects on climate are calculated and are a major component of the large uncertainty in anthropogenic aerosol-cloud radiative forcing. This uncertainty would be reduced if aerosol environments unperturbed by air pollution could be studied in the present--day atmosphere, but the pervasiveness of air pollution makes identification of unperturbed regions difficult. Here, we use global model simulations to define unperturbed aerosol regions in terms of two measures that compare 1750 and 2000 conditions-the number of days with similar aerosol concentrations and the similarity of the aerosol response to perturbations in model processes and emissions. The analysis shows that the aerosol system in many present-day environments looks and behaves like it did in the preindustrial era. On a global annual mean, unperturbed aerosol regions cover 12% of the Earth (16% of the ocean surface and 2% of the land surface). There is a strong seasonal variation in unperturbed regions of between 4% in August and 27% in January, with the most persistent conditions occurring over the equatorial Pacific. About 90% of unperturbed regions occur in the Southern Hemisphere, but in the Northern Hemisphere, unperturbed conditions are transient and spatially patchy. In cloudy regions with a radiative forcing relative to 1750, model results suggest that unperturbed aerosol conditions could still occur on a small number of days per month. However, these environments are mostly in the Southern Hemisphere, potentially limiting the usefulness in reducing Northern Hemisphere forcing uncertainty.

Potential negative consequences of geoengineering on crop production: A study of Indian groundnut.

Geoengineering has been proposed to stabilize global temperature, but its impacts on crop production and stability are not fully understood. A few case studies suggest that certain crops are likely to benefit from solar dimming geoengineering, yet we show that geoengineering is projected to have detrimental effects for groundnut. Using an ensemble of crop-climate model simulations, we illustrate that groundnut yields in India undergo a statistically significant decrease of up to 20% as a result of solar dimming geoengineering relative to RCP4.5. It is somewhat reassuring, however, to find that after a sustained period of 50 years of geoengineering crop yields return to the nongeoengineered values within a few years once the intervention is ceased.

HPTAD: A computational method to identify topologically associating domains from HiChIP and PLAC-seq datasets.

High-throughput chromatin conformation capture technologies, such as Hi-C and Micro-C, have enabled genome-wide view of chromatin spatial organization. Most recently, Hi-C-derived enrichment-based technologies, including HiChIP and PLAC-seq, offer attractive alternatives due to their high signal-to-noise ratio and low cost. While a series of computational tools have been developed for Hi-C data, methods tailored for HiChIP and PLAC-seq data are still under development. Here we present HPTAD, a computational method to identify topologically associating domains (TADs) from HiChIP and PLAC-seq data. We performed comprehensive benchmark analysis to demonstrate its superior performance over existing TAD callers designed for Hi-C data. HPTAD is freely available at https://github.com/yunliUNC/HPTAD.

SnapFISH: a computational pipeline to identify chromatin loops from multiplexed DNA FISH data.

Multiplexed DNA fluorescence in situ hybridization (FISH) imaging technologies have been developed to map the folding of chromatin fibers at tens of nanometers and up to several kilobases in resolution in single cells. However, computational methods to reliably identify chromatin loops from such imaging datasets are still lacking. Here we present a Single-Nucleus Analysis Pipeline for multiplexed DNA FISH (SnapFISH), to process the multiplexed DNA FISH data and identify chromatin loops. SnapFISH can identify known chromatin loops from mouse embryonic stem cells with high sensitivity and accuracy. In addition, SnapFISH obtains comparable results of chromatin loops across datasets generated from diverse imaging technologies. SnapFISH is freely available at https://github.com/HuMingLab/SnapFISH .

Connecting pathogen transmission and healthcare worker cognition: a cognitive task analysis of infection prevention and control practices during simulated patient care.

BACKGROUND: Relatively little is known about the cognitive processes of healthcare workers that mediate between performance-shaping factors (eg, workload, time pressure) and adherence to infection prevention and control (IPC) practices. We taxonomised the cognitive work involved in IPC practices and assessed its role in how pathogens spread. METHODS: Forty-two registered nurses performed patient care tasks in a standardised high-fidelity simulation. Afterwards, participants watched a video of their simulation and described what they were thinking, which we analysed to obtain frequencies of macrocognitive functions (MCFs) in the context of different IPC practices. Performance in the simulation was the frequency at which participants spread harmless surrogates for pathogens (bacteriophages). Using a tertiary split, participants were categorised into a performance group: high, medium or low. To identify associations between the three variables-performance groups, MCFs and IPC practices-we used multiblock discriminant correspondence analysis (MUDICA). RESULTS: MUDICA extracted two factors discriminating between performance groups. Factor 1 captured differences between high and medium performers. High performers monitored the situation for contamination events and mitigated risks by applying formal and informal rules or managing their uncertainty, particularly for sterile technique and cleaning. Medium performers engaged more in future-oriented cognition, anticipating contamination events and planning their workflow, across many IPC practices. Factor 2 distinguished the low performers from the medium and high performers who mitigated risks with informal rules and sacrificed IPC practices when managing tradeoffs, all in the context of minimising cross-contamination from physical touch. CONCLUSIONS: To reduce pathogen transmission, new approaches to training IPC (eg, cognitive skills training) and system design are needed. Interventions should help nurses apply their knowledge of IPC fluidly during patient care, prioritising and monitoring situations for risks and deciding how to mitigate risks. Planning IPC into one's workflow is beneficial but may not account for the unpredictability of patient care.

Nuclear condensates of YAP fusion proteins alter transcription to drive ependymoma tumourigenesis.

Nuclear localization of HIPPO-YAP fusion proteins has been implicated in supratentorial ependymoma development. Here, unexpectedly, we find that liquid-liquid phase separation, rather than nuclear localization, of recurrent patient-derived YAP fusions, YAP-MAMLD1 and C11ORF95-YAP, underlies ependymoma tumourigenesis from neural progenitor cells. Mutagenesis and chimaera assays demonstrate that an intrinsically disordered region promotes oligomerization of the YAP fusions into nuclear, puncta-like, membrane-less condensates. Oligomerization and nuclear condensates induced by YAP fusion with a coiled-coil domain of transcriptional activator GCN4 also promote ependymoma formation. YAP-MAMLD1 concentrates transcription factors and co-activators, including BRD4, MED1 and TEAD, in condensates while excluding transcriptional repressive PRC2, and induces long-range enhancer-promoter interactions that promote transcription and oncogenic programmes. Blocking condensate-mediated transcriptional co-activator activity inhibits tumourigenesis, indicating a critical role of liquid phase separation for YAP fusion oncogenic activity in ependymoma. YAP fusions containing the intrinsically disordered region features are common in human tumours, suggesting that nuclear condensates could be targeted to treat YAP-fusion-induced cancers.

WHO Functioning and Disability Disaggregation (FDD11) tool: a reliable approach for disaggregating data by disability.

BACKGROUND: There is a global scarcity of good quality disability data, which has contributed to a lack of political will to address the challenges that persons with disabilities face. The current paper proposes a way forward to overcome this gap by demonstrating the psychometric properties of the World Health Organization Functioning and Disability Disaggregation Tool (FDD11) - a brief disability disaggregation instrument that countries can use. RESULTS: The study demonstrated that FDD11 is a valid and reliable tool. Unidimensionality of the scale produced by each calibration was supported by the factor analysis performed. The analysis indicated good fit of the items, and targeting of the items was deemed to be sufficient. The person separation index was 0.82, indicating good reliability of the final scale. CONCLUSION: FDD11 provides a good opportunity to researchers and governments to capture good quality disability data and to disaggregate existing data by disability. The tool can facilitate low- and middle-income countries in their efforts to develop evidenced-based policies to address any barriers faced by persons with disabilities, to monitor the implementation of the Convention on the Rights of Persons with Disabilities and the Sustainable Development Goals, and to take stock of the challenges that still remain.

SnapHiC2: A computationally efficient loop caller for single cell Hi-C data.

Single cell Hi-C (scHi-C) technologies enable the study of chromatin spatial organization directly from complex tissues at single cell resolution. However, the identification of chromatin loops from single cells is challenging, largely due to the extremely sparse data. Our recently developed SnapHiC pipeline provides the first tool to map chromatin loops from scHi-C data, but it is computationally intensive. Here we introduce SnapHiC2, which adapts a sliding window approximation when imputing missing contacts in each single cell and reduces both memory usage and computational time by 70%. SnapHiC2 can identify 5 Kb resolution chromatin loops with high sensitivity and accuracy and help to suggest target genes for GWAS variants in a cell-type-specific manner. SnapHiC2 is freely available at: https://github.com/HuMingLab/SnapHiC/releases/tag/v0.2.2.

Generating comprehensive functioning and disability data worldwide: development process, data analyses strategy and reliability of the WHO and World Bank Model Disability Survey.

BACKGROUND: Data on functioning and disability collected at population level is essential to complement mortality and morbidity, to estimate rehabilitation needs of countries and regions and to monitor the Convention on the Rights of Persons with Disabilities (CRPD) and the Sustainable Development Goals (SDGs). The objective of this paper is to briefly report the development process of the WHO Model Disability Survey, its data analysis strategy as well as its reliability and ability to measure low to high levels of functioning and disability across countries. METHODS: The development process is described in detail, and a secondary analysis using Rasch methods is conducted to report reliability and targeting using data from eight national and two regional implementations of the survey. RESULTS: The currently available versions of the Model Disability Survey are presented. The survey has good to very good internal reliability and good targeting in all included countries. CONCLUSION: The participatory and evidence-based development, consideration of the expertise of stakeholders, the availability of previously developed ICF-based surveys, and WHO tools targeting functioning and disability are reflected in its good to very good psychometric properties. The survey has been implemented to date in Afghanistan, Cameroon, Chile, Costa Rica, India, Laos, Pakistan, Philippines, Sri Lanka, and Tajikistan, and is used to inform policy-making, to monitor the CRPD and SDGs and to plan the delivery of rehabilitation services.

Identifying key environmental barriers experienced by persons with mild, moderate, or severe disability in Bankim Health District, Cameroon: a policy-targeted secondary analysis of data obtained with the World Bank and WHO model disability survey.

BACKGROUND: Comprehensive data is key for evidence-informed policy aiming to improve the lives of persons experiencing different levels of disability. The objective of this paper was to identify the environmental barriers - including physical, social, attitudinal, and political barriers - that might become priorities for cross-cutting policies and policies tailored to the needs of persons experiencing severe disability in Cameroon. METHODS: A secondary analysis of data obtained with the WHO Model Disability Survey was completed in the Bankim Health District (N = 559) using random forest regression to determine and compare the impact of the environmental factors on the experience of disability. RESULTS: The physical environment had by far the highest influence on disability, with transportation, toilet of the dwelling, and the dwelling itself being the most important factors. Factors inside one's own home (toilet of the dwelling, and the dwelling itself) were the most important for persons with moderate and severe disability, followed by attitudes of others and issues with accessing health care. CONCLUSION: Our study provides country policy makers with evidence for setting priorities and for the development of evidence-informed policies for the Bankim Health District in Cameroon.

Measuring functioning and disability using household surveys: metric properties of the brief version of the WHO and World Bank model disability survey.

BACKGROUND: The Model Disability Survey (MDS) is the current standard recommended by WHO to collect functioning and disability data. Answering calls from countries requesting a version to be implemented as a module that could be integrated into existing surveys and be used for monitoring disability trends and for data disaggregation, WHO developed the brief MDS. The objectives of this paper are to evaluate the metric properties of the disability metrics generated with the Brief MDS and the precision of the Brief MDS in comparison with the full MDS. RESULTS: The partial credit model, a unidimensional model for polytomous data from the Rasch family, was applied to evaluate psychometric properties using data from national MDS implementations in Chile (N = 12,265) and in Sri Lanka (N = 3000). The Brief MDS generates valid metrics for measuring disability, from the perspectives of capacity and performance, thereby achieving good levels of measurement precision in comparison with its full counterpart. CONCLUSION: Given the scarcity of valid functioning and disability modules for household surveys, the Brief MDS represents a milestone in disability measurement. The Brief MDS is currently used by countries to monitor disability trends over time, which is especially important to evaluate the impact of health policies and public health interventions, to disaggregate indicators of the Sustainable Development Goals, and to monitor the implementation of the UN Convention on the Rights of Persons with Disabilities (CRPD).