Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders.

Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.

A maternally inherited frameshift CDKL5 variant in a male with global developmental delay and late-onset generalized epilepsy.

Pathogenic CDKL5 variants cause an X-linked dominant infantile epileptic encephalopathy, predominantly in females. This condition is characterized by an early-onset severe mixed seizure disorder. We present a maternally inherited frameshift CDKL5 c.2809_2810insA p.(Cys937Ter) variant in a 13-year-old male with severe intellectual disability and late-onset generalized epilepsy. Interestingly, the variant segregation in the family is consistent with an X-linked recessive inheritance pattern, which has not previously been described with this gene. This variant is expected to result in truncation of some CDKL5 transcripts, which could potentially account for the later seizure onset and atypical inheritance pattern. Though the possibility of this variant not being causal cannot be completely excluded, this case adds to the variability of the documented phenotypic profile and to the debate around the role of C-terminus variants in CDKL5-related disease.

The Process of Disclosure: Mothers' Experiences of Communicating X-Linked Carrier Risk Information to At-Risk Daughters.

When a boy is diagnosed with an X-linked condition such as Duchenne or Becker muscular dystrophy (D/BMD), the mother learns not only of her own potential carrier risk but also that of her daughters. Before the daughters are seen in the Genetics Clinic, responsibility for disclosing carrier risk information falls mainly to their mothers. We know little about if when and how these daughters are being told about their risk, and how mothers find the experience. Should we be doing more to help and support them? Using qualitative methods, six mothers known to the Manchester Centre for Genomic Medicine were interviewed about the disclosure of D/BMD carrier risk information to their daughters. The four key themes that arose are presented: communication process, facilitators of disclosure, barriers to disclosure and support and information. Despite the participants' endeavours to be open and honest with their daughters and their belief that they had fully disclosed, key information was often withheld. Major barriers to discussion of the future, including reproductive options, were apparent. These were partly overcome by the involvement of genetic counsellors (GCs). The participants suggested a greater involvement of GCs, proactively sending appointments and written information, and offering carrier testing more flexibly.

Methane Ebullition in Temperate Hydropower Reservoirs and Implications for US Policy on Greenhouse Gas Emissions.

The United States is home to 2198 dams actively used for hydropower production. With the December 2015 consensus adoption of the United Nations Framework Convention on Climate Change Paris Agreement, it is important to accurately quantify anthropogenic greenhouse gas emissions. Methane ebullition, or methane bubbles originating from river or lake sediments, has been shown to account for nearly all methane emissions from tropical hydropower reservoirs to the atmosphere. However, distinct ebullitive methane fluxes have been studied in comparatively few temperate hydropower reservoirs globally. This study measures ebullitive and diffusive methane fluxes from two eastern Washington reservoirs, and synthesizes existing studies of methane ebullition in temperate, boreal, and tropical hydropower reservoirs. Ebullition comprises nearly all methane emissions (>97%) from this study's two eastern Washington hydropower reservoirs to the atmosphere. Summer methane ebullition from these reservoirs was higher than ebullition in six southeastern U.S. hydropower reservoirs, however it was similar to temperate reservoirs in other parts of the world. Our literature synthesis suggests that methane ebullition from temperate hydropower reservoirs can be seasonally elevated compared to tropical climates, however annual emissions are likely to be higher within tropical climates, emphasizing the possible range of methane ebullition fluxes and the need for the further study of temperate reservoirs. Possible future changes to the Intergovernmental Panel on Climate Change and UNFCCC guidelines for national greenhouse gas inventories highlights the need for accurate assessment of reservoir emissions.

Exploring international gender differences in mathematics self-concept.

This study provides an international perspective on mathematics by examnnng mathematics self-concept, achievement, and the desire to enter a career involving mathematics among eighth graders in 49 countries. Using data from the Trends in International Mathematics and Science Study, this study shows that self-concept in mathematics is more closely related to the desire to enter a career using mathematics than achievement is. Further, while gender differences in mathematics self-concept are smaller in more egalitarian countries, both girls and boys have lower mathematics self-concepts and less interest in mathematics careers in these countries. These findings reveal a policy paradox: policies aimed at training the next generation of STEM professionals often highlight the need to close the gender gap, but countries with smaller gender gaps have fewer boys and girls interested in mathematics-intensive careers. We conclude by highlighting the importance of disentangling instrumental and expressive aspects of gender inequality in STEM fields.

Spatial and temporal metagenomics of river compartments reveals viral community dynamics in an urban impacted stream.

Although river ecosystems comprise less than 1% of Earth's total non-glaciated area, they are critical modulators of microbially and virally orchestrated global biogeochemical cycles. However, most studies either use data that is not spatially resolved or is collected at timepoints that do not reflect the short life cycles of microorganisms. As a result, the relevance of microbiome interactions and the impacts they have over time on biogeochemical cycles are poorly understood. To assess how viral and microbial communities change over time, we sampled surface water and pore water compartments of the wastewater-impacted River Erpe in Germany every 3 hours over a 48-hour period resulting in 32 metagenomes paired to geochemical and metabolite measurements. We reconstructed 6,500 viral and 1,033 microbial genomes and found distinct communities associated with each river compartment. We show that 17% of our vMAGs clustered to viruses from other ecosystems like wastewater treatment plants and rivers. Our results also indicated that 70% of the viral community was persistent in surface waters, whereas only 13% were persistent in the pore waters taken from the hyporheic zone. Finally, we predicted linkages between 73 viral genomes and 38 microbial genomes. These putatively linked hosts included members of the Competibacteraceae, which we suggest are potential contributors to carbon and nitrogen cycling. Together, these findings demonstrate that microbial and viral communities in surface waters of this urban river can exist as stable communities along a flowing river; and raise important considerations for ecosystem models attempting to constrain dynamics of river biogeochemical cycles.

A functional microbiome catalog crowdsourced from North American rivers.

Predicting elemental cycles and maintaining water quality under increasing anthropogenic influence requires understanding the spatial drivers of river microbiomes. However, the unifying microbial processes governing river biogeochemistry are hindered by a lack of genome-resolved functional insights and sampling across multiple rivers. Here we employed a community science effort to accelerate the sampling, sequencing, and genome-resolved analyses of river microbiomes to create the Genome Resolved Open Watersheds database (GROWdb). This resource profiled the identity, distribution, function, and expression of thousands of microbial genomes across rivers covering 90% of United States watersheds. Specifically, GROWdb encompasses 1,469 microbial species from 27 phyla, including novel lineages from 10 families and 128 genera, and defines the core river microbiome for the first time at genome level. GROWdb analyses coupled to extensive geospatial information revealed local and regional drivers of microbial community structuring, while also presenting a myriad of foundational hypotheses about ecosystem function. Building upon the previously conceived River Continuum Concept 1 , we layer on microbial functional trait expression, which suggests the structure and function of river microbiomes is predictable. We make GROWdb available through various collaborative cyberinfrastructures 2, 3 so that it can be widely accessed across disciplines for watershed predictive modeling and microbiome-based management practices.

A cross-sectional assessment of stroke rehabilitation in Nebraska hospitals.

OBJECTIVE: To assess the structure and process of stroke rehabilitation in Nebraska hospitals. DESIGN: Cross-sectional mail survey using the Dillman tailored-design method of administration. SETTING: Hospitals in Nebraska. PARTICIPANTS: Approximately 77% of the 84 Nebraska hospitals that provide stroke rehabilitation are critical access hospitals (CAHs) that are limited to 25 beds. Our study sample of hospitals (N=53) included the 19 hospitals licensed for 47 to 689 beds (non-CAHs) and a stratified random sample of 34 of the 65 CAHs. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Self-reported stroke rehabilitation team structure and processes, purposes of and barriers to the use of evidence-based standardized assessments, specific assessments used, and access to specialized stroke rehabilitation services and community resources. RESULTS: Thirty-six (68%) of the 53 hospitals responded to the survey. Approximately 61% of the hospitals used an organized team to provide stroke rehabilitation; 8% of the hospitals-all non-CAHs-had a team dedicated to stroke rehabilitation. After adjusting for hospital size, having an organized team was significantly associated with the use of standardized assessments to improve communication, measure progress and outcomes, evaluate effectiveness of practice, and compare patient outcomes across conditions. Access to specialized stroke rehabilitation professionals and services was significantly greater in non-CAHs. CONCLUSIONS: Hospital size and the presence of a team are determinants of the structure and process of stroke rehabilitation in Nebraska hospitals. Further research is needed to determine (1) whether team structure is a determinant of stroke rehabilitation outcomes across the continuum of care settings, (2) the needs of rural stroke survivors, and (3) whether technology can facilitate the use of stroke rehabilitation standardized assessments by rural health care professionals.

It's Never Too Late: Debunking Myths About Communication and Adults With Severe Disabilities.

Communication infuses all dimensions and stages of life, influencing one's self-determination and quality of life. A number of empirical studies have demonstrated that people with severe disabilities continue to develop communication and language skills well into their adult years and make measurable gains when provided with appropriate communication services and supports. Several myths about age, ability, and experiences limit opportunities for persons with severe disabilities. In this paper, we confront and address these myths.

Enabling FAIR data in Earth and environmental science with community-centric (meta)data reporting formats.

Research can be more transparent and collaborative by using Findable, Accessible, Interoperable, and Reusable (FAIR) principles to publish Earth and environmental science data. Reporting formats-instructions, templates, and tools for consistently formatting data within a discipline-can help make data more accessible and reusable. However, the immense diversity of data types across Earth science disciplines makes development and adoption challenging. Here, we describe 11 community reporting formats for a diverse set of Earth science (meta)data including cross-domain metadata (dataset metadata, location metadata, sample metadata), file-formatting guidelines (file-level metadata, CSV files, terrestrial model data archiving), and domain-specific reporting formats for some biological, geochemical, and hydrological data (amplicon abundance tables, leaf-level gas exchange, soil respiration, water and sediment chemistry, sensor-based hydrologic measurements). More broadly, we provide guidelines that communities can use to create new (meta)data formats that integrate with their scientific workflows. Such reporting formats have the potential to accelerate scientific discovery and predictions by making it easier for data contributors to provide (meta)data that are more interoperable and reusable.

Ecological theory applied to environmental metabolomes reveals compositional divergence despite conserved molecular properties.

Stream and river systems transport and process substantial amounts of dissolved organic matter (DOM) from terrestrial and aquatic sources to the ocean, with global biogeochemical implications. However, the underlying mechanisms affecting the spatiotemporal organization of DOM composition are under-investigated. To understand the principles governing DOM composition, we leverage the recently proposed synthesis of metacommunity ecology and metabolomics, termed 'meta-metabolome ecology.' Applying this novel approach to a freshwater ecosystem, we demonstrated that despite similar molecular properties across metabolomes, metabolite identity significantly diverged due to environmental filtering and variations in putative biochemical transformations. We refer to this phenomenon as 'thermodynamic redundancy,' which is analogous to the ecological concept of functional redundancy. We suggest that under thermodynamic redundancy, divergent metabolomes can support equivalent biogeochemical function just as divergent ecological communities can support equivalent ecosystem function. As these analyses are performed in additional ecosystems, potentially generalizable concepts, like thermodynamic redundancy, can be revealed and provide insight into DOM dynamics.

WHONDRS-GUI: a web application for global survey of surface water metabolites.

BACKGROUND: The Worldwide Hydrobiogeochemistry Observation Network for Dynamic River Systems (WHONDRS) is a consortium that aims to understand complex hydrologic, biogeochemical, and microbial connections within river corridors experiencing perturbations such as dam operations, floods, and droughts. For one ongoing WHONDRS sampling campaign, surface water metabolite and microbiome samples are collected through a global survey to generate knowledge across diverse river corridors. Metabolomics analysis and a suite of geochemical analyses have been performed for collected samples through the Environmental Molecular Sciences Laboratory (EMSL). The obtained knowledge and data package inform mechanistic and data-driven models to enhance predictions of outcomes of hydrologic perturbations and watershed function, one of the most critical components in model-data integration. To support efforts of the multi-domain integration and make the ever-growing data package more accessible for researchers across the world, a Shiny/R Graphical User Interface (GUI) called WHONDRS-GUI was created. RESULTS: The web application can be run on any modern web browser without any programming or operational system requirements, thus providing an open, well-structured, discoverable dataset for WHONDRS. Together with a context-aware dynamic user interface, the WHONDRS-GUI has functionality for searching, compiling, integrating, visualizing and exporting different data types that can easily be used by the community. The web application and data package are available at https://data.ess-dive.lbl.gov/view/doi:10.15485/1484811, which enables users to simultaneously obtain access to the data and code and to subsequently run the web app locally. The WHONDRS-GUI is also available for online use at Shiny Server (https://xmlin.shinyapps.io/whondrs/).

Using metacommunity ecology to understand environmental metabolomes.

Environmental metabolomes are fundamentally coupled to microbially-linked biogeochemical processes within ecosystems. However, significant gaps exist in our understanding of their spatiotemporal organization, limiting our ability to uncover transferrable principles and predict ecosystem function. We propose that a theoretical paradigm, which integrates concepts from metacommunity ecology, is necessary to reveal underlying mechanisms governing metabolomes. We call this synthesis between ecology and metabolomics 'meta-metabolome ecology' and demonstrate its utility using a mass spectrometry dataset. We developed three relational metabolite dendrograms using molecular properties and putative biochemical transformations and performed ecological null modeling. Based upon null modeling results, we show that stochastic processes drove molecular properties while biochemical transformations were structured deterministically. We further suggest that potentially biochemically active metabolites were more deterministically assembled than less active metabolites. Understanding variation in the influences of stochasticity and determinism provides a way to focus attention on which meta-metabolomes and which parts of meta-metabolomes are most likely to be important to consider in mechanistic models. We propose that this paradigm will allow researchers to study the connections between ecological systems and their molecular processes in previously inaccessible detail.

Using Community Science to Reveal the Global Chemogeography of River Metabolomes.

River corridor metabolomes reflect organic matter (OM) processing that drives aquatic biogeochemical cycles. Recent work highlights the power of ultrahigh-resolution mass spectrometry for understanding metabolome composition and river corridor metabolism. However, there have been no studies on the global chemogeography of surface water and sediment metabolomes using ultrahigh-resolution techniques. Here, we describe a community science effort from the Worldwide Hydrobiogeochemistry Observation Network for Dynamic River Systems (WHONDRS) consortium to characterize global metabolomes in surface water and sediment that span multiple stream orders and biomes. We describe the distribution of key aspects of metabolomes including elemental groups, chemical classes, indices, and inferred biochemical transformations. We show that metabolomes significantly differ across surface water and sediment and that surface water metabolomes are more rich and variable. We also use inferred biochemical transformations to identify core metabolic processes shared among surface water and sediment. Finally, we observe significant spatial variation in sediment metabolites between rivers in the eastern and western portions of the contiguous United States. Our work not only provides a basis for understanding global patterns in river corridor biogeochemical cycles but also demonstrates that community science endeavors can enable global research projects that are unfeasible with traditional research models.

WHONDRS: a Community Resource for Studying Dynamic River Corridors.

The Worldwide Hydrobiogeochemistry Observation Network for Dynamic River Systems (WHONDRS) aims to galvanize a global community to provide the scientific basis for improved management of dynamic river corridors. WHONDRS is a global research consortium working to understand connections among dynamic hydrology, biogeochemistry, and microbiology in river corridors from local to global scales. WHONDRS ascribes to the perspective that resources, knowledge, and data belong to the community as a whole and that science advances more rapidly and more robustly through community ownership. As such, WHONDRS provides free access to novel instrumentation, molecular analysis, and well-curated data associated with river corridor hydrology, biogeochemistry, and microbiology. There are a number of ways to be involved in WHONDRS, ranging from one-time surface water sampling to installation of WHONDRS-developed multiparameter sensors for continuous monitoring. WHONDRS hinges on broad involvement, and we encourage all interested parties to contact us and become part of the consortium.

MAGDALENA: study protocol of a randomised, placebo-controlled trial on cognitive development at 2 years of age in children exposed to SSRI in utero.

INTRODUCTION: Ten per cent of all pregnant women are depressed. Standard therapy of pregnant women with moderate depression is selective serotonin reuptakeinhibitors (SSRI). Observational studies on neurodevelopment after fetal SSRI exposure show conflicting results. Our primary objective is to compare the cognitive development in children exposed to sertraline and maternal depression with those exposed to maternal depression and placebo in utero. We hypothesise that there is a significant neurodevelopmental difference between the groups. As a secondary objective, we study the add-on effect of sertraline to internet-based cognitive behavioural therapy (ICBT) to treat moderate depression during pregnancy. METHODS AND ANALYSIS: MAGDALENA is a randomised, placebo-controlled, double-blinded trial in Stockholm Healthcare Region with 2.3 million inhabitants. The women are recruited in weeks 9-21 of pregnancy either through Antenatal Health Clinics or through social media. They are to be diagnosed with moderate depression without ongoing antidepressive therapy or any serious comorbidity. The women in the intervention arm receive sertraline combined with a 12-week period of ICBT; the control arm is treated with placebo and ICBT. We assess the cognitive development in the offspring at the age of 2 years using Bayley Scales of Infant and Toddler Development, third edition (BSID-III). We aim at recruiting 200 women, 100 women in each treatment arm, to ensure statistical power to detect a clinically relevant difference between the groups. ETHICS AND DISSEMINATION: This randomised trial will provide long-sought evidence about the effects of SSRI and maternal depression during pregnancy on the neurodevelopment in the offspring. The study is approved by the Regional Ethical Review Board at Karolinska Institutet in Stockholm and the Swedish Medical Products Agency. It is registered with the European Clinical Trials Database (EudraCT), Number: 2013-004444-31. Results will be disseminated at scientific conferences, published in peer-reviewed journals and made available to the public. TRIAL REGISTRATION NUMBER: EudraCT2013-004444-31; Pre-results.

Partial body weight support treadmill training speed influences paretic and non-paretic leg muscle activation, stride characteristics, and ratings of perceived exertion during acute stroke rehabilitation.

BACKGROUND: Intensive task-specific training is promoted as one approach for facilitating neural plastic brain changes and associated motor behavior gains following neurologic injury. Partial body weight support treadmill training (PBWSTT), is one task-specific approach frequently used to improve walking during the acute period of stroke recovery (<1month post infarct). However, only limited data have been published regarding the relationship between training parameters and physiologic demands during this early recovery phase. OBJECTIVE: To examine the impact of four walking speeds on stride characteristics, lower extremity muscle demands (both paretic and non-paretic), Borg ratings of perceived exertion (RPE), and blood pressure. DESIGN: A prospective, repeated measures design was used. METHODS: Ten inpatients post unilateral stroke participated. Following three familiarization sessions, participants engaged in PBWSTT at four predetermined speeds (0.5, 1.0, 1.5 and 2.0mph) while bilateral electromyographic and stride characteristic data were recorded. RPE was evaluated immediately following each trial. RESULTS: Stride length, cadence, and paretic single limb support increased with faster walking speeds (p⩽0.001), while non-paretic single limb support remained nearly constant. Faster walking resulted in greater peak and mean muscle activation in the paretic medial hamstrings, vastus lateralis and medial gastrocnemius, and non-paretic medial gastrocnemius (p⩽0.001). RPE also was greatest at the fastest compared to two slowest speeds (p<0.05). CONCLUSIONS: During the acute phase of stroke recovery, PBWSTT at the fastest speed (2.0mph) promoted practice of a more optimal gait pattern with greater intensity of effort as evidenced by the longer stride length, increased between-limb symmetry, greater muscle activation, and higher RPE compared to training at the slowest speeds.

Communication Services and Supports for Individuals With Severe Disabilities: Guidance for Assessment and Intervention.

The National Joint Committee for the Communication Needs of People With Severe Disabilities (NJC) reviewed literature regarding practices for people with severe disabilities in order to update guidance provided in documents originally published in 1992. Changes in laws, definitions, and policies that affect communication attainments by persons with severe disabilities are presented, along with guidance regarding assessment and intervention practices. A revised version of the Communication Bill of Rights, a powerful document that describes the communication rights of all individuals, including those with severe disabilities is included in this article. The information contained within this article is intended to be used by professionals, family members, and individuals with severe disabilities to inform and advocate for effective communication services and opportunities.

Comparative kinematic and electromyographic assessment of clinician- and device-assisted sit-to-stand transfers in patients with stroke.

BACKGROUND: Workplace injuries from patient handling are prevalent. With the adoption of no-lift policies, sit-to-stand transfer devices have emerged as one tool to combat injuries. However, the therapeutic value associated with sit-to-stand transfers with the use of an assistive apparatus cannot be determined due to a lack of evidence-based data. OBJECTIVE: The aim of this study was to compare clinician-assisted, device-assisted, and the combination of clinician- and device-assisted sit-to-stand transfers in individuals who recently had a stroke. DESIGN: This cross-sectional, controlled laboratory study used a repeated-measures design. METHODS: The duration, joint kinematics, and muscle activity of 4 sit-to-stand transfer conditions were compared for 10 patients with stroke. Each patient performed 4 randomized sit-to-stand transfer conditions: clinician-assisted, device-assisted with no patient effort, device-assisted with the patient's best effort, and device- and clinician-assisted. RESULTS: Device-assisted transfers took nearly twice as long as clinician-assisted transfers. Hip and knee joint movement patterns were similar across all conditions. Forward trunk flexion was lacking and ankle motion was restrained during device-assisted transfers. Encouragement and guidance from the clinician during device-assisted transfers led to increased lower extremity muscle activation levels. LIMITATIONS: One lifting device and one clinician were evaluated. Clinician effort could not be controlled. CONCLUSIONS: Lack of forward trunk flexion and restrained ankle movement during device-assisted transfers may dissuade clinicians from selecting this device for use as a dedicated rehabilitation tool. However, with clinician encouragement, muscle activation increased, which suggests that it is possible to safely practice transfers while challenging key leg muscles essential for standing. Future sit-to-stand devices should promote safety for the patient and clinician and encourage a movement pattern that more closely mimics normal sit-to-stand biomechanics.