Applying data science methodologies with artificial intelligence variant reinterpretation to map and estimate genetic disorder prevalence utilizing clinical data.

Data science methodologies can be utilized to ascertain and analyze clinical genetic data that is often unstructured and rarely used outside of patient encounters. Genetic variants from all genetic testing resulting to a large pediatric healthcare system for a 5-year period were obtained and reinterpreted utilizing the previously validated Franklin© Artificial Intelligence (AI). Using PowerBI©, the data were further matched to patients in the electronic healthcare record to associate with demographic data to generate a variant data table and mapped by ZIP codes.

Alpha-mannosidosis: a case with novel ultrastructural and light microscopy findings.

Objectives: Alpha-mannosidosis is a rare genetic lysosomal storage condition leading to the systemic buildup of oligomannoside. Clinical presentation and associated conditions, as well as the full extent of histopathologic changes associated with this disease process, are not fully understood.

Case Presentation: We present the case of an 8-year-1-month old patient with persistent anemia and who was initially diagnosed with Celiac disease before ultimately being diagnosed with alpha-mannosidosis.

Transcriptomic analysis of paired healthy human skeletal muscles to identify modulators of disease severity in DMD.

Muscle damage and fibro-fatty replacement of skeletal muscles is a main pathologic feature of Duchenne muscular dystrophy (DMD) with more proximal muscles affected earlier and more distal affected later in the disease course, suggesting that different skeletal muscle groups possess distinctive characteristics that influence their susceptibility to disease. To explore transcriptomic factors driving differential gene expression and modulating DMD skeletal muscle severity, we characterized the transcriptome of vastus lateralis (VL), a more proximal and susceptible muscle, relative to tibialis anterior (TA), a more distal and protected muscle, in 15 healthy individuals using bulk RNA sequencing to identify gene expression differences that may mediate their relative susceptibility to damage with loss of dystrophin. Matching single nuclei RNA sequencing data was generated for 3 of the healthy individuals, to infer cell composition in the bulk RNA sequencing dataset and to improve mapping of differentially expressed genes to their cell source of expression.

Expression of SRP-9001 dystrophin and stabilization of motor function up to 2 years post-treatment with delandistrogene moxeparvovec gene therapy in individuals with Duchenne muscular dystrophy.

Delandistrogene moxeparvovec (SRP-9001) is an investigational gene transfer therapy designed for targeted expression of SRP-9001 dystrophin protein, a shortened dystrophin retaining key functional domains of the wild-type protein. This Phase 2, double-blind, two-part (48 weeks per part) crossover study (SRP-9001-102 [Study 102]; NCT03769116) evaluated delandistrogene moxeparvovec in patients, aged ≥4 to <8 years with Duchenne muscular dystrophy. Primary endpoints (Part 1) were change from baseline (CFBL) in SRP-9001 dystrophin expression (Week 12), by Western blot, and in North Star Ambulatory Assessment (NSAA) score (Week 48).

An integrated framework for optimal infrastructure planning for decarbonising heating.

This paper presents the HEGIT (Heat, Electricity and Gas Infrastructure and Technology) model for optimal infrastructure planning for decarbonising heating in buildings. HEGIT is an optimisation model based on Mixed Integer Linear Programming. The model co-optimises the integrated operation and capacity expansion planning of electricity and gas grids as well as heating technologies on the consumer side while maintaining the security of supply and subject to different environmental, operational and system-wide constraints.

A homozygous Gly470Ala variant in PEX6 causes severe Zellweger spectrum disorder.

Zellweger spectrum disorder (ZSD) is a group of autosomal recessive disorders caused by biallelic pathogenic variants in any one of the 13 PEX genes essential for peroxisomal biogenesis. We report a cohort of nine infants who presented at birth with severe neonatal features suggestive of ZSD and found to be homozygous for a variant in PEX6 (NM_000287.4:c.

MT-ATP6 mitochondrial disease identified by newborn screening reveals a distinct biochemical phenotype.

Although decreased citrulline is used as a newborn screening (NBS) marker to identify proximal urea cycle disorders (UCDs), it is also a feature of some mitochondrial diseases, including MT-ATP6 mitochondrial disease. Here we describe biochemical and clinical features of 11 children born to eight mothers from seven separate families who were identified with low citrulline by NBS (range 3-5 μM; screening cutoff >5) and ultimately diagnosed with MT-ATP6 mitochondrial disease. Follow-up testing revealed a pattern of hypocitrullinemia together with elevated propionyl-(C3) and 3-hydroxyisovaleryl-(C5-OH) acylcarnitines, and a homoplasmic pathogenic variant in MT-ATP6 in all cases.

Next generation phenotyping with quantitative narration for DEGCAGS syndrome.

The diagnosis of rare Mendelian disorders usually relies upon the interpretation of prose and is complicated by a lack of objective, reproducible phenotypic data. To address this limitation, we developed a next generation phenotyping workflow to phenotypically characterize developmental delay with gastrointestinal, cardiovascular, genitourinary, and skeletal abnormalities (DEGCAGS). We identified 15 people affected with DEGCAGS, including one novel patient identified at our hospital and 14 patients previously reported in the literature.

Accompanying effects of sewage sludge and pine needle biochar with selected organic additives on the soil and plant variables.

The effects of synthetic fertilizer and nutrient leaching are causing serious problems impacting soil function and its fertility. Mitigation of nutrient leaching and use of chemical fertilizer is crucial as fertile land adds up sustainability to climate changes. Biochar produced from agricultural bio-waste and municipal solid waste has been used for crop production and when applied in combination with organic nutrients may support mitigation of nutrient loss and adverse effects of chemical fertilizers.

The use of system dynamics for energy and environmental education.

The use of system dynamics as a learning tool for developing sustainable energy strategies and environmental education has advanced in recent years with the availability of new modelling software and webtools. Among the existing models, we highlight the online 2050 Calculators, which aim at simulating scenarios for greenhouse gas emissions, energy planning, sustainable land use, and food consumption. The objective of this study is to assess the available calculators and their contribution to an interdisciplinary education via systems thinking.

Life cycle assessment (LCA): informing the development of a sustainable circular bioeconomy?

The role of life cycle assessment (LCA) in informing the development of a sustainable and circular bioeconomy is discussed. We analyse the critical challenges remaining in using LCA and propose improvements needed to resolve future development challenges. Biobased systems are often complex combinations of technologies and practices that are geographically dispersed over long distances and with heterogeneous and uncertain sets of indicators and impacts.

A hybrid approach to identifying and assessing interactions between climate action (SDG13) policies and a range of SDGs in a UK context.

Unlabelled: In 2015 the United Nations drafted the Paris Agreement and established the Sustainable Development Goals (SDGs) for all nations. A question of increasing relevance is the extent to which the pursuit of climate action (SDG 13) interacts both positively and negatively with other SDGs. We tackle this question through a two-pronged approach: a novel, automated keyword search to identify linkages between SDGs and UK climate-relevant policies; and a detailed expert survey to evaluate these linkages through specific examples.

A well-tolerated core needle muscle biopsy process suitable for children and adults.

Serial muscle biopsies within clinical trials for Duchenne muscular dystrophy (DMD) are critical to document therapeutic responses. Less invasive means of sampling muscle are needed. We analyzed a retrospective consecutive case-series cohort of vacuum-assisted core needle muscle biopsy procedures performed on healthy and dystrophic individuals at a single institution assessing for safety and reliability of obtaining sufficient high-quality biopsy tissue for histologic assessment in adult and pediatric subjects.

Myopathy associated with homozygous PYROXD1 pathogenic variants detected by genome sequencing.

Biallelic pathogenic variants in the gene PYROXD1 have recently been described to cause early-onset autosomal recessive myopathy. Myopathy associated with PYROXD1 pathogenic variants is rare and reported in only 17 individuals. Known pathogenic variants in PYROXD1 include missense, insertion and essential splice-site variants.

Technoeconomic and life-cycle analysis of single-step catalytic conversion of wet ethanol into fungible fuel blendstocks.

Technoeconomic and life-cycle analyses are presented for catalytic conversion of ethanol to fungible hydrocarbon fuel blendstocks, informed by advances in catalyst and process development. Whereas prior work toward this end focused on 3-step processes featuring dehydration, oligomerization, and hydrogenation, the consolidated alcohol dehydration and oligomerization (CADO) approach described here results in 1-step conversion of wet ethanol vapor (40 wt% in water) to hydrocarbons and water over a metal-modified zeolite catalyst. A development project increased liquid hydrocarbon yields from 36% of theoretical to >80%, reduced catalyst cost by an order of magnitude, scaled up the process by 300-fold, and reduced projected costs of ethanol conversion 12-fold.

Myopathy, lactic acidosis and sideroblastic anemia 1 (MLASA1): A 25-year follow-up.

Mitochondrial myopathy, lactic acidosis and sideroblastic anemia 1 (MLASA1) is a rare disease caused by biallelic pathogenic variants in the gene. There are eleven MLASA1 patients reported worldwide with the majority of the patients originating from the Shiraz region of Iran. The rarity of this disease poses challenges to counseling patients due to a lack of natural history data.

Diagnostic utility of transcriptome sequencing for rare Mendelian diseases.

Purpose: We investigated the value of transcriptome sequencing (RNAseq) in ascertaining the consequence of DNA variants on RNA transcripts to improve the diagnostic rate from exome or genome sequencing for undiagnosed Mendelian diseases spanning a wide spectrum of clinical indications.

Methods: From 234 subjects referred to the Undiagnosed Diseases Network, University of California-Los Angeles clinical site between July 2014 and August 2018, 113 were enrolled for high likelihood of having rare undiagnosed, suspected genetic conditions despite thorough prior clinical evaluation. Exome or genome sequencing and RNAseq were performed, and RNAseq data was integrated with genome sequencing data for DNA variant interpretation genome-wide.

Non-Cystic Fibrosis-Related Meconium Ileus: GUCY2C-Associated Disease Discovered through Rapid Neonatal Whole-Exome Sequencing.

Meconium ileus is caused by cystic fibrosis; however, mutations in the GUCY2C gene also cause this disease. We report non-cystic fibrosis meconium ileus in an infant of non-Middle Eastern origin with compound heterozygous mutations in GUCY2C.

The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling.

Studies have suggested a role for the mammalian (or mechanistic) target of rapamycin (mTOR) in skeletal development and homeostasis, yet there is no evidence connecting mTOR with the key signaling pathways that regulate skeletogenesis. We identified a parathyroid hormone (PTH)/PTH-related peptide (PTHrP)-salt-inducible kinase 3 (SIK3)-mTOR signaling cascade essential for skeletogenesis. While investigating a new skeletal dysplasia caused by a homozygous mutation in the catalytic domain of SIK3, we observed decreased activity of mTOR complex 1 (mTORC1) and mTORC2 due to accumulation of DEPTOR, a negative regulator of both mTOR complexes.

Lego bricks and the octet rule: Molecular models for biochemical pathways with plastic, interlocking toy bricks.

The 8 studs on a 2 × 4 Lego brick conveniently represent the outer shell of electrons for carbon, nitrogen, and oxygen atoms. We used Lego bricks to model these atoms, which are then joined together to form molecules by following the Lewis octet rule. A variety of small biological molecules can be modeled in this way, such as most amino acids, fatty acids, glucose, and various intermediate metabolites.

Bioenergy and African transformation.

Among the world's continents, Africa has the highest incidence of food insecurity and poverty and the highest rates of population growth. Yet Africa also has the most arable land, the lowest crop yields, and by far the most plentiful land resources relative to energy demand. It is thus of interest to examine the potential of expanded modern bioenergy production in Africa.

Development of a Peptide-derived orally-active kappa-opioid receptor agonist targeting peripheral pain.

Kappa-opioid agonists are particularly efficacious in the treatment of peripheral pain but suffer from central nervous system (CNS)-mediated effects that limit their development. One promising kappa-agonist is the peptidic compound CR665. Although not orally available, CR665 given i.