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Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy are a spectrum of rare lysosomal storage disorders characterized by acid ceramidase deficiency (ACD), resulting from pathogenic variants in N-acylsphingosine amidohydrolase 1 (ASAH1). Other than simple listings provided in literature reviews, a curated, comprehensive list of ASAH1 mutations associated with ACD clinical phenotypes has not yet been published. This publication includes mutations in ASAH1 collected through the Observational and Cross-Sectional Cohort Study of the Natural History and Phenotypic Spectrum of Farber Disease (NHS), ClinicalTrials.gov identifier NCT03233841, in combination with an up-to-date curated list of published mutations. The NHS is the first to collect retrospective and prospective data on living and deceased patients with ACD presenting as Farber disease, who had or had not undergone hematopoietic stem cell transplantation. Forty-five patients representing the known clinical spectrum of Farber disease (living patients aged 1-28 years) were enrolled. The curation of known ASAH1 pathogenic variants using a single reference transcript includes 10 previously unpublished from the NHS and 63 that were previously reported. The publication of ASAH1 variants will be greatly beneficial to patients undergoing genetic testing in the future by providing a significantly expanded reference list of disease-causing variants.

Pathogenic variants in ALDH5A1 cause succinic semialdehyde dehydrogenase (SSADH) deficiency, with >180 cases reported worldwide. However, a nonspecific neurologic presentation and inconsistent variant nomenclature have limited diagnoses. In this study, pathogenic variants in ALDH5A1 were curated and variant prevalence assessed in the Genome Aggregation Database (gnomAD) to determine a minimum carrier frequency and to estimate disease prevalence. Stringent population variant analysis, including 98 reported disease-associated ALDH5A1 variants, indicates a pan-ethnic carrier frequency of ∼1/340, supporting a prevalence of SSADH deficiency of ∼1/460 000 worldwide, with highest carrier frequencies observed in East Asian and South Asian populations. Because heterozygous loss of function alleles are rare in gnomAD and >60% of reported disease-causing variants were missense changes that were not present in gnomAD, the pan-ethnic carrier frequency for SSADH deficiency is likely not fully represented in this study. Additional analyses to investigate the potential impact of more common ALDH5A1 variants with reduced but not deficient enzyme activity, including analysis in diverse populations, are needed to fully assess the prevalence of this ultra-rare disease.

Background: Administrative claims data show variability in post-acute stroke care. Stroke survivors without health insurance are not included in claims data statistics. The PASES survey was developed and tested to describe stroke care experience of underserved survivors participating in V-STOP a telehealth self-management program. Methods: Semi-structured interviews were completed to elicit feedback from survivors on experiences during their stroke event, emergency and hospital care, and after discharge. Items on PASES were established based on participants’ responses and survey was piloted in a sample of underserved survivors (N=95). Descriptive statistics and Chi-square analysis were applied to describe stroke survivors’ experiences and differences based on health insurance status. Results: The sample was 45% female, mean age 57, 18% Black and 60% Hispanic. Most (60%) had an annual income of less than $25,000 and 44% had no insurance. Only 25% reported calling 911. However (60%) report presenting to a hospital within 2 hours of stroke symptoms recognition. Nearly half (42%) reported not knowing whether they received a “clot dissolving” medication. Fifty-four percent did not receive rehabilitation after discharge. Eighty-percent reported seeing a healthcare provider after discharge. Most (61%) saw a primary care provider and 22% saw a neurologist. However, only 24% reported seeing a provider within one month of hospital discharge. No significant differences were identified between insured vs. uninsured with respect to race, ethnicity, income, calling 911, receiving inpatient rehab, seeing a provider after discharge and follow up with primary care provider vs. neurologist. Significant differences were identified between insured vs. uninsured with respect to presenting to a hospital within 2 hours of stroke symptoms (35 vs 18 [p=0.023]) and in receiving no rehab after discharge (27 vs 12 [p=0.02]). Conclusion: Results suggest low utilization of EMS, delayed presentation to hospital, limited access to rehabilitation after discharge and limited access to timely follow-up with stroke specialist among underserved stroke survivors. Health insurance status may influence delayed hospital presentation and access to rehabilitation services.

Within the last few decades, there has been a steady decline in physicians conducting research. The U.S. biomedical workforce is aging which affects improving health care in this country. As they age, we need innovative ways to increase the physician-scientist pool. Along with shortages of under-represented minorities in this field, there is a scarcity of people able to analyze biological data. In an effort to increase the number of under-represented minorities conducting bioinformatics/genomics research, the Human Genome Sequencing Center-Genetics/Genomics Research Education Training (G/GREAT) program created a bioinformatics mini course. The Bioinformatics Bootcamp course offers an opportunity to learn a skill that will increase summer interns’ self-confidence, interest, and proficiency in seeking future computational research opportunities. This study will determine the best training approach to accomplish this goal for the novice (non-experienced) student. We surveyed course instructors to understand their bioinformatics teaching method and G/GREAT interns for their perspectives concerning the course. The results provided value information that guided curriculum design for all future G/GREAT training courses. These outcomes suggest that similar courses aimed at clinicians interested in research could increase physician scientists to begin replacing those about to retire. Terms: Interns=students=participants, programming=coding, non-experienced=novice.

Arsenic is a carcinogenic element that occurs naturally in the environment. High levels of arsenic are found in water in some parts of the world, including Texas. The aims of this study were to determine the distribution of arsenic in muskmelon (Cucumis melo) plants accumulated from arsenic spiked water and to observe effects on plant biomass. Plants were grown and irrigated using water spiked with variable concentrations of arsenic. Inductively coupled plasma mass spectrometry was used to quantify arsenic in different parts of the plant and fruit. Under all conditions tested in this study, the highest concentrations of arsenic were found in the leaves, soil, and roots. Arsenic in the water had no significant effect on plant biomass. Fruits analyzed in this study had arsenic concentrations of 101 μg/kg or less. Consuming these fruits would result in less arsenic exposure than drinking water at recommended levels.

Current knowledge about the integration of cellulose synthesis into cellular carbon metabolism and the cool temperature sensitivity of cellulose synthesis is reviewed briefly. Roles for sucrose synthase (to channel UDP-glucose to the cellulose synthase) and sucrose phosphate synthase (to recycle the fructose released by sucrose synthase to more sucrose) in secondary wall cellulose synthesis are described. Data are presented that implicate sucrose synthesis within cotton fibers as a particularly cool temperature-sensitive step in the partitioning of carbon to cellulose. Sugar metabolism during fiber secondary wall deposition was analyzed in in vitro cultures of ovules from two cultivars of Gossypium hirsutum L. (cv. Acala SJ-1 and cv. Paymaster HS 200), which had different levels of cool temperature sensitivity. The sizes of the sucrose, glucose, and fructose pools within fibers at 4 and 7 h after a temperature shift to 15 or 34 °C did not change in either cultivar. Feeding exogenous U-14C-glucose in pulse and pulse/chase experiments showed that uptake of glucose and transport through the ovule into fibers occurred at the same rate at 34 and 15 °C. In contrast, the flux from glucose to sucrose within fibers was greatly hindered at 15 °C in both cultivars. Since sucrose is the preferred donor of UDP-Glc to the cellulose synthase during secondary wall deposition, this sensitivity in sucrose synthesis is likely to at least partially explain the cool temperature sensitivity of cotton fiber cellulose synthesis that is observed in the field.

A comparison of 8 cyanobacterial genomes reveals that there are 181 shared genes that do not have obvious orthologs in other bacteria. These signature genes define aspects of the genotype that are uniquely cyanobacterial. Approximately 25% of these genes have been associated with some function. These signature genes may or may not be involved in photosynthesis but likely they will be in many cases. In addition, several examples of widely conserved gene order involving two or more signature genes were observed. This suggests there may be regulatory processes that have been preserved throughout the long history of the cyanobacterial phenotype. The results presented here will be especially useful because they identify which of the many genes of unassigned function are likely to be of the greatest interest.

This article discusses the importance and implications of regulating carbon partitioning to cellulose synthesis, the characteristics of cells that serve as major sinks for cellulose deposition, and enzymes that participate in the conversion of supplied carbon to cellulose. Cotton fibers, which deposit almost pure cellulose into their secondary cell walls, are referred to as a primary model system. For sucrose synthase, we discuss its proposed role in channeling UDP-Glc to cellulose synthase during secondary wall deposition, its gene family, its manipulation in transgenic plants, and mechanisms that may regulate its association with sites of polysaccharide synthesis. For cellulose synthase, we discuss the organization of the gene family and how protein diversity could relate to control of carbon partitioning to cellulose synthesis. Other enzymes emphasized include UDP-Glc pyrophosphorylase and sucrose phosphate synthase. New data are included on phosphorylation of cotton fiber sucrose synthase, possible regulation by Ca2+ of sucrose synthase localization, electron microscopic immunolocalization of sucrose synthase in cotton fibers, and phylogenetic relationships between cellulose synthase proteins, including three new ones identified in differentiating tracheary elements of Zinnia elegans. We develop a model for metabolism related to cellulose synthesis that implicates the changing intracellular localization of sucrose synthase as a molecular switch between survival metabolism and growth and/or differentiation processes involving cellulose synthesis. Abbreviations: CesA, cellulose synthase; Csl, cellulose-like synthase (genes); DCB, dichlobenil; DPA, days after anthesis; SPS, sucrose phosphate synthase; SuSy, sucrose synthase; P-SuSy, particulate SuSy; S-SuSy, soluble SuSy

Five complete bacterial genome sequences have been released to the scientific community. These include four (eu)Bacteria, Haemophilus influenzae, Mycoplasma genitalium, M. pneumoniae, and Synechocystis PCC 6803, as well as one Archaeon, Methanococcus jannaschii. Features of organization shared by these genomes are likely to have arisen very early in the history of the bacteria and thus can be expected to provide further insight into the nature of early ancestors. Results of a genome comparison of these five organisms confirm earlier observations that gene order is remarkably unpreserved. There are, nevertheless, at least 16 clusters of two or more genes whose order remains the same among the four (eu)Bacteria and these are presumed to reflect conserved elements of coordinated gene expression that require gene proximity. Eight of these gene orders are essentially conserved in the Archaea as well. Many of these clusters are known to be regulated by RNA-level mechanisms in Escherichia coli, which supports the earlier suggestion that this type of regulation of gene expression may have arisen very early. We conclude that although the last common ancestor may have had a DNA genome, it likely was preceded by progenotes with an RNA genome.

An isolated left common carotid artery (LCA) is an extremely rare condition with only four reported cases. In each case, the isolated carotid artery connects to the right or left pulmonary artery via the ductus arteriosus and the embryologic basis for the abnormalities is believed to reflect an error in the development of the branchial arches. We present a case of an isolated LCA connecting to the main pulmonary artery in association with a right aortic arch and an anomalous origin of the left subclavian artery from the descending aorta. The left ligamentus arteriosus was identified separately. This may represent a disturbance in the septation of the truncoaortic sac secondary to abnormal migration of neural crest cells rather than a pure developmental anomaly of the branchial arches.

The purpose of this paper is to evaluate the capability of feature space analysis (FSA) for quantifying the relative volumes of principal components (thrombus, calcification, fibrous, normal intima, and lipid) of atherosclerotic plaque tissue in multicontrast magnetic resonance images (mc-MRI) acquired in a setup resembling clinical conditions ex vivo. Utilizing endogenous contrast, proton density, T1-weighted, and T2-weighted images were acquired for 13 carotid endarterectomy (CEA) tissues under near-clinical conditions (human 1.5 T GE Excite scanner with sequence parameters comparable to an in vivo acquisition). An FSA algorithm was utilized to segment and quantify the principal components of atherosclerotic plaques. Pilot in vivo mc-MRI images were analyzed in the same way as the ex vivo images for exploring the possible adaptation of this technique to in vivo imaging. Relative abundance of principal plaque components in CEA tissues as determined by mc-MRI/FSA were compared to those measured by histology. Mean differences plusmn standard deviations were 5.8nplusmnn4.1% for thrombus, 1.5 plusmn1.4 % for calcification, 4.0 plusmn2.8% for fibrous, 8.2 plusmn 10% for normal intima, and 2.4 plusmn 2.2% for lipid. Reasonable quantitative agreement between the classification results obtained with FSA and histological data was obtained for near-clinical imaging conditions. Combination of mc-MRI and FSA may have an application for determining atherosclerotic lesion composition and monitoring treatment in vivo.

A previous study demonstrated the efficacy of a phospholipid (PL) complexed with a protein (apoAI Milano) in causing 4.6% regression of atheroma volume as assessed by intravascular ultrasonography (IVUS) in a group of 47 patients with carotid atherosclerosis. The results of this study raised the question of whether the phospholipid alone could produce a similar effect.To answer this question a trial of 39 subjects at five sites was designed. Patients with15% stenosis of at least one carotid artery as determined by US underwent intravenous PL (200 mg/kg) or placebo infusions weekly for 8 weeks. The wall/outer wall ratio, percent lipid-rich/necrotic core, and percent calcification were measured as a proportion of the vessel wall by magnetic resonance imaging (MRI) at 0, 4, 8, and 14 weeks.The substudy of seven of these patients evaluated at our site allowed comparison of the dimensions of five unoperated-unoperated carotid pairs and two operated-unoperated pairs. In patient 1, MRI measurements on unoperated left and unoperated right carotids tracked almost identically over the 14-week study. Both carotids showed similar increases in the volumes of the total wall (+61% vs. 56%), the normal wall (+51% vs. 49%), and plaque (+99% vs. 85%). Both carotids showed similar decreases in lumen volume (-11% vs. -17%). The other four unoperated-unoperated carotid pairs showed dimensional changes over 14 weeks similar to those of patient 1. In patient 2, who underwent left endarterectomy, the operated carotid had a total artery volume of 2300 mm(3), about twofold greater than the unoperated carotid (1100 mm(3)). Operated and unoperated carotid measurements tracked in parallel. The unoperated carotid had volume increases of 25% (+200 mm(3)) in total wall, +19% (+100 mm(3)) in normal wall, and 43% (+75 mm(3)) in plaque. The operated carotid lumen showed no significant changes. Patient 7, who also underwent left endarterectomy, exhibited carotid changes similar to those of patient 2.Individual unoperated carotid pairs have volumes that track almost identically. In unilateral operated carotid pairs, the operated artery has 1.5- to 2.0-fold greater volume than unoperated carotids. In each of our two unilaterally operated patients, the operated carotid had decreased plaque volume (-3%, -58%), whereas the unoperated carotid had increased plaque volume (+43%, +7%). Among the five unoperated patients, one pair had 85%/99% increase in plaque volume; one pair had -15%/-10% decrease; and the other three pairs had intermediate changes. This study provides additional support to the view that unoperated human carotid arteries are bilaterally symmetrical.

The laboratory rat (Rattus norvegicus) is an indispensable tool in experimental medicine and drug development, having made inestimable contributions to human health. We report here the genome sequence of the Brown Norway (BN) rat strain. The sequence represents a high-quality 'draft' covering over 90% of the genome. The BN rat sequence is the third complete mammalian genome to be deciphered, and three-way comparisons with the human and mouse genomes resolve details of mammalian evolution. This first comprehensive analysis includes genes and proteins and their relation to human disease, repeated sequences, comparative genome-wide studies of mammalian orthologous chromosomal regions and rearrangement breakpoints, reconstruction of ancestral karyotypes and the events leading to existing species, rates of variation, and lineage-specific and lineage-independent evolutionary events such as expansion of gene families, orthology relations and protein evolution.

Presentation of stimuli in a Y maze showed that Peromyscus maniculatus which inhabit hibernacula used by bats may use auditory stimuli to locate bats which have fallen from their hibernation perches. However, the intense calls (95 dB sound pressure level, linear at 10 cm) given by bats (mainly Myotis lucifugus) as they arouse from torpor may serve a defensive function by repelling the mice.