Human Resource Accounting: An Aid to Managerial Decision Making

Human Resource Accounting, although not entirely new to the field of accounting, is finding resistance in becoming established. Certain problems must be settled before HRA can be completely accepted by accountants and managers alike. The many proposals that have emerged, both the traditional approaches and those departing from traditional accounting, have not been fully tested. Only a few instances are reported wherein Human Resource Accounting applications have been attempted. However, much more research and testing will be needed in · order to make HRA a fully acceptable form of accounting. Until such time, Human Resource Accounting can be effectively used as an aid to managerial decision making

Magnetic resonance imaging in the diagnosis of white matter signal abnormalities.

Background White matter abnormalities (WMAs) pose a diagnostic challenge when trying to establish etiologic diagnoses. During childhood and adult years, genetic disorders, metabolic disorders and acquired conditions are included in differential diagnoses. To assist clinicians and radiologists, a structured algorithm using cranial magnetic resonance imaging (MRI) has been recommended to aid in establishing working diagnoses that facilitate appropriate biochemical and genetic investigations. This retrospective pilot study investigated the validity and diagnostic utility of this algorithm when applied to white matter signal abnormalities (WMSAs) reported on imaging studies of patients seen in our clinics. Methods The MRI algorithm was applied to 31 patients selected from patients attending the neurometabolic/neurogenetic/metabolic/neurology clinics at a tertiary care hospital. These patients varied in age from 5 months to 79 years old, and were reported to have WMSAs on cranial MRI scans. Twenty-one patients had confirmed WMA diagnoses and 10 patients had non-specific WMA diagnoses (etiology unknown). Two radiologists, blinded to confirmed diagnoses, used clinical abstracts and the WMSAs present on patient MRI scans to classify possible WMA diagnoses utilizing the algorithm. Results The MRI algorithm displayed a sensitivity of 100%, a specificity of 30.0% and a positive predicted value of 74.1%. Cohen\u27s kappa statistic for inter-radiologist agreement was 0.733, suggesting good agreement between radiologists. Conclusions Although a high diagnostic utility was not observed, results suggest that this MRI algorithm has promise as a clinical tool for clinicians and radiologists. We discuss the benefits and limitations of this approach

Analysis of LMNB1 duplications in autosomal dominant leukodystrophy provides insights into duplication mechanisms and allele-specific expression

Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication-based mechanisms such fork stalling and template switching or microhomology-mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients’ fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele-specific LMNB1 expression levels

UFM1 founder mutation in the Roma population causes recessive variant of H-ABC.

OBJECTIVE: To identify the gene defect in patients with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) who are negative for TUBB4A mutations. METHODS: We performed homozygosity mapping and whole exome sequencing (WES) to detect the disease-causing variant. We used a Taqman assay for population screening. We developed a luciferase reporter construct to investigate the effect of the promoter mutation on expression. RESULTS: Sixteen patients from 14 families from different countries fulfilling the MRI criteria for H-ABC exhibited a similar, severe clinical phenotype, including lack of development and a severe epileptic encephalopathy. The majority of patients had a known Roma ethnic background. Single nucleotide polymorphism array analysis in 5 patients identified one large overlapping homozygous region on chromosome 13. WES in 2 patients revealed a homozygous deletion in the promoter region of UFM1. Sanger sequencing confirmed homozygosity for this variant in all 16 patients. All patients shared a common haplotype, indicative of a founder effect. Screening of 1,000 controls from different European Roma panels demonstrated an overall carrier rate of the mutation of 3%-25%. Transfection assays showed that the deletion significantly reduced expression in specific CNS cell lines. CONCLUSIONS: UFM1 encodes ubiquitin-fold modifier 1 (UFM1), a member of the ubiquitin-like family involved in posttranslational modification of proteins. Its exact biological role is unclear. This study associates a UFM1 gene defect with a disease and sheds new light on possible UFM1 functional networks

Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III

A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B. Here we report eight of these cases carrying recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, also mutated in some Treacher Collins syndrome (TCS) cases. Using shotgun proteomics and ChIP sequencing, we demonstrate that leukodystrophy-causative mutations, but not TCS mutations, in POLR1C impair assembly and nuclear import of POLR3, but not POLR1, leading to decreased binding to POLR3 target genes. This study is the first to show that distinct mutations in a gene coding for a shared subunit of two RNA polymerases lead to selective modification of the enzymes’ availability leading to two different clinical conditions and to shed some light on the pathophysiological mechanism of one of the most common hypomyelinating leukodystrophies, POLR3-related leukodystrophy

Levels of glycosaminoglycans in the cerebrospinal fluid of healthy young adults, surrogate-normal children, and Hunter syndrome patients with and without cognitive impairment.

In mucopolysaccharidoses (MPS), glycosaminoglycans (GAG) accumulate in tissues. In MPS II, approximately two-thirds of patients are cognitively impaired. We investigated levels of GAG in cerebrospinal fluid (CSF) in different populations from four clinical studies (including NCT00920647 and NCT01449240). Data indicate that MPS II patients with cognitive impairment have elevated levels of CSF GAG, whereas those with the attenuated phenotype typically have levels falling between those of the cognitively affected patients and healthy controls

Thiamine pyrophosphokinase deficiency causes a Leigh disease like phenotype in a sibling pair: Identification through whole exome sequencing and management strategies

We present a sibling pair with Leigh-like disease, progressive hypotonia, regression, and chronic encephalopathy. Whole exome sequencing in the younger sibling demonstrated a homozygous thiamine pyrophosphokinase (TPK) mutation. Initiation of high dose thiamine, niacin, biotin, α-lipoic acid and ketogenic diet in this child demonstrated improvement in neurologic function and re-attainment of previously lost milestones. The diagnosis of TPK deficiency was difficult due to inconsistent biochemical and diagnostic parameters, rapidity of clinical demise and would not have been made in a timely manner without the use of whole exome sequencing. Molecular diagnosis allowed for attempt at dietary modification with cofactor supplementation which resulted in an improved clinical cours

Umberto Eco, Narratives of Conspiracy and the Anti-Semite Among Us

http://www.quest-cdecjournal.it/discussion.php?id=3

ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism

Background Acyl-CoA binding domain containing protein 5 (ACBD5) is a peroxisomal membrane protein with a cytosolic acyl-CoA binding domain. Because of its acyl-CoA binding domain, ACBD5 has been assumed to function as an intracellular carrier of acyl-CoA esters. In addition, a role for ACBD5 in pexophagy has been suggested. However, the precise role of ACBD5 in peroxisomal metabolism and/or functioning has not yet been established. Previously, a genetic ACBD5 deficiency was identified in three siblings with retinal dystrophy and white matter disease. We identified a pathogenic mutation in ACBD5 in another patient and studied the consequences of the ACBD5 defect in patient material and in ACBD5-deficient HeLa cells to uncover this role. Methods We studied a girl who presented with progressive leukodystrophy, syndromic cleft palate, ataxia and retinal dystrophy. We performed biochemical, cell biological and molecular studies in patient material and in ACBD5-deficient HeLa cells generated by CRISPR-Cas9 genome editing. Results We identified a homozygous deleterious indel mutation in ACBD5, leading to complete loss of ACBD5 protein in the patient. Our studies showed that ACBD5 deficiency leads to accumulation of very longchain fatty acids (VLCFAs) due to impaired peroxisomal beta-oxidation. No effect on pexophagy was found. Conclusions Our investigations strongly suggest that ACBD5 plays an important role in sequestering C26-CoA in the cytosol and thereby facilitates transport into the peroxisome and subsequent beta-oxidation. Accordingly, ACBD5 deficiency is a novel single peroxisomal enzyme deficiency caused by impaired VLCFA metabolism and leading to retinal dystrophy and white matter disease.Supported in part by funding through the Marie Curie Initial Training Networks (ITN) action to KDF, MS and HRW (FP7-2012-PERFUME-316723). MS is supported by the Biotechnology and Biological Sciences Research Council (BB/K006231/1; BB/N01541X/1)

ADAR1 Facilitates HIV-1 Replication in Primary CD4+ T Cells.

Unlike resting CD4+ T cells, activated CD4+T cells are highly susceptible to infection of human immunodeficiency virus 1 (HIV-1). HIV-1 infects T cells and macrophages without activating the nucleic acid sensors and the anti-viral type I interferon response. Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA editing enzyme that displays antiviral activity against several RNA viruses. Mutations in ADAR1 cause the autoimmune disorder Aicardi-Goutieères syndrome (AGS). This disease is characterized by an inappropriate activation of the interferon-stimulated gene response. Here we show that HIV-1 replication, in ADAR1-deficient CD4+T lymphocytes from AGS patients, is blocked at the level of protein translation. Furthermore, viral protein synthesis block is accompanied by an activation of interferon-stimulated genes. RNA silencing of ADAR1 in Jurkat cells also inhibited HIV-1 protein synthesis. Our data support that HIV-1 requires ADAR1 for efficient replication in human CD4+T cells