Enzyme Defects in the Porphyrias and their Relevance to the Biochemical Abnormalities in these Disorders

Defects in enzymes of the heme biosynthesis pathway underlie the biochemical abnormalities which occur in the porphyrias. Porphyrins and porphyrin precursors are accumulated and excreted in excessive amounts because of the enzyme defects. This is illustrated by studies in protoporphyria and variegate porphyria, disorders in which the biochemical abnormalities indicate a defect(s) in the terminal part of the heme biosynthesis pathway. The activity of heme synthease (ferrochelatase), which catalyzes the chelation of ferrous iron to protoporphyrin, is deficient in tissues of patients with protoporphyria. This causes protoporphyrin to be accumulated and excreted excessively. In variegate porphyria protoporphyrinogen oxidase, which catalyzes the oxidation of protoporphyrinogen to protoporphyrin, appears to be defective. As a result, protoporphyrinogen may be excreted in increased amounts in bile, where it is subsequently auto-oxidized to protoporphyrin. The following questions have arisen as a result of the demonstrations of enzyme defects in tissues of patients with porphyria: (1) Will different defects in the same enzyme be found among patients who fulfill the clinical and biochemical criteria for diagnosis of a specific porphyria? That is, does genetic heterogeneity exist in each of the porphyrias? (2) Why do some patients with an enzyme defect not have biochemical abnormalities? (3) Why is one type of tissue, usually the liver, the major site of expression of the biochemical abnormality, when the enzyme defect can be demonstrated in all tissues

A principal component analysis of gravitational-wave signals from extreme-mass-ratio sources

The Laser Interferometer Space Antenna (LISA) will detect the gravitational wave emissions from a vast number of astrophysical sources, but extracting useful information about individual sources or source types is an extremely challenging prospect; the large number of parameters governing the behaviour of some sources make exhaustively searching this parameter space computationally expensive. We investigate the potential of an alternative approach, with a focus on detecting the presence of particular inspiraling binary source signals within a timeseries of gravitational wave data, and quickly providing estimates of their coalescence times. Specically, we use Principal Component Analysis (PCA) to identify redundancy within the parameter space of Extreme Mass Ratio Inspiral (EMRI) sources and construct a new, smaller parameter space containing only relevant signal information. We then create a simple search method based on how gravitational wave signals project into this new parameter space. Test cases indicate that a small number of principal components span a space occupied by the majority of EMRI spectrograms, but non-EMRI signals (including noise) do not inhabit this space. A PCA-based search method is capable of indicating the presence of gravitational waves from EMRI sources within a new test spectrogram. The results of our PCA-based searches show that the method could be used to provide initial estimates of EMRI coalescence times quickly, to be used as initial data for a more thorough search

Metagenomic deep sequencing of aqueous fluid detects intraocular lymphomas.

IntroductionCurrently, the detection of pathogens or mutations associated with intraocular lymphomas heavily relies on prespecified, directed PCRs. With metagenomic deep sequencing (MDS), an unbiased high-throughput sequencing approach, all pathogens as well as all mutations present in the host's genome can be detected in the same small amount of ocular fluid.MethodsIn this cross-sectional case series, aqueous fluid samples from two patients were submitted to MDS to identify pathogens as well as common and rare cancer mutations.ResultsMDS of aqueous fluid from the first patient with vitreal lymphoma revealed the presence of both Epstein-Barr virus (HHV-4/EBV) and human herpes virus 8 (HHV-8) RNA. Aqueous fluid from the second patient with intraocular B-cell lymphoma demonstrated a less common mutation in the MYD88 gene associated with B-cell lymphoma.ConclusionMDS detects pathogens that, in some instances, may drive the development of intraocular lymphomas. Moreover, MDS is able to identify both common and rare mutations associated with lymphomas