Overexpression of branched-chain amino acid aminotransferases rescues the growth defects of cells lacking the Barth syndrome-related gene TAZ1.

The yeast protein Taz1 is the orthologue of human Tafazzin, a phospholipid acyltransferase involved in cardiolipin (CL) remodeling via a monolyso CL (MLCL) intermediate. Mutations in Tafazzin lead to Barth syndrome (BTHS), a metabolic and neuromuscular disorder that primarily affects the heart, muscles, and immune system. Similar to observations in fibroblasts and platelets from patients with BTHS or from animal models, abolishing yeast Taz1 results in decreased total CL amounts, increased levels of MLCL, and mitochondrial dysfunction. However, the biochemical mechanisms underlying the mitochondrial dysfunction in BTHS remain unclear. To better understand the pathomechanism of BTHS, we searched for multi-copy suppressors of the taz1Δ growth defect in yeast cells. We identified the branched-chain amino acid transaminases (BCATs) Bat1 and Bat2 as such suppressors. Similarly, overexpression of the mitochondrial isoform BCAT2 in mammalian cells lacking TAZ improves their growth. Elevated levels of Bat1 or Bat2 did not restore the reduced membrane potential, altered stability of respiratory complexes, or the defective accumulation of MLCL species in yeast taz1Δ cells. Importantly, supplying yeast or mammalian cells lacking TAZ1 with certain amino acids restored their growth behavior. Hence, our findings suggest that the metabolism of amino acids has an important and disease-relevant role in cells lacking Taz1 function. KEY MESSAGES: Bat1 and Bat2 are multi-copy suppressors of retarded growth of taz1Δ yeast cells. Overexpression of Bat1/2 in taz1Δ cells does not rescue known mitochondrial defects. Supplementation of amino acids enhances growth of cells lacking Taz1 or Tafazzin. Altered metabolism of amino acids might be involved in the pathomechanism of BTSH

Prognostic Significance of Lymph Node Metastases in Small Intestinal Neuroendocrine Tumors

Background/Aims: Current staging guidelines for small intestinal neuroendocrine tumors (SI-NETs) differentiate between the presence (N1) and absence (N0) of lymph node (LN) metastases. However, the prognostic significance of the extent of LN involvement remains unknown. In this study, we used data from a population-based cancer registry to examine whether involvement of a higher number of LNs is associated with worse survival. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients with histologically confirmed, surgically resected SI-NETS diagnosed between 1988 and 2010. Patients were classified into three groups by the LN ratio (number of positive LNs/number of total LNs examined, LNR):0.2-0.5, and \u3e0.5. We used the Kaplan-Meier method and Cox models to assess NET cancer-specific survival differences (up to 10 years from diagnosis) according to LNR status. Results: We identified 2,984 surgically resected patients with stage IIIb (N1, M0) SI-NETs with detailed LN data. More than half of the NETs were located in the ileum. A higher LNR was significantly associated with worse NET cancer-specific survival (p \u3c 0.0001). Ten-year NET-specific survival was 85, 77, and 74% for patients in the0.2-0.5, and \u3e0.5 LNR groups, respectively. In stratified analyses, higher LNR groups had worse survival only in early tumor (T1, T2) disease (p \u3c 0.0001). Conclusions: The extent of LN involvement provides independent prognostic information on patients with LN-positive SI-NETs. This information may be used to identify patients at high risk of recurrence and inform decisions about the use of adjuvant therapy. (C) 2015 S. Karger AG, Base

Changes in mental health among U.S. military veterans during the COVID-19 pandemic: A network analysis

Increases of symptoms of posttraumatic stress disorder (PTSD), anxiety and depression have been observed among individuals exposed to potentially traumatic events in the first months of the COVID-19 pandemic. Similarly, associations among different aspects of mental health, such as symptoms of PTSD and suicidal ideation, have also been documented. However, studies including an assessment prior to the onset and during the height of the pandemic are lacking. We investigated changes in symptoms of PTSD, depression, anxiety, suicidal ideation, and posttraumatic growth in a population-based sample of 1232 U.S. military veterans who experienced a potentially traumatic event during the first year of the pandemic. Symptoms were assessed prior to (fall/winter 2019) and one year into the pandemic (fall/winter 2020). We compared changes in symptom interrelations using network analysis, and assessed their associations with pandemic-related PTSD and posttraumatic growth symptoms. A subtle increase in psychopathological symptoms and a decrease in posttraumatic growth was observed one year into the pandemic. The peripandemic network was more densely connected, and pandemic-related PTSD symptoms were positively associated with age, anxiety, worst-event PTSD symptoms, and pandemic-related posttraumatic growth. Our findings highlight the resilience of veterans exposed to a potentially traumatic event during the first year of a pandemic. Similarly, the networks did not fundamentally change from prepandemic to one year into the pandemic. Despite this relative stability on a group level, individual reactions to potentially traumatic events could have varied substantially. Clinicians should individualize their assessments but be aware of the general resilience of most veterans

The Galactic Population of Low- and Intermediate-Mass X-ray Binaries

(abridged) We present the first study that combines binary population synthesis in the Galactic disk and detailed evolutionary calculations of low- and intermediate-mass X-ray binaries (L/IMXBs). We show that the formation probability of IMXBs with initial donor masses of 1.5--4 Msun is typically >~5 times higher than that of standard LMXBs, and suggest that the majority of the observed systems may have descended from IMXBs. Distributions at the current epoch of the orbital periods, donor masses, and mass accretion rates have been computed, as have orbital-period distributions of BMPs. Several significant discrepancies between the theoretical and observed distributions are discussed. The orbital-period distribution of observed BMPs strongly favors cases where the envelope of the neutron-star progenitor is more easily ejected during the common-envelope phase. However, this leads to a >~100-fold overproduction of the theoretical number of luminous X-ray sources relative to the total observed number of LMXBs. X-ray irradiation of the donor star may result in a dramatic reduction in the X-ray active lifetime of L/IMXBs, thus possibly resolving the overproduction problem, as well as the long-standing BMP/LMXB birthrate problem.Comment: 12 pages, emulateapj, submitted to Ap

Annotation analysis for testing drug safety signals using unstructured clinical notes

BackgroundThe electronic surveillance for adverse drug events is largely based upon the analysis of coded data from reporting systems. Yet, the vast majority of electronic health data lies embedded within the free text of clinical notes and is not gathered into centralized repositories. With the increasing access to large volumes of electronic medical data-in particular the clinical notes-it may be possible to computationally encode and to test drug safety signals in an active manner.ResultsWe describe the application of simple annotation tools on clinical text and the mining of the resulting annotations to compute the risk of getting a myocardial infarction for patients with rheumatoid arthritis that take Vioxx. Our analysis clearly reveals elevated risks for myocardial infarction in rheumatoid arthritis patients taking Vioxx (odds ratio 2.06) before 2005.ConclusionsOur results show that it is possible to apply annotation analysis methods for testing hypotheses about drug safety using electronic medical records