Neurocognitive markers of suicidal ideation in patients with anxiety and mood disorders

Abstract

Objective: This study aims at identifying associations between cognitive function and suicidal ideation in the sample of patients with anxiety and mood disorders (AMD).

Methods: In sum, 186 (age = 39?±?12.3 years; 142 [76.3%] females) patients with AMD were enrolled in the study. Assessment included evaluation of socio-demographic information, medication use, anxiety and depression symptoms. Cognitive tests included measures of psychomotor performance and incidental learning using the Digit Symbol Test. Trail Making Tests respectively measured perceptual speed, task-switching and executive control. Additionally, 21 patients completed tests from the Cambridge Automated Neuropsychological Test Battery measuring set shifting (Interdimensional/extradimensional set-shift), executive planning (Stockings of Cambridge), and decision making (Cambridge Gamble Task [CGT]).

Results: Almost half (45.0%, n?=?86) of the study sample patients had experienced suicidal ideations. In multivariable regression analysis, suicidal ideation was associated with a greater overall proportion of bet and risk taking on the CGT task (β?=?0.726, p?=?.010 and β?=?0.634, p?=?.019), when controlling for socio-demographic characteristics, medication use, anxiety and depression symptoms.

Conclusions: Outpatients with AMD and suicidal ideation could be distinguished by the presence of cognitive deficits in the executive function domain, particularly in impulse-control and risk taking.     

Estimating the audiogram using multiple auditory steady-state responses

Multiple auditory steady-state responses were evoked by eight tonal stimuli (four per ear), with each stimulus simultaneously modulated in both amplitude and frequency. The modulation frequencies varied from 80 to 95 Hz and the carrier frequencies were 500, 1000, 2000, and 4000 Hz. For air conduction, the differences between physiologic thresholds for these mixed-modulation (MM) stimuli and behavioral thresholds for pure tones in 31 adult subjects with a sensorineural hearing impairment and 14 adult subjects with normal hearing were 14+/-11, 5+/-9, 5+/-9, and 9+/-10 dB (correlation coefficients .85, .94, .95, and .95) for the 500-, 1000-, 2000-, and 4000-Hz carrier frequencies, respectively. Similar results were obtained in subjects with simulated conductive hearing losses. Responses to stimuli presented through a forehead bone conductor showed physiologic-behavioral threshold differences of 22+/-8, 14+/-5, 5+/-8, and 5+/-10 dB for the 500-, 1000-, 2000-, and 4000-Hz carrier frequencies, respectively. These responses were attenuated by white noise presented concurrently through the bone conductor.     

<Emphasis Type="Italic">BIRC5</Emphasis> promoter SNPs do not affect nuclear survivin expression and survival of malignant pleural mesothelioma patients

Purpose  

Malignant pleural mesothelioma is an incurable, asbestos-associated cancer. Its incidence is rapidly increasing and survival remains short. Apoptosis deregulation is an important feature of cancer and survivin, a member of the inhibitor-of-apoptosis-protein family encoded by the BIRC5 gene, has been suggested to have a role in the development and progression of several cancers. Genetic variability, in particular single nucleotide polymorphisms in the BIRC5 promoter, may affect the protein’s expression levels. The aim of our study was to elucidate the effects of BIRC5 promoter single nucleotide polymorphisms on survivin expression, patient survival and age at diagnosis in malignant pleural mesothelioma.     

An in vitro vesicle formation assay reveals cargo clients and factors that mediate vesicular trafficking

The fidelity of protein transport in the secretory pathway relies on the accurate sorting of proteins to their correct destinations. To deepen our understanding of the underlying molecular mechanisms, it is important to develop a robust approach to systematically reveal cargo proteins that depend on specific sorting machinery to be enriched into transport vesicles. Here, we used an in vitro assay that reconstitutes packaging of human cargo proteins into vesicles to quantify cargo capture. Quantitative mass spectrometry (MS) analyses of the isolated vesicles revealed cytosolic proteins that are associated with vesicle membranes in a GTP-dependent manner. We found that two of them, FAM84B (also known as LRAT domain containing 2 or LRATD2) and PRRC1, contain proline-rich domains and regulate anterograde trafficking. Further analyses revealed that PRRC1 is recruited to endoplasmic reticulum (ER) exit sites, interacts with the inner COPII coat, and its absence increases membrane association of COPII. In addition, we uncovered cargo proteins that depend on GTP hydrolysis to be captured into vesicles. Comparing control cells with cells depleted of the cargo receptors, SURF4 or ERGIC53, we revealed specific clients of each of these two export adaptors. Our results indicate that the vesicle formation assay in combination with quantitative MS analysis is a robust and powerful tool to uncover novel factors that mediate vesicular trafficking and to uncover cargo clients of specific cellular factors.

The eukaryotic secretory pathway plays important roles in delivering a variety of newly synthesized proteins to their specific resident compartments. The fidelity of protein transport in the secretory pathway depends on accurate sorting of specific cargo proteins into transport vesicles. Defects in cargo sorting cause protein mistargeting and induce defects in establishing cell polarity, immunity, as well as other physiological processes (1).A variety of cytosolic proteins are recruited to the membrane and play important roles in the protein sorting process. These cytosolic proteins include small GTPases of the Arf family and cargo adaptors (1, 2). The Arf family GTPases cycle between a GDP-bound cytosolic state and a GTP-bound state. Upon GTP binding, Arf proteins undergo conformational changes in which the N-terminal amphipathic helix is exposed to bind membranes and the switch domains change their conformation to recruit various cytosolic cargo adaptors. Once recruited onto the membranes, these cargo adaptors recognize sorting motifs on the cargo proteins. This recognition step is important for efficiently capturing cargo proteins into vesicles.The Arf family protein, Sar1, regulates packaging of cargo proteins into vesicles at the endoplasmic reticulum (ER). GTP-bound Sar1 mediates membrane recruitment of the coat protein complex II (COPII) to capture cargo proteins (2). Soluble cargo proteins in the lumen of the ER cannot be directly recognized by COPII coat and such proteins are thought to be linked to the cargo sorting machinery on the cytosolic side by transmembrane cargo receptors. One cargo receptor in mammalian cells, ERGIC53, is a mannose lectin and functions in capturing specific N-linked glycoproteins in the lumen of the ER (3). ERGIC53 regulates ER export of blood coagulation factors V and VIII, a cathepsin-Z–related protein, and alpha1-antittrypsin (4–7). Another cargo receptor, SURF4, binds amino-terminal tripeptide motifs of soluble cargo proteins and regulates ER export of soluble cargo proteins, including the yolk protein VIT-2 in Caenorhabditis elegans (8), and PCSK9 and apolipoprotein B in mammalian cells (9–11).Although significant progress has been made in understanding the general steps of cargo sorting, the spectrum of cargo clients of a specific Arf family member, cargo adaptor, or cargo receptor remains largely underinvestigated. To deepen our understanding of protein sorting in the secretory pathway, it is important to develop a robust approach to systematically reveal cargo proteins that depend on a specific factor to be efficiently packaged into vesicles. Revealing this will provide significant insight into the functions and the specificity of cargo sorting. Since distinct cytosolic proteins are recruited to membranes by different GTP-bound Arf family proteins, systematic approaches are needed to characterize budding events associated with a specific GTP-bound Arf family protein.A cellular imaging approach, pairing analysis of cargo receptors (PAIRS), has been utilized to identify the spectrum of cargo proteins that depend on a specific cargo receptor for ER export in yeast. This analysis focused on around 150 cargo molecules labeled with fluorescent tags (12). An in vitro assay that reconstitutes packaging of cargo proteins into vesicles has been used to reveal protein profiles of vesicles budded with purified COPII or COPI proteins (13). However, this analysis did not identify any non-ER resident transmembrane proteins or secretory proteins (13). This is possibly due to an unappreciated requirement for other cytosolic factors in addition to the COP coats. Affinity chromatography has been utilized to reveal cytosolic proteins that specifically interact with GTP-bound Arf or Rab proteins (14–16). In this approach, the membranes are disrupted, which might preclude identification of membrane-associated effectors. Thus, it is important to develop additional approaches to reveal novel cytosolic proteins that associate with GTP-bound Arf proteins on membranes.Here, we used an in vitro assay to reconstitute packaging of cargo proteins into transport vesicles utilizing rat liver cytosol (RLC) as a source of cytosolic proteins. Analysis of vesicle fractions by quantitative mass spectrometry (MS) revealed cytosolic proteins that are associated with vesicles dependent on GTP or GTP-bound Sar1A, and that regulate protein trafficking. One of the identified proteins, PRRC1, regulates membrane association of the COPII coat and facilitates ER-to-Golgi trafficking. We also revealed cargo proteins that depend on specific cargo receptors, ERGIC53 or SURF4, to be efficiently packaged into vesicles. Our study indicates that the vesicle formation assay is a robust tool to reveal functional roles of specific factors in protein sorting, and to uncover novel factors that regulate vesicular trafficking in the secretory pathway.     

Protective effects of propolis and related polyphenolic/flavonoid compounds against toxicity induced by irinotecan

Despite the excellent chemotherapeutic effect of irinotecan, its cytotoxicity and genotoxicity in normal cells remains a major problem in chemotherapy. This study was carried out to find whether propolis preparations and related flavonoids (quercetin, naringin) might enhance irinotecan-induced cytotoxicity to tumor cells in mice bearing Ehrlich ascites tumors (EAT) while protecting normal blood, liver, and kidney cells. The preparation of propolis and their flavonoids were given to mice intraperitoneally at a dose of 100 mg kg⁻¹ body weight for three consecutive days before the ip injection of EAT cells (2 × 10⁶). Irinotecan was administered ip at dose of 50 mg kg⁻¹ on days 3, 4, and 5 after tumor cell inoculation. The combination treatment resulted in substantial inhibition of the growth of EAT cells as well as treatment with quercetin or irinotecan alone, whereas other treatment by itself showed little effect. However, when mice were pre-treated with test components prior to irinotecan, the frequencies of irinotecan-induced micronuclei (MN) was decreased but in mice bearing tumor QU and EEP increased number of micronucleated cells. Propolis preparation and related flavonoids were found to exhibit an important immunomodulatory effect and could decrease irinotecan-induced toxic and genotoxic effects to normal cells without effecting irinotecan cytotoxicity in EAT cells.     

The Influence of Iron Ions on Optical Brighteners and Their Application to Cotton Fabrics

The influence of iron ions at concentrations of 0.2, 0.5, and 1.0 g/L on optical brighteners of the groups stilbene and biphenyl in solution and on cotton fabric was investigated. Both groups of optical brighteners are intended for detergent formulations. The influence of iron ions was studied by absorption and fluorescence spectra in solution and by whiteness degree, identifying color differences using CIEL*a*b* coordinates and Ultraviolet Protection Factor (UPF) of cotton fabrics. The obtained results in solutions and cotton fabrics showed different behavior of optical brighteners stilbene and biphenyl in the presence of iron. Stilbene compounds with metal ions produced new species capable of absorbing in the UV-B region of the spectrum. A biphenyl compound in combination with iron had no effect on the absorption properties. Both optical brighteners were influenced by iron ions in the sense of fluorescence quenching. The influence of iron ions in single- and two-bath treatments of cotton fabrics after one cycle on whiteness degree and UPF was negligible.