A Network Model of Positive Resources,Temperament, Childhood Trauma,and Comorbid Symptoms for Patient with Depressive Disorders

ObjectiveTemperament, positive resources, childhood trauma, and other clinical comorbid symptoms are related to depressive symptom severity. Here, we used network analysis to examine the interrelations between these clinical factors in patients with depressive disorders. MethodsPatients with depressive disorders (n=454) completed self-report questionnaires evaluating clinical symptoms, childhood trauma, temperament, and positive resources. To identify network pattern and the most central aspect, we performed network analysis and centrality analyses. First, we analyzed the network pattern in total participants. Second, we established two groups of those with severe depressive symptoms and those with mild depressive symptoms and compared their network patterns. ResultsDeficient optimism and depression were the central factors in the network of total participants. In the group with severe depressive symptoms, lack of social support and childhood emotional trauma showed high centrality. Deficient social support and other positive resources played central roles in the group with mild depressive symptoms. ConclusionNetwork pattern of psychological factors was different between those with mild or severe depression. Lack of positive resources is an important factor in psychological processes in both mild and severe depression. However, childhood emotional trauma may play a relatively important role in patients with severe depressive symptoms.     

Genome-wide bimolecular fluorescence complementation analysis of SUMO interactome in yeast

The definition of protein–protein interactions (PPIs) in the natural cellular context is essential for properly understanding various biological processes. So far, however, most large-scale PPI analyses have not been performed in the natural cellular context. Here, we describe the construction of a Saccharomyces cerevisiae fusion library in which each endogenous gene is C-terminally tagged with the N-terminal fragment of Venus (VN) for a genome-wide bimolecular fluorescence complementation assay, a powerful technique for identifying PPIs in living cells. We illustrate the utility of the VN fusion library by systematically analyzing the interactome of the small ubiquitin-related modifier (SUMO) and provide previously unavailable information on the subcellular localization, types, and protease dependence of SUMO interactions. Our data set is highly complementary to the existing data sets and represents a useful resource for expanding the understanding of the physiological roles of SUMO. In addition, the VN fusion library provides a useful research tool that makes it feasible to systematically analyze PPIs in the natural cellular context.Most biological processes are mediated by complicated networks of protein–protein interactions (PPIs). Thus, the identification of the occurrence and components of PPIs provides invaluable insights into the cellular functions of proteins. In addition to conventional coimmunoprecipitation techniques, several methods have been developed to study PPIs, including the yeast two-hybrid analysis (Fields and Song 1989), the split ubiquitin system (Johnsson and Varshavsky 1994), fluorescence resonance energy transfer (FRET) assays (Periasamy and Day 1999; Pollok and Heim 1999), tandem affinity purification (TAP) followed by mass spectrometry (MS) analysis (Rigaut et al. 1999), and protein fragment complementation (PFC) assays (Remy and Michnick 1999; Ghosh et al. 2000; Wehrman et al. 2002; Paulmurugan and Gambhir 2003). Recently, the bimolecular fluorescence complementation (BiFC) assay, a specialized form of the PFC assay that uses fluorescent proteins as a reporter, has been developed (Hu et al. 2002). The BiFC assay is based on the formation of a fluorescent complex when two proteins fused to nonfluorescent fragments of a fluorescent protein interact with each other. This approach enables direct visualization of the occurrence and subcellular localization of PPIs with simple equipment.The budding yeast Saccharomyces cerevisiae has been a valuable eukaryotic model system, not only for traditional molecular and cell biology but also for the fields of functional genomics and proteomics. In S. cerevisiae, several large-scale analyses of PPIs have been performed with the yeast two-hybrid method (Uetz et al. 2000; Ito et al. 2001) or TAP-MS analysis (Gavin et al. 2002, 2006; Ho et al. 2002; Krogan et al. 2006). However, these approaches do not measure PPI in the natural cellular context; the yeast two-hybrid method is not appropriate for analyzing the interactions between proteins that cannot be transported to the nucleus or that form interactions only in the presence of other stabilizing interactions, and TAP-MS analysis is not amenable to studying protein complexes that are weakly or transiently formed or that do not survive in vitro purification. Compared with the yeast two-hybrid method and TAP-MS analysis, the FRET, PFC, and BiFC assays have several advantages in that they can detect the interactions between proteins in their natural cellular environment. Recently, a large-scale PPI screen using the PFC assay based on reconstituted dihydrofolate reductase (DHFR) activity has been reported (Tarassov et al. 2008), which is the first example of genome-wide PPI analysis using the PFC assay. However, because positive PPIs are selected by methotrexate resistance in the DHFR PFC assay, it is possible that the addition of methotrexate to the assay medium may perturb cellular physiology and proper PPI networks. In this regard, large-scale PPI screens using the BiFC or FRET assay that do not require any exogenous reagents would provide more accurate information about the structural organization of PPI networks in cells. To date, however, there is no report describing the application of the BiFC or FRET assay to genome-wide PPI analyses, particularly using proteins expressed from their own native promoters.The small ubiquitin-related modifier (SUMO) proteins are ∼10 kDa in size and comprise a family of evolutionarily conserved polypeptides that are post-translationally attached to the lysine residues of target proteins to regulate their subcellular localization, stability, and activity (Kerscher et al. 2006; Geiss-Friedlander and Melchior 2007). SUMO conjugation plays a variety of important roles in diverse eukaryotic cellular processes. SUMO can also mediate the non-covalent interaction of substrate proteins with proteins containing SUMO-interacting motifs and modulate their function (Song et al. 2004). In this regard, the identification of SUMO target proteins is crucial for the elucidation of the function of SUMO. Recent genome-wide PPI screens have identified over 500 putative SUMO conjugates in S. cerevisiae (Panse et al. 2004; Wohlschlegel et al. 2004; Zhou et al. 2004; Denison et al. 2005; Hannich et al. 2005; Wykoff and O''Shea 2005). More recently, an elegant study integrating the information of PPIs and genetic interactions has been conducted and has uncovered novel functional relationships between the SUMO pathway and various biological processes (Makhnevych et al. 2009). These systematic analyses have expanded the pool of SUMO substrates and the understanding of the biological function of sumoylation. However, because SUMO substrates can undergo rapid cycles of modification and demodification, and most target proteins appear to be modified to a small percentage at steady state (Geiss-Friedlander and Melchior 2007), it is likely that many unknown SUMO substrates remain to be discovered. Moreover, previous systematic PPI screens to identify SUMO substrates have primarily been performed with the yeast two-hybrid method and TAP-MS, which do not measure PPIs in the natural cellular context. The low agreement between the data from previous systematic screens demonstrates the limitation of the experimental methods used in those analyses and indicates that no single screen has been comprehensive. For this reason, different systematic approaches, with methods that can detect the interactions between proteins in their natural cellular environment, would greatly contribute to the identification of novel SUMO substrates and thus to the understanding of the function of the SUMO pathway.In the present study, we generated a collection of yeast strains expressing full-length proteins tagged with the N-terminal fragment of Venus (VN), a yellow fluorescent protein variant, from their own native promoters. Through a systematic analysis with the VN fusion library, we identified the interactome of SUMO, comprising 367 proteins, and also obtained previously unavailable information on the subcellular localization, types, and protease dependence of SUMO interactions in living yeast cells. Our data not only highlight a novel relationship between sumoylation and various biological processes but also represent a valuable resource that can be used to study the functional roles of the SUMO pathway. This is the first report that describes the application of the BiFC assay to a genome-wide PPI analysis using proteins expressed from their own native promoters. As demonstrated here, the VN fusion library provides a useful research tool that makes it feasible to systematically analyze PPIs in the natural cellular context.     

Effect of age and sex on fully automated deep learning assessment of left ventricular function,volumes, and contours in cardiac magnetic resonance imaging

The International Journal of Cardiovascular Imaging - Deep learning algorithms for left ventricle (LV) segmentation are prone to bias towards the training dataset. This study assesses sex- and...     

Albumin-associated free fatty acids induce macropinocytosis in podocytes

Podocytes are specialized epithelial cells in the kidney glomerulus that play important structural and functional roles in maintaining the filtration barrier. Nephrotic syndrome results from a breakdown of the kidney filtration barrier and is associated with proteinuria, hyperlipidemia, and edema. Additionally, podocytes undergo changes in morphology and internalize plasma proteins in response to this disorder. Here, we used fluid-phase tracers in murine models and determined that podocytes actively internalize fluid from the plasma and that the rate of internalization is increased when the filtration barrier is disrupted. In cultured podocytes, the presence of free fatty acids (FFAs) associated with serum albumin stimulated macropinocytosis through a pathway that involves FFA receptors, the Gβ/Gγ complex, and RAC1. Moreover, mice with elevated levels of plasma FFAs as the result of a high-fat diet were more susceptible to Adriamycin-induced proteinuria than were animals on standard chow. Together, these results support a model in which podocytes sense the disruption of the filtration barrier via FFAs bound to albumin and respond by enhancing fluid-phase uptake. The response to FFAs may function in the development of nephrotic syndrome by amplifying the effects of proteinuria.     

Comparison of changes in retentive force of three stud attachments for implant overdentures

PURPOSEThe aim of this study was to compare the changes in retentive force of stud attachments for implant overdentures by in vitro 2-year-wear simulation.RESULTSA comparison of the initial retentive force revealed the highest value for Kerator, followed by the O-ring and EZ lock attachments. However, no significant difference was detected between Kerator and O-ring (P>.05). After 2500 insertion and removal cycles, the highest retention loss was recorded for O-ring, and no significant difference between Kerator and EZ lock (P>.05). Also, Kerator showed the highest retentive force, followed by EZ lock and O-ring, after 2500 cycles (P<.05). Based on SEM analysis, the polymeric components in O-ring and Kerator were observed to exhibit surface wear and deformation.CONCLUSIONAfter 2500 insertion and removal cycles, all attachments exhibited significant loss in retention. Mechanism of retention loss can only be partially explained by surface changes.     

Automatically Detecting Failures in Natural Language Processing Tools for Online Community Text

Background

The prevalence and value of patient-generated health text are increasing, but processing such text remains problematic. Although existing biomedical natural language processing (NLP) tools are appealing, most were developed to process clinician- or researcher-generated text, such as clinical notes or journal articles. In addition to being constructed for different types of text, other challenges of using existing NLP include constantly changing technologies, source vocabularies, and characteristics of text. These continuously evolving challenges warrant the need for applying low-cost systematic assessment. However, the primarily accepted evaluation method in NLP, manual annotation, requires tremendous effort and time.

Objective

The primary objective of this study is to explore an alternative approach—using low-cost, automated methods to detect failures (eg, incorrect boundaries, missed terms, mismapped concepts) when processing patient-generated text with existing biomedical NLP tools. We first characterize common failures that NLP tools can make in processing online community text. We then demonstrate the feasibility of our automated approach in detecting these common failures using one of the most popular biomedical NLP tools, MetaMap.

Methods

Using 9657 posts from an online cancer community, we explored our automated failure detection approach in two steps: (1) to characterize the failure types, we first manually reviewed MetaMap’s commonly occurring failures, grouped the inaccurate mappings into failure types, and then identified causes of the failures through iterative rounds of manual review using open coding, and (2) to automatically detect these failure types, we then explored combinations of existing NLP techniques and dictionary-based matching for each failure cause. Finally, we manually evaluated the automatically detected failures.

Results

From our manual review, we characterized three types of failure: (1) boundary failures, (2) missed term failures, and (3) word ambiguity failures. Within these three failure types, we discovered 12 causes of inaccurate mappings of concepts. We used automated methods to detect almost half of 383,572 MetaMap’s mappings as problematic. Word sense ambiguity failure was the most widely occurring, comprising 82.22% of failures. Boundary failure was the second most frequent, amounting to 15.90% of failures, while missed term failures were the least common, making up 1.88% of failures. The automated failure detection achieved precision, recall, accuracy, and F1 score of 83.00%, 92.57%, 88.17%, and 87.52%, respectively.

Conclusions

We illustrate the challenges of processing patient-generated online health community text and characterize failures of NLP tools on this patient-generated health text, demonstrating the feasibility of our low-cost approach to automatically detect those failures. Our approach shows the potential for scalable and effective solutions to automatically assess the constantly evolving NLP tools and source vocabularies to process patient-generated text.     

Neuropathic Pain Model of Peripheral Neuropathies Mediated by Mutations of Glycyl-tRNA Synthetase

Charcot-Marie-Tooth disease (CMT) is the most common inherited motor and sensory neuropathy. Previous studies have found that, according to CMT patients, neuropathic pain is an occasional symptom of CMT. However, neuropathic pain is not considered to be a significant symptom associated with CMT and, as a result, no studies have investigated the pathophysiology underlying neuropathic pain in this disorder. Thus, the first animal model of neuropathic pain was developed by our laboratory using an adenovirus vector system to study neuropathic pain in CMT. To this end, glycyl-tRNA synthetase (GARS) fusion proteins with a FLAG-tag (wild type [WT], L129P and G240R mutants) were expressed in spinal cord and dorsal root ganglion (DRG) neurons using adenovirus vectors. It is known that GARS mutants induce GARS axonopathies, including CMT type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V). Additionally, the morphological phenotypes of neuropathic pain in this animal model of GARS-induced pain were assessed using several possible markers of pain (Iba1, pERK1/2) or a marker of injured neurons (ATF3). These results suggest that this animal model of CMT using an adenovirus may provide information regarding CMT as well as a useful strategy for the treatment of neuropathic pain.

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Impact of Enzyme Replacement Therapy on Linear Growth in Korean Patients with Mucopolysaccharidosis Type II (Hunter Syndrome)

Hunter syndrome (or mucopolysaccharidosis type II [MPS II]) arises because of a deficiency in the lysosomal enzyme iduronate-2-sulfatase. Short stature is a prominent and consistent feature in MPS II. Enzyme replacement therapy (ERT) with idursulfase (Elaprase®) or idursulfase beta (Hunterase®) have been developed for these patients. The effect of ERT on the growth of Korean patients with Hunter syndrome was evaluated at a single center. This study comprised 32 patients, who had received ERT for at least 2 yr; they were divided into three groups according to their ages at the start of ERT: group 1 (<6 yr, n=14), group 2 (6-10 yr, n=11), and group 3 (10-20 yr, n=7). The patients showed marked growth retardation as they got older. ERT may have less effect on the growth of patients with the severe form of Hunter syndrome. The height z-scores in groups 2 and 3 revealed a significant change (the estimated slopes before and after the treatment were -0.047 and -0.007, respectively: difference in the slope, 0.04; P<0.001). Growth in response to ERT could be an important treatment outcome or an endpoint for future studies.

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