Citations

Abstract Understanding the molecular profile of every human cell type is essential for understanding its role in normal physiology and disease. Technological advancements in DNA sequencing, mass spectrometry, and computational methods allow us to carry out multiomics analyses although such approaches are not routine yet. Human umbilical vein endothelial cells (HUVECs) are a widely used model system to study pathological and physiological processes associated with the cardiovascular system. In this study, next‐generation sequencing and high‐resolution mass spectrometry to profile the transcriptome and proteome of primary HUVECs is employed. Analysis of 145 million paired‐end reads from next‐generation sequencing confirmed expression of 12 186 protein‐coding genes (FPKM ≥0.1), 439 novel long non‐coding RNAs, and revealed 6089 novel isoforms that were not annotated in GENCODE. Proteomics analysis identifies 6477 proteins including confirmation of N ‐termini for 1091 proteins, isoforms for 149 proteins, and 1034 phosphosites. A database search to specifically identify other post‐translational modifications provide evidence for a number of modification sites on 117 proteins which include ubiquitylation, lysine acetylation, and mono‐, di‐ and tri‐methylation events. Evidence for 11 “missing proteins,” which are proteins for which there was insufficient or no protein level evidence, is provided. Peptides supporting missing protein and novel events are validated by comparison of MS/MS fragmentation patterns with synthetic peptides. Finally, 245 variant peptides derived from 207 expressed proteins in addition to alternate translational start sites for seven proteins and evidence for novel proteoforms for five proteins resulting from alternative splicing are identified. Overall, it is believed that the integrated approach employed in this study is widely applicable to study any primary cell type for deeper molecular characterization.

The possible association between the membrane-associated guanylate kinase with inverted domain structure-1 (MAGI1) and inflammation has been suggested, but the molecular mechanisms underlying this link, especially during atherogenesis, remain unclear. In endothelial cells (ECs) exposed to disturbed flow (d-flow), p90 ribosomal S6 kinase (p90RSK) bound to MAGI1, causing MAGI1-S741 phosphorylation and sentrin/SUMO-specific protease 2 T368 phosphorylation-mediated MAGI1-K931 deSUMOylation. MAGI1-S741 phosphorylation upregulated EC activation via activating Rap1. MAGI1-K931 deSUMOylation induced both nuclear translocation of p90RSK-MAGI1 and ATF-6-MAGI1 complexes, which accelerated EC activation and apoptosis, respectively. Microarray screening revealed key roles for MAGI1 in the endoplasmic reticulum (ER) stress response. In this context, MAGI1 associated with activating transcription factor 6 (ATF-6). MAGI1 expression was upregulated in ECs and macrophages found in atherosclerotic-prone regions of mouse aortas as well as in the colonic epithelia and ECs of patients with inflammatory bowel disease. Further, reduced MAGI1 expression in Magi1 –/+ mice inhibited d-flow–induced atherogenesis. In sum, EC activation and ER stress–mediated apoptosis are regulated in concert by two different types of MAGI1 posttranslational modifications, elucidating attractive drug targets for chronic inflammatory disease, particularly atherosclerosis.

Four patients with primary progressive aphasia displayed a greater deficit in understanding words they heard than words they read, and a further deficiency in naming objects orally rather than in writing. All four had frontotemporal lobar degeneration-transactive response DNA binding protein Type A neuropathology, three determined postmortem and one surmised on the basis of granulin gene (GRN) mutation. These features of language impairment are not characteristic of any currently recognized primary progressive aphasia variant. They can be operationalized as manifestations of dysfunction centered on a putative auditory word-form area located in the superior temporal gyrus of the left hemisphere. The small size of our sample makes the conclusions related to underlying pathology and auditory word-form area dysfunction tentative. Nonetheless, a deeper assessment of such patients may clarify the nature of pathways that link modality-specific word-form information to the associations that mediate their recognition as concepts. From a practical point of view, the identification of these features in patients with primary progressive aphasia should help in the design of therapeutic interventions where written communication modalities are promoted to circumvent some of the oral communication deficits.

This paper presents the diagnostic criteria for hemodynamic orthostatic dizziness/vertigo to be included in the International Classification of Vestibular Disorders (ICVD). The aim of defining diagnostic criteria of hemodynamic orthostatic dizziness/vertigo is to help clinicians to understand the terminology related to orthostatic dizziness/vertigo and to distinguish orthostatic dizziness/vertigo due to global brain hypoperfusion from that caused by other etiologies. Diagnosis of hemodynamic orthostatic dizziness/vertigo requires: A) five or more episodes of dizziness, unsteadiness or vertigo triggered by arising or present during upright position, which subsides by sitting or lying down; B) orthostatic hypotension, postural tachycardia syndrome or syncope documented on standing or during head-up tilt test; and C) not better accounted for by another disease or disorder. Probable hemodynamic orthostatic dizziness/vertigo is defined as follows: A) five or more episodes of dizziness, unsteadiness or vertigo triggered by arising or present during upright position, which subsides by sitting or lying down; B) at least one of the following accompanying symptoms: generalized weakness/tiredness, difficulty in thinking/concentrating, blurred vision, and tachycardia/palpitations; and C) not better accounted for by another disease or disorder. These diagnostic criteria have been derived by expert consensus from an extensive review of 90 years of research on hemodynamic orthostatic dizziness/vertigo, postural hypotension or tachycardia, and autonomic dizziness. Measurements of orthostatic blood pressure and heart rate are important for the screening and documentation of orthostatic hypotension or postural tachycardia syndrome to establish the diagnosis of hemodynamic orthostatic dizziness/vertigo.

Non-canonical IκB kinases (IKKs) TBK1 and IKKε have essential roles as regulators of innate immunity and cancer. Recent work has also implicated these kinases in distinctively controlling glucose homeostasis and repressing adaptive thermogenic and mitochondrial biogenic response upon obesity-induced inflammation. Additionally, TBK1 and IKKε regulate pancreatic β-cell regeneration. In this review, we summarize current data on the functions and molecular mechanisms of TBK1 and IKKε in orchestrating inflammation to cancer, obesity, and diabetes.

Background Minnesota has an ethnically diverse labor force, with the largest number of refugees per capita in the United States. In recent years, Minnesota has been and continues to be a major site for immigrant and refugee resettlement in the United States, with a large population of both immigrant and native born Hmong, Hispanic, and East Africans. This study seeks to evaluate the injury risk among the evolving minority workforce in the Minnesota Twin Cities region. Methods A retrospective cohort study identifying work‐related injuries following pre‐employment examinations was performed using electronic health records from a large multi‐clinic occupational medicine practice. Preplacement examinations and subsequent work‐related injuries were pulled from the electronic health record using representative ICD‐10 codes for surveillance examinations and injuries. This study included patient records collected over a 2‐year period from January 1, 2015, through December, 2016. The patients in this cohort worked in a wide‐array of occupations including production, assembly, construction, law enforcement, among others. Results Hispanic minority workers were twice as likely to be injured at work compared with White workers. Hispanics were 2.89 times more likely to develop back injuries compared with non‐Hispanic workers, and 1.86 times more likely to develop upper extremity injuries involving the hand, wrist, or elbow. Conclusion Clinical practice data shows that Hispanic workers are at increased risk for work‐related injuries in Minnesota. They were especially susceptible to back and upper extremity injuries. Lower injury rates in non‐Hispanic minority workers, may be the result of injury underreporting and require further investigation.

Summary The World Health Organization has set the goal of reducing the hepatitis‐related mortality rate by 65% between 2015 and 2030. Diagnosis and awareness of infection is the first essential step towards achieving this goal. Our study examined the current awareness rate of chronic viral hepatitis in the United States and the potentially associated factors. In the National Health Nutrition and Examination Survey 2013‐2016, there were 11 488 persons who participated in serology testing for chronic viral hepatitis. We defined chronic hepatitis B virus (HBV) infection by HbsAg, HBV past exposure by anti‐HBc and hepatitis C virus (HCV) infection by HCV RNA. At risk for significant fibrosis was determined by AST to Platelet Ratio Index >0.7. Awareness of chronic HBV infection, past HBV exposure and HCV infection were present in 33.9%, 11.7% and 55.6% of participants, respectively. Among HCV‐infected baby boomers, the awareness was in 61.5%. The awareness of HBV infection was significantly higher in individuals with high education level. Age group (40‐60 years), women, non‐Black race/ethnicity and those with high household income who were born in the United States with insurance plans tend to be aware of their infection. For HCV, awareness was the lowest in Hispanics and Asians, foreign‐born who lived below the federal poverty level and low education level. Awareness among chronic viral hepatitis patients at risk for significant fibrosis was 62.0% in HBV and 38.2% in HCV infection. In conclusion, current awareness of chronic viral hepatitis in the United States remains suboptimal. Active public health policy to identify persons at risk and provide appropriate management is warranted.

AbstractWnt signaling is a well‐known molecular pathway in age‐related pathogenesis and therapy of disease. While prior studies have mainly focused on Wnt ligands or Wnt activators, the in vivo functions of naturally secreted Wnt inhibitors are not clear, especially in brain aging. Using BubR1H/H mice as a novel mouse model of accelerated aging, we report that genetic inhibition of sFRP3 restores the reduced body and brain size observed in BubR1H/H mice. Furthermore, sFRP3 inhibition ameliorates hypomyelination in the corpus callosum and rescues neural progenitor proliferation in the hippocampal dentate gyrus of BubR1H/H mice. Taken together, our study identifies sFRP3 as a new molecular factor that cooperates with BubR1 function to regulate brain development, myelination, and hippocampal neurogenesis.

Abstract Background: To evaluate the association between opioid use and treatment outcome (symptom severity, quality of life [QOL]) after a brief interdisciplinary fibromyalgia treatment program (FTP). Method: Subjects (n = 971) with fibromyalgia participated in the FTP. They filled out the Fibromyalgia Impact Questionnaire (FIQ) and the Short Form-36 Health Status Questionnaire (SF-36) at baseline and 6 to 12 months after the FTP. Post-treatment changes in FIQ and SF-36 scores were compared after stratifying the participants into opioid user and non-opioid user groups. Results: A total of 236 patients (24.3%) were opioid users. Compared with non-opioid users, the opioid users had worse symptom severity measured using FIQ total score (p < .001) and all subscales at baseline and post treatment, as well as worse QOL measured using all SF-36 subscales and physical and mental components. Comparison of least-square means of mean change of QOL between opioid users and non-opioid users after analysis of covariance adjusted patient characteristics and baseline scores showed that the FIQ subscale scores of physical impairment (p < .05), job ability (p < .05), and fatigue (p < .05) were significantly less improved in the opioid users compared with the non-opioid users. Moreover, the SF-36 subscale score of general health perception (p < .05) was significantly less improved in the opioid users compared with non-opioid users. However, post-treatment changes in mean scores for QOL subscale generally did not significantly differ in both groups. Conclusions: Opioid use did not affect response to the FTP, as measured using the FIQ total score or SF-36 physical and mental component summary scores. Furthermore, the opioid user group showed less improvement in the FIQ subscale scores of physical impairment, job ability, and fatigue and in the SF-36 subscale scores of general health perception.