• Abnormal Development of the Earliest Cortical Circuits in a Mouse Model of Autism Spectrum Disorder

      Nagode, D.A.; Meng, X.; Winkowski, D.E. (Elsevier B.V., 2017)
      Autism spectrum disorder (ASD) involves deficits in speech and sound processing. Cortical circuit changes during early development likely contribute to such deficits. Subplate neurons (SPNs) form the earliest cortical microcircuits and are required for normal development of thalamocortical and intracortical circuits. Prenatal valproic acid (VPA) increases ASD risk, especially when present during a critical time window coinciding with SPN genesis. Using optical circuit mapping in mouse auditory cortex, we find that VPA exposure on E12 altered the functional excitatory and inhibitory connectivity of SPNs. Circuit changes manifested as “patches” of mostly increased connection probability or strength in the first postnatal week and as general hyper-connectivity after P10, shortly after ear opening. These results suggest that prenatal VPA exposure severely affects the developmental trajectory of cortical circuits and that sensory-driven activity may exacerbate earlier, subtle connectivity deficits. Our findings identify the subplate as a possible common pathophysiological substrate of deficits in ASD. Copyright 2017 The Author(s)
    • The effect of cigarette smoking on the oral and nasal microbiota

      Humphrys, Michael S.; Yu, G.; Phillips, S. (BioMed Central Ltd., 2017)
      Background: The goal of the study was to investigate whether cigarette smoking alters oral and nasal microbial diversity, composition, and structure. Twenty-three current smokers and 20 never smokers were recruited. From each subject, nine samples including supra and subgingiva plaque scrapes, saliva, swabs from five soft oral tissue sites, and one nasal swab from both the anterior nares were collected. 16S rRNA V3-V4 region was sequenced for microbial profiles. Results: We found that alpha diversity was lower in smokers than in nonsmokers in the buccal mucosa, but in other sample sites, microbial diversity and composition were not significantly different by smoking status. Microbial profiles differed significantly among eight oral sites. Conclusions: This study investigates the effect of cigarette smoking on different sites of the oral cavity and shows a potential effect of cigarette smoking on the buccal mucosa microbiota. The marked heterogeneity of the oral microbial ecosystem that we found may contribute to the stability of the oral microbiota in most sites when facing environmental perturbations such as that caused by cigarette smoking. Copyright The Author(s) 2017.
    • Prognosis for women diagnosed with melanoma during, before, or after pregnancy: Weighing the evidence

      Todd, S.P.; Driscoll, M.S. (Elsevier Inc, 2017)
      Approximately one third of women who are diagnosed with malignant melanoma are of childbearing age. Therefore, it is not surprising that some studies have found malignant melanoma to be one of the most common malignancies diagnosed in pregnant women. The impact of pregnancy-related hormonal changes on melanoma development and progression remains controversial. Women undergo immunologic changes during pregnancy that may decrease tumor surveillance. Additionally, hormone receptors are found on some melanomas. Unfortunately, many of the past and even recent studies that have been published and are reviewed herein did not uniformly use appropriate control groups, account for confounding covariates, or employ appropriate statistical analysis, which makes it difficult to rely on the conclusions they reach. However, a review of the better controlled and preponderant studies demonstrates that pregnancy-associated melanomas are not associated with a poorer prognosis.
    • Location, Location, Location: Microglia Are Where They Live

      McCarthy, M.M. (Cell Press, 2017)
      A deep dive into microglia form and function reveals startling regional heterogeneity in number, morphology, activity, and transcriptomics in nuclei relevant to motor control and motivation (De Biase et al., 2017). Differences appear 2 weeks after birth, and depletion and recolonization in adulthood recapitulate the original phenotype, implicating local environment as mediators of microglial phenotype. A deep dive into microglia form and function reveals startling regional heterogeneity in number, morphology, activity, and transcriptomics in nuclei relevant to motor control and motivation (De Biase et al.). Differences appear 2 weeks after birth, and depletion and recolonization in adulthood recapitulate the original phenotype, implicating local environment as mediators of microglial phenotype.
    • Certification test prep: This is the year to listen to yourself

      Rauen, C.; Knippa, S.; Clark, C.A. (American Association of Critical Care Nurses, 2017)
    • Catastrophic Consequence of Gauze During Percutaneous Coronary Intervention

      Mori, H.; Kutys, R.; Romero, M. (Elsevier Inc., 2017)
    • Performance of microscopic observation drug susceptibility for the rapid diagnosis of tuberculosis and detection of drug resistance in Bamako, Mali

      Sanogo, M.; Kone, B.; Diarra, B. (Elsevier B.V., 2017)
      Objectives: In Mali early detection and treatment of multidrug-resistant tuberculosis (MDR-TB) are still challenging due to the cost, time and/or complexity associated with regular tests. Microscopic Observation Drug Susceptibility (MODS) is a low-cost assay validated by WHO in 2010. It is a liquid-culture-based assay to detect the ‘cording’ characteristic of Mycobacterium tuberculosis complex and to assess susceptibility to both isoniazid and rifampicin defining multidrug-resistant tuberculosis (MDR-TB). In this study we aimed to evaluate the performance of MODS as diagnostic tool compared with a validated method—Mycobacteria Growth Indicator Tube/Antimicrobial Susceptibility Testing/Streptomycin, Isoniazid, Rifampicin and Ethambutol (MGIT/AST/SIRE). Methods and Results: Between January 2010 and October 2015 we included 98 patients with suspected TB in an observational cohort study. The sensitivity and specificity of MODS assay for detecting TB were respectively 94.12% and 85.71% compared with the reference MGIT/7H11 culture, with a Cohen κ coefficient of 0.78 (95% CI 0.517–1.043). The median time to culture positivity for MODS assay and MGIT (plus interquartile range, IQR) was respectively 8 days (IQR 5–11) and 6 days (IQR 5–6). In detecting patients with MDR-TB, the sensitivity and specificity of MODS assay were respectively 100% and 95.92%. The positive predictive value and negative predictive value were, respectively, 66.7% and 100%. The median turnaround times for obtaining MDR-TB results using MODS assay and MGIT/AST/SIRE was respectively 9 days and 35 days. Hence, the MODS assay rapidly identifies MDR-TB in Mali compared with the MGIT/AST/SIRE. Conclusion As an easy, simple, fast and affordable method, the MODS assay could significantly improve the management of TB. Copyright 2017 European Society of Clinical Microbiology and Infectious Diseases
    • Binding of a C-type lectin's coiled-coil domain to the Domeless receptor directly activates the JAK/STAT pathway in the shrimp immune response to bacterial infection

      Sun, J.-J.; Lan, J.-F.; Zhao, X.-F. (Public Library of Science, 2017)
      C-type lectins (CTLs) are characterized by the presence of a C-type carbohydrate recognition domain (CTLD) that by recognizing microbial glycans, is responsible for their roles as pattern recognition receptors in the immune response to bacterial infection. In addition to the CTLD, however, some CTLs display additional domains that can carry out effector functions, such as the collagenous domain of the mannose-binding lectin. While in vertebrates, the mechanisms involved in these effector functions have been characterized in considerable detail, in invertebrates they remain poorly understood. In this study, we identified in the kuruma shrimp (Marsupenaeus japonicus) a structurally novel CTL (MjCC-CL) that in addition to the canonical CTLD, contains a coiled-coil domain (CCD) responsible for the effector functions that are key to the shrimp's antibacterial response mediated by antimicrobial peptides (AMPs). By the use of in vitro and in vivo experimental approaches we elucidated the mechanism by which the recognition of bacterial glycans by the CTLD of MjCC-CL leads to activation of the JAK/STAT pathway via interaction of the CCD with the surface receptor Domeless, and upregulation of AMP expression. Thus, our study of the shrimp MjCC-CL revealed a striking functional difference with vertebrates, in which the JAK/STAT pathway is indirectly activated by cell death and stress signals through cytokines or growth factors. Instead, by cross-linking microbial pathogens with the cell surface receptor Domeless, a lectin directly activates the JAK/STAT pathway, which plays a central role in the shrimp antibacterial immune responses by upregulating expression of selected AMPs. Copyright 2017 Sun et al.
    • The binding effect of proteins on medications and its impact on electrochemical sensing: Antipsychotic clozapine as a case study

      Banis, G.E.; Winkler, T.; Barton, P. (MDPI AG, 2017)
      Clozapine (CLZ), a dibenzodiazepine, is demonstrated as the optimal antipsychotic for patients suffering from treatment-resistant schizophrenia. Like many other drugs, understanding the concentration of CLZ in a patient’s blood is critical for managing the patients’ symptoms, side effects, and overall treatment efficacy. To that end, various electrochemical techniques have been adapted due to their capabilities in concentration-dependent sensing. An open question associated with electrochemical CLZ monitoring is whether drug–protein complexes (i.e., CLZ bound to native blood proteins, such as serum albumin (SA) or alpha-1 acid-glycoprotein (AAG)) contribute to electrochemical redox signals. Here, we investigate CLZ-sensing performance using fundamental electrochemical methods with respect to the impact of protein binding. Specifically, we test the activity of bound and free fractions of a mixture of CLZ and either bovine SA or human AAG. Results suggest that bound complexes do not significantly contribute to the electrochemical signal for mixtures of CLZ with AAG or SA. Moreover, the fraction of CLZ bound to protein is relatively constant at 31% (AAG) and 73% (SA) in isolation with varying concentrations of CLZ. Thus, electrochemical sensing can enable direct monitoring of only the unbound CLZ, previously only accessible via equilibrium dialysis. The methods utilized in this work offer potential as a blueprint in developing electrochemical sensors for application to other redox-active medications with high protein binding more generally. This demonstrates that electrochemical sensing can be a new tool in accessing information not easily available previously, useful toward optimizing treatment regimens. Copyright 2017 by the authors. Licensee MDPI, Basel, Switzerland.
    • Molecular characterization of the human stomach microbiota in Gastric Cancer Patients

      Yu, G.; Torres, J.; Hu, N. (Frontiers Media S.A., 2017)
      Helicobacter pylori (Hp) is the primary cause of gastric cancer but we know little of its relative abundance and other microbes in the stomach, especially at the time of gastric cancer diagnosis. Here we characterized the taxonomic and derived functional profiles of gastric microbiota in two different sets of gastric cancer patients, and compared them with microbial profiles in other body sites. Paired non-malignant and tumor tissues were sampled from 160 gastric cancer patients with 80 from China and 80 from Mexico. The 16S rRNA gene V3-V4 region was sequenced using MiSeq platform for taxonomic profiles. PICRUSt was used to predict functional profiles. Human Microbiome Project was used for comparison. We showed that Hp is the most abundant member of gastric microbiota in both Chinese and Mexican samples (51 and 24%, respectively), followed by oral-associated bacteria. Taxonomic (phylum-level) profiles of stomach microbiota resembled oral microbiota, especially when the Helicobacter reads were removed. The functional profiles of stomach microbiota, however, were distinct from those found in other body sites and had higher inter-subject dissimilarity. Gastric microbiota composition did not differ by Hp colonization status or stomach anatomic sites, but did differ between paired non-malignant and tumor tissues in either Chinese or Mexican samples. Our study showed that Hp is the dominant member of the non-malignant gastric tissue microbiota in many gastric cancer patients. Our results provide insights on the gastric microbiota composition and function in gastric cancer patients, which may have important clinical implications. Copyright 2017 Yu, Torres, Hu, Medrano-Guzman, Herrera-Goepfert, Humphrys, Wang, Wang, Ding, Ravel, Taylor, Abnet and Goldstein.
    • Immune reconstitution inflammatory syndrome associated with pulmonary pathogens

      Gopal, R.; Rapaka, R.R.; Kolls, J.K. (European Respiratory Society, 2017)
      Immune reconstitution inflammatory syndrome (IRIS) is an exaggerated immune response to a variety of pathogens in response to antiretroviral therapy-mediated recovery of the immune system in HIV-infected patients. Although IRIS can occur in many organs, pulmonary IRIS, associated with opportunistic infections such as Mycobacterium tuberculosis and Pneumocystis jirovecii, is particularly associated with high morbidity and mortality. The pathology of IRIS is associated with a variety of innate and adaptive immune factors, including CD4+ T-cells, CD8+ T-cells, γδ T-cells, natural killer cells, macrophages, the complement system and surfactant proteins, Toll-like receptors and pro-inflammatory cytokines and chemokines. Although there are numerous reports about the immune factors involved in IRIS, the mechanisms involved in the development of pulmonary IRIS are poorly understood. Here, we propose that studies using gene-deficient murine and nonhuman primate models will help to identify the specific molecular targets associated with the development of IRIS. An improved understanding of the mechanisms involved in the pathology of pulmonary IRIS will help to identify potential biomarkers and therapeutic targets in this syndrome.
    • Expression level of human TLR4 rather than sequence is the key determinant of LPS responsiveness

      Hajjar, A.M.; Ernst, R.K.; Yi, J. (Public Library of Science, 2017)
      To address the role of Toll-like receptor 4 (TLR4) single nucleotide polymorphisms (SNP) in lipopolysaccharide (LPS) recognition, we generated mice that differed only in the sequence of TLR4. We used a bacterial artificial chromosome (BAC) transgenic approach and TLR4/ MD-2 knockout mice to specifically examine the role of human TLR4 variants in recognition of LPS. Using in vitro and in vivo assays we found that the expression level rather than the sequence of TLR4 played a larger role in recognition of LPS, especially hypoacylated LPS. Copyright 2017 Hajjar et al.
    • Evidence-Based TAM Classic Herbal Formula: From Myth to Science

      Xiong, X.; Che, C.-T.; Borrelli, F. (Hindawi Limited, 2017)
    • An in vitro model yields ‘importin’ new insights into chronic traumatic encephalopathy: damaged astrocytes stop ‘thrombospondin’ to the injury An Editorial Highlight for ‘Defective synthesis and release of astrocytic thrombospondin‐1 mediates the neuronal TDP‐43 proteinopathy, resulting in defects in neuronal integrity associated with chronic traumatic encephalopathy: in vitro studies’

      Jaber, S.M.; Polster, B.M. (Blackwell Publishing Ltd, 2017)
      This Editorial highlights a study by Jayakumar and colleagues (2016) in the current issue of Journal of Neurochemistry. The authors introduce an in vitro model of chronic traumatic encephalopathy (CTE) to explore the mechanistic underpinnings of CTE pathogenesis, including investigation of how traumatized astrocytes affect traumatized neurons through the release of secreted factors. The model recapitulates two key features of the human post-mortem CTE brain: neuronal tauopathy and TDP-43 proteinopathy—the respective accretion of hyperphosphorylated tau and cytoplasmic hyperphosphorylated and ubiquitinated TDP-43. Oxidative stress and casein kinase 1 episilon (CK1ε) are identified as key upstream regulators of cytoplasmic TDP-43 phosphorylation, and this phosphorylation is found to correlate with decreased importin-β protein level and a decline in synaptic integrity. RNA silencing of importin-β is sufficient to mimic both the phospho-TDP-43 accumulation and synaptic injury observed after mild in vitro trauma. Strikingly, Jayakumar et al. find that thrombospondin-1 (TSP-1), a protein secreted by traumatized astrocytes at elevated levels during the initial 5 days after damage, can attenuate CK1ε phosphorylation of TDP-43 and synaptic injury. However, TSP-1 secretion by astrocytes is lost at 10–15 days post-injury, and neurons succumb to unchecked TDP-43 pathogenesis.
    • Mixed signals: Co-stimulation in invariant natural killer T cell-mediated cancer immunotherapy

      Shissler, S.C.; Lee, M.S.; Webb, T.J. (Frontiers Media S.A., 2017)
      Invariant natural killer T (iNKT) cells are an integral component of the immune system and play an important role in antitumor immunity. Upon activation, iNKT cells can directly kill malignant cells as well as rapidly produce cytokines that stimulate other immune cells, making them a front line defense against tumorigenesis. Unfortunately, iNKT cell number and activity are reduced in multiple cancer types. This anergy is often associated with upregulation of co-inhibitory markers such as programmed death-1. Similar to conventional T cells, iNKT cells are influenced by the conditions of their activation. Conventional T cells receive signals through the following three types of receptors: (1) T cell receptor (TCR), (2) co-stimulation molecules, and (3) cytokine receptors. Unlike conventional T cells, which recognize peptide antigen presented by MHC class I or II, the TCRs of iNKT cells recognize lipid antigen in the context of the antigen presentation molecule CD1d (Signal 1). Co-stimulatory molecules can positively and negatively influence iNKT cell activation and function and skew the immune response (Signal 2). This study will review the background of iNKT cells and their co-stimulatory requirements for general function and in antitumor immunity. We will explore the impact of monoclonal antibody administration for both blocking inhibitory pathways and engaging stimulatory pathways on iNKT cell-mediated antitumor immunity. This review will highlight the incorporation of co-stimulatory molecules in antitumor dendritic cell vaccine strategies. The use of co-stimulatory intracellular signaling domains in chimeric antigen receptor-iNKT therapy will be assessed. Finally, we will explore the influence of innate-like receptors and modification of immunosuppressive cytokines (Signal 3) on cancer immunotherapy. Copyright 2017 Shissler, Lee and Webb.
    • Human hepatocyte metabolism of novel synthetic cannabinoids MN-18 and its 5-fluoro analog 5F-MN-18

      Diao, X.; Carlier, J.; Zhu, M. (American Association for Clinical Chemistry Inc., 2017)
      BACKGROUND: In 2014, 2 novel synthetic cannabinoids, MN-18 and its 5-fluoro analog, 5F-MN-18, were first identified in an ongoing survey of novel psychoactive substances in Japan. In vitro pharmacological assays revealed that MN-18 and 5F-MN-18 displayed high binding affinities to human CB1 and CB2 receptors, with Ki being 1.65- 3.86 nmol/L. MN-18 and 5F-MN-18 were scheduled in Japan and some other countries in 2014. Despite increasing prevalence, no human metabolism data are currently available, making it challenging for forensic laboratories to confirm intake of MN-18 or 5F-MN-18. METHODS: We incubated 10 ?mol/L of MN-18 and 5F-MN-18 in human hepatocytes for 3 h and analyzed the samples on a TripleTOF 5600+ high-resolution mass spectrometer to identify appropriate marker metabolites. Data were acquired via full scan and informationdependent acquisition-triggered product ion scans with mass defect filter. RESULTS: In total, 13 MN-18 metabolites were detected, with the top 3 abundant metabolites being 1-pentyl-1Hindazole- 3-carboxylic acid, pentyl-carbonylated MN-18, and naphthalene-hydroxylated MN-18. For 5F-MN-18, 20 metabolites were observed, with the top 3 abundant metabolites being 5'-OH-MN-18, MN-18 pentanoic acid, and 1-(5-fluoropentyl)-1H-indazole-3-carboxylic acid. CONCLUSIONS: We have characterized MN-18 and 5FMN- 18 metabolism with human hepatocytes and highresolution mass spectrometry, and we recommend characteristic major metabolites for clinical and forensic laboratories to identify MN-18 and 5F-MN-18 intake and link observed adverse events to these novel synthetic cannabinoids.
    • Computational dynamic approaches for temporal omics data with applications to systems medicine

      Liang, Y.; Kelemen, A. (BioMed Central Ltd., 2017)
      Modeling and predicting biological dynamic systems and simultaneously estimating the kinetic structural and functional parameters are extremely important in systems and computational biology. This is key for understanding the complexity of the human health, drug response, disease susceptibility and pathogenesis for systems medicine. Temporal omics data used to measure the dynamic biological systems are essentials to discover complex biological interactions and clinical mechanism and causations. However, the delineation of the possible associations and causalities of genes, proteins, metabolites, cells and other biological entities from high throughput time course omics data is challenging for which conventional experimental techniques are not suited in the big omics era. In this paper, we present various recently developed dynamic trajectory and causal network approaches for temporal omics data, which are extremely useful for those researchers who want to start working in this challenging research area. Moreover, applications to various biological systems, health conditions and disease status, and examples that summarize the state-of-the art performances depending on different specific mining tasks are presented. We critically discuss the merits, drawbacks and limitations of the approaches, and the associated main challenges for the years ahead. The most recent computing tools and software to analyze specific problem type, associated platform resources, and other potentials for the dynamic trajectory and interaction methods are also presented and discussed in detail. Copyright The Author(s). 2017.
    • Nonvitamin, Nonmineral Dietary Supplement Use among Adults with Fibromyalgia: United States, 2007-2012

      Feinberg, T.; Lilly, C.; Innes, K. (Hindawi Limited, 2017)
      Background. Fibromyalgia (FMS) is a pain condition affecting 2-6% of US adults; effective treatment remains limited. Determinants of nonvitamin, nonmineral dietary supplement (NVNM) use among adults with FMS are not well-studied. We investigated the relation of NVNM use to FMS, and trends, in two nationally representative samples of US adults ?18 years. Methods. Data were drawn from 2007 and 2012 National Health Interview Surveys (N's = 20127 and 30672, resp.). Logistic regression was used to examine associations of FMS to NVNM use (past 12 months) and evaluate potential modifying influences of gender and comorbidities. Multivariate models adjusted for sampling design, demographic, lifestyle, and health-related factors. Results. FMS was significantly higher in 2012 than in 2007 (1.7% versus 1.3%), whereas NVNM use decreased (57% versus 41%; p<0.0001). Adults reporting diagnosis were more likely to use NVNMs within 12 months, 30 days, or ever relative to adults without; positive associations remained significant after controlling for demographics, lifestyle characteristics, medical history, and other confounders (ranges: 2007 and 2012 AORs = 2.3-2.7; 1.5-1.6, resp.; p's < 0.0001). Conclusion. In this cross-sectional study of two national samples, NVNM use was strongly and positively associated with FMS, highlighting the need for further study. Copyright 2017 Termeh Feinberg et al.