Literature Watch
Negative Regulation Gene Circuits for Efflux Pump Control.
Negative Regulation Gene Circuits for Efflux Pump Control.
Methods Mol Biol. 2018;1772:25-43
Authors: Charlebois DA, Diao J, Nevozhay D, Balázsi G
Abstract
Synthetic biologists aim to design biological systems for a variety of industrial and medical applications, ranging from biofuel to drug production. Synthetic gene circuits regulating efflux pump protein expression can achieve this by driving desired substrates such as biofuels, pharmaceuticals, or other chemicals out of the cell in a precisely controlled manner. However, efflux pumps may introduce implicit negative feedback by pumping out intracellular inducer molecules that control gene circuits, which then can alter gene circuit function. Therefore, synthetic gene circuits must be carefully designed and constructed for precise efflux control. Here, we provide protocols for quantitatively modeling and building synthetic gene constructs for efflux pump regulation.
PMID: 29754221 [PubMed - in process]
Long-term hindlimb unloading causes a preferential reduction of medullary thymic epithelial cells expressing autoimmune regulator (Aire).
Long-term hindlimb unloading causes a preferential reduction of medullary thymic epithelial cells expressing autoimmune regulator (Aire).
Biochem Biophys Res Commun. 2018 May 10;:
Authors: Horie K, Kudo T, Yoshinaga R, Akiyama N, Sasanuma H, Kobayashi TJ, Shimbo M, Jeon H, Miyao T, Miyauchi M, Shirakawa M, Shiba D, Yoshida N, Muratani M, Takahashi S, Akiyama T
Abstract
Hindlimb unloading (HU) of rodents has been used as a ground-based model of spaceflight. In this study, we investigated the detailed impact of 14-day HU on the murine thymus. Thymic mass and cell number were significantly reduced after 14 days of hindlimb unloading, which was accompanied by an increment of plasma corticosterone. Although corticosterone reportedly causes selective apoptosis of CD4+CD8+ thymocytes (CD4+CD8+DPs) in mice treated with short-term HU, the reduction of thymocyte cellularity after the 14-day HU was not selective for CD4+CD8+DPs. In addition to the thymocyte reduction, the cellularity of thymic epithelial cells (TECs) was also reduced by the 14-day HU. Flow cytometric and RNA-sequencing analysis suggested that medullary TECs (mTECs) were preferentially reduced after HU. Moreover, immunohistochemical staining suggested that the 14-day HU caused a reduction of the mTECs expressing autoimmune regulator (Aire). Our data suggested that HU impacts both thymocytes and TECs. Consequently, these data imply that thymic T cell repertoire formation could be disturbed during spaceflight-like stress.
PMID: 29753741 [PubMed - as supplied by publisher]
Reserve Flux Capacity in the Pentose Phosphate Pathway Enables Escherichia coli's Rapid Response to Oxidative Stress.
Reserve Flux Capacity in the Pentose Phosphate Pathway Enables Escherichia coli's Rapid Response to Oxidative Stress.
Cell Syst. 2018 May 02;:
Authors: Christodoulou D, Link H, Fuhrer T, Kochanowski K, Gerosa L, Sauer U
Abstract
To counteract oxidative stress and reactive oxygen species (ROS), bacteria evolved various mechanisms, primarily reducing ROS through antioxidant systems that utilize cofactor NADPH. Cells must stabilize NADPH levels by increasing flux through replenishing metabolic pathways like pentose phosphate (PP) pathway. Here, we investigate the mechanism enabling the rapid increase in NADPH supply by exposing Escherichia coli to hydrogen peroxide and quantifying the immediate metabolite dynamics. To systematically infer active regulatory interactions governing this response, we evaluated ensembles of kinetic models of glycolysis and PP pathway, each with different regulation mechanisms. Besides the known inactivation of glyceraldehyde 3-phosphate dehydrogenase by ROS, we reveal the important allosteric inhibition of the first PP pathway enzyme by NADPH. This NADPH feedback inhibition maintains a below maximum-capacity PP pathway flux under non-stress conditions. Relieving this inhibition instantly increases PP pathway flux upon oxidative stress. We demonstrate that reducing cells' capacity to rapidly reroute their flux through the PP pathway increases their oxidative stress sensitivity.
PMID: 29753645 [PubMed - as supplied by publisher]
Human Parasitology and Parasitic Diseases: Heading Towards 2050.
Human Parasitology and Parasitic Diseases: Heading Towards 2050.
Adv Parasitol. 2018;100:29-38
Authors: Hotez PJ
Abstract
By 2050 our civilized planet may be comprised predominantly of networked megacities embedded in warm subtropical and tropical climates, and under stress from climate change and catastrophic weather events. Urban slum areas in these cities, including those found in wealthier middle- and high-income nations (blue marble health), will be especially vulnerable to disease. Moreover, regional conflicts fought over shifting and limited resources, including water, will collapse health systems infrastructures to further promote disease emergence and reemergence. Thus while by 2050 we might congratulate ourselves for successfully eliminating some key parasitic and neglected tropical diseases such as dracunculiasis, lymphatic filariasis, onchocerciasis, and human African trypanosomiasis, there could be a commensurate rise in other parasitic diseases based on the scenarios highlighted above. Of particular concern are urban and newly urbanized helminth infections, including schistosomiasis and some soil-transmitted helminth infections, as well zoonotic helminthiases, such as toxocariasis, food-borne trematodiases, and cysticercosis. Protozoan infections persisting in urban environments, including leishmaniasis, Chagas disease, malaria, and intestinal protozoan infections, will also remain, as will zoonotic diseases such as toxoplasmosis. Our best hope to counteract the parasitic diseases emerging in our steaming 21st century megacities is to develop new and innovative technologies through gene editing, systems biology, and immunology, and the new single-celled OMICs. However, success on this front will require our ability to contain the globalization of antiscience beliefs and sentiments.
PMID: 29753341 [PubMed - in process]
Exposure Analysis Services for the Environmental Influences on Child Health Outcomes (ECHO) Program (Admin Supp - Clinical Trial Not Allowed)
Second Round of the NIH Applicant Assistance Program (AAP) for New or Previously Unawarded Small Businesses
Using Archived Data and Specimen Collections to Advance Maternal and Pediatric HIV/AIDS Research (R21 - Clinical Trial Not Allowed)
Old Drugs as New Treatments for Neurodegenerative Diseases.
Old Drugs as New Treatments for Neurodegenerative Diseases.
Pharmaceuticals (Basel). 2018 May 11;11(2):
Authors: Durães F, Pinto M, Sousa E
Abstract
Neurodegenerative diseases are increasing in number, given that the general global population is becoming older. They manifest themselves through mechanisms that are not fully understood, in many cases, and impair memory, cognition and movement. Currently, no neurodegenerative disease is curable, and the treatments available only manage the symptoms or halt the progression of the disease. Therefore, there is an urgent need for new treatments for this kind of disease, since the World Health Organization has predicted that neurodegenerative diseases affecting motor function will become the second-most prevalent cause of death in the next 20 years. New therapies can come from three main sources: synthesis, natural products, and existing drugs. This last source is known as drug repurposing, which is the most advantageous, since the drug’s pharmacokinetic and pharmacodynamic profiles are already established, and the investment put into this strategy is not as significant as for the classic development of new drugs. There have been several studies on the potential of old drugs for the most relevant neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Multiple Sclerosis and Amyotrophic Lateral Sclerosis.
PMID: 29751602 [PubMed]
Genetic Mechanisms of Asthma and the Implications for Drug Repositioning.
Genetic Mechanisms of Asthma and the Implications for Drug Repositioning.
Genes (Basel). 2018 May 03;9(5):
Authors: Huo Y, Zhang HY
Abstract
Asthma is a chronic disease that is caused by airway inflammation. The main features of asthma are airway hyperresponsiveness (AHR) and reversible airway obstruction. The disease is mainly managed using drug therapy. The current asthma drug treatments are divided into two categories, namely, anti-inflammatory drugs and bronchodilators. However, disease control in asthma patients is not very efficient because the pathogenesis of asthma is complicated, inducing factors that are varied, such as the differences between individual patients. In this paper, we delineate the genetic mechanisms of asthma, and present asthma-susceptible genes and genetic pharmacology in an attempt to find a diagnosis, early prevention, and treatment methods for asthma. Finally, we reposition some clinical drugs for asthma therapy, based on asthma genetics.
PMID: 29751569 [PubMed]
A phase II study evaluating the efficacy of zoledronic acid in prevention of aromatase inhibitor-associated musculoskeletal symptoms: the ZAP trial.
A phase II study evaluating the efficacy of zoledronic acid in prevention of aromatase inhibitor-associated musculoskeletal symptoms: the ZAP trial.
Breast Cancer Res Treat. 2018 May 11;:
Authors: Santa-Maria CA, Bardia A, Blackford AL, Snyder C, Connolly RM, Fetting JH, Hayes DF, Jeter SC, Miller RS, Nguyen A, Quinlan K, Rosner GL, Slater S, Storniolo AM, Wolff AC, Zorzi J, Henry NL, Stearns V
Abstract
PURPOSE: Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) are common adverse events of AIs often leading to drug discontinuation. We initiated a prospective clinical trial to evaluate whether bisphosphonates are associated with reduced incidence of AIMSS.
METHODS: In the single-arm trial, the Zoledronic Acid Prophylaxis (ZAP) trial, we compared the incidence of AIMSS against historical controls from the Exemestane and Letrozole Pharmacogenomics (ELPh) trial. Eligible women were postmenopausal with stage 0-III breast cancer planning to receive adjuvant AIs. AIMSS was assessed using the Health Assessment Questionnaire and Visual Analog Scale over 12 months in both trials. Participants in the ZAP trial received zoledronic acid prior to initiating letrozole and after 6 months; ELPh participants included in the analysis were taking letrozole but not bisphosphonates. We analyzed patient-reported outcomes (PROs) and bone density in the ZAP trial using mixed-effects linear regression models and paired t tests, respectively.
RESULTS: From 2011 to 2013, 59 postmenopausal women enrolled in ZAP trial. All 59 (100%) women received baseline and 52 (88%) received 6-month zoledronic acid, and had similar characteristics to historical controls from the ELPh trial (n = 206). Cumulatively during the first year of AI, 37 and 67% of ZAP and ELPh participants reported AIMSS (p < 0.001), respectively. Within the ZAP trial, we did not observe significant changes in other PROs; however, we report improvements in bone mineral density.
CONCLUSIONS: Compared to historical controls, zoledronic acid administered concomitantly with adjuvant AIs was associated with a reduced incidence of AIMSS. A randomized controlled trial is required to confirm these findings.
PMID: 29752687 [PubMed - as supplied by publisher]
Discovering novel SNPs that are correlated with patient outcome in a Singaporean cancer patient cohort treated with gemcitabine-based chemotherapy.
Discovering novel SNPs that are correlated with patient outcome in a Singaporean cancer patient cohort treated with gemcitabine-based chemotherapy.
BMC Cancer. 2018 May 11;18(1):555
Authors: Limviphuvadh V, Tan CS, Konishi F, Jenjaroenpun P, Xiang JS, Kremenska Y, Mu YS, Syn N, Lee SC, Soo RA, Eisenhaber F, Maurer-Stroh S, Yong WP
Abstract
BACKGROUND: Single Nucleotide Polymorphisms (SNPs) can influence patient outcome such as drug response and toxicity after drug intervention. The purpose of this study is to develop a systematic pathway approach to accurately and efficiently predict novel non-synonymous SNPs (nsSNPs) that could be causative to gemcitabine-based chemotherapy treatment outcome in Singaporean non-small cell lung cancer (NSCLC) patients.
METHODS: Using a pathway approach that incorporates comprehensive protein-protein interaction data to systematically extend the gemcitabine pharmacologic pathway, we identified 77 related nsSNPs, common in the Singaporean population. After that, we used five computational criteria to prioritize the SNPs based on their importance for protein function. We specifically selected and screened six candidate SNPs in a patient cohort with NSCLC treated with gemcitabine-based chemotherapy.
RESULT: We performed survival analysis followed by hematologic toxicity analyses and found that three of six candidate SNPs are significantly correlated with the patient outcome (P < 0.05) i.e. ABCG2 Q141K (rs2231142), SLC29A3 S158F (rs780668) and POLR2A N764K (rs2228130).
CONCLUSIONS: Our computational SNP candidate enrichment workflow approach was able to identify several high confidence biomarkers predictive for personalized drug treatment outcome while providing a rationale for a molecular mechanism of the SNP effect.
TRIAL REGISTRATION: NCT00695994. Registered 10 June, 2008 'retrospectively registered'.
PMID: 29751792 [PubMed - in process]
Prevention of ESKAPE pathogen biofilm formation by antimicrobial peptides WLBU2 and LL37.
Prevention of ESKAPE pathogen biofilm formation by antimicrobial peptides WLBU2 and LL37.
Int J Antimicrob Agents. 2018 May 09;:
Authors: Lin Q, Deslouches B, Montelaro RC, Di YP
Abstract
OBJECTIVES: Bacterial biofilm-dependent infections (e.g., cystic fibrosis, surgical sites, and medical implants) are associated with enhanced drug-resistance and thus difficult to eradicate. The goal of this study was to systematically compare three distinct classes of antimicrobial peptides (AMPs) that include the clinically used antibiotic colistin, the natural AMP LL37, the engineered cationic-AMP WLBU2, and four commonly used antibiotics with different bactericidal mechanisms (tobramycin, ciprofloxacin, ceftazidime and vancomycin) for biofilm prevention properties.
METHODS: Using biofilm-prevention assays, we detected bacterial biomass post-attachment in subinhibitory concentrations (1/3 of the MIC) for each AMP, by the crystal violet method, to distinguish the commonly known bactericidal from potentially distinct mechanisms of biofilm prevention. Biofilm regulatory gene expression was assessed using RT-qPCR for correlation with biofilm growth inhibition.
RESULTS: Commonly used antibiotics at 1x MIC showed modest ESKAPE biofilm prevention while 1/3 MIC of AMPs demonstrated up to 90% of biofilm prevention. WLBU2 was generally more effective in preventing bacterial attachment than colistin and LL37. Changes in expression of bacterial genes known to affect biofilm regulation were consistent with biofilm prevention.
CONCLUSION: The data warrant further exploration of AMPs with optimized structures to fill a knowledge gap on the potential application of AMPs to difficult-to-cure bacterial biofilm-related infections.
PMID: 29753132 [PubMed - as supplied by publisher]
TG2 regulates the heat-shock response by the post-translational modification of HSF1.
TG2 regulates the heat-shock response by the post-translational modification of HSF1.
EMBO Rep. 2018 May 11;:
Authors: Rossin F, Villella VR, D'Eletto M, Farrace MG, Esposito S, Ferrari E, Monzani R, Occhigrossi L, Pagliarini V, Sette C, Cozza G, Barlev NA, Falasca L, Fimia GM, Kroemer G, Raia V, Maiuri L, Piacentini M
Abstract
Heat-shock factor 1 (HSF1) is the master transcription factor that regulates the response to proteotoxic stress by controlling the transcription of many stress-responsive genes including the heat-shock proteins. Here, we show a novel molecular mechanism controlling the activation of HSF1. We demonstrate that transglutaminase type 2 (TG2), dependent on its protein disulphide isomerase activity, triggers the trimerization and activation of HSF1 regulating adaptation to stress and proteostasis impairment. In particular, we find that TG2 loss of function correlates with a defect in the nuclear translocation of HSF1 and in its DNA-binding ability to the HSP70 promoter. We show that the inhibition of TG2 restores the unbalance in HSF1-HSP70 pathway in cystic fibrosis (CF), a human disorder characterized by deregulation of proteostasis. The absence of TG2 leads to an increase of about 40% in CFTR function in a new experimental CF mouse model lacking TG2. Altogether, these results indicate that TG2 plays a key role in the regulation of cellular proteostasis under stressful cellular conditions through the modulation of the heat-shock response.
PMID: 29752334 [PubMed - as supplied by publisher]
The aging lung: tissue telomere shortening in health and disease.
The aging lung: tissue telomere shortening in health and disease.
Respir Res. 2018 May 11;19(1):95
Authors: Everaerts S, Lammertyn EJ, Martens DS, De Sadeleer LJ, Maes K, van Batenburg AA, Goldschmeding R, van Moorsel CHM, Dupont LJ, Wuyts WA, Vos R, Gayan-Ramirez G, Kaminski N, Hogg JC, Janssens W, Verleden GM, Nawrot TS, Verleden SE, McDonough JE, Vanaudenaerde BM
Abstract
BACKGROUND: Telomere shortening has been associated with several lung diseases. However, telomere length is generally measured in peripheral blood leucocytes rather than in lung tissue, where disease occurs. Consequently, telomere dynamics have not been established for the normal human lung nor for diseased lung tissue. We hypothesized an age- and disease-dependent shortening of lung tissue telomeres.
METHODS: At time of (re-)transplantation or autopsy, 70 explant lungs were collected: from unused donors (normal, n = 13) and patients with cystic fibrosis (CF, n = 12), chronic obstructive pulmonary disease (COPD, n = 11), chronic hypersensitivity pneumonitis (cHP, n = 9), bronchiolitis obliterans syndrome (BOS) after prior transplantation (n = 11) and restrictive allograft syndrome (RAS) after prior transplantation (n = 14). Lungs were inflated, frozen and then scanned using CT. Four tissue cores from distinct lung regions were sampled for analysis. Disease severity was evaluated using CT and micro CT imaging. DNA was extracted from the samples and average relative telomere length (RTL) was determined using real-time qPCR.
RESULTS: The normal lungs showed a decrease in RTL with age (p < 0.0001). Of the diseased lungs, only BOS and RAS showed significant RTL decrease with increasing lung age (p = 0.0220 and p = 0.0272 respectively). Furthermore, we found that RTL showed considerable variability between samples within both normal and diseased lungs. cHP, BOS and RAS lungs had significant shorter RTL in comparison with normal lungs, after adjustment for lung age, sex and BMI (p < 0.0001, p = 0.0051 and p = 0.0301 respectively). When investigating the relation between RTL and regional disease severity in CF, cHP and RAS, no association was found.
CONCLUSION: These results show a progressive decline in telomere length with age in normal, BOS and RAS lungs. cHP, BOS and RAS lungs demonstrated shorter RTL compared to normal lungs. Lung tissue RTL does not associate with regional disease severity within the lung. Therefore, tissue RTL does not seem to fully reflect peripheral blood telomere length.
PMID: 29751799 [PubMed - in process]
Novel Guanidine Compound against Multidrug-Resistant Cystic Fibrosis-Associated Bacterial Species.
Novel Guanidine Compound against Multidrug-Resistant Cystic Fibrosis-Associated Bacterial Species.
Molecules. 2018 May 11;23(5):
Authors: Saeed A, Bosch A, Bettiol M, Nossa González DL, Erben MF, Lamberti Y
Abstract
Chronic pulmonary infection is a hallmark of lung disease in cystic fibrosis (CF). Infections dominated by non-fermentative Gram-negative bacilli are particularly difficult to treat and highlight an urgent need for the development of new class of agents to combat these infections. In this work, a small library comprising thiourea and guanidine derivatives with low molecular weight was designed; these derivatives were studied as antimicrobial agents against Gram-positive, Gram-negative, and a panel of drug-resistant clinical isolates recovered from patients with CF. One novel compound, a guanidine derivative bearing adamantane-1-carbonyl and 2-bromo-4,6-difluouro-phenyl substituents (H-BDF), showed potent bactericidal activity against the strains tested, at levels generally higher than those exhibited by tobramycin, ceftazimide and meropenem. The role that different substituents exert in the antimicrobial activity has been determined, highlighting the importance of the halo-phenyl group in the guanidine moiety. The new compound displays low levels of cytotoxicity against THP-1 and A549 cells with a selective index (SI) > 8 (patent application PCT/IB2017/054870, August 2017). Taken together, our results indicate that H-BDF can be considered as a promising antimicrobial agent.
PMID: 29751676 [PubMed - in process]
Whole Exome Sequencing Identifies New Host Genomic Susceptibility Factors in Empyema Caused by Streptococcus pneumoniae in Children: A Pilot Study.
Whole Exome Sequencing Identifies New Host Genomic Susceptibility Factors in Empyema Caused by Streptococcus pneumoniae in Children: A Pilot Study.
Genes (Basel). 2018 May 03;9(5):
Authors: Salas A, Pardo-Seco J, Barral-Arca R, Cebey-López M, Gómez-Carballa A, Rivero-Calle I, Pischedda S, Currás-Tuala MJ, Amigo J, Gómez-Rial J, Martinón-Torres F, GENDRES Network
Abstract
Pneumonia is the leading cause of death amongst infectious diseases. Streptococcus pneumoniae is responsible for about 25% of pneumonia cases worldwide, and it is a major cause of childhood mortality. We carried out a whole exome sequencing (WES) study in eight patients with complicated cases of pneumococcal pneumonia (empyema). An initial assessment of statistical association of WES variation with pneumonia was carried out using data from the 1000 Genomes Project (1000G) for the Iberian Peninsula (IBS) as reference controls. Pseudo-replication statistical analyses were carried out using different European control groups. Association tests pointed to single nucleotide polymorphism (SNP) rs201967957 (gene MEIS1; chromosome 2; p-valueIBS = 3.71 × 10-13) and rs576099063 (gene TSPAN15; chromosome 10; p-valueIBS = 2.36 × 10-8) as the best candidate variants associated to pneumococcal pneumonia. A burden gene test of pathogenicity signaled four genes, namely, OR9G9, MUC6, MUC3A and APOB, which carry significantly increased pathogenic variation when compared to controls. By analyzing various transcriptomic data repositories, we found strong supportive evidence for the role of MEIS1, TSPAN15 and APOBR (encoding the receptor of the APOB protein) in pneumonia in mouse and human models. Furthermore, the association of the olfactory receptor gene OR9G9 has recently been related to some viral infectious diseases, while the role of mucin genes (MUC6 and MUC3A), encoding mucin glycoproteins, are well-known factors related to chronic obstructive airway disease. WES emerges as a promising technique to disentangle the genetic basis of host genome susceptibility to infectious respiratory diseases.
PMID: 29751582 [PubMed]
Voltammetric determination of 4-nitrophenol using a glassy carbon electrode modified with a gold-ZnO-SiO2 nanostructure.
Voltammetric determination of 4-nitrophenol using a glassy carbon electrode modified with a gold-ZnO-SiO2 nanostructure.
Mikrochim Acta. 2018 May 11;185(6):296
Authors: Ghazizadeh AJ, Afkhami A, Bagheri H
Abstract
A nanostructured material of the type Au-ZnO-SiO2 is described that consists of ZnO and gold nanoparticles (NPs) dispersed into a silica matrix and used to construct a voltammetric sensor for 4-nitrophenol. The AuNPs and ZnO NPs are anchored onto the silica network which warrants the nanostructures to be stable in various environments. It also facilitates the electron transfer between the electrolyte and the glassy carbon electrode (GCE). The properties of the nanostructure as a modifier for the GCE were investigated by energy dispersive spectrometry, X-ray diffraction spectroscopy, and transmission electron microscopy. It is shown that the nanostructure increases the surface area. Hence, the cathodic and anodic current in differential pulse voltammetry of 4-nitrophenol are considerably enhanced in comparison to a bare GCE. Under optimum conditions, the currents for oxidation and reduction are proportional to the concentration of 4-nitrophenol in the 0.05-3.5 μM and 0.01-1.2 μM concentration ranges, with 13.7 and 2.8 nM detection limits, respectively. The sensor has excellent sensitivity, fast response, long-term stability, and good reproducibility. It is perceived to be a valuable tool for monitoring 4-nitrophenol in real water samples. Graphical abstract Schematic of voltammetric sensor for 4-nitrophenol. It is based on GCE modified with gold-ZnO-SiO2 nanostructure. It exhibited the improvement in performance for both oxidation and reduction peaks in terms of linearity, concentration range, detection limit, and sensitivity.
PMID: 29752544 [PubMed - in process]
Publisher Correction: Single-cell analysis of experience-dependent transcriptomic states in the mouse visual cortex.
Publisher Correction: Single-cell analysis of experience-dependent transcriptomic states in the mouse visual cortex.
Nat Neurosci. 2018 May 11;:
Authors: Hrvatin S, Hochbaum DR, Nagy MA, Cicconet M, Robertson K, Cheadle L, Zilionis R, Ratner A, Borges-Monroy R, Klein AM, Sabatini BL, Greenberg ME
Abstract
In the version of this article initially published, the x-axis labels in Fig. 3c read Vglut, Gad1/2, Aldh1l1 and Pecam1; they should have read Vglut+, Gad1/2+, Aldh1l1+ and Pecam1+. In Fig. 4, the range values were missing from the color scales; they are, from left to right, 4-15, 0-15, 4-15 and 0-15 in Fig. 4a and 4-15, 4-15 and 4-8 in Fig. 4h. In the third paragraph of the main text, the phrase reading "Previous approaches have analyzed a limited number of inhibitory cell types, thus masking the full diversity of excitatory populations" should have read "Previous approaches have analyzed a limited number of inhibitory cell types and masked the full diversity of excitatory populations." In the second paragraph of Results section "Diversity of experience-regulated ERGs," the phrase reading "thus suggesting considerable divergence within the gene expression program responding to early stimuli" should have read "thus suggesting considerable divergence within the early stimulus-responsive gene expression program." In the fourth paragraph of Results section "Excitatory neuronal LRGs," the sentence reading "The anatomical organization of these cell types into sublayers, coupled with divergent transcriptional responses to a sensory stimulus, suggested previously unappreciated functional subdivisions located within the laminae of the mouse visual cortex and resembling the cytoarchitecture in higher mammals" should have read "The anatomical organization of these cell types into sublayers, coupled with divergent transcriptional responses to a sensory stimulus, suggests previously unappreciated functional subdivisions located within the laminae of the mouse visual cortex, resembling the cytoarchitecture in higher mammals." In the last sentence of the Results, "sensory-responsive genes" should have read "sensory-stimulus-responsive genes." The errors have been corrected in the HTML and PDF versions of the article.
PMID: 29752482 [PubMed - as supplied by publisher]
Assigning matrix metalloproteinase roles in ischaemic cardiac remodelling.
Assigning matrix metalloproteinase roles in ischaemic cardiac remodelling.
Nat Rev Cardiol. 2018 May 11;:
Authors: Lindsey ML
Abstract
Matrix metalloproteinases (MMPs) and their endogenous inhibitors have been studied in the myocardium for the past 2 decades. An incomplete knowledge base and experimental design issues with inhibitors have hampered attempts at translation, but clinical interest remains high because of strong associations between MMPs and outcomes after myocardial infarction (MI) as well as mechanistic studies showing MMP involvement at multiple stages of the MI wound-healing process. This Review focuses on how our understanding of MMPs has evolved from a one-dimensional early focus on measuring MMP activity, monitoring MMP:inhibitor ratios, and evaluating one MMP-substrate pair to the current use of systems biology approaches to integrate the whole MMP repertoire of roles in the left ventricular response to MI. MMP9 is used as an example MMP to explain these concepts and to provide a template for examining MMPs as mechanistic mediators of cardiac remodelling.
PMID: 29752454 [PubMed - as supplied by publisher]
Prescription Drug Shortages: Implications for Ambulatory Pediatrics.
Prescription Drug Shortages: Implications for Ambulatory Pediatrics.
J Pediatr. 2018 May 08;:
Authors: Donnelly KA, Zocchi MS, Katy TA, Fox ER, van den Anker JN, Mazer-Amirshahi ME
Abstract
OBJECTIVE: To describe contemporary drug shortages affecting general ambulatory pediatrics.
STUDY DESIGN: Data from January 2001 to December 2015 were obtained from the University of Utah Drug Information Service. Two pediatricians reviewed drug shortages and identified agents used in ambulatory pediatrics. Shortage data were analyzed by the type of drug, formulation, reason for shortage, duration, marketing status, if a pediatric friendly-formulation was available, or if it was a single-source product. The availability of an alternative, and whether that alternative was affected by a shortage, also was noted.
RESULTS: Of 1883 products in shortage during the study period, 314 were determined to be used in ambulatory pediatrics. The annual number of new pediatric shortages decreased initially but then increased to a high of 38 in 2011. Of the 314 pediatric shortages, 3.8% were unresolved at the end of the study. The median duration of resolved shortages was 7.6 months. The longest shortage was for ciprofloxacin 500-mg tablets. The most common class involved was infectious disease drugs. Pediatric-friendly dosage forms were affected in 19.1% of shortages. An alternative agent was available for 86% drugs; however, 29% of these also were affected. The most common reason for shortage was manufacturing problems.
CONCLUSIONS: Drug shortages affected a substantial number of agents used in general ambulatory pediatrics. Shortages for single-source products are a concern if a suitable alternative is unavailable. Providers working in the ambulatory setting must be aware of current shortages and implement mitigation strategies to optimize patient care.
PMID: 29752177 [PubMed - as supplied by publisher]
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