Functional analysis of human alpha 1(I) procollagen gene promoter. Differential activity in collagen-producing and -nonproducing cells and response to transforming growth factor beta 1.

To gain a further understanding of the regulation of human type I collagen gene expression under physiologic and pathologic conditions, we characterized 5.3 kilobase pairs (kb) of the human alpha 1(I) procollagen gene promoter. A series of deletion constructs containing portions of the alpha 1(I) procollagen 5\u27-flanking region (with end points from -5.3 kb to -84 base pairs (bp)) ligated to the chloramphenicol acetyltransferase (CAT) reporter gene were transiently transfected into NIH/3T3 cells. Maximal CAT activity was observed with constructs having 5\u27 end points from -804 to -174 bp. A further 5\u27 deletion to -84 bp caused a marked reduction in CAT activity. Cells transfected with plasmids containing longer 5\u27-flanking fragments of the alpha 1(I) procollagen gene (-2.3 or -5.3 kb) showed reduced CAT activity compared with the -804 bp construct. The activity of the alpha 1(I) procollagen promoter was much lower in cells that do not normally express type I collagen (HeLa cells) compared with collagen-producing NIH/3T3 cells. The CAT activity of deletion constructs containing longer 5\u27 regions than -84 bp was increased by approximately 2-fold in NIH/3T3 cells treated with transforming growth factor beta 1 (TGF beta 1). Electrophoretic mobility shift assays indicated that protein-DNA complex formation with a probe corresponding to the -170 to -80 bp fragment of the alpha 1(I) procollagen promoter was markedly enhanced in nuclear extracts prepared from TGF beta 1-treated fibroblasts as compared with untreated fibroblasts. The DNA binding activity stimulated by TGF beta 1 was specific for an Sp1-like sequence at positions -164 to -142 bp in the promoter. These results demonstrate that 1) there are both positive and negative cis-acting regulatory elements in the human alpha 1(I) procollagen promoter, 2) these regulatory regions function differently in collagen-producing and -nonproducing cells, 3) the alpha 1(I) procollagen promoter contains TGF beta 1-responsive sequences located between -174 and -84 bp from the transcription start site, and 4) TGF beta 1 caused marked stimulation of the DNA binding activity of a nuclear factor interacting with an Sp1-like binding site located within a region encompassing -164 to -142 bp of the alpha 1(I) procollagen promoter

Temporal Trends and Patterns in Heart Failure with Improved Left Ventricular Ejection Fraction: A Retrospective Cohort Study

Heart failure (HF) with reduced ejection fraction (HFrEF) remains a leading cause of morbidity and mortality. Heart failure withimproved ejection fraction (HFimpEF) has better prognosis and outcomes. However, improvement only occurs in a subpopulationof HFrEF

Screening for and Diagnosing Malnutrition in Hospitalized Pediatric Patients

Background: Malnutrition is often underdiagnosed, and consequently undertreated, in hospitalized patients. A nationwide study is being conducted to validate indicators (the Malnutrition Clinical Characteristics [MCC]) to diagnose malnutrition in hospitalized patients. Methods: For the full study, sixty pediatric hospitals will collect patient medical history, patient STRONGKids malnutrition screening score, and nutrition intervention data. Six hundred pediatric patients will be randomly selected from the cohort to be assessed for the MCC and the Nutrition Focused Physical Exam (NFPE). Medical outcomes will be collected for all patients for a three-month period thereafter. Baseline data from a subset of sites that have started data collection were descriptively analyzed using Stata 15. Results: As of March 2020, 113 pediatric patients are enrolled in the study, with 50 children ages 1-24 months and 63 children and adolescents ages 2-17. Based on the STRONGkids screener, 73% (n = 82) of participants were “at risk” for malnutrition. A higher proportion of participants in the older age group screened at risk (n=54; 86%) compared to the younger group (n=28; 56%). Fifty-seven of the 113 participants were included in the MCC subgroup, of whom 35 (61%) screened at-risk for malnutrition. Based on the MCC criteria, 49% (n = 28) were diagnosed with malnutrition. Inadequate nutrient intake was the MCC indicator most often used to support a malnutrition diagnosis in younger participants, while weight loss was the most commonly used indicator for older participants. Across both age groups, muscle wasting and subcutaneous fat loss were the most commonly reported NFPE indicators that further supported a malnutrition diagnosis. Conclusion: Screening-based risk for malnutrition and malnutrition indicators differ for infants and young children compared to older children and teens. Differences in risk factors for malnutrition by age group and the validity of the MCC will be assessed as more data are collected

Plan estratégico de la alianza Levitat-Shimano

Levitat-Shimano es la propuesta que se presenta luego de evaluar las sinergias que pueden presentar estas dos compañías a modo de joint venture. Por un lado, Levitat es una empresa que se dedica a la fabricación de bicicletas con marco de carbono. Además, realiza bastante inversión en investigación y desarrollo (I+D) para poder fabricar componentes de alta calidad. Cuenta con presencia global de manera física con tiendas en Norteamérica, Latinoamérica, Europa, Medio Oriente y Asia-Pacífico. Busca mejorar su estrategia para incrementar su presencia en los Estados Unidos. Por otro lado, Shimano, reconocida compañía de origen japonés por la gran calidad de componentes de bicicletas incluyendo manubrios, descarriladores, frenos, entre otros, para sus múltiples gamas cuenta también con presencia global bastante consolidada debido al tamaño de la red de mayoristas y distribuidores que posee. Como parte de la propuesta, Levitat-Shimano se planea la expansión física en Estados Unidos realizando la implementación de dos tiendas físicas adicionales en las ciudades de San Francisco y Chicago. Adicionalmente, se planea la implementación de un marketplace para poder incrementar el alcance a todo lugar y poder exponer un nuevo catálogo de bicicletas que son diseñadas utilizando los marcos de carbono creados por Levitat y utilizando los componentes de alta calidad de Shimano. Finalmente, se concluye con la presentación de conclusiones y recomendaciones para la gerencia de la alianza.Levitat-Shimano is the proposal that is presented after evaluating the synergies that these two companies present as a joint venture. On the one hand, Levitat is a company dedicated to the manufacture of bicycles with a carbon frame. In addition, it invests heavily in research and development (R&D) to be able to manufacture high-quality components. It has a global physical presence with stores in North America, Latin America, Europe, the Middle East and Asia-Pacific. It seeks to improve its strategy to increase its presence in the United States. On the other hand, Shimano, a renowned company of Japanese origin for the high quality of bicycle components including handlebars, derailleurs, brakes, among others, for its multiple ranges also has a fairly consolidated global presence due to the size of its network of wholesalers and distributors. As part of the proposal, Levitat-Shimano plans for physical expansion in the United States by implementing two additional physical stores in the cities of San Francisco and Chicago. Additionally, the implementation of a marketplace is planned to increase the reach everywhere and to expose a new catalog of bicycles that are designed using the carbón frames created by Levitat and using high-quality components from Shimano.Finally, it concludes with the presentation of conclusions and recommendations for the management of the alliance

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

Drug discovery for malaria has been transformed in the last 5 years by the discovery of many new lead compounds identified by phenotypic screening. The process of developing these compounds as drug leads and studying the cellular responses they induce i

The liver receptor homolog-1 (LRH-1) is expressed in human islets and protects β-cells against stress-induced apoptosis

Liver receptor homolog (LRH-1) is an orphan nuclear receptor (NR5A2) that regulates cholesterol homeostasis and cell plasticity in endodermal-derived tissues. Estrogen increases LRH-1 expression conveying cell protection and proliferation. Independently, estrogen also protects isolated human islets against cytokine-induced apoptosis. Herein, we demonstrate that LRH-1 is expressed in islets, including β-cells, and that transcript levels are modulated by 17β-estradiol through the estrogen receptor (ER)α but not ERβ signaling pathway. Repression of LRH-1 by siRNA abrogated the protective effect conveyed by estrogen on rat islets against cytokines. Adenoviral-mediated overexpression of LRH-1 in human islets did not alter proliferation but conferred protection against cytokines and streptozotocin-induced apoptosis. Expression levels of the cell cycle genes cyclin D1 and cyclin E1 as well as the antiapoptotic gene bcl-xl were unaltered in LRH-1 expressing islets. In contrast, the steroidogenic enzymes CYP11A1 and CYP11B1 involved in glucocorticoid biosynthesis were both stimulated in transduced islets. In parallel, graded overexpression of LRH-1 dose-dependently impaired glucose-induced insulin secretion. Our results demonstrate the crucial role of the estrogen target gene nr5a2 in protecting human islets against-stressed-induced apoptosis. We postulate that this effect is mediated through increased glucocorticoid production that blunts the pro-inflammatory response of islet

Pharmacodynamics of Meropenem and Tobramycin for Neonatal Meningoencephalitis: Novel Approaches to Facilitate the Development of New Agents to Address the Challenge of Antimicrobial Resistance

Neonatal sepsis is an underrecognized burden on health care systems throughout the world. Antimicrobial drug resistance (AMR) is increasingly prevalent and compromises the use of currently recommended first-line agents. The development of new antimicrobial agents for neonates and children is mandated by regulatory agencies. However, there remains uncertainty about suitable development pathways, especially because of the propensity of premature babies to develop meningoencephalitis as a complication of neonatal sepsis and difficulties studying this disease in clinical settings. We developed a new platform and approach to accelerate the development of antimicrobial agents for neonatal bacterial meningoencephalitis using Pseudomonas aeruginosa as the challenge organism. We defined the pharmacodynamics of meropenem and tobramycin in these models. The percentage of partitioning of meropenem and tobramycin into the cerebrospinal fluid was comparable at 14.3 and 13.7%, respectively. Despite this similarity, there were striking differences in their pharmacodynamics. Meropenem resulted in bactericidal activity in both the cerebrospinal fluid and cerebrum, whereas tobramycin had minimal antibacterial activity. A hollow fiber infection model (HFIM) using neonatal CSF concentration time profiles yielded pharmacodynamics comparable to those observed in the rabbit model. These new experimental models can be used to estimate the pharmacodynamics of currently licensed agents and those in development and their potential efficacy for neonatal bacterial meningoencephalitis

Germline IKAROS dimerization haploinsufficiency causes hematologic cytopenias and malignancies

IKAROS is a transcription factor forming homo- and heterodimers and regulating lymphocyte development and function. Germline mutations affecting the IKAROS N-terminal DNA binding domain, acting in a haploinsufficient or dominant-negative manner, cause immunodeficiency. Herein, we describe 4 germline heterozygous IKAROS variants affecting its C-terminal dimerization domain, via haploinsufficiency, in 4 unrelated families. Index patients presented with hematologic disease consisting of cytopenias (thrombocytopenia, anemia, neutropenia)/Evans syndrome and malignancies (T-cell acute lymphoblastic leukemia, Burkitt lymphoma). These dimerization defective mutants disrupt homo- and heterodimerization in a complete or partial manner, but they do not affect the wild-type allele function. Moreover, they alter key mechanisms of IKAROS gene regulation, including sumoylation, protein stability, and the recruitment of the nucleosome remodeling and deacetylase complex; none affected in N-terminal DNA binding defects. These C-terminal dimerization mutations are largely associated with hematologic disorders, display dimerization haploinsufficiency and incomplete clinical penetrance, and differ from previously reported allelic variants in their mechanism of action. Dimerization mutants contribute to the growing spectrum of IKAROS-associated diseases displaying a genotype-phenotype correlation

Instrumentation and control of anaerobic digestion processes: a review and some research challenges

The final publication is available at Springer via http://dx.doi.org/10.1007/s11157-015-9382-6[EN] To enhance energy production from methane or resource recovery from digestate, anaerobic digestion processes require advanced instrumentation and control tools. Over the years, research on these topics has evolved and followed the main fields of application of anaerobic digestion processes: from municipal sewage sludge to liquid mainly industrial then municipal organic fraction of solid waste and agricultural residues. Time constants of the processes have also changed with respect to the treated waste from minutes or hours to weeks or months. Since fast closed loop control is needed for short time constant processes, human operator is now included in the loop when taking decisions to optimize anaerobic digestion plants dealing with complex solid waste over a long retention time. Control objectives have also moved from the regulation of key variables measured online to the prediction of overall process perfor- mance based on global off-line measurements to optimize the feeding of the processes. Additionally, the need for more accurate prediction of methane production and organic matter biodegradation has impacted the complexity of instrumentation and should include a more detailed characterization of the waste (e.g., biochemical fractions like proteins, lipids and carbohydrates)andtheirbioaccessibility andbiodegradability characteristics. However, even if in the literature several methodologies have been developed to determine biodegradability based on organic matter characterization, only a few papers deal with bioaccessibility assessment. 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Molecular pharmacodynamics of meropenem for nosocomial pneumonia caused by <i>Pseudomonas aeruginosa</i>.

ImportanceThe emergence of antimicrobial resistance (AMR) during antimicrobial treatment for hospital-acquired pneumonia (HAP) is a well-documented problem (particularly in pneumonia caused by Pseudomonas aeruginosa) that contributes to the wider global antimicrobial resistance crisis. During drug development, regimens are typically determined by their sufficiency to achieve bactericidal effect. Prevention of the emergence of resistance pharmacodynamics is usually not characterized or used to determine the regimen. The innovative experimental platform described here allows characterization of the emergence of AMR during the treatment of HAP and the development of strategies to mitigate this. We have demonstrated this specifically for meropenem-a broad-spectrum antibiotic commonly used to treat HAP. We have characterized the antimicrobial resistance pharmacodynamics of meropenem when used to treat HAP, caused by initially meropenem-susceptible P. aeruginosa, phenotypically and genotypically. We have also shown that intensifying the regimen and using combination therapy are both strategies that can both treat HAP and suppress the emergence of resistance