Characterization of the ZFX family of transcription factors that bind downstream of the start site of CpG island promoters

Our study focuses on a family of ubiquitously expressed human C₂H₂ zinc finger proteins comprised of ZFX, ZFY and ZNF711. Although their protein structure suggests that ZFX, ZFY and ZNF711 are transcriptional regulators, the mechanisms by which they influence transcription have not yet been elucidated. We used CRISPR-mediated deletion to create bi-allelic knockouts of ZFX and/or ZNF711 in female HEK293T cells (which naturally lack ZFY). We found that loss of either ZFX or ZNF711 reduced cell growth and that the double knockout cells have major defects in proliferation. RNA-seq analysis revealed that thousands of genes showed altered expression in the double knockout clones, suggesting that these TFs are critical regulators of the transcriptome. To gain insight into how these TFs regulate transcription, we created mutant ZFX proteins and analyzed them for DNA binding and transactivation capability. We found that zinc fingers 11–13 are necessary and sufficient for DNA binding and, in combination with the N terminal region, constitute a functional transactivator. Our functional analyses of the ZFX family provides important new insights into transcriptional regulation in human cells by members of the large, but under-studied family of C₂H₂ zinc finger proteins

Identifying patients with nonalcoholic fatty liver disease in primary care: how and for what benefit?

Despite its increasing prevalence, nonalcoholic fatty liver disease (NAFLD) remains under-diagnosed in primary care. Timely diagnosis is critical, as NAFLD can progress to nonalcoholic steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma, and death; furthermore, NAFLD is also a risk factor linked to cardiometabolic outcomes. Identifying patients with NAFLD, and particularly those at risk of advanced fibrosis, is important so that healthcare practitioners can optimize care delivery in an effort to prevent disease progression. This review debates the practical issues that primary care physicians encounter when managing NAFLD, using a patient case study to illustrate the challenges and decisions that physicians face. It explores the pros and cons of different diagnostic strategies and tools that physicians can adopt in primary care settings, depending on how NAFLD presents and progresses. We discuss the importance of prescribing lifestyle changes to achieve weight loss and mitigate disease progression. A diagnostic and management flow chart is provided, showing the key points of assessment for primary care physicians. The advantages and disadvantages of advanced fibrosis risk assessments in primary care settings and the factors that influence patient referral to a hepatologist are also reviewed

Characterization of the ZFX family of transcription factors that bind downstream of the start site of CpG island promoters

Our study focuses on a family of ubiquitously expressed human C₂H₂ zinc finger proteins comprised of ZFX, ZFY and ZNF711. Although their protein structure suggests that ZFX, ZFY and ZNF711 are transcriptional regulators, the mechanisms by which they influence transcription have not yet been elucidated. We used CRISPR-mediated deletion to create bi-allelic knockouts of ZFX and/or ZNF711 in female HEK293T cells (which naturally lack ZFY). We found that loss of either ZFX or ZNF711 reduced cell growth and that the double knockout cells have major defects in proliferation. RNA-seq analysis revealed that thousands of genes showed altered expression in the double knockout clones, suggesting that these TFs are critical regulators of the transcriptome. To gain insight into how these TFs regulate transcription, we created mutant ZFX proteins and analyzed them for DNA binding and transactivation capability. We found that zinc fingers 11–13 are necessary and sufficient for DNA binding and, in combination with the N terminal region, constitute a functional transactivator. Our functional analyses of the ZFX family provides important new insights into transcriptional regulation in human cells by members of the large, but under-studied family of C₂H₂ zinc finger proteins

An Independent Assessment of the Technical Feasibility of the Mars One Mission Plan

In mid-2012, the Mars One program was announced, aiming to build the first human settlement on the surface of Mars. Following a series of precursor missions to develop and deploy key technologies, the first crewed mission would depart Earth in 2024, sending four people on a one-way journey to the surface of Mars. Additional four-person crews would be sent to Mars at every subsequent launch opportunity to further support and expand the Martian colony. While this program has been received with great fanfare, very little has been published in the technical literature on this mission architecture. As the Mars One mission plan represents a dramatic departure from more conservative exploration approaches, there are many uncertainties in the mission design. The establishment of a colony on Mars will rely on in-situ resource utilization (ISRU) and life support technologies that are more capable than the current state of the art. Moreover, resupply logistics and sparing will play a large role in the proposed colony, though the magnitude and behavior of these two effects is not well understood. In light of this, we develop a Mars settlement analysis tool that integrates a habitat simulation with an ISRU sizing model and a sparing analysis. A logistics model is utilized to predict the required number of launchers and provide a preliminary estimate of a portion of the program cost. We leverage this tool to perform an independent assessment of the technical feasibility of the Mars One mission architecture. Our assessment revealed a number of insights into architecture decisions for establishing a colony on the Martian surface. If crops are used as the sole food source, they will produce unsafe oxygen levels in the habitat. Furthermore, the ISRU system mass estimate is 8% of the mass of the resources it would produce over a two year period. That being said, the ISRU technology required to produce nitrogen, oxygen, and water on the surface of Mars is at a relatively low Technology Readiness Level (TRL), so such findings are preliminary at best. A spare parts analysis revealed that spare parts quickly come to dominate resupply mass as the settlement grows: after 130 months on the Martian surface, spare parts compose 62% of the mass brought from Earth to the Martian surface. The space logistics analysis revealed that, for the best scenario considered, establishing the first crew for a Mars settlement will require approximately 15 Falcon Heavy launchers and require $4.5 billion in funding, and these numbers will grow with additional crews. It is important to note that these numbers are derived only when considering the launch of life support and ISRU systems with spare parts. To capture a more realistic estimate of mission cost, future work should consider development and operations costs, as well as the integration of other key mission elements, such as communications and power systems. Technology development towards improving the reliability of life support systems, the TRL of ISRU systems, and the capability of Mars in-situ manufacturing will have a significant impact on reducing the mass and cost of Mars settlement architectures.United States. National Aeronautics and Space Administration (Grant NNX13AL76H)United States. National Aeronautics and Space Administration (Grant NNX14AM42H)Josephine De Karman Fellowship Trus

Respiration of \u3cem\u3eEscherichia coli\u3c/em\u3e in the Mouse Intestine

Mammals are aerobes that harbor an intestinal ecosystem dominated by large numbers of anaerobic microorganisms. However, the role of oxygen in the intestinal ecosystem is largely unexplored. We used systematic mutational analysis to determine the role of respiratory metabolism in the streptomycin-treated mouse model of intestinal colonization. Here we provide evidence that aerobic respiration is required for commensal and pathogenic Escherichia coli to colonize mice. Our results showed that mutants lacking ATP synthase, which is required for all respiratory energy-conserving metabolism, were eliminated by competition with respiratory-competent wild-type strains. Mutants lacking the high-affinity cytochrome bd oxidase, which is used when oxygen tensions are low, also failed to colonize. However, the low-affinity cytochrome bo3 oxidase, which is used when oxygen tension is high, was found not to be necessary for colonization. Mutants lacking either nitrate reductase or fumarate reductase also had major colonization defects. The results showed that the entire E. coli population was dependent on both microaerobic and anaerobic respiration, consistent with the hypothesis that the E. coli niche is alternately microaerobic and anaerobic, rather than static. The results indicate that success of the facultative anaerobes in the intestine depends on their respiratory flexibility. Despite competition for relatively scarce carbon sources, the energy efficiency provided by respiration may contribute to the widespread distribution (i.e., success) of E. coli strains as commensal inhabitants of the mammalian intestine

Twenty year fitness trends in young adults and incidence of prediabetes and diabetes: the CARDIA study

The prospective association between cardiorespiratory fitness (CRF) measured in young adulthood and middle age on development of prediabetes, defined as impaired fasting glucose and/or impaired glucose tolerance, or diabetes by middle age remains unknown. We hypothesised that higher fitness levels would be associated with reduced risk for developing incident prediabetes/diabetes by middle age

Unraveling the effects of management and climate on carbon fluxes of U.S. croplands using the USDA Long-Term Agroecosystem (LTAR) network

Understanding the carbon fluxes and dynamics from a broad range of agricultural systems has the potential to improve our ability to increase carbon sequestration while maintaining crop yields. Short-term, single-location studies have limited applicability, but long-term data from a network of many locations can provide a broader understanding across gradients of climate and management choices. Here we examine eddy covariance measured carbon dioxide (CO2) fluxes from cropland sites across the United States Department of Agriculture’s Long-Term Agroecosystem Research (LTAR) network. The dataset was collected between 2001 and 2020, spanning 13 sites for a total of 182 site-years. Average seasonal patterns of net ecosystem CO2 exchange (NEE), gross primary productivity (GPP), and ecosystem respiration (Reco) were determined, and subsequent regression analysis on these “flux climatologies” was used to identify relationships to mean annual temperature (MAT), mean annual precipitation (MAP), cropping systems, and management practices. At rainfed sites, carbon fluxes were better correlated with MAP (r2 ≤ 0.5) than MAT (r2 ≤ 0.22). Net carbon balance was different among cropping systems (p \u3c 0.001), with the greatest net carbon uptake occurring in sugarcane (Saccharum spp. hybrids) and the least in soybean (Glycine max) fields. Crop type had a greater effect on carbon balance than irrigation management at a Nebraska site. Across cropping systems, grain crops often had higher GPP and were more likely to have net uptake when compared to legume crops. This multi-site analysis highlights the potential of the LTAR network to further carbon flux research using eddy covariance measurements

IEEE 4003-2021

27 páginasThe scope of this effort is to develop a standard for data and metadata content arising from spaceborne global navigation satellite system-reflectometry (GNSS-R) missions, which uses GNSS signals as signals of opportunity, as described in “The IEEE SA Working Group on Spaceborne GNSS-R: Scene Study.” In particular, this standard would provide a means for describing: a) The terminology assigned to GNSS-R data and products, such as the product levels. b) The structure and content of the data. This includes, but is not limited to, units of measure, data organization, data description, data encoding, and data storage format. c) The metadata. This includes and is not limited to metadata, methods and algorithms applied to the data, parameters related to the algorithms, citation information, instrument calibration and characterization, and description of the input signals. The purpose of this standard is to provide a set of specifications and recommended practices that can be used to describe any known and future spaceborne GNSS-R data set, allowing users to work with different GNSS-R data sets at the same time. The definition of such standard would also allow any software that uses these data to fully operate and ingest any spaceborne GNSS-R input data as they will conform to the same standard

Guideline for the management of myasthenic syndromes

Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS) represent an etiologically heterogeneous group of (very) rare chronic diseases. MG and LEMS have an autoimmune-mediated etiology, while CMS are genetic disorders. A (strain dependent) muscle weakness due to neuromuscular transmission disorder is a common feature. Generalized MG requires increasingly differentiated therapeutic strategies that consider the enormous therapeutic developments of recent years. To include the newest therapy recommendations, a comprehensive update of the available German-language guideline ‘Diagnostics and therapy of myasthenic syndromes’ has been published by the German Neurological society with the aid of an interdisciplinary expert panel. This paper is an adapted translation of the updated and partly newly developed treatment guideline. It defines the rapid achievement of complete disease control in myasthenic patients as a central treatment goal. The use of standard therapies, as well as modern immunotherapeutics, is subject to a staged regimen that takes into account autoantibody status and disease activity. With the advent of modern, fast-acting immunomodulators, disease activity assessment has become pivotal and requires evaluation of the clinical course, including severity and required therapies. Applying MG-specific scores and classifications such as Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Foundation of America allows differentiation between mild/moderate and (highly) active (including refractory) disease. Therapy decisions must consider age, thymic pathology, antibody status, and disease activity. Glucocorticosteroids and the classical immunosuppressants (primarily azathioprine) are the basic immunotherapeutics to treat mild/moderate to (highly) active generalized MG/young MG and ocular MG. Thymectomy is indicated as a treatment for thymoma-associated MG and generalized MG with acetylcholine receptor antibody (AChR-Ab)-positive status. In (highly) active generalized MG, complement inhibitors (currently eculizumab and ravulizumab) or neonatal Fc receptor modulators (currently efgartigimod) are recommended for AChR-Ab-positive status and rituximab for muscle-specific receptor tyrosine kinase (MuSK)-Ab-positive status. Specific treatment for myasthenic crises requires plasmapheresis, immunoadsorption, or IVIG. Specific aspects of ocular, juvenile, and congenital myasthenia are highlighted. The guideline will be further developed based on new study results for other immunomodulators and biomarkers that aid the accurate measurement of disease activity