The lung epithelium is derived from the endodermal germ layer, which undergoes a complex series of endoderm-mesoderm-mediated signaling events to generate the final arborized network of conducting ...airways (bronchi, bronchioles) and gas-exchanging units (alveoli). These stages include endoderm induction, anterior-posterior and dorsal-ventral patterning, lung specification, lung budding, branching morphogenesis, and, finally, maturation. Here we describe a protocol that recapitulates several of these milestones in order to differentiate human pluripotent stem cells (hPSCs) into ventral-anterior foregut spheroids and further into two distinct types of organoids: human lung organoids and bud tip progenitor organoids. The resulting human lung organoids possess cell types and structures that resemble the bronchi/bronchioles of the developing human airway surrounded by lung mesenchyme and cells expressing alveolar-cell markers. The bud tip progenitor organoids possess a population of highly proliferative multipotent cells with in vitro multilineage differentiation potential and in vivo engraftment potential. Human lung organoids can be generated from hPSCs in 50-85 d, and bud tip progenitor organoids can be generated in 22 d. The two hPSC-derived models presented here have been benchmarked with human fetal tissue and found to be representative of human fetal-like tissue. The bud tip progenitor organoids are thus ideal for exploring epithelial fate decisions, while the human lung organoids can be used to model epithelial-mesenchymal cross-talk during human lung development. In addition to their applications in developmental biology, human lung organoids and bud tip progenitor organoids may be implemented in regenerative medicine, tissue engineering, and pharmaceutical safety and efficacy testing.
Iron is a central micronutrient needed by all living organisms. Competition for iron in the intestinal tract is essential for the maintenance of indigenous microbial populations and for host health. ...How symbiotic relationships between hosts and native microbes persist during times of iron limitation is unclear. Here, we demonstrate that indigenous bacteria possess an iron-dependent mechanism that inhibits host iron transport and storage. Using a high-throughput screen of microbial metabolites, we found that gut microbiota produce metabolites that suppress hypoxia-inducible factor 2α (HIF-2α) a master transcription factor of intestinal iron absorption and increase the iron-storage protein ferritin, resulting in decreased intestinal iron absorption by the host. We identified 1,3-diaminopropane (DAP) and reuterin as inhibitors of HIF-2α via inhibition of heterodimerization. DAP and reuterin effectively ameliorated systemic iron overload. This work provides evidence of intestine-microbiota metabolic crosstalk that is essential for systemic iron homeostasis.
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•Lactobacillus species sense intestinal iron levels and attenuate host iron absorption•Microbial metabolites DAP and reuterin are novel HIF-2α inhibitors•Gut microbial metabolites regulate intestinal iron storage via ferritin regulation•Gut microbiota can be therapeutically targeted for iron-related disorders
Das et al. show that gut microbiota regulate host iron metabolism. Lactobacillus species are the major bacterial players involved in sensing intestinal iron levels and attenuating host iron absorption. The authors further show that mammalian iron disorders can be therapeutically targeted by modulating microbial species or their metabolites.
BackgroundA major cause of enteric infection, Gram-negative pathogenic bacteria activate mucosal inflammation through lipopolysaccharide (LPS) binding to intestinal toll-like receptor 4 (TLR4). ...Breast feeding lowers risk of disease, and human milk modulates inflammation.ObjectiveThis study tested whether human milk oligosaccharides (HMOSs) influence pathogenic Escherichia coli-induced interleukin (IL)-8 release by intestinal epithelial cells (IECs), identified specific proinflammatory signalling molecules modulated by HMOSs, specified the active HMOS and determined its mechanism of action.MethodsModels of inflammation were IECs invaded by type 1 pili enterotoxigenic E. coli (ETEC) in vitro: T84 modelled mature, and H4 modelled immature IECs. LPS-induced signalling molecules co-varying with IL-8 release in the presence or absence of HMOSs were identified. Knockdown and overexpression verified signalling mediators. The oligosaccharide responsible for altered signalling was identified.ResultsHMOSs attenuated LPS-dependent induction of IL-8 caused by ETEC, uropathogenic E. coli, and adherent-invasive E. coli (AIEC) infection, and suppressed CD14 transcription and translation. CD14 knockdown recapitulated HMOS-induced attenuation. Overexpression of CD14 increased the inflammatory response to ETEC and sensitivity to inhibition by HMOSs. 2′-fucosyllactose (2′-FL), at milk concentrations, displayed equivalent ability as total HMOSs to suppress CD14 expression, and protected AIEC-infected mice.ConclusionsHMOSs and 2′-FL directly inhibit LPS-mediated inflammation during ETEC invasion of T84 and H4 IECs through attenuation of CD14 induction. CD14 expression mediates LPS-TLR4 stimulation of portions of the ‘macrophage migration inhibitory factors’ inflammatory pathway via suppressors of cytokine signalling 2/signal transducer and activator of transcription 3/NF-κB. HMOS direct inhibition of inflammation supports its functioning as an innate immune system whereby the mother protects her vulnerable neonate through her milk. 2′-FL, a principal HMOS, quenches inflammatory signalling.
The intestine is a vital organ responsible for nutrient absorption, bile and waste excretion, and a major site of host immunity. In order to keep up with daily demands, the intestine has evolved a ...mechanism to expand the absorptive surface area by undergoing a morphogenetic process to generate finger-like units called villi. These villi house specialized cell types critical for both absorbing nutrients from food, and for protecting the host from commensal and pathogenic microbes present in the adult gut. In this review, we will discuss mechanisms that coordinate intestinal development, growth, and maturation of the small intestine, starting from the formation of the early gut tube, through villus morphogenesis and into early postnatal life when the intestine must adapt to the acquisition of nutrients through food intake, and to interactions with microbes.
Traveler’s Diarrhea: A Clinical Review Steffen, Robert; Hill, David R; DuPont, Herbert L
JAMA : the journal of the American Medical Association,
01/2015, Letnik:
313, Številka:
1
Journal Article
Recenzirano
IMPORTANCE: Acute diarrhea is the most common illness that affects travelers to low-income regions of the world. Although improved hygiene has reduced the risk of traveler’s diarrhea in many ...destinations, the risk remains high in others. OBJECTIVE: To review the current state of knowledge on the etiology, risk factors, prevention, and management of traveler’s diarrhea. EVIDENCE REVIEW: A search of the PubMed, Google Scholar, and Cochrane Library databases for the period 2012–April 2014 was performed for articles on traveler’s diarrhea. The database search yielded 2976 articles, of which 37 were included in this review. These were added to 85 articles previously identified by the authors. FINDINGS: Improved hygiene has reduced the risk of traveler’s diarrhea from 20% or more (for a 2-week stay) to between 8% and 20% in some parts of the world. Acquiring traveler’s diarrhea causes 12% to 46% of travelers to change their travel plans. Returning travelers seeking medical care have a diagnosis of gastrointestinal disturbance in approximately one-third of all cases. Postinfectious irritable bowel syndrome may occur in 3% to 17% of patients who have had traveler’s diarrhea. Prevention of traveler’s diarrhea by dietary avoidance measures is often not successful. Chemoprophylaxis should be restricted to travelers who are at risk of severe complications of diarrhea. Ciprofloxacin is the standard treatment in self-therapy of traveler’s diarrhea except when patients are in South or Southeast Asia, where azithromycin is preferred. CONCLUSIONS AND RELEVANCE: Diarrhea remains a common problem for international travelers. Persons intending to travel to at-risk countries should be counseled regarding prevention measures and may be given a travel pack that includes medications for self-treatment should they become ill.
The ability to control the size of the electronic bandgap is an integral part of solid-state technology. Atomically thin two-dimensional crystals offer a new approach for tuning the energies of the ...electronic states based on the unusual strength of the Coulomb interaction in these materials and its environmental sensitivity. Here, we show that by engineering the surrounding dielectric environment, one can tune the electronic bandgap and the exciton binding energy in monolayers of WS
and WSe
by hundreds of meV. We exploit this behaviour to present an in-plane dielectric heterostructure with a spatially dependent bandgap, as an initial step towards the creation of diverse lateral junctions with nanoscale resolution.
ABSTRACT The NASA Kepler mission ha s discovered thousands of new planetary candidates, many of which have been confirmed through follow-up observations. A primary goal of the mission is to determine ...the occurrence rate of terrestrial-size planets within the Habitable Zone (HZ) of their host stars. Here we provide a list of HZ exoplanet candidates from the Kepler Q1-Q17 Data Release 24 data-vetting process. This work was undertaken as part of the Kepler HZ Working Group. We use a variety of criteria regarding HZ boundaries and planetary sizes to produce complete lists of HZ candidates, including a catalog of 104 candidates within the optimistic HZ and 20 candidates with radii less than two Earth radii within the conservative HZ. We cross-match our HZ candidates with the stellar properties and confirmed planet properties from Data Release 25 to provide robust stellar parameters and candidate dispositions. We also include false-positive probabilities recently calculated by Morton et al. for each of the candidates within our catalogs to aid in their validation. Finally, we performed dynamical analysis simulations for multi-planet systems that contain candidates with radii less than two Earth radii as a step toward validation of those systems.
This article describes the application of machine learning techniques to develop state-of-the-art detection and prediction system for spatiotemporal events found within remote sensing data; ...specifically, harmful algal bloom (HAB) events. We propose HAB detection system based on a ground truth historical record of HAB events, a novel spatiotemporal datacube representation of each event (from MODIS and GEBCO bathymetry data), and a variety of machine learning architectures utilizing the state-of-the-art spatial and temporal analysis methods based on convolutional neural networks, long short-term memory components together with random forest, and support vector machine classification methods. This work has focused specifically on the case study of the detection of Karenia brevis algae (K. brevis) HAB events within the coastal waters of Florida (over 2850 events from 2003 to 2018; an order of magnitude larger than any previous machine learning detection study into HAB events). The development of multimodal spatiotemporal datacube data structures and associated novel machine learning methods give a unique architecture for the automatic detection of environmental events. Specifically, when applied to the detection of HAB events, it gives a maximum detection accuracy of 91% and a Kappa coefficient of 0.81 for the Florida data considered. A HAB forecast system was also developed where a temporal subset of each datacube was used to predict the presence of a HAB in the future. This system was not significantly less accurate than the detection system being able to predict with 86% accuracy up to 8 d in the future.
Recent breakthroughs in 3-dimensional (3D) organoid cultures for many organ systems have led to new physiologically complex in vitro models to study human development and disease. Here, we report the ...step-wise differentiation of human pluripotent stem cells (hPSCs) (embryonic and induced) into lung organoids. By manipulating developmental signaling pathways hPSCs generate ventral-anterior foregut spheroids, which are then expanded into human lung organoids (HLOs). HLOs consist of epithelial and mesenchymal compartments of the lung, organized with structural features similar to the native lung. HLOs possess upper airway-like epithelium with basal cells and immature ciliated cells surrounded by smooth muscle and myofibroblasts as well as an alveolar-like domain with appropriate cell types. Using RNA-sequencing, we show that HLOs are remarkably similar to human fetal lung based on global transcriptional profiles, suggesting that HLOs are an excellent model to study human lung development, maturation and disease.
U.S. adults may have lower levels of ambulatory physical activity compared with adults living in other countries.
The purpose of this study was to provide descriptive, epidemiological data on the ...average number of steps per day estimated to be taken by U.S. adults and to identify predictors of pedometer-measured physical activity on the basis of demographic characteristics and self-reported behavioral characteristics.
The America On the Move study was conducted in 2003. Individuals (N = 2522) aged 13 yr and older consented to fill out a survey, including 1921 adults aged 18 yr and older. Valid pedometer data were collected on 1136 adults with Accusplit AE120 pedometers. Data were weighted to reflect the general U.S. population according to several variables (age, gender, race/ethnicity, education, income, level of physical activity, and number of 5- to 17-yr-old children in the household). Differences in steps per day between subgroups were analyzed using unpaired t-tests when only two subgroups were involved or one-way ANOVA if multiple subgroups were involved.
Adults reported taking an average of 5117 steps per day. Male gender, younger age, higher education level, single marital status, and lower body mass index were all positively associated with steps per day. Steps per day were positively related to other self-reported measures of physical activity and negatively related to self-reported measures on physical inactivity. Living environment (urban, suburban, or rural) and eating habits were not associated with steps per day.
In the current study, men and women living in the United States took fewer steps per day than those living in Switzerland, Australia, and Japan. We conclude that low levels of ambulatory physical activity are contributing to the high prevalence of adult obesity in the United States.
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