The intestinal microbiota plays a crucial role in influencing the development of host immunity, and in turn the immune system also acts to regulate the microbiota through intestinal barrier ...maintenance and immune exclusion. Normally, these interactions are homeostatic, tightly controlled, and organized by both innate and adaptive immune responses. However, a combination of environmental exposures and genetic defects can result in a break in tolerance and intestinal homeostasis. The outcomes of these interactions at the mucosal interface have broad, systemic effects on host immunity and the development of chronic inflammatory or autoimmune disease. The underlying mechanisms and pathways the microbiota can utilize to regulate these diseases are just starting to emerge. Here, we discuss the recent evidence in this area describing the impact of microbiota-immune interactions during inflammation and autoimmunity, with a focus on barrier function and CD4
+
T cell regulation.
A substantial and increasing number of human diseases are associated with changes in the gut microbiota, and discovering the molecules and mechanisms underlying these associations represents a major ...research goal. Multiple studies associate Ruminococcus gnavus, a prevalent gut microbe, with Crohn’s disease, a major type of inflammatory bowel disease. We have found that R. gnavus synthesizes and secretes a complex glucorhamnan polysaccharide with a rhamnose backbone and glucose sidechains. Chemical and spectroscopic studies indicated that the glucorhamnan was largely a repeating unit of five sugars with a linear backbone formed from three rhamnose units and a short sidechain composed of two glucose units. The rhamnose backbone is made from 1,2- and 1,3-linked rhamnose units, and the sidechain has a terminal glucose linked to a 1,6-glucose. This glucorhamnan potently induces inflammatory cytokine (TNFα) secretion by dendritic cells, and TNFα secretion is dependent on toll-like receptor 4 (TLR4). We also identify a putative biosynthetic gene cluster for this molecule, which has the four biosynthetic genes needed to convert glucose to rhamnose and the five glycosyl transferases needed to build the repeating pentasaccharide unit of the inflammatory glucorhamnan.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The human microbiome encodes extensive metabolic capabilities, but our understanding of the mechanisms linking gut microbes to human metabolism remains limited. Here, we focus on the conversion of ...cholesterol to the poorly absorbed sterol coprostanol by the gut microbiota to develop a framework for the identification of functional enzymes and microbes. By integrating paired metagenomics and metabolomics data from existing cohorts with biochemical knowledge and experimentation, we predict and validate a group of microbial cholesterol dehydrogenases that contribute to coprostanol formation. These enzymes are encoded by ismA genes in a clade of uncultured microorganisms, which are prevalent in geographically diverse human cohorts. Individuals harboring coprostanol-forming microbes have significantly lower fecal cholesterol levels and lower serum total cholesterol with effects comparable to those attributed to variations in lipid homeostasis genes. Thus, cholesterol metabolism by these microbes may play important roles in reducing intestinal and serum cholesterol concentrations, directly impacting human health.
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•Bioinformatics enabled discovery of ismA, a microbial cholesterol dehydrogenase•Metagenomic species with ismA genes form coprostanol in microbial communities•ismA+ species are associated with decreased fecal and serum cholesterol in humans•Effect sizes of ismA+ species on serum cholesterol are on par with human genetics
The consequences of cholesterol metabolism by the gut microbiome were largely unknown. Kenny, Plichta et al. identified and characterized microbial cholesterol dehydrogenase enzymes encoded by uncultured metagenomic species of bacteria. The presence of these cholesterol-metabolizing bacteria is associated with decreased stool and serum total cholesterol in human cohorts.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Microbes living within host-associated microbial communities (microbiotas) rely on chemical communication to interact with surrounding organisms. These interactions serve many purposes, from ...supplying the multicellular host with nutrients to antagonizing invading pathogens, and breakdown of chemical signaling has potentially negative consequences for both the host and microbiota. Efforts to engineer microbes to take part in chemical interactions represent a promising strategy for modulating chemical signaling within these complex communities. In this review, we discuss prominent examples of chemical interactions found within host-associated microbial communities, with an emphasis on the plant-root microbiota and the intestinal microbiota of animals. We then highlight how an understanding of such interactions has guided efforts to engineer microbes to participate in chemical signaling in these habitats. We discuss engineering efforts in the context of chemical interactions that enable host colonization, promote host health, and exclude pathogens. Finally, we describe prominent challenges facing this field and propose new directions for future engineering efforts.
Microbes can be engineered to participate in chemical signaling within host-associated microbial communities (microbiotas).
Retrospective review of a prospectively maintained surgical database.
To report the indications, surgical procedures performed, and outcomes from the largest series of thoracoscopically treated ...herniated thoracic discs (HTDs). We also compared approach-related complications with an unmatched cohort undergoing thoracotomy for HTD.
Symptomatic HTDs are rare, and their surgical management is technically challenging.
A prospectively maintained surgical database of all patients undergoing surgery for symptomatic HTDs by the senior author (blinded for review) was reviewed. As needed, the database was supplemented with hospital and clinic charts and telephone conversations with patients. A triportal method of thoracoscopic discectomy was performed in all cases.
Between 1994 and 2008, 121 patients underwent 125 thoracoscopic-assisted operations for 139 HTDs. Their mean age at surgery was 46.6 years. Indications for thoracoscopic resection currently include small symptomatic disc, anterior location, nonmorbidly obese patient, favorable chest anatomy, and T4-T11 location. Symptom duration averaged 32 months. Radiculopathy was the most common presentation, followed by myelopathy and pain (radiculopathic or back). The mean hospital stay was 4.8 days. Chest tubes remained in place for a mean of 3.2 days. At a mean follow-up of 2.4 years, myelopathy, radiculopathy, and back pain had resolved or improved at a rate of 91.1%, 97.6%, and 86.5%, respectively. Patients reported worsening in 0%, 1.2%, and 0% of cases, respectively. Most patients (97.4%) would be willing to undergo the operation again. The complication rate was acceptable. Patients undergoing thoracoscopic excision had less approach-related morbidity than an unmatched cohort undergoing excision using thoracotomy.
Thoracoscopic-assisted microsurgical resection is a safe, effective, and minimally invasive method of treating symptomatic HTDs in appropriately selected patients. The symptoms of most patients improve or resolve with minimal morbidity.
Introduction
The recommended treatment for exertional heat stroke is immediate, whole-body immersion in < 10 °C water until rectal temperature (T
re
) reaches ≤ 38.6 °C. However, real-time T
re
...assessment is not always feasible or available in field settings or emergency situations. We defined and validated immersion durations for water temperatures of 2–26 °C for treating exertional heat stroke.
Methods
We compiled data for 54 men and 18 women from 7 previous laboratory studies and derived immersion durations for reaching 38.6 °C T
re
. The resulting immersion durations were validated against the durations of cold-water immersion used to treat 162 (98 men; 64 women) exertional heat stroke cases at the Falmouth Road Race between 1984 and 2011.
Results
Age, height, weight, body surface area, body fat, fat mass, lean body mass, and peak oxygen uptake were weakly associated with the cooling time to a safe T
re
of 38.6 °C during immersions to 2–26 °C water (
R
2
range: 0.00–0.16). Using a specificity criterion of 0.9, receiver operating characteristics curve analysis showed that exertional heat stroke patients must be immersed for 11–12 min when water temperature is ≤ 9 °C, and for 18–19 min when water temperature is 10–26 °C (Cohen’s Kappa: 0.32–0.75,
p
< 0.001; diagnostic odds ratio: 8.63–103.27).
Conclusion
The reported immersion durations are effective for > 90% of exertional heat stroke patients with pre-immersion T
re
of 39.5–42.8 °C. When available, real-time T
re
monitoring is the standard of care to accurately diagnose and treat exertional heat stroke, avoiding adverse health outcomes associated with under- or over-cooling, and for implementing cool-first transport second exertional heat stroke policies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
When athletes, warfighters, and laborers perform intense exercise in the heat, the risk of exertional heat stroke (EHS) is ever present. The recent data regarding the fatalities due to EHS within the ...confines of organized American sport are not promising: during the past 35 years, the highest number of deaths in a 5-year period occurred from 2005 to 2009. This reminds us that, regardless of the advancements of knowledge in the area of EHS prevention, recognition, and treatment, knowledge has not been translated into practice. This article addresses important issues related to EHS cause and care. We focus on the predisposing factors, errors in care, physiology of cold water immersion, and return-to-play or duty considerations.
, the causative agent of glanders, is a gram-negative intracellular bacterium. Depending on different routes of infection, the disease is manifested by pneumonia, septicemia, and chronic infections ...of the skin.
poses a serious biological threat due to its ability to infect via aerosol route, resistance to multiple antibiotics and to date there are no US Food and Drug Administration (FDA) approved vaccines available. Induction of innate immunity, inflammatory cytokines and chemokines following
infection, have been observed in
and small rodent models; however, a global characterization of host responses has never been systematically investigated using a non-human primate (NHP) model. Here, using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach, we identified alterations in expression levels of host proteins in peripheral blood mononuclear cells (PBMCs) originating from naïve rhesus macaques (
), African green monkeys (
), and cynomolgus macaques (
) exposed to aerosolized
. Gene ontology (GO) analysis identified several statistically significant overrepresented biological annotations including complement and coagulation cascade, nucleoside metabolic process, vesicle-mediated transport, intracellular signal transduction and cytoskeletal protein binding. By integrating an LC-MS/MS derived proteomics dataset with a previously published
host-pathogen interaction dataset, a statistically significant predictive protein-protein interaction (PPI) network was constructed. Pharmacological perturbation of one component of the PPI network, specifically ezrin, reduced
mediated interleukin-1β (IL-1β). On the contrary, the expression of IL-1β receptor antagonist (IL-1Ra) was upregulated upon pretreatment with the ezrin inhibitor. Taken together, inflammasome activation as demonstrated by IL-1β production and the homeostasis of inflammatory response is critical during the pathogenesis of glanders. Furthermore, the topology of the network reflects the underlying molecular mechanism of
infections in the NHP model.
Phloem transport of photoassimilates from leaves to non-photosynthetic organs, such as the root and shoot apices and reproductive organs, is crucial to plant growth and yield. For nearly 90 years, ...evidence has been generally consistent with the theory of a pressure-flow mechanism of phloem transport. Central to this hypothesis is the loading of osmolytes, principally sugars, into the phloem to generate the osmotic pressure that propels bulk flow. Here we used genetic and light manipulations to test whether sugar import into the phloem is required as the driving force for phloem sap flow. Using carbon-11 radiotracer, we show that a maize sucrose transporter1 (sut1) loss-of-function mutant has severely reduced export of carbon from photosynthetic leaves (only ~4% of the wild type level). Yet, the mutant remarkably maintains phloem pressure at ~100% and sap flow speeds at ~50-75% of those of wild type. Potassium (K
) abundance in the phloem was elevated in sut1 mutant leaves. Fluid dynamic modelling supports the conclusion that increased K
loading compensated for decreased sucrose loading to maintain phloem pressure, and thereby maintained phloem transport via the pressure-flow mechanism. Furthermore, these results suggest that sap flow and transport of other phloem-mobile nutrients and signalling molecules could be regulated independently of sugar loading into the phloem, potentially influencing carbon-nutrient homoeostasis and the distribution of signalling molecules in plants encountering different environmental conditions.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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