Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeostasis

Neutrophil influx into the intestinal lumen is a critical response to infectious agents, but is also associated with severe intestinal damage observed in idiopathic inflammatory bowel disease. The chemoattractant hepoxilin A3, an eicosanoid secreted from intestinal epithelial cells by the apically restricted efflux pump multidrug resistance protein 2 (MRP2), mediates this neutrophil influx. Information about a possible counterbalance pathway that could signal the lack of or resolution of an apical inflammatory signal, however, has yet to be described. We now report a system with such hallmarks. Specifically, we identify endocannabinoids as the first known endogenous substrates of the apically restricted multidrug resistance transporter P-glycoprotein (P-gp) and reveal a mechanism, which we believe is novel, for endocannabinoid secretion into the intestinal lumen. Knockdown or inhibition of P-gp reduced luminal secretion levels of N-acyl ethanolamine-type endocannabinoids, which correlated with increased neutrophil transmigration in vitro and in vivo. Additionally, loss of CB2, the peripheral cannabinoid receptor, led to increased pathology and neutrophil influx in models of acute intestinal inflammation. These results define a key role for epithelial cells in balancing the constitutive secretion of antiinflammatory lipids with the stimulated secretion of proinflammatory lipids via surface efflux pumps in order to control neutrophil infiltration into the intestinal lumen and maintain homeostasis in the healthy intestine

Sparse Gamma Rhythms Arising through Clustering in Adapting Neuronal Networks

Gamma rhythms (30–100 Hz) are an extensively studied synchronous brain state responsible for a number of sensory, memory, and motor processes. Experimental evidence suggests that fast-spiking interneurons are responsible for carrying the high frequency components of the rhythm, while regular-spiking pyramidal neurons fire sparsely. We propose that a combination of spike frequency adaptation and global inhibition may be responsible for this behavior. Excitatory neurons form several clusters that fire every few cycles of the fast oscillation. This is first shown in a detailed biophysical network model and then analyzed thoroughly in an idealized model. We exploit the fact that the timescale of adaptation is much slower than that of the other variables. Singular perturbation theory is used to derive an approximate periodic solution for a single spiking unit. This is then used to predict the relationship between the number of clusters arising spontaneously in the network as it relates to the adaptation time constant. We compare this to a complementary analysis that employs a weak coupling assumption to predict the first Fourier mode to destabilize from the incoherent state of an associated phase model as the external noise is reduced. Both approaches predict the same scaling of cluster number with respect to the adaptation time constant, which is corroborated in numerical simulations of the full system. Thus, we develop several testable predictions regarding the formation and characteristics of gamma rhythms with sparsely firing excitatory neurons

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Are there gender-related differences in the psychometric properties of the Oswestry Disability Index?

BACKGROUND: Despite the wide body of research on the properties of the Oswestry Disability Index (ODI), only a few studies have investigated whether ODI scores can be interpreted similarly in both genders. A few previous studies suggested that the ODI may behave differently in different populations, e.g. in different age groups. AIM: The objective was to investigate gender-related differences in the psychometric properties of the ODI amongst patients with chronic low back pain. DESIGN: Observational cross-sectional cohort study. SETTINGS: University outpatient Physical and Rehabilitation Medicine clinic. POPULATION: Consecutive patients seen in an outpatient Physical and Rehabilitation Medicine clinic at a university hospital between April 2014 and February 2017. METHODS: Internal consistency was evaluated using Cronbach\u27s alpha. Factor structure was investigated using exploratory factor analysis. Gender-related differences in psychometric properties of ODI items were assessed using item response theory analysis. RESULTS: 912 patients, 579 women (63%), with an average age of 45.8 (SD 14.2) years old, were included in the study. The Cronbach\u27s alpha for both genders was good at 0.88. The discrimination abilities of all 10 ODI items were mostly high to perfect for both men and women with only small fluctuations. The item information function curves were similar for most of the items. Exploratory factor analysis resulted in a unidimensional one-factor structure for both genders. CONCLUSIONS: The ODI appears to be a similarly unidimensional and internally consistent questionnaire in both genders without any substantial variability in the items\u27 difficulty and discrimination. CLINICAL REHABILITATION IMPACT: The ODI produces psychometrically similar results in both genders. Small and clinically hardly significant gender-related differences in the properties of ODI can be neglected