Chemical modulation of alveolar epithelial permeability.

The volume and composition of fluid on the surface of the alveoli can affect alveolar ventilation, gas diffusion, and macrophage function. The passive permeability and active processes of the alveolar epithelial lining play a role in regulating surface fluid and are a potential site of damage by airborne chemicals. Like other epithelial barriers, the alveolar lining is permeable to lipophilic substances but restricts the transmural flow of small ions and hydrophilic nonelectrolytes (equivalent pore radius ca. 0.5-1.5 nm). The mammalian fetal lung and alveolar sacs of the adult bullfrog secrete Cl- and K+ into the airspace. Secretion by the fetal lung ceases at birth. Many environmental agents increase the permeability of the capillary endothelium and/or respiratory epithelium and induce pulmonary edema. Studies with bullfrog alveolar sacs have demonstrated that selective effects may or may not be followed by general derangement of the epithelial barrier. Exposure of the luminal surface to HgCl2 (10(-6) to 10(-4) M) induces a selective increase in Cl- secretion that is followed by a fall in transport and a general increase in ion permeation. CdCl2 (10(-5) to 10(-3) M) depresses ciliomotion on cells on the trabecula of the alveolus but does not affect Cl- secretion or transepithelial conductance. HNO3, like other mineral acids, increases conductance and the radii or pores in the barrier, whereas NaNO3 selectively inhibits Cl- secretion. Amphotericin B(10(7) to 10(-5) MJ) induces K+ secretion into the lumen of both bullfrog and rat lung. We conclude that environmental agents induce changes in epithelial function that may compromise the lung's ability to regulate respiratory fluid without destroying the characteristic permeability of the epithelial lining

Detecting Distracted Driving with Deep Learning

© Springer International Publishing AG 2017Driver distraction is the leading factor in most car crashes and near-crashes. This paper discusses the types, causes and impacts of distracted driving. A deep learning approach is then presented for the detection of such driving behaviors using images of the driver, where an enhancement has been made to a standard convolutional neural network (CNN). Experimental results on Kaggle challenge dataset have confirmed the capability of a convolutional neural network (CNN) in this complicated computer vision task and illustrated the contribution of the CNN enhancement to a better pattern recognition accuracy.Peer reviewe

Status of Fluid and Electrolyte Absorption in Cystic Fibrosis

Salt and fluid absorption is a shared function of many of the body’s epithelia, but its use is highly adapted to the varied physiological roles of epithelia-lined organs. These functions vary from control of hydration of outward-facing epithelial surfaces to conservation and regulation of total body volume. In the most general context, salt and fluid absorption is driven by active Na+ absorption. Cl− is absorbed passively through various available paths in response to the electrical driving force that results from active Na+ absorption. Absorption of salt creates a concentration gradient that causes water to be absorbed passively, provided the epithelium is water permeable. Key differences notwithstanding, the transport elements used for salt and fluid absorption are broadly similar in diverse epithelia, but the regulation of these elements enables salt absorption to be tailored to very different physiological needs. Here we focus on salt absorption by exocrine glands and airway epithelia. In cystic fibrosis, salt and fluid absorption by gland duct epithelia is effectively prevented by the loss of cystic fibrosis transmembrane conductance regulator (CFTR). In airway epithelia, salt and fluid absorption persists, in the absence of CFTR-mediated Cl− secretion. The contrast of these tissue-specific changes in CF tissues is illustrative of how salt and fluid absorption is differentially regulated to accomplish tissue-specific physiological objectives

Physician–Patient Communication About Sexual Functioning in Patients with Multiple Sclerosis

Sexual dysfunction is quite common among individuals with multiple sclerosis (MS); however, severity of dysfunction alone does not account for the tremendous variation in sexual satisfaction across individuals living with MS. Individual characteristics, relationships with intimate partners, and environmental factors all likely contribute to the multidimensional experience of sexual satisfaction. Health care provider variables, including how one communicates with providers about sexual concerns, may also be influential. The purpose of this study was to examine factors that are associated with patients’ sex-related communications with their MS physicians and to overall patient sexual satisfaction. Individuals in an MS clinic (n = 73) completed a survey packet which included measures of physical and mental health, sexual dysfunction, sexual satisfaction, sex communication, health care provider relationships, and health care satisfaction. Findings suggest that while more than half of patients with MS reported experiencing sexual dysfunction, only a third of patients indicated addressing their sexual concerns with their physician during the past year. Interestingly, the frequency of communication about sexual concerns was associated with satisfaction with physician variables, whereas selfefficacy for these interactions was associated with emotional health variables. These results indicate that when considering interventions to increase confidence for communication and frequency of communication that differing factors may be taken into account

Na+ transport in cystic fibrosis respiratory epithelia. Abnormal basal rate and response to adenylate cyclase activation.

The transepithelial potential difference (PD) of cystic fibrosis (CF) airway epithelium is abnormally raised and the Cl- permeability is low. We studied the contribution of active Na+ absorption to the PD and attempted to increase the Cl- permeability of CF epithelia. Nasal epithelia from CF and control subjects were mounted in Ussing chambers and were short-circuited. The basal rate of Na+ absorption was raised in CF polyps compared with control tissues. Whereas beta agonists induced Cl- secretion in normal and atopic epithelia, beta agonists further increased the rate of Na+ absorption in CF epithelia without inducing Cl- secretion. This unusual effect is not due to an abnormal CF beta receptor because similar effects were induced by forskolin, and because cAMP production was similar in normal and CF epithelia. We conclude that CF airway epithelia absorb Na+ at an accelerated rate. The abnormal response to beta agonists may reflect a primary abnormality in a cAMP-modulated path, or a normal cAMP-modulated process in a Cl- impermeable epithelial cell

Regulation of Cl- channels in normal and cystic fibrosis airway epithelial cells by extracellular ATP.

The rate of Cl- secretion by human airway epithelium is determined, in part, by apical cell membrane Cl- conductance. In cystic fibrosis airway epithelia, defective regulation of Cl- conductance decreases the capability to secrete Cl-. Here we report that extracytosolic ATP in the luminal bath of cultured human airway epithelia increased transepithelial Cl- secretion and apical membrane Cl- permeability. Single-channel studies in excised membrane patches revealed that ATP increased the open probability of outward rectifying Cl- channels. The latter effect occurs through a receptor mechanism that requires no identified soluble second messengers and is insensitive to probes of G protein function. These results demonstrate a mode of regulation of anion channels by binding ATP at the extracellular surface. Regulation of Cl- conductance by external ATP is preserved in cystic fibrosis airway epithelia

β-Arrestins Regulate Protease-activated Receptor-1 Desensitization but Not Internalization or Down-regulation

The widely expressed beta-arrestin isoforms 1 and 2 bind phosphorylated G protein-coupled receptors (GPCRs) and mediate desensitization and internalization. Phosphorylation of protease-activated receptor-1 (PAR1), a GPCR for thrombin, is important for desensitization and internalization, however, the role of beta-arrestins in signaling and trafficking of PAR1 remains unknown. To assess beta-arrestin function we examined signaling and trafficking of PAR1 in mouse embryonic fibroblasts (MEFs) derived from beta-arrestin (betaarr) knockouts. Desensitization of PAR1 signaling was markedly impaired in MEFs lacking both betaarr1 and betaarr2 isoforms compared with wild-type cells. Strikingly, in cells lacking only betaarr1 PAR1 desensitization was also significantly impaired compared with betaarr2-lacking or wild-type cells. In wild-type MEFs, activated PAR1 was internalized through a dynamin- and clathrin-dependent pathway and degraded. Surprisingly, in cells lacking both betaarr1 and betaarr2 activated PAR1 was similarly internalized through a dynamin- and clathrin-dependent pathway and degraded, whereas the beta(2)-adrenergic receptor (beta(2)-AR) failed to internalize. A PAR1 cytoplasmic tail mutant defective in agonist-induced phosphorylation failed to internalize in both wild-type and beta-arrestin knockout cells. Thus, PAR1 appears to utilize a distinct phosphorylation-dependent but beta-arrestin-independent pathway for internalization through clathrin-coated pits. Together, these findings strongly suggest that the individual beta-arrestin isoforms can differentially regulate GPCR desensitization and further reveal a novel mechanism by which GPCRs can internalize through a dynamin- and clathrin-dependent pathway that is independent of arrestins

Functional consequences of heterologous expression of the cystic fibrosis transmembrane conductance regulator in fibroblasts

We studied the consequences of cystic fibrosis transmembrane conductance regulator (CFTR) expression in NIH-3T3 fibroblasts as a model for the effects of virally transduced CFTR expression in non-epithelial cells. Fibroblasts were infected with a retrovirus vector that contained the human CFTR and neor cDNAs. We selected and expanded G418-resistant clones that encompassed a range of CFTR expression. CFTR-mediated Cl-conductance function was measured as whole cell current, and CFTR protein was quantitated by immunoblot analysis. Overall, there was a good relationship between CFTR protein levels and CFTR-mediated Cl- conductance. Some clones had consistently high basal levels of CFTR-mediated Cl- conductance. This variation in function was partially explained by CFTR protein levels and was not due to clonal variation in cAMP metabolism. High levels of CFTR expression were associated with depolarization of fibroblast membrane potential. The CFTR-expressing clones with the largest basally active CFTR Cl- conductances and the most depolarized membrane potentials also exhibited slower growth rates. These results suggest that potential side effects of gene replacement therapy for cystic fibrosis include functional consequences of CFTR expression in non-epithelial cells