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Gut microbiota communities are fundamental ecological components in the aquatic food web. Their potential to mediate how organisms respond to multiple environmental stressors remains understudied. Here we explored how manipulations of the gut microbiome of Daphnia pulex, a keystone species in aquatic communities, influenced life history (size at maturity, age at maturity, somatic growth rate and clutch size), morphology (induced defence) and body condition (lipid status deposits) responses to combined anthropogenic (copper) and natural (predation risk) stress. Data from a factorial experiment revealed that the effect of predation risk on traits was often mediated by copper (predation risk and copper interact). These patterns align with theory linking predation risk and copper contamination via digestive physiology. We also found that each stressor, and their combination, was associated with the same community composition of the D. pulex microbiome. However, antibiotic manipulation of the microbiome reversed 7/12 the trait responses across life history, morphology and body condition. This was associated with dramatically different communities to control conditions, with clear and unique patterns of microbiome community composition for each stressor and their combination. Our study revealed that microbiome community composition is highly correlated with the response of organisms to multiple, simultaneous stressors.

Silver nanoparticles (AgNPs) are widely used in commercial applications as antimicrobial agents, but there have recently been increasing concerns raised about their possible environmental and health impacts. In this study, zebrafish embryos were exposed to two sizes of AgNP, 4 and 10 nm, through a continuous exposure from 4 to 96 h post-fertilisation (hpf), to study their uptake, impact and molecular defense responses. Results showed that zebrafish embryos were significantly impacted by 72 hpf when continuously exposed to 4 nm AgNPs. At concentrations above 0.963 mg/L, significant in vivo uptake and delayed yolk sac absorption was evident, at 1.925 mg/L, significantly reduced body length was recorded compared to control embryos. Additionally, 4 nm AgNP treatment at the same concentration resulted in significantly upregulated hypoxia inducible factor 4 (HIF4) and peroxisomal membrane protein 2 (Pxmp2) mRNA expression in exposed embryos 96 hpf. In contrast, no significant differences in terms of larvae body length, yolk sac absorption or gene expression levels were observed following exposure to 10 nm AgNPs. These results demonstrated that S4 AgNPs are available for uptake, inducing developmental (measured as body length and yolk sac area) and transcriptional (specifically HIF4 and Pxmp2) perturbations in developing embryos. This study suggests the importance of particle size as one possible factor in determining the developmental toxicity of AgNPs in fish embryos.

The aims of this work were to compare the effects of methyl mercury chloride and thimerosal on neurite/process outgrowth and microtubule proteins in differentiating mouse N2a neuroblastoma and rat C6 glioma cells. Exposure for 4h to sublethal concentrations of both compounds inhibited neurite outgrowth to a similar extent in both cells lines compared to controls. In the case of N2a cells, this inhibitory effect by both compounds was associated with a fall in the reactivity of western blots of cell extracts with monoclonal antibody T1A2, which recognises C-terminally tyrosinated alpha-tubulin. By contrast, reactivity with monoclonal antibody B512 (which recognises total alpha-tubulin) was unaffected at the same time point. These findings suggest that decreased tubulin tyrosination represents a neuron-specific early marker of mercury toxicity associated with impaired neurite outgrowth.

A selective cyclic nucleotide PDE5 inhibitor corrected the defective mucin secretion response to the β-agonist isoproterenol in submandibular acinar cells inhibited by antibody directed against the cystic fibrosis transmembrane conductance regulator. The PDE5 inhibitor was as effective as cpt-cyclic AMP or a selective PDE4 inhibitor. However, the PDE5 inhibitor had no effect on basal or isoproterenol-stimulated cyclic AMP levels and did not stimulate mucin secretion. The results showing, for the first time, correction of the CFTR mucin secretion defect by a PDE5 inhibitor, which may involve cyclic GMP, will have a major impact in development of a rational drug treatment for cystic fibrosis.

1 The cystic fibrosis gene protein, the cystic fibrosis transmembrane conductance regulator (CFTR) acts as a chloride channel and is a key regulator of mucin secretion. The mechanism by which 3-isobutyl-1-methylxanthine (IBMX) corrects the defect in CFTR mediated β-adrenergic stimulation of mucin secretion has not been determined. The present study has investigated the actions of adenosine A1 and A2 receptor antagonists to determine whether ability to stimulate mucin secretion correlates with correction of CFTR antibody inhibited β-adrenergic response and whether excessive cyclic AMP rise is required. 2 CFTR antibodies were introduced into living rat submandibular acini by hypotonic swelling. Following recovery, mucin secretion in response to isoproterenol was measured. 3 The adenosine A1 receptor antagonist, 8 cyclopentyltheophylline (CPT) was a less potent stimulator of mucin secretion than was the A2 receptor antagonist dimethylpropargylxanthine (DMPX). A concentration of CPT close to the Ki for A1 receptor antagonism (10 nM) did not stimulate mucin secretion. 4 DMPX, although a potent stimulator of mucin secretion, did not correct CFTR antibody inhibited mucin secretion. 5 CPT corrected defective CFTR antibody inhibited mucin secretion at a high (1 mM) concentration, suggesting a mechanism other than adenosine receptor antagonism. 6 DMPX potentiated the isoproterenol induced cyclic AMP rise, whereas CPT did not. 7 Correction of the defective CFTR mucin secretion response did not correlate with ability to stimulate mucin secretion and did not require potentiation of β-adrenergic induced increases in cyclic AMP. This affords real promise for the development of a selective drug treatment for cystic fibrosis. British Journal of Pharmacology (1998) 125, 697–704; doi:10.1038/sj.bjp.0702128

An antibody raised against a peptide in the first nucleotide-binding domain (NBD) of CFTR [1], incorporated into intact rat submandibular acini by hypotonic swelling, inhibited beta-adrenergic stimulated mucin secretion, without affecting cyclic AMP rise. The data are the first to show that a CFTR-antibody-containing cell results in defective stimulation of mucin secretion, as is seen in CF cells, and that this can be reversed by an excessive increase in cyclic AMP.

1. The cystic fibrosis gene protein, the cystic fibrosis transmembrane conductance regulator (CFTR) acts as a chloride channel and is a key regulator of mucin secretion. The mechanism by which 3-isobutyl-1-methylxanthine (IBMX) corrects the defect in CFTR mediated beta-adrenergic stimulation of mucin secretion has not been determined. The present study has investigated the actions of adenosine A1 and A2 receptor antagonists to determine whether ability to stimulate mucin secretion correlates with correction of CFTR antibody inhibited beta-adrenergic response and whether excessive cyclic AMP rise is required. 2. CFTR antibodies were introduced into living rat submandibular acini by hypotonic swelling. Following recovery, mucin secretion in response to isoproterenol was measured. 3. The adenosine A1 receptor antagonist, 8 cyclopentyltheophylline (CPT) was a less potent stimulator of mucin secretion than was the A2 receptor antagonist dimethylpropargylxanthine (DMPX). A concentration of CPT close to the Ki for A1 receptor antagonism (10 nM) did not stimulate mucin secretion. 4. DMPX, although a potent stimulator of mucin secretion, did not correct CFTR antibody inhibited mucin secretion. 5. CPT corrected defective CFTR antibody inhibited mucin secretion at a high (1 mM) concentration, suggesting a mechanism other than adenosine receptor antagonism. 6. DMPX potentiated the isoproterenol induced cyclic AMP rise, whereas CPT did not. 7. Correction of the defective CFTR mucin secretion response did not correlate with ability to stimulate mucin secretion and did not require potentiation of beta-adrenergic induced increases in cyclic AMP. This affords real promise for the development of a selective drug treatment for cystic fibrosis.

Increases in cytoplasmic free Ca2+ concentration in rat submandibular acini were observed in response to isoprenaline (10 microM), noradrenaline (10 microM) and carbamoylcholine (10 microM). Noradrenaline and carbamoylcholine responses were decreased to 27% and 33% respectively in the absence of extracellular Ca2+, suggesting a major requirement for Ca2+ entry. beta-Adrenergic stimulation elicited a small (35-40 nM) free Ca2+ rise, approx. 75% of which was mobilized from an intracellular store. Results suggest that this Ca2+ rise is a key event in the physiological triggering of mucin secretion by exocytosis.

A link between alteration in the protein coded for by the CF gene (Riordan et al., 1989) and the abnormal epithelial cell physiology in CF must be established in order to recognise potential site(s) of intervention to correct the secretory abnormality. Defective B-adrenergic responses are seen in all affected epithelial cells in CF (McPherson and Dormer, 1987, 1988). Thus, sweating was stimulated by isoproterenol in control but not in CF sweat glands (Sato and Sato, 1984). Secretion of mucins was increased in response to isoproterenol in control but not in CF submandibular acinar cells (McPherson et al., 1985, 1986). CF submandibular acinar cells also showed a much reduced secretion of amylase in response to isoproterenol and noradrenaline, both agonists acting via a B-adrenergic effect (McPherson et al., 1985, 1986). Cl- transport in cultured CF sweat duct cells (Pedersen, 1986) and airways epithelial cells (Welsh and Liedtke, 1986; Frizzell et al., 1986; Widdicombe et al., 1986; Cotton et al., 1987) was also shown to be defective in response to isoproterenol. In all of these epithelial cells cyclic AMP rise was shown to be normal in response to isoproterenol (McPherson and Dormer, 1987, 1988), indicating either that the defect is beyond the site of cyclic AMP formation, or that this measurement is not relevant to the function of isoproterenol in opening Cl- channels or stimulating protein secretion.

The tendency to lateral asymmetry in man extends to the functions of the eyes and hands. The dominance of the right or the left eye and greater facility of using the right or left hand are designated as “eyedness and handedness.” The latter may depend upon the former. In any case the relations of one to the other are interesting and of practical importance in the treatment of ametropia and defects of the ocular movements.

The value of experience is not in seeing much, but in seeing wisely.—Sir William Osler. It is natural that the opthalmologist should develop an analytic attitude in regard to the visual capacities of artists and that he should search for evidences of normal and abnormal sight as revealed in their paintings. A scientific rendition of the visual truths of central and side vision is not to be expected. That knowledge is still largely the possession of the medical profession, but it was hoped that the uncanny instinct which is one of the significant endowments of the great artist would have produced pictorial evidence of the recognition of these natural forms of sight. Many great artists have shown occasional flashes of partial recognition of visual truth, but only in the genre work of Rembrandt and in that of the middle periods of Renoir and Monet have I found with any consistency

Two recent legal decisions relative to unrecognized magnetic intraocular foreign bodies clearly define the degree to which improvement in medical knowledge and skill creates a corresponding responsibility and legal liability. In the case of Kosal v. Boyce, 201 N. W. 757, decided by the Supreme Court of Wisconsin in 1925,1the plaintiff-patient was struck in the eye by part of a steel spring. The defendant-physician, who specialized in diseases of the eye, ear, nose and throat, treated the injury. According to the record, this physician examined the eye by the use of the ophthalmoscope, direct illumination and oblique focal rays, but failed to discover any foreign body in the eye. Several months later another physician, with the aid of roentgenograms, discovered a piece of steel in the eye. The plaintiff brought suit, and the lower court awarded him damages to the extent of $2,000. The Supreme Court of

Incorporation of the calcium chelator BAPTA into isolated, intact rat submandibular acini by hypotonic swelling, resulted in complete inhibition of carbamylcholine, noradrenaline and isoproterenol stimulation of mucin secretion. No effects or intracellular BAPTA on cell viability or β-adrenergic stimulation of cyclic AMP formation were observed. The data are the first to demonstrate that calcium is necessary for β-adrenergic stimulation of secretion and suggest that Ca2+ provides a common link in the triggering of exocytosis.

Faulty posture of the head and spinal curvature are generally recognized as effects of ocular anomalies. This paper points out the reverse relation may be true, and the ocular symptoms relieved by orthopedic treatment.

In June, 1914, I was privileged to become a voluntary assistant in the second eye clinic of the Vienna General Hospital, the service of Hofrat Fuchs. At the outbreak of the war two wards of this service were placed under Professor Budinger, and on volunteering to serve without pay, I was given charge, with the understanding that all the eye cases of this division were to be referred to these wards so far as possible. I was active here for over three months, doing practically all the eye and brain surgery as well as all of the general major surgery of these wards, and assisting in the surgery of the five other wards of Professor Budinger's service. Including 322 cases of my own, I had the privilege of observing about 1,100 cases of projectile wounds and war injuries of various kinds during this period, and my generalizations are drawn from