Experimental peripheral administration of oxytocin elevates a suite of cooperative behaviours in a wild social mammal

The evolution and expression of different forms of cooperative behaviour (e.g. feeding, guarding, sentinel duties, etc.) are usually studied independently, with few studies considering them as a single syndrome. However, studies investigating individuals' investment across a suite of different behaviours reveal that they are correlated, suggesting a single mechanism determining the evolution and expression of cooperative behaviours. A hormonal mechanism could achieve this, and one possibility is oxytocin (OT), which affects several prosocial or alloparental behaviours independently. We show, using a double-blind experiment, that peripheral administration of OT to social, free-living meerkats Suricata suricatta elevates a suite of cooperative behaviours. Treated individuals increase their contributions to communal, cooperative activities (digging, guarding, pup-feeding and associating with pups) and decrease initiation of aggressive interactions, compared with a saline control. This suggests that different forms of cooperative behaviour form a single syndrome with a common causal basis. If our peripherally administered OT acts in the same way as the naturally released hormone, then a general tendency to prosociality may be modulated by this hormonal system. Therefore, it may be difficult for an individual to decouple expression of cooperative behaviours that provide the practitioner with benefits from those that provide the recipient with benefits. It may also explain why social species typically exhibit a suite of cooperative behaviours, without having to invoke independent evolution of each.     

Human epidermal growth factor receptor bispecific ligand trap RB200: abrogation of collagen-induced arthritis in combination with tumour necrosis factor blockade

Introduction  

Rheumatoid arthritis (RA) is a chronic disease associated with inflammation and destruction of bone and cartilage. Although inhibition of TNFα is widely used to treat RA, a significant number of patients do not respond to TNFα blockade, and therefore there is a compelling need to continue to identify alternative therapeutic strategies for treating chronic inflammatory diseases such as RA. The anti-epidermal growth factor (anti-EGF) receptor antibody trastuzumab has revolutionised the treatment of patients with EGF receptor-positive breast cancer. Expression of EGF ligands and receptors (known as HER) has also been documented in RA. The highly unique compound RB200 is a bispecific ligand trap that is composed of full-length extracellular domains of HER1 and HER3 EGF receptors. Because of its pan-HER specificity, RB200 inhibits responses mediated by HER1, HER2 and HER3 in vitro and in vivo. The objective of this study was to assess the effect of RB200 combined with TNF blockade in a murine collagen-induced arthritis (CIA) model of RA.     

Structural basis for c-di-GMP-mediated inside-out signaling controlling periplasmic proteolysis

The bacterial second messenger bis-(3'-5') cyclic dimeric guanosine monophosphate (c-di-GMP) has emerged as a central regulator for biofilm formation. Increased cellular c-di-GMP levels lead to stable cell attachment, which in Pseudomonas fluorescens requires the transmembrane receptor LapD. LapD exhibits a conserved and widely used modular architecture containing a HAMP domain and degenerate diguanylate cyclase and phosphodiesterase domains. c-di-GMP binding to the LapD degenerate phosphodiesterase domain is communicated via the HAMP relay to the periplasmic domain, triggering sequestration of the protease LapG, thus preventing cleavage of the surface adhesin LapA. Here, we elucidate the molecular mechanism of autoinhibition and activation of LapD based on structure-function analyses and crystal structures of the entire periplasmic domain and the intracellular signaling unit in two different states. In the absence of c-di-GMP, the intracellular module assumes an inactive conformation. Binding of c-di-GMP to the phosphodiesterase domain disrupts the inactive state, permitting the formation of a trans-subunit dimer interface between adjacent phosphodiesterase domains via interactions conserved in c-di-GMP-degrading enzymes. Efficient mechanical coupling of the conformational changes across the membrane is realized through an extensively domain-swapped, unique periplasmic fold. Our structural and functional analyses identified a conserved system for the regulation of periplasmic proteases in a wide variety of bacteria, including many free-living and pathogenic species.     

Implications of paper vs stainless steel biological indicator substrates for formaldehyde gas decontamination

Aims: This study was undertaken to determine the effectiveness of biological indicators currently being employed during formaldehyde decontamination. Data suggest that detectable amounts of formaldehyde are absorbed into the paper strips contained in currently used biological indicators. Absorbed formaldehyde has the potential to inhibit the growth of indicator spores, thus leading to false negative results. Indicators composed of either stainless steel carriers or paper strips were investigated to determine whether stainless steel carriers can be used as an alternative to paper strip indicators. Methods and Results: Biological indicators were exposed to formaldehyde gas and were tested for the presence of formaldehyde and any possible inhibition of spore growth. Absorbed formaldehyde was detected in the paper strip carriers while no formaldehyde was detected from any of the stainless steel carriers. Exposed paper strips were found to inhibit growth of up to 1 × 10⁶ spores while the stainless steel carriers did not inhibit the growth of spores. Conclusions: During decontamination, biological indicators composed of paper spore strips absorb formaldehyde and inhibit growth of any surviving spores. Stainless steel carriers do not absorb formaldehyde and are an ideal alternative substrate for biological indicators. Significance and Impact of the Study: The popular paper strip biological indicator can lead to false negative results during decontamination and is unsuitable for validating formaldehyde decontamination.     

A Laminin G-EGF-Laminin G module in Neurexin IV is essential for the apico-lateral localization of Contactin and organization of septate junctions

Septate junctions (SJs) display a unique ultrastructural morphology with ladder-like electron densities that are conserved through evolution. Genetic and molecular analyses have identified a highly conserved core complex of SJ proteins consisting of three cell adhesion molecules Neurexin IV, Contactin, and Neuroglian, which interact with the cytoskeletal FERM domain protein Coracle. How these individual proteins interact to form the septal arrays that create the paracellular barrier is poorly understood. Here, we show that point mutations that map to specific domains of neurexin IV lead to formation of fewer septae and disorganization of SJs. Consistent with these observations, our in vivo domain deletion analyses identified the first Laminin G-EGF-Laminin G module in the extracellular region of Neurexin IV as necessary for the localization of and association with Contactin. Neurexin IV protein that is devoid of its cytoplasmic region is able to create septae, but fails to form a full complement of SJs. These data provide the first in vivo evidence that specific domains in Neurexin IV are required for protein-protein interactions and organization of SJs. Given the molecular conservation of SJ proteins across species, our studies may provide insights into how vertebrate axo-glial SJs are organized in myelinated axons.     

Modes of regeneration in <Emphasis Type="Italic">Pelargonium × hortorum (Geraniaceae)</Emphasis> and three closely related species

Summary Modes of regeneration from hypocotyl explants were studied in Pelargonium × hortorum ‘Scarlet Orbit,’ and three wild relatives, P. zonale, P. alchemilloides, and P. inquinans, on different cytokinin treatments [1 μM thidiazuron (TDZ), 4 μM TDZ, or 8 μM N⁶-benzylaminopurine (BA) and 1 μM indole-3-acetic acid (IAA)]. P. × hortorum ‘Scarlet Orbit’ and P. zonale showed similar high numbers of easily detached, embryo-like structures in response to 1 μM TDZ; P. alchemilloides and P. inquinans showed weak embryogenic responses to all treatments. To revisit whether P. × hortorum produces somatic embryos, and to examine modes of regeneration in the wild species, the histology of regenerating structures on hypocotyl explants in 1 μM TDZ was examined. Both P. × hortorum and P. zonale produced embryo-like structures from single cell derivatives of epidermal cells. Globular-shaped structures transitioned into heart-shaped structures that had loose attachments to explant surfaces and no vascular connection to the explant. Roots with direct vascular connections to the rest of the embryo-like structures were never observed; root organogenesis appeared to be secondary. We propose that P. × hortorum and P. zonale exhibit partial somatic embryogenesis, in which all of the criteria for somatic embryos are met except formation of a root pole. In both species, explants forming embryo-like structures could also undergo shoot organogenesis, where shoots exhibited a broad base of attachment to the explant and a vascular connection to vascular nodules within the explant. Epidermally derived embryo-like structures were not observed in P. alchemilloides or P. inquinans in response to 1 μM TDZ. Shoot organogenesis occurred in P. alchemilloides but not in P. inquinans.     

Mapping sites of protein phosphorylation by mass spectrometry utilizing a chemical-enzymatic approach: characterization of products from alpha-S1 casein phosphopeptides

A novel chemical-enzymatic approach was developed to facilitate identification of phosphorylation sites in isolated phosphoproteins. ESI-TOF mass spectrometry was used to characterize products from the chemical-enzymatic cleavage of specific phosphorylation sites in bovine alpha-S1 casein and synthetic phosphopeptides containing substitutions at a single phosphorylation site. Further refinements to this approach for identification of protein phosphorylation sites and its utility for the quantification of phosphopeptides by isotope-dilution mass spectrometry are presented.     

Impact of vitamin E or selenium deficiency on nematode-induced alterations in murine intestinal function

The effects of deficiencies in the antioxidant nutrients, vitamin E and selenium, on the host response to gastrointestinal nematode infection are unknown. The aim of the study was to determine the effect of antioxidant deficiencies on nematode-induced alterations in intestinal function in mice. BALB/c mice were fed control diets or diets deficient in selenium or vitamin E and the response to a secondary challenge inoculation with Heligmosomoides polygyrus was determined. Egg and worm counts were assessed to determine host resistance. Sections of jejunum were mounted in Ussing chambers to measure changes in permeability, absorption, and secretion, or suspended in organ baths to determine smooth muscle contraction. Both selenium and vitamin E deficient diets reduced resistance to helminth infection. Vitamin E, but not selenium, deficiency prevented nematode-induced decreases in glucose absorption and hyper-contractility of smooth muscle. Thus, vitamin E status is an important factor in the physiological response to intestinal nematode infection and may contribute to antioxidant-dependent protective mechanisms in the small intestine.     

Gastric and thymic assay of acute oral treatment of rats with nitric oxide esters of ibuprofen or indomethacin

Two common non-steroidal anti-inflammatory drugs (NSAIDs) and their nitric oxide (NO) adducts were evaluated for effects on stomach and thymus. Following 4-h duration (acute) oral dosing of fasted male Wistar rats, 1.33 x 10(-4)mol/kg of ibuprofen caused significant visual irritation score and microscopic thinning, although an ulceration assay proved insensitive. Ibuprofen esterified with NO abolished irritation and significantly reduced thinning. Gastro-protective effects of NO-linked ibuprofen were associated with higher levels of diaphorase by optical density, an enzymatic marker of local synthesis of nitric oxide. Both indomethacin and its congener at 2 x 10(-5)mol/kg produced microscopic signs of thinning only, not visible irritation or alteration of diaphorase staining. Results suggest that NO-linked ibuprofen can promote resistance to mucosal injury, possibly via local synthesis of NO. All NO-congeners and parent NSAIDs produced comparable reductions in the abundance of medullary nitrergic cells, those synthesising NO in thymus, without significantly lowering T-cellularity, the relative size of cortex wherein T-cells are produced. Findings indicate disturbance of T-cell tolerance, consistent with increased risk of autoimmune susceptibility.