Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice

Class IA phosphoinositide 3-kinases (PI3Ks) are a family of p85/p110 heterodimeric lipid kinases that generate second messenger signals downstream of tyrosine kinases, thereby controlling cell metabolism, growth, proliferation, differentiation, motility, and survival. Mammals express three class IA catalytic subunits: p110alpha, p110beta, and p110delta. It is unclear to what extent these p110 isoforms have overlapping or distinct biological roles. Mice expressing a catalytically inactive form of p110delta (p110delta(D910A)) were generated by gene targeting. Antigen receptor signaling in B and T cells was impaired and immune responses in vivo were attenuated in p110delta mutant mice. They also developed inflammatory bowel disease. These results reveal a selective role for p110delta in immunity.     

Supernova shock breakout from a red supergiant

Massive stars undergo a violent death when the supply of nuclear fuel in their cores is exhausted, resulting in a catastrophic "core-collapse" supernova. Such events are usually only detected at least a few days after the star has exploded. Observations of the supernova SNLS-04D2dc with the Galaxy Evolution Explorer space telescope reveal a radiative precursor from the supernova shock before the shock reached the surface of the star and show the initial expansion of the star at the beginning of the explosion. Theoretical models of the ultraviolet light curve confirm that the progenitor was a red supergiant, as expected for this type of supernova. These observations provide a way to probe the physics of core-collapse supernovae and the internal structures of their progenitor stars.     

A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis

The incidence of tuberculosis has been increasing substantially on a worldwide basis over the past decade, but no tuberculosis-specific drugs have been discovered in 40 years. We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (minimum inhibitory concentration 0.06 mug/ml). In mice, R207910 exceeded the bactericidal activities of isoniazid and rifampin by at least 1 log unit. Substitution of drugs included in the World Health Organization's first-line tuberculosis treatment regimen (rifampin, isoniazid, and pyrazinamide) with R207910 accelerated bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations. A single dose of R207910 inhibited mycobacterial growth for 1 week. Plasma levels associated with efficacy in mice were well tolerated in healthy human volunteers. Mutants selected in vitro suggest that the drug targets the proton pump of adenosine triphosphate (ATP) synthase.     

The structure of an open form of an E. coli mechanosensitive channel at 3.45 A resolution

How ion channels are gated to regulate ion flux in and out of cells is the subject of intense interest. The Escherichia coli mechanosensitive channel, MscS, opens to allow rapid ion efflux, relieving the turgor pressure that would otherwise destroy the cell. We present a 3.45 angstrom-resolution structure for the MscS channel in an open conformation. This structure has a pore diameter of approximately 13 angstroms created by substantial rotational rearrangement of the three transmembrane helices. The structure suggests a molecular mechanism that underlies MscS gating and its decay of conductivity during prolonged activation. Support for this mechanism is provided by single-channel analysis of mutants with altered gating characteristics.     

Oxidative burst and phagocytic activity of phagocytes in canine parvoviral enteritis

Canine parvoviral enteritis (CPE) is a severe disease characterized by systemic inflammation and immunosuppression. The function of circulating phagocytes (neutrophils and monocytes) in affected dogs has not been fully investigated. We characterized the functional capacity of canine phagocytes in CPE by determining their oxidative burst and phagocytic activities using flow cytometry. Blood was collected from 28 dogs with CPE and 11 healthy, age-matched, control dogs. Oxidative burst activity was assessed by stimulating phagocytes with opsonized Escherichia coli or phorbol 12-myristate 13-acetate (PMA) and measuring the percentage of phagocytes producing reactive oxygen species and the magnitude of this production. Phagocytosis was measured by incubating phagocytes with opsonized E. coli and measuring the percentage of phagocytes containing E. coli and the number of bacteria per cell. Complete blood counts and serum C-reactive protein (CRP) concentrations were also determined. Serum CRP concentration was negatively and positively correlated with segmented and band neutrophil concentrations, respectively. Overall, no differences in phagocyte function were found between dogs with CPE and healthy control dogs. However, infected dogs with neutropenia or circulating band neutrophils had decreased PMA-stimulated oxidative burst activity compared to healthy controls. Additionally, CPE dogs with neutropenia or circulating band neutrophils had decreased PMA- and E. coli–stimulated oxidative burst activity and decreased phagocytosis of E. coli compared to CPE dogs without neutropenia or band neutrophils. We conclude that phagocytes have decreased oxidative burst and phagocytic activity in neutropenic CPE dogs and in CPE dogs with circulating band neutrophils.     

Anti-TB activity of Evodia elleryana bark extract

An ethyl acetate extract of bark from Evodia elleryana produced significant growth inhibition of Mycobacterium tuberculosis at concentrations only minimally inhibitory to human T cells. The crude extract yielded 95% inhibition of TB at 50 microg/ml. The crude extract yielded 29% growth inhibition of human T-cells in culture at that concentration.     

Deep-Sea Anemones Are Prospective Source of New Antimicrobial and Cytotoxic Compounds

The peculiarities of the survival and adaptation of deep-sea organisms raise interest in the study of their metabolites as promising drugs. In this work, the hemolytic, cytotoxic, antimicrobial, and enzyme-inhibitory activities of tentacle extracts from five species of sea anemones (Cnidaria, orders Actiniaria and Corallimorpharia) collected near the Kuril and Commander Islands of the Far East of Russia were evaluated for the first time. The extracts of Liponema brevicorne and Actinostola callosa demonstrated maximal hemolytic activity, while high cytotoxic activity against murine splenocytes and Ehrlich carcinoma cells was found in the extract of Actinostola faeculenta. The extracts of Corallimorphus cf. pilatus demonstrated the greatest activity against Ehrlich carcinoma cells but were not toxic to mouse spleen cells. Sea anemones C. cf. pilatus and Stomphia coccinea are promising sources of antimicrobial and antifungal compounds, being active against Gram-positive bacteria Bacillus subtilis, Staphylococcus aureus, and yeast Candida albicans. Moreover, all sea anemones contain α-galactosidase inhibitors. Peptide mass fingerprinting of L. brevicorne and C. cf. pilatus extracts provided a wide range of peptides, predominantly with molecular masses of 4000–5900 Da, which may belong to a known or new structural class of toxins. The obtained data allow concluding that deep-sea anemones are a promising source of compounds for drug discovery.     

ASAS-NANP SYMPOSIUM: Review of systems thinking concepts and their potential value in animal science research

Worldwide, our collective research and policy institutions, including the American Society of Animal Science (ASAS), are calling for more systems-based research and analysis of society’s most pressing and complex problems. However, the use of systems analysis within animal science remains limited and researchers may not have the tools to answer this call. This review thus introduces important concepts in systems thinking methodology, such as policy resistance, feedback processes, and dynamic complexity. An overall rationale for systems thinking and analysis is presented, along with examples of the application of these concepts in current animal science research. In order to contrast systems approaches to more frequently employed event-oriented research frameworks, both frameworks are then applied to the ASAS’ identified “Grand Challenge” problem of antimicrobial resistance (AMR) in order to compare these two kinds of analyses. Systems thinking stresses the importance of underlying system structures that lead to persistent problem behaviors vs a focus on unidirectional cause-and-effect relationships. A potential systems framework for animal production decisions to use antimicrobials is shown that more explicitly accounts for AMR in a way that can lead to different animal production decisions than the event-oriented framework. Acknowledging and accounting for fundamental system structures that can explain persistent AMR will lead to different potential solutions to this problem than would be suggested from more linear approaches. The challenges and benefits of incorporating systems methods into animal science research are then discussed.     

Response of laying hens to L-arginine,L-citrulline and guanidinoacetic acid supplementation in reduced protein diet

A study was conducted with Hy-Line Brown laying hens to examine the effects of reduced protein diet, deficiency of arginine (Arg), and addition of crystalline Arg, citrulline (Cit) and guanidinoacetic acid (GAA) as substitutes for Arg. Hen performance, egg quality, serum uric acid, liver and reproductive organ weights, and energy and protein digestibility were measured using a completely randomized design with 5 treatments. Treatments were a standard diet (17% protein diet; SP), a reduced diet (13% protein diet deficient in Arg; RP) and RP with added Arg (0.35%, RP-Arg), GAA (0.46% equivalent to 0.35% Arg, RP-GAA) or Cit (0.35%, RP-Cit) to the level of SP. It was hypothesized that performance would decrease with Arg deficient RP diet and the addition of GAA or Cit in RP would allow birds to perform similar or greater than Arg-added RP treatment. The experiment was conducted from 20 to 39 wk of age but the treatment effect was seen only after 29 wk of age. The birds offered RP had reduced egg and albumin weights (P < 0.01), lower yolk color score (P < 0.01), lower protein intake and excretion (P < 0.01) than those offered SP. When Arg or Cit were added to RP to make them equivalent to SP, feed intake (FI) and egg production were not different than those of RP (P > 0.05). The birds offered RP-GAA decreased FI and egg production (P < 0.01) compared to those offered RP. The addition of Arg, Cit or GAA to the RP had no effect on egg quality parameters, protein and energy digestibilities (P > 0.05). However, birds offered the RP-Cit diet tended to have higher Haugh unit (P = 0.095) and lower shell breaking strength (P = 0.088) compared to all other treatments while those offered RP-GAA had higher energy digestibility (P < 0.05) than all other groups but RP. The limited performance response of hens fed RP with added Arg, GAA, or Cit may be due to deficiency of some other nutrients in RP such as phenylalanine, potassium or non-essential amino acids and other components of soybean meal in the diet.