Lysozyme, a mediator of sepsis, impairs the cardiac neural adrenergic response by nonendothelial release of NO and inhibitory G protein signaling

We previously showed that lysozyme (Lzm-S), derived from leukocytes, caused myocardial depression in canine sepsis by binding to the endocardial endothelium to release nitric oxide (NO). NO then diffuses to adjacent myocytes to activate the cGMP pathway. In a canine right ventricular trabecular (RVT) preparation, Lzm-S also decreased the inotropic response to field stimulation (FSR) during which the sympathetic and parasympathetic nerves were simulated to measure the adrenergic response. In the present study, we determined whether the pathway by which Lzm-S decreased FSR was different from the pathway by which Lzm-S reduced steady-state (SS) contraction. Furthermore, we determined whether the decrease in FSR was due to a decrease in sympathetic stimulation or enhanced parasympathetic signaling. In the RVT preparation, we found that the inhibitory effect of Lzm-S on FSR was prevented by NO synthase (NOS) inhibitors. A cGMP inhibitor also blocked the depressant activity of Lzm-S. However, in contrast to the Lzm-S-induced decline in SS contraction, chemical removal of the endocardial endothelium by Triton X-100 to eliminate endothelial NO release did not prevent the decrease in FSR. An inhibitory G protein was involved in the effect of Lzm-S, since FSR could be restored by treatment with pertussis toxin. Atropine prevented the Lzm-S-induced decline in FSR, whereas beta(1)- and beta(2)-adrenoceptor function was not impaired by Lzm-S. These results indicate that the Lzm-S-induced decrease in FSR results from a nonendothelial release of NO. NO then acts through inhibitory G protein to enhance parasympathetic signaling.     

Characterization of neurophysiologic and neurocognitive biomarkers for use in genomic and clinical outcome studies of schizophrenia

Background

Endophenotypes are quantitative, laboratory-based measures representing intermediate links in the pathways between genetic variation and the clinical expression of a disorder. Ideal endophenotypes exhibit deficits in patients, are stable over time and across shifts in psychopathology, and are suitable for repeat testing. Unfortunately, many leading candidate endophenotypes in schizophrenia have not been fully characterized simultaneously in large cohorts of patients and controls across these properties. The objectives of this study were to characterize the extent to which widely-used neurophysiological and neurocognitive endophenotypes are: 1) associated with schizophrenia, 2) stable over time, independent of state-related changes, and 3) free of potential practice/maturation or differential attrition effects in schizophrenia patients (SZ) and nonpsychiatric comparison subjects (NCS). Stability of clinical and functional measures was also assessed.

Methods

Participants (SZ n = 341; NCS n = 205) completed a battery of neurophysiological (MMN, P3a, P50 and N100 indices, PPI, startle habituation, antisaccade), neurocognitive (WRAT-3 Reading, LNS-forward, LNS-reorder, WCST-64, CVLT-II). In addition, patients were rated on clinical symptom severity as well as functional capacity and status measures (GAF, UPSA, SOF). 223 subjects (SZ n = 163; NCS n = 58) returned for retesting after 1 year.

Results

Most neurophysiological and neurocognitive measures exhibited medium-to-large deficits in schizophrenia, moderate-to-substantial stability across the retest interval, and were independent of fluctuations in clinical status. Clinical symptoms and functional measures also exhibited substantial stability. A Longitudinal Endophenotype Ranking System (LERS) was created to rank neurophysiological and neurocognitive biomarkers according to their effect sizes across endophenotype criteria.

Conclusions

The majority of neurophysiological and neurocognitive measures exhibited deficits in patients, stability over a 1-year interval and did not demonstrate practice or time effects supporting their use as endophenotypes in neural substrate and genomic studies. These measures hold promise for informing the “gene-to-phene gap” in schizophrenia research.     

Evaluating dispensers loaded with codlemone and pear ester for disruption of codling moth (Lepidoptera: Tortricidae)

Polyvinyl chloride polymer (PVC) dispensers loaded with ethyl (E,Z)-2,4-decadienoate (pear ester) plus the sex pheromone, (E,E)-8,10-dodecadien-1-ol (codlemone) of codling moth, Cydia pomonella (L.), were compared with PVC dispensers and a commercial dispenser (Isomate-C Plus) loaded with codlemone. Evaluations were conducted in replicated plots (0.1-0.2 ha) in apple, Malus domestica (Borkhausen) during both generations of codling moth from 2007 to 2009. Dispensers were applied at 1,000 ha(-1). Male captures in traps baited with virgin female moths and codlemone lures were recorded. Residual analysis of field-aged dispensers over both moth generations was conducted. Dispensers exhibited linear declines in release rates of both attractants, and pear ester was released at a significantly higher rate than codlemone during both time periods. The proportion of virgin female-baited traps catching males was significantly lower with combo dispenser TRE24 (45/110, mg codlemone/mg pear ester) during the second generation in 2007 and the combo dispensers TRE144 (45/75) and TRE145 (75/45) during the first generation in 2008 compared with Isomate-C Plus. Similarly, male catches in female-baited traps in plots treated with the combo dispensers TRE144 during the first generation in 2008 and TRE23 (75/110) during the second generation, in 2007 were significantly lower than in plots treated with Isomate-C Plus. No significant differences were found for male catches in codlemone-baited traps in plots treated with Isomate-C Plus and any of the combo dispensers. However, male catches were significantly lower in plots treated with Cidetrak CM (codlemone-only dispenser) than the combo TRE144 dispenser during both generations in 2009.     

The role of oxidised regenerated cellulose/collagen in chronic wound repair and its potential mechanism of action

Normal wound healing is a carefully controlled balance of destructive processes necessary to remove damaged tissue and repair processes which lead to new tissue formation. Proteases and growth factors play a pivotal role in regulating this balance, and if disrupted in favour of degradation then delayed healing ensues; a trait of chronic wounds. Whilst there are many types of chronic wounds, biochemically they are thought to be similar in that they are characterised by a prolonged inflammatory phase, which results in elevated levels of proteases and diminished growth factor activity. This increase in proteolytic activity and subsequent degradation of growth factors is thought to contribute to the net tissue loss associated with these chronic wounds.

In this study, we describe a new wound treatment, comprising oxidised regenerated cellulose and collagen (ORC/collagen), which can redress this imbalance and modify the chronic wound environment. We demonstrate that ORC/collagen can inactivate potentially harmful factors such as proteases, oxygen free radicals and excess metal ions present in chronic wound fluid, whilst simultaneously protecting positive factors such as growth factors and delivering them back to the wound.

These characteristics suggest a beneficial role for this material in helping to re-balance the chronic wound environment and therefore promote healing.     

Effects of aging and calorie restriction on the global gene expression profiles of mouse testis and ovary

Background  

The aging of reproductive organs is not only a major social issue, but of special interest in aging research. A long-standing view of 'immortal germ line versus mortal soma' poses an important question of whether the reproductive tissues age in similar ways to the somatic tissues. As a first step to understand this phenomenon, we examine global changes in gene expression patterns by DNA microarrays in ovaries and testes of C57BL/6 mice at 1, 6, 16, and 24 months of age. In addition, we compared a group of mice on ad libitum (AL) feeding with a group on lifespan-extending 40% calorie restriction (CR).     

Human herpesvirus 8 molecular mimicry of ephrin ligands facilitates cell entry and triggers EphA2 signaling

Human herpesvirus 8 (HHV-8) is an oncogenic virus that enters cells by fusion of the viral and endosomal cellular membranes in a process mediated by viral surface glycoproteins. One of the cellular receptors hijacked by HHV-8 to gain access to cells is the EphA2 tyrosine kinase receptor, and the mechanistic basis of EphA2-mediated viral entry remains unclear. Using X-ray structure analysis, targeted mutagenesis, and binding studies, we here show that the HHV-8 envelope glycoprotein complex H and L (gH/gL) binds with subnanomolar affinity to EphA2 via molecular mimicry of the receptor’s cellular ligands, ephrins (Eph family receptor interacting proteins), revealing a pivotal role for the conserved gH residue E52 and the amino-terminal peptide of gL. Using FSI-FRET and cell contraction assays, we further demonstrate that the gH/gL complex also functionally mimics ephrin ligand by inducing EphA2 receptor association via its dimerization interface, thus triggering receptor signaling for cytoskeleton remodeling. These results now provide novel insight into the entry mechanism of HHV-8, opening avenues for the search of therapeutic agents that could interfere with HHV-8–related diseases.

Herpesviruses are known to hijack cellular receptors to enter cells, but this study shows that human herpesvirus 8 takes this to another level by using its envelope glycoprotein complex gH/gL to mimic the EphA2 receptor’s natural ligands, ephrins.     

Success and failure in a lotic crayfish invasion: the roles of hydrologic variability and habitat alteration

1. This paper examines the distribution, habitat relationships, and potential for spread of non‐native signal crayfish (Pacifastacus leniusculus) in streams of the Truckee River catchment, California, U.S.A. Crayfish associations with natural features and with impoundments and flow alteration were examined in a survey of 33 streams. Abundance changes were followed over 5 years, which included some of the highest and lowest flows on record, in three streams, two unregulated and one regulated. Movement of marked crayfish was studied in one 0.5 km stream reach just upstream from a reservoir. 2. Signal crayfish were most abundant in low‐gradient streams and were positively associated with proximity to reservoirs (both upstream and downstream). Crayfish were more likely to be found in regulated than unregulated sites, and did not occur in sites upstream of barriers, such as culverts, that separated them from reservoirs or lakes. 3. Crayfish declined in abundance in years following particularly intense and prolonged wet‐season spates, leading to a negative association between crayfish abundance and both peak discharge and duration of bankfull flows. 4. Crayfish moved distances of up to 277 m, and at rates of up to 120 m day^?1, suggesting significant dispersal ability. Larger crayfish moved greater distances and were more likely to move downstream. Female crayfish showed a pattern of upstream movement in early summer and downstream movement late in the summer, opposite the pattern found in two other studies. 5. These results suggest that natural or artificial gradient barriers and, in regulated systems, management of flow regimes to include bankfull or greater flows may help to control invasive crayfish in streams.     

Beta carotene is associated with the regression of hamster buccal pouch carcinoma and the induction of tumor necrosis factor in macrophages

Beta carotene (250 micrograms/ml) dissolved in mineral oil applied either topically or injected locally (190 ng/ml dissolved in media) into DMBA (7,12-dimethylbenz(a)anthracene)-induced or HCPC-1 cell line-produced oral squamous cell carcinoma of the hamster buccal pouch was observed to result in the regression of these tumors. (p less than or equal to .005) Beta carotene application to tumor bearing pouches was observed to produce a dramatic increase in positively stained macrophages for tumor necrosis factor (TNF-alpha) as compared to macrophages in control pouches. Macrophages from hamsters with regressed tumor were shown to produce a significant increase in cytotoxicity to HCPC-1 tumor cells. Regression of the hamster oral carcinoma was correlated with the increased capacity of macrophages to lyse tumor cells, and related to the induction of tumor necrosis factor which was associated with the administration of the carotenoid, beta carotene.