Mechanisms underlying mouse TNF-α stimulated neutrophil derived microparticle generation

Despite advances in understanding and treatment of sepsis, it remains a disease with high mortality. Neutrophil Derived Microparticles (NDMPs) are present during sepsis and can modulate the immune system. As TNF-α is a cytokine that predominates in the initial stages of sepsis, we evaluated whether and how TNF-α can induce NDMPs in mice. We observed that TNF-α treatment results in increased NDMP numbers. We also determined that the activation of either TNF receptor 1 (TNFr1) or TNF receptor 2 (TNFr2) resulted in increased NDMP numbers and that activation of both resulted in an additive increase. Inhibition of Caspase 8 diminishes NDMPs generated through TNFr1 activation and inhibition of NF-κB abrogates NDMPs generated through activation of both TNFr1 and TNFr2. We conclude that the early production of TNF-α during sepsis can increase NDMP numbers through activation of the Caspase 8 pathway or NF-κB.     

Novel tetrahydropyran analogs as dipeptidyl peptidase IV inhibitors: Profile of clinical candidate (2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine (23)

A series of novel tri-2,3,5-substituted tetrahydropyran analogs were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the series provided inhibitors with good DPP-4 potency and selectivity over other peptidases (QPP, DPP8, and FAP). Compound 23, which is very potent, selective, efficacious in the diabetes PD model, and has an excellent pharmacokinetic profile, is selected as a clinical candidate.     

A mechanistic assessment of seasonal microhabitat selection by drift-feeding rainbow trout <Emphasis Type="Italic">Oncorhynchus mykiss</Emphasis> in a Southwestern headwater stream

The positioning of fishes within a riverscape is dependent on the proximity of complementary habitats. In this study, foraging and non-foraging habitat were quantified monthly over an entire year for a rainbow trout (Oncorhynchus mykiss) population in an isolated, headwater stream in southcentral New Mexico. The stream follows a seasonal thermal and hydrologic pattern typical for a Southwestern stream and was deemed suitable for re-introduction of the native and close relative, Rio Grande cutthroat trout (O. clarkii virginalis). However, uncertainty associated with limited habitat needed to be resolved if repatriation of the native fish was to be successful. Habitat was evaluated using resource selection functions with a mechanistic drift-foraging model to explain trout distributions. Macroinvertebrate drift was strongly season- and temperature-dependent (lower in winter and spring, higher in summer and fall). Models identified stream depth as the most limiting factor for habitat selection across seasons and size-classes. Additionally, positions closer to cover were selected during the winter by smaller size-classes (0, 1, 2), while net energy intake was important during the spring for most size-classes (0, 1, 2, 3). Drift-foraging models identified that 81% of observed trout selected positions that could meet maintenance levels throughout the year. Moreover, 40% of selected habitats could sustain maximum growth. Stream positions occupied by rainbow trout were more energetically profitable than random sites regardless of season or size-class. Larger size-classes (3, 4+) were energetically more limited throughout the year than were smaller size-classes. This research suggests that habitat in the form of deep pools is of paramount importance for rainbow trout or native cutthroat trout.     

Development and Characterization of Lactose-Positive Pediococcus Species for Milk Fermentation

Bacteriophages against Streptococcus thermophilus are a growing problem in the Italian cheese industry. One possible control method involves replacing S. thermophilus in mozzarella starter blends with lactic acid bacteria from a different genus or species. In this study, we evaluated lactose-positive pediococci for this application. Because we could not identify any commercially available pediococci with fast acid-producing ability in milk, we transformed Pediococcus pentosaceus ATCC 25744, P. pentosaceus ATCC 25745, and Pediococcus acidilactici ATCC 12697 by electroporation with pPN-1, a 35-kb Lactococcus lactis lactose plasmid. Transformants of P. pentosaceus ATCC 25745 and P. acidilactici ATCC 12697 were then used to examine lactose-positive pediococci for properties related to milk fermentation. Both transformants rapidly produced acid and efficiently retained pPN-1 in lactose broth, and neither bacterium was attacked by bacteriophages in whey collected from commercial cheese facilities. Paired starter combinations of Pediococcus spp. and Lactobacillus helveticus LH100 exhibited synergistic pH reduction in milk, and small-scale cheese trials showed that these cultures could be used to manufacture part-skim mozzarella cheese. Results demonstrate that lactose-positive pediococci have potential as replacement cocci for S. thermophilus in Italian cheese starter blends and may facilitate development of new strain rotation schemes to combat S. thermophilus bacteriophage problems in mozzarella cheese plants.     

MK-8325: A silyl proline-containing NS5A inhibitor with pan-genotype activity for treatment of HCV

HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination regimen. Herein, we describe the discovery and characterization of silyl proline-containing HCV NS5A inhibitor MK-8325 with good pan-genotype activity and acceptable pharmacokinetic properties.     

Myth and Religion in Mircea Eliade

Myth and Religion in Mircea Eliade. Douglas Allen. Levittown, PA: Taylor and Francis, Inc., 1998. 375 pp.     

Conservatism in laboratory microsocieties: unpredictable payoffs accentuate group-specific traditions

Theoretical work predicts that individuals should strategically increase their reliance on social learning when individual learning would be costly or risky, or when the payoffs for individually learned behaviors are uncertain. Using a method known to elicit cumulative cultural evolution in the laboratory, we investigated the degree of within-group similarity, and between-group variation, in design choices made by participants under conditions of varying uncertainty about the likely effectiveness of those designs. Participants were required to build a tower from spaghetti and modeling clay, their goal being to build the tower as high as possible. In one condition, towers were measured immediately on completion and, therefore, participants were able to judge the success of their design during building. In the other condition, participants' towers were measured 5 min after completion, following a deliberate attempt to test the tower's stability, making it harder for participants to judge whether an innovative solution was liable to result in a good score on the final measurement. Cultural peculiarity (i.e., the extent to which a design could be identified as belonging to a particular chain) was stronger in the delayed measure condition, indicating that participants were placing greater reliance on social learning. Furthermore, in this condition, there was only very weak evidence of successive improvement in performance over learner generations, whereas in the immediate measure condition there was a clear effect of steadily increasing scores on the goal measurement. Increasing the risk associated with learning for oneself may favor the development of arbitrary traditions.     

Mechanical stimulation induces pp125(FAK) and pp60(src) activity in an in vivo model of trabecular bone formation.

Utilizing an in vivo model of trabecular bone formation, we demonstrated the temporal and spatial activation of pp125(FAK) in response to specific mechanical load stimuli. Bone chambers equipped with hydraulic actuators were aseptically inserted into each proximal tibial metaphysis of adult, male dogs under general anesthesia. The load stimulus consisted of a trapezoidal waveform, with a maximum compressive load of 17.8 N, loading rate of 89 N/s, at 1 Hz frequency. One chamber was loaded for 2 (120 cycles), 15 (900 cycles), or 30 min (1,800 cycles), whereas the contralateral chamber served as unloaded control. Bone chambers were biopsied at postload time points of 0, 15, and 45 min. Load-induced activation of FAK was rapid, and the duration of activation was dependent on the number of applied load cycles. Mechanical stimulation increased the association of FAK with Src and the time course of complex formation paralleled the temporal activation of FAK. Evaluation of cryosections revealed prominent FAK immunoreactivity among marrow fibroblasts and stromal cells.     

180 Relationships Between Water and Sediment Characteristics and Benthic Green Macroalgal Abundance in Yaquina Bay,Oregon: 1999–2002

“Green tides” or blooms of ulvoid green algae are frequent in Yaquina Bay estuary on the central Oregon coast, USA. Measurements of their biomass were made from late spring to early winter in 1999 at six intertidal sites in the estuary, and were continued through the winter of 2002 at two sites that showed the greatest accumulation. The dominant blooming species were the Enteromorpha linza complex, Ulva fenestrata, E. flexuosa, and E. intestinalis. Red and brown algal abundance was negligable. Nutrients in the central channel were monitored, along with incident light and water column absorbence, and sediment temperature. The abundance of benthic amphipods was negatively correlated with the concentration of dissolved sulfides in porewater. However, dissolved sulfide levels were not correlated with green macroalgae biomass. Additional correlations were sought between the variables measured in an effort to suggest or negate major cause and effect relationships. This research is relevant to discerning the effects of eutrophication as a stressor on estuarine processes and could contribute toward an understanding of anthropogenic impacts on biological communities in coastal ecosystems.     

Comparing Tuberculosis Diagnostic Yield in Smear/Culture and Xpert? MTB/RIF-Based Algorithms Using a Non-Randomised Stepped-Wedge Design

Setting

Primary health services in Cape Town, South Africa.

Study Aim

To compare tuberculosis (TB) diagnostic yield in an existing smear/culture-based and a newly introduced Xpert^® MTB/RIF-based algorithm.

Methods

TB diagnostic yield (the proportion of presumptive TB cases with a laboratory diagnosis of TB) was assessed using a non-randomised stepped-wedge design as sites transitioned to the Xpert^® based algorithm. We identified the full sequence of sputum tests recorded in the electronic laboratory database for presumptive TB cases from 60 primary health sites during seven one-month time-points, six months apart. Differences in TB yield and temporal trends were estimated using a binomial regression model.

Results

TB yield was 20.9% (95% CI 19.9% to 22.0%) in the smear/culture-based algorithm compared to 17.9% (95%CI 16.4% to 19.5%) in the Xpert^® based algorithm. There was a decline in TB yield over time with a mean risk difference of -0.9% (95% CI -1.2% to -0.6%) (p<0.001) per time-point. When estimates were adjusted for the temporal trend, TB yield was 19.1% (95% CI 17.6% to 20.5%) in the smear/culture-based algorithm compared to 19.3% (95% CI 17.7% to 20.9%) in the Xpert^® based algorithm with a risk difference of 0.3% (95% CI -1.8% to 2.3%) (p = 0.796). Culture tests were undertaken for 35.5% of smear-negative compared to 17.9% of Xpert^® negative low MDR-TB risk cases and for 82.6% of smear-negative compared to 40.5% of Xpert^® negative high MDR-TB risk cases in respective algorithms.

Conclusion

Introduction of an Xpert^® based algorithm did not produce the expected increase in TB diagnostic yield. Studies are required to assess whether improving adherence to the Xpert^® negative algorithm for HIV-infected individuals will increase yield. In light of the high cost of Xpert^®, a review of its role as a screening test for all presumptive TB cases may be warranted.