Design and synthesis of quinolin-2(1H)-one derivatives as potent CDK5 inhibitors

Cyclin-dependent kinase 5 (CDK5) is a serine/threonine protein kinase and its deregulation is implicated in a number of neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and ischemic stroke. Using active site homology modeling between CDK5 and CDK2, we explored several different chemical series of potent CDK5 inhibitors. In this report, we describe the design, synthesis, and CDK5 inhibitory activities of quinolin-2(1H)-one derivatives.     

Localization and organization of protein factors involved in chromosome inheritance in Dictyostelium discoideum

Heterochromatin protein 1 (HP1) proteins are highly conserved heterochromatin components required for genomic integrity. We have previously shown that the two HP1 isoforms expressed in Dictyostelium, HcpA and HcpB, are mainly localized to (peri-)centromeric heterochromatin and have largely overlapping functions. However, they cause distinct phenotypes when overexpressed. We show here that these isoforms display quantitative differences in dimerization behavior. Dimerization preference, as well as the mutant phenotype in overexpression strains, depends on the C-terminus containing the hinge and chromo shadow domains. Both Hcp proteins are targeted to distinct subnuclear regions by different chromo shadow domain-dependent and -independent mechanisms. In addition, both proteins bind to DNA and RNA in vitro and binding is independent of the chromo shadow domain. Thus, this DNA and/or RNA binding activity may contribute to protein targeting. To further characterize heterochromatin, we cloned the Dictyostelium homolog of the origin recognition complex subunit 2 (OrcB). OrcB localizes to distinct subnuclear foci that were also targeted by HcpA. In addition, it is associated with the centrosome throughout the cell cycle. The results indicate that, similar to Orc2 homologs from other organisms, it is required for different processes in chromosome inheritance.     

Short-term decompositional state does not influence use of wood by macroinvertebrates in subtropical, coastal plain streams

Woody debris is an important habitat component, particularly in streams that lack other hard substrates. Research suggests a general relationship between increasing invertebrate density, diversity, and taxa richness with increasing wood decay in lotic systems, with some authors observing invertebrate taxonomic succession as decay proceeds. We designed a field experiment using colonization of known-aged woody debris in two streams to examine patterns in invertebrate colonization, density, diversity, richness, and succession. After aging woody debris 0–6 weeks in laboratory tanks and then placing the debris in the two subtropical, coastal plain streams for five additional weeks, we did not detect any statistical relationship between invertebrate density, diversity, evenness, richness, or life-history pattern with increasing woody debris decay, nor did we detect any relationships between the colonization or abundance of individual taxa and the decompositional state of the wood. In this paper, we propose two non-exclusive explanations for these trends based on opportunistic colonization and evolutionary filtering. Despite the apparent unimportance of decompositional state, woody debris still supported many taxa and remains an important habitat component. Our research further supports the importance of flooding and maintenance of intact riparian and floodplain forests to the woody debris dynamics and macroinvertebrates in coastal plain lotic systems.     

Effects of spatial scale on assessment of dissolved oxygen dynamics in the Atchafalaya River Basin,Louisiana

Low levels of dissolved oxygen (DO) are potential stressors of fishes and invertebrates in freshwater and marine systems. Because of the incredibly nutrient-rich and warm nature of the Atchafalaya River Basin (ARB), microbial decomposition in backwater areas with limited flow often results in potentially stressful, if not lethal, DO levels during and after the annual flood pulse. As water temperatures increase and flood levels fall, DO levels often stratify, restricting fish habitat. In order to better guide development of water management projects, we investigated the relationship between DO and DO stratification (DOD; surface DO − bottom DO) and a suite of environmental variables potentially linked to DO and DOD. Based on continuous monitoring data collected from 2000 to 2007, we used a variable selection procedure to construct statistical generalized linear models to describe the relationship between DO levels and DOD and several potentially important predictor variables at three spatial scales: the entire sampled area of the ARB; individual water management units (WMUs) or subunits (WMSs); and individual sampling sites. We conducted these analyses using models that assume the normal distribution and compared them to models that incorporate alternate error terms based on other error term distributions. Goodness of fit statistics suggested that our analyses best described the relationship between DO and structuring variables at the WMU/WMS scale. At this scale, water temperature, river stage height, current velocity, and to a lesser extent, water depth appeared to be the most important measured variables that influence DO levels. We suggest that management decisions at the WMU and WMS scales will offer the greatest potential benefits for improvement of DO conditions in the ARB.     

A multigear protocol for sampling crayfish assemblages in Gulf of Mexico coastal streams

Identifying an effective protocol for sampling crayfish in streams that vary in habitat and physical/chemical characteristics has proven problematic. We evaluated an active, combined-gear (backpack electrofishing and dipnetting) sampling protocol in 20 Coastal Plain streams in Louisiana. Using generalized linear models and rarefaction curves, we evaluated environmental and gear (separate and combined) effects on crayfish catch-per-unit-effort (CPUE), orbital carapace lengths, sex ratios, frequencies of rare species, and sample richness. Although pooled data from combined gears showed greater total numbers of crayfishes, CPUE, and richness compared to either gear individually, combined gear and backpack electrofisher results differed minimally. Overall, richness was negatively related to specific conductance, indicating potential agricultural influence. Neither crayfish sex ratios, lengths, nor frequencies of rare species differed by gear; however, combining data from both gears ensured crayfish were captured in all study streams, which was not found for electrofishing or dipnetting alone. Species accumulation and rarefaction curves indicated sampling was sufficient for recording crayfish diversity at the scale of the study and that adding streams (versus sites within streams) would be most effective for watershed-scale studies. Our results suggested the combined gear protocol was effective for assessing crayfish population and assemblage characteristics in these Coastal Plain streams.     

Differential patterns of planning impairments in Parkinson's disease and sub-clinical signs of dementia? A latent-class model-based approach

Planning impairments mark a well-documented consequence of neurodegenerative diseases such as Parkinson's disease (PD). Recently, using the Tower of London task we demonstrated that, rather than being generally impaired, PD patients selectively fail when planning requires flexible in-breadth search strategies. For a better understanding of the interindividual patterns underlying specific planning impairments, here we performed an explorative re-analysis of the original data using a latent-class model-based approach. Data-driven classification according to subjects' performance was based on a multinomial processing tree (MPT) model accommodating the impact of increased breadth versus depth of looking ahead during planning. In order to assess interindividual variability in coping with these different task demands, an extension of MPT models was used in which sample-immanent heterogeneity is accounted for by identifying different latent classes of individuals. Two latent classes were identified that differed considerably in performance for problems placing high demands on the depth of anticipatory search processes. In addition, these impairments were independent of PD diagnosis. However, latent-class mediated search depth-related deficits in planning performance were associated with poorer outcomes in dementia screenings, albeit sub-clinical. PD patients exhibited additional deficits related to the breadth of searching ahead. Taken together, results revealed dissociable impairments in specific planning processes within a single task of visuospatial problem solving. Present analyses put forward the hypothesis that cognitive sequelae of PD and sub-clinical signs of dementia may be related to differential patterns of planning impairments.