Modelling foraging movements of diving predators : A theoretical study exploring the effect of heterogeneous landscapes on foraging efficiency

Peer reviewedPublisher PD

Crystal Structure of Prolyl 4-Hydroxylase from Bacillus anthracis

Prolyl 4-hydroxylases (P4H) catalyze the posttranslational hydroxylation of proline residues and play a role in collagen production, hypoxia response, and cell wall development. P4Hs belong to the Fe(II)/αKG oxygenases and require Fe(II), α-ketoglutarate (αKG), and O2 for activity. We report the 1.40 Å structure of a P4H from Bacillus anthracis, the causative agent of anthrax, whose immunodominant exosporium protein BclA contains collagen-like repeat sequences. The structure reveals the double stranded β-helix core fold characteristic of Fe(II)/αKG oxygenases. This fold positions Fe-binding and αKG-binding residues in what is expected to be catalytically-competent orientations and is consistent with proline peptide substrate binding at the active site mouth. Comparisons of the anthrax-P4H structure with Cr-P4H-1 structures reveal similarities in a peptide surface groove. However, sequence and structural comparisons suggest differences in conformation of adjacent loops may change the interaction with peptide substrates. These differences may be the basis of substantial disparity between the KM values for the Cr-P4H-1 vs. the anthrax and human P4H enzymes. Additionally, while previous structures of P4H enzymes are monomers, Bacillus anthracis P4H forms an α2 homodimer and suggests residues important for interactions between the α2 subunits of the α2β2 human collagen P4H. Thus the anthrax-P4H structure provides insight into the structure and function of the α subunit of human-P4H, which may aid in the development of selective inhibitors of the human-P4H enzyme involved in fibrotic disease

Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1

Human steroidogenic cytochrome P450 17A1 (CYP17A1) is a bifunctional enzyme that performs both hydroxylation and lyase reactions, with the latter required to generate androgens that fuel prostate cancer proliferation. The steroid abiraterone, the active form of the only CYP17A1 inhibitor approved by the Food and Drug Administration, binds the catalytic heme iron, nonselectively impeding both reactions and ultimately causing undesirable corticosteroid imbalance. Some nonsteroidal inhibitors reportedly inhibit the lyase reaction more than the preceding hydroxylase reaction, which would be clinically advantageous, but the mechanism is not understood. Thus, the nonsteroidal inhibitors seviteronel and orteronel and the steroidal inhibitors abiraterone and galeterone were compared with respect to their binding modes and hydroxylase versus lyase inhibition. Binding studies and X-ray structures of CYP17A1 with nonsteroidal inhibitors reveal coordination to the heme iron like the steroidal inhibitors. (S)-seviteronel binds similarly to both observed CYP17A1 conformations. However, (S)-orteronel and (R)-orteronel bind to distinct CYP17A1 conformations that differ in a region implicated in ligand entry/exit and the presence of a peripheral ligand. To reconcile these binding modes with enzyme function, side-by-side enzymatic analysis was undertaken and revealed that neither the nonsteroidal seviteronel nor the (S)-orteronel inhibitors demonstrated significant lyase selectivity, but the less potent (R)-orteronel was 8- to 11-fold selective for lyase inhibition. While active-site iron coordination is consistent with competitive inhibition, conformational selection for binding of some inhibitors and the differential presence of a peripheral ligand molecule suggest the possibility of CYP17A1 functional modulation by features outside the active site

Expression, Purification, Crystallization and Preliminary X-ray Studies of Histamine Dehydroganase from Nocardioides simplex

This is the publisher's version, also available electronically from http://scripts.iucr.org/cgi-bin/paper?S1744309108023336.Histamine dehydrogenase (HADH) from Nocardioides simplex catalyzes the oxidative deamination of histamine to produce imidazole acetaldehyde and an ammonium ion. HADH is functionally related to trimethylamine dehydrogenase (TMADH), but HADH has strict substrate specificity towards histamine. HADH is a homodimer, with each 76 kDa subunit containing two redox cofactors: a [4Fe-4S] cluster and an unusual covalently bound flavin mononucleotide, 6-S-cysteinyl-FMN. In order to understand the substrate specificity of HADH, it was sought to determine its structure by X-ray crystallography. This enzyme has been expressed recombinantly in Escherichia coli and successfully crystallized in two forms. Diffraction data were collected to 2.7 Å resolution at the SSRL synchrotron with 99.7% completeness. The crystals belonged to the orthorhombic space group P212121, with unit-cell parameters a = 101.14, b = 107.03, c = 153.35 Å

Monitoring of Nesting Songbirds Detects Established Population of Blacklegged Ticks and Associated Lyme Disease Endemic Area in Canada.

This study provides a novel method of documenting established populations of bird-feeding ticks. Single populations of the blacklegged tick, Ixodes scapularis, and the rabbit tick, Haemaphysalis leporispalustris, were revealed in southwestern Québec, Canada. Blacklegged tick nymphs and, similarly, larval and nymphal rabbit ticks were tested for the Lyme disease bacterium, Borrelia burgdorferi sensu lato (Bbsl), using PCR and the flagellin (flaB) gene, and 14 (42%) of 33 of blacklegged tick nymphs tested were positive. In contrast, larval and nymphal H. leporsipalustris ticks were negative for Bbsl. The occurrence of Bbsl in I. scapularis nymphs brings to light the presence of a Lyme disease endemic area at this songbird nesting locality. Because our findings denote that this area is a Lyme disease endemic area, and I. scapularis is a human-biting tick, local residents and outdoor workers must take preventive measures to avoid tick bites. Furthermore, local healthcare practitioners must include Lyme disease in their differential diagnosis

Consequences of warming and acidification for the temperate articulated coralline alga, Calliarthron tuberculosum (Florideophyceae, Rhodophyta)

Global climate changes, such as warming and ocean acidification (OA), are likely to negatively impact calcifying marine taxa. Abundant and ecologically important coralline algae may be particularly susceptible to OA; however, multi-stressor studies and those on articulated morphotypes are lacking. Here, we use field observations and laboratory experiments to elucidate the impacts of warming and acidification on growth, calcification, mineralogy, and photophysiology of the temperate articulated coralline alga, Calliarthron tuberculosum. We conducted a 4-week fully factorial mesocosm experiment exposing individuals from a southern CA kelp forest to current and future temperature and pH/pCO2 conditions (+2°C, −0.5 pH units). Calcification was reduced under warming (70%) and further reduced by high pCO2 or high pCO2 x warming (~150%). Growth (change in linear extension and surface area) was reduced by warming (40% and 50%, respectively), high pCO2 (20% and 40%, respectively), and high pCO2 x warming (50% and 75%, respectively). The maximum photosynthetic rate (Pmax) increased by 100% under high pCO2 conditions, but we did not detect an effect of pCO2 or warming on photosynthetic efficiency (α). We also did not detect the effect of warming or pCO2 on mineralogy. However, variation in Mg incorporation in cell walls of different cell types (i.e., higher mol % Mg in cortical vs. medullary) was documented for the first time in this species. These results support findings from a growing body of literature suggesting that coralline algae are often more negatively impacted by warming than OA, with the potential for antagonistic effects when factors are combined

Improving Models for Student Retention and Graduation using Markov Chains

Graduation rates are a key measure of the long-term efficacy of academic interventions. However, challenges to using traditional estimates of graduation rates for underrepresented students include inherently small sample sizes and high data requirements. Here, we show that a Markov model increases confidence and reduces biases in estimated graduation rates for underrepresented minority and first-generation students. We use a Learning Assistant program to demonstrate the Markov model's strength for assessing program efficacy. We find that Learning Assistants in gateway science courses are associated with a 9% increase in the six-year graduation rate. These gains are larger for underrepresented minority (21%) and first-generation students (18%). Our results indicate that Learning Assistants can improve overall graduation rates and address inequalities in graduation rates for underrepresented students

Benzylmorpholine Analogs as Selective Inhibitors of Lung Cytochrome P450 2A13 for the Chemoprevention of Lung Cancer in Tobacco Users

The original publication is available at www.springerlink.comPURPOSE 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), one of the most prevalent and procarcinogenic compounds in tobacco, is bioactivated by respiratory cytochrome P450 (CYP) 2A13, forming DNA adducts and initiating lung cancer. CYP2A13 inhibition offers a novel strategy for chemoprevention of tobacco-associated lung cancer. METHODS Twenty-four analogs of a 4-benzylmorpholine scaffold identified by high throughput screening were evaluated for binding and inhibition of both functional human CYP2A enzymes, CYP2A13 and the 94%-identical hepatic CYP2A6, whose inhibition is undesirable. Thus, selectivity is the major challenge in compound design. RESULTS A key feature resulting in CYP2A13-selective binding and inhibition was substitution at the benzyl ortho position, with three analogs being >25-fold selective for CYP2A13 over CYP2A6. CONCLUSIONS Two such analogs were negative for genetic and hERG toxicities and metabolically stable in human lung microsomes, but displayed rapid metabolism in human liver and in mouse and rat lung and liver microsomes, likely due to CYP2B-mediated degradation. A specialized knockout mouse mimicking the human lung demonstrates compound persistence in lung and provides an appropriate test model. Compound delivered by inhalation may be effective in the lung but rapidly cleared otherwise, limiting systemic exposure