Bastimolide B, an Antimalarial 24-Membered Marine Macrolide Possessing a tert-Butyl Group

We reported previously the discovery of the potent antimalarial 40-membered macrolide bastimolide A (1) from the tropical marine cyanobacterium Okeania hirsute. Continued investigation has led to the discovery of a new analogue, bastimolide B (2), a 24-membered polyhydroxy macrolide with a long aliphatic chain and unique terminal tertbutyl group. Its complete structure was determined by a combination of extensive spectroscopic methods and comparative analysis of its methanolysis products with those of bastimolide A. A methanolysis mechanism for bastimolide A is proposed, and one unexpected isomerization product of the C2−C3 double bond, 2-(E)-bastimolide A (3), was obtained. Bastimolide B (2) showed strong antimalarial activity against chloroquine-sensitive Plasmodium falciparum strain HB3. A preliminary investigation of the structure−activity relationship based on six analogues revealed the importance of the double bond as well as the 1,3-diol and 1,3,5-triol functionalities.We reported previously the discovery of the potent antimalarial 40-membered macrolide bastimolide A (1) from the tropical marine cyanobacterium Okeania hirsute. Continued investigation has led to the discovery of a new analogue, bastimolide B (2), a 24-membered polyhydroxy macrolide with a long aliphatic chain and unique terminal tertbutyl group. Its complete structure was determined by a combination of extensive spectroscopic methods and comparative analysis of its methanolysis products with those of bastimolide A. A methanolysis mechanism for bastimolide A is proposed, and one unexpected isomerization product of the C2−C3 double bond, 2-(E)-bastimolide A (3), was obtained. Bastimolide B (2) showed strong antimalarial activity against chloroquine-sensitive Plasmodium falciparum strain HB3. A preliminary investigation of the structure−activity relationship based on six analogues revealed the importance of the double bond as well as the 1,3-diol and 1,3,5-triol functionalities

Sharing vs. Caring - The relative impact of sharing decisions versus managing emotions on patient outcomes

Objective: To assess the relative impact of cognitive and emotional aspects of shared decision making (SDM) on patient outcomes. Methods: Cognitive and emotional aspects of SDM in consultations between 20 oncologists and 55 early breast cancer patients were coded using the Observing Patient Involvement (OPTION) scale and the Response to Emotional Cues and Concerns (RECC) coding system, plus blocking and facilitating behaviour scales. Patient outcomes including anxiety, decisional conflict, and satisfaction with: i) the decision, ii) the consultation, and iii) doctor SDM skills, were assessed. Relationships between cognitive and emotional aspects of SDM, and patient outcomes were examined using hierarchical regression. Results: The OPTION score predicted satisfaction with doctor SDM skills 2 weeks post-consultation (p=.010), and with the treatment decision 4 months post-consultation (p=.004). Emotional blocking predicted decisional conflict (p=.039), while the number of emotional cues emitted (p=.003), and the degree of empathy provided (p=.011), predicted post-consultation anxiety. Conclusion: Cognitive and emotional aspects of SDM in oncology consultations have different effects on various patient outcomes. Practice Implications: It is important that doctors focus on both sharing decisions and managing emotions in consultations. Communication skills training addressing both these areas may be an effective way to improve diverse patient outcomes.None

Multimetric structural covariance in first-episode major depressive disorder: a graph theoretical analysis

Background: Abnormalities of cortical morphology have been consistently reported in major depressive disorder (MDD), with widespread focal alterations in cortical thickness, surface area and gyrification. However, it is unclear whether these distributed focal changes disrupt the system-level architecture (topology) of brain morphology in MDD. If present, such a topological disruption might explain the mechanisms that underlie altered cortical morphology in MDD. Methods: Seventy-six patients with first-episode MDD (33 male, 43 female) and 66 healthy controls (32 male, 34 female) underwent structural MRI scans. We calculated cortical indices, including cortical thickness, surface area and local gyrification index, using FreeSurfer. We constructed morphological covariance networks using the 3 cortical indices separately, and we analyzed the topological properties of these group-level morphological covariance networks using graph theoretical approaches. Results: Topological differences between patients with first-episode MDD and healthy controls were restricted to the thickness-based network. We found a significant decrease in global efficiency but an increase in local efficiency of the left superior frontal gyrus and the right paracentral lobule in patients with first-episode MDD. When we simulated targeted lesions affecting the most highly connected nodes, the thickness-based networks in patients with first-episode MDD disintegrated more rapidly than those in healthy controls. Limitations: Our sample of patients with first-episode MDD has limited generalizability to patients with chronic and recurrent MDD. Conclusion: A systems-level disruption in cortical thickness (but not surface area or gyrification) occurs in patients with first-episode MDD

Transcriptome analysis of a respiratory Saccharomyces cerevisiae strain suggests the expression of its phenotype is glucose insensitive and predominantly controlled by Hap4, Cat8 and Mig1

BACKGROUND: We previously described the first respiratory Saccharomyces cerevisiae strain, KOY.TM6*P, by integrating the gene encoding a chimeric hexose transporter, Tm6*, into the genome of an hxt null yeast. Subsequently we transferred this respiratory phenotype in the presence of up to 50 g/L glucose to a yeast strain, V5 hxt1-7Delta, in which only HXT1-7 had been deleted. In this study, we compared the transcriptome of the resultant strain, V5.TM6*P, with that of its wild-type parent, V5, at different glucose concentrations. RESULTS: cDNA array analyses revealed that alterations in gene expression that occur when transitioning from a respiro-fermentative (V5) to a respiratory (V5.TM6*P) strain, are very similar to those in cells undergoing a diauxic shift. We also undertook an analysis of transcription factor binding sites in our dataset by examining previously-published biological data for Hap4 (in complex with Hap2, 3, 5), Cat8 and Mig1, and used this in combination with verified binding consensus sequences to identify genes likely to be regulated by one or more of these. Of the induced genes in our dataset, 77% had binding sites for the Hap complex, with 72% having at least two. In addition, 13% were found to have a binding site for Cat8 and 21% had a binding site for Mig1. Unexpectedly, both the up- and down-regulation of many of the genes in our dataset had a clear glucose dependence in the parent V5 strain that was not present in V5.TM6*P. This indicates that the relief of glucose repression is already operable at much higher glucose concentrations than is widely accepted and suggests that glucose sensing might occur inside the cell. CONCLUSION: Our dataset gives a remarkably complete view of the involvement of genes in the TCA cycle, glyoxylate cycle and respiratory chain in the expression of the phenotype of V5.TM6*P. Furthermore, 88% of the transcriptional response of the induced genes in our dataset can be related to the potential activities of just three proteins: Hap4, Cat8 and Mig1. Overall, our data support genetic remodelling in V5.TM6*P consistent with a respiratory metabolism which is insensitive to external glucose concentrations

Resting and injury-induced inflamed periosteum contain multiple macrophage subsets that are located at sites of bone growth and regeneration

Better understanding of bone growth and regeneration mechanisms within periosteal tissues will improve understanding of bone physiology and pathology. Macrophage contributions to bone biology and repair have been established but specific investigation of periosteal macrophages has not been undertaken. We used an immunohistochemistry approach to characterize macrophages in growing murine bone and within activated periosteum induced in a mouse model of bone injury. Osteal tissue macrophages (osteomacs) and resident macrophages were distributed throughout resting periosteum. In tissues collected from 4-week-old mice, osteomacs were observed intimately associated with sites of periosteal diaphyseal and metaphyseal bone dynamics associated with normal growth. This included F4/80(+)Mac-2(-/low) osteomac association with extended tracks of bone formation (modeling) on diphyseal periosteal surfaces. Although this recapitulated endosteal osteomac characteristics, there was subtle variance in the morphology and spatial organization of periosteal modeling-associated osteomacs, which likely reflects.the greater structural complexity of periosteum. Osteomacs, resident macrophages and inflammatory macrophages (F4/80(+)Mac-2(hi) were associated with the complex bone dynamics occurring within the periosteum at the metaphyseal corticalization zone. These three macrophage subsets were also present within activated native periosteum after bone injury across a 9-day time course that spanned the inflammatory through remodeling bone healing phases. This included osteomac association with foci of endochondral ossification within the activated native periosteum. These observations confirm that osteomacs are key components of both osteal tissues, in spite of salient differences between endosteal and periosteal structure and that multiple macrophage subsets are involved in periosteal bone dynamics

Common Raven Impacts on Nesting Western Snowy Plovers: Integrating Management to Facilitate Species Recovery

The U.S. Pacific coast population of the western snowy plover (Charadrius nivosus nivosus; plover) has declined due to loss and degradation of coastal habitats, predation, and anthropogenic disturbance. The U.S. Fish and Wildlife Service listed the subspecies in 1993 as threatened under the Endangered Species Act due to the population declines and habitat loss. Predation of nests and chicks has been identified as an important cause of historic population declines, and thus, most predator management actions for this subspecies are focused on reducing this pressure. In recent years, common ravens (Corvus corax; ravens) have become the most common and pervasive predators of plover nests and chicks, especially in areas with subsidized food sources for ravens and sites without predator management. We compiled data from a variety of sources to document the impact of raven predation on plover nesting success. We discuss current raven management and suggest several tools and strategies to increase plover nesting success, including multi-state approval for the use of the avicide DRC-1339, the use of lures and new trap types, and an increase in funding for predator management. The lack of coordinated and integrated management continues to impede the recovery of the Pacific coast plover population

Tetraspanin (TSP-17) Protects Dopaminergic Neurons against 6-OHDA-Induced Neurodegeneration in <i>C. elegans</i>

Parkinson's disease (PD), the second most prevalent neurodegenerative disease after Alzheimer's disease, is linked to the gradual loss of dopaminergic neurons in the substantia nigra. Disease loci causing hereditary forms of PD are known, but most cases are attributable to a combination of genetic and environmental risk factors. Increased incidence of PD is associated with rural living and pesticide exposure, and dopaminergic neurodegeneration can be triggered by neurotoxins such as 6-hydroxydopamine (6-OHDA). In C. elegans, this drug is taken up by the presynaptic dopamine reuptake transporter (DAT-1) and causes selective death of the eight dopaminergic neurons of the adult hermaphrodite. Using a forward genetic approach to find genes that protect against 6-OHDA-mediated neurodegeneration, we identified tsp-17, which encodes a member of the tetraspanin family of membrane proteins. We show that TSP-17 is expressed in dopaminergic neurons and provide genetic, pharmacological and biochemical evidence that it inhibits DAT-1, thus leading to increased 6-OHDA uptake in tsp-17 loss-of-function mutants. TSP-17 also protects against toxicity conferred by excessive intracellular dopamine. We provide genetic and biochemical evidence that TSP-17 acts partly via the DOP-2 dopamine receptor to negatively regulate DAT-1. tsp-17 mutants also have subtle behavioral phenotypes, some of which are conferred by aberrant dopamine signaling. Incubating mutant worms in liquid medium leads to swimming-induced paralysis. In the L1 larval stage, this phenotype is linked to lethality and cannot be rescued by a dop-3 null mutant. In contrast, mild paralysis occurring in the L4 larval stage is suppressed by dop-3, suggesting defects in dopaminergic signaling. In summary, we show that TSP-17 protects against neurodegeneration and has a role in modulating behaviors linked to dopamine signaling

CA 15-3 is predictive of response and disease recurrence following treatment in locally advanced breast cancer

BACKGROUND: Primary chemotherapy (PC) is used for down-staging locally advanced breast cancer (LABC). CA 15-3 measures the protein product of the MUC1 gene and is the most widely used serum marker in breast cancer. METHODS: We retrospectively investigated the role of CA 15-3 in conjunction with other clinico-pathological variables as a predictor of response and time to disease recurrence following treatment in LABC. Pre and post primary chemotherapy serum concentrations of CA 15-3 together with other variables were reviewed and related to four outcomes following primary chemotherapy (clinical response, pathological response, time to recurrence and time to progression). Persistently elevated CA 15-3 after PC was considered as consecutively high levels above the cut off point during and after PC. RESULTS: 73 patients were included in this study. Patients received PC (AC or AC-T regimen) for locally advanced breast cancer. 54 patients underwent surgery. The median follow up was 790 days. Patients with high concentrations of CA 15-3 before PC treatment had a poor clinical (p = 0.013) and pathological (p = 0.044) response. Together with Her-2/neu expression (p = 0.009) and tumour lympho-vascular space invasion (LVI) (p = 0.001), a persistently elevated CA 15-3 post PC (p = 0.007) was an independent predictive factor of recurrence following treatment in LABC. CONCLUSION: Elevated CA 15-3 level is predictive of a poor response to chemotherapy. In addition, persistently elevated CA 15-3 levels post chemotherapy in conjunction with lympho-vascular invasion and HER2 status predict a reduced disease free survival following treatment in locally advanced breast cancer