Decoding the mannitol enigma in filamentous fungi

Mannitol is a 6-carbon polyol that is among the most abundant biochemical compounds in the biosphere. Mannitol has been ascribed a multitude of roles in filamentous fungi including carbohydrate storage, reservoir of reducing power, stress tolerance and spore dislodgement and/or dispersal. The advancement of genetic manipulation techniques in filamentous fungi has rapidly accelerated our understanding of the roles and metabolism of mannitol. The targeted deletion of genes encoding proteins of mannitol metabolism in several fungi, including phytopathogens, has proven that the metabolism of mannitol does not exist as a cycle and that many of the postulated roles are unsupported. These recent studies have provided a much needed focus on this mysterious metabolite and make this a fitting time to review the roles and metabolism of mannitol in filamentous fungi.     

Synthesis and biological evaluation of thiazolidine-2-one 1,1-dioxide as inhibitors of Escherichia coli beta-ketoacyl-ACP-synthase III (FabH)

A series of cyclic sulfones has been synthesized and their activity against beta-ketoacyl-ACP-synthase III (FabH) has been investigated. The compounds are selectively active against Escherichia coli FabH (ecFabH), but not Mycobacterium tuberculosis FabH (mtFabH) or Plasmodium falciparum KASIII (PfKASIII). The activity against ecFabH ranges from 0.9 to >100microM and follows a consistent general SAR trend. Many of the compounds were shown to have antimalarial activity against chloroquine (CQ)-sensitive (D6) P. falciparum (IC(50)=5.3microM for the most potent inhibitor) and some were active against E. coli (MIC=6.6microg/ml for the most potent inhibitor).     

Discovery of orally bioavailable and novel urea agonists of the high affinity niacin receptor GPR109A

A urea class of high affinity niacin receptor agonists was discovered. Compound 1a displayed good PK, better in vivo efficacy in reducing FFA in mouse than niacin, and no vasodilation in a mouse model. Compound 1q demonstrated equal affinity to GPR109A as niacin.     

Comparative genomic analysis of the Hsp70s from five diverse photosynthetic eukaryotes

We have identified 24 members of the DnaK subfamily of heat shock 70 proteins (Hsp70s) in the complete genomes of 5 diverse photosynthetic eukaryotes. The Hsp70s are a ubiquitous protein family that is highly conserved across all domains of life. Eukaryotic Hsp70s are found in a number of subcellular compartments in the cell: cytoplasm, mitochondrion (MT), chloroplast (CP), and endoplasmic reticulum (ER). Although the Hsp70s have been the subject of intense study in model organisms, very little is known of the Hsp70s from early diverging photosynthetic lineages. The sequencing of the complete genomes of Thalassiosira pseudonana (a diatom), Cyanidioschyzon merolae (a red alga), and 3 green algae (Chlamydomonas reinhardtii, Ostreococcus lucimarinus, Ostreococcus tauri) allow us to conduct comparative genomics of the Hsp70s present in these diverse photosynthetic eukaryotes. We have found that the distinct lineages of Hsp70s (MT, CP, ER, and cytoplasmic) each have different evolutionary histories. In general, evolutionary patterns of the mitochondrial and endoplasmic reticulum Hsp70s are relatively stable even among very distantly related organisms. This is not true of the chloroplast Hsp70s and we discuss the distinct evolutionary patterns between "green" and "red" plastids. Finally, we find that, in contrast to the angiosperms Arabidopsis thaliana and Oryza sativa that have numerous cytoplasmic Hsp70, the 5 algal species have only 1 cytoplasmic Hsp70 each. The evolutionary and functional implications of these differences are discussed.     

Enabling high-throughput data management for systems biology: the Bioinformatics Resource Manager

The Bioinformatics Resource Manager (BRM) is a software environment that provides the user with data management, retrieval and integration capabilities. Designed in collaboration with biologists, BRM simplifies mundane analysis tasks of merging microarray and proteomic data across platforms, facilitates integration of users' data with functional annotation and interaction data from public sources and provides connectivity to visual analytic tools through reformatting of the data for easy import or dynamic launching capability. BRM is developed using Java and other open-source technologies for free distribution. AVAILABILITY: BRM, sample data sets and a user manual can be downloaded from http://www.sysbio.org/dataresources/brm.stm.     

Sphingosine 1-phosphate rapidly increases endothelial barrier function independently of VE-cadherin but requires cell spreading and Rho kinase

Sphingosine 1-phosphate (S1P) rapidly increases endothelial barrier function and induces the assembly of the adherens junction proteins vascular endothelial (VE)-cadherin and catenins. Since VE-cadherin contributes to the stabilization of the endothelial barrier, we determined whether the rapid, barrier-enhancing activity of S1P requires VE-cadherin. Ca(2+)-dependent, homophilic VE-cadherin binding of endothelial cells, derived from human umbilical veins and grown as monolayers, was disrupted with EGTA, an antibody to the extracellular domain of VE-cadherin, or gene silencing of VE-cadherin with small interfering RNA. All three protocols caused a reduction in the immunofluorescent localization of VE-cadherin at intercellular junctions, the separation of adjacent cells, and a decrease in basal endothelial electrical resistance. In all three conditions, S1P rapidly increased endothelial electrical resistance. These findings demonstrate that S1P enhances the endothelial barrier independently of homophilic VE-cadherin binding. Junctional localization of VE-cadherin, however, was associated with the sustained activity of S1P. Imaging with phase-contrast and differential interference contrast optics revealed that S1P induced cell spreading and closure of intercellular gaps. Pretreatment with latrunculin B, an inhibitor of actin polymerization, or Y-27632, a Rho kinase inhibitor, attenuated cell spreading and the rapid increase in electrical resistance induced by S1P. We conclude that S1P rapidly closes intercellular gaps, resulting in an increased electrical resistance across endothelial cell monolayers, via cell spreading and Rho kinase and independently of VE-cadherin.     

Decolonizing Primate Conservation Practice: A Case Study from North Morocco

Understanding the historical context of an area enables an incoming conservationist to reflect on their role in communities and to better position themselves both politically and socially within them. Here, we explore how outside agencies and institutions, including a former colonial power, have affected and influenced local communities who share their landscape with Barbary macaques (Macaca sylvanus) in Bouhachem forest, north Morocco. In the context of initiating Barbary macaque conservation activities, we interviewed representatives from local governmental and nongovernmental organizations, city dwellers, and villagers about the historical, political, and social context of the study site. We found that villages around Bouhachem were politically and socially marginalized and discriminated against by the state and urban society. The existence of these divisions and the outside agencies’ simplistic view of villages as homogeneous communities negatively influenced conservation interventions, because people resisted initiatives imposed on them without prior consultation. We found that Bouhachem villagers have been, and still are, excluded from meaningful participation in the conservation of the forest and this finding encouraged us to decolonize our own practice. We engaged meaningfully with members of the surrounding communities and responded to news of erroneous stories about our activities by developing a project working in three villages that included all households. Based on our experiences, we recommend that all conservationists conduct historical and qualitative research to gain a deeper, more nuanced understanding of the communities they work in. This understanding should encourage conservationists to recognize their own social and cultural biases and to decolonize their practice. Attending to our own position may help us to avoid underestimating and alienating people who view conservation actions through a very different but equally valid lens.

التخلص من التداعيات الاستعمارية في المحافظة على الرئيسيات :دراسة حالة من شمال المغربخلاصة : إن فهم السياق التاريخي لمنطقة معينة، يمكّن المحافظ البيئي الوافد من التفكير في دوره في المجتمعات، ولانسجامٍ سياسيٍ واجتماعي أفضل داخلها. هنا نكتشف كيف أثرت الوكالات والمؤسسات الخارجية ، بما في ذلك القوة الاستعمارية السابقة، على المجتمعات المحلية التي تتعايش مع قرود المكاك البربري (Macaca sylvanus) في غابة بوهاشم شمال المغرب. في سياق بدء أنشطة الحفاظ على المكاك البربري، أجرينا مقابلات مع ممثلين من المنظمات الحكومية وغير الحكومية المحلية وسكان المدن والقرويين حول السياق التاريخي والسياسي والاجتماعي لموقع الدراسة. وجدنا أن القرى المحيطة بغابة بوهاشم كانت مهمشة و معرضة للتمييز ضدها سياسياً واجتماعياً من قبل الدولة والمجتمع الحضري. و أثر بشكل سلبي وجود هذه الانقسامات والنظرة السطحية للوكالات الخارجية للقرى على أنها مجتمعات متجانسة، على تدخلات الحفظ البيئي، لأن الناس رفضوا أي مبادرة مفروضة عليهم دون استشارة مسبقة. و وجدنا أن القرويين في بوهاشم كانوا ولا يزالون مستبعدين من المشاركة الهادفة في الحفاظ على الغابة، وهذا الاكتشاف شجعنا على التخلص من التداعيات الاستعمارية في ممارستنا. لقد تواصلنا بشكل هادف بأعضاء من المجتمعات المحيطة، واستجبنا لأخبار القصص الخاطئة حول أنشطتنا من خلال تطوير مشروع يعمل في ثلاث قرى شمل جميع الأسر. بناءً على تجاربنا، نوصي جميع دعاة الحفاظ على البيئة بإجراء بحث تاريخي ونوعي لاكتساب فهم أعمق وأكثر دقة للمجتمعات التي يعملون فيها. يجب أن يشجع هذا الفهم دعاة الحفاظ على البيئة على التعرف على التحيزات الاجتماعية والثقافية الخاصة بهم، والتخلص من التداعيات الاستعمارية في ممارساتهم.قد يساعدنا الاهتمام بموقفنا الخاص على تجنب الإبعاد و التقليل من شأن الأشخاص، الذين ينظرون إلى إجراءات الحفاظ على البيئة من منظور مختلف تمامًا لكن عادل .