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Manipulating Neuronal Circuits With Endogenous And Recombinant Cell-Surface Tethered Modulators, Mande Holford, Sebastian Auer, Martin Laqua, Ines Ibanez-Tallon

Publications and Research

Neuronal circuits depend on the precise regulation of cell-surface receptors and ion channels. An ongoing challenge in neuroscience research is deciphering the functional contribution of specifi c receptors and ion channels using engineered modulators. A novel strategy, termed “tethered toxins”, was recently developed to characterize neuronal circuits using the evolutionary derived selectivity of venom peptide toxins and endogenous peptide ligands, such as lynx1 prototoxins. Herein, the discovery and engineering of cell-surface tethered peptides is reviewed, with particular attention given to their cell-autonomy, modular composition, and genetic targeting in different model organisms. The relative ease with which tethered peptides can be …

Mercury Exposure, Nutritional Deficiencies And Metabolic Disruptions May Affect Learning In Children, Renee Dufault, Roseanne Schnoll, Walter J. Lukiw, Blaise Leblanc, Charles Cornett, Lyn Patrick, David Wallinga, Steven G. Gilbert, Raquel Crider

Publications and Research

Among dietary factors, learning and behavior are influenced not only by nutrients, but also by exposure to toxic food contaminants such as mercury that can disrupt metabolic processes and alter neuronal plasticity. Neurons lacking in plasticity are a factor in neurodevelopmental disorders such as autism and mental retardation. Essential nutrients help maintain normal neuronal plasticity. Nutritional deficiencies, including deficiencies in the long chain polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid, the amino acid methionine, and the trace minerals zinc and selenium, have been shown to influence neuronal function and produce defects in neuronal plasticity, as well as impact behavior …

Oldest Evidence Of Toolmaking Hominins In A Grassland-Dominated Ecosystem, Thomas W. Plummer, Peter W. Ditchfield, Laura C. Bishop, John D. Kingston, Joseph V. Ferraro, David R. Braun, Fritz Hertel, Richard Potts

Publications and Research

Background Major biological and cultural innovations in late Pliocene hominin evolution are frequently linked to the spread or fluctuating presence of C4 grass in African ecosystems. Whereas the deep sea record of global climatic change provides indirect evidence for an increase in C4 vegetation with a shift towards a cooler, drier and more variable global climatic regime beginning approximately 3 million years ago (Ma), evidence for grassland-dominated ecosystems in continental Africa and hominin activities within such ecosystems have been lacking. Methodology/Principal Findings We report stable isotopic analyses of pedogenic carbonates and ungulate enamel, as well as faunal data from ∼2.0 …

Cooperative Social Clusters Are Not Destroyed By Dispersal In A Ciliate, Nicolas Schtickzelle, Else J. Fjerdingstad, Alexis Chaine, Jean Clobert

Publications and Research

Background The evolution of social cooperation is favored by aggregative behavior to facilitate stable social structure and proximity among kin. High dispersal rates reduce group stability and kin cohesion, so it is generally assumed that there is a fundamental trade-off between cooperation and dispersal. However, empirical tests of this relationship are rare. We tested this assumption experimentally using ten genetically isolated strains of a ciliate, Tetrahymena thermophila. Results The propensity for social aggregation was greater in strains with reduced cell quality and lower growth performance. While we found a trade-off between costly aggregation and local dispersal in phenotypic analyses, aggregative …

Harnessing Gene Expression To Identify The Genetic Basis Of Drug Resistance, Bo-Juen Chen, Helen C. Causton, Denesy Mancenido, Noel L. Goddard, Ethan O. Perlstein, Dana Pe'er

Publications and Research

The advent of cost-effective genotyping and sequencing methods have recently made it possible to ask questions that address the genetic basis of phenotypic diversity and how natural variants interact with the environment. We developed Camelot (CAusal Modelling with Expression Linkage for cOmplex Traits), a statistical method that integrates genotype, gene expression and phenotype data to automatically build models that both predict complex quantitative phenotypes and identify genes that actively influence these traits. Camelot integrates genotype and gene expression data, both generated under a reference condition, to predict the response to entirely different conditions. We systematically applied our algorithm to data …

Activation Of Cyclin-Dependent Kinase 5 Is A Consequence Of Cell Death, Yixia Ye, Antonella Tinari, Walter Malorni, Zahra Zakeri

Publications and Research

Cyclin-dependent kinase 5 (Cdk5) is similar to other Cdks but is activated during cell differentiation and cell death rather than cell division. Since activation of Cdk5 has been reported in many situations leading to cell death, we attempted to determine if it was required for any form of cell death. We found that Cdk5 is activated during apoptotic deaths and that the activation can be detected even when the cells continue to secondary necrosis. This activation can occur in the absence of Bim, calpain, or neutral cathepsins. The kinase is typically activated by p25, derived from p35 by calpain-mediated cleavage, …

Poly-Paraphyly Of Hirudinidae: Many Lineages Of Medicinal Leeches, Anna J. Phillips, Mark E. Siddall

Publications and Research

Background: Medicinal leeches became infamous for their utility in bloodletting popularized in the 19th century, and have seen a recent resurgence in post-operative treatments for flap and replantation surgeries, and in terms of characterization of salivary anticoagulants. Notorious throughout the world, the quintessential leech family Hirudinidae has been taken for granted to be monophyletic, as has the non-bloodfeeding family Haemopidae.

Results: This study is the first to evaluate molecular evidence from hirudinid and haemopid leeches in a manner that encompasses the global scope of their taxonomic distributions. We evaluated the presumed monophyly of the Hirudinidae and assessed previous well-accepted classification …

Comparison Of Spatial Summation Properties Of Neurons In Macaque V1 And V2, S. Shushruth, Jennifer M. Ichida, Jonathan B. Levitt, Alessandra Angelucci

Publications and Research

In visual cortex, responses to stimulation of the receptive field (RF) are modulated by simultaneous stimulation of the RF surround. The mechanisms for surround modulation remain unidentified. We previously proposed that in the primary visual cortex (V1), near surround modulation is mediated by geniculocortical and horizontal connections and far surround modulation by interareal feedback connections. To understand spatial integration in the secondary visual cortex (V2) and its underlying circuitry, we have characterized spatial summation in different V2 layers and stripe compartments and compared it to that in V1. We used grating stimuli in circular and annular apertures of different sizes …

Cooperation Between A Coenzyme A-Independent Stand-Alone Initiation Module And An Iterative Type I Polyketide Synthase During Synthesis Of Mycobacterial Phenolic Glycolipids, Weiguo He, Clifford E. Soll, Sivagami Sundaram Chavadi, Guangtao Zhang, J. David Warren, Luis E. N. Quadri

Publications and Research

Several Mycobacterium tuberculosis strains, Mycobacterium leprae, and other mycobacterial pathogens produce a group of small-molecule virulence factors called phenolic glycolipids (PGLs). PGLs play key roles in pathogenicity and host−pathogen interaction. Thus, elucidation of the PGL biosynthetic pathway will not only expand our understanding of natural product biosynthesis, but may also illuminate routes to novel therapeutics to afford alternative lines of defense against mycobacterial infections. In this study, we report an investigation of the enzymatic requirements for the production of long-chain p-hydroxyphenylalkanoate intermediates of PGL biosynthesis. We demonstrate a functional cooperation between a coenzyme A-independent stand-alone didomain initiation module (FadD22) and …

Optimizing Taq Polymerase Concentration For Improved Signal-To-Noise In The Broad Range Detection Of Low Abundance Bacteria, Rudolph Spangler, Noel L. Goddard, David S. Thaler

Publications and Research

Background PCR in principle can detect a single target molecule in a reaction mixture. Contaminating bacterial DNA in reagents creates a practical limit on the use of PCR to detect dilute bacterial DNA in environmental or public health samples. The most pernicious source of contamination is microbial DNA in DNA polymerase preparations. Importantly, all commercial Taq polymerase preparations inevitably contain contaminating microbial DNA. Removal of DNA from an enzyme preparation is problematical. Methodology/Principal Findings This report demonstrates that the background of contaminating DNA detected by quantitative PCR with broad host range primers can be decreased greater than 10-fold through the …

Xmc Mediates Xctr1-Independent Morphogenesis In Xenopus Laevis†, Tomomi Haremaki, Daniel C. Weinstein

Publications and Research

In the frog, Xenopus laevis, fibroblast growth factor (FGF) signaling is required for both mesoderm formation and the morphogenetic movements that drive the elongation of the notochord, a dorsal mesodermal derivative; the coordination of these distinct roles is mediated by the Xenopus Ctr1 (Xctr1) protein: maternal Xctr1 is required for mesodermal differentiation, while the subsequent loss of Xctr1 promotes morphogenesis. The signaling cascade activated by FGF in the presence of Ctr1 has been well characterized; however, the Xctr1-independent, FGF-responsive network remains poorly defined. We have identified Xenopus Marginal Coil (Xmc) as a gene whose expression is highly enriched following Xctr1 …

Three-Dimensional Structure Of The Enveloped Bacteriophage Φ12: An Incomplete T = 13 Lattice Is Superposed On An Enclosed T = 1 Shell, Hui Wei, R. Holland Cheng, John Berriman, William J. Rice, David L. Stokes, A. Katz, David Gene Morgan, Paul Gottlieb

Publications and Research

Background Bacteriophage φ12 is a member of the Cystoviridae, a unique group of lipid containing membrane enveloped bacteriophages that infect the bacterial plant pathogen Pseudomonas syringae pv. phaseolicola. The genomes of the virus species contain three double-stranded (dsRNA) segments, and the virus capsid itself is organized in multiple protein shells. The segmented dsRNA genome, the multi-layered arrangement of the capsid and the overall viral replication scheme make the Cystoviridae similar to the Reoviridae. Methodology/Principal Findings We present structural studies of cystovirus φ12 obtained using cryo-electron microscopy and image processing techniques. We have collected images of isolated φ12 virions and generated …

Molecular Plasticity Of E-Cadherin And Sialyl Lewis X Expression, In Two Comparative Models Of Mammary Tumorigenesis, Salomé S. Pinho, Celso A. Reis, Fátima Gärtner, Mary L. Alpaugh

Publications and Research

Background The process of metastasis involves a series of steps and interactions between the tumor embolus and the microenvironment. Key alterations in adhesion molecules are known to dictate progression from the invasive to malignant phenotype followed by colonization at a distant site. The invasive phenotype results from the loss of expression of the E-cadherin adhesion molecule, whereas the malignant phenotype is associated with an increased expression of the carbohydrate ligand-binding epitopes, (e.g. Sialyl Lewis x/a) that bind endothelial E-selectin of the lymphatics and vasculature. Methodology Our study analyzed the expression of two adhesion molecules, E-cadherin and Sialyl Lewis x (sLex), …

Subchronic Infusion Of The Product Of Inflammation Prostaglandin J2 Models Sporadic Parkinson's Disease In Mice, Sha-Ron Pierre, Marijke Am Lemmens, Maria E. Figueiredo-Pereira

Publications and Research

Background Chronic neuroinflammation is implicated in Parkinson's disease (PD). Inflammation involves the activation of microglia and astrocytes that release high levels of prostaglandins. There is a profound gap in our understanding of how cyclooxygenases and their prostaglandin products redirect cellular events to promote PD neurodegeneration. The major prostaglandin in the mammalian brain is prostaglandin D2, which readily undergoes spontaneous dehydration to generate the bioactive cyclopentenone prostaglandins of the J2 series. These J2 prostaglandins are highly reactive and neurotoxic products of inflammation shown in cellular models to impair the ubiquitin/proteasome pathway and cause the accumulation of ubiquitinated proteins. PD is a …

Growth And Differentiation Of The Larval Mosquito Midgut, Kathryn Ray, Maria Mercedes, Doris Chan, Chi Yan Choi, James T. Nishiura

Publications and Research

Factors affecting larval growth and nutrition have consequences on adult fecundity. Since the mosquito larval midgut is the primary organ of digestion and nutrient absorption, factors that affect the growth and development of the midgut may have potential consequences on the reproductive potential of the adult. To gain a better understanding of mosquito midgut development the growth and metamorphic remodeling of the Aedes aegypti L. and Culex pipiens L. (Diptera: Culicidae) midguts were investigated. Cytological evidence was obtained suggesting that, in both the anterior and posterior Ae. aegypti larval midgut, diploid regenerative cells give rise to new endoreplicating cells that …

In Vivo Colocalisation Of Oskar Mrna And Trans-Acting Proteins Revealed By Quantitative Imaging Of The Drosophila Oocyte, Musa M. Mhlanga, Diana P. Bratu, Auguste Genovesio, Agata Rybarska, Nicolas Chenouard, Ulf Nehrbass, Jean-Christophe Olivo-Marin

Publications and Research

Efficient mRNA transport in eukaryotes requires highly orchestrated relationships between nuclear and cytoplasmic proteins. For oskar mRNA, the Drosophila posterior determinant, these spatio-temporal requirements remain opaque during its multi-step transport process. By in vivo covisualization of oskar mRNA with Staufen, its putative trafficking protein, we find oskar mRNA to be present in particles distinct from Staufen for part of its transport. oskar mRNA stably associated with Staufen near the posterior pole. We observe oskar mRNA to oligomerize as hundreds of copies forming large particles which are necessary for its long range transport and localization. We show the formation of these …

Genomic And Systems Evolution In Vibrionaceae Species, Jianying Gu, Jennifer Neary, Hong Cai, Audrey Moshfeghian, Stephen A. Rodriguez, Timothy G. Lilburn, Yufeng Wang

Publications and Research

Background The steadily increasing number of prokaryotic genomes has accelerated the study of genome evolution; in particular, the availability of sets of genomes from closely related bacteria has facilitated the exploration of the mechanisms underlying genome plasticity. The family Vibrionaceae is found in the Gammaproteobacteria and is abundant in aquatic environments. Taxa from the family Vibrionaceae are diversified in their life styles; some species are free living, others are symbiotic, and others are human pathogens. This diversity makes this family a useful set of model organisms for studying bacterial evolution. This evolution is driven by several forces, among them gene …

Journals Not Included In Biosis Have A Notable Impact In Biology, Philip Barnett, Claudia Lascar

Publications and Research

No abstract provided.

Direct Intra-Tumoral Injection Of Zinc-Acetate Halts Tumor Growth In A Xenograft Model Of Prostate Cancer, Maulik R. Shah, Christopher L. Kriedt, Nathan H. Lents, Mary K. Hoyer, Nimah Jamaluddin, Claudette Klein, Joseph Baldassare

Publications and Research

Intracellular levels of zinc have shown a strong inverse correlation to growth and malignancy of prostate cancer. To date, studies of zinc supplementation in prostate cancer have been equivocal and have not accounted for bioavailability of zinc. Therefore, we hypothesized that direct intra-tumoral injection of zinc could impact prostate cancer growth. In this study, we evaluated the cytotoxic properties of the pH neutral salt zinc acetate on the prostate cancer cell lines PC3, DU145 and LNCaP. Zinc acetate killed prostate cancer cell lines in vitro, independent of androgen sensitivity, in a dose-dependent manner in a range between 200 and 600 …

Molecular Signatures Of Prostate Stem Cells Reveal Novel Signaling Pathways And Provide Insights Into Prostate Cancer, Roy Blum, Rashmi Gupta, Patricia E. Burger, Christopher S. Ontiveros, Sarah N. Salm, Xiaozhong Xiong, Alexander Kamb, Holger Wesche, Lisa Marshall, Gene Cutler, Xiangyun Wang, Jiri Zavadil, David Moscatelli, E. Lynette Wilson

Publications and Research

Background The global gene expression profiles of adult and fetal murine prostate stem cells were determined to define common and unique regulators whose misexpression might play a role in the development of prostate cancer. Methodology/Principal Findings A distinctive core of transcriptional regulators common to both fetal and adult primitive prostate cells was identified as well as molecules that are exclusive to each population. Elements common to fetal and adult prostate stem cells include expression profiles of Wnt, Shh and other pathways identified in stem cells of other organs, signatures of the aryl-hydrocarbon receptor, and up-regulation of components of the aldehyde …

Dpr Acts As A Molecular Switch, Inhibiting Wnt Signaling When Unphosphorylated, But Promoting Wnt Signaling When Phosphorylated By Casein Kinase Iδ/Ε, Evelyn Teran, Aron D. Branscomb, Joni M. Seeling

Publications and Research

The Wnt pathway is a key regulator of development and tumorigenesis. Dpr (Dact/Frodo) influences Wnt signaling in part through the interaction of its PDZ-B domain with Dsh's PDZ domain. Studies have shown that XDpr1a and its close relative, Frodo, are involved in multiple steps of the Wnt pathway in either inhibitory or activating roles. We found that XDpr1a is phosphorylated by casein kinase Iδ/ε (CKIδ/ε), an activator of Wnt signaling, in the presence of XDsh. Abrogating XDpr1a's ability to bind XDsh through mutation of XDpr1a's PDZ-B domain blocks CK1δ/ε's phosphorylation of XDpr1a. Conversely, XDsh possessing a mutation in its PDZ …

Pivotal Role Of The A2a-Adrenoceptor In Producing Inflammation And Organ Injury In A Rat Model Of Sepsis, Michael Miksa, Padmalaya Des, Mian Zhou, Rongqian Wu, Weifeng Dong, Youxin Ji, Sanna M. Goyert, Thanjavur S. Ravikumar, Ping Wang

Publications and Research

Background: Norepinephrine (NE) modulates the responsiveness of macrophages to proinflammatory stimuli through the activation of adrenergic receptors (ARs). Being part of the stress response, early increases of NE in sepsis sustain adverse systemic inflammatory responses. The intestine is an important source of NE release in the early stage of cecal ligation and puncture (CLP)-induced sepsis in rats, which then stimulates TNF-a production in Kupffer cells (KCs) through the activation of the a2-AR. It is important to know which of the three a2-AR subtypes (i.e., a2A, a2B or a2C) is responsible for the upregulation of TNF-a production. The aim of this …

Testis-Expressed Profilins 3 And 4 Show Distinct Functional Characteristics And Localize In The Acroplaxome-Manchette Complex In Spermatids, Martina Behnen, Kai Murk, Petri Kursula, Heike Cappallo-Obermann, Martin Rothkegel, Abraham L. Kierszenbaum, Christiane Kirchhoff

Publications and Research

Background Multiple profilin isoforms exist in mammals; at least four are expressed in the mammalian testis. The testis-specific isoforms profilin-3 (PFN3) and profilin-4 (PFN4) may have specialized roles in spermatogenic cells which are distinct from known functions fulfilled by the "somatic" profilins, profilin-1 (PFN1) and profilin-2 (PFN2). Results Ligand interactions and spatial distributions of PFN3 and PFN4 were compared by biochemical, molecular and immunological methods; PFN1 and PFN2 were employed as controls. β-actin, phosphoinositides, poly-L-proline and mDia3, but not VASP, were confirmed as in vitro interaction partners of PFN3. In parallel experiments, PFN4 bound to selected phosphoinositides but not to …

Follower Is The New Leader, Or Leading From Anywhere, Jean Amaral

Publications and Research

This invited lecture calls on librarians and others to explore and embrace servant leadership and leading from anywhere in the organization as a model for contributing to the success of communities. "I am a follower, therefore I must lead. It’s up to all of us to make our libraries and communities better places, just places . . . ."

The Post-Synaptic Density Of Human Postmortem Brain Tissues: An Experimental Study Paradigm For Neuropsychiatric Illnesses, Chang-Gyu Hahn, Anamika Banerjee, Matthew L. Macdonald, Dan-Sung Cho, Joshua Kamins, Zhiping Nie, Karin E. Borgmann-Winter, Tilo Grosser, Angel Pizarro, Eugene Ciccimaro, Steven E. Arnold, Hoau-Yan Wang, Ian A. Blair

Publications and Research

Recent molecular genetics studies have suggested various trans-synaptic processes for pathophysiologic mechanisms of neuropsychiatric illnesses. Examination of pre- and post-synaptic scaffolds in the brains of patients would greatly aid further investigation, yet such an approach in human postmortem tissue has yet to be tested. We have examined three methods using density gradient based purification of synaptosomes followed by detergent extraction (Method 1) and the pH based differential extraction of synaptic membranes (Methods 2 and 3). All three methods separated fractions from human postmortem brains that were highly enriched in typical PSD proteins, almost to the exclusion of pre-synaptic proteins. We …

De Novo Establishment Of Wild-Type Song Culture In The Zebra Finch, Olga Feher, Haibin Wang, Sigal Saar, Partha P. Mitra, Ofer Tchernichovski

Publications and Research

What sort of culture would evolve in an island colony of naive founders? This question cannot be studied experimentally in humans. We performed the analogous experiment using socially learned birdsong. Culture is typically viewed as consisting of traits inherited epigenetically, via social learning. However, cultural diversity has species-typical constraints1, presumably of genetic origin. A celebrated, if contentious, example is whether a universal grammar constrains syntactic diversity in human languages2. Oscine songbirds exhibit song learning and provide biologically tractable models of culture: members of a species show individual variation in song3 and geographically separated groups have local song dialects 4,5. Different …

The Trials And Tribulations Of Two Historians: Adjudicating Responsibility For Pollution And Personal Harm, David Rosner, Gerald Markowitz

Publications and Research

No abstract provided.

It's All Happening At The Zoo: Children's Environmental Learning After School, Jason A. Douglas, Cindi Katz

Publications and Research

Pairing dynamic out-of-school-time (OST) programs with zoos can encourage young people's relationships with and sense of responsibility for animals and the environment. The project presented in this article, Animal Rescuers, gave the authors the opportunity to examine how such a pairing can work. OST programs enable learning in settings that are generally unavailable during school time (Honig & McDonald, 2005). They provide space for collaboration among students, teachers, and others such as program visitors or outside educators. Taking advantage of the flexibility, location, and educational playfulness of an OST setting, the authors worked intensively with a small number of 10-12-year-old …

Lip-Reading Aids Word Recognition Most In Moderate Noise: A Bayesian Explanation Using High-Dimensional Feature Space, Wei Ji Ma, Xiang Zhou, Lars A. Ross, John J. Foxe, Lucas C. Parra

Publications and Research

Watching a speaker's facial movements can dramatically enhance our ability to comprehend words, especially in noisy environments. From a general doctrine of combining information from different sensory modalities (the principle of inverse effectiveness), one would expect that the visual signals would be most effective at the highest levels of auditory noise. In contrast, we find, in accord with a recent paper, that visual information improves performance more at intermediate levels of auditory noise than at the highest levels, and we show that a novel visual stimulus containing only temporal information does the same. We present a Bayesian model of optimal …

To See Or Not To See: Prestimulus Α Phase Predicts Visual Awareness, Kyle E. Mathewson, Gabriele Gratton, Monica Fabiani, Diane M. Beck, Tony Ro

Publications and Research

We often fail to see something that at other times is readily detectable. Because the visual stimulus itself is unchanged, this variability in conscious awareness is likely related to changes in the brain. Here we show that the phase of EEG α rhythm measured over posterior brain regions can reliably predict both subsequent visual detection and stimulus-elicited cortical activation levels in a metacontrast masking paradigm. When a visual target presentation coincides with the trough of an α wave, cortical activation is suppressed as early as 100 ms after stimulus onset, and observers are less likely to detect the target. Thus, …