106 research outputs found
Manipulating Neuronal Circuits with Endogenous and Recombinant Cell-Surface Tethered Modulators
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 specific receptors and ion channels using engineered modulators. A novel strategy, termed âtethered toxinsâ, 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 engineered, coupled with the increasing number of neuroactive venom toxins and ligand peptides being discovered, imply a multitude of potentially innovative applications for manipulating neuronal circuits and tissue-specific cell networks, including treatment of disorders caused by malfunction of receptors and ion channels
The Biochemical Anatomy of Cortical Inhibitory Synapses
Classical electron microscopic studies of the mammalian brain revealed two major classes of synapses, distinguished by the presence of a large postsynaptic density (PSD) exclusively at type 1, excitatory synapses. Biochemical studies of the PSD have established the paradigm of the synapse as a complex signal-processing machine that controls synaptic plasticity. We report here the results of a proteomic analysis of type 2, inhibitory synaptic complexes isolated by affinity purification from the cerebral cortex. We show that these synaptic complexes contain a variety of neurotransmitter receptors, neural cell-scaffolding and adhesion molecules, but that they are entirely lacking in cell signaling proteins. This fundamental distinction between the functions of type 1 and type 2 synapses in the nervous system has far reaching implications for models of synaptic plasticity, rapid adaptations in neural circuits, and homeostatic mechanisms controlling the balance of excitation and inhibition in the mature brain
Mild fetal cerebral ventriculomegaly as a prenatal sonographic marker for Kartagener syndrome
Primary ciliary dyskinesia (PCD), also referred to as immotile-cilia syndrome or Kartagener syndrome, is a group of genetic disorders caused by defective cilia leading to chronic sinupulmonary infection, situs inversus and reduced fertility. Some PCD patients also have cerebral ventriculomegaly or hydrocephalus. We report here two fetuses and one newborn with mild cerebral ventriculomegaly and a suspected and/or confirmed diagnosis of PCD. These cases demonstrate that mild fetal cerebral ventriculomegaly can be a prenatal sonographic marker of PCD, certainly in fetuses with situs inversus or a history of a previous sib with PCD. Copyrigh
Fluid transport at low Reynolds number with magnetically actuated artificial cilia
By numerical modeling we investigate fluid transport in low-Reynolds-number
flow achieved with a special elastic filament or artifical cilium attached to a
planar surface. The filament is made of superparamagnetic particles linked
together by DNA double strands. An external magnetic field induces dipolar
interactions between the beads of the filament which provides a convenient way
of actuating the cilium in a well-controlled manner. The filament has recently
been used to successfully construct the first artificial micro-swimmer [R.
Dreyfus at al., Nature 437, 862 (2005)]. In our numerical study we introduce a
measure, which we call pumping performance, to quantify the fluid transport
induced by the magnetically actuated cilium and identify an optimum stroke
pattern of the filament. It consists of a slow transport stroke and a fast
recovery stroke. Our detailed parameter study also reveals that for
sufficiently large magnetic fields the artificial cilium is mainly governed by
the Mason number that compares frictional to magnetic forces. Initial studies
on multi-cilia systems show that the pumping performance is very sensitive to
the imposed phase lag between neighboring cilia, i.e., to the details of the
initiated metachronal wave.Comment: 12 pages, 10 figures. To appear in EPJE, available online at
http://dx.doi.org/10.1140/epje/i2008-10388-
Recessive <i>HYDIN</i> mutations cause primary ciliary dyskinesia without randomization of left-right body asymmetry
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous
recessive disorder characterized by defective cilia and flagella
motility. Chronic destructive-airway disease is caused by
abnormal respiratory-tract mucociliary clearance. Abnormal
propulsion of sperm flagella contributes to male infertility.
Genetic defects in most individuals affected by PCD cause
randomization of left-right body asymmetry; approximately half
show situs inversus or situs ambiguous. Almost 70 years after
the hy3 mouse possessing Hydin mutations was described as a
recessive hydrocephalus model, we report HYDIN mutations in PCD-
affected persons without hydrocephalus. By homozygosity mapping,
we identified a PCD-associated locus, chromosomal region 16q21-
q23, which contains HYDIN. However, a nearly identical 360 kb
paralogous segment (HYDIN2) in chromosomal region 1q21.1
complicated mutational analysis. In three affected German
siblings linked to HYDIN, we identified homozygous c.3985G>T
mutations that affect an evolutionary conserved splice acceptor
site and that subsequently cause aberrantly spliced transcripts
predicting premature protein termination in respiratory cells.
Parallel whole-exome sequencing identified a homozygous nonsense
HYDIN mutation, c.922A>T (p.Lys307( *)), in six individuals from
three Faroe Island PCD-affected families that all carried an 8.8
Mb shared haplotype across HYDIN, indicating an ancestral
founder mutation in this isolated population. We demonstrate by
electron microscopy tomography that, consistent with the effects
of loss-of-function mutations, HYDIN mutant respiratory cilia
lack the C2b projection of the central pair (CP) apparatus;
similar findings were reported in Hydin-deficient Chlamydomonas
and mice. High-speed videomicroscopy demonstrated markedly
reduced beating amplitudes of respiratory cilia and stiff sperm
flagella. Like the hy3 mouse model, all nine PCD-affected
persons had normal body composition because nodal cilia function
is apparently not dependent on the function of the CP
apparatus
The Terebridae and teretoxins: Combining phylogeny and anatomy for concerted discovery of bioactive compounds
The Conoidea superfamily, comprised of cone snails, terebrids, and turrids, is an exceptionally promising group for the discovery of natural peptide toxins. The potential of conoidean toxins has been realized with the distribution of the first Conus (cone snail) drug, Prialt (ziconotide), an analgesic used to alleviate chronic pain in HIV and cancer patients. Cone snail toxins (conotoxins) are highly variable, a consequence of a high mutation rate associated to duplication events and positive selection. As Conus and terebrids diverged in the early Paleocene, the toxins from terebrids (teretoxins) may demonstrate highly divergent and unique functionalities. Recent analyses of the Terebridae, a largely distributed family with more than 300 described species, indicate they have evolutionary and pharmacological potential. Based on a three gene (COI, 12S and 16S) molecular phylogeny, including ~50 species from the West-Pacific, five main terebrid lineages were discriminated: two of these lineages independently lost their venom apparatus, and one venomous lineage was previously unknown. Knowing the phylogenetic relationships within the Terebridae aids in effectively targeting divergent lineages with novel peptide toxins. Preliminary results indicate that teretoxins are similar in structure and composition to conotoxins, suggesting teretoxins are an attractive line of research to discover and develop new therapeutics that target ion channels and receptors. Using conotoxins as a guideline, and innovative natural products discovery strategies, such as the Concerted Discovery Strategy, the potential of the Terebridae and their toxins are explored as a pioneering pharmacological resource
Poised Transcription Factories Prime Silent uPA Gene Prior to Activation
The association of poised genes with transcription factories may contribute to rapid transcriptional activation in response to stimuli and to silencing when genes are located at the interior of their chromosome territories
Noninvasive optical inhibition with a red-shifted microbial rhodopsin
Optogenetic inhibition of the electrical activity of neurons enables the causal assessment of their contributions to brain functions. Red light penetrates deeper into tissue than other visible wavelengths. We present a red-shifted cruxhalorhodopsin, Jaws, derived from Haloarcula (Halobacterium) salinarum (strain Shark) and engineered to result in red lightâinduced photocurrents three times those of earlier silencers. Jaws exhibits robust inhibition of sensory-evoked neural activity in the cortex and results in strong light responses when used in retinas of retinitis pigmentosa model mice. We also demonstrate that Jaws can noninvasively mediate transcranial optical inhibition of neurons deep in the brains of awake mice. The noninvasive optogenetic inhibition opened up by Jaws enables a variety of important neuroscience experiments and offers a powerful general-use chloride pump for basic and applied neuroscience.McGovern Institute for Brain Research at MIT (Razin Fellowship)United States. Defense Advanced Research Projects Agency. Living Foundries Program (HR0011-12-C-0068)Harvard-MIT Joint Research Grants Program in Basic NeuroscienceHuman Frontier Science Program (Strasbourg, France)Institution of Engineering and Technology (A. F. Harvey Prize)McGovern Institute for Brain Research at MIT. Neurotechnology (MINT) ProgramNew York Stem Cell Foundation (Robertson Investigator Award)National Institutes of Health (U.S.) (New Innovator Award 1DP2OD002002)National Institute of General Medical Sciences (U.S.) (EUREKA Award 1R01NS075421)National Institutes of Health (U.S.) (Grant 1R01DA029639)National Institutes of Health (U.S.) (Grant 1RC1MH088182)National Institutes of Health (U.S.) (Grant 1R01NS067199)National Science Foundation (U.S.) (Career Award CBET 1053233)National Science Foundation (U.S.) (Grant EFRI0835878)National Science Foundation (U.S.) (Grant DMS0848804)Society for Neuroscience (Research Award for Innovation in Neuroscience)Wallace H. Coulter FoundationNational Institutes of Health (U.S.) (RO1 MH091220-01)Whitehall FoundationEsther A. & Joseph Klingenstein Fund, Inc.JPB FoundationPIIF FundingNational Institute of Mental Health (U.S.) (R01-MH102441-01)National Institutes of Health (U.S.) (DP2-OD-017366-01)Massachusetts Institute of Technology. Simons Center for the Social Brai
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