Papers by peter scheifele
Proceedings of the National Academy of Sciences, 2008
Neuroligins (NLs) are catalytically inactive members of a family of cholinesterase-like transmemb... more Neuroligins (NLs) are catalytically inactive members of a family of cholinesterase-like transmembrane proteins that mediate cell adhesion at neuronal synapses. Postsynaptic neuroligins engage in Ca 2+ -dependent transsynaptic interactions via their extracellular cholinesterase domain with presynaptic neurexins (NRXs). These interactions may be regulated by two short splice insertions (termed A and B) in the NL cholinesterase domain. Here, we present the 3.3-Å crystal structure of the ectodomain from NL2 containing splice insertion A (NL2A). The overall structure of NL2A resembles that of cholinesterases, but several structural features are unique to the NL proteins. First, structural elements surrounding the esterase active-site region differ significantly between active esterases and NL2A. On the opposite surface of the NL2A molecule, the positions of the A and B splice insertions identify a candidate NRX interaction site of the NL protein. Finally, sequence comparisons of NL isofo...
Neuron, 2002
and Cell Biology the transcriptional level; for example, the coordinated 2 Functional Genomics La... more and Cell Biology the transcriptional level; for example, the coordinated 2 Functional Genomics Laboratory expression of transcription factors in functionally con-3 Helen Wills Neuroscience Institute and nected pools of sensory and motor neurons suggests 4 Department of Statistics that synaptic circuits might be specified at the transcrip-University of California, Berkeley tional level (Arber et al., 2000; Lin et al., 1998). However, Berkeley, California 94720 we are far from a complete understanding of the molecu-5 Riken Genomic Sciences Center lar basis of such differentiation processes. Genome Exploration Research Group The cerebellar cortex is an attractive model system Yokohama, Kanagawa 230-0045 for the study of neuronal differentiation, as it consists Japan of a small number of neuronal cell types that are morpho-6 Division of Genetics and Bioinformatics logically and molecularly well characterized. Granule The Walter and Eliza Hall Institute neurons are the major cell type in the cerebellar cortex. of Medical Research The abundance of these cells and the simple anatomy Parkville, Victoria 3050 of the cerebellum make these cells very accessible for Australia an analysis of their differentiation program, from their initial specification to the acquisition of synaptic specificity. Summary Granule neurons are generated in the first postnatal week from proliferating granule cell precursors (GCPs) As an approach toward understanding the molecuin the external granule layer (EGL) of the cerebellum. lar mechanisms of neuronal differentiation, we uti-Terminally differentiated cells migrate inward to form lized DNA microarrays to elucidate global patterns of the internal granular layer (IGL). Mature granule cells gene expression during pontocerebellar development. extend multiple short dendrites that receive synaptic Through this analysis, we identified groups of genes input from mossy fiber afferents and Golgi cells, whereas specific to neuronal precursor cells, associated with granule cell axons (the parallel fibers of the cerebellum) axon outgrowth, and regulated in response to contact synapse on distal dendritic spines of Purkinje cells. The with synaptic target cells. In the cerebellum, we identidevelopment of both granule and Purkinje cells is greatly fied a phase of granule cell differentiation that is indeaffected by bidirectional cell-cell interactions between pendent of interactions with other cerebellar cell these two cell types (Baptista et al., 1994; Wechslertypes. Analysis of pontine gene expression revealed Reya and Scott, 1999). This is also apparent in naturally that distinct programs of gene expression, correlated occurring mouse mutants in which degeneration of one with axon outgrowth and synapse formation, can be cell type frequently affects the other. For example, in decoupled and are likely influenced by different cells weaver (wv) mice, granule cells die in the EGL, resulting in the cerebellar target environment. Our approach in strongly reduced numbers of mature granule cells in provides insight into the genetic programs underlying the IGL (Heintz and Zoghbi, 2000; Sotelo, 1990). This in the differentiation of specific cell types in the pontoturn results in defects in Purkinje cell development and cerebellar projection system. aberrant morphologies of Purkinje cell dendrites (Rakic and Sidman, 1973a; Salinas et al., 1994). In heterozygous
Nature, 1995
In epithelial Madin-Darby canine kidney (MDCK) cells newly synthesized molecules are sorted in th... more In epithelial Madin-Darby canine kidney (MDCK) cells newly synthesized molecules are sorted in the trans-Golgi network and directly delivered to their apical and basolateral surface destinations. Sorting is mediated by signals in the cytoplasmic domains of basolateral transmembrane proteins whereas glycosylphosphatidylinositol-linked proteins have apical sorting information in their glycolipid tails. Signals for apical transmembrane proteins are thought to reside in their ectodomains, because truncated forms lacking the cytoplasmic tail and the membrane anchor are secreted apically. Here we demonstrate that carbohydrates act as an apical targeting signal for secretory proteins. Growth hormone, which is non-glycosylated and secreted from both sides of MDCK cell layers, is secreted from the apical side when glycosylated. Thus glycans not only play a general role in protein folding but also appear to function in protein sorting in biosynthetic traffic.
Journal of Biological Chemistry, 1999
Human Molecular Genetics, 2004
Autism is a neuro-developmental syndrome that affects 0.1-0.5% of the population. It has been pro... more Autism is a neuro-developmental syndrome that affects 0.1-0.5% of the population. It has been proposed that alterations in neuronal circuitry and/or neuronal signaling are responsible for the behavioral and cognitive aberrations in autism patients. However, the cellular basis of such alterations is unknown. Recently, point mutations in a family of neuronal cell adhesion molecules called neuroligins have been linked to autismspectrum disorders and mental retardation. We investigated the consequences of these disease-associated mutations on neuroligin function. We demonstrate that the point mutation at arginine 451 and a nonsense mutation at aspartate 396 of neuroligin-3 and-4 (NL3 and NL4), respectively, result in intracellular retention of the mutant proteins. Over-expression of wild-type NL3 and NL4 proteins in hippocampal neurons stimulates the formation of presynaptic terminals, whereas the disease-associated mutations result in a loss of this synaptic function. Our findings suggest that the previously identified mutations in neuroligin genes are likely to be relevant for the neuro-developmental defects in autism-spectrum disorders and mental retardation since they impair the function of a synaptic cell adhesion molecule.
Biological Psychiatry, 2010
We created the FAST (Flexible Accelerated STOP TetO-knockin) system, an efficient method for mani... more We created the FAST (Flexible Accelerated STOP TetO-knockin) system, an efficient method for manipulating gene expression in vivo to rapidly screen animal models of disease. A single gene targeting event yields 2 distinct knockin mice-STOP-tetO and tetO knockin-which permit generation of multiple strains with variable expression patterns: 1) knockout, 2) Cre-mediated rescue; 3) tTA-mediated misexpression; 4) tTA-mediated overexpression; and 5) tTS-mediated conditional knockout/knockdown. Using the FAST system, multiple gain-and loss-of-function strains can therefore be generated on a timescale not previously achievable. These strains can then be screened for clinically-relevant abnormalities. We demonstrate the flexibility and broad applicability of the FAST system by targeting several genes encoding proteins implicated in neuropsychiatric disorders: Mlc1, Neuroligin 3, the serotonin 1A receptor, and the serotonin 1B receptor. Keywords genetics; gene targeting; animal model; mouse; conditional modulation of gene expression; developmental change Gain-of-function and loss-of-function studies are commonly used to examine gene function in vivo, particularly in attempts to model human disease in animals. Developing animal models of disease is key to the process of elucidating neuropsychiatric disease pathophysiology, in turn leading to drug discovery and translation to patient populations.
Advances in Experimental Medicine and Biology, 2012
Protected habitats include rocky coasts, kelp forests, coral reefs, sea grass beds, estuarine hab... more Protected habitats include rocky coasts, kelp forests, coral reefs, sea grass beds, estuarine habitats, hard and soft bottom habitats, segments of whale migration routes, and shipwrecks. Because of considerable differences in settings, resources, and threats, each marine sanctuary has a tailored management plan. Conservation, education, research, monitoring and enforcement programs vary accordingly. The integration of these programs is fundamental to marine protected area management. The Marine Sanctuaries Conservation Series reflects and supports this integration by providing a forum for publication and discussion of the complex issues currently facing the National Marine Sanctuary Program. Topics of published reports vary substantially and may include descriptions of educational programs, discussions on resource management issues, and results of scientific research and monitoring projects. The series facilitates integration of natural sciences, socioeconomic and cultural sciences, education, and policy development to accomplish the diverse needs of NOAA's resource protection mandate.
International Journal of Audiology, Aug 8, 2017
To assess the utility of noise cancelation earphones (NCE) in audiometric evaluations. Degree of ... more To assess the utility of noise cancelation earphones (NCE) in audiometric evaluations. Degree of noise reduction of Bose QuietComfort 15 NCE was assessed through probe-microphone measures and sound-field audiometry. Occlusion effects from NCE were assessed for potential effects on bone-conduction thresholds. Twenty participants were tested to determine average occlusion effect values during bone-conduction testing with and without NCE. Noise reduction values of the NCE were assessed on a single subject through probe-microphone measures and sound-field testing. NCE sufficiently reduced ambient noise to levels acceptable for air-conduction testing as well as for bone-conduction testing for most patients when adding minimal adjustment to acceptable levels as outlined by the ANSI S3.1-1999 standard. In addition, NCE did not create a clinically significant change in the occlusion effect for bone-conduction testing. NCE placed over insert earphones provide a sound pressure level at the tympanic membrane that is below ANSI standards for routine air-conduction testing and result in sufficient ambient noise reduction for bone-conduction testing with most patients. There is no clinically significant occlusion effect from NCE during routine bone-conduction audiometry. These findings support the utility of using NCE for offsite audiometric testing.
Journal of the Acoustical Society of America, Jul 1, 2015
Veterinary Medicine and Science
The United States military employs multipurpose canines as force multipliers. A newly developed b... more The United States military employs multipurpose canines as force multipliers. A newly developed baseline audiology program applicable to noise effects on the hearing threshold for these dogs has just been developed by the University of Cincinnati FETCHLAB using brainstem auditory evoked potentials to detect estimated threshold shifts in this population. Dogs that are routinely deployed are subject to consistent exposure to noise in the field. Few investigations have focused on the effects of transport noise on the auditory system in multipurpose dogs. The consequence of these dogs having a significant hearing threshold shift is a failure of the dog to properly respond to voice commands and to miss critical acoustic cues while on target. This chapter specifically discusses the baseline protocol for audiological testing of special operations’ multipurpose canines related to helicopter transport.
Journal of Veterinary Behavior
Bulletin of the American Physical Society, 2017
Submitted for the NEF17 Meeting of The American Physical Society Global warming impact on low fre... more Submitted for the NEF17 Meeting of The American Physical Society Global warming impact on low frequency sound transmission in the ocean-Jurassic acoustics here we come. DAVID BROWNING, PETER HERSTEIN, Browning Biotech, PETER SCHEIFELE, Fetch Lab, Univ. of Cincinnati-Amazingly, 2.4 MILLION pounds of carbon dioxide are ejected into the atmosphere every SECOND, about a quarter of which is absorbed into the oceans of the world. This results in ocean acidification, which negatively impacts the boron chemical reaction principally responsible for low frequency sound absorption in seawater, hence low frequency sound transmission improves. Already there is a measurable decrease in ocean surface pH and if this continues and migrates throughout the water column it is projected that the sound transmission will eventually become similar to that in the high CO2 Jurassic Age of the distant past.
The Journal of the Acoustical Society of America, 2017
Asian Small-Clawed Otters (Amblonyx cinerea) are small creatures found in many areas of southern ... more Asian Small-Clawed Otters (Amblonyx cinerea) are small creatures found in many areas of southern and southeastern Asia, as well as Indonesia. They mate for life and communicate with one another using a wide variety of vocalizations from long, drawn out cries, to small yipping noises. The vocalizations of these otters were recorded in the back up area of the Newport Aquarium and Wellington Zoo and analyzed in Spectra Plus to determine the spectrogram contour of each vocalization. The goal of this research was to gather and compile data on the way the Asian Small-Clawed Otter communicates in order to better understand the way these animals live. These data will now be used to perform vocal clustering and classification using a Hidden Markov model, spectral moments, and geometric contour classification (Lofft, 2009; Williamson, 2014).
OCEANS '88. 'A Partnership of Marine Interests'. Proceedings
ABSTRACT The attenuation of low-frequency sound in the sea increases with pH. In most ocean areas... more ABSTRACT The attenuation of low-frequency sound in the sea increases with pH. In most ocean areas, the value of pH changes significantly with depth, and must be included in an accurate attenuation computation. Previous determinations of other parameters, such as surface loss, which were based on older attenuation formulas, are therefore inaccurate. An analysis of a previously reported surface loss formula indicates that the predicted values are too high
The Journal of the Acoustical Society of America, 2014
The principal mechanism for low frequency absorption in seawater is a boron reaction that is pH d... more The principal mechanism for low frequency absorption in seawater is a boron reaction that is pH dependent; the lower the pH, the lower the absorption. Twenty seven years ago, Mellen et al. [J. Acoust. Soc. Am. 82, S30 (1987)] computed the low frequency sound absorption for the Arctic Ocean. Since the time the carbon dioxide (CO2) level in the atmosphere has been continually increasing. Experts predict that the resulting ocean acidification may increase by up to 170% this century. Acoustically, the Arctic Ocean is most sensitive to rapid change not only because the cold water readily absorbs CO2, but also because the sound channel axis is at or near the surface. The range of reduction in the low frequency sound absorption is presented based on possible future acidification scenarios, mindful that this is just one component of a complex evolution that is occurring in the Arctic.
The "fog-bound" coast of New England has posed a hazard to all forms of transportation ... more The "fog-bound" coast of New England has posed a hazard to all forms of transportation for centuries, yet relatively little study, especially in recent times, has been done on the physics of fog. The singular study of sound propagation, conducted in 1959, found no apparent increase over the normal frequency dependent absorption in air. However, a recent text (W. Binhua, SEA FOG, Springer-Verlag, 1985) indicates that this was only a moderate fog and not the much more intense ("killer") fogs. For these the aggregaton of water droplets may lead to increased low frequency absorption thus reducing the effective range of existing foghorns. On land, advances in light scattering might be applied to provide a simple mobile means (mounted on a police car, for example) to quickly identify extreme conditions and take precautionary action on the highway to prevent the horrific multi-car collisions that can occur.
Ionic relaxations involving magnesium sulfate, boric acid and magnesium, carbonate are known to a... more Ionic relaxations involving magnesium sulfate, boric acid and magnesium, carbonate are known to account for sound absorption in sea water. Regional dependence of sound absorption has been shown to be caused mainly by the pH-dependence of the boric acid relaxation. In the nominal sea water pH range 7.7-8.3, the magnitude can be expected to vary over neatly a factor of four at lower frequencies. Since pH varies with depth as well as locations, net absorption will also depend on the ray paths. An interim global model, based on published pH contours for the World Ocean, has been proposed. Correction factors for the sound-channel, convergence-zone and surface-duct modes are provided by individual contour charts. However, if there is no clearly dominant propagation mode, integrations of loss over all ray paths may be indicated, which requires profiles of correction-factor vs depth. Part-2 reports analysis of pH data obtained during the GEOSECS expeditions 1972-1978. The purpose is to chec...
Acoustics Research Letters Online, 2003
Whitetail deer (Odocileus virginianus) are common across much of the United States. In areas wher... more Whitetail deer (Odocileus virginianus) are common across much of the United States. In areas where deer populations are prevalent, there is a propensity for interactions with automobiles. Various methods have been suggested for reducing the number of automobile-deer collisions, including acoustic devices such as deer whistles. Six different whistles were tested in the laboratory and on motor vehicles. Frequencies and intensities generated by the devices when mounted on vehicles at speeds from 30-45 mile per hour were determined. The primary frequency of operation of the closed end whistles on vehicles was determined to be approximately 3.3 kHz with little variation with changes in air pressure. Open-end whistles had a primary frequency of about 12 kHz, with significant variation with changes in air pressure. The best frequency range of hearing for whitetail deer appears to be between 2 and 6 kHz. The effectiveness of these devices was concluded based on the comparison of the acoustical attributes of the devices to deer hearing thresholds and acoustic behavior.
Uploads
Papers by peter scheifele