bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and Evaluation of a TG/DTA/Raman System
Authors: Collins Wendy J. , DuBois Corey , Cambron R. Thomas , Redman-Furey Nancy L. , Bigalow Kern Adrienne S.
Published: September 2009

Modification of a commercially available TG/DTA instrument enabled development of a working TG/DTA/Raman system. The TG/DTA was modified by replacing a portion of the furnace wall above the sample and reference holders with a double layer insulated quartz window. The quartz window provided ready access for Raman spectroscopy, enabling simultaneous collection of TGA, DTA, and Raman data during thermal analytical experiments. Insertion of the quartz glass window did not impact TGA or DTA performance as demonstrated by the comparison of baseline drift and temperature calibration for modified and unmodified furnaces.
The Role of TGA-DTA in the Initial Evaluation of the Solid State Forms for Pharmaceutical New Chemical Entities, Part 1: Evaluation of Pure Forms
Authors: Redman-Furey Nancy L. , Dicks Michael L. , Godlweski Jane , Vaughn Dana C. , Collins Wendy J.
Published: September 2009

TGA-DTA plays a central role in the strategy outlined for early evaluation of the solid state forms available to pharmaceutical new chemical entities. At this early stage of development, compound and time are typically at a premium, so a successful strategy requires making the best possible use of the materials and time available. In addition, because of time and compound limitations, the goal of a solid state investigation is focused upon early stage objectives rather than development of a complete understanding of all available solid state forms. The TGA-DTA is well suited to addressing these needs.
Characterization of Modified Carbon Nanotubes by TG-MS and Pyrolysis-GC/MS
Authors: Lineberry Quentin , Buthelezi Thandi , Pan Wei-Ping
Published: September 2009

Two evolved gas analysis techniques were used to study modified single-wall carbon nanotubes (SWNTs). These techniques were thermogravimetry-mass spectrometry (TG-MS) and pyrolysis-gas chromatography/mass spectrometry (pyrolysis-GC/MS). Increased weight loss was exhibited in the modified SWNTs below 800°C, which was attributed to the addition of methoxide introduced during the modification. The localized environments of the SWNT provide bonding sites of varying strength that results in the staged evolution of the methoxide masses. The continued evolution of methoxide related masses is a result of the variations in the localized environments of the SWNTs, including the curved ends and various other possible sites along the sidewalls. However, once all the modifications have been removed, the overall structure of the SWNT still remains as intact as the pristine sample as indicated by the slope of the weight loss at higher temperatures.
Characterization Of Epoxy Curing Using High Heating Rate DSC
Authors: Bilyeu Bryan , Brostow Witold , Menard Kevin P.
Published: September 2009

Two common techniques to characterize the curing reaction of an epoxy as a function of time and temperature are heat of reaction and the shift in glass transition. These techniques can both be performed by Differential Scanning Calorimetry. However, both techniques share a common limitation, namely that the curing exotherm may occur during the ramp to isothermal temperature or may overlap with the glass transition event. Since the curing reaction and thus the exotherm is a kinetic event, it is rate dependent. As faster rates are used, the scan can be completed before the onset of the reaction. In an isothermal heat of reaction study, the material can be brought to temperature fast enough that the curing reaction does not begin until it is at temperature. Also, since the glass transition can be measured at high scanning rates, it can be measured before the curing reaction begins. At 100°C/min, the two overlapping events are separated, whereas at 200°C/min, the curing does not occur in the temperature range studied. The glass transition temperature can be measured without affecting the degree of cure, or the exotherm can be shifted to separate it from the glass transition for accurate measurement of enthalpy and the glass transition.
Fast Scan Differential Scanning Calorimetry Distinguishes Melting, Melting-Degradation/Sublimation and Thermal Stability of Drugs
Authors: Riga Alan T. , Golinar Michael , Alexander Kenneth S.
Published: September 2009

In order to establish a structure and property (melting and oxidative or thermal degradation, or both) relationship for a United States Pharmacopeias (USP) set of standard drugs, they were evaluated by fast scan differential scanning calorimetry. A critical problem in characterizing the endothermic melting of a drug is to determine the melting range and if a chemical melts and immediately degrades. The stability of standard drugs is based on a comparison of their thermal properties at widely varying ramp or heating rates from 10 to 100°C/min. A stable crystalline drug has an obvious melting endotherm followed by a stable baseline. An unstable crystalline drug melts and immediately degrades as viewed by a shifting melt endotherm with heating rate. The USP thermally stable standards evaluated in this study include vanillin (melt temperature, (Tm, 80.4°C), acetanilide (Tm, 114°C), acetophenetidin (Tm, 135°C), sulfanilamide (Tm, 165°C), sulfapyridine (Tm, 191°C), and caffeine (Tm, 235°C and Tsublimation, (220°C). In addition to the USP samples a number of commercial and model drugs, like benzoic acid (Tm, 122°C and Tsublimation, (120°C), lidocaine-.HCl and procaine. HCl were also examined. Their melt profiles were ranked as stable or unstable post fusion by the fast scan DSC technique and are reported.
Martensite Transformations and Fatigue Behavior of Nitinol
Authors: Adler P. H. , Allen J. , Lessar J. , Francis R.
Published: September 2009

In addition to excellent biocompatibility and corrosion resistance, the unique flow behavior of NiTi pseudo-elastic alloys renders them ideally suited for several medical device applications utilizing minimally invasive technologies. For example, self-expanding stents are indicated chronic therapies for treatment of a variety of vascular diseases. Long-term device integrity is thus critical with the FDA recommending a minimum 10-year life. Historically, the majority of published fatigue data on NiTi alloys have been generated under strain-controlled conditions using wire or single-diamond cell samples designed to replicate the behavior of the repetitive unit within a stent. Resulting data are then presented on modified Goodman or Soderberg diagrams in order to define regions of acceptable device life. Consistent with their unusual monotonic flow characteristics these alloys are found to exhibit unique cyclic behavior in fatigue: published data clearly demonstrate that increasing mean strain often increases high-cycle fatigue life. This anomalous behavior is generally attributed to any of a number of possible microstructural or mechanical effects associated with the reversible stress-assisted austenite-to-martensite phase transformation. Although the majority of published work has focused on these macroscopic properties in order to characterize and adequately define device life, various efforts are currently underway to better understand the more fundamental metallurgical and mechanical aspects controlling fatigue life in this alloy. Such studies include crack initiation and propagation rates, determining the roles of absolute and relative inherent flow behavior of the transforming structures, mechanical instabilities resulting from the heterogeneous nature of the transformation, latent heat effects during cyclic transformation, as well as the effects of testing frequency, crystallographic texture, grain-shape anisotropy, and stress-state on fatigue life. A review of existing literature delineating these behaviors and current efforts is presented in light of known beneficial effects of transformation plasticity and toughening in enhancing fatigue and fracture properties of a variety of metallic and nonmetallic materials.
Application of Low Plasticity Burnishing (LPB) to Improve the Fatigue Performance of Ti-6Al-4V Femoral Hip Stems
Authors: Hornbach Douglas J. , Prevey Paul S. , Loftus Edmund F.
Published: September 2009

Low plasticity burnishing (LPB) is a surface enhancement method that produces a deep layer of compressive residual stress with minimal cold working and an improved surface finish. Extensive fatigue testing, performed on numerous metal alloys in simulated environmental conditions, demonstrates that LPB significantly improves fatigue strength of highly stressed components. LPB is a flexible process, capable of being implemented on a wide variety of CNC machine tools. A product-specific LPB process was developed and applied to the modular neck taper junction of a Ti-6Al-4V total hip prosthesis (THP). LPB produced a compressive residual stress field with an improved surface finish, which enhanced component fatigue strength and resistance to fretting damage. X-ray diffraction (XRD) residual stress measurements, made before and after LPB application, are shown. High cycle fatigue (HCF) results obtained on LPB-processed hip stems are shown along with baseline data for unprocessed hip stems. HCF tests demonstrate complete elimination of fretting fatigue failures in the LPB processed area of the taper junction and a substantial increase in overall THP fatigue strength.
Comparison of the Corrosion Fatigue Characteristics of 23Mn-21Cr-1Mo Low Nickel, 22Cr-13Ni-5Mn, and 18Cr-14Ni-2.5Mo Stainless Steels
Authors: Roach Michael D. , Williamson R. Scott , Zardiackas Lyle D.
Published: September 2009

The purpose of this study was to evaluate and compare the notched corrosion fatigue (CF) characteristics of a series of stainless steel alloys including 18Cr-14Ni-2.5Mo (ASTM F 138), 22Cr-13Ni-5Mn (ASTM F 1314), and 23Mn-21Cr-1Mo low nickel stainless steel (ASTM F 2229). Evaluation of alloy composition, microstructure, static single cycle mechanical properties, stress corrosion cracking, and smooth sample corrosion fatigue was performed on the same lots of each material in a previous study in our laboratories. Notched CF tensile samples of each alloy were machined using low stress grind techniques to a 2.5 mm notch root diameter (Kt=3.2) and tested at 1 Hz according to ASTM F 1801 in Ringer's solution at 37°C. A minimum of three samples was tested at five tension-tension sinusoidal load levels including a run-out level at 106 cycles. SEM analysis was performed on the fractured surfaces of representative samples of each alloy to characterize and compare the failure mechanisms. Previous evaluation of corrosion fatigue on smooth samples of these alloys found no significant differences in the fracture modes or cycles to failure between the samples run in distilled deionized water and those run in Ringer's solution indicating corrosion fatigue mechanisms were not in effect. However, a significant lowering of fatigue strength was observed for the notched samples of each alloy compared to the smooth samples previously tested. This suggests that even though the notch sensitivity of these alloys under static single cycle conditions has been shown to be acceptable, a notch under dynamic fatigue mechanisms may cause a substantial reduction in strength and implant life. Despite this reduction in fatigue strength, in high strength applications where the implant must be bent during surgery or may be scratched during implantation BioDur 108 proved to be the best alternative. For lower strength applications, 316LS revealed the least fatigue notch sensitivity of any of the alloys tested.
Verification of Strain Level Calculations in Nitinol Fatigue Resistance Predictions
Authors: Pike Kelly
Published: September 2009

A method to confirm FEA strain level predictions was developed for small nitinol-compressive specimens by taking micron magnitude measurements from SEM images. The technique was used to confirm predictions of an earlier report of fatigue resistance.
Prediction of Failure in Existing Heart Valve Designs
Authors: Koppenhoefer Kyle C. , Crompton Jeffrey S. , Dydo James R.
Published: September 2009

Artificial heart valves must be designed to survive greater than 109 cycles over 40 years of operation. Thus, fatigue represents one of the primary driving forces for safe operation of these devices. The inability to maintain the long term performance of critical devices in the future may lead to catastrophic failure and patient loss of life. The Bjork-Shiley convexo-concave (BSCC) heart valve provides an excellent case study in heart valve design. Approximately 86 000 valves were implanted from 1979 to 1987 and approximately 1 % of the valves experienced failure due to fatigue. Failures of this type are likely to yield a 70 % mortality rate in patients. To understand the conditions that produced failure, a detailed engineering assessment was conducted to determine valve designs, manufacturing processes, and physiologically related loading conditions that gave rise to an increased risk of failure. The material used in constructing the valve, Haynes 25, possesses good long crack threshold fatigue properties (ΔKth=4.5 MPa√m). However, continued operation of the valves produced cracking under certain physiological circumstances. These assessments indicate that a small subset of valves may operate under conditions that are close to the boundary between continued safe operation and catastrophic failure. These findings should be considered when using materials with inherently lower threshold fatigue properties. Crack growth data show that Nitinol has a threshold stress intensity factor ≈2 MPa√m, or less than half that of Haynes 25. Thus, current heart valve designs that use Nitinol should incorporate lessons learned from analyses of the BSCC heart valve to assess the likelihood of premature valve failure due to repeated loading.
Experimental Studies of NiTi Self-Expanding Stent Designs
Authors: Eaton-Evans J. , Dulieu-Barton J. M. , Little E. G. , Brown I. A.
Published: September 2009

Preliminary investigations to apply thermoelastic stress analysis (TSA) to Nitinol selfexpanding stents are described. Tests conducted at high resolution indicated that a viable thermoelastic signal can be obtained from the fine stent structure. It is shown that it is possible to digitally compensate for errors arising from motion at this high resolution. High variability in Nitinol's material properties with stress and temperature result in a complex thermoelastic response. Correction strategies are proposed to account for variation in material properties and to minimize errors due to thermal variations in order to derive calibration factors for the austenite and martensite material phases. The greatest challenge is identified as calibrating the thermoelastic response from the radially loaded stent structure where it is likely the material is highly inhomogeneous.
FDA Recommendations for Nitinol Stent and Endovascular Graft Fatigue Characterization and Fracture Reporting
Authors: Cavanaugh Kenneth J. , Holt Vivianne M. , Goode Jennifer L. , Anderson Evan
Published: September 2009

Intravascular stents and endovascular stent-grafts provide a minimally invasive option for treating vascular disease and injury. Medical device manufacturers typically conduct radial pulsatile fatigue testing of intravascular stents and endovascular grafts to demonstrate that these devices will maintain their durability for ten years of implant life. While they are useful indicators of device performance, these test regimens do not always predict device durability in the clinical setting with perfect accuracy. In this paper, we address some of the common issues that should be considered in the design of fatigue tests, including appropriate sample sizes for fatigue testing, sample selection, loading conditions, and test setup issues. We also discuss finite element analysis of long-term cyclic fatigue. In addition, we describe appropriate methods for reporting the incidence of stent fractures after implantation. Our goals are to assist manufacturers and test laboratories in refining their in vitro fatigue testing methods to allow more accurate prediction of clinical device fractures, and to maximize the amount of useful data contained in clinical fracture reports.
Modeling the Heat, Air, and Moisture Response of Building Envelopes: What Material Properties are Needed, How Trustful Are the Predictions?
Authors: Hens Hugo S. L. C.
Published: September 2009

The physical models which form the basis for the different software tools used to predict heat, air, and moisture response of building envelopes seem quite diverse. For example, various “potentials” are used, and each individual potential demands apparently different properties. Anyhow, when digging into the physics and confronting the theory with what is measurable, then an array of eight basic material characteristics appear, all backed by an experimental rationale. Adapting that array to the potentials in use is not a question of creating new properties but of implementing the basic ones into potential-adapted expressions. A different problem, however, is that these basic properties are macroscopic in nature, i.e., represent the complexity of a material at the micro-scale by one single “average” number. That introduces restrictions as to the use of the property values measured experimentally. Hence, those restrictions are typically mixed up with the inability of the actual software packages to represent reality in full detail. Too many times, assumed incorrectness of the property values are blamed for causing the differences found between the predicted and real heat, air, moisture response of envelope parts. That inability, instead, should convince researchers and building engineers that the way to gain a well balanced understanding of the heat, air, and moisture response of envelopes is not by modeling only but by combining modeling with testing and field experience.
Effects of Drying Conditions, Phase Transformations, and Carbonation Reactions on Measurements of Sorption Isotherms of Building Materials
Authors: Wilkes Kenneth E. , Atchley Jerry A. , Childs Phillip W. , Desjarlais Andre
Published: September 2009

The sorption isotherm is one of the basic material properties used in hygrothermal modeling of building envelope performance. Measurement of this properly is deceptively simple. Specimens are first dried and then exposed to a series of higher relative humidities to develop a curve of moisture content versus relative humidity at constant temperature. This paper discusses some confounding effects that we have observed while performing measurements on a number of common building materials. Materials studied included gypsum products, wood and wood products, and cementitious materials.
Determination of Equilibrium Moisture Content of Building Materials: Some Practical Difficulties
Authors: Kumaran Mavinkal K , Mukhopadhyaya Phalguni , Normandin Nicole
Published: September 2009

Though the definition of equilibrium moisture content of porous materials is straightforward from the point of view of equilibrium thermodynamics, experimental determination of this quantity may not always be easy. Many factors play roles from an experimentalist's point of view. Hysteresis, the reference dry state, the initial moisture content, the history of the test specimen, the size of the test specimen, the drying technique, and drying temperature—all influence the value that is arrived at by an experimentalist. This paper reports results from several series of measurements on gypsum board, eastern white pine, aerated concrete, and calcium silicate brick using the ASTM Standard C 1498 in the hygroscopic ranges and pressure plate techniques above the hygroscopic range of equilibrium moisture content. These results show the ambiguities that may surround the experimental definition of equilibrium moisture content. The results presented in the paper demand a few refinements in the existing ASTM Standard C 1498 as well as in the procedure that is used in the pressure plate method. The paper proposes a few refinements for both. The need for the development of an ASTM standard for the pressure plate technique is identified.
Interlaboratory Comparison of the Thickness of the Destroyed Surface Layer of Closed-cell Foam Insulation Specimens
Authors: Stovall Therese K.
Published: September 2009

The preparation of closed-cell foam insulation test specimens can affect the results of a number of hygrothermal property measurements. In particular, the thickness of the destroyed surface layer affects the measurement of gas diffusion coefficients and thermal conductivity. Multiple specimen preparation methods are in use, as well as multiple methods to measure the thickness of the destroyed surface layer. A ruggedness test, including an interlaboratory comparison, was conducted by an ASTM technical committee to examine the variations due to both of these factors. The results are important in understanding the likely range in values for each preparation technique. The results also demonstrate a sensitivity to the measurement technique.
Temporary Viscosity Loss and its Relationship to Journal Bearing Performance
Authors: McMillan Michael L. , Murphy Chester K.
Published: September 2009

To determine the correlation between journal bearing performance and viscosity loss in a capillary, viscosities of eleven base oil-polymer blends were measured in a high-shear, pressurized capillary viscometer (High-Shear Capillary Viscometer, HSCV) at shear rates from 100 to nearly 1 000 000 s-1. Although low-shear kinematic viscosities do not predict bearing performance differences found by Rosenberg with the same oil blends, HSCV viscosities at shear rates near 500 000 s-1 correlate well with the bearing performance data. Differences among polymers are strongly related to molecular weight.
Oil Viscosity at High Shear Rates Measured by a Floating Journal Bearing
Authors: DenHerder M. J. , Harnach J. W. , Wester D. W.
Published: September 2009

A high shear rate, 1 ×106sec-1, viscometer uses a commercial tool post grinder fitted with a three-bearing internal type spindle to drive a one inch (2.54 cm) diameter journal at 10,400 rpm. A 0.0005 inch (0.00127 cm) thick fluid film between the journal and a floating bearing transfers a torque to the bearing. An oil pump built into the journal minimizes temperature and oil flow problems. Torques measured with Newtonian oils provide a torqueviscosity calibration that is used to convert torques of non-Newtonian oils to viscosities. Two bearings are used; one measures viscosities from 1.6 to 5 cp, the other, 3.4 to 10 cp. Less than one hour is required to measure an oil's viscosity over the range of either bearing at temperatures up to 370°F (188°C). This apparatus measures viscosities at the shear rate and temperatures of critical high shear sections of operating engines and hydraulic systems. The differences between ASTM D 445 kinematic viscosities and viscosities at 1x106sec-1 shear rate were determined for multigraded oils formulated with a number of polymeric viscosity index improvers. At the high shear rate the percent loss of the kinematic viscosity contributed by the polymers increases as temperature decreases.
Development of an ASTM Method for Measurement of the Extensional Viscosity of Agricultural Spray Solutions
Authors: Dexter Robin W.
Published: September 2009

Polymeric drift control agents are used to modify the droplet size distribution of pesticide sprays. These agents function by increasing the extensional viscosity of the spray liquid, enabling it to resist disruption as it emerges from the spray nozzle, usually leading to an increase in the median droplet diameter of the spray droplets. Extensional viscosity is often the most important physical property controlling the spray droplet size, especially when soluble polymers are present, but methods available for measurement of extensional viscosity of dilute solutions are complicated and are not generally available. This paper describes a simple, portable apparatus that can detect and quantify a relative extensional viscosity (screen factor) that is useful in evaluating the properties of drift control agents. The apparatus has been used to determine the screen factors of test substances used by the Spray Drift Task Force and to correlate them with independent measurements of extensional viscosity obtained using a Rheometrics RFX Extensional Rheometer. The method has been adopted as ASTM Method E 2408-04, “Relative Extensional Viscosity of Agricultural Spray Tank Mixes.”
Cationic-based Crop Oil Concentrates
Authors: Stridde Howard M. , Elsik Curtis M. , Tann R. Scott
Published: September 2009

For most of six decades, crop oil concentrates (COCs) have been used as important tank mix adjuvants for increased pesticidal penetration. For the past 30 years, cationic surfactants have been known to enhance the bio-efficacy of numerous acid-based herbicides, especially glyphosate. With the advent of glyphosate-tolerant crops, glyphosate has become almost universal in its use. This has led to some issues with weeds hard to control with glyphosate alone. Recently a practice has developed where other herbicides and COC formulations are mixed with glyphosate to address problems with glyphosate-tolerant plants. A field study was conducted to develop a COC containing cationic surfactants that would deliver excellent, stable emulsification of the oil phase and boost the herbicidal activity of both glyphosate and the admixed herbicide. This COC worked very efficiently in a broad range of waters as well as ultra-high electrolyte environments such as ammonium sulfate solutions common to glyphosate applications.
Wind Tunnel Evaluation of Drift Reduction Potential and Spray Characteristics with Drift Retardants at High Operating Pressure
Authors: Guler H. , Zhu H. , Ozkan E. , Derksen R. , Krause C.
Published: September 2009

Although considerable research has been done on effectiveness of drift retardants for many years, answers to some questions are still unclear to applicators. Laboratory tests were conducted to evaluate drift potentials associated with off-target ground and airborne spray deposits discharged with a hollow cone nozzle spraying three different drift retardants at a high operating pressure and various wind velocities in a wind tunnel. Droplet sizes and spray widths were also determined with a laser imaging system and a portable spray patternator. At 1655 kPa pressure and 4.65 L/m flow rate, the volume median diameters of droplets from the hollow cone nozzle discharging spray mixtures containing water only, polyvinyl polymer, nonionic colloidal polymer and polyacrylamide polymer drift retardants were 201, 222, 239, and 210 µm, respectively. The major spray pattern width was not changed after drift retardants were added into the spray carrier. For the wind velocity from 1 to 5 m/s in the wind tunnel, the polyacrylamide drift retardant produced the highest airborne deposit among the three drift retardants, followed by polyvinyl, and then nonionic colloidal. Also, the polyacrylamide drift retardant produced the highest ground drift potential, followed by nonionic colloidal and then polyvinyl. According to the results from this laboratory study, both nonionic colloidal and polyvinyl polymer drift retardants reduced the drift potential compared to the spray carrier containing water only.
Introduction
Authors: Mellon M. G.
Published: September 2009

This bibliography brings up to 1959 the one published by Stillman and Dunlop. In general, the same basis of selection has been followed in this compilation; but in addition to Analytical Chemistry and The Analyst, Analytica Chimica Acta has been covered, because of its connection with the International Union of Pure and Applied Chemistry. The references are not necessarily limited to the use of photoelectric spectrophotometers, as other means of detection are used. A small number of papers deal with ultraviolet measurements, as reagents are being found which make work in this region feasible. Thus far, similar application of reagents to make inorganic systems measurable in the infrared region apparently has found little use. A few references concern substances not in the ionic condition.
Bibliographical Abstracts of Methods for Analysis of Synthetic Detergents
Authors: Harris Jay C.
Published: September 2009

The continued effort to standardize methods for surface active agent analysis has necessitated continuous scrutiny of the literature. Ordinarily a compilation of this kind might be issued at less frequent intervals, but to be of greatest assistance to those working in this field, the abstracts should follow the original literature as closely as possible. Hence though the number of references may be fewer, their availability should outweigh the inconvenience of more frequent preparation. Thorough indexing with the analyst's needs in mind has been continued: Methods have been classified as to type, as have the surface active agents. References have been numbered and lettered to maintain the proper author sequence. The seven abstracts for 1956 in Special Technical Publication 150-A have been renumbered and included to simplify their ready identification. Users of these abstracts are urged to supply corrections or additions so that these abstracts may become complete.
Netrin Participates in the Development of Retinotectal Synaptic Connectivity by Modulating Axon Arborization and Synapse Formation in the Developing Brain
Authors: Manitt Colleen , Nikolakopoulou Angeliki M. , Almario David R. , Nguyen Sarah A. , Cohen-Cory Susana
Published: September 2009

Netrin has been implicated in retinal ganglion cell (RGC) axon pathfinding in a number of species. InXenopus laevis, RGC axons reaching their target in the optic tectum can be repelled by a netrin-1 gradientin vitro, suggesting that netrin may also function in wiring events that follow successful axon pathfinding. Here, we examined the contribution of netrin to RGC axon arborization and synapse formation at the target. Time-lapse confocal microscopy imaging of individual RGC axons coexpressing GFP-synaptobrevin and DsRed in the intactXenopusbrain demonstrated a role for deleted in colorectal cancer (DCC)-mediated netrin signaling. Microinjection of netrin-1 into the tectum induced a rapid and transient increase in presynaptic site addition that resulted in higher presynaptic site density over a 24 h observation period. Moreover, netrin induced dynamic axon branching, increasing branch addition and retraction; a behavior that ultimately increased total branch number. In contrast, microinjection of DCC function-blocking antibodies prevented the increase in presynaptic site number normally observed in control axons as well as the associated increase in branch number and axon arbor growth. Dynamic analysis of axon arbors demonstrated that the effects of anti-DCC on axon morphology and presynaptic connectivity were attributable to a specific decrease in new synapse and branch additions, without affecting the stability of existing synapses and branches. Together, these results indicate that, in the absence of DCC signaling, RGC axons fail to branch and differentiate, and support a novel role for netrin in later phases of retinotectal development.
Overlapping Function ofLmx1aandLmx1bin Anterior Hindbrain Roof Plate Formation and Cerebellar Growth
Authors: Mishima Yuriko , Lindgren Anne G. , Chizhikov Victor V. , Johnson Randy L. , Millen Kathleen J.
Published: September 2009

The roof plate is an organizing center in the dorsal CNS that controls specification and differentiation of adjacent neurons through secretion of the BMP and WNT signaling molecules.Lmx1a, a member of the LIM-homeodomain (LIM-HD) transcription factor family, is expressed in the roof plate and its progenitors at all axial levels of the CNS and is necessary and sufficient for roof plate formation in the spinal cord. In the anterior CNS, however, a residual roof plate develops in the absence ofLmx1a. Lmx1b, another member of the LIM-HD transcription factor family which is highly related toLmx1a, is expressed in the roof plate in the anterior CNS. AlthoughLmx1b-null mice do not show a substantial deficiency in hindbrain roof plate formation,Lmx1a/Lmx1bcompound-null mutants fail to generate hindbrain roof plate. This observation indicates that both genes act in concert to direct normal hindbrain roof plate formation. Since the requirement ofLmx1bfunction for normal isthmic organizer at the mid–hindbrain boundary complicates analysis of a distinct dorsal patterning role of this gene, we also used a conditional knock-out strategy to specifically delete dorsal midlineLmx1bexpression. Phenotypic analysis of single and compound conditional mutants confirmed overlapping roles forLmx1genes in regulating hindbrain roof plate formation and growth and also revealed roles in regulating adjacent cerebellar morphogenesis. Our data provides the first evidence of overlapping function of theLmx1genes during embryonic CNS development.
Intact Long-Term Potentiation but Reduced Connectivity between Neocortical Layer 5 Pyramidal Neurons in a Mouse Model of Rett Syndrome
Authors: Dani Vardhan S. , Nelson Sacha B.
Published: September 2009

Mutations inMECP2cause Rett syndrome and some related forms of mental retardation and autism.Mecp2-null mice exhibit symptoms reminiscent of Rett syndrome including deficits in learning. Previous reports demonstrated impaired long-term potentiation (LTP) in slices of symptomaticMecp2-null mice, and decreased excitatory neurotransmission, but the causal relationship between these phenomena is unclear. Reduced plasticity could lead to altered transmission, or reduced excitatory transmission could alter the ability to induce LTP. To help distinguish these possibilities, we compared LTP induction and baseline synaptic transmission at synapses between layer 5 cortical pyramidal neurons in slices of wild-type andMecp2-null mice. Paired recordings reveal that LTP induction mechanisms are intact inMecp2-null connections, even after the onset of symptoms. However, fewer connections were found inMecp2-null mice and individual connections were weaker. These data suggest that loss of MeCP2 function reduces excitatory synaptic connectivity and that this precedes deficits in plasticity.
Cannabinoid Receptor Activation in the Basolateral Amygdala Blocks the Effects of Stress on the Conditioning and Extinction of Inhibitory Avoidance
Authors: Ganon-Elazar Eti , Akirav Irit
Published: September 2009

Despite the efficacy of behavior therapy for human anxiety disorders, extinction-like treatments require repeated cue exposures and are vulnerable to reversal by a number of environmental factors, particularly stress. The endocannabinoid system has recently emerged as important in the regulation of extinction learning and in the regulation of the hypothalamic–pituitary–adrenal axis. Here, we aimed to examine the involvement of the cannabinoid CB1receptor in the basolateral amygdala (BLA) in inhibitory avoidance (IA) conditioning and extinction and to test whether cannabinoid activation would reverse the effects of stress on these memory processes. The synthetic full agonist of the CB1/CB2receptor WIN55,212-2 [R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-de]-1,4- benzoxazin-6-yl)(1-naphthalenyl) methanone monomethanesulfonate] (5 μg/0.5 μl) microinjected into the BLA had no effect on IA conditioning or extinction by itself. However, microinjecting WIN55,212-2 into the BLA before exposing the rats to a stressor reversed the enhancing effects of the stressor on IA conditioning and its impairing effects on IA extinction. Importantly, WIN55,212-2 microinjected into the BLA reduced stress-induced elevations in corticosterone levels. Control experiments demonstrated the following: (1) the effects of WIN55,212-2 could not be attributed to sensorimotor deficits, because these parameters seemed unchanged by WIN55,212-2 microinjected into the BLA; and (2) the CB1receptor in the BLA is crucially involved in the extinction of IA, because the CB1receptor antagonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide] (6 ng/0.5 μl) microinjected into the BLA significantly blocked extinction. Together, our findings may support a wide therapeutic application for cannabinoids in the treatment of conditions associated with the inappropriate retention of aversive memories and stress-related disorders.
The Spatiotemporal Frequency Tuning of LGN Receptive Field Facilitates Neural Discrimination of Natural Stimuli
Authors: Tan Zhongchao , Yao Haishan
Published: September 2009

The efficient coding hypothesis suggests that the early visual system is optimized to represent stimuli in the natural environment. While it is believed that LGN processing removes the redundant information of natural scenes, it is not clear whether the early visual processing can selectively amplify important signals in natural stimuli to facilitate discrimination. In this study, we examined the functional role of LGN spatiotemporal frequency tuning in the processing of natural scenes. First, we characterized the relationship between spatial and temporal frequency tuning for LGN receptive fields. We found that LGN neurons exhibit inseparable spatiotemporal frequency tuning in a manner consistent with the feature of optimal filters that can maximize information transmission of natural scenes. Second, we analyzed the spatiotemporal power spectrum of natural scenes and found that some frequencies exhibit larger variation in power across different scenes. Interestingly, the preferred frequency of ensemble LGN neurons matches the range of frequencies in which natural power spectrum varies most. Comparison of neural discrimination for natural stimuli and for artificial stimuli with similar mean power spectra but different variation structure showed that the match between LGN tuning and natural spectra variation enhances neural discrimination for natural stimuli. Our results indicate that, in addition to removing redundancy, the spatiotemporal frequency characteristics of LGN neurons can facilitate neural discrimination of natural stimuli.
Nonlinear Spectrotemporal Interactions Underlying Selectivity for Complex Sounds in Auditory Cortex
Authors: Sadagopan Srivatsun , Wang Xiaoqin
Published: September 2009

In the auditory cortex of awake animals, a substantial number of neurons do not respond to pure tones. These neurons have historically been classified as “unresponsive” and even been speculated as being nonauditory. We discovered, however, that many of these neurons in the primary auditory cortex (A1) of awake marmoset monkeys were in fact highly selective for complex sound features. We then investigated how such selectivity might arise from the tone-tuned inputs that these neurons likely receive. We found that these non-tone responsive neurons exhibited nonlinear combination-sensitive responses that require precise spectral and temporal combinations of two tone pips. The nonlinear spectrotemporal maps derived from these neurons were correlated with their selectivity for complex acoustic features. These non-tone responsive and nonlinear neurons were commonly encountered at superficial cortical depths in A1. Our findings demonstrate how temporally and spectrally specific nonlinear integration of putative tone-tuned inputs might underlie a diverse range of high selectivity of A1 neurons in awake animals. We propose that describing A1 neurons with complex response properties in terms of tone-tuned input channels can conceptually unify a wide variety of observed neural selectivity to complex sounds into a lower dimensional description.
Neurofilaments Form a Highly Stable Stationary Cytoskeleton after Reaching a Critical Level in Axons
Authors: Yuan Aidong , Sasaki Takahiro , Rao Mala V. , Kumar Asok , Kanumuri Vivek , Dunlop David S. , Liem Ronald K. , Nixon Ralph A.
Published: September 2009

The ultrastructural view of the axonal cytoskeleton as an extensively cross-linked network of neurofilaments (NFs) and other cytoskeletal polymers contrasts with the dynamic view suggested by axonal transport studies on cytoskeletal elements. Here we reconcile these perspectives by showing that neurons form a large NF network along axons which is unequivocally stationary, metabolically stable, and maintained by NFs and nonfilamentous subunit assemblies undergoing slow transport by intermittent rapid movements and pauses. In mouse primary cortical neurons transfected with EGFP-NFL, formation of this stationary NF network requires a critical level of NFs, which explains its absence in NF-poor developing neurons studied previously. Most NFs at proximal axon regions were in a stationary structure coexisting with a smaller pool of moving EGFP-NFL assemblies that were mainly nonfilamentous. Distally along the same axon, EGFP-labeled NFL was much less abundant, and we detected only short filaments moving bidirectionally by slow transport (rapid movements and pauses) as previously described. In living mice, >25% of radiolabeled newly synthesized NFs remained in optic axons after slowly transported NFs had exited. Retained NF remained fixed over several months in a nonuniform distribution and exhibited exceptionally slow turnover (t1/2>2.5 months), implying that, at steady state, >90% of NFs in mature optic axons comprise the stationary cytoskeleton and <10% are undergoing slow transport. These findings reconcilein vitroandin vivoaxonal transport observations, showing that slowly transported NFs or subunit oligomers are precursors to a highly stable stationary cytoskeletal network that supports mature axons.
Aβ Immunotherapy: Intracerebral Sequestration of Aβ by an Anti-Aβ Monoclonal Antibody 266 with High Affinity to Soluble Aβ
Authors: Yamada Kaoru , Yabuki Chiori , Seubert Peter , Schenk Dale , Hori Yukiko , Ohtsuki Sumio , Terasaki Tetsuya , Hashimoto Tadafumi , Iwatsubo Takeshi
Published: September 2009

Amyloid β (Aβ) immunotherapy is emerging as a promising disease-modifying therapy for Alzheimer's disease, although the precise mechanisms whereby anti-Aβ antibodies act against amyloid deposition and cognitive deficits remain elusive. To test the “peripheral sink” theory, which postulates that the effects of anti-Aβ antibodies in the systemic circulation are to promote the Aβ efflux from brain to blood, we studied the clearance of125I-Aβ1-40microinjected into mouse brains after intraperitoneal administration of an anti-Aβ monoclonal antibody 266.125I-Aβ1-40was rapidly eliminated from brains with a half-life of ∼30 min in control mice, whereas 266 significantly retarded the elimination of Aβ, presumably due to formation of Aβ-antibody complex in brains. Administration of 266 to APP transgenic mice increased the levels of monomer Aβ species in an antibody-bound form, without affecting that of total Aβ. We propose a novel mechanism of Aβ immunotherapy by the class of anti-Aβ antibodies that preferentially bind soluble Aβ, i.e., intracerebral, rather than peripheral, sequestration of soluble, monomer form of Aβ, thereby preventing the accumulation of multimeric toxic Aβ species in brains.
Atoh1-Lineal Neurons Are Required for Hearing and for the Survival of Neurons in the Spiral Ganglion and Brainstem Accessory Auditory Nuclei
Authors: Maricich Stephen M. , Xia Anping , Mathes Erin L. , Wang Vincent Y. , Oghalai John S. , Fritzsch Bernd , Zoghbi Huda Y.
Published: September 2009

Atoh1is a basic helix–loop–helix transcription factor necessary for the specification of inner ear hair cells and central auditory system neurons derived from the rhombic lip. We used theCre–loxPsystem and twoCre-driver lines (Egr2CreandHoxb1Cre) to deleteAtoh1from different regions of the cochlear nucleus (CN) and accessory auditory nuclei (AAN). AdultAtoh1-conditional knock-out mice (Atoh1CKO) are behaviorally deaf, have diminished auditory brainstem evoked responses, and have disrupted CN and AAN morphology and connectivity. In addition,Egr2; Atoh1CKOmice lose spiral ganglion neurons in the cochlea and AAN neurons during the first 3 d of life, revealing a novel critical period in the development of these neurons. These new mouse models of predominantly central deafness illuminate the importance of the CN for support of a subset of peripheral and central auditory neurons.
Multiple Transcriptional Mechanisms Control Ptf1a Levels during Neural Development Including Autoregulation by the PTF1-J Complex
Authors: Meredith David M. , Masui Toshihiko , Swift Galvin H. , MacDonald Raymond J. , Johnson Jane E.
Published: September 2009

Ptf1a, along with an E protein and Rbpj, forms the transcription factor complex PTF1-J that is essential for proper specification of inhibitory neurons in the spinal cord, retina, and cerebellum. Here we show that two highly conserved noncoding genomic regions, a distal 2.3 kb sequence located 13.4 kb 5′ and a 12.4 kb sequence located immediately 3′ of thePtf1acoding region, have distinct activity in controllingPtf1aexpression in all of these domains. The 5′ 2.3 kb sequence functions as an autoregulatory element and directs reporter gene expression to allPtf1adomains in the developing nervous system. The autoregulatory activity of this element was demonstrated by binding of the PTF1-J complexin vitro, Ptf1a localization to this genomic regionin vivo, and thein vivorequirement of Ptf1a for the activity of the regulatory element in transgenic mice. In contrast, the 12.4 kb 3′ regulatory region does not contain any conserved PTF1 sites, and its expression in transgenic mice is independent of Ptf1a. Thus, regulatory information for initiation ofPtf1aexpression in the developing nervous system is located within the 12.4 kb sequence 3′ of thePtf1agene. Together, these results identify multiple transcriptional mechanisms that control Ptf1a levels, one modulating levels by autoregulation through the PTF1-J complex, and the other a Ptf1a-independent mechanism for initial activation.
Spontaneous Glial Calcium Waves in the Retina Develop over Early Adulthood
Authors: Kurth-Nelson Zeb L. , Mishra Anusha , Newman Eric A.
Published: September 2009

Intercellular glial Ca2+waves constitute a signaling pathway between glial cells. Artificial stimuli have previously been used to evoke these waves, and their physiological significance has been questioned. We report here that Ca2+waves occur spontaneously in rat retinal glial cells, both in the isolated retina andin vivo. These spontaneous waves are propagated by ATP release. In the isolated retina, suramin (P2 receptor antagonist) reduces the frequency of spontaneous wave generation by 53%, and apyrase (ATP-hydrolyzing enzyme) reduces frequency by 95–100%. Luciferin-luciferase chemiluminescence reveals waves of ATP matching the spontaneous Ca2+waves, indicating that ATP release occurs as spontaneous Ca2+waves are generated. Wave generation also depends on age. Spontaneous wave frequency rises from 0.27 to 1.0 per minute per mm2, as rats age from 20 to 120 d. The sensitivity of glia to ATP does not increase with age, but the ATP released by evoked waves is 31% greater in 120-d-old than in 20-d-old rats, suggesting that increased ATP release in older animals could account for the higher frequency of wave generation. Simultaneous imaging of glial Ca2+and arterioles in the isolated retina demonstrates that spontaneous waves alter vessel diameter, implying that spontaneous waves may have a significant impact on retinal physiology. Spontaneous intercellular glial Ca2+waves also occur in the retinain vivo, with frequency, speed, and diameter similar to the isolated retina. Increased spontaneous wave occurrence with age suggests that wave generation may be related to retinal pathology.