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LIM-domain containing transcription factors (LIM-TFs) are conserved factors important for embryogenesis. The specificity of these factors in transcriptional regulation is conferred by the complexes that they form with other proteins such as LIM-domain-binding (Ldb) proteins and LIM-domain only (LMO) proteins. Unlike LIM-TFs, these proteins do not bind DNA directly. LMO proteins are negative regulators of LIM-TFs and function by competing with LIM-TFs for binding to Ldb's. Although the LIM-TF Lmx1a is expressed in the developing mouse hindbrain, which provides many of the extrinsic signals for inner ear formation, conditional knock-out embryos of both sexes show that the inner ear source of Lmx1a is the major contributor of ear patterning. In addition, we have found that the reciprocal interaction between Lmx1a and Lmo4 (a LMO protein within the inner ear) mediates the formation of both vestibular and auditory structures. Lmo4 negatively regulates Lmx1a to form the three sensory cristae, the anterior semicircular canal, and the shape of the utricle in the vestibule. Furthermore, this negative regulation blocks ectopic sensory formation in the cochlea. In contrast, Lmx1a negatively regulates Lmo4 in mediating epithelial resorption of the canal pouch, which gives rise to the anterior and posterior semicircular canals. We also found that Lmx1a is independently required for the formation of the endolymphatic duct and hair cells in the basal cochlear region.SIGNIFICANCE STATEMENT The mammalian inner ear is a structurally complex organ responsible for detecting sound and maintaining balance. Failure to form the intricate 3D structure of this organ properly during development most likely will result in sensory deficits on some level. Here, we provide genetic evidence that a transcription factor, Lmx1a, interacts with its negative regulator, Lmo4, to pattern various vestibular and auditory components of the mammalian inner ear. Identifying these key molecules that mediate formation of this important sensory organ will be helpful for designing strategies and therapeutics to alleviate hearing loss and balance disorders.

Recent studies have demonstrated the importance of R- spondins, a novel family of secreted proteins, in canonical Wnt signaling and FGF signaling, two pathways that play significant roles in the development of the cochlea, the hearing organ. Cochlear development requires several events including growth, proliferation and cell fate specification. Furthermore, normal cellular patterning in the cochlea, the organ of Corti, is crucial for auditory function as any patterning defects result in hearing deficit. R- spondins (Rspo) consist of four members in mammals encoded by separate genes. To begin to investigate a possible role in cochlear development, the expression of all Rspo members was assayed at the time of mechanosensory hair cell differentiation. Rspo2 and Rspo3 were detected by PCR but not Rspo1 or Rspo4. The role of Rspo2 in the development of the mouse cochlea was investigated in this study by examining the Rspo2-/- mice. Within the organ of Corti, a single row of inner hair cells and three rows of outer hair cells extend along the basal-to-apical axis of the cochlea. Every sensory hair cell is separated from the next by an intervening non- sensory supporting cell resulting in an invariant mosaic. In the Rspo2 mutant cochleae, there was an extra row of outer hair cells along with an extra row of support cells in the apical half of the cochlea. These data suggest that R-spondin2 is involved in cell fate determination in the mammalian cochlea

Canonical Wnt/β-catenin signaling has been implicated in multiple developmental events including the regulation of proliferation, cell fate, and differentiation. In the inner ear, Wnt/β-catenin signaling is required from the earliest stages of otic placode specification through the formation of the mature cochlea. Within the avian inner ear, the basilar papilla (BP), many Wnt pathway components are expressed throughout development. Here, using reporter constructs for Wnt/β-catenin signaling, we show that this pathway is active throughout the BP (E6-E14) in both hair cells (HCs) and supporting cells. To characterize the role of Wnt/β-catenin activity in developing HCs, we performed gain- and loss-of-function experiments in vitro and in vivo in the chick BP and zebrafish lateral line systems, respectively. Pharmacological inhibition of Wnt signaling in the BP and lateral line neuromasts during the periods of proliferation and HC differentiation resulted in reduced proliferation and decreased HC formation. Conversely, pharmacological activation of this pathway significantly increased the number of HCs in the lateral line and BP. Results demonstrated that this increase was the result of up-regulated cell proliferation within the Sox2-positive cells of the prosensory domains. Furthermore, Wnt/β-catenin activation resulted in enhanced HC regeneration in the zebrafish lateral line following aminoglycoside-induced HC loss. Combined, our data suggest that Wnt/β-catenin signaling specifies the number of cells within the prosensory domain and subsequently the number of HCs. This ability to induce proliferation suggests that the modulation of Wnt/β-catenin signaling could play an important role in therapeutic HC regeneration. © 2013 Wiley Periodicals, Inc. Develop Neurobiol 74: 438–456, 2014

Background: In the cochlea, patterning of the organ of Corti is tightly regulated to produce a single row of sound-detecting inner hair cells and three rows of outer hair cells, which amplify and refine the signal. The recently identified R-Spondin family of signaling molecules usually act as co-activators of Wnt signaling; it is thought that they regulate turnover of Wnt receptors at the membrane. We sought to test whether R-Spondins function in the developing cochlea. Results: Expression analysis of all four members of the R-Spondin family showed that only R-Spondin2 (Rspo2) is expressed in the cochlea during development of the sensory epithelium. Examination of an Rspo2−/− mouse showed that loss of Rspo2 results in an additional single row of outer hair cells and disruption of peripheral innervation pattern. Addition of Rspo2 recombinant protein to organotypic cochlear cultures resulted in a small but significant decrease in the number of outer hair cells. Conclusions: Rspo2 is required to limit the number of outer hair cells to three rows and for optimal arrangement of peripheral nerve fibers. The Rspo2 gain- and loss-of-function studies show that in the ear, Rspo2 function is not consistent with its assigned role as a Wnt potentiator. Developmental Dynamics 242:179–188, 2013. © 2012 Wiley Periodicals, Inc.

This paper describes new target interrogation and terminal ballistic loading and response models for partial impacts between tumbling long rod penetrators and spaced plate targets. The partial impact rod response algorithms differentiate full impacts from overlapping and overlaying partial impact geometries. For a partial impact, existing full impact penetration models are applied to just the portion of the rod that engages the plate to determine its immediate post-impact linear and angular momentum vectors and its integrity (shattered, shear fracture, bent, etc.). The unengaged portions of the rod are presumed to momentarily retain their pre-impact momentum vectors. The immediate post-impact velocity differentials between the engaged and unengaged portions of the rod are used to determine if the rod fractures or deforms. Momentum conservation routines are applied to determine the final post-impact linear and angular momentum vectors for the combined rod or fractured rod pieces. A plastic shear wave model is used to compute the associated rod deformation and shape change. Sample model predictions are compared with numerical simulation results to confirm the reasonableness of the model and its underlying assumptions. 2003 Elsevier Ltd. All rights reserved.

This paper describes experiments to record deformation profiles versus time in metallic rods subjected to transverse ballistic impacts. Rod materials included a tungsten alloy, four alloys of steel, titanium, and copper. The deformation profiles were analyzed to determine time resolved transverse plastic deformation wave speeds in all the rod materials and to estimate effective fracture shear strains in some of the materials. These material parameters are key elements in an analytical model to estimate deformations and failure in long rod penetrators subjected to transverse loads arising from non-ideal plate penetration geometries (yaw and obliquity). The rod materials were also subjected to tensile tests and Taylor anvil impact tests to measure static tensile and dynamic compressive strengths and longitudinal plastic wave speeds. The Taylor anvil and transverse rod impact tests together furnish the required dynamic material properties for comparing the penetration effectiveness of candidate rod materials and geometries.

Summary This paper describes the development of mechanically coupled engineering models to predict transverse loading and response of long rod penetrators associated with high velocity perforation of thin to moderately thick plates. Test results for L/D = 20 tungsten alloy rods are presented to illustrate the distinct effects of impact yaw and obliquity on terminal ballistic transverse loading and response of rod penetrators. The yaw effects loading model considers the plate cutting contact force that travels down the side of the rod when yaw is sufficient for contact with the edge of the breaching hole. The obliquity effects model addresses transverse loading due to asymmetric pressure relief as the rod approaches the rear surface and exits the plate. In both cases, the loading is presumed to be impulsive and three-dimensional vector relationships are used to account for the complex encounter geometries associated with arbitrary combinations of impact yaw and obliquity. The response model includes predictions of rod deformation and fracture and post-perforation linear and angular velocity vectors of the residual rod. Model predictions are compared with test results for titanium and tungsten alloy rods.

Canonical Wnt/β-catenin signaling has been implicated in multiple developmental events including the regulation of proliferation, cell fate, and differentiation. In the inner ear, Wnt/β-catenin signaling is required from the earliest stages of otic placode specification through the formation of the mature cochlea. Within the avian inner ear, the basilar papilla (BP), many Wnt pathway components are expressed throughout development. Here, using reporter constructs for Wnt/β-catenin signaling, we show that this pathway is active throughout the BP (E6-E14) in both hair cells (HCs) and supporting cells. To characterize the role of Wnt/β-catenin activity in developing HCs, we performed gain- and loss-of-function experiments in vitro and in vivo in the chick BP and zebrafish lateral line systems, respectively. Pharmacological inhibition of Wnt signaling in the BP and lateral line neuromasts during the periods of proliferation and HC differentiation resulted in reduced proliferation and decreased HC formation. Conversely, pharmacological activation of this pathway significantly increased the number of HCs in the lateral line and BP. Results demonstrated that this increase was the result of up-regulated cell proliferation within the Sox2-positive cells of the prosensory domains. Furthermore, Wnt/β-catenin activation resulted in enhanced HC regeneration in the zebrafish lateral line following aminoglycoside-induced HC loss. Combined, our data suggest that Wnt/β-catenin signaling specifies the number of cells within the prosensory domain and subsequently the number of HCs. This ability to induce proliferation suggests that the modulation of Wnt/β-catenin signaling could play an important role in therapeutic HC regeneration.

In the cochlea, patterning of the organ of Corti is tightly regulated to produce a single row of sound-detecting inner hair cells and three rows of outer hair cells, which amplify and refine the signal. The recently identified R-Spondin family of signaling molecules usually act as co-activators of Wnt signaling; it is thought that they regulate turnover of Wnt receptors at the membrane. We sought to test whether R-Spondins function in the developing cochlea.Expression analysis of all four members of the R-Spondin family showed that only R-Spondin2 (Rspo2) is expressed in the cochlea during development of the sensory epithelium. Examination of an Rspo2(-/-) mouse showed that loss of Rspo2 results in an additional single row of outer hair cells and disruption of peripheral innervation pattern. Addition of Rspo2 recombinant protein to organotypic cochlear cultures resulted in a small but significant decrease in the number of outer hair cells.Rspo2 is required to limit the number of outer hair cells to three rows and for optimal arrangement of peripheral nerve fibers. The Rspo2 gain- and loss-of-function studies show that in the ear, Rspo2 function is not consistent with its assigned role as a Wnt potentiator.

This paper describes experiments and the development of a model to predict damage to metallic plates impacted by high velocity, multi-particle debris clouds. The experiments involved single steel spheres fired at a steel shatter plate at speeds near 1.5 and 2.0 km/sec to generate the debris clouds. In each series of tests, the impact velocity was controlled, and a witness plate was placed at increasing distances behind the shatter plate to observe the effects of debris particle dispersion on plate damage. This paper focuses on the variations, with plate spacing, in the size of the central region removed from the witness plates. The central hole size model compares the post impact kinetic energy distribution in a witness plate impacted by a debris cloud to the free impact residual kinetic energy in an equivalent plate impacted by an L/D =1 steel cylinder, at the ballistic limit velocity. This approach permits extension of the model to other plate materials through utilization of existing ballistic limit velocity data.

Measurements of ClO (Brune et al., 1990) acquired during the Airborne Arctic Stratospheric Expedition are used to infer concentrations of reactive chlorine (ClO + 2 x Cl2O2). Observed fields of potential temperature and potential vorticity are used to extrapolate in situ data to larger regions of the vortex. Calculated values of the loss rate of O3, based on estimates of reactive chlorine and measurements of BrO (Toohey et al., 1990), suggest that the loss of O3 was abut 12 pct for levels of the atmosphere with potential temperatures between 440 and 470 K over the 39 day duration of the ER-2 flights into the polar vortex. Calculated loss rates agree with observed rates of removal of O3, although significant uncertainties exist for each.

It is argued that the reaction COF2 + H2O - 2HF + CO2 should proceed on surfaces of polar stratospheric clouds, based on laboratory evidence for this reaction in condensed phase and on analysis of column observations of HF during the Airborne Arctic Stratospheric Expedition. If the hypothesis is confirmed, observations of COF2 and HF could provide unambiguous indication of heterogeneous processing of polar air, and could help elucidate the influence of heterogeneous chemistry on concentrations of HCl, ClNO3, and chlorine oxide radicals.

In the absence of heterogeneous processes, distributions of NO(y), HNO3, Cl(x) and HCl in the polar winter stratosphere should be determined by transport. A model simulating distributions of these species in the arctic for January and February 1989 is developed using observed fields of potential vorticity and potential temperature. Comparison of model results with column measurements from the DC-8 indicates conversion of NO(x) to HNO3, condensation of HNO3, conversion of HCl to CINO3, and conversion of HCl plus CINO3 to an unmeasured species. Heterogeneous processes strongly affect abundances of NO(y) and Cl(x) species in the winter arctic stratosphere.

Ice particles created in polar stratospheric cooling events are predicted to descend into Type I PSCs and accrete a coating of nitric acid trihydrate (NAT) that inhibits evaporation. Coated particles efficiently strip HNO3 from the atmosphere, providing a mechanism for denitrification without significant dehydration. Coatings that disintegrate may release large particles of NAT that influence subsequent particle growth.

Don't despair, says this family physician. Even in mature managed care markets, doctors can protect their independence and the value of of their practices by forming a primary care network. California's BayCare, for example, has grown from 13 doctors to 220 in a little over a year--and it's still expanding.

Clinical, hemodynamic and angiographic data were analyzed in 66 patients with coronary artery disease and severe generalized left ventricular dysfunction (ischemic cardiomyopathy) in order to determine their prognosis and examine the results of medical and surgical management. Seventy-six percent of patients had angina, 85 percent a history of one or more myocardial infarctions, 73 percent cardiomegaly, 38 percent mitral regurgitation, 98 percent severe stenosis of two or three major coronary arteries, and 100 percent a left ventricular ejection fraction of 25 percent or less. Forty-two patients were managed medically, and 24 surgically with aortocoronary bypass grafts or ventricular plication, or both. The clinical and hemodynamic findings in both groups were nearly identical. In a follow-up period of 12 months, the mortality rate was 31 percent in the medical group and 50 percent in the surgical group, with 83 percent of the surgical deaths occurring within 1 month of operation. There was no significant difference in the functional status of medical and surgical survivors. Regardless of therapy, patients with mitral regurgitation or a left ventricular end-diastolic pressure of 24 mm Hg or greater had a significantly higher mortality rate than patients without these findings. This study indicates that patients with ischemic cardiomyopathy have a poor prognosis, and surgical intervention with current available techniques has a high operative mortality rate without significantly altering the symptoms in the survivors.

dc and ac plasma-density and vector-electric-field detectors on a polar orbiting satellite have measured spatially confined regions of extremely large (\ensuremath{\sim}\textonehalf{} V/m) electric fields in the auroral zone at altitudes below 8000 km. Such regions frequently have double structures of opposing electric fields containing characteristic and different wave spectra internal and external to themselves. These structures are identified as paired electrostatic shocks which are associated with electrostatic ion cyclotron wave turbulence.

PAROXYSMAL nocturnal hemoglobinuria (PNH)1 and erythroleukemia2 are both characterized by acquired abnormalities of red blood cells and also feature involvement of other hematopoietic cell lines. With recent reports of PNH terminating in myelogenous leukemia,3 4 5 Dameshek6 hypothesized that PNH may fit into the category of myeloproliferative diseases and, indeed, be a variant of erythroleukemia. This report describes the concomitant occurrence of PNH and erythroleukemia. Such an association is a logical link in the progression of PNH to acute leukemia. Case Report L.G., a 32-year-old man, was transferred to Wilford Hall USAF Medical Center in July, 1969, with the diagnosis of PNH. . . .

PACEMAKERS have been subject to interference from a variety of sources. In the case reported below, pacemaker failure arose from commercial radar. Case Report A 65-year-old man with angina pectoris was hospitalized for syncope. His previously normal electrocardiogram showed complete atrioventricular block, with a rate of 35 per minute. A bipolar electrode catheter was inserted and attached to a demand pacing unit.† He was then evacuated by air to Wilford Hall USAF Medical Center. The blood pressure was 164/74, and the pulse 86, with a regular rate. A transvenous pacing catheter was in place via the right brachial vein. The . . .