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Cosmological $N$-body simulations show that Milky Way-sized galaxies harbor a population of unmerged dark matter subhalos. These subhalos could shine in gamma-rays and be eventually detected in gamma-ray surveys as unidentified sources. We performed a thorough selection among unidentified Fermi-LAT Objects (UFOs) to identify them as possible TeV-scale dark matter subhalo candidates. We search for very-high-energy (E $\gtrsim$ 100 GeV) gamma-ray emissions using H.E.S.S. observations towards four selected UFOs. Since no significant very-high-energy gamma-ray emission is detected in any dataset of the four observed UFOs nor in the combined UFO dataset, strong constraints are derived on the product of the velocity-weighted annihilation cross section $\langle \sigma v \rangle$ by the $J$-factor for the dark matter models. The 95% C.L. observed upper limits derived from combined H.E.S.S. observations reach $\langle \sigma v \rangle J$ values of 3.7$\times$10$^{-5}$ and 8.1$\times$10$^{-6}$ GeV$^2$cm$^{-2}$s$^{-1}$ in the $W^+W^-$ and $\tau^+\tau^-$ channels, respectively, for a 1 TeV dark matter mass. Focusing on thermal WIMPs, the H.E.S.S. constraints restrict the $J$-factors to lie in the range 6.1$\times$10$^{19}$ - 2.0$\times$10$^{21}$ GeV$^2$cm$^{-5}$, and the masses to lie between 0.2 and 6 TeV in the $W^+W^-$ channel. For the $\tau^+\tau^-$ channel, the $J$-factors lie in the range 7.0$\times$10$^{19}$ - 7.1$\times$10$^{20}$ GeV$^2$cm$^{-5}$ and the masses lie between 0.2 and 0.5 TeV. Assuming model-dependent predictions from cosmological N-body simulations on the $J$-factor distribution for Milky Way-sized galaxies, the dark matter models with masses greater than 0.3 TeV for the UFO emissions can be ruled out at high confidence level., Comment: 11 pages, 7 figures, matches accepted version in The Astrophysical Journal

TRANSIENT MAGNETOTHERMOELASTIC WAVES IN A HALF-SPACE WITH THERMAL RELAXATIONS

PTP69D is a receptor protein tyrosine phosphatase that was identified as a key regulator of neuromuscular axon guidance in Drosophila, and has subsequently been shown to play a similar role in the central nervous system and retina. Three Ptp69D alleles with mutations involving catalytically important residues exhibit a high degree of phenotypic variation with viability of mutant adult flies ranging from 0 to 96%, and ISNb motor nerve defects ranging from 11 to 57% [Desai and Purdy, 2003]. To determine whether mutations in Ptp69D affecting axon guidance and viability demonstrate losses of phosphatase activity and whether differences in catalytic potential underlie phenotypic variability, we expressed full-length wild-type and mutant PTP69D protein in Schneider 2 cells, and assessed phosphatase activity using the fluorogenic substrate 6,8-difluoro-4-methylumbelliferone phosphate (DiFMUP). Detailed biochemical characterization of wild-type PTP69D, including an examination of sensitivity to various inhibitors, in vitro catalytic efficiency, and the pH-k(cat) profile of the enzyme, suggests a common tyrosine phosphatase reaction mechanism despite lack of sequence conservation in the WPD loop. Analysis of mutant proteins revealed that every mutant had less than 1% activity relative to the wild-type enzyme, and these rates did not differ significantly from one another. These results indicate that mutations in Ptp69D resulting in axon guidance defects and lethality significantly compromise catalytic activity, yet the range of biological activity exhibited by Ptp69D mutants cannot be explained by differences in catalytic activity, as gauged by their ability to hydrolyze the substrate DiFMUP.

The neural receptor tyrosine phosphatases DPTP69D, DPTP99A and DLAR are involved in motor axon guidance in the Drosophila embryo. Here we analyze the requirements for these three phosphatases in growth cone guidance decisions along the ISN and SNb motor pathways. Any one of the three suffices for the progression of ISN pioneer growth cones beyond their first intermediate target in the dorsal muscle field. DLAR or DPTP69D can facilitate outgrowth beyond a second intermediate target, and DLAR is uniquely required for formation of a normal terminal arbor. A different pattern of partial redundancy among the three phosphatases is observed for the SNb pathway. Any one of the three suffices to allow SNb axons to leave the common ISN pathway at the exit junction. When DLAR is not expressed, however, SNb axons sometimes bypass their ventrolateral muscle targets after leaving the common pathway, instead growing out as a separate bundle adjacent to the ISN. This abnormal guidance decision can be completely suppressed by also removing DPTP99A, suggesting that DLAR turns off or counteracts a DPTP99A signal that favors the bypass axon trajectory. Our results show that the relationships among the tyrosine phosphatases are complex and dependent on cellular context. At growth cone choice points along one nerve, two phosphatases cooperate, while along another nerve these same phosphatases can act in opposition to one another.

The receptor tyrosine phosphatases DPTP69D and DPTP99A are expressed on motor axons in Drosophila embryos. In mutant embryos lacking DPTP69D protein, motor neuron growth cones stop growing before reaching their muscle targets, or follow incorrect pathways that bypass these muscles. Mutant embryos lacking DPTP99A are indistinguishable from wild type. Motor axon defects in dptp69D dptp99A double mutant embryos, however, are much more severe than in embryos lacking only DPTP69D. Our results demonstrate that DPTP69D and DPTP99A are required for motor axon guidance and that they have partially redundant functions during development of the neuromuscular system.

Recent studies have defined several cell surface glycoproteins expressed in the developing nervous system of insect embryos that may be involved in axon outgrowth and guidance processes. These glycoproteins include the fasciclins and a group of receptor-linked protein tyrosine phosphatases (R-PTPs). In embryos, the fasciclins are localized to axonal subsets, while the R-PTPs appear to be expressed on most or all CNS axons. To identify other neuronal cell surface glycoproteins in the Drosophila embryo, we have taken a biochemical approach. This is based on the observation that antisera against horseradish peroxidase (HRP) recognize a carbohydrate epitope that is selectively expressed in the insect nervous system. A large number of neuronal glycoproteins (denoted “HRP proteins”) apparently bear the HRP carbohydrate epitope. We have used polyclonal anti-HRP antibodies to purify these proteins from Drosophila embryos, and have obtained protein sequences from seven HRP protein bands. These data define three major HRP proteins as neurotactin, fasciclin I, and an R-PTP, DPTP69D. Western blotting data suggest that fasciclin II, neuroglian, DPTP10D, and DPTP99A are also HRP proteins. We show that DPTP69D, like the previously characterized R-PTPs, is localized to CNS axons in the embryo. In third instar larvae, DPTP69D expression is restricted to subsets of neuronal processes in the brain, ventral nerve cord, and eye disk. In the optic lobes, DPTP69D is localized to the neuropils of the lamina and medulla, and to an array of parallel thick bundles that may be the transmedullary fibers of the developing lobula complex.

During Drosophila embryogenesis, both the cytoplasmic Abelson tyrosine kinase (Abl) and the membrane bound tyrosine phosphatase PTP69D are required for proper guidance of CNS and motor axons. We provide evidence that PTP69D modulates signaling by Abl and its antagonist, Ena. An Abl loss-of function mutation dominantly suppresses most Ptp69D mutant phenotypes including larval/pupal lethality and CNS and motor axon defects, while increased Abl and decreased Ena expression dramatically increase the expressivity of Ptp69D axonal defects. In contrast, Ptp69D mutations do not affect Abl mutant phenotypes. These results support the hypothesis that PTP69D antagonizes the Abl/Ena genetic pathway, perhaps as an upstream regulator. We also find that mutation of the gene encoding the cytoplasmic Src64B tyrosine kinase exacerbates Ptp69D phenotypes, suggesting that two different cytoplasmic tyrosine kinases, Abl and Src64B, modify PTP69D-mediated axon patterning in quite different ways.

We have isolated and characterized a series of 18 chemically induced alleles of Ptp69D ranging in strength from viable to worse than null, which represent unique tools for probing the structure, function, and signaling pathway of DPTP69D. Three alleles are strongly temperature sensitive and were used to define the developmental periods requiring DPTP69D function; adult health requires DPTP69D during the mid- to late-pupal stage, eclosion requires DPTP69D during the early to mid-larval stage, and larval survival requires DPTP69D during embryogenesis. Mutations predicted to abolish the phosphatase activity of the membrane proximal D1 domain severely reduce but do not abolish DPTP69D function. Six alleles appear null; only 20% of null homozygotes pupate and

Background: Akathisia has been reported to predict more severe symptoms and poorer treatment response to typical neuroleptics among patients with schizophrenia. Akathisia has also been associated with symptom exacerbation. This study addressed four questions: 1) Does akathisia predict greater severity in global psychopathology? 2) Is this effect global or specific? 3) Does clozapine treatment alter this relationship? 4) Does severity of psychopathology covary with the level of akathisia? Methods: Akathisia and clinical symptoms were examined in 33 "treatment refractory" schizophrenic patients treated with clozapine across 16 weeks. Weekly ratings were Barnes Akathisia Rating Scale, Abbreviated Dyskinesia Rating Scale, and Brief Psychiatric Rating Scale (BPRS). Patients were classified as "with" ( n = 15) or "without" ( n = 18) akathisia. Data analyses involved independent t -test comparisons of selected variables, between-group multivariate analyses of variance across time for BPRS Total scores and Guy's five factors, and partial correlations to assess covariation between BPRS scores and level of akathisia. Results: Akathisia predicted more severe global psychopathology, specific to the Activation (AC) and Thought Disturbance (TH) factors. These relationships did not change with clozapine treatment even when akathisia declined. Interestingly, level of akathisia did not covary with severity of psychopathology. Conclusions: In this sample, akathisia predicted more severe psychopathology, specific to AC and TH BPRS factor scores. Clozapine treatment did not alter this relationship. Although the presence of akathisia predicted more severe symptoms, the level of akathisia did not covary across time with severity of psychopathology, suggesting an "uncoupling" of these symptom domains.

Different Drosophila photoreceptors (R cells) connect to neurons in different optic lobe layers. R1–R6 axons project to the lamina; R7 and R8 axons project to separate layers of the medulla. We show a receptor tyrosine phosphatase, PTP69D, is required for lamina target specificity. In Ptp69D mutants, R1–R6 project through the lamina, terminating in the medulla. Genetic mosaics, transgene rescue, and immunolocalization indicate PTP69D functions in R1–R6 growth cones. PTP69D overexpression in R7 and R8 does not respecify their connections, suggesting PTP69D acts in combination with other factors to determine target specificity. Structure–function analysis indicates the extracellular fibronectin type III domains and intracellular phosphatase activity are required for targeting. We propose PTP69D promotes R1–R6 targeting in response to extracellular signals by dephosphorylating substrate(s) in R1–R6 growth cones.

The Dock SH2-SH3 domain adapter protein, a homolog of the mammalian Nck oncoprotein, is required for axon guidance and target recognition by photoreceptor axons in Drosophila larvae. Here we show that Dock is widely expressed in neurons and at muscle attachment sites in the embryo, and that this expression pattern has both maternal and zygotic components. In motoneurons, Dock is concentrated in growth cones. Loss of zygotic dock function causes a selective delay in synapse formation by the RP3 motoneuron at the cleft between muscles 7 and 6. These muscles often completely lack innervation in late stage 16 dock mutant embryos. RP3 does form a synapse later in development, however, because muscles 7 and 6 are normally innervated in third-instar mutant larvae. The absence of zygotically expressed Dock also results in subtle defects in a longitudinal axon pathway in the embryonic central nervous system. Concomitant loss of both maternally and zygotically derived Dock dramatically enhances these central nervous system defects, but does not increase the delay in RP3 synaptogenesis. These results indicate that Dock facilitates synapse formation by the RP3 motoneuron and is also required for guidance of some interneuronal axons The involvement of Dock in the conversion of the RP3 growth cone into a presynaptic terminal may reflect a role for Dock-mediated signaling in remodeling of the growth cone's cytoskeleton.

The Dock SH2-SH3 domain adapter protein, a homolog of the mammalian Nck oncoprotein, is required for axon guidance and target recognition by photoreceptor axons in Drosophila larvae. Here we show that Dock is widely expressed in neurons and at muscle attachment sites in the embryo, and that this expression pattern has both maternal and zygotic components. In motoneurons, Dock is concentrated in growth cones. Loss of zygotic dock function causes a selective delay in synapse formation by the RP3 motoneuron at the cleft between muscles 7 and 6. These muscles often completely lack innervation in late stage 16 dock mutant embryos. RP3 does form a synapse later in development, however, because muscles 7 and 6 are normally innervated in third-instar mutant larvae. The absence of zygotically expressed Dock also results in subtle defects in a longitudinal axon pathway in the embryonic central nervous system. Concomitant loss of both maternally and zygotically derived Dock dramatically enhances these central nervous system defects, but does not increase the delay in RP3 synaptogenesis. These results indicate that Dock facilitates synapse formation by the RP3 motoneuron and is also required for guidance of some interneuronal axons The involvement of Dock in the conversion of the RP3 growth cone into a presynaptic terminal may reflect a role for Dock-mediated signaling in remodeling of the growth cone’s cytoskeleton.

Kinesin is a heterotetramer composed of two 115-kD heavy chains and two 58-kD light chains. The microtubule motor activity of kinesin is performed by the heavy chains, but the functions of the light chains are poorly understood. Mutations were generated in the Drosophila gene Kinesin light chain (Klc), and the phenotypic consequences of loss of Klc function were analyzed at the behavioral and cellular levels. Loss of Klc function results in progressive lethargy, crawling defects, and paralysis followed by death at the end of the second larval instar. Klc mutant axons contain large aggregates of membranous organelles in segmental nerve axons. These aggregates, or organelle jams (Hurd, D.D., and W.M. Saxton. 1996. Genetics. 144: 1075–1085), contain synaptic vesicle precursors as well as organelles that may be transported by kinesin, kinesin-like protein 68D, and cytoplasmic dynein, thus providing evidence that the loss of Klc function blocks multiple pathways of axonal transport. The similarity of the Klc and Khc (Saxton et al. 1991. Cell 64:1093–1102; Hurd, D.D., and W.M. Saxton. 1996. Genetics 144: 1075–1085) mutant phenotypes indicates that KLC is essential for kinesin function, perhaps by tethering KHC to intracellular cargos or by activating the kinesin motor.

A two-frequency CO2 laser beam was used to beat-excite a large amplitude electron plasma wave in a resonant density plasma. The accelerating fields of the relativistic plasma wave were probed with collinear injected 2.1 MeV electrons from an electron linac. Some electrons gained at least 7 MeV in traversing the approximately 1 cm length of the beat wave accelerator, with the measurement limited by the 9.1 MeV high energy cut-off of the detection system. The corresponding average acceleration gradient is > 0.7 GeV/m and the average wave amplitude n1/n0 is > 8%. Estimates based on collective Thomson scattering indicate that peak wave amplitudes of 15 - 30% may have been achieved.© (1993) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

A compact 20 MeV linac with an RF laser-driven electron gun will drive a high-gain (10 cm gain length), 10.6 micrometers wavelength FEL amplifier, operating in the SASE mode. FEL physics in the high-gain regime will be studied, including start-up from noise, optical guiding, sidebands, saturation, and superradiance, with emphasis on the effects important for future short wavelength operation of FEL's. The hybrid undulator, designed and built at the Kurchatov Institute of Atomic Energy in the U.S.S.R., has forty periods, each 1.5 cm long. The magnetic material is a hybrid combination of SmCo5 blocks and Nd-Fe-B blocks, with vanadium-permendur yokes. The gap distance between pole-tips is fixed at 5 mm. On axis the peak value of the completed undulator's magnetic field was measured to be 7.3 kGauss (+/- 0.25%). Measurements during the conditioning phase of the RF gun for the electron beam's peak dark-current show 6 mA without the longitudinal magnetic focusing field in the gun and 34 mA with the focusing field active. The peak current from photoemission is calculated to be 200 A.© (1992) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

A novel, compact S-band LINAC has been designed and is currently under construction at UCLA. It is expected to deliver high brightness, 200 A, 20 MeV electron pulses, less than 4 ps in duration from a device that is about 1 meter long. It comprises; (1) a laser photocathode driven gun that produces 4.5 MeV electron bunches from a 1 1/2 cell cavity operating in the (pi) -mode and (2) an accelerating structure known as a plane wave transformer (PWT) designed by Swenson. The design considerations of the machine and initial operating experience of the gun are discussed. The linac will be used for free electron laser, advanced accelerator research and beam-plasma experiments.

1407_51Saturnus is an infrared FEL operating in the 10 micrometers wavelength region, driven by a compact 20 MeV linac with a photoinjector, under construction at UCLA. The 1.5 cm period, 0.6 (Tau) peak field undulator is being built at the Kurchatov IAE. The FEL is designed to operate primarily in the self-amplified spontaneous emission mode. This paper covers the start-up from noise, optical guiding, saturation, sidebands and superradiance, with emphasis on the effects important for future short wavelength operation of FELs. The photoinjector follows closely the Brookhaven design. Electrons are injected into an accelerating section based on the plane-wave transformer design developed by Swenson at SAIC. Simulation of the linac and FEL show a gain length of 10 cm, and a saturation power of 50 MW.© (1991) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.