Showing papers by "Jun Lu published in 2006"

A putative flip–flop switch for control of REM sleep

Abstract: Rapid eye movement (REM) sleep consists of a dreaming state in which there is activation of the cortical and hippocampal electroencephalogram (EEG), rapid eye movements, and loss of muscle tone. Although REM sleep was discovered more than 50 years ago, the neuronal circuits responsible for switching between REM and non-REM (NREM) sleep remain poorly understood. Here we propose a brainstem flip–flop switch, consisting of mutually inhibitory REM-off and REM-on areas in the mesopontine tegmentum. Each side contains GABA (γ-aminobutyric acid)-ergic neurons that heavily innervate the other. The REM-on area also contains two populations of glutamatergic neurons. One set projects to the basal forebrain and regulates EEG components of REM sleep, whereas the other projects to the medulla and spinal cord and regulates atonia during REM sleep. The mutually inhibitory interactions of the REM-on and REM-off areas may form a flip–flop switch that sharpens state transitions and makes them vulnerable to sudden, unwanted transitions—for example, in narcolepsy. Rapid eye movement (REM) sleep is a dreaming state in which the brain is highly active. The mechanism responsible for switching between REM and non-REM sleep (also called slow-wave sleep, when cortical activity is slow) is poorly understood. Now, based on detailed anatomy and lesion experiments, Lu et al. have identified brainstem regions that control the transition from REM to non-REM sleep. The REM-off and REM-on areas are mutually inhibitory. This appears to produce a flip-flop switch relationship that could explain many of the properties of the abrupt switching into and out of REM states seen in sleep disorders such as narcolepsy.

Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter.

Abstract: Recent evidence suggests that dopamine plays an important role in arousal, but the location of the dopaminergic neurons that may regulate arousal remains unclear. It is sometimes assumed that the dopaminergic neurons in the ventral tegmental area that project to the prefrontal cortex and striatum may regulate the state of arousal; however, the firing of these dopaminergic neurons does not correlate with overall levels of behavioral wakefulness. We identified wake-active dopaminergic neurons by combining immunohistochemical staining for Fos and tyrosine hydroxylase (TH) in awake and sleeping rats. Approximately 50% of the TH-immunoreactive (TH-ir) cells in the ventral periaqueductal gray matter (vPAG) expressed Fos protein during natural wakefulness or wakefulness induced by environmental stimulation, but none expressed Fos during sleep. Fos immunoreactivity was not seen in the substantia nigra TH-immunoreactive cells in either condition. Injections of 6-hydroxydopamine into the vPAG, which killed 55–65% of wake-active TH-ir cells but did not injure nearby serotoninergic cells, increased total daily sleep by ∼20%. By combining retrograde and anterograde tracing, we showed that these wake-active dopaminergic cells have extensive reciprocal connections with the sleep–wake regulatory system. The vPAG dopaminergic cells may provide the long-sought ascending dopaminergic waking influence. In addition, their close relationship with the dorsal raphe nucleus will require reassessment of previous studies of the role of the dorsal raphe nucleus in sleep, because many of those experiments may have been confounded by the then-unrecognized presence of intermingled wake-active dopaminergic neurons.

Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch.

Abstract: C(2) domains are well characterized as Ca(2+)/phospholipid-binding modules, but little is known about how they mediate protein-protein interactions. In neurons, a Munc13-1 C(2)A-domain/RIM zinc-finger domain (ZF) heterodimer couples synaptic vesicle priming to presynaptic plasticity. We now show that the Munc13-1 C(2)A domain homodimerizes, and that homodimerization competes with Munc13-1/RIM heterodimerization. X-ray diffraction studies guided by nuclear magnetic resonance (NMR) experiments reveal the crystal structures of the Munc13-1 C(2)A-domain homodimer and the Munc13-1 C(2)A-domain/RIM ZF heterodimer at 1.44 A and 1.78 A resolution, respectively. The C(2)A domain adopts a beta-sandwich structure with a four-stranded concave side that mediates homodimerization, leading to the formation of an eight-stranded beta-barrel. In contrast, heterodimerization involves the bottom tip of the C(2)A-domain beta-sandwich and a C-terminal alpha-helical extension, which wrap around the RIM ZF domain. Our results describe the structural basis for a Munc13-1 homodimer-Munc13-1/RIM heterodimer switch that may be crucial for vesicle priming and presynaptic plasticity, uncovering at the same time an unexpected versatility of C(2) domains as protein-protein interaction modules, and illustrating the power of combining NMR spectroscopy and X-ray crystallography to study protein complexes.

Solution-based methods for rna expression profiling

Abstract: The present invention is directed to novel high-throughput, low-cost, and flexible solution-based methods for RNA expression profiling, including expression of microRNAs and mRNAs.

Sleep circuitry and the hypnotic mechanism of GABAA drugs.

Abstract: Early in the twentieth century, von Economo provided the first evidence linking the hypothalamus with sleep-wake behavior. His studies concluded that the anterior hypothalamus was associated with sleep, whereas the posterior hypothalamus was associated with waking. In the decades following these observations, a wealth of research has shown that an elaborate circuitry comprising a number of brain regions, cell types, and extracellular messengers underlies sleep-wake behavior. In this review, we discuss data generated in the past 10 years that highlight the role of the hypothalamus in sleep-wake behavior and control. In particular, we will focus on the identification of the ventrolateral preoptic nucleus (VLPO) as a sleep center and the hypocretin/orexin cells in the perifornical region of the hypothalamus as constituting a waking center; these two centers are critical for the maintenance of normal sleep-wake architecture, and provide a foundation for our understanding of sleep-wake behavior and its underlying physiology. The data from these and other regions traditionally associated with the sleep-wake cycle have led to a flip-flop switch model of sleep-wake control. The switch is composed of two sets of mutually inhibitory groups of neurons: a sleep group and an arousal group, with the latter modulated by orexin-containing neurons in the lateral hypothalamus. The sleep-promoting GABA (gamma-amino-butyric acid) receptor agonists are a diverse class of drugs, which include barbiturates, benzodiazepines, chloral hydrate, ethanol, and gaseous anesthetics, that have been used to study sleep physiology for many years. Recent studies suggest that these drugs may exert their hypnotic effects in a regionally specific manner. For example, some GABAA agonists appear to promote sleep by inhibiting the histaminergic cells in the tuberomammillary nucleus and weakly activating the VLPO via agonist binding to the alpha1 subunit of GABAA receptors; whereas, gaboxadol (THIP; 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) binds to the alpha4delta-subunits, potentially promoting sleep by activation of the VLPO. The integration of these data into the flip-flop switch model can be used to better understand sleep-wake control and augment existing therapeutic treatments for sleep disorders.

Synthesis, structure, and resolution of exceptionally twisted pentacenes.

Abstract: 9,10,11,20,21,22-hexaphenyltetrabenzo[a,c,l,n]pentacene (2) and a dimethyl derivative (2m) were prepared by the reaction of 1,3-diphenylphenanthro[9,10-c]furan with bisaryne equivalents generated from 1,2,4,5-tetrabromo-3,6-diarylbenzenes in the presence of n-butyllithium, followed by deoxygenation of the double adducts with low-valent titanium. Both are bright red solids with a strong orange fluorescence in solution. The X-ray structures of these compounds show them to be the most highly twisted polycyclic aromatic hydrocarbons known. Compound 2 has an end-to-end twist of 144 degrees , and the two crystallographically independent molecules of 2m have twists of 138 degrees and 143 degrees. Both molecules were resolved by chromatography on chiral supports, and the pure enantiomers have extremely high specific rotations (for 2, [alpha]D = 7400 degrees; for 2m, 5600 degrees), but the molecules racemize slowly at room temperature (DeltaG++rac = 24 kcal/mol). Both the experimental geometry and the observed racemization barrier for 2 are in good agreement with computational studies of the molecule at a variety of levels. Attempts to prepare compound 2 by reaction of tetraphenylbenzyne with 9,10,12,13-tetraphenyl-11-oxacyclopenta[b]triphenylene (3, a twisted isobenzofuran) gave no adducts, and attempts to prepare tetradecaphenylpentacene by reaction of hexaphenylisobenzofuran (11) with bisaryne equivalents gave only monoadducts.

HfO2 Films Grown by ALD Using Cyclopentadienyl-Type Precursors and H2O or O3 as Oxygen Source

Abstract: HfO 2 thin films have been deposited onto p-Si(100) substrates by atomic layer deposition (ALD) using Cp 2 Hf(CH 3 ) 2 (Cp = cyclopentadienyl) or Cp 2 HfCl 2 and water or ozone as precursors. The purity of HfO 2 films was better when ozone instead of water was used as oxygen precursor. The use of Cp 2 Hf(CH 3 ) 2 together with ozone in the ALD window range, viz. 350-400°C, yielded HfO 2 films with less than 0.1 atom % C and H impurities. Cp 2 HfCl 2 /H 2 O-processed film contained C and Cl, but again the use of ozone considerably reduced the impurity levels. When using Cp 2 Hf(CH 3 ) 2 as the metal source, the higher reactivity of ozone as compared to H 2 O yielded slightly higher growth rate, smoother morphology, higher degree of crystallinity for thicker films, and a close to ideal density. Furthermore, with ozone no inhibition of the growth during initial ALD cycles could be detected. The growth of HfO 2 film on H-terminated Si with the Cp 2 Hf(CH 3 ) 2 /H 2 O process was retarded and the initial island-like growth took place resulting in rougher surface. With the Cp 2 Hf(CH 3 ) 2 /O 3 process, the films showed the best leakage current density characteristics. Slightly higher capacitance equivalent oxide thickness values were calculated for the ozone-processed films.

Molecular changes evoked by triethylenetetramine treatment in the extracellular matrix of the heart and aorta in diabetic rats.

Abstract: Most patients with diabetes die from cardiac or arterial disease, for which there are limited therapeutic options. Free Cu(2+) ions are strongly pro-oxidant, and chelatable-Cu(II) is increased in the diabetic heart. We reported previously that treatment by Cu(II)-selective chelation with triethylenetetramine (TETA) evokes elevated urinary Cu(II) in diabetic rats and humans in whom it also improved hallmarks of established left ventricular (LV) disease. Here, we treated diabetic rats with TETA and evaluated its ability to ameliorate Cu(2+)-mediated LV and arterial damage by modifying the expression of molecular targets that included transforming growth factor (TGF)-beta1, Smad4, extracellular matrix (ECM) proteins, extracellular superoxide dismutase (EC-SOD), and heparan sulfate (HS). Eight-weeks of TETA treatment significantly improved cardiac diastolic function but not [glucose](plasma) in diabetic animals. LV and aortic mRNAs corresponding to TGF-beta1, Smad4, collagen types I, III, and IV, and fibronectin-1, and plasminogen activator inhibitor-1, were elevated in untreated diabetic animals and normalized after TETA treatment. EC-SOD mRNA and protein, and [HS](tissue) were significantly decreased in diabetes and restored by drug treatment. Candidate molecular mechanisms by which TETA could ameliorate diabetic cardiac and arteriovascular disease include the suppression of an activated TGF-beta/Smad signaling pathway that mediates increased ECM gene expression and restoration of normal EC-SOD and HS regulation. These findings are relevant to the restoration toward normal by TETA treatment of cardiac and arterial structure and function in diabetes.

Microstructure and thermal characteristic of Si-coated multi-walled carbon nanotubes

Abstract: The carbon nanotube (CNT) is a promising reinforcement material for manufacturing metal-or ceramic-based composites. However, CNTs are prone to interact with the matrix in a reactive atmosphere that often alters the structure and properties of CNTs and depresses their reinforcing effect. To overcome this problem, a protective silicon layer has been deposited on multi-walled carbon nanotubes (MWNTs) using cycled vacuum-feeding chemical vapour deposition by the in situ decomposition of gaseous SiH4. The silicon coating is well covered and continuous with a cubic-phase structure. It effectively improves the thermal stability of MWNTs by acting as a protective film, which inhibits and delays the onset of oxidation. Thermogravimetric analysis (TGA) reveals that the oxidation of Si-coated MWNTs occurs at a temperature of 676.3 °C, which is 105.1 °C higher than that of uncoated MWNTs, and the weight loss decreases with the increasing thickness of silicon coating.

Robust, scalable self-aligned platinum silicide process

Abstract: A robust, scalable PtSix process is developed. The process consists of two consecutive annealing steps in a single run; the first is silicidation of Pt films on Si substrates carried out in N-2, wh ...

Electrically robust ultralong nanowires of NiSi, Ni2Si and Ni31Si12

Abstract: Mass fabrication of directly accessible, ultralong, uniform Si nanowires is realized by employing a controllable and reproducible method based on standard Si technology. High-conductivity polycrystalline Ni-silicide nanowires around 30 nm by 30 nm in cross section, able to support extremely high currents at ∼108A∕cm2, are obtained by means of solid-state reaction of the Si nanowires with subsequently deposited Ni films. By properly adjusting the Ni film thickness, NiSi, Ni2Si, and Ni31Si12 nanowires characterized with distinct resistivity and temperature coefficient of resistance are obtained. Upon annealing, the electrical continuity of the nanowires breaks at temperatures about 0.7 times the melting points of the silicides.

Nanostructure and temperature-dependent photoluminescence of Er-doped Y2O3 thin films for micro-optoelectronic integrated circuits

Abstract: The nanostructure and photoluminescence of polycrystalline Er-doped Y2O3 thin films, deposited by radical-enhanced atomic layer deposition (ALD), were investigated in this study. The controlled distribution of erbium separated by layers of Y2O3, with erbium concentrations varied from 6to14at.%, was confirmed by elemental electron energy loss spectroscopy (EELS) mapping of Er M4 and M5. This unique feature is characteristic of the alternating radical-enhanced ALD of Y2O3 and Er2O3. The results are also consistent with the extended x-ray absorption fine structure (EXAFS) modeling of the Er distribution in the Y2O3 thin films, where the EXAFS data were best fitted to a layer-like structure. X-ray diffraction (XRD) and selected-area electron diffraction (SAED) patterns revealed a preferential film growth in the [111] direction, showing a lattice contraction with increasing Er doping concentration, likely due to Er3+ of a smaller ionic radius replacing the slightly larger Y3+. Room-temperature photoluminescenc...

Ni2Si nanowires of extraordinarily low resistivity

Abstract: Ultralong, polycrystalline Ni2Si nanowires are fabricated by combining sidewall transfer lithography with self-aligned silicidation Upon formation at 500°C, the nanowires that are 400μm long with a rectangular cross section of 375 by 253nm are characterized by a resistivity of 25±1μΩcm which is similar to the value for Ni2Si thin films Further annealing at 800°C results in an extraordinarily low wire resistivity of 10μΩcm Such a drastic decrease in resistivity is attributed to a significant grain growth and a low density of defects in the nanowires

Distribution of diatoms in the water and surface sediments of southern South China Sea

Abstract: The relationship of species and abundance between the diatoms in the water and sediments from the southern South China Sea (SCS) were discussed, and the key environmental controlling factors were also investigated. Studies show that the diatom abundance is high in both water and sediments in the southeast part of the southern SCS and the varying trend is similar, while in the northwest part, the abundance is low, and the varying trend is different, The dominant diatom species are Thalassionema nitzschioides and Nitzschia bicapitata in water, and T. nitzschioides and Chaetoceros messanensis in sediments. The diatom species of small size and thin shell in water are more than in the sediments, while the diatom species of large size and thick shell in water are less. The percentage of species T nitzschioides is higher in water of southeast part than in that of northwest part, but it is similar in sediments of both areas. It is shown that the southwest monsoon is the important factor influencing diatom abundance and T nitzschioides percentage, and when the southwest monsoon is well developed, the distribution of diatom abundance and T nitzschioides percentage are consistent in both water and sediments of the study area.

Structural and Morphological Properties of Ultrathin HfO2 Dielectrics on 4H-SiC (0001)

Abstract: The material properties of HfO2 thin films were studied to evaluate their potential as a high-κ gate dielectric in 4H-SiC power metal-oxide-semiconductor field effect transistors. Stoichiometric HfO2 films were deposited on n-type 4H-SiC (0001) by atomic layer deposition (ALD) at substrate temperatures of 250-450°C. No significant interfacial layer formation was observed by in-situ X-ray photoelectron spectroscopy (XPS) and an abrupt interface was confirmed by high-resolution transmission electron microscopy (HRTEM). A temperature-dependent transition from amorphous layer-by-layer growth to crystalline three-dimensional island growth was identified by in-situ reflection high-energy electron diffraction (RHEED) and ex-situ atomic force microscopy (AFM). X-ray diffraction (XRD) confirmed the presence of monoclinic HfO2 domains in crystallized films.

Growth of Epitaxial γ-Al2O3 Dielectrics on 4H-SiC

Abstract: Highly oriented γ-Al2O3 thin films on 4H-SiC were engineered to demonstrate their potential as a crystalline high-k gate dielectric in SiC power MOSFETs. As-deposited Al2O3 thin films grown on 4H-SiC (0001) by thermal atomic layer deposition (ALD) were amorphous as determined by in-situ reflection high-energy electron diffraction (RHEED). Upon annealing in N2 at 1100°C, the film crystallized to the γ-Al2O3 phase as observed by RHEED, high-resolution transmission electron microscopy (HRTEM) and X-ray diffraction (XRD). Based on Fourier transforms of the HRTEM image, an epitaxial relationship of γ-Al2O3 (111) on 4H-SiC (0001) was observed in which γ-Al2O3 (110) is oriented with 4H-SiC (1210). This orientation was further confirmed by XRD analysis in which only the γ-Al2O3 (111) and (222) peaks were observed. An abrupt interface of both amorphous and crystalline Al2O3 with 4H-SiC was determined by HRTEM.

Hematopoietic gene promoters subjected to a group-combinatorial study of DNA samples: identification of a megakaryocytic selective DNA signature

Abstract: Identification of common sub-sequences for a group of functionally related DNA sequences can shed light on the role of such elements in cell-specific gene expression. In the megakaryocytic lineage, no one single unique transcription factor was described as linage specific, raising the possibility that a cluster of gene promoter sequences presents a unique signature. Here, the megakaryocytic gene promoter group, which consists of both human and mouse 5 0 non-coding regions, served as a case study. A methodology for group-combinatorial search has been implemented as a customized software platform. It extracts the longest common sequences for a group of related DNA sequences and allows for single gaps of varying length, as well as double- and multiple-gap sequences. The results point to common DNA sequences in a group of genes that is selectively expressed in megakaryocytes, and which does not appear in a large group of control, random and specific sequences. This suggests a role for a combination of these sequences in cell-specific gene expression in the megakaryocytic lineage. The data also point to an intrinsic cross-species difference in the organization of 5 0 non-coding sequences within the mammalian genomes. This methodology may be used for the identification of regulatory sequences in other lineages.

Investigation of TiW Contacts to 4H-SiC Bipolar Junction Devices

Abstract: One important challenge in SiC Bipolar Junction Transistor (BJT) fabrication is to form good ohmic contacts to both n-type and p-type SiC. In this paper, we have examined contact study in a SiC BJT process with sputter deposition of titanium tungsten contacts to both n-type and p-type regions followed by annealing at different temperatures between 750 oC and 950 oC. The contacts were characterized using linear transmission line method (LTLM) structures. To see the formation of compound phases, X-ray Diffraction (XRD) θ-2θ scans were performed before and after annealing. The results indicate that 5 minutes annealing at 950 oC of the n+ contact is sufficient whereas the p+ contacts remain non-ohmic after 30 minutes annealing. The n+ emitter structure contact resistivity after 5 min annealing with 750 oC and 950 oC was 1.08 × 10-3 5cm2 and 4.08 × 10-4 5cm2, respectively. Small amorphous regions of silicon and carbon as well as titanium tungsten carbide regions were observed by high-resolution transmission electron microscopy (HRTEM), whereas less carbide formation and no amorphous regions were found in a sample with unsuccessful formation of TiW ohmic contacts.