Sequencing of multiple related species followed by comparative genomics analysis constitutes a powerful approach for the systematic understanding of any genome. Here, we use the genomes of 12 Drosophila species for the de novo discovery of functional elements in the fly. Each type of functional element shows characteristic patterns of change, or 'evolutionary signatures', dictated by its precise selective constraints. Such signatures enable recognition of new protein-coding genes and exons, spurious and incorrect gene annotations, and numerous unusual gene structures, including abundant stop-codon readthrough. Similarly, we predict non-protein-coding RNA genes and structures, and new microRNA (miRNA) genes. We provide evidence of miRNA processing and functionality from both hairpin arms and both DNA strands. We identify several classes of pre-and post-transcriptional regulatory motifs, and predict individual motif instances with high confidence. We also study how discovery power scales with the divergence and number of species compared, and we provide general guidelines for comparative studies.The sequencing of the human genome and the genomes of dozens of other metazoan species has intensified the need for systematic methods to extract biological information directly from DNA sequence. Comparative genomics has emerged as a powerful methodology for this endeavour 1,2 . Comparison of few (two-four) closely related genomes has proven successful for the discovery of protein-coding genes 3-5 , RNA genes 6,7 , miRNA genes 8-11 and catalogues of regulatory elements 3,4,12-14 . The resolution and discovery power of these studies should increase with the number of genomes [15][16][17][18][19][20] , in principle enabling the systematic discovery of all conserved functional elements.The fruitfly Drosophila melanogaster is an ideal system for developing and evaluating comparative genomics methodologies. Over the past century, Drosophila has been a pioneering model in which many of the basic principles governing animal development and population biology were established 21 . In the past decade, the genome sequence of D. melanogaster provided one of the first systematic views *These authors contributed equally to this work. {Lists of participants and affiliations appear at the end of the paper.

The preparation of 2D layered SnS2 nanoplates with nanoscale lateral confinement (less than 150 nm) is described (see figure). Their unique nanoscale characteristics, including finite lateral 2D morphology, make the discharge capacity of Li ion batteries remarkably high‐almost close to the theoretical possible value.

Two-dimensional crystals, which possess a nanoscale dimension only in the c axis and have infinite length in the plane, have been emerging as important new materials owing to their unique properties and potential applications in areas ranging from electronics to catalysis. [1][2][3][4][5] In particular, recent developments of 2D nanosheet crystals such as stable graphene and transition-metal chalcogenides (TMCs) have sparked new discoveries in condensed-matter physics and electronics.[6] Further miniaturization of these 2D structures by lateral confinements can potentially bring not only the modulation of electron-transport phenomena [7] but also the enhancement of their 2D host capabilities which arise from the enlarged surface area and improved diffusion processes upon the intercalation of guest molecules.[8] However, synthetic routes for such laterally confined 2D crystals, especially for TMCs, have been challenging since they are unstable and immediately scroll up into closed structures such as quasi-0D onions or 1D tubes owing to increased peripheral dangling bonds. [9][10][11] Herein, we have developed an entirely new "shapetransformation" concept that proceeds by a rolling out of 1D tungsten oxide nanorods for the fabrication of laterally confined (less than 100 nm) 2D WS 2 nanosheet crystals. Here, a surfactant-assisted low-temperature (lower than 350 8C) solution process is also critical in stabilizing 2D nanosheet structures as opposed to conventional high-temperature (higher than 700 8C) gas-solid routes which yield only 0D or 1D structures. [12][13][14] Our 2D WS 2 nanosheet crystals are synthesized from tungsten oxide (W 18 O 49 ) nanorods [15,16] in the presence of carbon disulfide in hot hexadecylamine solution.Figure 1 a shows an overview of our shape-transformation scheme for the generation of 2D WS 2 nanosheet crystals from the tungsten oxide rods. The reaction between the carbon disulfide and hexadecylamine generates in situ hydrogen disulfide and hexadecylisothiocyanate via N-hexadecyldithiocarbamate as a transient species [Eq. (1); see also Figures S1 and S2 in the Supporting Information], and subsequent

Transient focal ischemia is known to induce proliferation of neural progenitors in adult rodent brain. We presently report that doublecortin positive neuroblasts formed in the subventricular zone (SVZ) and the posterior peri-ventricle region migrate towards the cortical and striatal penumbra after transient middle cerebral artery occlusion (MCAO) in adult rodents. Cultured neural progenitor cells grafted into the non-infarcted area of the ipsilateral cortex migrated preferentially towards the infarct. As chemokines are known to induce cell migration, we investigated if monocyte chemoattractant protein-1 (MCP-1) has a role in post-ischemic neuroblast migration. Transient MCAO induced an increased expression of MCP-1 mRNA in the ipsilateral cortex and striatum. Immunostaining showed that the expression of MCP-1 was localized in the activated microglia and astrocytes present in the ischemic areas between days 1 and 3 of reperfusion. Furthermore, infusion of MCP-1 into the normal striatum induced neuroblast migration to the infusion site. The migrating neuroblasts expressed the MCP-1 receptor CCR2. In knockout mice that lacked either MCP-1 or its receptor CCR2, there was a significant decrease in the number of migrating neuroblasts from the ipsilateral SVZ to the ischemic striatum. These results show that MCP-1 is one of the factors that attract the migration of newly formed neuroblasts from neurogenic regions to the damaged regions of brain after focal ischemia.

Thiazolidinediones (TZDs) are potent synthetic agonists of the ligand-activated transcription factor peroxisome proliferatoractivated receptor-␥ (PPAR␥). TZDs were shown to induce neuroprotection after cerebral ischemia by blocking inflammation. As spinal cord injury (SCI) induces massive inflammation that precipitates secondary neuronal death, we currently analyzed the therapeutic efficacy of TZDs pioglitazone and rosiglitazone after SCI in adult rats. Both pioglitazone and rosiglitazone (1.5 mg/kg i.p.; four doses at 5 min and 12, 24, and 48 h) significantly decreased the lesion size (by 57 to 68%, p Ͻ 0.05), motor neuron loss (by 3-to 10-fold, p Ͻ 0.05), myelin loss (by 66 to 75%, p Ͻ 0.05), astrogliosis (by 46 to 61%, p Ͻ 0.05), and microglial activation (by 59 to 78%, p Ͻ 0.05) after SCI. TZDs significantly enhanced the motor function recovery (at 7 days after SCI, the motor scores were 37 to 45% higher in the TZD groups over the vehicle group; p Ͻ 0.05), but the treatment was effective only when the first injection was given by 2 h after SCI. At 28 days after SCI, chronic thermal hyperalgesia was decreased significantly (by 31 to 39%; p Ͻ 0.05) in the pioglitazone group compared with the vehicle group. At 6 h after SCI, the pioglitazone group showed significantly less induction of inflammatory genes [interleukin (IL)-6 by 83%, IL-1␤ by 87%, monocyte chemoattractant protein-1 by 75%, intracellular adhesion molecule-1 by 84%, and early growth response-1 by 67%] compared with the vehicle group (p Ͻ 0.05 in all cases). Pioglitazone also significantly enhanced the post-SCI induction of neuroprotective heat shock proteins and antioxidant enzymes. Pretreatment with a PPAR␥ antagonist, 2-chloro-5-nitro-N-phenyl-benzamide (GW9662), prevented the neuroprotection induced by pioglitazone.Peroxisome proliferator-activated receptor (PPAR) and retinoid X receptor are ligand-activated transcription factors of the nuclear hormone receptor superfamily. Upon ligand binding, PPAR forms a heterodimeric complex with retinoid X receptor that binds to the cis-acting sequences (peroxisome proliferator response element) on DNA to initiate or repress the transcription of target genes (Blanquart et al., 2003). PPAR exists as three isoforms (␣, ␥, and ␦/␤) that control many cellular functions including lipid metabolism, glucose absorption, and cell growth and differentiation (Escher and Wahli, 2000). 15-Deoxy-⌬-12,14-prostaglandin J 2 (15-d-PGJ 2 ) is the natural agonist and thiazolidinediones (TZDs) (troglitazone, ciglitazone, rosiglitazone, and pioglitazone) are potent synthetic agonists of PPAR␥. Of these, troglitazone was removed from the market because of hepatotoxicity, whereas rosiglitazone and pioglitazone are currently ap-

Peroxisome proliferator-activated receptor (PPAR)-γ is a ligand-activated transcription factor of nuclear hormone receptor superfamily. Thiazolidinedione rosiglitazone is a potent agonist of PPARγ which was shown to induce neuroprotection in animal models of focal ischemia and spinal cord injury. We currently evaluated the therapeutic potential of rosiglitazone (6 mg/kg at 5 min, 6 h and 24 h; i.p.) following controlled cortical impact (CCI)-induced traumatic brain injury (TBI) in adult mice. CCI injury increased the cortical PPARγ mRNA levels which were further elevated by rosiglitazone treatment. In addition, rosiglitazone treatment significantly decreased the cortical lesion volume measured at 7 days compared to vehicle treatment (by 56 ± 7%; p < 0.05; n = 6/group). Following TBI, the spared cortex of the rosiglitazone group showed significantly less numbers of GSI-B4+ activated microglia/macrophages and ICAM1+ capillaries, and curtailed induction of pro-inflammatory genes IL6, MCP1 and ICAM1 compared to vehicle group. Rosiglitazone-treated mice also showed significantly less number of TUNEL+ apoptotic neurons and curtailed induction of caspase-3 and Bax, compared to vehicle control. In addition, rosiglitazone significantly enhanced the post-TBI expression of the neuroprotective chaperones HSP27, HSP70 and HSP32/HO1, and the anti-oxidant enzymes catalase, Cu/Zn-SOD and Mn-SOD, compared to vehicle. Treatment with GW9662 (a specific PPARγ antagonist) prevented all the above PPARγ-mediated actions. Thus, PPARγ activation confers neuroprotection after TBI by anti-inflammatory, anti-apoptotic and anti-oxidative mechanisms.

Together with our data, DHI and sROM showed a significant correlation with the incidence of recurrent lumbar disc herniation, suggesting that preoperative biomechanical conditions of the spine can be an important pathogenic factor in the site of lumbar disc surgery.

No abstract