Geographical Indications in China: Why Protect GIS with Both Trademark and OAC-Type Legislation?

Geographical indications identify the place of origin of a good and signify a distinctive quality, reputation, or other characteristic of the good that is essentially attributable to that geographic source. Besides serving as source-identifiers and guarantees of quality, they are valuable business interests. Consequently, World Trade Organization members are required to afford them protection under the Agreement on Trade Related Aspects of Intellectual Property Rights. Signatories are free to choose the legal means by which they comply with TRIPS. While a few states rely solely on unfair competition law to meet their obligations, most primarily rely on either trademark law or GI-specific laws often modeled on the appellation of controlled origin (“AOC”) system first developed by France. The People’s Republic of China utilizes both trademark law and GI-specific legislation. China would benefit from abandoning its AOC-type system of GI protection. Protecting GIs with both of the world’s primary protection systems generates uncertainty and conflict; the hierarchy of rights granted by the two systems is unclear. China’s AOC-type system of GI protection does not confer benefits beyond those provided by its trademark-based system of protection. China’s trademark-based system is not perfect, but it satisfies China’s international GI-protection obligations, better reflects the motivations behind China’s recent amendments to its intellectual property laws, and better serves China’s current economic and legal goals

HPV16 E7-driven epithelial hyperplasia promotes impaired antigen presentation and regulatory T cell development

Human papillomaviruses (HPV) infect keratinocytes and can lead to hyperproliferative dysplasia and malignant transformation if not cleared by the immune system. HPV has evolved an array of mechanisms to evade and manipulate the immune system to improve replication efficiency and promote persistent infection. We here demonstrate that hyperproliferative skin expressing the high-risk HPV16 E7 oncogene as a transgene drives immune-modulation of dendritic cells (DCs) resulting in reduced capacity to take up antigen and prime effector CD4 T cell responses. The phenotype of DCs in the E7-expressing hyperproliferative skin was not reversible by activation through intradermal immunization. Naïve CD4 T cells primed by E7-driven hyperproliferative skin acquired FoxP3 expression and an anergic phenotype. DC and T help modulation was dependent on E7-Rb interaction-driven epithelial hyperproliferation, rather than on expression of E7, as inhibition of binding of E7 to retinoblastoma protein, and of consequent epithelial hyperplasia was associated with normal skin DC phenotype, and Th1 effector responses to immunization were restored. We conclude that HPV-induced epithelial hyperplasia modulates epithelial DCs and inhibits Th1 immunity while polarizing T cell differentiation to a regulatory or anergic phenotype

Experimental brood enlargement differentially influences the magnitude of the corticosterone stress response in closely related, co-occurring songbirds

1. Rearing environments can shape offspring phenotype across taxa, yet little is known about how brood size influences hypothalamic-pituitary axis functioning, whether its expression trades off with growth, and the degree to which these -relationships vary between species. 2. We evaluated how brood size influenced nestling physiological (glucocorticoids) and somatic traits (growth), and the extent to which their relationship differed between two closely related, sympatric songbirds when experiencing identical rearing environments. Specifically, we used a cross-fostering approach to alter brood size and create an experimental gradient of nestmate competition, and then tested whether experimentally manipulated brood sizes resulted in nestlings with altered concentrations of corticosterone and whether corticosterone responses traded off with growth. 3. Nestlings of both species experienced elevated concentrations of baseline and stressor-induced corticosterone when raised in enlarged broods, relative to control and reduced broods, but neither measurement was found to trade off with growth or be linked to survival to fledging. 4. In contrast, we found divergence in the magnitude of the corticosterone stress response between species across all brood treatments, with greater stressor-induced corticosterone concentrations found in the Violet-green Swallow (Tachycineta thalassina) relative to the closely related Tree Swallow (T. bicolor). 5. Our study demonstrated that brood size can lead to changes in offspring corticosterone concentrations in swallows and that nestlings of sympatric species, even those that are closely related and ecologically similar, can diverge in their corticosterone stress response when experiencing identical rearing conditions. 6. We conclude that corticosterone appears to play a key role for balancing energetic demands that arise in the face of nestmate competition in Tachycineta swallows and that elevated concentrations of corticosterone may enhance offspring survival during challenging environmental conditions, such as when brood competition is strong

Pharmacokinetic profile of a 24-hour controlled-release OROS(® )formulation of hydromorphone in the presence and absence of food

BACKGROUND: The objective of this study was to compare the pharmacokinetic profile of a novel, once-daily, controlled-release formulation of hydromorphone (OROS(® )hydromorphone) under fasting conditions with that immediately after a high-fat breakfast in healthy volunteers. The effect of the opioid antagonist naltrexone on fasting hydromorphone pharmacokinetics also was evaluated. METHODS: In an open-label, three-way, crossover study, 30 healthy volunteers were randomized to receive a single dose of 16 mg OROS(® )hydromorphone under fasting conditions, 16 mg OROS(® )hydromorphone under fed conditions, or 16 mg OROS(® )hydromorphone under fasting conditions with a naltrexone 50-mg block. Plasma samples taken pre-dose and at regular intervals up to 48 hours post-dose were assayed for hydromorphone concentrations. Analysis of variance was performed on log-transformed data; for mean ratios of 0.8 to 1.2 (20%), differences were considered minimal. Bioequivalence was reached if 90% confidence intervals (CI) of treatment mean ratios were between 80% and 125%. RESULTS: The mean geometric ratios of the fed and fasting treatment groups for maximum plasma concentration (C(max)) and area under the concentration-time curve (AUC(0-t); AUC(0-∞)) were within 20%. Confidence intervals were within 80% to 125% for AUC(0-t )and AUC(0-∞ )but were slightly higher for C(max )(105.9% and 133.3%, respectively). With naltrexone block, the hydromorphone C(max )increased by 39% and the terminal half-life decreased by 4.5 hours. There was no significant change in T(max), AUC(0-t )or AUC(0-∞). CONCLUSION: Standard bioavailability measures show minimal effect of food on the bioavailability of hydromorphone from OROS(® )hydromorphone. Naltrexone co-administration results in a slight increase in the rate of absorption but not the extent of absorption. TRIAL REGISTRATION: Clinical Trials.gov NCT0039929

Redundant Mechanisms for Regulation of Midline Crossing in Drosophila

During development, all neurons have to decide on whether to cross the longitudinal midline to project on the contralateral side of the body. In vertebrates and invertebrates regulation of crossing is achieved by interfering with Robo signalling either through sorting and degradation of the receptor, in flies, or through silencing of its repulsive activity, in vertebrates. Here I show that in Drosophila a second mechanism of regulation exists that is independent from sorting. Using in vitro and in vivo assays I mapped the region of Robo that is sufficient and required for its interaction with Comm, its sorting receptor. By modifying that region, I generated new forms of Robo that are insensitive to Comm sorting in vitro and in vivo, yet still able to normally translate repulsive activity in vivo. Using gene targeting by homologous recombination I created new conditional alleles of robo that are sorting defective (roboSD). Surprisingly, expression of these modified proteins results in phenotypically normal flies, unveiling a sorting independent mechanism of regulation

Single neuron transcriptomics identify SRSF/ SR protein B52 as a regulator of axon growth and Choline acetyltransferase splicing.

We removed single identified neurons from living Drosophila embryos to gain insight into the transcriptional control of developing neuronal networks. The microarray analysis of the transcriptome of two sibling neurons revealed seven differentially expressed transcripts between both neurons (threshold: log(2)1.4). One transcript encodes the RNA splicing factor B52. Loss of B52 increases growth of axon branches. B52 function is also required for Choline acetyltransferase (ChAT ) splicing. At the end of embryogenesis, loss of B52 function impedes splicing of ChAT, reduces acetylcholine synthesis, and extends the period of uncoordinated muscle twitches during larval hatching. ChAT regulation by SRSF proteins may be a conserved feature since changes in SRSF5 expression and increased acetylcholine levels in brains of bipolar disease patients have been reported recently

Midline Signalling Systems Direct the Formation of a Neural Map by Dendritic Targeting in the Drosophila Motor System

During embryonic development of the motor system of Drosophila, motorneurons target their dendrites to different regions along the body axis in response to midline guidance cues

Sex-biased transcription enhancement by a 5' tethered Gal4-MOF histone acetyltransferase fusion protein in Drosophila

<p>Abstract</p> <p>Background</p> <p>In male <it>Drosophila melanogaster</it>, the male specific lethal (MSL) complex is somehow responsible for a two-fold increase in transcription of most X-linked genes, which are enriched for histone H4 acetylated at lysine 16 (H4K16ac). This acetylation requires MOF, a histone acetyltransferase that is a component of the MSL complex. MOF also associates with the non-specific lethal or NSL complex. The MSL complex is bound within active genes on the male X chromosome with a 3' bias. In contrast, the NSL complex is enriched at promoter regions of many autosomal and X-linked genes in both sexes. In this study we have investigated the role of MOF as a transcriptional activator.</p> <p>Results</p> <p>MOF was fused to the DNA binding domain of Gal4 and targeted to the promoter region of UAS-reporter genes in <it>Drosophila</it>. We found that expression of a UAS-red fluorescent protein (DsRed) reporter gene was strongly induced by Gal4-MOF. However, DsRed RNA levels were about seven times higher in female than male larvae. Immunostaining of polytene chromosomes showed that Gal4-MOF co-localized with MSL1 to many sites on the X chromosome in male but not female nuclei. However, in female nuclei that express MSL2, Gal4-MOF co-localized with MSL1 to many sites on polytene chromosomes but DsRed expression was reduced. Mutation of conserved active site residues in MOF (Glu714 and Cys680) reduced HAT activity <it>in vitro </it>and UAS-DsRed activation in <it>Drosophila</it>. In the presence of Gal4-MOF, H4K16ac levels were enriched over UAS-<it>lacZ </it>and UAS-<it>arm-lacZ </it>reporter genes. The latter utilizes the constitutive promoter from the <it>arm </it>gene to drive <it>lacZ </it>expression. In contrast to the strong induction of UAS-DsRed expression, UAS-<it>arm-lacZ </it>expression increased by about 2-fold in both sexes.</p> <p>Conclusions</p> <p>Targeting MOF to reporter genes led to transcription enhancement and acetylation of histone H4 at lysine 16. Histone acetyltransferase activity was required for the full transcriptional response. Incorporation of Gal4-MOF into the MSL complex in males led to a lower transcription enhancement of UAS-<it>DsRed </it>but not UAS-<it>arm-lacZ </it>genes. We discuss how association of Gal4-MOF with the MSL or NSL proteins could explain our results.</p

Somatic sex-specific transcriptome differences in Drosophila revealed by whole transcriptome sequencing

<p>Abstract</p> <p>Background</p> <p>Understanding animal development and physiology at a molecular-biological level has been advanced by the ability to determine at high resolution the repertoire of mRNA molecules by whole transcriptome resequencing. This includes the ability to detect and quantify rare abundance transcripts and isoform-specific mRNA variants produced from a gene.</p> <p>The sex hierarchy consists of a pre-mRNA splicing cascade that directs the production of sex-specific transcription factors that specify nearly all sexual dimorphism. We have used deep RNA sequencing to gain insight into how the Drosophila sex hierarchy generates somatic sex differences, by examining gene and transcript isoform expression differences between the sexes in adult head tissues.</p> <p>Results</p> <p>Here we find 1,381 genes that differ in overall expression levels and 1,370 isoform-specific transcripts that differ between males and females. Additionally, we find 512 genes not regulated downstream of <it>transformer </it>that are significantly more highly expressed in males than females. These 512 genes are enriched on the × chromosome and reside adjacent to dosage compensation complex entry sites, which taken together suggests that their residence on the × chromosome might be sufficient to confer male-biased expression. There are no transcription unit structural features, from a set of features, that are robustly significantly different in the genes with significant sex differences in the ratio of isoform-specific transcripts, as compared to random isoform-specific transcripts, suggesting that there is no single molecular mechanism that generates isoform-specific transcript differences between the sexes, even though the sex hierarchy is known to include three pre-mRNA splicing factors.</p> <p>Conclusions</p> <p>We identify thousands of genes that show sex-specific differences in overall gene expression levels, and identify hundreds of additional genes that have differences in the abundance of isoform-specific transcripts. No transcription unit structural feature was robustly enriched in the sex-differentially expressed transcript isoforms. Additionally, we found that many genes with male-biased expression were enriched on the × chromosome and reside adjacent to dosage compensation entry sites, suggesting that differences in sex chromosome composition contributes to dimorphism in gene expression. Taken together, this study provides new insight into the molecular underpinnings of sexual differentiation.</p