The Application of National Law and Composite Procedures in the Single Supervisory Mechanism. Did the Court of Justice of the EU find a New Van Gend en Loos?

The Single Supervisory Mechanism (SSM) represents the most recent legal novelty in EU law. The SSM has created a hybrid dual administration formed by both national and European authorities. The application of national law and composite procedures make it more difficult to distinguish, in practice, which courts should be responsible for evaluating the legality of the measures adopted. This article attempts to analyse the existence of a gap in the current system of legal protection, and suggests some proposals to continue to guarantee access to courts and a complete and coherent system of judicial remedies under EU law. A possible extension of the approach used by the Court of Justice in the Rimšēvičs case could be considered in areas where there is a less marked distinction between EU and national law, such as in the SSM. Following this principle, the Court should be able to directly annul any national act that contravenes EU law.

GST and its Impact on Small and Medium Scale Enterprises - A Study of Peenya Industrial Area in Banglaore, Karnataka

The introduction of Goods and Service Tax on 1st July, 2017 has revamped the tax structure and carved out a new path for the Indian economy. The new tax regime was envisioned to be free of all the problems of the previous tax system but, however since its proposal it has received mixed reviews from industries, academia and others. With extensive changes aimed at One Nation One Tax, it has left massive impact on the Small Scale Industries too. Hence this paper critically analyses the impact of Goods and Service Tax (GST) on Small Scale Industries specifically in Karnataka. Existing literature says that GST shall reduce the cost of doing business, increases transparency, decreases prices of product, increase tax compliance and improve ease of doing business. This paper proves some of these assertions through a primary data research and further identifies the need of reforms with respect to separation of definition of job work and labour work, penalties for non-payment of GST, dual administration and issues pending from the previous tax regime. It has also clearly established that composition scheme has been a non-performer and the reverse charge mechanism must be re-introduced later or revamped to balance its costs and benefits. Thus the study has implications for policy makers, industries and academia and also provides a better understanding of the new tax system itself.

Cyclin-dependent kinase inhibitors exert distinct effects on patient-derived 2D and 3D glioblastoma cell culture models

Current therapeutic approaches have met limited clinical success for glioblastoma multiforme (GBM). Since GBM harbors genomic alterations in cyclin-dependent kinases (CDKs), targeting these structures with specific inhibitors (CDKis) is promising. Here, we describe the antitumoral potential of selective CDKi on low-passage GBM 2D- and 3D models, cultured as neurospheres (NSCs) or glioma stem-like cells (GSCs). By applying selective CDK4/6i abemaciclib and palbociclib, and the more global CDK1/2/5/9-i dinaciclib, different effects were seen. Abemaciclib and dinaciclib significantly affected viability in 2D- and 3D models with clearly visible changes in morphology. Palbociclib had weaker and cell line-specific effects. Motility and invasion were highly affected. Abemaciclib and dinaciclib additionally induced senescence. Also, mitochondrial dysfunction and generation of mitochondrial reactive oxygen species (ROS) were seen. While autophagy was predominantly visible after abemaciclib treatment, dinaciclib evoked γ-H2AX-positive double-strand breaks that were boosted by radiation. Notably, dual administration of dinaciclib and abemaciclib yielded synergistic effects in most cases, but the simultaneous combination with standard chemotherapeutic agent temozolomide (TMZ) was antagonistic. RNA-based microarray analysis showed that gene expression was significantly altered by dinaciclib: genes involved in cell-cycle regulation (different CDKs and their cyclins, SMC3), mitosis (PLK1, TTK), transcription regulation (IRX3, MEN1), cell migration/division (BCAR1), and E3 ubiquitination ligases (RBBP6, FBXO32) were downregulated, whereas upregulation was seen in genes mediating chemotaxis (CXCL8, IL6, CCL2), and DNA-damage or stress (EGR1, ARC, GADD45A/B). In a long-term experiment, resistance development was seen in 1/5 cases treated with dinaciclib, but this could be prevented by abemaciclib. Vice versa, adding TMZ abrogated therapeutic effects of dinaciclib and growth was comparable to controls. With this comprehensive analysis, we confirm the therapeutic activity of selective CDKi in GBM. In addition to the careful selection of individual drugs, the timing of each combination partner needs to be considered to prevent resistance.

Management and “Administerization” in China's Higher Education System: A View from the Trenches

Scholarship on university autonomy in China's higher education system in the past three decades has focused on the macro-relationship between the party-state and university leadership. This paper focuses instead on university-level management practices and college-level academic autonomy. Drawing on the discourse of “administerization” and “de-administerization” within Chinese academia, we demonstrate how the dual administration system and outdated management practices common in the higher education system limit academic quality and educational autonomy at the college level.

Targeting Thymidine Phosphorylase With Tipiracil Hydrochloride Attenuates Thrombosis Without Increasing Risk of Bleeding in Mice

Objective: Current antiplatelet medications increase the risk of bleeding, which leads to a clear clinical need in developing novel mechanism-based antiplatelet drugs. TYMP (Thymidine phosphorylase), a cytoplasm protein that is highly expressed in platelets, facilitates multiple agonist-induced platelet activation, and enhances thrombosis. Tipiracil hydrochloride (TPI), a selective TYMP inhibitor, has been approved by the Food and Drug Administration for clinical use. We tested the hypothesis that TPI is a safe antithrombotic medication. Approach and Results: By coexpression of TYMP and Lyn, GST (glutathione S-transferase) tagged Lyn-SH3 domain or Lyn-SH2 domain, we showed the direct evidence that TYMP binds to Lyn through both SH3 and SH2 domains, and TPI diminished the binding. TYMP deficiency significantly inhibits thrombosis in vivo in both sexes. Pretreatment of platelets with TPI rapidly inhibited collagen- and ADP-induced platelet aggregation. Under either normal or hyperlipidemic conditions, treating wild-type mice with TPI via intraperitoneal injection, intravenous injection, or gavage feeding dramatically inhibited thrombosis without inducing significant bleeding. Even at high doses, TPI has a lower bleeding side effect compared with aspirin and clopidogrel. Intravenous delivery of TPI alone or combined with tissue plasminogen activator dramatically inhibited thrombosis. Dual administration of a very low dose of aspirin and TPI, which had no antithrombotic effects when used alone, significantly inhibited thrombosis without disturbing hemostasis. Conclusions: This study demonstrated that inhibition of TYMP, a cytoplasmic protein, attenuated multiple signaling pathways that mediate platelet activation, aggregation, and thrombosis. TPI can be used as a novel antithrombotic medication without the increase in risk of bleeding.

Brain-Specific Inhibition of mTORC1 by a Dual Drug Strategy: A Novel Approach for the Treatment of Alcohol Use Disorder

Alcohol Use Disorder (AUD) is a devastating psychiatric disorder affecting a large portion of the population. Unfortunately, efficacious medications to treat the disease are limited and thus AUD represents an area of unmet medical need. mTORC1 plays a crucial role in neuroadaptations underlying alcohol use. mTORC1 also contributes to alcohol craving, habit, and relapse. Thus, mTORC1 inhibitors are promising therapeutic agents to treat AUD. However, chronic inhibition of mTORC1 in the periphery produces undesirable side effects in humans, which limit their potential clinical use for the treatment of AUD. To overcome these limitations, we utilized a binary drug strategy in which mice were co-administered the mTORC1 inhibitor RapaLink-1 together with a novel small molecule (RapaBlock) to protect mTORC1 activity in the periphery. We show that the dual administration of RapaLink-1 with RapaBlock, abolishes RapaLink-1-dependent mTORC1 inhibition in the liver and blocks adverse side effects detected in humans including body weight loss, glucose intolerance and liver toxicity. Importantly, we show that co-administration of RapaLink-1 and RapaBlock inhibits alcohol-dependent mTORC1 activation in the Nucleus Accumbens and robustly moderates the level of alcohol use. Our data present a novel approach that could be used to treat individuals suffering from AUD.

Targeting Thymidine Phosphorylase with Tipiracil Hydrochloride is a Safe and Effective Antithrombotic Therapy

RationaleMost of the current anti-platelet drugs inhibit platelet function permanently and have systemic side effects, including thrombocytopenia and hemorrhage. We previously found that thymidine phosphorylase (TYMP), a platelet cytoplasmic protein, facilitates multiple agonist induced platelet activation and enhances thrombosis. A specific TYMP inhibitor, namely, tipiracil hydrochloride (TPI), has been approved by the U.S. Food and Drug Administration for clinical use as an auxiliary drug making it possible to be repositioned as an anti-platelet medicine.ObjectiveWe aimed to test the hypothesis that TPI is a novel and safe anti-platelet drug by examining its role in platelet activation and thrombosis using both in vitro and in vivo studies.Methods and ResultsBy co-expression of TYMP and Lyn or Lyn-SH3 domain tagged with glutathione S-transferase, we showed the direct evidence that TYMP binds to the SH3 domain in its partners. TYMP haplodeficiency is sufficient to inhibit thrombosis in vivo regardless of gender. TPI treatment rapidly inhibited collagen- and ADP-induced platelet aggregation, which copied the phenotype of TYMP deficient platelets. Under both normal and hyperlipidemic conditions, treating wild type (WT) mice with TPI via intraperitoneal injection, intravenous injection, or gavage feeding dramatically inhibited thrombosis without inducing significant bleeding. Even administered above the effective dose, TPI has a lower bleeding side effect compared to aspirin and clopidogrel. Most importantly, intravenously delivery of TPI alone or combined with tissue plasminogen activator dramatically inhibited the growth of developing thrombi. Dual administration of very low dose of aspirin and TPI also dramatically inhibited thrombosis without disturbing hemostasis.ConclusionThis pharmacological study demonstrated that TYMP participates in multiple signaling pathways in platelet and plays a mechanistic role in regulating platelet activation and thrombosis. TPI, a specific TYMP inhibitor, would be a novel safe anti-platelet and anti-thrombosis medicine.

Inhibition of 15-PGDH Protects Mice from Immune-mediated Bone Marrow Failure

Aplastic anemia (AA) is a human immune mediated bone-marrow failure syndrome that is treated by stem cell transplantation for patients who have a matched related donor or immunosuppressive therapy (IST) for those who do not. Responses to IST are variable, with patients still at risk for prolonged neutropenia, transfusion-dependence, immune suppression, and severe opportunistic infections. Therefore, additional therapies to accelerate hematologic recovery in patients receiving front line IST are needed. We have shown that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) with the small molecule SW033291 (PGDHi) increases bone marrow (BM) prostaglandin E2 levels, expands hematopoietic stem cell (HSC) numbers, and accelerates hematologic reconstitution following murine BM transplantation. We now report that in a murine model of immune-mediated BM failure, PGDHi therapy mitigated cytopenias, increased BM HSC and progenitor cells, and significantly extended survival compared to vehicle-treated mice. PGDHi protection was not immune-mediated, as serum IFNγ levels and BM CD8+ T lymphocyte frequencies were not impacted. Moreover, dual administration of PGDHi plus low dose IST enhanced total white blood cell, neutrophil and platelet recovery, achieving responses similar to maximal dose IST at lesser toxicity. Together these data demonstrate that PGDHi can complement IST to accelerate hematologic recovery and reduce morbidity in severe AA.