Fostering Innovation and Entrepreneurship: Shark Tank Shouldn\u27t be the Model

For the past half century, innovation has driven the economic growth that has made the American economy the envy of the world. For most of this period, venture capitalists provided not only the capital that new innovative companies needed, but also the management expertise

University Technology Transfer - Profit Centers or Black Holes: Moving Toward a More Productive University Innovation Ecosystem Policy

A great deal has been written over the years commenting on the strengths and weaknesses of the current system by which federal research funding has not produced the ideal results in terms of commercialization of inventions which are developed from such funding. The Bayh-Doyle Act was enacted in an attempt to provide a single uniform national policy which would cut through the government bureaucracy and encourage collaboration between universities and private industry to ensure that federally funded, commercially viable inventions were brought to market in an efficient manner. The question remains however, with the myriad of competing political and economic interests, can any legislation effectively address the myriad of conflicting interests and optimize such a complex system? This article looks at the various interest groups that provided amicus briefs in the 2011 Supreme Court decision in Stanford v. Roche, which highlights the diverse interests that attempted to weigh in on the case in an effort to ensure that their individual concerns were protected. As is the case with all legislation, it is difficult if not impossible to draw the proper balance between such interest groups when the ultimate objective is to develop a policy which is intended to promote the welfare of society in general, otherwise such optimal results would never be achieved. This article will provide a brief historical background on how our current policy has evolved over time, focusing on Roche to highlight the competing interests of the members of those organizations that are intimately involved in the research and commercialization process which bring discoveries that lead to inventions that benefit all of mankind. The articles will conclude by arguing that policy changes can and are being made to improve the commercialization process without the need for major legislative reform. What is required however is for collaboration to take place at the university level, with the keen understanding of the competing interests and economic realities particular to the local or regional environment in order to develop well-focused management strategies which form commercialization ecosystems to achieve the desired results. This is not a one size fits all proposition, but a coordinated effort that will take on many different forms depending on the particular university setting

Peptide ligand recognition by G protein-coupled receptors

Introduction: This study was conducted to investigate the effects of thyme extract in drinking water on immune response of broiler chickens. Methods: A total of 245-day-old broiler chicks were purchased and 20 chicks were bled for determination maternal antibody and remaining chicks were divided into 5 equal groups. Chickens of group A, B and C received 0.1%, 0.15% and 0.2% of Pediatric Cough Syrup including thyme extract respectively in drinking water for all of the experimental period. Chickens of group D were not received Pediatric Cough Syrup but vaccinated against Influenza disease. Chickens of group E were kept as control group and were not received Pediatric Cough Syrup and Influenza disease vaccine. Chickens of group A, B, C and D were vaccinated with AI-ND killed vaccine (subtype H9N2), subcutaneously in neck back. Blood samples were collected before vaccination as well as on days 14, 28 and 35 after vaccination. Ten chickens of each group were bled randomly and antibody titer against influenza vaccine virus was determined by hemagglutination inhibition (HI) test. Results: The results of the present study showed that Pediatric Cough Syrup including thyme extract at 0.2%, increased the specific antibody response against Influenza vaccine virus compared to all groups. Conclusion: Pediatric Cough Syrup including thyme extract can improve the specific antibody response against Influenza vaccine virus

Identification of small molecule inhibitors of Interleukin-18

Interleukin-18 (IL-18) is a pleiotropic pro-inflammatory cytokine belonging to the IL-1 superfamily. IL-18 plays an important role in host innate and adaptive immune defense but its aberrant activities are also associated with inflammatory diseases such as rheumatoid arthritis and Crohn's disease. IL-18 activity is modulated in vivo by its naturally occurring antagonist, IL-18 Binding Protein (IL-18BP). Recent crystal structures of human IL-18 (hIL-18) in complex with its antagonists or cognate receptor(s) have revealed a conserved binding interface on hIL-18. Through virtual screening of the National Cancer Institute Diversity Set II and in vitro competitive ELISA we have identified three compounds (NSC201631, NSC80734, and NSC61610) that disrupt hIL-18 binding to the ectromelia virus IL-18BP. Through cell-based bioassay, we show that NSC80734 inhibits IL-18-induced production of IFN-γ in a dose-dependent manner with an EC50 of ~250 nM. Our results and methodology presented here demonstrate the feasibility of developing small molecule inhibitors that specifically target the rather large interface of IL-18 that is involved in extensive protein-protein interactions with both IL-18BP and its cognate receptor(s). Our data therefore provide the basis for an approach by which small molecules can be identified that modulate IL-18 activity

Gambogic Acid, a Natural Product Inhibitor of Hsp90

A high-throughput screening of natural product libraries identified (−)-gambogic acid (1), a component of the exudate of Garcinia harburyi, as a potential Hsp90 inhibitor, in addition to the known Hsp90 inhibitor celastrol (2). Subsequent testing established that 1 inhibited cell proliferation, brought about the degradation of Hsp90 client proteins in cultured cells, and induced the expression of Hsp70 and Hsp90, which are hallmarks of Hsp90 inhibition. Gambogic acid also disrupted the interaction of Hsp90, Hsp70, and Cdc37 with the heme-regulated eIF2α kinase (HRI, an Hsp90-dependent client) and blocked the maturation of HRI in vitro. Surface plasmon resonance spectroscopy indicated that 1 bound to the N-terminal domain of Hsp90 with a low micromolar Kd, in a manner that was not competitive with the Hsp90 inhibitor geldanamycin (3). Molecular docking experiments supported the posit that 1 binds Hsp90 at a site distinct from Hsp90s ATP binding pocket. The data obtained have firmly established 1 as a novel Hsp90 inhibitor and have provided evidence of a new site that can be targeted for the development of improved Hsp90 inhibitors

Structure and dynamics of a constitutively active neurotensin receptor

Many G protein-coupled receptors show constitutive activity, resulting in the production of a second messenger in the absence of an agonist; and naturally occurring constitutively active mutations in receptors have been implicated in diseases. To gain insight into mechanistic aspects of constitutive activity, we report here the 3.3 Å crystal structure of a constitutively active, agonist-bound neurotensin receptor (NTSR1) and molecular dynamics simulations of agonist-occupied and ligand-free receptor. Comparison with the structure of a NTSR1 variant that has little constitutive activity reveals uncoupling of the ligand-binding domain from conserved connector residues, that effect conformational changes during GPCR activation. Furthermore, molecular dynamics simulations show strong contacts between connector residue side chains and increased flexibility at the intracellular receptor face as features that coincide with robust signalling in cells. The loss of correlation between the binding pocket and conserved connector residues, combined with altered receptor dynamics, possibly explains the reduced neurotensin efficacy in the constitutively active NTSR1 and a facilitated initial engagement with G protein in the absence of agonist

The R1441C mutation alters the folding properties of the ROC domain of LRRK2

LRRK2 is a 250 kDa multidomain protein, mutations in which cause familial Parkinson's disease. Previously, we have demonstrated that the R1441C mutation in the ROC domain decreases GTPase activity. Here we show that the R1441C alters the folding properties of the ROC domain, lowering its thermodynamic stability. Similar to small GTPases, binding of different guanosine nucleotides alters the stability of the ROC domain, suggesting that there is an alteration in conformation dependent on GDP or GTP occupying the active site. GTP/GDP bound state also alters the self-interaction of the ROC domain, accentuating the impact of the R1441C mutation on this property. These data suggest a mechanism whereby the R1441C mutation can reduce the GTPase activity of LRRK2, and highlights the possibility of targeting the stability of the ROC domain as a therapeutic avenue in LRRK2 disease

A Tribute to Joseph Edward Ulrich

This tribute honors Joseph Edward Ulrich, who in thirty-one years on the W&L Law faculty and in recent years as one-called-out-of-retirement, attained legendary status amidst fellow giants Roger Groot, Uncas McThenia, and Lash LaRue

Ligand and G-protein selectivity in the κ-opioid receptor

The κ-opioid receptor (KOR) represents a highly desirable therapeutic target for treating not only pain but also addiction and affective disorder