Substitution Laws and Innovation in the Pharmaceutical Industry

When the sensors readings are perturbed by an unknown stochastic time jitter, classical system identification algorithms based on additive amplitude perturbations will give biased estimates. We here outline the maximum likelihood procedure, for the case of both time and amplitude noise, in the frequency domain, based on the measurement DFT. The method directly applies to output error continuous time models, while a simple sinusoid in noise example is used to illustrate the bias removal of the proposed method

Efficiently Combining Human Demonstrations and Interventions for Safe Training of Autonomous Systems in Real-Time

This paper investigates how to utilize different forms of human interaction to safely train autonomous systems in real-time by learning from both human demonstrations and interventions. We implement two components of the Cycle-of-Learning for Autonomous Systems, which is our framework for combining multiple modalities of human interaction. The current effort employs human demonstrations to teach a desired behavior via imitation learning, then leverages intervention data to correct for undesired behaviors produced by the imitation learner to teach novel tasks to an autonomous agent safely, after only minutes of training. We demonstrate this method in an autonomous perching task using a quadrotor with continuous roll, pitch, yaw, and throttle commands and imagery captured from a downward-facing camera in a high-fidelity simulated environment. Our method improves task completion performance for the same amount of human interaction when compared to learning from demonstrations alone, while also requiring on average 32% less data to achieve that performance. This provides evidence that combining multiple modes of human interaction can increase both the training speed and overall performance of policies for autonomous systems.Comment: 9 pages, 6 figure

Mexico\u27s Accession to the GATT: A Catalyst at Odds with the Outcome.

The history behind Mexico’s accession to the General Agreement on Tariffs and Trade (GATT) sheds light on Mexico’s progression toward improved bilateral trade relations with the United States. Mexico embarked on its modernization and reform path with its accession to the GATT in 1987. The recent initialing of the North American Free Trade Agreement (NAFTA) by Canada, Mexico, and the United States is a symbolic event in the continued globalization of the world economy. The trilateral NAFTA is revolutionary because of Mexico’s participation. Part II of this article addresses Mexico’s progression toward accession to the GATT. Part III provides an overview of stages in improved bilateral trade relations between the United States and Mexico and negotiations in the multilateral Uruguay Round, all of which aid the foundation for the NAFTA. Finally, Part IV addresses the relationship of the NAFTA and the GATT in light of their probable coexistence in the future and focuses on dispute resolution. The turning point for Mexico’s departure from its protectionist trade policies of the past was accession to the GATT. This move symbolized Mexico’s commitment to liberalization and modernization. Accession to the GATT was critical to improving trade relations between Mexico and its trading partners. In 1986, Mexico and the United States embarked on the road towards the free trade proposed under the initialed NAFTA text. These negotiations led to a series of bilateral trade understandings between the countries which proved freer trade could be negotiated, and thus laid the foundation for the NAFTA. The NAFTA preserves the GATT’s dispute-resolution procedures by allowing the complaining party to choose between the NAFTA and the GATT. This provision reflects the NAFTA’s respect for the multilateral trading system and the belief that regional trading agreements may exist within the multilateral trading system established by the GATT

Montpellier broom (Genista monspessulana) and Spanish broom (Spartium junceum) in South Africa: An assessment of invasiveness and options for management

AbstractThe legumes (Fabaceae) Genista monspessulana and Spartium junceum are major invaders in several other parts of the world, but not yet so in South Africa. We determine their current distributions in South Africa at different spatial scales, assess population structure (soil seed banks and size at reproduction) evaluate current management activities, and provide recommendations for control (including assessing the feasibility of nation-wide eradication). G. monspessulana occurs at nine localities in three quarter-degree cells, covering a total of 22.7ha. S. junceum is much more widespread, occurring in 33 quarter-degree cells and is frequently cultivated in private gardens. All naturalised or invasive populations are in disturbed areas, mostly along roadsides. Once established, G. monspessulana and S. junceum accumulate large, persistent soil-stored seed banks, ranging in size between 909 and 22,727 (median 1970)seeds/m2 and 0 and 21,364 (median 455)seeds/m2 for the two species respectively. Both species resprout vigorously after cutting and stump herbicide application (60% of G. monspessulana and 43% of S. junceum plants resprouted) which necessitates regular follow-ups. We estimate that over 10years, at a cost of about ZAR 81,000 (1 ZAR=0.114 US$ as on 6 October 2012), G. monspessulana could be extirpated from South Africa. S. junceum is far more widespread and coupled with low effectiveness of control, abundance of seeds and seed longevity, eradication is unfeasible. We recommend that control methods used for S. junceum be improved to prevent resprouting, and that areas are managed to limit the movement of seeds and avoid further spread and establishment. Further studies are required to understand why these two species have failed to replicate the invasiveness shown in other parts of the world

Planning for Free Trade: Taking Advantage of the Transition.

After two decades of restrictive policies regarding foreign involvement, Mexico is transforming its legal and regulatory structure. The progression of foreign investment, technology transfer, and industrial property laws and regulations is revealing. The significance of the overhaul of the industrial property and technology transfer framework in Mexico is evident considering the historical context in which it developed. With these reforms in place, Mexico significantly improved the conditions for placing U.S. franchises across the border. Mexico decreased tariff rates, eliminated import licenses for numerous products, and divested over half of the businesses previously owned or operated by the state. It also tempered restrictions on foreign investment, increased protection of industrial property, and abolished impediments to the transfer of technology. Part II of this Article addresses Mexico’s approach to foreign investment in its economy over a period of approximately seventy years, concluding with the 1989 regulatory enactments by President Salinas. Part III deals specifically with the gradual implementation of restrictions on the transfer of technology and the limitations on industrial property protections. The resulting web of regulations implemented over the years was torn down by the 1991 industrial property law, the specifications of which are discussed in part IV. Concluding remarks are made in part V. The recent initiatives President Salinas took are testimony to the economic transformation underway in Mexico. There is no need to wait on the full realization of a NAFTA. With the reforms the Salinas Administration made, Mexico made itself a more inviting destination for U.S. investors. A corresponding increase in the level of foreign activity in the country shows no signs of reversal. The walls surrounding the business opportunities in Mexico are rapidly disintegrating and, for the well positioned business, the time for expansion is now

Protein coingestion with alcohol following strenuous exercise attenuates alcohol-induced intramyocellular apoptosis and inhibition of autophagy

Alcohol ingestion decreases postexercise rates of muscle protein synthesis, but the mechanism(s) (e.g., increased protein breakdown) underlying this observation is unknown. Autophagy is an intracellular “recycling” system required for homeostatic substrate and organelle turnover; its dysregulation may provoke apoptosis and lead to muscle atrophy. We investigated the acute effects of alcohol ingestion on autophagic cell signaling responses to a bout of concurrent (combined resistance- and endurance-based) exercise. In a randomized crossover design, eight physically active males completed three experimental trials of concurrent exercise with either postexercise ingestion of alcohol and carbohydrate (12 ± 2 standard drinks; ALC-CHO), energy-matched alcohol and protein (ALC-PRO), or protein (PRO) only. Muscle biopsies were taken at rest and 2 and 8 h postexercise. Select autophagy-related gene (Atg) proteins decreased compared with rest with ALC-CHO (P < 0.05) but not ALC-PRO. There were parallel increases (P < 0.05) in p62 and PINK1 commensurate with a reduction in BNIP3 content, indicating a diminished capacity for mitochondria-specific autophagy (mitophagy) when alcohol and carbohydrate were coingested. DNA fragmentation increased in both alcohol conditions (P < 0.05); however, nuclear AIF accumulation preceded this apoptotic response with ALC-CHO only (P < 0.05). In contrast, increases in the nuclear content of p53, TFEB, and PGC-1α in ALC-PRO were accompanied by markers of mitochondrial biogenesis at the transcriptional (Tfam, SCO2, and NRF-1) and translational (COX-IV, ATPAF1, and VDAC1) level (P < 0.05). We conclude that alcohol ingestion following exercise triggers apoptosis, whereas the anabolic properties of protein coingestion may stimulate mitochondrial biogenesis to protect cellular homeostasis

The muscle proteome reflects changes in mitochondrial function, cellular stress and proteolysis after 14 days of unilateral lower limb immobilization in active young men

Skeletal muscle unloading due to joint immobilization induces muscle atrophy, which has primarily been attributed to reductions in protein synthesis in humans. However, no study has evaluated the skeletal muscle proteome response to limb immobilization using SWATH proteomic methods. This study characterized the shifts in individual muscle protein abundance and corresponding gene sets after 3 and 14 d of unilateral lower limb immobilization in otherwise healthy young men. Eighteen male participants (25.4 ±5.5 y, 81.2 ±11.6 kg) underwent 14 d of unilateral knee-brace immobilization with dietary provision and following four-weeks of training to standardise acute training history. Participant phenotype was characterized before and after 14 days of immobilization, and muscle biopsies were obtained from the vastus lateralis at baseline (pre-immobilization) and at 3 and 14 d of immobilization for analysis by SWATH-MS and subsequent gene-set enrichment analysis (GSEA). Immobilization reduced vastus group cross sectional area (-9.6 ±4.6%, P <0.0001), immobilized leg lean mass (-3.3 ±3.9%, P = 0.002), unilateral 3-repetition maximum leg press (-15.6 ±9.2%, P <0.0001), and maximal oxygen uptake (-2.9 ±5.2%, P = 0.044). SWATH analyses consistently identified 2281 proteins. Compared to baseline, two and 99 proteins were differentially expressed (FDR <0.05) after 3 and 14 d of immobilization, respectively. After 14 d of immobilization, 322 biological processes were different to baseline (FDR <0.05, P <0.001). Most (77%) biological processes were positively enriched and characterized by cellular stress, targeted proteolysis, and protein-DNA complex modifications. In contrast, mitochondrial organization and energy metabolism were negatively enriched processes. This study is the first to use data independent proteomics and GSEA to show that unilateral lower limb immobilization evokes mitochondrial dysfunction, cellular stress, and proteolysis. Through GSEA and network mapping, we identify 27 hub proteins as potential protein/gene candidates for further exploration

Complete Spontaneous Regression of Pulmonary Metastatic Melanoma

Complete spontaneous regression of melanoma metastatic to the lungs is a rare event. objective . To report a case of biopsy-proven melanoma metastatic to the lung with complete spontaneous regression. methods . Multidisciplinary case report. results . A 35-year-old white female was diagnosed with metastatic melanoma to the lung. A pleural biopsy confirmed the diagnosis. Partial spontaneous regression was noted by a staging computed tomography scan prior to enrollment in an investiga-tional protocol. Complete spontaneous regression occurred over 5 months without any form of conventional or alternative therapy, and the patient remains disease-free 3 years after diagnosis. conclusions . Our case represents the seventh case of complete spontaneous regression of melanoma metastatic to the lung, and the only case with histologic confirmation of both the primary and pulmonary metastatic lesions. The patient was pregnant twice between the time of her initial diagnosis of primary melanoma and pulmonary metastatic disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75559/1/j.1524-4725.1998.tb04275.x.pd