New Synthetic Cannabinoids Metabolism and Strategies to Best Identify Optimal Marker Metabolites.

Synthetic cannabinoids (SCs) were initially developed as pharmacological tools to probe the endocannabinoid system and as novel pharmacotherapies, but are now highly abused. This is a serious public health and social problem throughout the world and it is highly challenging to identify which SC was consumed by the drug abusers, a necessary step to tie adverse health effects to the new drug\u27s toxicity. Two intrinsic properties complicate SC identification, their often rapid and extensive metabolism, and their generally high potency relative to the natural psychoactive Δ 9 -tetrahydrocannabinol in cannabis. Additional challenges are the lack of reference standards for the major urinary metabolites needed for forensic verification, and the sometimes differing illicit and licit status and, in some cases, identical metabolites produced by closely related SC pairs, i.e., JWH-018/AM-2201, THJ-018/THJ-2201, and BB-22/MDMB-CHMICA/ADB-CHMICA. We review current SC prevalence, establish the necessity for SC metabolism investigation and contrast the advantages and disadvantages of multiple metabolic approaches. The human hepatocyte incubation model for determining a new SC\u27s metabolism is highly recommended after comparison to human liver microsomes incubation, in silico prediction, rat in vivo, zebrafish, and fungus Cunninghamella elegans models. We evaluate SC metabolic patterns, and devise a practical strategy to select optimal urinary marker metabolites for SCs. New SCs are incubated first with human hepatocytes and major metabolites are then identified by high-resolution mass spectrometry. Although initially difficult to obtain, authentic human urine samples following the specified SC exposure are hydrolyzed and analyzed by high-resolution mass spectrometry to verify identified major metabolites. Since some SCs produce the same major urinary metabolites, documentation of the specific SC consumed may require identification of the SC parent itself in either blood or oral fluid. An encouraging trend is the recent reduction in the number of new SC introduced per year. With global collaboration and communication, we can improve education of the public about the toxicity of new SC and our response to their introduction

An intertemporal, multi-region general equilibrium model of agricultural trade liberalization in the South Mediterranean NICs, Turkey, and the European Union

With the aid of an intertemporal, multi-region general equilibrium model, the authors study issues of agricultural trade liberalization, growth and capital accumulation in the context of a world economy moving towards a multi-polar structure. They specifically focus on Turkey, the European Union, the Middle East, and the Economies in Transition; and study alternative scenarios of formation of customs unions and increased trade orientation. The model is based on intertemporal general equilibrium theory with Ramsey-type dynamics. The world economy is fully endogenized within a 9-region specification, with Turkey, EU, Middle East and the Transition Economies constituting as one of the indigenous regions. A key feature of the model is its explicit recognition of both the commodity and foreign capital flows across regions in an endogenous setting, and its explicit portrayal of the out-of-steady state dynamics under an intertemporal optimization framework. They explore the short- versus the long-run economic impacts of alternative trade and investment policies on agricultural production, foreign trade, resource allocation, accumulation, consumer welfare, and income distribution in the regions of analyis. The results reveal significant gains from increased bilateral trade between the identified regions, and further underscore the crucial importance of financing commodity trade deficits in sustaining the accumulation patterns.Economics Models. ,Trade liberalization. ,Foreign trade Mathematical models. ,Agricultural trade. ,TMD ,

How Fiscal (Mis)-Management May Impede Trade Reform: Lessons From an Intertemporal, Multi-Sector General Equilibrium Model for Turkey

We utilize a multi-sector general equilibrium model based on intertemporally optimizing agents to study issues of trade liberalization and fiscal adjustments in the context of the Turkish economy. A key feature of the model is its explicit recognition of the distortionary consequences of excessive borrowing requirements of the public sector through increased domestic interest costs. The model results suggest that the postponement of adjustment to growing public debt and fiscal imbalances could be detrimental; and that in the absence of coordinated fiscal reforms, the welfare gains expected from trade liberalization may significantly be negated.International Relations/Trade,

Market opportunities for African agriculture: A General Equilibrium examination of demand-side constraints on agricultural growth in East and Southern Africa

"This report focuses on demand-side constraints on agricultural growth and their implications for three broad alternative agricultural development strategies: promoting traditional exports, developing nontraditional exports, and increasing food staple growth. We address three major questions. First, how constraining will demand be for future agricultural growth in East and Southern Africa and, in particular, is there sufficient demand to permit agriculture to grow at a rate that can significantly reduce poverty and hunger? Second, if technological change and increase in supply are achieved, which agricultural subsectors offer the greatest potential and can become the most powerful vehicles for raising real incomes and increasing food consumption? Finally, what are the implications of reductions in marketing costs and growth linkages with nonagricultural sectors for achieving increased market demand for agricultural products? The report applies a general equilibrium framework for the analysis, focusing on seven East and Southern African countries—Madagascar, Malawi, Mozambique, Tanzania, Uganda, Zambia, and Zimbabwe—and finds that an export-led agricultural growth strategy is unlikely to generate substantial overall income growth in these countries." from Authors' SummaryAgricultural growth, exports, Poverty reduction, General equilibrium model, food consumption, Markets, income growth,

Market opportunities for African agriculture

"Rapid growth in the agricultural sector is central to any strategy for slashing poverty and hunger on the African continent. Yet investments aimed at increasing agricultural productivity need to be linked to market opportunities if they are not to depress commodity prices and farm incomes. It is widely perceived that high market transaction costs, weak domestic consumer demand, and lack of export possibilities are major constraints on agricultural growth prospects for Africa. But just how severe are these constraints, and what can be done to enhance market opportunities to enable agriculture to become a more powerful engine of growth for the continent? This study addresses these questions. It concludes that non-traditional exports have the fewest constraints and remain the most profitable option for increasing export earnings.....Thus, investments in agriculture and other efforts to promote higher agricultural productivity growth need to be complemented with policies and investments to spur non-agricultural growth. More generally, investments in rural infrastructure can help to maximize positive linkage effects of agricultural growth. Agricultural growth can play a major role in increasing food supply, but sustained increases in incomes and reductions in poverty are likely to require a combination of labor-intensive growth in both agricultural and nonagricultural activities." from Authors' Abstract

Penetrance estimates for incidental genomic findings in ACMG-59

The dropping costs and rising popularity of next-generation sequencing has introduced the possibility of personalizing medical treatments and screening for genetic diseases. Still, the clinical community’s understanding remains incomplete, with limited consensus on the proper interpretation for many genetic variants. Thus, the standard procedure when returning sequencing results has been to report findings only in genes related to the diagnostic indication, and not incidental findings in other genes. To balance the threat of false positives with the medical benefits of true findings, the American College on Medical Genetics and Genomics (ACMG) recommends an exception: that clinical sequencing laboratories seek and report incidental findings in a specific set of 56 genes (ACMG-56), in which variants are considered to have a greater likelihood of causing disease. The clinical value of these recommendations are evaluated using the metric of penetrance, defined as the probability that a patient who tests positive will later develop the disease. We queried the public 1000 Genomes Project to obtain whole genome data for 2,504 healthy individuals from diverse ethnic populations. Pathogenic variants were identified using the central repository ClinVar, and found to be distributed unevenly across ancestral groups in this cohort, and incidental findings were found to be inflated relative to empirical disease prevalence. Quantitative risk estimates were derived by modeling penetrance as a function of disease prevalence, allele frequency, and allelic heterogeneity. Plausible ranges for these parameters were estimated from the 1000 Genomes Project cohort and the medical literature. Under the most generous assumptions, the maximum overall penetrance estimates for the majority of diseases fall under 50%, with many under 5%. Penetrance estimates were also shown to vary significantly between ancestral groups, stemming from allele frequency differences between these groups

A Dynamic CGE Model: An Application of R&D- Based Endogenous Growth Model Theory

An R&D based endogenous growth - applied general equilibrium model is developed from an underlying analytical model which combines Romer's capital variety with Grossman and Helpman's multi-sector open economy model. The transitional dynamics of the analytical model are derived. For numerical implementation, a time discrete empirical model, with an Armington structure, is fit to East Asian data of the social accounting matrix variety. Simulations of trade reform are performed and their static and dynamic effects compared. The transition paths of the state variables are found to have a half-life of five to six periods. A solution of the Social Planner's problem, and interventions which seek to obtain this outcome from the decentralized model are also obtained'.Applied General Equilibrium, Trade, Growth, International Relations/Trade, F11, 031, 041,

Functional study of a novel missense single-nucleotide variant of NUP107 in two daughters of Mexican origin with premature ovarian insufficiency.

BackgroundHypergonadotropic hypogonadism (HH) is a genetically heterogeneous disorder that usually presents with amenorrhea, atrophic ovaries, and low estrogen. Most cases of HH are idiopathic and nonsyndromic. Nucleoporin 107 (NUP107), a protein involved in transport between cytoplasm and nucleus with putative roles in meiosis/mitosis progression, was recently implicated as a cause of HH. We identified a NUP107 genetic variant in a nonconsanguineous family with two sisters affected with primary amenorrhea and HH, and generated a mouse model that carried the human variant.MethodsWe performed a high-resolution X-chromosome microarray and whole exome sequencing on parents and two sisters with HH to identify pathogenic variants. We generated a mouse model of candidate NUP107 variant using CRISPR/Cas9.ResultsWhole exome sequencing identified a novel and rare missense variant in the NUP107 gene (c.1063C>T, p.R355C) in both sisters with HH. In order to determine functional significance of this variant, we used CRISPR/Cas9 to introduce the human variant into the mouse genome. Mice with the homolog of the R355C variant, as well as the nine base pairs deletion in Nup107 had female subfertility.ConclusionsOur findings indicate that NUP107 R355C variant falls in the category of variant of unknown significance as the cause of HH and infertility

Thermo-mechanical sensitivity calibration of nanotorsional magnetometers

We report on the fabrication of sensitive nanotorsional resonators, which can be utilized as magnetometers for investigating the magnetization dynamics in small magnetic elements. The thermo-mechanical noise is calibrated with the resonator displacement in order to determine the ultimate mechanical torque sensitivity of the magnetometer.Comment: 56th Annual Conference on Magnetism and Magnetic Material