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During the 2008 to 2012 period, the US Border Patrol enacted new sanctions on migrants apprehended while attempting to enter the United States illegally. Using administrative records on apprehensions of Mexican nationals that include fingerprint-based IDs and other details, we detect if an apprehended migrant is subject to penalties and if he is later reapprehended. Exploiting plausibly random variation in the rollout of sanctions, we estimate econometrically that exposure to penalties reduced the 18-month reapprehension rate for males by 4.6 to 6.1 percentage points off of a baseline rate of 24.2 percent. These magnitudes imply that sanctions can account for 28 to 44 percent of the observed decline in recidivism in apprehensions. Further results suggest that the drop in recidivism was associated with a reduction in attempted illegal entry. (JEL K37, J15, J18)

A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound 2), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound 24, a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 24 led to a rapid dose- and time-dependent decrease of pSer2-RNAP2 and Mcl-1, resulting in cell apoptosis in multiple hematological cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound 24 is currently in clinical trials for the treatment of hematological malignancies.

We evaluate the impacts of the Customs and Border Protection (CBP) Center of Excellence and Expertise (CEE) Program on the U.S. trade community. CBP established ten CEEs in order to facilitate trade by removing non‐tariff barriers. CEEs process importers at “virtual” centres as opposed to individual ports of entry, and they are specialised according to particular sectors. CEEs were anticipated to use government resources more efficiently, reduce paperwork, improve information flows and contribute towards a single window for documenting trade. We use difference‐in‐difference (DID) analysis of CBP administrative data to identify the impacts of importer membership in a CEE on key outcomes, including import shipment examination rates and form filings. We also use survey‐generated data on importer administrative and business costs in order to monetise the value of impacts. These data reveal that the cost to importers of having a shipment examined at a port is roughly ten to twenty times higher than the cost of importers having to file a form with a CEE. Estimated impact results suggest that two of the ten CEEs‐‐Electronics and Automotive‐‐had a statistically significant negative impact on examination rates. We review the reasons for these results, which underscore the need when doing an impact analysis for careful understanding of the underlying data and processes involved in order to develop and explain impact results. For the two CEEs that had significant impacts on import examinations, we quantify the monetary value of these impacts and estimate that they saved their members roughly $1 million in trade examination costs in FY 2014. We also estimate that expanding membership to cover more importers could yield savings of between $7 million and $18 million annually. Finally, we find that CBP could redirect approximately 9,000 import examinations and 7,000 form filings from lower‐risk CEE importers to higher‐risk importers, possibly increasing trade‐enforcement effectiveness.

Phosphatidyl inositol (4,5)-bisphosphate (PI(4,5)P

As part of a medicinal chemistry program, we adapted known synthetic methods for the late-stage diversification of 2,4-substituted 7-azaindoles. The strengths and weaknesses of these strategies are discussed. In the course of this work, three optimized conditions were identified from an iterative catalyst screen for the conversion of Boc-protected 4-chloro-2-(piperidin-4-yl)-7-azaindole to the corresponding pinacol borate ester. Additionally, a scalable route to previously unreported Boc-protected 4-bromo-2-(piperidin-4-yl)-7-azaindole and efficient conversion to the corresponding pinacol borate ester in 72% isolated yield are also disclosed.

A novel estrogen receptor down-regulator, 7-hydroxycoumarin (5, SS5020), has been reported with antitumor effects against chemically induced mammary tumors. Here, we report on our own investigation of 7-hydroxycoumarins as potential selective estrogen receptor down-regulators, which led us to the discovery of potent down-regulating antagonists, such as 33. Subsequent optimization and removal of the 7-hydroxy group led to coumarin 59, which had increased potency and improved rat bioavailability relative to SS5020.

N-(5-Bromo-3-methoxypyrazin-2-yl)-5-chlorothiophene-2-sulfonamide 1 was identified as a hit in a CCR4 receptor antagonist high-throughput screen (HTS) of a subset of the AstraZeneca compound bank. As a hit with a lead-like profile, it was an excellent starting point for a CCR4 receptor antagonist program and enabled the rapid progression through the Lead Identification and Lead Optimization phases resulting in the discovery of two bioavailable CCR4 receptor antagonist candidate drugs.

Although desirable from a medicinal chemistry perspective, the differentially substituted 3,6-diaminopyridazine moiety is a highly challenging target using current literature approaches. Recent methods of Ullmann-type couplings are evaluated and a mild route to prepare these structures from iodide precursors is presented.

A series of pyrazole inhibitors of the human FPR1 receptor have been identified from high throughput screening. The compounds demonstrate potent inhibition in human neutrophils and attractive physicochemical and in vitro DMPK profiles to be of further interest.

A new, efficient and practical synthesis of quinazolin-4(3H)-ones is reported via molybdenum-mediated cyclocarbonylation using microwave irradiation. These methods allow access to a wide range of quinazolin-4(3H)-ones in reasonable yields without the need for gaseous carbon monoxide and palladium catalysts. A range of reactions illustrating the wide scope of this chemistry was carried out and all proceeded in reasonable yields.

We report a mild and efficient method for introducing deuterium into a range of heterocycles by reacting readily available halide analogues in a deuterodehalogenation reaction using D8-IPA or Et3SiD under palladium-catalysed conditions.

A new, practical synthesis of aryl and heteroaryl N-acylureas has been developed via palladium-catalysed carbonylation of aryl or heteroaryl halides in the presence of urea nucleophiles. A range of reactions illustrating the wide scope of this reaction was carried out under microwave irradiation, using either carbon monoxide gas in a vessel equipped with a gas inlet adapter, or molybdenum hexacarbonyl as the carbon monoxide source in standard microwave vials. The reactions proceeded in good to excellent yields. To illustrate the usefulness of this method a one-step synthesis of the important insecticide diflubenzuron is reported.

A novel, simple synthesis of aryl and heteroaryl acyl sulfamides has been developed via palladium-catalyzed carbonylation of aryl or heteroaryl halides in the presence of sulfamide nucleophiles. A range of reactions illustrating the wide scope of this reaction was carried out under microwave irradiation in a vessel equipped with a gas inlet adapter and proceeded in good to excellent yields.

A series of tetrahydroisoquinoline phenols was modified to give an estrogen receptor downregulator-antagonist profile. Optimization around the core, alkyl side chain, and pendant aryl ring resulted in compounds with subnanomolar levels of potency. The phenol functionality was shown to be required to achieve highly potent compounds, but unusually this was compatible with obtaining high oral bioavailabilities in rat.

In the absence of any steric directing group, the title reaction proceeds selectively at C-3 of the indazole skeleton.

In the absence of a steric directing group, iridium-catalyzed C–H borylation of N-protected indazoles occurs rapidly and selectively at C-3 and the resulting boronate esters can be utilized in a range of downstream conversions. The functional group tolerance of the iridium-catalyzed C–H borylation reaction enables simple and efficient multidirectional syntheses of substituted indazoles to be realized.

Although desirable from a medicinal chemistry perspective, the differentially substituted 3,6-diaminopyridazine moiety is a highly challenging target using current literature approaches. Recent methods of Ullmann-type couplings are evaluated and a mild route to prepare these structures from iodide precursors is presented.

The treatment of alkyl or aryl halides with an excess of tetrakis(pyridine)lithium tetrakis( N -dihydropyridyl)aluminate affords the corresponding 3-substituted-1,2,3,6-tetrahydropyridines in moderate to good yields via a tandem alkylation–reduction reaction.

Optimized reaction conditions including 2-propanol-d8 as the deuterium source are developed for the deuterodehalogenation of various bromo- and chloro-substituted heterocycles.

Mo(CO)6 acts as a source of carbon monoxide for the palladium-catalysed, microwave-assisted, carbonylative coupling of aryl or heteroaryl halides with sulfamide nucleophiles to yield aryl and heteroaryl acyl sulfamides.

One Pager No. 178 ? Do Universalismo à Segmentação e o Caminho Inverso: Transferências Condicionadas de Renda e o Desenvolvimento da Cidadania Social por Bryan Roberts, da Universidade do Texas em Austin Roberts (2012), partindo da premissa de que a pobreza não é simplesmente a falta de recursos, mas também uma relação por meio da qual os pobres passam a estar diretamente sob o controle do Estado, explora o papel dos Programas de Transferência de Renda (PTCs) ? tais como o Programa Oportunidades, do México ? na evolução da cidadania e das políticas sociais na América Latina, avaliando o impacto desses programas em relação a como os pobres percebem seus direitos e à qualidade de sua participação cívica. No mundo industrializado, as políticas de redução da pobreza foram, inicialmente, fortemente influenciadas pela preocupação de que os regimes destinados a ajudar as pessoas pobres possam, no fim das contas, ter o efeito de desincentivar os pobres a realizar trabalhos remunerados. Foi só mais tarde ? e principalmente em países em desenvolvimento ? que o discurso subsidiário das políticas começou a se concentrar na capacitação das pessoas pobres, de modo geral, como meio de romper o ciclo vicioso da pobreza. (?) http://www.ipc-undp.org/pub/port/IPCOnePager178.pdf

Roberts (2012) explora el lugar que los programas de transferencias en efectivo (TMC) ocupan en la evolución de la política social y la ciudadanía en América Latina, teniendo en cuenta las consecuencias que estos conllevan en la percepción de los pobres sobre sus derechos y en la calidad de su participación cívica. La pobreza desde esta perspectiva no es simplemente una falta de recursos, sino una relación a través del cual los pobres terminan directamente bajo el control del Estado. En el mundo industrializado, las políticas de lucha contra la pobreza fueron inicialmente influenciadas por los debates sobre si debería ser un incentivo o desincentivo para trabajar. Es relativamente reciente y aun más en los países en vías de desarrollo, el hecho de que las políticas de lucha contra la pobreza se hayan centrado en la construcción de capacidades para romper el ciclo de la pobreza. (...)

"Moving forward from the premise that poverty is not simply a lack of resources, but in fact at the same time a relation through which the poor come directly under the control of the State, Roberts (2012) explores the place of Cash Transfer Programs (CCTs) such as Mexico's Oportunidades Programme in the evolution of social policy and citizenship in Latin America, assessing the impact of these programmes in terms of poor peoples' perceptions of their rights and the quality of their civic participation. In the industrialized world, poverty reduction policy was initially strongly influenced by concern that schemes intended to help poor people might in fact have the ultimate effect of generating disincentives among the poor to engage in paid work. It was only later, and in developing countries particularly, that policy discourse began to focus on building poor peoples' capabilities, in broad terms, as a means toward breaking the vicious cycle of poverty."(?)

Treatment of aryl or alkyl halides with Landsbury′s reagent (generated from pyridine and LiAlH4) results in an alkylation—reduction sequence which affords the title compounds as suitable intermediates or products of pharmaceutical interest.

A new, efficient and practical synthesis of quinazolin-4(3H)-ones is reported via molybdenum-mediated cyclocarbonylation using microwave irradiation. These methods allow access to a wide range of quinazolin-4(3H)-ones in reasonable yields without the need for gaseous carbon monoxide and palladium catalysts. A range of reactions illustrating the wide scope of this chemistry was carried out and all proceeded in reasonable yields.

Optimisation of a series of pyrazole inhibitors of the human FPR1 receptor has been achieved. The use of an in vitro media loss assay was utilised to identify sub-series with more robust DMPK profiles. These were subsequently improved to generate analogues with attractive overall profiles.

Either CO or Mo(CO)6 are used as carbon monoxide sources for the carbonylation of various ureas in the presence of aryl bromides.

Studies of biological systems are often facilitated by diagram models that summarize the current understanding of underlying mechanisms. The increasing complexity of our understanding of biology necessitates computational models that can extend these representations to include their dynamic behavior. We present here a new tool we call Synthesizing Biological Theories which enables biologists and modelers to construct high-level theories and models of biological systems, capturing biological hypotheses, inferred mechanisms, and experimental results within the same framework. Among the key features of the tool are convenient ways to represent several competing theories and the interactive nature of building and running the models using an intuitive, rigorous scenario-based visual language. The definition of the modeling language is geared towards enabling formal verification and analysis.

A new, efficient, and practical molybdenum-mediated carbonylation of aryl and heteroaryl halides with a variety of nucleophiles is described using microwave irradiation. A range of reactions illustrating the wide scope of this chemistry were carried out and proceeded in good to excellent yields.

A novel, simple synthesis of aryl and heteroaryl acyl sulfamides has been developed via palladium-catalyzed carbonylation of aryl or heteroaryl halides in the presence of sulfamide nucleophiles. A range of reactions illustrating the wide scope of this reaction was carried out under microwave irradiation in a vessel equipped with a gas inlet adapter and proceeded in good to excellent yields.

A structured rugby-specific wearer trial to extract meaningful on-field garment performance data does not exist. To address this, a novel rugby-specific garment evaluation protocol was developed and trialled using a rugby-union international prototype shirt. Three wearer trial elements were investigated namely, rugby-specific wear-service conditions, players’ perceptions of the shirt and, the determination of garment performance on the field of play. Methods: A field test mimicking the demands of the game was devised using published international match-play time-motion analysis. Fifteen non-professional club players (age 26.1 yrs ± 5.2 SD, height 1.83 m ± 0.05 SD, pre-trial body mass 95.8 kg ± 10.7 SD) participated and completed the aforementioned field test. Heart rate was recorded throughout and protocol intensity determined. Garment performance was assessed using controlled visual assessment techniques and dimensional stability measurements. Structured questionnaires were administered during and post-trial to determine player perceptions. Results: Forwards’ mean and peak heart rates (153.3 bpm ± 24.1SD and 181.9 bpm ± 10.0 SD) were lower than match-play target values. Backs’ mean and peak heart rates (147.2 bpm ± 26.8 SD and 185.0 bpm ± 10.7 SD) were similar to target values. Dimensional changes and defects were identified and quantified successfully. Players conformed well to the protocol and responded favourably to the questionnaire. Conclusion: The protocol described represents the first rugby-specific garment evaluation protocol to be documented. It is hoped that this will be adopted and refined thereby adding structure to the sports-specific garment development process.

The growth of the human population has profoundly affected the global ecosystem, influencing the animal population balance, the availability of fresh water, arable land, biotic production, and atmospheric gases. The human ecological impact has significantly accelerated the evolutionary change of numerous organisms. For example, the production of human medicine and food has resulted in the rapid evolution of drug-resistant pathogenic organisms as well as plants and insects resistant to pesticides (Palumbi, 2001). Recently, the nutritional support of the human population has relied on the vast monoculture of domestic mammals and birds, which has facilitated the emergence of pathogenic enzootic organisms that infect both animals and humans. This chapter will focus on the global threat to human health represented by the highly contagious enzootic virus influenza. It will also discuss current efforts and future improvements to protect humans from global influenza epidemics and pandemics.

Contact sports such as rugby demand high performance apparel capable of withstanding large stresses during game-play. In order to ensure that failures are minimised the fabric requires testing. Current British standards detail methods of tensile testing fabrics from bulk stock as opposed to fully manufactured garments. It is important for the sporting goods industry that tensile strength data is tested from panels of the made-up garment instead of material from bulk stock. Generally manufacturers are interested in the minimum force required for a garment to fail. This paper describes a protocol for tensile testing of made-up rugby shirts and their critical components. Summarised are findings from one full protocol test which illustrate typical strengths, and design weaknesses for a modern rugby shirt.

A Hit-to-Lead optimisation programme was carried out on the high throughput screening hit, the triazolethiol 1, resulting in the discovery of the potent, orally bioavailable triazolethiol CXCR2 receptor antagonist 45.