Fluorinated Organic Molecules for Medicinal Applications

The significant applications of fluorinated molecules in the pharmaceutical, agrochemical, and material sciences make them attractive synthetic targets. Difluoromethylation methods are of exceptional value and a limited number of techniques are available to perform that transformation. The primary method for introducing CF2 groups is through the use of difluoroenolates. Difluoroenolates can be generated from α-keto pentafluoro gem -diols under mild conditions. The process involves the cleavage of carbon-carbon bond and the release of trifluoroacetate. The release of trifluoroacetate is a versatile method to generate fluorinated molecules. We explored the utility of this method in generating various fluorinated moieties including α,α-difluoroketones, α-deutero-α,α-difluoroketones, α,α-difluoromethyl sulfones, ?-deutero-α,α-difluoromethyl sulfones, monofluoro α-hydroxy ketones and α,α-difluorohalohydrins. We also endeavored to design and synthesize fluorinated molecules for biological applications. Our efforts were aimed at the use of a novel fluorinated β-hydroxy ketone scaffold developed in our lab to develop new agonists of the GABAB receptor. The value of GABAB agonists as muscle relaxants is well established, and interest in these agonists has been rekindled due to reports of new applications in managing drug and alcohol tolerance. We have developed several new analogues, characterized new structure-activity relationships of the fluorinated ?-hydroxy ketone scaffold, and identified more active agents. We are also interested in using fluorine as a tag to track anti-body drug conjugates (ADCs). The chemistry of ADC linkers has attracted a lot of interest recently. The cleavage of the linker is essential for the function of ADCs and in addition to this traditional role, linkers can provide a handle for tagging ADCs. The incorporation of fluorine into linkers minimally affects the sterics of the linker owing to the small size of fluorine atom while at the same time provides a tractable tag. A fluorinated ADC linker has been designed and its synthesis was explored

The role of upstream water use on water stress in transboundary river basins: a global analysis

Upstream-downstream relationship remains one of the many challenges of transboundary water management. Water use of upstream countries has always impact on the downstream water availability and in some cases it might lead to increased water scarcity in downstream part of a basin. In this study, aim is to assess the change in water stress level due to water use of upstream countries in the world’s transboundary river basins. Water stress level was first calculated considering only own water use of a sub-basin and this was then compared to the situation when both, own and upstream water use, were taken into account. When only own water use was considered, 955 million people lived under water stress in world’s transboundary river basins. When the upstream water use was taken into account, the population under water stress increased by 6 percentage points (194 million people). The stress increased most in Asia (central and north-east parts), Africa and some parts of Europe. Further, the results were compared with International water Event Database (1950-2008) by Oregon State University to assess whether there is a link between increased water stress due to upstream water use and the occurrence of conflictive and cooperation events in the transboundary river basins. Although no direct relationship between these two variables was found, in many basins with high number of events also the stress index increased considerably due to upstream water use. In case of transboundary river basin management, one of the key challenges is allocating shared water resources, and their benefits. My findings are thus important for international water bodies where equitable water allocation is at the center of water conflicts

Techniques of Humiliation: Neoliberalism and the Noncitizen\u27s Body

This article argues that the disciplining of noncitizens becomes a constitutive characteristic of neoliberalism. Examining two narratives about bodily deprivation in detention centers, the study pursues the psychic life of statelessness through tragic testimonies that not only point to subjection, induced through techniques of humiliation, but also to the neoliberal contradiction between “inclusion” and practices of regulation. Readings interrogate the problem of normativity in neoliberalism. In particular, the article argues against normative presuppositions about both race and gender, demonstrating how this leads to the denial of medication and death in detention facilities

The Determinants of Rural Outmigration in the United States: 2010-2014

This study focuses on both economic and noneconomic determinants of geographical migration out of rural areas in the United States. In line with existing studies on individual’s decision to migrate from rural to urban areas, our analysis compares expected returns in rural to those in urban areas. Using annual U.S. countylevel count data spanning the period from 2010 to 2014, Fixed Effect and Negative Binomial methods are used to evaluate the effects of both economic and noneconomic variables on geographical outmigration from rural to urban areas. Determining factors investigated include distance between place of origin and potential destination, median household income, educational attainment, the poverty rate, the unemployment rate, a natural amenity index, the prevalence of primary healthcare providers and social associations. Findings suggest that higher expected returns in urban compared to rural areas contribute to releasing people out of rural areas in the United States. A large distance between origin and destination associated with high migration costs demotivate rural people to migrate to urban areas. On the other side, relatively high median household incomes, low unemployment rates, high level of education, a high presence of natural amenities, high level of access to primary healthcare providers in urban destination areas encourage rural people to migrate to urban areas. The poverty rate and social associations did not significantly affect rural outmigration decisions in the United States during the period studied

Split histidine kinases enable ultrasensitivity and bistability in two-component signaling networks

Bacteria sense and respond to their environment through signaling cascades generally referred to as two-component signaling networks. These networks comprise histidine kinases and their cognate response regulators. Histidine kinases have a number of biochemical activities: ATP binding, autophosphorylation, the ability to act as a phosphodonor for their response regulators, and in many cases the ability to catalyze the hydrolytic dephosphorylation of their response regulator. Here, we explore the functional role of “split kinases” where the ATP binding and phosphotransfer activities of a conventional histidine kinase are split onto two distinct proteins that form a complex. We find that this unusual configuration can enable ultrasensitivity and bistability in the signal-response relationship of the resulting system. These dynamics are displayed under a wide parameter range but only when specific biochemical requirements are met. We experimentally show that one of these requirements, namely segregation of the phosphatase activity predominantly onto the free form of one of the proteins making up the split kinase, is met in Rhodobacter sphaeroides. These findings indicate split kinases as a bacterial alternative for enabling ultrasensitivity and bistability in signaling networks. Genomic analyses reveal that up 1.7% of all identified histidine kinases have the potential to be split and bifunctional

Complex Signs and Pseudo-composites

The purpose of the present paper is to try to find an answer to the question: how are complex signs analyzed in English morphology in the context of Axiomatic Functionalist Theory? The paper provides the tools for analyzing items like hatless, penniless, lioness, countess, hooliganism, and Marxism which are traditionally recognized as morphologically complex, each consisting of two morphemes: a free morpheme and a bound morpheme. With an eye to the notions sign and complex sign as envisaged in Axiomatic Functionalist Linguistics three of these items namely, penniless, countess and Marxism turn out to be unanalyzable, i.e. pseudo-composite

The Female-moneme in English: Semantic Considerations in Testing Moneme-ldentity

The purpose of the present paper is to explore the possibility of testing hypotheses for moneme identity by using an additional criterion of adequation with respect to semantic factors: a criterion concerning the assumption of recoverability of denotations of complex pleremes from the denotations of their constituents. I have taken the position that, in the final analysis, a particular complex plereme is a combination of two or more monemes holds on condition that the overall denotation of the complex in question is recoverable from the denotations of its constituents, plus, of course, from having a relatively clear (though necessarily rather approximate) idea of the semantic role played by the constructional relation between these constituents

Residual Deficits Observed In Athletes Following Concussion: Combined Eeg And Cognitive Study

The neurocognitive sequelae of a sport-related concussion and its management are poorly defined. Emerging evidence suggests that the residual deficits can persist one year or more following a brain injury. Detecting and quantifying the residual deficits are vital in making a decision about the treatment plan and may prevent further damage. For example, improper return to play (RTP) decisions in sports such as football have proven to be associated with the further chance of recurring injury, long-term neurophysiological impairments, and worsening of brain functional activity. The reliability of traditional cognitive assessment tools is debatable, and thus attention has turned to assessments based on electroencephalogram (EEG) to evaluate subtle post-concussive alterations. In this study, we calculated neurocognitive deficits in two different datasets. One dataset contains a combination of EEG analysis with three standard post-concussive assessment tools. The data for this dataset were collected for all testing modalities from 21 adolescent athletes (seven concussive and fourteen healthy) in three different trials. Another dataset contains post-concussion eyes closed EEG signal for twenty concussed and twenty age-matched controls. For EEG assessment, along with linear frequency-based features, we introduced a set of time-frequency and nonlinear features for the first time to explore post-concussive deficits. In conjunction with traditional frequency band analysis, we also presented a new individual frequency based approach for EEG assessment. A set of linear, time-frequency and nonlinear EEG markers were found to be significantly different in the concussed group compared to their matched peers in the healthy group. Although EEG analysis exhibited discrepancies, none of the cognitive assessment resulted in significant deficits. Therefore, the evidence from the study highlight that our proposed EEG analysis and markers are more efficient at deciphering post-concussion residual neurocognitive deficits and thus has a potential clinical utility of proper concussion assessment and management. Moreover, a number of studies have clearly demonstrated the feasibility of supervised and unsupervised pattern recognition algorithms to classify patients with various health-related issues. Inspired by these studies, we hypothesized that a set of robust features would accurately differentiate concussed athletes from control athletes. To verify it, features such as power spectral, statistical, wavelet, and other nonlinear features were extracted from the EEG signal and were used as an input to various classification algorithms to classify the concussed individuals. Various techniques were applied to classify control and concussed athletes and the performance of the classifiers was compared to ensure the best accuracy. Finally, an automated approach based on meaningful feature detection and efficient classification algorithm were presented to systematically identify concussed athletes from healthy controls with a reasonable accuracy. Thus, the study provides sufficient evidence that the proposed analysis is useful in evaluating the post-concussion deficits and may be incorporated into clinical assessments for a standard evaluation of athletes after a concussion

The Case for an EU Protagonist Role on Third Party Funding Regulation

The Lisbon Treaty has enlarged the EU’s competences in external investment policy. The EU could thus increase its protagonist role in third-party funding (TPF) regulation in a manner analogous to its achievements in the investment regime, where the EU managed to rally the member states behind DG Trade’s vision. A treaty-based analysis combined with a political evaluation suggest the EU is expanding its field of competences either when it has a clear mandate or by establishing a modus vivendi as it has been the case with its external relations, particularly at the United Nations. There is therefore a case to be made that the EU would have the competence and the interest to expand its investment reform leadership to encompass TPF regulation. Hong Kong and Singapore have added provisions on TPF in their respective national arbitration legislation explicitly allowing TPF as part of a neoliberal strategy to attract arbitration while ignoring the risk of increased forum shopping. In contrast, the EU CETA and EU-Vietnam Treaties are the only treaties to conceptualize and impose a disclosure of TPF, which nevertheless falls short of addressing concerning the adverse consequences of TPF in ISDS

A New Ranking Algorithm for A Round-Robin Tournament

The problem of ranking players in a round- robin tournament, in which outcome of any match is a win or a loss, is to rank players according to their performances in the tournament. In this paper, we have improved previously developed MST (Majority Spanning Tree) algorithm for solving this problem, where the number of violations has been chosen as the criterion of optimality. We have compared the performance of our algorithm with the MST algorithm and GIK algorithm