Synthesis, Structural Determination, and Pharmacology of Putative Dinitroaniline Antimalarials

A series of novel, homologous compounds possessing the general formula N1‐Nn‐bis(2,6‐dinitro‐4‐trifluormethylphenyl)‐1,n‐diamino alkanes (where n=4, 6, 10 or 12), were designed to probe inter‐ and intra‐ binding site dimensions in malarial parasite (Plasmodium) tubulin. Various crystal structures, including chloralin and trifluralin, an isopropyl dimer, and 2,6‐dinitro‐4‐trifluoromethyl‐phenylamine, were determined. Dinitroanilines, when soluble, were evaluated both in culture and in vivo. Trifluralin was up to 2‐fold more active than chloralin against cultured parasites. The isopropyl dimer was water soluble (>5 mM) and revealed activity superior to that of chloralin in culture. The effects of selected dinitroanilines upon the mitotic microtubular structures of Plasmodium, the putative target of these dinitroanilines, were also determined. Electronic properties of the molecules were calculated using DFT (B3LYP/6‐31+G* level) to ascertain whether incorporation of such a pharmacophore could allow both QSAR and rational development of more selectively toxic antiparasitic agents

Modulation of Antimalarial Activity at a Putative Bisquinoline Receptor in vivo Using Fluorinated Bisquinolines

Antimalarials can interact with heme covalently, by - interactions or hydrogen bonding. Consequently, the prototropy of 4-aminoquinolines and quinoline methanols was investigated using quantum mechanics. Calculations showed mefloquine protonated preferentially at the piperidine and was impeded at the endocyclic nitrogen due to electronic rather than steric factors. In gas phase calculations, 7-substituted mono- and bis-4-aminoquinolines were preferentially protonated at the endocyclic quinoline nitrogen. By contrast, compounds with a trifluoromethyl substituent on both the 2- and 8-positions, reversed the order of protonation which now favored the exocyclic secondary amine nitrogen at the 4-position. Loss of antimalarial efficacy by CF3 groups simultaneously occupying the 2- and 8-positions was recovered if the CF3 group occupied the 7-position. Hence, trifluromethyl groups buttressing quinolinyl nitrogen shifted binding of antimalarials to hematin, enabling switching from endocyclic to the exocyclic N. Both theoretical calculations (DFT calculations: B3LYP/6- 31+G*) and crystal structure of (±)-trans-N1,N2-bis-(2,8-ditrifluoromethylquinolin-4- yl)cyclohexane-1,2-diamine were used to reveal preferred mode(s) of interaction with hematin. The order of antimalarial activity in vivo followed the capacity for a redox change of the iron(III)state which has important implications for the future rational design of 4- aminoquinoline antimalarials

Feminist geographies of digital work

Feminist thought challenges essentialist and normative categorizations of ‘work’. Therefore, feminism provides a critical lens on ‘working space’ as a theoretical and empirical focus for digital geographies. Digital technologies extend and intensify working activity, rendering the boundaries of the workplace emergent. Such emergence heightens the ambivalence of working experience: the possibilities for affirmation and/or negation through work. A digital geography is put forward through feminist theorizations of the ambivalence of intimacy. The emergent properties of working with digital technologies create space through the intimacies of postwork places where bodies and machines feel the possibilities of being ‘at’ work

Maps, Memories and Manchester: The Cartographic Imagination of the Hidden Networks of the Hydraulic City

The largely unseen channelling, culverting and controlling of water into, through and out of cities is the focus of our cartographic interpretation. This paper draws on empirical material depicting hydraulic infrastructure underlying the growth of Manchester in mapped form. Focusing, in particular, on the 19th century burst of large-scale hydraulic engineering, which supplied vastly increased amounts of clean drinking water, controlled unruly rivers to eliminate flooding, and safely removed sewage, this paper explores the contribution of mapping to the making of a more sanitary city, and towards bold civic minded urban intervention. These extensive infrastructures planned and engineered during Victorian and Edwardian Manchester are now taken-for-granted but remain essential for urban life. The maps, plans and diagrams of hydraulic Manchester fixed particular forms of elite knowledge (around planning foresight, topographical precision, civil engineering and sanitary science) but also facilitated and freed flows of water throughout the city. The survival of these maps and plans in libraries, technical books and obscure reports allows the changing cultural work of water to be explored and evokes a range of socially specific memories of a hidden city. Our aetiology of hydraulic cartographics is conducted using ideas from science and technology studies, semiology, and critical cartography with the goal of revealing how they work as virtual witnesses to an 1 unseen city, dramatizing engineering prowess and envisioning complex and messy materiality into a logical, holistic and fluid network underpinning the urban machine. 1

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

A survey of clinical features of allergic rhinitis in adults

Background: Allergic rhinitis (AR) has high prevalence and substantial socio-economic burden. Material/Methods: The study included 35 Italian Centers recruiting an overall number of 3383 adult patients with rhinitis (48% males, 52% females, mean age 29.1, range 18\u201345 years). For each patient, the attending physician had to fill in a standardized questionnaire, covering, in particular, some issues such as the ARIA classification of allergic rhinitis (AR), the results of skin prick test (SPT), the kind of treatment, the response to treatment, and the satisfaction with treatment. Results: Out of the 3383 patients with rhinitis, 2788 (82.4%) had AR: 311 (11.5%) had a mild intermittent, 229 (8.8%) a mild persistent, 636 (23.5%) a moderate-severe intermittent, and 1518 (56.1%) a moderate-severe persistent form. The most frequently used drugs were oral antihistamines (77.1%) and topical corticosteroids (60.8%). The response to treatment was judged as excellent in 12.2%, good in 41.3%, fair in 31.2%, poor in 14.5%, and very bad in 0.8% of subjects. The rate of treatment dissatisfaction was significantly higher in patients with moderate-to-severe AR than in patients with mild AR (p<0.0001). Indication to allergen immunotherapy (AIT) was significantly more frequent (p<0.01) in patients with severe AR than with mild AR. . Conclusions: These fndings confirm the appropriateness of ARIA guidelines in classifying the AR patients and the association of severe symptoms with unsuccessful drug treatment. The optimal targeting of patients to be treated with AIT needs to be reassessed

Modification of pollen proteins induced by growth substances and fungicides

The present study investigated the effects of the fungicides benomyl, dodine and penconazole and the growth regulators CPPU and paclobutrazol on pollen germination and tube growth, the microtubular organization of pollen tubes and total pollen polypeptides in the apple cvs Golden Delicious and Red Delicious. Each chemical showed a specific effect in at least one of the assayed functions. The fungicides confirmed their inhibitory effect on pollen germinaton. The most marked effects were recorded in both cultivars for dodine and benomyl when applied at field rates; penconazole showed a stronger inhibition in Golden Delicious than in Red Delicious when applied at field rate. By contrast, the tested growth regulators exerted a slight promotion of pollen germination. CPPU seemed not to alter the microtubular organization in Golden Delicious when applied ar rates ranging from routine field concentration to as much as three times this dosage, while paclobutrazol induced an anomalous disposition of tubuline when applied ar triple the field rate. The three assayed fungicides produced polypeptide patterns in a different way when compared to their effect on pollen germination, The effects of these chemicals on pollen gene regulation needs to be elucidated as their mechanisms of action are in many cases still unknown

Cytoplasmic motors and pollen tube growth

The growth of pollen tubes is characterized by an intense cytoplasmic streaming, during which the movements of smaller organelles (like secretory vesicles) and larger ones (including the generative cell and vegetative nucleus) are precisely coordinated. A well-characterized cytoskeletal apparatus is likely responsible for these intracellular movements. In recent years both microfilament- and microtubule-based motor proteins have been identified and assumed to be the translocators of the several organelle categories. Their precise function during pollen tube growth is not yet clear, but apparently an actomyosin-based system is mainly responsible for pollen tube elongation. On the other hand, microtubules and microtubule-based motors have been thought to play a role in the maintenance of cell polarity. Both cytoskeletal systems (and their respective motor activities) could cooperate to ensure a precise regulation of pollen tube growth