Alchemical Design of Pharmacological Chaperones with Higher Affinity for Phenylalanine Hydroxylase

Phenylketonuria (PKU) is a rare metabolic disease caused by variations in a human gene, PAH, encoding phenylalanine hydroxylase (PAH), and the enzyme converting the essential amino acid phenylalanine into tyrosine. Many PKU-causing variations compromise the conformational stability of the encoded enzyme, decreasing or abolishing its catalytic activity, and leading to an elevated concentration of phenylalanine in the blood, which is neurotoxic. Several therapeutic approaches have been developed to treat the more severe manifestations of the disorder, but they are either not entirely effective or difficult to adhere to throughout life. In a search for novel pharmacological chaperones to treat PKU, a lead compound was discovered (compound IV) that exhibited promising in vitro and in vivo chaperoning activity on PAH. The structure of the PAH-IV complex has been reported. Here, using alchemical free energy calculations (AFEC) on the structure of the PAH-IV complex, we design a new generation of compound IV-analogues with a higher affinity for the enzyme. Seventeen novel analogues were synthesized, and thermal shift and isothermal titration calorimetry (ITC) assays were performed to experimentally evaluate their stabilizing effect and their affinity for the enzyme. Most of the new derivatives bind to PAH tighter than lead compound IV and induce a greater thermostabilization of the enzyme upon binding. Importantly, the correspondence between the calculated alchemical binding free energies and the experimentally determined ΔΔG_b values is excellent, which supports the use of AFEC to design pharmacological chaperones to treat PKU using the X-ray structure of their complexes with the target PAH enzyme.     

Mathematical modelling of soybean oil solubility in supercritical carbon dioxide

The solubility of soybean oil in supercritical carbon dioxide has been determined in the pressure range of 100–300 bar and in the temperature range of 313–323 K. The obtained values (from 0.0005 to 0.02055 g L^?1) have been correlated using four different empirical equations proposed correspondingly by Chrastil, del Valle and Aquilera, Adachi and Lu and Sparks et al. Since the Sparks et al. equation provided the lowest average absolute relative deviation (AARD) (10.25%) than other models in the examined experimental range, a modified equation of Sparks et al. model was developed for predicting the solubility of soybean oil in supercritical carbon dioxide as a function of temperature and density. An improved equation showed the lowest deviation (2.15%) between experimental data than the other empirical equations considered in this study. The proposed equation was also applied for correlating the solubility of linoleic acid (AARD was 2.40%).     

Do ‘green’ buildings have better indoor environments? New evidence

A post-occupancy evaluation (POE) of 12 green and 12 conventional office buildings across Canada and the northern United States was conducted. Occupants (N = 2545) completed an online questionnaire related to environmental satisfaction, job satisfaction and organizational commitment, health and well-being, environmental attitudes, and commuting. In each building on-site physical measurements at a sample of workstations (N= 974) were taken, including: thermal conditions, air quality, acoustics, lighting, workstation size, ceiling height, window access and shading, and surface finishes. Green buildings exhibited superior performance compared with similar conventional buildings. Better outcomes included: environmental satisfaction, satisfaction with thermal conditions, satisfaction with the view to the outside, aesthetic appearance, less disturbance from heating, ventilation and air-conditioning (HVAC) noise, workplace image, night-time sleep quality, mood, physical symptoms, and reduced number of airborne particulates. A variety of physical features led to improved occupant outcomes across all buildings, including: conditions associated with speech privacy, lower background noise levels, higher light levels, greater access to windows, conditions associated with thermal comfort, and fewer airborne particulates. Green building rating systems might benefit from further attention in several areas, including: credits related to acoustic performance, a greater focus on reducing airborne particulates, enhanced support for the interdisciplinary design process and development of POE protocols.

Il a été mené une évaluation après occupation (POE) de 12 immeubles de bureaux verts et 12 immeubles de bureaux classiques répartis à travers le Canada et le nord des Etats-Unis. Les occupants (N?=?2545) ont rempli un questionnaire en ligne portant sur la satisfaction environnementale, la satisfaction au travail et l'implication organisationnelle, la santé et le bien-être, les attitudes environnementales, et les trajets réguliers. Dans chaque immeuble, des mesures physiques in situ sur un échantillon de postes de travail (N?=?974) ont été effectuées, comprenant : les conditions thermiques, la qualité de l'air, l'acoustique, l'éclairage, la taille des postes de travail, la hauteur de plafond, l'accès aux fenêtres et leur occultation, et les finitions de surface. Les bâtiments verts ont affiché des performances supérieures par rapport aux bâtiments classiques similaires. De meilleurs résultats ont été obtenus concernant la satisfaction environnementale, la satisfaction à l'égard des conditions thermiques, la satisfaction à l'égard de la vue sur l'extérieur, l'aspect esthétique, la diminution des perturbations liées aux bruits provenant du chauffage, de la ventilation et de la climatisation (CVC), l'image du lieu de travail, la qualité du sommeil nocturne, l'humeur, les symptômes physiques, et la réduction du nombre de particules en suspension dans l'air. Différentes caractéristiques physiques ont conduit à une amélioration des résultats pour les occupants dans tous les immeubles, concernant notamment les conditions liées à la confidentialité des conversations, les niveaux inférieurs de bruit de fond, les niveaux de luminosité plus élevés, l'accès accru aux fenêtres, les conditions associées au confort thermique, et le nombre moindre de particules en suspension dans l'air. Les systèmes de notation des bâtiments verts pourraient bénéficier d'une plus grande attention apportée à plusieurs domaines, s'agissant en particulier des crédits relatifs aux performances acoustiques, d'un accent accru sur la réduction des particules en suspension dans l'air, d'un soutien renforcé en faveur du processus de conception interdisciplinaire et du développement de protocoles POE.

Mots clés: performances des bâtiments, bilan environnemental, bâtiments verts, environnement intérieur, Leadership in Energy and Environmental Design (LEED), satisfaction des occupants, évaluation après occupation     

Collaborating to Compete—The Governance Implications of Stakeholder Agendas at Mount Pulag National Park,the Philippines

Regional planning has long sought to manage places that extend across political boundaries. The international trend to decentralize governance and promote co-management of protected areas is consistent with emerging collaborative spatial planning theory (Healey, 1997, 1999, 2006), which suggests that through dialogue, parties assert multiple cultural perspectives, share knowledge, and forge shared landscape values as the basis of decisions. As a form of collaborative spatial planning, co-management specifies shared resource management power between national government and one or more local or indigenous communities. Both approaches assume decentralized governance systems. Although critics fault collaborative planning for glossing over historical and cultural contexts, and for ignoring power in decision making, few case studies ask why partners participate or how specific decentralized governance institutions affect plan implementation. This paper draws from a study of co-management at Mount Pulag National Park, the Philippines—a shared indigenous cultural landscape that was to be managed by a board representing multiple local, indigenous, and national jurisdictions. Tracing road decisions by two municipal partners, the paper summarizes how and why major stakeholders adopted and then circumvented protective policies by building duplicative road projects across fragile forests. In this context of changing indigenous rights, the same decentralization laws that enabled co-management also rewarded competition and strategic behavior that weakened the collaborative and fragmented the shared landscape. The case demonstrates the need to interrogate, rather than assume the benefits of decentralized governance and to study why stakeholders participate before relying on voluntary collaboration to manage regional landscapes. The initial version of this paper was presented to the 2006 annual meetings of the Association of Collegiate Schools of Planning, Fort Worth, Texas.     

Hyperbranched polyglycerols,obtained from environmentally benign monomer,as reactive clays inhibitors for water‐based drilling fluids

To prevent the degradation of the borehole and also the disintegration and dispersion of drilled cuttings, different shale stabilizing additives are used in water‐based drilling fluids (WBFs). Glycols, poly(ethylene glycol), glycerols, and polyglycerol derivatives, also called polyols, have been used to inhibit shales containing reactive clays in WBF. These additives are normally used in conjunction with KCl to reduce clay swelling and dispersion of drilled cuttings. Highly branched polymers have become an important field in current polymer science. Such materials typically exhibit compact, globular structures in combination with an exceptionally high number of sites with functional groups. They have unique properties that differ significantly from their linear counterparts, and the hyperbranched polyglycerol (hPG) is an important hyperbranched polymer that can be produced from an environmentally benign monomer, the glycerol carbonate. In this article, the clay inhibitive properties of hPG were evaluated by different test methods including bentonite inhibition test, cuttings recovery, and X‐ray diffraction measurements. The results show that the hPG has a great potential to be used as an environmental friendly inhibitor additive in WBFs. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40384.     

Photo-vulcanization using thiol-ene chemistry: Film formation,morphology and network characteristics of UV crosslinked rubber latices

The photo-vulcanization with versatile thiol-ene chemistry represents an innovative approach to crosslink diene-rubber materials both in latex and in solid film state. In this work, the structure of elastomer-based thiol-ene networks and the morphology after film formation are studied in detail using electron microscopic techniques, atomic force microscopy and multiple-quantum solid-state NMR spectroscopy. Additionally, film formation properties and corresponding macroscopic properties of photo-vulcanized natural rubber (NR) latex and its synthetic counterpart, isoprene rubber (IR) latex, are determined in dependence on the curing procedure (pre- and post-vulcanization). The results reveal that thiol-ene cured elastomers comprise homogenously distributed crosslinks with a low amount of short chain defects. Whilst photochemically pre-cured NR latex particles provide coherent films, the film formation and mechanical properties of IR are strongly governed by the crosslink density of the latex particles. In film state, photo-vulcanization promotes narrow crosslink distributions and excellent tensile properties of both NR and IR.     

连二硫酸金属盐和连二硫酸在电镀和金属精饰领域的应用

在电镀溶液中使用连二硫酸和连二硫酸金属盐作为可溶性金属离子和电解质的来源具有潜在的应用。为有助于具有创新精神的配方研究者考虑采用诸如连二硫酸这种新型电解质,文章总结了连二硫酸盐电镀液近期的发展,用实例说明了连二硫酸盐在电镀液中的应用。众所周知,连二硫酸在强酸溶液中发生歧化反应,但这并不妨碍在适宜的条件下使用连二硫酸盐以及连二硫酸。(由于篇幅限制,有关连二硫酸及连二硫酸金属盐的化学性质、稳定性、制备方法等补充材料及学术综述、研究报告所涉及的参考文献均在本刊网站上详细全文发表,见http:／／www．plating．org／web／20060901．mht。)     

Gemini and Bicephalous Surfactants: A Review on Their Synthesis,Micelle Formation,and Uses

The use of surfactants in polymerization reactions is particularly important, mainly in emulsion polymerizations. Further, micelles from biocompatible surfactants find use in pharmaceutical dosage forms. This paper reviews recent developments in the synthesis of novel gemini and bicephalous surfactants, micelle formation, and their applications in polymer and nanoparticle synthesis, oil recovery, catalysis, corrosion, protein binding, and biomedical area, particularly in drug delivery.