bluuebunny/crossref_metadata_2025 huggingface dataset:
An overview of the MILAGRO 2006 Campaign: Mexico City emissions and their transport and transformation
Authors: Molina L. T. , Madronich S. , Gaffney J. S. , Apel E. , de Foy B. , Fast J. , Ferrare R. , Herndon S. , Jimenez J. L. , Lamb B. , Osornio-Vargas A. R. , Russell P. , Schauer J. J. , Stevens P. S. , Volkamer R. , Zavala M.
Published: September 2010

Abstract. MILAGRO (Megacity Initiative: Local And Global Research Observations) is an international collaborative project to examine the behavior and the export of atmospheric emissions from a megacity. The Mexico City Metropolitan Area (MCMA) – one of the world's largest megacities and North America's most populous city – was selected as the case study to characterize the sources, concentrations, transport, and transformation processes of the gases and fine particles emitted to the MCMA atmosphere and to evaluate the regional and global impacts of these emissions. The findings of this study are relevant to the evolution and impacts of pollution from many other megacities. The measurement phase consisted of a month-long series of carefully coordinated observations of the chemistry and physics of the atmosphere in and near Mexico City during March 2006, using a wide range of instruments at ground sites, on aircraft and satellites, and enlisting over 450 scientists from 150 institutions in 30 countries. Three ground supersites were set up to examine the evolution of the primary emitted gases and fine particles. Additional platforms in or near Mexico City included mobile vans containing scientific laboratories and mobile and stationary upward-looking lidars. Seven instrumented research aircraft provided information about the atmosphere over a large region and at various altitudes. Satellite-based instruments peered down into the atmosphere, providing even larger geographical coverage. The overall campaign was complemented by meteorological forecasting and numerical simulations, satellite observations and surface networks. Together, these research observations have provided the most comprehensive characterization of the MCMA's urban and regional atmospheric composition and chemistry that will take years to analyze and evaluate fully. In this paper we review over 120 papers resulting from the MILAGRO/INTEX-B Campaign that have been published or submitted, as well as relevant papers from the earlier MCMA-2003 Campaign, with the aim of providing a road map for the scientific community interested in understanding the emissions from a megacity such as the MCMA and their impacts on air quality and climate. This paper describes the measurements performed during MILAGRO and the results obtained on MCMA's atmospheric meteorology and dynamics, emissions of gases and fine particles, sources and concentrations of volatile organic compounds, urban and regional photochemistry, ambient particulate matter, aerosol radiative properties, urban plume characterization, and health studies. A summary of key findings from the field study is presented.
The spatial distribution of mineral dust and its shortwave radiative forcing over North Africa: modeling sensitivities to dust emissions and aerosol size treatments
Authors: Zhao C. , Liu X. , Leung L. R. , Johnson B. , McFarlane S. A. , Gustafson W. I. , Fast J. D. , Easter R.
Published: September 2010

Abstract. A fully coupled meteorology-chemistry-aerosol model (WRF-Chem) is applied to simulate mineral dust and its shortwave (SW) radiative forcing over North Africa. Two dust emission schemes (GOCART and DUSTRAN) and two aerosol models (MADE/SORGAM and MOSAIC) are adopted in simulations to investigate the modeling sensitivities to dust emissions and aerosol size treatments. The modeled size distribution and spatial variability of mineral dust and its radiative properties are evaluated using measurements (ground-based, aircraft, and satellites) during the AMMA SOP0 campaign from 6 January to 3 February of 2006 (the SOP0 period) over North Africa. Two dust emission schemes generally simulate similar spatial distributions and temporal evolutions of dust emissions. Simulations using the GOCART scheme with different initial (emitted) dust size distributions require ~40% difference in total emitted dust mass to produce similar SW radiative forcing of dust over the Sahel region. The modal approach of MADE/SORGAM retains 25% more fine dust particles (radius<1.25 μm) but 8% less coarse dust particles (radius>1.25 μm) than the sectional approach of MOSAIC in simulations using the same size-resolved dust emissions. Consequently, MADE/SORGAM simulates 11% higher AOD, up to 13% lower SW dust heating rate, and 15% larger (more negative) SW dust radiative forcing at the surface than MOSAIC over the Sahel region. In the daytime of the SOP0 period, the model simulations show that the mineral dust heats the lower atmosphere with an average rate of 0.8 ± 0.5 K day−1 over the Niamey vicinity and 0.5 ± 0.2 K day−1 over North Africa and reduces the downwelling SW radiation at the surface by up to 58 W m−2 with an average of 22 W m−2 over North Africa. This highlights the importance of including dust radiative impact in understanding the regional climate of North Africa. When compared to the available measurements, the WRF-Chem simulations can generally capture the measured features of mineral dust and its radiative properties over North Africa, suggesting that the model is suitable for more extensive simulations of dust impact on regional climate over North Africa.
The invigoration of deep convective clouds over the Atlantic: aerosol effect, meteorology or retrieval artifact?
Authors: Koren I. , Feingold G. , Remer L. A.
Published: September 2010

Abstract. Associations between cloud properties and aerosol loading are frequently observed in products derived from satellite measurements. These observed trends between clouds and aerosol optical depth suggest aerosol modification of cloud dynamics, yet there are uncertainties involved in satellite retrievals that have the potential to lead to incorrect conclusions. Two of the most challenging problems are addressed here: the potential for retrieved aerosol optical depth to be cloud-contaminated, and as a result, artificially correlated with cloud parameters; and the potential for correlations between aerosol and cloud parameters to be erroneously considered to be causal. Here these issues are tackled directly by studying the effects of the aerosol on convective clouds in the tropical Atlantic Ocean using satellite remote sensing, a chemical transport model, and a reanalysis of meteorological fields. Results show that there is a robust positive correlation between cloud fraction or cloud top height and the aerosol optical depth, regardless of whether a stringent filtering of aerosol measurements in the vicinity of clouds is applied, or not. These same positive correlations emerge when replacing the observed aerosol field with that derived from a chemical transport model. Model-reanalysis data is used to address the causality question by providing meteorological context for the satellite observations. A correlation exercise between the full suite of meteorological fields derived from model reanalysis and satellite-derived cloud fields shows that observed cloud top height and cloud fraction correlate best with model pressure updraft velocity and relative humidity. Observed aerosol optical depth does correlate with meteorological parameters but usually different parameters from those that correlate with observed cloud fields. The result is a near-orthogonal influence of aerosol and meteorological fields on cloud top height and cloud fraction. The results strengthen the case that the aerosol does play a role in invigorating convective clouds.
The Chemistry of Atmosphere-Forest Exchange (CAFE) Model – Part 2: Application to BEARPEX-2007 observations
Authors: Wolfe G. M. , Thornton J. A. , Bouvier-Brown N. C. , Goldstein A. H. , Park J.-H. , McKay M. , Matross D. M. , Mao J. , Brune W. H. , LaFranchi B. W. , Browne E. C. , Min K.-E. , Wooldridge P. J. , Cohen R. C. , Crounse J. D. , Faloona I. C. , Gilman J. B. , Kuster W. C. , de Gouw J. A. , Huisman A. , Keutsch F. N.
Published: September 2010

Abstract. In a companion paper, we have introduced the Chemistry of Atmosphere-Forest Exchange (CAFE) model, a vertically-resolved 1-D chemical transport model designed to probe the details of near-surface reactive gas exchange. Here, we use CAFE to interpret noontime observations from the 2007 phase of the Biosphere Effects on Aerosols and Photochemistry Experiment (BEARPEX-2007), conducted at a young Ponderosa pine plantation in the western Sierra Nevada. The model reproduces many features of the BEARPEX-2007 data and offers new insights into the forest-atmosphere exchange of reactive molecules at this location. Nitrogen oxide (NOx = NO + NO2) fluxes are driven by soil emissions of NO, while the partitioning between NO and NO2 fluxes is sensitive to in-canopy photochemical gradients. Enhanced thermolysis at the ground increases downward acyl peroxy nitrate (APN) fluxes by as much as 50%, in general agreement with previous findings. APN fluxes are also influenced by in-canopy chemical production, especially when their formation is tied closely to oxidation of BVOC emissions. Gross dry N deposition is typically dominated by nitric acid, though other reactive nitrogen (NOy) species can comprise up to 28% of the N deposition budget under cooler conditions. Upward NO2 fluxes cause the net above-canopy NOy flux to be ~30% lower than the gross depositional flux. Model-measurement comparison of hydrogen peroxide mixing ratios suggests this molecule deposits at the aerodynamic limit. CAFE under-predicts ozone fluxes by ~20%, which may indicate additional in-canopy chemical losses that are missing from the current model.
Sub-millennial climate variability during MIS 11 revealed by high resolution EPICA Dome C isotopic data – a comparison with the Holocene
Authors: Pol K. , Debret M. , Masson-Delmotte V. , Capron E. , Cattani O. , Dreyfus G. , Falourd S. , Johnsen S. , Jouzel J. , Landais A. , Minster B. , Stenni B.
Published: September 2010

Abstract. We expand here the description of the Antarctic temperature variability during the long interglacial period occurring ~400 thousand years before present (Marine Isotopic Stage, MIS 11). This is achieved thanks to new detailed deuterium measurements conducted on the EPICA Dome C ice core, Antarctica, with a ~50 year temporal resolution. Despite an ice diffusion length reaching ~8 cm at MIS 11 depth, the data allow to highlight a variability at multi-centennial scale for MIS 11, as it has already been observed for the Holocene (MIS 1). Differences between MIS 1 and MIS 11 are analysed regarding the links between multi-millennial trends and sub-millennial variability. The EPICA Dome C deuterium record shows an increased variability and a shift in the observed periodicities at the onset of the final cooling phase of MIS 11, with stronger millennial to multi-millennial variability. Our findings are robust with respect to sensitivity tests on the somewhat uncertain MIS 11 duration.
Geostatistical radar-raingauge combination with nonparametric correlograms: methodological considerations and application in Switzerland
Authors: Schiemann R. , Erdin R. , Willi M. , Frei C. , Berenguer M. , Sempere-Torres D.
Published: September 2010

Abstract. Modelling spatial covariance is an essential part of all geostatistical methods. Traditionally, parametric semivariogram models are fit from available data. More recently, it has been suggested to use nonparametric correlograms obtained from spatially complete data fields. Here, both estimation techniques are compared. Nonparametric correlograms are shown to have a substantial negative bias. Nonetheless, when combined with the sample variance of the spatial field under consideration, they yield an estimate of the semivariogram that is unbiased for small lag distances. This justifies the use of this estimation technique in geostatistical applications. Various formulations of geostatistical combination (Kriging) methods are used here for the construction of hourly precipitation grids for Switzerland based on data from a sparse realtime network of raingauges and from a spatially complete radar composite. Two variants of Ordinary Kriging (OK) are used to interpolate the sparse gauge observations. In both OK variants, the radar data are only used to determine the semivariogram model. One variant relies on a traditional parametric semivariogram estimate, whereas the other variant uses the nonparametric correlogram. The variants are tested for three cases and the impact of the semivariogram model on the Kriging prediction is illustrated. For the three test cases, the method using nonparametric correlograms performs equally well or better than the traditional method, and at the same time offers great practical advantages. Furthermore, two variants of Kriging with external drift (KED) are tested, both of which use the radar data to estimate nonparametric correlograms, and as the external drift variable. The first KED variant has been used previously for geostatistical radar-raingauge merging in Catalonia (Spain). The second variant is newly proposed here and is an extension of the first. Both variants are evaluated for the three test cases as well as an extended evaluation period. It is found that both methods yield merged fields of better quality than the original radar field or fields obtained by OK of gauge data. The newly suggested KED formulation is shown to be beneficial, in particular in mountainous regions where the quality of the Swiss radar composite is comparatively low. An analysis of the Kriging variances shows that none of the methods tested here provides a satisfactory uncertainty estimate. A suitable variable transformation is expected to improve this.
History of Quantitative Structure–Activity Relationships
Authors: Selassie Cynthia , Verma Rajeshwar P.
Published: September 2010

This chapter gives an overview of the historical development of the quantitative structure–activity relationship (QSAR) paradigm with a particular emphasis on the past 50 years. Parameters used to formulate various mathematical models are described as originally delineated. Refinement and fine‐tuning of these variables as they evolved and were utilized, is also described. They are sequestered according to their electronic, hydrophobic, steric, and molecular orbital properties. Recent emphasis on molecular descriptors in high‐throughput screening mandates their inclusion in this chapter. Various QSAR models spanning two‐dimensional space to six‐dimensional space are described and applied to various chemicobiological systems in isolated receptors,in vitrosystems andin vivosystems. The presence of outliers in QSAR is also discussed in this chapter. Validation methods that are pertinent to QSAR model development are also addressed. The development of databases that encapsulate significant data on variables and models that allow for rapid retrieval, usage, and validation of chemical reactions and biological interactions is included in this analysis of QSAR.
Chirality and Biological Activity
Authors: Singh Jasbir , Hagen Timothy J.
Published: September 2010

The relationship between chirality and biological activity has been of increasing importance to the pharmaceutical and biopharmaceutical areas as evidenced by a growing number of chiral drugs that have been developed within the last two decades. This chapter covers several areas of importance in the design and synthesis of novel small molecule chiral drugs for medicinal chemists. The focus of this chapter is to provide an overview of the impact of chirality in medicinal chemistry and pharmaceutical sciences, and this should not be considered an exhaustive review of the topic. Several examples reported in the recent literature have been used to highlight the impact of chirality on development of therapeutics for various molecular targets. Chirality, as used in this chapter, also includes examples of atropisomers. The effects of chirality on pharmacological activities, absorption, distribution, metabolism, and excretion and toxicity are exemplified. In addition to chirality at carbon, examples of chiral compounds involving chirality at noncarbon atoms are included. A section on chirality in drug design provides several examples from recent literature covering diverse target classes. Regulatory considerations that apply to chiral drugs are addressed briefly. Section 10 covers recent drug development and marketed single enantiomers. Multiple synthetic approaches to produce chiral compounds with high enantiomeric purity, including chromatographic separation and enantioselective syntheses, were covered adequately in the 6th edition, and thus these areas and general definitions of chirality are not repeated in this chapter.
Principles of Drug Metabolism
Authors: Testa Bernard
Published: September 2010

The focus of this chapter is essentially on drug metabolism reactions and their enzymes. Connected information of significance to medicinal chemists is also given attention. Introductory principles of drug metabolism are presented in the introduction. Oxidoreductases are discussed in the next section together with a systematic and extensive treatment of the chemical groups they target and the functionalization reactions they catalyze. Attention is paid to the cytochromes P450, their multiplicity, specificities and relative importance. Hydrolases are also treated. The next section is dedicated to the transferases and the conjugation reactions they catalyze, for example, glucuronidation and glutathione conjugation. The last section, which is particularly close to the interests of medicinal chemists, discusses pharmacological and toxicological consequences of metabolism, structure‐metabolism relationships and the prediction of metabolism, and briefly outlines the biological factors that influence biotransformation.
Retrometabolism‐Based Drug Design and Targeting
Authors: Bodor Nicholas , Buchwald Peter
Published: September 2010

Retrometabolic drug design (RMDD) approaches are systematic methodologies aimed to design safe compounds with an improved therapeutic index. RMDDs thoroughly integrate structure– activity and structure‐metabolism considerations into the entire design process and incorporate two major concepts aimed to design soft drugs and chemical delivery systems, respectively. Soft drugs (SDs) are new, active therapeutic agents designed to undergo predictable metabolism resulting in inactive metabolites after exerting their desired therapeutic effect(s). Chemical delivery systems (CDSs) are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps. Here, we present a comprehensive review including a general overview of the RMDD principles and a large number of specific examples from various pharmacological areas, including many recent developments, to illustrate RMDD concepts. Whenever possible, the rationale for the design as well as the pharmacokinetic and pharmacodynamic properties of the new therapeutic agents are briefly summarized and compared to those of the other compounds used in the same field.
Oxygen DeliveryviaAllosteric Effectors of Hemoglobin and Blood Substitutes
Authors: Bruno Stefano , Ronda Luca , Faggiano Serena , Bettati Stefano , Mozzarelli Andrea
Published: September 2010

Hemorrhages, disease‐ or genetics‐caused anemic conditions, and ischemic events prevent an adequate supply of oxygen to peripheral tissues. The most common therapy for these conditions is transfusion with whole blood from healthy donors. However, blood transfusions may suffer from side effects, potential shortages in donor availability, limited time storage, and applicability only within hospitals. Moreover, in cases such as immunoreactivity against all blood types, hypo‐oxygenation pathologies in preterm infants and refusal of transfusions on religious grounds, a blood substitute might be the only therapeutic option. In the past 30 years, several approaches have been pursued for the development of blood substitutes, based either on compounds capable to allosterically modulate the oxygen binding properties of endogenous hemoglobin or on artificial oxygen carriers directly administered in the blood stream. The latter are represented by oxygen‐solubilizing perfluorocarbons, chemically or genetically modified hemoglobins and artificial erythrocytes. Their successful development as safe alternatives to blood transfusions has been so far hampered by an incomplete understanding of the complex mechanisms controlling oxygen and NO homeostasis and hemodynamics. However, the knowledge accumulated in the past years brings hope for the development in the near future of effective and safe blood substitutes.
Selective Toxicity
Authors: Block John H.
Published: September 2010

A drug can be considered toxic in that it replaces the natural ligand for a receptor. A goal in drug design is develop a molecule that is selective for a particular receptor located on a specific target organ or tissue. Therefore, an ideal biologically active molecule will produce a specific pharmacological response without causing adverse reactions. There are at least four ways to improve a drug's selectivity. These methodologies are based on the biochemistry of the disease or the biochemistry of the drug's receptor, unequal distribution of the drug, differences in the target cell's structure and the drug's stereochemical properties. Pharmacological classes differ in their ability to show selectivity. Cancer chemotherapeutic agents generally show poor selectivity whereas phosphodiesterase inhibitors can be selective for a specific enzyme isoform. Most bacterial antibiotics show excellent selective toxicity for bacteria with minimal serious adverse reactions experienced by the patient. In contrast, antiviral and antifungal drugs can produce untoward reactions in patients. Monoclonal antibodies exhibit excellent antigen–antibody specificity, but can disrupt the normal immune response. The nonsedating antihistamines distribute less to the central nervous system relative to the first generation of antihistamines. The initially inactive proton pump inhibitors readily distribute to an extracellular space with high acidity that converts them to the active drug. To improve patient acceptance, an important goal is to design the drug such that it be transported to the desired receptor and ignore other sites.
Anticonvulsants
Authors: Gitto Rosaria , Luca Laura De , Sarro Giovanbattista De
Published: September 2010

This chapter focuses on the chemical structures, the mechanism of action and the main structure–activity relationships of selected current and prospective anticonvulsant agents. Particular attention will be addressed to molecular targets involved in the mechanism of action of not only currently used drugs but also now being developed drugs. The pharmacokinetic and pharmacodynamic aspects of the most representative anticonvulsant agents will be also considered.
Design of Peptidomimetics
Authors: Perez Juan J. , Corcho Francesc J. , Rubio‐Martinez Jaime
Published: September 2010

The scope of the present report is to review the concept of peptidomimetic and provide examples of a few stories behind their discovery and design, taken from the literature. Emphasis is given on the process of design, stressing a hierarchical approach, where it is evidenced how the information about the necessary chemical moieties and their spatial arrangement is gathered stepwise. The necessary multidisciplinary approach required is also highlighted, where medicinal chemistry, biophysical, and computational methods are used together to design small‐molecule therapeutic agents. Finally, the general ideas developed are applied to a few examples taken from the literature, classified into three major categories of peptide–protein interactions that may be object of peptidomimetic design: enzyme inhibitors, G‐protein‐coupled receptors, and protein–protein interactions.
Prodrugs: Strategic Deployment, Metabolic Considerations, and Chemical Design Principles
Authors: Erhardt Paul W. , Khupse Rahul , Sarver Jeffrey G. , Trendel Jill A.
Published: September 2010

This chapter offers a review of the historical and present‐day design and development of prodrugs. Several case studies are presented to further illustrate the principles being discussed.
Provisional
BCS
Classification of the Leading Oral Drugs on the Global Market
Authors: Dahan Arik , Amidon Gordon L.
Published: September 2010

In the early 1990s, a collaborative research effort between academia and the U.S. Food and Drug Administration (FDA) was initiated to establish a database of human jejunal permeabilities based on a Biopharmaceutics Classification System (BCS). The BCS broadly allowed the prediction of human absorption, Fraction absorbed (
F
abs
) and the rate‐limiting step in the intestinal absorption process of drugs following oral administration. The BCS classified compounds into one of four biopharmaceutical classes according to water solubility and membrane permeability characteristics. Today, the BCS has generated remarkable impact on the global pharmaceutical sciences arena, in drug discovery, development and regulation, and an extensive validation/discussion of the BCS is continuously published in the literature. BCS has been effectively implanted by drug regulatory agencies around the world, and widely practiced by the pharmaceutical industry. The aim of this chapter is to present the BCS and its scientific basis, to describe its impact on regulatory practice of oral drug products, and to access the BCS classification of the top drugs on the global market. Finally, current and future directions in BCS related extensions, and their impact on the pharmaceutical industry, will be discussed.
Salt Screening and Selection
Authors: Semin David J. , Jona Janan , Peterson Matthew L. , Zanon Roger
Published: September 2010

Salt screening and selection is a critical factor for the developability of an active pharmaceutical ingredient (API). The main benefit to screening, identifying, and selecting the optimal salt form early in the lifecycle is to improve the bioavailability of the compound while addressing its associated physicochemical, stability, and mechanical properties. The role of the scientist in the screening process involves the selection of the counterions and solvents and to bring valuable experience during the crystallization process. There are numerous manual and automated assisted strategies across the pharmaceutical industry for salt screening; however, determining crystalline salts that have a low potential for polymorphism is the common goal. The selection of the optimal salt not only improves the manufacturing and marketability of the drug product but also positions and protects the intellectual property of the product through composition of matter patents.
Enzymatic Assays for High‐Throughput Screening
Authors: Carettoni Daniele , Verwaerde Philippe
Published: September 2010

High‐throughput screening (HTS) is a multidisciplinary approach to investigate in parallel the pharmacological properties of a large number of small molecules, with the aim of identifying target‐specific lead compounds to be progressed as bioactive probes or therapeutic drugs. The complex integration of chemistry, biology, automation, informatics, and medicinal chemistry has prompted the evolution of HTS as an autonomous discipline integrated in the drug discovery process. Thus, HTS assays are differentiated from traditional laboratory assays by the requirement of extensive assay development and by the strict quality criteria that must be fulfilled to approach a screening campaign. In this perspective, biochemistry and enzymology have provided an essential support for the design and configuration of functional HTS assays for enzymatic targets. In turn, the impressive technological improvements of HTS have made available an unprecedented array of novel methods and instrumentations that have contributed to advance the biochemical and kinetic characterization of enzymes. In this chapter, the paradigms for the configuration of enzymatic assays for HTS are reviewed, emphasizing the tight interdependence between type and quality of the HTS assay and the outcome of a screening campaign. The sequential steps of assay development for HTS are examined, providing examples of alternative approaches to configure the activity of enzyme drug targets as HTS‐compatible assays.
Current and Emerging Therapies in Chronic Obstructive Pulmonary Disease
Authors: Montana John G. , Dyke Hazel J. , Craig Fox J. , Ray Nicholas C.
Published: September 2010

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease that is a leading cause of morbidity and mortality worldwide with an overall prevalence in adults >40 years estimated at 9–10%. The World Health Organization (WHO) estimates that, by 2020, COPD will be the third leading cause of mortality and the fifth leading cause of morbidity in the world. This smoking‐related disease is characterized by progressive airway obstruction that, unlike asthma, is relatively insensitive to bronchodilators and to the classic anti‐inflammatory therapy, corticosteroids. Current therapy focuses mainly on reducing symptoms using inhaled short‐acting and long‐acting bronchodilators either as monotherapies or in combination with inhaled corticosteroids. During the last decade, the pharmaceutical industry has focused on treating COPD distinctly from asthma but no novel agents that target the disease itself have been launched as therapies for this disease. As our understanding of the pathology of COPD has increased it has been established that the progressive pulmonary inflammation that is associated with COPD relates to disease severity. Thus, it is anticipated that drugs that reduce pulmonary inflammation will provide effective, disease‐modifying therapies. Here, we consider the potential of anti‐inflammatory drugs that are currently in clinical development for COPD and discuss how these might reduce pulmonary inflammation in this disease.
Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH2Sand their Prodrugs
Authors: Szabo Csaba
Published: September 2010

Nitric oxide(NO),carbon monoxide(CO), andhydrogen sulfide(H2S) are the main endogenous gasotransmitters. These gases are produced by the body by enzymatic reactions and serve physiological regulatory purposes including vasodilatation and anti‐inflammatory effects. Over the past decades, multiple approaches have been identified for the therapeutic exploitation of these three gasotransmitters, based on inhalation of the gases and/or the parenteral or enteral administration of various formulations of these molecules or their prodrugs. Here we overview the medicinal chemistry and the therapeutic applications of NO, CO, and H2S and their prodrugs. Inhaled NO is used clinically to selectively dilate the pulmonary vasculature in the therapy of the primary pulmonary hypertension of the newborn. Organic nitrates such as glyceryl trinitrate or nitroglycerin are used in the therapy of acute and chronic angina. Sodium nitroprusside is used to counteract acute hypertensive crisis. Another class of clinical‐stage NO donor drugs is the sydnonimines (molsidomine, linsidomine). Additional classes of NO donors include diazeniumdiolates (NONOates) andS‐nitrosothiols, with beneficial effects in various preclinical models of disease. With respect to CO, the main therapeutic approaches are CO inhalation (currently in clinical trials for the experimental therapy of delayed graft function associated with kidney transplantation) and carbon monoxide releasing compounds of various classes (in preclinical stage). With respect to H2S, a parenteral injectable formulation of the gas is currently is Phase I trials. Several classes of H2S donor molecules have also been identified, which are used in preclinical studies.
Dipeptidyl Peptidase 4 Inhibitors
Authors: Weber Ann E. , Thornberry Nancy A.
Published: September 2010

Defective insulin secretion is a hallmark of type 2 diabetes (T2DM), and agents that increase the concentration of circulating insulin have proven beneficial in the treatment of diabetes. Dipeptidyl peptidase 4 (DPP‐4) inhibitors are a new oral approach to T2DM that lower glucose via stabilization of the incretin hormone glucagon‐like peptide 1 (GLP‐1), which has clearly established roles in insulin secretion and inhibition of glucagon production. These agents have been shown to produce clinically meaningful glucose control in a range of patients with type 2 diabetes without many of the liabilities that are associated with other oral therapies, including weight gain, edema, GI intolerability, and hypoglycemia. Accordingly, DPP‐4 inhibitors have excellent potential for use in both monotherapy and combination with established agents. Extensive structure–activity relationship (SAR) studies in many different laboratories have resulted in the identification of a number of clinical candidates. The most advanced of these have recently been approved for the treatment of T2DM, representing the first new oral therapy for treatment of this disease since the introduction of troglitazone in 1998.
Osteoporosis Therapy: Mechanistic Antiresorptives
Authors: Dodge Jeffrey A. , Bryant Henry U.
Published: September 2010

Osteoporosis is defined as the thinning of bone resulting from the imbalance between bone resorption and bone formation, the two cellular mechanisms that regulate the remodeling of skeletal tissue. This loss of bone ultimately results in an increased risk of fracture. One therapeutic approach to treating patients with osteoporosis is to inhibit the process of bone resorption. This has been clinically manifested by the development of a number of large and small molecules that include calcitonin, integrin inhibitors, cathepsin K inhibitors, OPG/RANKL inhibitors, bisphosponates, and SERMS. This chapter describes recent advances in the anti‐resorptive field with a focus on clinically validated targets and the molecules that have been developed to regulate these pathways.
Proteasome Inhibitors
Authors: Wehenkel Marie , Kim Kyung Bo
Published: September 2010

The proteasome has emerged as a major player in regulating essential cellular activities such as cell proliferation and inflammation. The FDA approval of bortezomib, the first‐in‐class proteasome inhibitor drug, for treatment of recurring multiple myeloma, has validated the proteasome as a target for treatment of cancer. This has catalyzed intense medicinal chemistry and library screening efforts to develop novel or improved proteasome inhibitors. Currently, a number of proteasome inhibitors are being investigated in clinical trials for cancer therapy. In this section, particular attention is focused on these inhibitors under clinical trials as well as traditional medicine recently identified as proteasome inhibitors. In addition, we discuss some of the medicinal chemistry efforts in the course of development of proteasome inhibitors with better efficacy. Finally, we describe novel proteasome inhibitors that target specific subunits of proteasomes.
Opioid Receptor Ligands
Authors: McCurdy Christopher R. , Prisinzano Thomas E.
Published: September 2010

Opioid agonists, exemplified by morphine, have been the most prescribed class of drugs for the management of moderate to severe pain for many years. These drugs have significant liabilities of addiction and constipation over long‐term use and acute overdoses can result in respiratory depression. For over thousands of years, opium and opium‐derived drugs have nonetheless been utilized for their therapeutic and recreational benefits. Due to their liabilities, medicinal chemists and clinicians have worked for years to discover novel agents or treatment courses that would be devoid of these side effects. Still to this day, there are no agents that meet these criteria. Therefore, efforts continue vigorously in the quest for drugs with potent analgesic effects without abuse or side‐effect potential. Many chemical classes have been sought after in this quest and the range from peptides to synthetic compounds to natural products. Morphine offered a template that was rigid and able to provide an enormous amount of structure–function relationships that many of the market analgesics are based on. To complicate matters, the endogenous opioid system is comprised of four distinct receptor subtypes. These receptors are all members of the G‐protein superfamily and are designated as mu (μ, MOP), delta (δ, DOP), kappa (κ, KOP), and nociception (ORL1, NOP). It has been realized over the years that a combination of activities at these receptors may result in agents that could be devoid of liabilities. Intensive efforts have been directed at improved probes for each receptor subtype and combinations of agonists and antagonists for combinations of these receptors. This review will discuss the structure–activity relationships, as they are currently understood, with regard to each of the major classes of compounds that interact with these protein targets.
Flexible Nanosomes (SECosomes) Enable Efficient siRNA Delivery in Cultured Primary Skin Cells and in the Viable Epidermis of Ex Vivo Human Skin
Authors: Geusens Barbara , Van Gele Mireille , Braat Sien , De Smedt Stefaan C. , Stuart Marc C. A. , Prow Tarl W. , Sanchez Washington , Roberts Michael S. , Sanders Niek N. , Lambert Jo
Published: September 2010

The extent to which nanoscale‐engineered systems cross intact human skin and can exert pharmacological effects in viable epidermis is controversial. This research seeks to develop a new lipid‐based nanosome that enables the effective delivery of siRNA into human skin. The major finding is that an ultraflexible siRNA‐containing nanosome—prepared using DOTAP, cholesterol, sodium cholate, and 30% ethanol—penetrates into the epidermis of freshly excised intact human skin and is able to enter into the keratinocytes. The nanosomes, called surfactant‐ethanol‐cholesterol‐osomes (SECosomes), show excellent size, surface charge, morphology, deformability, transfection efficiency, stability, and skin penetration capacity after complexation with siRNA. Importantly, these nanosomes have ideal characteristics for siRNA encapsulation, in that the siRNA is stable for at least 4 weeks, they enable highly efficient transfection of in vitro cultured cells, and are shown to transport siRNA delivery through intact human skin where changes in the keratinocyte cell state are demonstrated. It is concluded that increasing flexibility in nanosomes greatly enhances their ability to cross the intact human epidermal membrane and to unload their payload into targeted epidermal cells.
Auditory Morphology and Hearing Sensitivity in Fossil New World Monkeys
Authors: Coleman Mark N. , Kay Richard F. , Colbert Matthew W.
Published: September 2010

In recent years it has become possible to investigate the hearing capabilities in fossils by analogy with studies in living taxa that correlate the bony morphology of the auditory system with hearing sensitivity. In this analysis, we used a jack‐knife procedure to test the accuracy of one such study that examined the functional morphology of the primate auditory system and we found that low‐frequency hearing (sound pressure level at 250 Hz) can be predicted with relatively high confidence (±3–8 dB depending on the structure). Based on these functional relationships, we then used high‐resolution computed tomography to examine the auditory region of three fossil New World monkeys (Homunculus, Dolicocebus, and Tremacebus) and compared their morphology and predicted low‐frequency sensitivity with a phylogenetically diverse sample of extant primates. These comparisons reveal that these extinct taxa shared many auditory characteristics with living platyrrhines. However, the fossil with the best preserved auditory region (Homunculus) also displayed a few unique features such as the relative size of the tympanic membrane and stapedial footplate and the degree of trabeculation of the anterior accessory cavity. Still, the majority of evidence suggests that these fossil species likely had similar low‐frequency sensitivity to extant South American monkeys. This research adds to the small but growing body of evidence on the evolution of hearing abilities in extinct taxa and lays the groundwork for predicting hearing sensitivity in additional fossil primate specimens. Anat Rec 293:1711–1721, 2010. © 2010 Wiley‐Liss, Inc.
Antler Transformation is Advanced by Inversion of Antlerogenic Periosteum Implants in Sika Deer (Cervus nippon)
Authors: Gao Xiuhua , Yang Fuhe , Zhao Haiping , Wang Wenying , Li Chunyi
Published: September 2010

Deer antlers offer a unique model for the study of tissue‐specific stem cells and organogenesis, as antler stem cells are confined to the antlerogenic periosteum (AP), a tissue that can be readily located (overlying a frontal crest) and experimentally manipulated. AP consists of an upper fibrous layer and a lower cellular layer. Tissue transplantation and membrane insertion experiments demonstrated that antler formation is triggered by the interactions between AP and the overlying skin. Interestingly, fairly normal antlers can be induced to grow by an inverted AP implant (the AP cellular layer facing the skin) at an ectopic site, raising the question whether the initial inductive signal is derived from the fibrous layer or cellular layer or both. To answer this question, in this study we used eight sika deer stag calves and selected one side of future antler growth region for implanting inverted AP and the contralateral side for noninverted AP as the control. The results showed that implantation of the AP discs in an inverted orientation generated pedicles with final height (17 ± 5.1 mm), less than half the height of those formed from the noninverted AP implants (45 ± 11.7 mm). Critically, antler transformation was initiated from a shorter pedicle, which was formed from the region where the AP cellular layer was brought in close proximity to the overlying skin. Therefore, the AP cellular layer, as opposed to the AP fibrous layer, is likely to be the main source of the initial inductive molecules for antlerogenesis. Anat Rec 293:1787–1796, 2010. © 2010 Wiley‐Liss, Inc.
Fiber Type Composition of the Sternomastoid and Diaphragm Muscles of Dystrophin‐Deficient mdx Mice
Authors: Guido Anderson Neri , Campos Gerson Eduardo Rocha , Neto Humberto Santo , Marques Maria Julia , Minatel Elaine
Published: September 2010

The muscle fiber phenotype is mainly determined by motoneuron innervation and changes in neuromuscular interaction alter the muscle fiber type. In dystrophin‐deficient mdx mice, changes in the molecular assembly of the neuromuscular junction and in nerve terminal sprouting occur in the sternomastoid (STN) muscle during early stages of the disease. In this study, we were interested to see whether early changes in neuromuscular assembly are correlated with alterations in fiber type in dystrophic STN at 2 months of age. A predominance of hybrid fast myofibers (about 52% type IIDB) was observed in control (C57Bl/10) STN. In mdx muscle, the lack of dystrophin did not change this profile (about 54% hybrid type IIDB). Pure fast type IID fibers predominated in normal and dystrophic diaphragm (DIA; about 39% in control and 30% in mdx muscle) and a population of slow Type I fibers was also present (about 10% in control and 13% in mdx muscle). In conclusion, early changes in neuromuscular assembly do not affect the fiber type composition of dystrophic STN. In contrast to the pure fast fibers of the more affected DIA, the hybrid phenotype of the STN may permit dynamic adaptations during progression of the disease. Anat Rec 293:1722–1728, 2010. © 2010 Wiley‐Liss, Inc.
First Evidence of a Leptin‐Like Peptide in a Cartilaginous Fish
Authors: Gambardella Chiara , Gallus Lorenzo , Ravera Silvia , Fasulo Salvatore , Vacchi Marino , Ferrando Sara
Published: September 2010

Leptin is a hormone involved in food intake. Although leptin is evolutionarily conserved, no studies have investigated its presence in cartilaginous fish. Here, we report the presence of leptin‐like immunoreactivity in the gastro‐intestinal tract and liver of the cartilaginous fish Scyliorhinus canicula using western blot and immunohistochemical analyses. A leptin‐like immunoreactive band of 16 kDa was detected in the homogenate of the stomach, whereas no immunoreactivity was observed in the intestine or the liver. Immunohistochemistry of the gastric mucosa revealed leptin‐like staining localized to mucous‐secreting cells and endocrine cells. This is the first report of a leptin‐like peptide in a cartilaginous fish. Anat Rec 293:1692–1697, 2010. © 2010 Wiley‐Liss, Inc.
Ground‐penetrating radar assessment of the medieval arch bridge of San Antón, Galicia, Spain
Authors: Solla M. , Lorenzo H. , Novo A. , Rial F.I.
Published: September 2010

Several arched masonry bridges are listed historical monuments in Spain, which are valued tourist attractions or local landmarks. They are maintained by several organizations dedicated to the cultural heritage such as the International Council on Monuments and Sites (ICOMOS). Many of these important structures are the oldest constructions still in use within the transportation infrastructure and as a result of the increase in traffic loads and their age they have undergone some structural decay. Ground‐penetrating radar (GPR) has been shown to be valuable in evaluating the state of conservation of the San Antón medieval bridge in order to help preserve its historical character. This bridge was surveyed by using the 200, 250 and 500 MHz antennas. Interpretation and analysis of GPR reflection data were supported by finite‐difference time domain numerical modelling, based on the accurate external geometry obtained with three‐dimensional laser scanning methods. Results show that GPR mapping provides valuable information for detecting an internal structural element used for reinforcement as well as a possible interior hidden arch that remains from ancient times. This information is noteworthy for archaeologists and civil engineers as it can be used to make decisions about stability and for future strengthening measures. Copyright © 2010 John Wiley & Sons, Ltd.
Cucurbit[7]uril as a Tool in the Green Synthesis of Gold Nanoparticles
Authors: Premkumar Thathan , Geckeler Kurt E.
Published: September 2010

A simple, green, one‐pot synthesis of gold nanoparticles was achieved through the reaction of an aqueous mixture of potassium tetrachloroaurate(III) and the macrocycle cucurbit[7]uril in the presence of sodium hydroxide at room temperature without introducing any kind of traditional reducing agents and/or external energy. The as‐prepared gold nanoparticles showed catalytic activity for the reduction reaction of 4‐nitrophenol in the presence of NaBH4, which has been established by visual inspection and UV/Vis spectroscopy. This report is the first for the preparation of gold nanoparticles using cucurbit[7]uril in aqueous media through chemical reduction without employing conventional reducing agents and/or external energy.