Alpha-selenoconotoxins, a new class of potent alpha(7) neuronal nicotinic receptor antagonists

Disulfide bonds are important structural motifs that play an essential role in maintaining the conformational stability of many bioactive peptides. Of particular importance are the conotoxins, which selectively target a wide range of ion channels that are implicated in numerous disease states. Despite the enormous potential of conotoxins as therapeutics, their multiple disulfide bond frameworks are inherently unstable under reducing conditions. Reduction or scrambling by thiol-containing molecules such as glutathione or serum albumin in intracellular or extracellular environments such as blood plasma can decrease their effectiveness as drugs. To address this issue, we describe a new class of selenoconotoxins where cysteine residues are replaced by selenocysteine to form isosteric and non-reducible diselenide bonds. Three isoforms of alpha-conotoxin ImI were synthesized by t-butoxycarbonyl chemistry with systematic replacement of one([ Sec(2,8)] ImI or [Sec(3,12)] ImI), or both([Sec(2,3,8,12)] ImI) disulfide bonds with a diselenide bond. Each analogue demonstrated remarkable stability to reduction or scrambling under a range of chemical and biological reducing conditions. Three-dimensional structural characterization by NMR and CD spectroscopy indicates conformational preferences that are very similar to those of native ImI, suggesting fully isomorphic structures. Additionally, full bioactivity was retained at the alpha(7) nicotinic acetylcholine receptor, with each seleno-analogue exhibiting a dose-response curve that overlaps with wild-type ImI, thus further supporting an isomorphic structure. These results demonstrate that selenoconotoxins can be used as highly stable scaffolds for the design of new drugs.

Zinc deposits and related mineralization of the Burketown mineral field, including the world-class Century Deposit, Northern Australia: Fluid inclusion and stable isotope evidence for basin fluid sources

The stratiform Century Zn-Pb deposit and the discordant Zn-Pb lode deposits of the Burketown mineral field, northern Australia, host ore and gangue minerals with primary fluid inclusions that have not been affected by the Isan orogeny, thus providing a unique opportunity to investigate the nature of the ore-forming brines. All of the deposits are hosted in shales and siltstones belonging to the Isa superbasin and comprise sphalerite, pyrite, carbonate, quartz, galena, minor chalcopyrite, and minor illite. According to Pb model ages, the main ore stage of mineralization at Century formed at I575 Ma, some 20 m.y. after deposition of the host shale sequence. Microthermometry on undeformed, primary fluid inclusions hosted in porous sphalerite shows that the Zn at Century was transported to the deposit by a homogeneous, Ca2+- and Na+-bearing brine with a salinity of 21.6 wt percent NaCl equiv. delta D-fluid of the fluid inclusion water ranges from -89 to -83 per mil, consistent with a basinal brine that evolved from meteoric water. Fluid inclusion homogenization temperatures range between 74 degrees and 125 degrees C, which are lower than the 120 degrees to 160 degrees C range calculated from vitrinite reflectance and illite crystallinity data from the deposit. This discrepancy indicates that mineralization likely formed at 50 to 85 Mpa, corresponding to a depth of 1,900 to 3,100 m. Transgressive galena-sphalerite veins that cut stratiform mineralization at Century and breccia-filled quartz-dolomite-sphalerite-galena veins in the discordant Zn-Pb lodes have Pb model ages between 1575 and 1485 Ma. Raman spectroscopy and microthermometry reveal that the primary fluid inclusions in these veins contain Ca2+, Na+. but they have lower salinities between 23 and 10 wt percent NaCl equiv and higher delta D-fluid values ranging from -89 to -61 per mil than fluid inclusions in porous sphalerite from Century. Fluid inclusion water from sphalerite in one of the lode deposits has delta O-18(fluid) values of 1.6 and 2.4 per mil, indistinguishable from delta O-18(fluid) values between -0.3 to +7.4 per mil calculated from the isotopic composition of coexisting quartz, dolomite, and illite. The trend toward lower salinities and higher delta D-fluid values relative to the earlier mineralizing fluids is attributed to mixing between the fluid that formed Century and a seawater-derived fluid from a different source. Based on seismic data from the Lawn Hill platform and paragenetic and geochemical results from the Leichhardt River fault trough to the south, diagenetic aquifers in the Underlying Calvert superbasin appear to have been the most likely sources for the fluids that formed Century and the discordant lode deposits. Paragenetically late sphalerite and calcite cut sphalerite, quartz, and dolomite in the lode deposits and contain Na+-dominated fluid inclusions with much lower salinities than their older counterparts. The isotopic composition of calcite also indicates delta O-18(fluid) from 3.3 to 10.7 per mil, which is larger than the range obtained from synmineralization minerals, supporting the idea that a unique fluid source was involved. The absolute timing of this event is unclear, but a plethora of Pb model, K-Ar, and Ar-40/Ar-39 ages between 1440 and 1300 Ma indicate that a significant volume of fluid was mobilized at this time. The deposition of the Roper superbasin from ca. 1492 +/- 4 Ma suggests that these late veins formed from fluids that may have been derived from aquifers in overlying sediments of the Roper superbasin. Clear, buck, and drusy quartz in veins unrelated to any form of Pb-Zn mineralization record the last major fluid event in the Burketown mineral field and form distinct outcrops and ridges in the district. Fluid inclusions in these veins indicate formation from a low-salinity, 300 degrees +/- 80 degrees C fluid. Temperatures approaching 300 degrees C recorded in organic matter adjacent to faults and at sequence boundaries correspond to K-Ar ages spanning 1300 to 1100 Ma, which coincides with regional hydrothermal activity in the northern Lawn Hill platform and the emplacement of the Lakeview Dolerite at the time of assemblage of the Rodinia supercontinent.

Unicellular pheromone glands of the pentatomid bug Nezara viridula (Heteroptera : Insecta): Ultrastructure, classification, and proposed function

Male Nezara viridula produce sex pheromones from many independent single cells, each with a duct that opens onto the ventral abdominal surface. Despite the presence of along duct and an associated end complex (in the form of a cupule and microvillus saccule), the structural organization of the cells that comprise the gland conform to Class 1 epidermal gland cell classification : a single cell surrounds the entire secretory complex. Each cuticular cupule contains a central bed of filaments and opens into a narrow tubular ductule that leads from the base of the cupule through the epidermis to the cuticle to open externally as a pore. The cuticle of the cupule is continuous with that of the ductule and has the appearance of three layers, although the inner (middle) layer may be a gap formed during construction of the complex. In young adult males, just molted, the ultrastructure of the cells and their inclusions indicate that they are not active. The region of the cell that is distal to the abdominal cuticle is reduced and the proximal region, surrounding the duct, is enlarged when compared with sexually mature (3-4 weeks old) adult males. At maturity the pheromone cells are enlarged distally around the cupule, but are reduced to a narrow sleeve proximally, around the ductule. Two characteristic cell profiles are evident, based on the shape of the cupule and the organelle content. Type A shows a broad opening to the cupule, an abundance of mitochondria, and few vesicular bodies. Type B has an elongated, narrow, vase-like opening to the cupule, few mitochondria, and numerous vesicular bodies. Type B cells are smaller and more abundant than Type A. Distribution within the epidermal layer also differs. It is likely that the different types represent cells producing different secretion profiles. However, the secretions retained by the standard fixation protocol within mature cells of both types look similar and appear to collect as crystalline bodies within the lumen. This may represent a common storage mechanism.

Compositional class refinement in object-Z

Object-Z allows coupling constraints between classes which, on the one hand, facilitate specification at a high level of abstraction, but, on the other hand, make class refinement non-compositional. The consequence of this is that refinement is not practical for large Systems. This paper overcomes this limitation by introducing a methodology for compositional class refinement in Object-Z. The key step is an equivalence transformation of an arbitrary Object-Z specification to one in which introduced constraints prohibit non-compositional refinements. The methodology also allows the constraints which couple classes to be refined yielding an unrestricted approach to compositional class refinement.

Multisensorial obstacles detection and classification for ADAS and autonomous driving

A reliable perception of the real world is a key-feature for an autonomous vehicle and the Advanced Driver Assistance Systems (ADAS). Obstacles detection (OD) is one of the main components for the correct reconstruction of the dynamic world. Historical approaches based on stereo vision and other 3D perception technologies (e.g. LIDAR) have been adapted to the ADAS first and autonomous ground vehicles, after, providing excellent results. The obstacles detection is a very broad field and this domain counts a lot of works in the last years. In academic research, it has been clearly established the essential role of these systems to realize active safety systems for accident prevention, reflecting also the innovative systems introduced by industry. These systems need to accurately assess situational criticalities and simultaneously assess awareness of these criticalities by the driver; it requires that the obstacles detection algorithms must be reliable and accurate, providing: a real-time output, a stable and robust representation of the environment and an estimation independent from lighting and weather conditions. Initial systems relied on only one exteroceptive sensor (e.g. radar or laser for ACC and camera for LDW) in addition to proprioceptive sensors such as wheel speed and yaw rate sensors. But, current systems, such as ACC operating at the entire speed range or autonomous braking for collision avoidance, require the use of multiple sensors since individually they can not meet these requirements. It has led the community to move towards the use of a combination of them in order to exploit the benefits of each one. Pedestrians and vehicles detection are ones of the major thrusts in situational criticalities assessment, still remaining an active area of research. ADASs are the most prominent use case of pedestrians and vehicles detection. Vehicles should be equipped with sensing capabilities able to detect and act on objects in dangerous situations, where the driver would not be able to avoid a collision. A full ADAS or autonomous vehicle, with regard to pedestrians and vehicles, would not only include detection but also tracking, orientation, intent analysis, and collision prediction. The system detects obstacles using a probabilistic occupancy grid built from a multi-resolution disparity map. Obstacles classification is based on an AdaBoost SoftCascade trained on Aggregate Channel Features. A final stage of tracking and fusion guarantees stability and robustness to the result.

QUALIDADE DE VIDA DE PARTICIPANTES DE PROGRAMAS DE ECONOMIA SOLIDÁRIA

Este estudo buscou estudar qualidade de vida em indivíduos que trabalhavam em cooperativas com a filosofia da Economia Solidária. Mais especificamente procurou: levantar o perfil sócio econômico cultural e demográfico de indivíduos adultos integrantes de programas de Economia Solidária; avaliar a qualidade de vida desses indivíduos integrantes de programas; descrever a compreensão desses trabalhadores sobre o conceito de qualidade de vida. Participaram desse estudo 69 pessoas, trabalhadores de três cooperativas distintas de catadores de lixo reciclável. Foi aplicado um questionário elaborado especialmente para esse estudo contendo dados de identificação dos participantes, com o propósito de fazer um levantamento relativo aos dados sócioeconômicos, culturais e demográficos e, nesse questionário foi agregado o critério de classificação de renda e classe social da Associação Brasileira dos Institutos de Pesquisa - ABIPEME e utilizou-se a Escala de Qualidade de vida Whoqol Bref . Verificou-se, que os trabalhadores apresentaram um bom nível de qualidade de vida. Em relação aos dados sócio-econômicos culturais, observou-se um predomínio da presença de mulheres, solteiras ou com parceiros, mas com filhos. Com relação aos domínios que compõem Qualidade de Vida, houve uma correlação significativa entre os domínios físico e psicológico e também uma correlação entre os domínios: psicológico e de relações sociais. Por outro lado, o domínio meio ambiente foi o que apresentou um índice menor de qualidade de vida em relação aos demais. Levanta-se a hipótese de que o fato dos cooperados estarem insatisfeitos com seus ganhos, por os considerarem insuficientes, acrescido de suas condições de moradia serem precárias, além da maioria ser oriunda de um sistema econômico competitivo e individualista e não terem ainda a devida adaptação que esse novo sistema exige, interferiram no domínio meio ambiente de forma negativa..(AU)

Blood type classification using computer vision and machine learning

In emergency situations, where time for blood transfusion is reduced, the O negative blood type (the universal donor) is administrated. However, sometimes even the universal donor can cause transfusion reactions that can be fatal to the patient. As commercial systems do not allow fast results and are not suitable for emergency situations, this paper presents the steps considered for the development and validation of a prototype, able to determine blood type compatibilities, even in emergency situations. Thus it is possible, using the developed system, to administer a compatible blood type, since the first blood unit transfused. In order to increase the system’s reliability, this prototype uses different approaches to classify blood types, the first of which is based on Decision Trees and the second one based on support vector machines. The features used to evaluate these classifiers are the standard deviation values, histogram, Histogram of Oriented Gradients and fast Fourier transform, computed on different regions of interest. The main characteristics of the presented prototype are small size, lightweight, easy transportation, ease of use, fast results, high reliability and low cost. These features are perfectly suited for emergency scenarios, where the prototype is expected to be used.

Gaussian processes for classification: mean field algorithms:mean-field algorithms

We derive a mean field algorithm for binary classification with Gaussian processes which is based on the TAP approach originally proposed in Statistical Physics of disordered systems. The theory also yields an approximate leave-one-out estimator for the generalization error which is computed with no extra computational cost. We show that from the TAP approach, it is possible to derive both a simpler 'naive' mean field theory and support vector machines (SVM) as limiting cases. For both mean field algorithms and support vectors machines, simulation results for three small benchmark data sets are presented. They show 1. that one may get state of the art performance by using the leave-one-out estimator for model selection and 2. the built-in leave-one-out estimators are extremely precise when compared to the exact leave-one-out estimate. The latter result is a taken as a strong support for the internal consistency of the mean field approach.

MHC class II binding prediction:a little help from a friend

Vaccines are the greatest single instrument of prophylaxis against infectious diseases, with immeasurable benefits to human wellbeing. The accurate and reliable prediction of peptide-MHC binding is fundamental to the robust identification of T-cell epitopes and thus the successful design of peptide- and protein-based vaccines. The prediction of MHC class II peptide binding has hitherto proved recalcitrant and refractory. Here we illustrate the utility of existing computational tools for in silico prediction of peptides binding to class II MHCs. Most of the methods, tested in the present study, detect more than the half of the true binders in the top 5% of all possible nonamers generated from one protein. This number increases in the top 10% and 15% and then does not change significantly. For the top 15% the identified binders approach 86%. In terms of lab work this means 85% less expenditure on materials, labour and time. We show that while existing caveats are well founded, nonetheless use of computational models of class II binding can still offer viable help to the work of the immunologist and vaccinologist.

Present perspectives on the automated classification of the G-protein coupled receptors (GPCRs) at the protein sequence level

The G-protein coupled receptors--or GPCRs--comprise simultaneously one of the largest and one of the most multi-functional protein families known to modern-day molecular bioscience. From a drug discovery and pharmaceutical industry perspective, the GPCRs constitute one of the most commercially and economically important groups of proteins known. The GPCRs undertake numerous vital metabolic functions and interact with a hugely diverse range of small and large ligands. Many different methodologies have been developed to efficiently and accurately classify the GPCRs. These range from motif-based techniques to machine learning as well as a variety of alignment-free techniques based on the physiochemical properties of sequences. We review here the available methodologies for the classification of GPCRs. Part of this work focuses on how we have tried to build the intrinsically hierarchical nature of sequence relations, implicit within the family, into an adaptive approach to classification. Importantly, we also allude to some of the key innate problems in developing an effective approach to classifying the GPCRs: the lack of sequence similarity between the six classes that comprise the GPCR family and the low sequence similarity to other family members evinced by many newly revealed members of the family.

On the solution of a class of capital investment problems

In this work the solution of a class of capital investment problems is considered within the framework of mathematical programming. Upon the basis of the net present value criterion, the problems in question are mainly characterized by the fact that the cost of capital is defined as a non-decreasing function of the investment requirements. Capital rationing and some cases of technological dependence are also included, this approach leading to zero-one non-linear programming problems, for which specifically designed solution procedures supported by a general branch and bound development are presented. In the context of both this development and the relevant mathematical properties of the previously mentioned zero-one programs, a generalized zero-one model is also discussed. Finally,a variant of the scheme, connected with the search sequencing of optimal solutions, is presented as an alternative in which reduced storage limitations are encountered.

The work situation and class position of Brazilian engineers

This thesis analyses the work situation and class position of Brazilian engineers through a Marxist perspective. The research is based on two case studies, one focused on a large German steel company based in Brazil and the other on a large Brazilian energy corporation. The fieldwork involved 114 interviews, with engineers from different hierarchical positions in these two companies. Data was also gathered through interviews with representatives from the companies, the Council of Engineering, the Engineering Education System and the Engineers Trade Unions. The findings show that the engineering profession in Brazil has shifted from its initial condition as a liberal profession to an organizational profession, with the country's industrial deployment. Both companies consider all salaried workers as employees, including managers. Hence they are subject to the company's general personnel policies. The multinational company controls labour more rigidly than the national company, as well as reserving its top positions for its home country's executives. Although no deskilling process was found, engineers of both companies performed simple work, which required less engineering knowledge than they had learned from school. Engineers have little autonomy, authority and participation in decision making and are subject to direct supervision, performance evaluation, time control, overtime work, productivity and to poor working conditions in the multinational company. The majority of the engineers supervised other workers without being in a managerial position. They found that to move into management, was a good way to improve their autonomy, authority, prestige, salary, status, power and professional pride. Despite ideological divisions between capital and labour, most of the engineers were unionised and saw unions as the right way to deal with the employer.

Professions, class and society:solicitors in 19th century Birmingham

The thesis provides an analysis of an occupation in the process of making itself a profession. The solicitors' profession in Birmingham underwent a great many changes during the 19th century against a background of industrialisation and urbanisation. The solicitors' conception of their status and role, in the face of these challenges, had implications for successful strategies of professionalisation. The increased prestige and power of the profession, and especially its elite, are examined in their social context rather than in terms of a technical process, or educational and organisational change. The thesis argues that -the profession's social relationships and broad concerns were significant in establishing solicitors as "professional men". In particular these are related to the profession's efforts to gain control of markets for legal services and increase social status. In the course of achieving these aims a concept of profession and a self-image were articulated by solicitors in order to persuade society and the state of the legitimacy of their claims. The concept of the gentlemanly professional was of critical importance in this instance. The successful creation of a provincial professional "community" by the end of the 19th century rested principally on a social and moral conception of professionalism rather than one which stressed specialised training and knowledge, professional organisations and credentials.

Use of amino acids as counterions improves the solubility of the BCS II model drug, indomethacin

The number of new chemical entities (NCE) is increasing every day after the introduction of combinatorial chemistry and high throughput screening to the drug discovery cycle. One third of these new compounds have aqueous solubility less than 20µg/mL [1]. Therefore, a great deal of interest has been forwarded to the salt formation technique to overcome solubility limitations. This study aims to improve the drug solubility of a Biopharmaceutical Classification System class II (BCS II) model drug (Indomethacin; IND) using basic amino acids (L-arginine, L-lysine and L-histidine) as counterions. Three new salts were prepared using freeze drying method and characterised by FT-IR spectroscopy, proton nuclear magnetic resonance ((1)HNMR), Differential Scanning Calorimetry (DSC) and Thermogravimetric analysis (TGA). The effect of pH on IND solubility was also investigated using pH-solubility profile. Both arginine and lysine formed novel salts with IND, while histidine failed to dissociate the free acid and in turn no salt was formed. Arginine and lysine increased IND solubility by 10,000 and 2296 fold, respectively. An increase in dissolution rate was also observed for the novel salts. Since these new salts have improved IND solubility to that similar to BCS class I drugs, IND salts could be considered for possible waivers of bioequivalence.

Classification of bacterial strains based on DNA profiles

The analysis of bacterial genomes for epidemiological purposes often results in the production of a banding profile of DNA fragments characteristic of the genome under investigation. These may be produced using various methods, many of which involve the cutting or amplification of DNA into defined and reproducible characteristic fragments. It is frequently of interest to enquire whether the bacterial isolates are naturally classifiable into distinct groups based on their DNA profiles. A major problem with this approach is whether classification or clustering of the data is even appropriate. It is always possible to classify such data but it does not follow that the strains they represent are ‘actually’ classifiable into well-defined separate parts. Hence, the act of classification does not in itself answer the question: do the strains consist of a number of different distinct groups or species or do they merge imperceptibly into one another because DNA profiles vary continuously? Nevertheless, we may still wish to classify the data for ‘convenience’ even though strains may vary continuously, and such a classification has been called a ‘dissection’. This Statnote discusses the use of classificatory methods in analyzing the DNA profiles from a sample of bacterial isolates.