Interfacial properties of most monofluorinated bile acids deviate markedly from the natural congeners: studies with the Langmuir-Pockels surface balance

We characterized the air-water interfacial properties of four monofluorinated bile acids alone and in binary mixtures with a common lecithin, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), using an automated Langmuir-Pockels surface balance. We compared 7alpha-fluoromurocholic acid (FMCA), 7alpha-fluorohyodeoxycholic acid (FHDCA), 6alpha-fluoroursodeoxycholic acid (FUDCA), and 6alpha-fluorochenodeoxycholic acid (FCDCA) with their natural dihydroxy homologs, murocholic acid (MCA), hyodeoxycholic acid (HDCA), ursodeoxycholic acid (UDCA), and chenodeoxycholic acid (CDCA). For further comparison, two trihydroxy bile acids, 3alpha,6beta,7alpha-trihydroxycholanoic acid [alpha-muricholic acid (alpha-MCA)] and 3alpha,6alpha,7beta-trihydroxycholanoic acid [omega-muricholic acid (omega-MCA)], with isologous OH polar functions to FMCA and FUDCA were also studied. Pressure-area isotherms of MCA, HDCA, UDCA, CDCA, and FMCA displayed sharp collapse points. In contrast, FHDCA, FUDCA, and FCDCA formed monolayers that were less stable than the trihydroxy bile acids, displaying second-order phase transitions in their isotherms. All natural and fluorinated bile acids condensed mixed monolayers with POPC, with maximal effects at molar bile acid concentrations between 30 and 50 mol%. Examination of molecular models revealed that the 7alpha-F atom of the interfacially stable FMCA projects away from the 6beta-OH function, resulting in minimal steric interactions, whereas in FHDCA, FUDCA, and FCDCA, close vicinal interactions between OH and F polar functions result in progressive bulk solubility upon monolayer compression. These results provide a framework for designing F-modified bile acids to mimic or diverge from the natural compounds in vivo

A Framework for Hybrid Manufacturing in Robotic Cells

Compared to other additive technologies, Wire and Arc Additive Manufacturing (WAAM) offers high deposition rates, flexibility and a larger build volume as well as reduction of material waste. WAAM can be combined with a subtractive technology in hybrid robotic cells to further increase the application scope, thus producing products with improved surface finish where needed. However, there are some open issues that limit this process. So, the main goal of this paper is to review current research developments and provide a framework aimed at manufacturing parts by hybrid cells. A procedure is defined which moves from the evaluation of the designed shapes, their analysis to identify a proper manufacturing sequence until the elaboration of the instructions for the cell automaton controllers. Main WAAM issues are outlined to identify main research directions, and a test case is presented to highlight the process phase

Physicochemical and biological properties of natural and synthetic C-22 and C-23 hydroxylated bile acids.

In order to define the effect of a side chain hydroxy group on bile acid (BA) physicochemical and biological properties, 23-hydroxylated bile acids were synthesized following a new efficient route involving the alpha-oxygenation of silylalkenes. 22-Hydroxylated bile acids were also studied. The synthesized bile acids included R and S epimers of 3 alpha,7 alpha,23-trihydroxy-5 beta-cholan-24-oic acid (23R epimer: phocaecholic acid), 3 alpha,12 alpha,23-trihydroxy-5 beta-cholan-24-oic (23R epimer: bitocholic acid), and 3 alpha,7 beta,23-trihydroxy-5 beta-cholan-24-oic acid. A 3 alpha,7 alpha,22-trihydroxy-5 beta-cholan-24-oic acid (haemulcholic acid) was also studied. The presence of a hydroxy group on the side chain slightly modified the physicochemical behavior in aqueous solution with respect to common BA: the critical micellar concentration (CMC) and the hydrophilicity were similar to naturally occurring trihydroxy BA such as cholic acid. The pKa value was lowered by 1.5 units with respect to common BA, being 3.8 for all the C-23 hydroxy BA. C-22 had a higher pKa (4.2) as a result of the increased distance of the hydroxy group from the carboxy group. When the C-23 hydroxylated BA were intravenously administered to bile fistula rats, they were efficiently recovered in bile (more than 80% unmodified) while the corresponding analogs, lacking the 23- hydroxy group, were almost completely glycine- or taurine-conjugated. On the other hand, the C-22 hydroxylated BA were extensively conjugated with taurine and less than 40% of the administered dose was secreted without being conjugated. In the presence of intestinal bacteria, they were mostly metabolized to the corresponding 7-dehydroxylated compound similar to common BA with the exception of bitocholic acid which was relatively stable. The presence of a hydroxy group at the C-23 position increased the acidity of the BA and this accounted for poor absorption within the biliary tree and efficient biliary secretion without the need for conjugation. 3 alpha,7 beta-23 R/S trihydroxy-5 beta-cholan-24-oic acids could improve the efficiency of ursodeoxycholic acid (UDCA) for gallstone dissolution or cholestatic syndrome therapy, as it is relatively hydrophilic and efficiently secreted into bile without altering the glycine and taurine hepatic pool

An Overview of Industrial Robots Control and Programming Approaches

Nowadays, manufacturing plants are required to be flexible to respond quickly to customer demands, adapting production and processes without affecting their efficiency. In this context, Industrial Robots (IRs) are a primary resource for modern factories due to their versatility which allows the execution of flexible, reconfigurable, and zero-defect manufacturing tasks. Even so, the control and programming of the commercially available IRs are limiting factors for their effective implementation, especially for dynamic production environments or when complex applications are required. These issues have stimulated the development of new technologies that support more efficient methods for robot control and programming. The goal of this research is to identify and evaluate the main approaches proposed in scientific papers and by the robotics industry in the last decades. After a critical review of the standard IR control schematic, the paper discusses the available control alternatives and summarizes their characteristics, range of applications, and remaining limitations

Benchmark on Human Simulation Tools: A Transdisciplinary Approach

Nowadays companies have to face a competitive market that requires small volumes with a high level of customisations. In this context, assembly quality and timeliness is crucial. To guarantee flexibility and personalization, manual operations still have a crucial role for a lot of manufacturing sectors, so that workers' conditions and ergonomics are important factors to achieve a better product quality and overall cost reduction. Ergonomics evaluation in manufacturing is a challenging and expensive activity that requires a transdisciplinary approach, to merge technical and social sciences to finally have a consolidated and reliable evaluation. This paper compared two digital human simulations tools offered by Siemens Tecnomatix: Jack and Process Simulate. They were applied on the same industrial case study, concerning the hood assembly of an agricultural machine, comparing results on ergonomics reports and usage time. Results confirmed the advantage of adopting a digital approach to predict the human effort and ergonomic risk related to a series of tasks. At the same time, they showed the major strengths and weaknesses of the two analysed tools and defined how they can be successfully adopted by companies. The paper finally provided guidelines to drive companies in choosing the best tool according to their needs

Progress and challenges of selective Farnesoid X Receptor modulation.

Bile acids are amphipathic molecules that were previously known to serve as fat solubilizers in the intestine in postprandial conditions. In the last two decades, bile acids have been recognized as signaling molecules regulating energy metabolism pathways via, amongst others, the farnesoid X receptor (FXR). Upon bile acid activation, FXR controls expression of genes involved in bile acid, lipid, glucose and amino acid metabolism. In addition, FXR activation has been shown to limit the inflammatory response. The central role of FXR in various aspects of metabolism and inflammation makes FXR an attractive drug target for several diseases, such as obesity, metabolic syndrome, non-alcoholic steatohepatitis, cholestasis and chronic inflammatory diseases of the liver and intestine. However, most of the currently available compounds impact on all discovered FXR-mediated functions and may have, on top of beneficial effects, undesired biological actions depending on the disease. Therefore, research efforts are increasingly focused on the development of selective FXR modulators, i.e. selective bile acid receptor modulators (SBARMs), aimed at limiting the potential side-effects of conventional full FXR agonists upon chronic treatment. Here, we review the rationale for the design of SBARMs comprising dissociation between metabolic and inflammatory signaling, gene-selective and tissue-specific targeting. We discuss the potential structural mechanisms underlying the binding properties of dissociating ligands of FXR in light of ongoing efforts on the generation of dissociated ligands for otxher nuclear receptors, as well as their pharmacological and therapeutic potential

Engineering Method and Tool for the Complete Virtual Commissioning of Robotic Cells

Intelligent robotic manufacturing cells must adapt to ever-varying operating conditions, developing autonomously optimal manufacturing strategies to achieve the best quality and overall productivity. Intelligent and cognitive behaviors are realized by using distributed controllers, in which complex control logics must interact and process a wide variety of input/output signals. In particular, programmable logic controllers (PLCs) and robot controllers must be coordinated and integrated. Then, there is the need to simulate the robotic cells’ behavior for performance verification and optimization by evaluating the effects of both PLC and robot control codes. In this context, this work proposes a method, and its implementation into an integrated tool, to exploit the potential of ABB RobotStudio software as a virtual prototyping platform for robotic cells, in which real robots control codes are executed on a virtual controller and integrated with Beckhoff PLC environment. For this purpose, a PLC Smart Component was conceived as an extension of RobotStudio functionalities to exchange signals with a TwinCAT instance. The new module allows the virtual commissioning of a complete robotic cell to be performed, assessing the control logics effects on the overall productivity. The solution is demonstrated on a robotic assembly cell, showing its feasibility and effectiveness in optimizing the final performance

Path Approximation Strategies for Robot Manufacturing: A Preliminary Experimental Evaluation

Industrial Robots (IRs) are increasingly adopted for material subtraction or deposition functions owing to their advantages over machine tools, like cost-effectiveness and versatility. Unfortunately, the development of efficient robot manufacturing processes still faces unsolved issues related to the IRs poor positioning accuracy and to the tool path generation process. Novel engineering methods and tools are needed for CAD based programming of accurate paths and continuous robot motions to obtain the required manufacturing quality and tolerances. Within this context, to achieve smoothness along the tool path formed by linear G-code segments, the IR controllers’ approximation strategies, summarily reported in the manufacturer’s manuals, must be considered. The aim of this paper is to present the preliminary work carried out to identify the approximation algorithms of a Kuka IR when executing linear moves. An experimental study is conducted by varying the controller settings and the maximum translational velocity. The robot behavior has been acquired thanks to the controller tracing function and then processed to yield relations readily employable for the interpretation of G-Code commands and the subsequent generation of proper robot motion instructions. The obtained formulas allow to accurately predict the robot geometric path and kinematics within the corner transition between two linear segments

Transdisciplinary Evaluation of Simulation Software for Industry 4.0 Assembly Lines

Industry 4.0 is driving the revolution of manufacturing processes by combining innovative technologies and new interaction paradigms among systems and operators. In particular, the layout, tasks and work sequences of assembly lines are designed according to several transdisciplinary Design Principles (DPs), such as process efficiency, product quality, ergonomics, safety and operators’ workload. A large variety of simulation software can be employed for evaluations. However, the related ability to assess multidisciplinary factors must be evaluated. The paper aims to provide a framework for guiding the assessment of simulation software in the context of Industry 4.0 assembly lines. Process requirements are first analyzed and mapped to select DPs, prioritized according to design goals by an analytical hierarchy process. Then, suitable simulation software is determined accordingly, and the virtual model is realized. Finally, the possibility of the software to provide meaningful elaborations for the selected DPs is assessed. The framework has been tested on a prototypal Industry 4.0 assembly line composed of automated logistic systems, cobots and systems to guide the execution of tasks. The line has been modeled in Siemens Process Simulate, analyzing the completeness and appropriateness of the functionalities of this software according to the defined DPs

Design, synthesis and biological evaluation of novel bicyclo[1.1.1]pentane-basedx-acidic amino acids as glutamate receptors ligands

A novel series of bicyclo[1.1.1]pentane-based x-acidic amino acids, including (2S)- and (2R)-3-(30-carboxybicyclo[ 1.1.1]pentyl)alanines (8 and 9), (2S)- and (2R)-2-(30-carboxymethylbicyclo[1.1.1]pentyl)glycines (10 and 11), and (2S)- and (2R)-3-(30-phosphonomethylbicyclo[1.1.1]pentyl)glycines (12 and 13), were synthesized and evaluated as glutamate receptor ligands. Among them, (2R)-3-(30-phosphonomethylbicyclo[ 1.1.1]pentyl)glycine (13) showed relatively high affinity and selectivity at the NMDA receptor. The results are also discussed in light of pharmacophoric modelling studies of NMDA agonists and antagonists