Aromatic Sulfonamides Including a Sulfonic Acid Tail: New Membrane Impermeant Carbonic Anhydrase Inhibitors for Targeting Selectively the Cancer-Associated Isoforms

We report here a new drug design strategy for producing membrane-impermeant carbonic anhydrase (CA; EC 4.2.1.1) inhibitors selectively targeting the tumor-associated, membrane-bound human CAs IX and XII over off-target cytosolic isoforms. To date, this approach has only been pursued by including permanent positively charged pyridinium type or highly hydrophilic glycosidic moieties into the structure of aromatic sulfonamide CA inhibitors (CAIs). Aliphatic (propyl and butyl) sulfonic acid tails, deprotonated at physiological pH, were thus incorporated onto a benzenesulfonamide scaffold by a common 1,2,3-triazole linker and different types of spacers. Twenty such derivatives were synthesized and tested for their inhibition of target (hCAs IV, IX, and XII) and off-target CAs (hCAs I and II). Most sulfonate CAIs induced a potent inhibition of hCAs II, IX, and XII up to a low nanomolar KI range (0.9–459.4 nM) with a limited target/off-target CA selectivity of action. According to the drug design schedule, a subset of representative derivatives was assessed for their cell membrane permeability using Caco-2 cells and a developed FIA-MS/MS method. The complete membrane impermeability of the sulfonate tailed CAIs (≥98%) validated these negatively charged moieties as being suitable for achieving, in vivo, the selective targeting of the tumor-associated CAs over off-target ones.

Effects of Design Quality on Delay in Residential Construction Projects

This study is conducted to establish the effect of design quality on project delay in building projects. It aims at: 1) investigating the major factors of design quality, 2) identifying the main delay factors in building projects, 2) establishing the relationship between design quality and delay in building projects. To achieve these objectives, a questionnaire survey is performed. Seventeen (17) factors that might affect design quality, and 15 delay factors are listed in a questionnaire form. Sixty (60) contractors and 40 consultants are asked to identify the severity of the identified factors. Results indicate that the top factors affecting design quality are: delay in payments by client for design services, staff allocation for many projects at the same time, copying and modifying from previous work to minimize time and cost, tight design schedule, lack of designer knowledge with techniques and materials available in the market. The study also concludes that the top five delay factors include: payments delay, poor labor productivity, lack of skilled manpower, frequent change orders and rework. Regression analysis for data collected from 36 building projects shows a good correlation between design quality and delay in projects. This study is the first one that addresses the problem of design quality in the West Bank in Palestine. Furthermore, it is the first study that addresses the effect of design quality on project delay in Palestine and the neighboring countries. It is hoped to be helpful for researchers and professionals to understand the impact of design quality on schedule delay.

An Exploratory Study on Optimal Iterative Design Schedules with the Consideration of Design Quality and Resource Constraints

The classical dependency structure matrix (DSM) can effectively deal with iterative schedules that are highly coupled and interdependent, such as the design process and the concurrent process. Classical DSM generally follows the assumption that the least iteration occurs to achieve the shortest completion time. Nevertheless, the assumption may not hold because tasks ought to be re-visited several times if the design qualities do not meet the requirements. This research proposed a novel iterative scheduling model that combines the classical DSM concept with quality equations. The quality equations were used to determine the number of tasks that ought to be re-visited for fulfilling quality requirements during the iterative design process. Moreover, resources for concurrent activities are generally limited in the real world. Resource allocation should be incorporated in scheduling to avoid the waste and shortage of resources on a design project. This research proposed a new iterative scheduling model based on the classical DSM to optimize the iterative activities’ structure in terms of minimizing completion time with the consideration of design quality under resource constraints. A practical design schedule was introduced to demonstrate the applicability of the proposed DSM algorithm.

Onshore Oil and Gas Design Schedule Management Process Through Time-Impact Simulations Analyses

Korean oil and gas contractors have recently incurred significant losses due to improper engineering performance on EPC (engineering procurement and construction) projects in overseas markets. Several previous studies have verified the significant impact engineering has on EPC construction cost and project lifecycle. However, no literature has studied the time impact engineering has on EPC projects, representing a gap in the existing body of knowledge. To fill this gap, a Monte Carlo simulation was performed with the Pertmaster, Primavera risk analysis software for three sample onshore oil and gas projects. From said simulation of all major EPC critical activities, the authors found that the engineering phase is up to 10 times as impactful as the procurement and construction phases on the overall schedule duration. In assessing the engineering activities, the authors found the piping design activities to have the greatest impact on the overall schedule performance. Using these findings, the authors present a design schedule management process which minimizes the delays of project completion in EPC projects. Said process includes the following six steps: (1) Milestone management, (2) drawing status management, (3) productivity management of engineering, (4) interface management, (5) management of major vendor documents, and (6) work front management. The findings of this paper add to the body of knowledge by confirming the design phase to be the most impactful on the overall project schedule success. Furthermore, the presented design schedule management will aid industry with successfully executing the design phase in a timely manner, including examples from case study projects for a greater understanding.

One Vanderbilt: Unprecedented Project Delivery Through Integrated Innovation

<p>One Vanderbilt Avenue, currently under construction in midtown Manhattan, will be one of the tallest buildings in New York. By collaborating with the construction teams in the early stages of the design, the foundations and the superstructure were able to proceed well in advance of a typical project. For example, the structural steel was erected to the 6th floor, was fabricated to the 32nd Floor, and the shop drawings were checked up to the 45th floor on the day that the 100% Construction Documents were issued.</p><p>The structural steel frame was designed so that its core columns only carried 12 levels of framing and construction loads during the tower’s erection. A concrete shear wall system followed the steel framing, permitting the steel erection to proceed without regard to the concrete operations. When complete, the project will stand 1,401 feet tall and contain 26,000 tons of structural steel, and 93,000 cubic yards of concrete.</p><p>The presentation focuses on the challenges and technological requirements for vertical construction in dense urban environments. It explains the amount of detail, thought, and knowledge of construction that must happen earlier in the design process and the participants will appreciate how the fast‐track process can be applied to complex architectural, mechanical and structural designs.</p><p>It describes the integration of design team parametric modelling with the construction process early in the design schedule. Fast‐track projects with complex designs like One Vanderbilt can be successfully completed by understanding and integrating an IPD process, even with competing objectives. The presentation discusses the challenges and technological requirements for vertical construction in dense urban environments, including the importance of direct links to mass transportation.</p><p>This type of team structure is the future of the industry, and One Vanderbilt is the first of its kind to illustrate how innovative design ambitions are being realized through the use of increasingly refined and advanced technology.</p>

Parametrization and BrIM in large infrastructure projects – project study from RV3/25 Norway

<p>RV 3/25 is a large infrastructure project consisting of a new 25 km highway in Hedmark County in Norway. The project is organized as a PPP-project and includes 20 concrete bridges and 8 timber glulam arch bridges.</p><p>In the project the use of BIM-models and parameterization has been significant and has evolved greatly throughout the project. The work ranged from macro BIM with large coordination models with all disciplines included, to micro BIM-models for bridges including all details needed for construction. For 5 concrete bridges, the BIM-model was the only product delivered to the contractor without producing design or construction drawings.</p><p>For the 8 glulam arch bridges in timber, parameterization was employed for establishing both the BIM-models and the analysis models. This was vital to achieving the goal of following the strict design schedule with a small design team. It also proved very valuable in the shaping phase of the bridges. Between 80% and 90% of the objects in the finalized BIM-models were included in the parameterization. The product delivered to the contractor was design drawings, most of which were generated directly from the BIM-model, thus benefiting from its advantages.</p><p>The use of BIM has proved to be cost and time-efficient during design. This paper presents the challenges and benefits of using parameterization and BIM in a large infrastructure project with focus on bridge design.</p>

A Unique Civil Engineering Capstone Design Course

The North Dakota State University, USA, capstone course was developed as a unique model in response to the effort of the Accreditation Board of Engineering and Technology, USA, to streamline and improve design instruction in the curriculum and has steadily evolved to keep pace with the ever-changing technology and the expectations of the profession and the society we serve. A capstone design course by definition should be a design experience for students in the final year before graduation integrating all major design concepts they have learned up until then in the program. Carefully chosen real world projects with design content in all sub-disciplines of civil engineering are assigned in this team-taught course. Faculty and practicing professionals make presentations on design process; project management; leadership in an engineering environment; and public policy; global perspectives in engineering; and professional career and licensure. Practicing professionals also critique the final student presentations. Students work in teams with number of faculty serving as technical consultants, and a faculty mentor for each team to provide non-technical guidance and direction. The course requires students to demonstrate mastery of the curriculum and to work with others in a team environment. Course assessment includes evaluation of the final design, presentations, written technical reports, project design schedule, a project design journal, and reaction papers.

Effectiveness of involving the industrial and business professions into mechanical engineering capstone course

Capstone design, along with the last courses before graduation, is one of the major performance indicators of the student outcome in an undergraduate mechanical engineering program. Educational topics on the capstone course, such as the instruction content, course design, procedures, and timeline schedule, have been deliberated by engineering instructors in higher education. Meanwhile, more and more universities started to invite mentorship or advisement from industrial personnel to the capstone design classes as practical experience is also a significant factor in the engineering study. In this article, a senior design course for undergraduate mechanical engineering program is introduced. Collaboration and mentoring by industrial and business professions are offered in the course, though optional for students. As a result, the students in the same capstone course, though got the same lecture classes and follow the same design schedule, can be divided into three different groups: Group 1 worked in traditional design format, Group 2 received mentorship not only from the instructor but also from industrial professions, and Group 3 received help from a business profession. The course and project outcome of the three groups are evaluated by various assessment and results are demonstrated and discussed.