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Motivation: Many software libraries for using Hidden Markov Models in bioinformatics focus on inference tasks, such as likelihood calculation, parameter-fitting, and alignment. However, construction of the state machines can be a laborious task, automation of which would be time-saving and less error-prone. Results. We present Machine Boss, a software tool implementing not just inference and parameter-fitting algorithms, but also a set of operations for manipulating and combining automata. The aim is to make prototyping of bioinformatics HMMs as quick and easy as the construction of regular expressions, with one-line "recipes" for many common applications. We report data from several illustrative examples involving protein-to-DNA alignment, DNA data storage, and nanopore sequence analysis.
Availability and Implementation: Machine Boss is released under the BSD-3 open source license and is available from http://machineboss.org/.
(© The Author(s) 2020. Published by Oxford University Press.)

The polyhydroxyalkanoates (PHAs) are microbially-produced biopolymers that could potentially be used as sustainable alternatives to oil-derived plastics. However, PHAs are currently more expensive to produce than oil-derived plastics. Therefore, more efficient production processes would be desirable. Cell-free metabolic engineering strategies have already been used to optimize several biosynthetic pathways and we envisioned that cell-free strategies could be used for optimizing PHAs biosynthetic pathways. To this end, we developed several Escherichia coli cell-free systems for in vitro prototyping PHAs biosynthetic operons, and also for screening relevant metabolite recycling enzymes. Furthermore, we customized our cell-free reactions through the addition of whey permeate, an industrial waste that has been previously used to optimize in vivo PHAs production. We found that the inclusion of an optimal concentration of whey permeate enhanced relative cell-free GFPmut3b production by approximately 50%. In cell-free transcription-translation prototyping reactions, gas chromatography-mass spectrometry quantification of cell-free 3-hydroxybutyrate (3HB) production revealed differences between the activities of the Native Δ PhaC_C319A (1.18 ± 0.39 µM), C104 Δ PhaC_C319A (4.62 ± 1.31 µM) and C101 Δ PhaC_C319A (2.65 ± 1.27 µM) phaCAB operons that were tested. Interestingly, the most active operon, C104 produced higher levels of PHAs (or PHAs monomers) than the Native phaCAB operon in both in vitro and in vivo assays. Coupled cell-free biotransformation/transcription-translation reactions produced greater yields of 3HB (32.87 ± 6.58 µM), and these reactions were also used to characterize a Clostridium propionicum Acetyl-CoA recycling enzyme. Together, these data demonstrate that cell-free approaches complement in vivo workflows for identifying additional strategies for optimizing PHAs production.
(© The Author(s) 2018. Published by Oxford University Press.)

Aged, 80 and over, Computed Tomography Angiography methods, Coronary Aneurysm diagnosis, Coronary Angiography methods, Coronary Vessels surgery, Humans, Male, Ultrasonography, Interventional methods, Coronary Aneurysm surgery, Coronary Vessels diagnostic imaging, Multimodal Imaging methods, and Percutaneous Coronary Intervention methods

Aged, Cardiac Surgical Procedures methods, Echocardiography, Transesophageal, Humans, Learning Curve, Male, Mitral Valve Insufficiency diagnostic imaging, Reproducibility of Results, Tomography, X-Ray Computed, Endoscopy, Mitral Valve Insufficiency surgery, Patient-Specific Modeling, and Precision Medicine

Objectives: Mitral valve repair performed by an experienced surgeon is superior to mitral valve replacement for degenerative mitral valve disease; however, many surgeons are still deterred from adapting this procedure because of a steep learning curve. Simulation-based training and planning could improve the surgical performance and reduce the learning curve. The aim of this study was to develop a patient-specific simulation for mitral valve repair and provide a proof of concept of personalized medicine in a patient prospectively planned for mitral valve surgery.
Methods: A 65-year old male with severe symptomatic mitral valve regurgitation was referred to our mitral valve heart team. On the basis of three-dimensional (3D) transoesophageal echocardiography and computed tomography, 3D reconstructions of the patient's anatomy were constructed. By navigating through these reconstructions, the repair options and surgical access were chosen (minimally invasive repair). Using rapid prototyping and negative mould fabrication, we developed a process to cast a patient-specific mitral valve silicone replica for preoperative repair in a high-fidelity simulator.
Results: Mitral valve and negative mould were printed in systole to capture the pathology when the valve closes. A patient-specific mitral valve silicone replica was casted and mounted in the simulator. All repair techniques could be performed in the simulator to choose the best repair strategy. As the valve was printed in systole, no special testing other than adjusting the coaptation area was required. Subsequently, the patient was operated, mitral valve pathology was validated and repair was successfully done as in the simulation.
Conclusions: The patient-specific simulation and planning could be applied for surgical training, starting the (minimally invasive) mitral valve repair programme, planning of complex cases and the evaluation of new interventional techniques. The personalized medicine could be a possible pathway towards enhancing reproducibility, patient's safety and effectiveness of a complex surgical procedure.
(© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Summary: We introduce matter , an R package for direct interactions with larger-than-memory datasets, stored in an arbitrary number of files of any size. matter is primarily designed for datasets in new and rapidly evolving file formats, which may lack extensive software support. matter enables a wide variety of data exploration and manipulation steps, and is extensible to many bioinformatics applications. It supports reproducible research by minimizing the need of converting and storing data in multiple formats. We illustrate the performance of matter in conjunction with the Bioconductor package Cardinal for analysis of high-resolution, high-throughput mass spectrometry imaging experiments.
Availability: The package, vignettes, and examples of applications in several areas of bioinformatics are available open-source at www.bioconductor.org under the Artistic-2.0 license.
Contact: o.vitek@neu.edu.
(© The Author(s) 2017. Published by Oxford University Press.)

Aged, Aortic Aneurysm, Abdominal diagnostic imaging, Aortic Aneurysm, Abdominal economics, Aortography methods, Blood Vessel Prosthesis, Computed Tomography Angiography, Hospital Costs, Humans, Imaging, Three-Dimensional, Male, Multidetector Computed Tomography, Prosthesis Design, Radiographic Image Interpretation, Computer-Assisted, Treatment Outcome, Aortic Aneurysm, Abdominal surgery, Blood Vessel Prosthesis Implantation instrumentation, Models, Anatomic, Models, Cardiovascular, and Printing, Three-Dimensional economics

3D printing provides the sequential addition of material layers and, thus, the opportunity to print parts and components made of different materials with variable mechanical and physical properties. It helps us create 3D anatomical models for the better planning of surgical procedures when needed, since it can reveal any complex anatomical feature. Images of abdominal aortic aneurysms received by computed tomographic angiography were converted into 3D images using a Google SketchUp free software and saved in stereolithography format. Using a 3D printer (Makerbot), a model made of polylactic acid material (thermoplastic filament) was printed. A 3D model of an abdominal aorta aneurysm was created in 138 min, while the model was a precise copy of the aorta visualized in the computed tomographic images. The total cost (including the initial cost of the printer) reached 1303.00 euros. 3D imaging and modelling using different materials can be very useful in cases when anatomical difficulties are recognized through the computed tomographic images and a tactile approach is demanded preoperatively. In this way, major complications during abdominal aorta aneurysm management can be predicted and prevented. Furthermore, the model can be used as a mould; the development of new, more biocompatible, less antigenic and individualized can become a challenge in the future.
(© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Aged, 80 and over, Female, Humans, Lung Neoplasms pathology, Tomography, X-Ray Computed, Treatment Outcome, Lung Neoplasms surgery, Models, Anatomic, Pneumonectomy methods, Printing, Three-Dimensional, Surgery, Computer-Assisted methods, and Thoracoscopy methods

Thoracoscopic segmentectomies and subsegmentectomies are more difficult than lobectomy because of the complexity of the procedure; therefore, preoperative decision-making and surgical procedure planning are essential. In the literature, we could successfully perform thoracoscopic anatomical subsegmentectomy of the right S2b + S3 using a 3D printing model with rapid prototyping. This innovative surgical support model is extremely useful for planning a surgical procedure and identifying the surgical margin.
(© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Animals, Cell Line, Cloning, Molecular, Gene Library, Humans, Cell Engineering methods, and Gene Regulatory Networks

Mammalian synthetic biology may provide novel therapeutic strategies, help decipher new paths for drug discovery and facilitate synthesis of valuable molecules. Yet, our capacity to genetically program cells is currently hampered by the lack of efficient approaches to streamline the design, construction and screening of synthetic gene networks. To address this problem, here we present a framework for modular and combinatorial assembly of functional (multi)gene expression vectors and their efficient and specific targeted integration into a well-defined chromosomal context in mammalian cells. We demonstrate the potential of this framework by assembling and integrating different functional mammalian regulatory networks including the largest gene circuit built and chromosomally integrated to date (6 transcription units, 27kb) encoding an inducible memory device. Using a library of 18 different circuits as a proof of concept, we also demonstrate that our method enables one-pot/single-flask chromosomal integration and screening of circuit libraries. This rapid and powerful prototyping platform is well suited for comparative studies of genetic regulatory elements, genes and multi-gene circuits as well as facile development of libraries of isogenic engineered cell lines.
(© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Epigenomics methods, High-Throughput Nucleotide Sequencing, and Software

Motivation: The development of computational tools to enable testing and analysis of high-throughput-sequencing data is essential to modern genomics research. However, although multiple frameworks have been developed to facilitate access to these tools, comparatively little effort has been made at implementing low-level programming libraries to increase the speed and ease of their development.
Results: We propose NGS++, a programming library in C++11 specialized in manipulating both next-generation sequencing (NGS) datasets and genomic information files. This library allows easy integration of new formats and rapid prototyping of new functionalities with a focus on the analysis of genomic regions and features. It offers a powerful, yet versatile and easily extensible interface to read, write and manipulate multiple genomic file formats. By standardizing the internal data structures and presenting a common interface to the data parser, NGS++ offers an effective framework for epigenomics tool development.
Availability: NGS++ was written in C++ using the C++11 standard. It requires minimal efforts to build and is well-documented via a complete docXygen guide, online documentation and tutorials. Source code, tests, code examples and documentation are available via the website at http://www.ngsplusplus.ca and the github repository at https://github.com/NGS-lib/NGSplusplus.
Contact: nicolas.gevry@usherbrooke.ca or arnaud.droit@crchuq.ulaval.ca.

DNA Ligases chemistry, DNA, Bacterial genetics, DNA, Circular genetics, Escherichia coli genetics, Gene Library, Genes, Bacterial, Models, Genetic, Polymerase Chain Reaction, Promoter Regions, Genetic, Protein Biosynthesis, Sequence Analysis, DNA, Synthetic Biology, Transcription, Genetic, Transcriptional Activation, and Regulatory Sequences, Nucleic Acid

A bottleneck in our capacity to rationally and predictably engineer biological systems is the limited number of well-characterized genetic elements from which to build. Current characterization methods are tied to measurements in living systems, the transformation and culturing of which are inherently time-consuming. To address this, we have validated a completely in vitro approach for the characterization of DNA regulatory elements using Escherichia coli extract cell-free systems. Importantly, we demonstrate that characterization in cell-free systems correlates and is reflective of performance in vivo for the most frequently used DNA regulatory elements. Moreover, we devise a rapid and completely in vitro method to generate DNA templates for cell-free systems, bypassing the need for DNA template generation and amplification from living cells. This in vitro approach is significantly quicker than current characterization methods and is amenable to high-throughput techniques, providing a valuable tool for rapidly prototyping libraries of DNA regulatory elements for synthetic biology.

Animals, Aorta surgery, Compliance, Computer Simulation, Humans, Imaging, Three-Dimensional, Materials Testing, Pressure, Prosthesis Design, Reproducibility of Results, Silicones, Stents, Swine, Vascular Surgical Procedures education, Vascular Surgical Procedures instrumentation, Aorta anatomy histology, Models, Anatomic, Models, Cardiovascular, and Replica Techniques

Adequate in-vitro training in valved stents deployment as well as testing of the latter devices requires compliant real-size models of the human aortic root. The casting methods utilized up to now are multi-step, time consuming and complicated. We pursued a goal of building a flexible 3D model in a single-step procedure. We created a precise 3D CAD model of a human aortic root using previously published anatomical and geometrical data and printed it using a novel rapid prototyping system developed by the Fab@Home project. As a material for 3D fabrication we used common house-hold silicone and afterwards dip-coated several models with dispersion silicone one or two times. To assess the production precision we compared the size of the final product with the CAD model. Compliance of the models was measured and compared with native porcine aortic root. Total fabrication time was 3 h and 20 min. Dip-coating one or two times with dispersion silicone if applied took one or two extra days, respectively. The error in dimensions of non-coated aortic root model compared to the CAD design was <3.0% along X, Y-axes and 4.1% along Z-axis. Compliance of a non-coated model as judged by the changes of radius values in the radial direction by 16.39% is significantly different (P<0.001) from native aortic tissue--23.54% at the pressure of 80-100 mmHg. Rapid prototyping of compliant, life-size anatomical models with the Fab@Home 3D printer is feasible--it is very quick compared to previous casting methods.

Adult, Burns physiopathology, Feasibility Studies, Female, Humans, Male, Middle Aged, Perfusion, Pressure, Silicones, Burns rehabilitation, Cicatrix prevention control, Face anatomy histology, Facial Injuries, Imaging, Three-Dimensional instrumentation, Laser-Doppler Flowmetry instrumentation, Masks, and Skin blood supply

A paradigm shift in management of postburn facial scarring is lurking "just beneath the waves" with the widespread availability of two recent technologies: precise three-dimensional scanning/digitizing of complex surfaces and computer-controlled rapid prototyping three-dimensional "printers". Laser Doppler imaging may be the sensible method to track the scar hyperemia that should form the basis of assessing progress and directing incremental changes in the digitized topographical face mask "prescription". The purpose of this study was to establish feasibility of detecting perfusion through transparent face masks using the Laser Doppler Imaging scanner. Laser Doppler images of perfusion were obtained at multiple facial regions on five uninjured staff members. Images were obtained without a mask, followed by images with a loose fitting mask with and without a silicone liner, and then with a tight fitting mask with and without a silicone liner. Right and left oblique images, in addition to the frontal images, were used to overcome unobtainable measurements at the extremes of face mask curvature. General linear model, mixed model, and t tests were used for data analysis. Three hundred seventy-five measurements were used for analysis, with a mean perfusion unit of 299 and pixel validity of 97%. The effect of face mask pressure with and without the silicone liner was readily quantified with significant changes in mean cutaneous blood flow (P < .5). High valid pixel rate laser Doppler imager flow data can be obtained through transparent face masks. Perfusion decreases with the application of pressure and with silicone. Every participant measured differently in perfusion units; however, consistent perfusion patterns in the face were observed.

Family Health, Humans, Needs Assessment, Software Design, Task Performance and Analysis, Information Services organization administration, Internet organization administration, Medical Records Systems, Computerized, and User-Computer Interface

As the Internet continues to grow as a delivery medium for health information, the design of effective Web sites becomes increasingly important. In this paper, the authors provide an overview of one effective model for Web site design, a user-centered process that includes techniques for needs assessment, goal/task analysis, user interface design, and rapid prototyping. They detail how this approach was employed to design a family health history Web site, Health Heritage . This Web site helps patients record and maintain their family health histories in a secure, confidential manner. It also supports primary care physicians through analysis of health histories, identification of potential risks, and provision of health care recommendations. Visual examples of the design process are provided to show how the use of this model resulted in an easy-to-use Web site that is likely to meet user needs. The model is effective across diverse content arenas and is appropriate for applications in varied media.

Internet, Protein Binding, Protein Structure, Tertiary, Software standards, Time Factors, User-Computer Interface, Algorithms, Computational Biology methods, Computer Simulation standards, Databases, Factual, and Software Validation

Motivation: Rapid software prototyping can significantly reduce development times in the field of computational molecular biology and molecular modeling. Biochemical Algorithms Library (BALL) is an application framework in C++ that has been specifically designed for this purpose.
Results: BALL provides an extensive set of data structures as well as classes for molecular mechanics, advanced solvation methods, comparison and analysis of protein structures, file import/export, and visualization. BALL has been carefully designed to be robust, easy to use, and open to extensions. Especially its extensibility which results from an object-oriented and generic programming approach distinguishes it from other software packages. BALL is well suited to serve as a public repository for reliable data structures and algorithms. We show in an example that the implementation of complex methods is greatly simplified when using the data structures and functionality provided by BALL.

DNA ultrastructure, Electrophoresis, Agar Gel, Microscopy, Electron, Transmission, Nanostructures ultrastructure, Nucleic Acid Conformation, DNA chemistry, Nanostructures chemistry, and Software

DNA nanotechnology exploits the programmable specificity afforded by base-pairing to produce self-assembling macromolecular objects of custom shape. For building megadalton-scale DNA nanostructures, a long 'scaffold' strand can be employed to template the assembly of hundreds of oligonucleotide 'staple' strands into a planar antiparallel array of cross-linked helices. We recently adapted this 'scaffolded DNA origami' method to producing 3D shapes formed as pleated layers of double helices constrained to a honeycomb lattice. However, completing the required design steps can be cumbersome and time-consuming. Here we present caDNAno, an open-source software package with a graphical user interface that aids in the design of DNA sequences for folding 3D honeycomb-pleated shapes A series of rectangular-block motifs were designed, assembled, and analyzed to identify a well-behaved motif that could serve as a building block for future studies. The use of caDNAno significantly reduces the effort required to design 3D DNA-origami structures. The software is available at http://cadnano.org/, along with example designs and video tutorials demonstrating their construction. The source code is released under the MIT license.

The increasing demand for bio-based compounds produced from waste or sustainable sources is driving biofoundries to deliver a new generation of prototyping biomanufacturing platforms. Integration and automation of the design, build, test and learn (DBTL) steps in centers like SYNBIOCHEM in Manchester and across the globe (Global Biofoundries Alliance) are helping to reduce the delivery time from initial strain screening and prototyping towards industrial production. Notably, a portfolio of producer strains for a suite of material monomers was recently developed, some approaching industrial titers, in a tour de force by the Manchester Centre that was achieved in less than 90 days. New in silico design tools are providing significant contributions to the front end of the DBTL pipelines. At the same time, the far-reaching initiatives of modern biofoundries are generating a large amount of high-dimensional data and knowledge that can be integrated through automated learning to expedite the DBTL cycle. In this Perspective, the new design tools and the role of the learning component as an enabling technology for the next generation of automated biofoundries are discussed. Future biofoundries will operate under completely automated DBTL cycles driven by in silico optimal experimental planning, full biomanufacturing devices connectivity, virtualization platforms and cloud-based design. The automated generation of robotic build worklists and the integration of machine-learning algorithms will collectively allow high levels of adaptability and rapid design changes toward fully automated smart biomanufacturing.
(© The Author(s) 2020. Published by Oxford University Press.)

Humans, Models, Anatomic, Cardiac Catheterization methods, Heart Valve Diseases surgery, Heart Valve Prosthesis Implantation methods, Heart Valves surgery, Inventions, and Printing, Three-Dimensional

Three-dimensional (3D)-printing technologies in cardiovascular surgery have provided a new way to tailor surgical and percutaneous treatments. Digital information from standard cardiac imaging is integrated into physical 3D models for an accurate spatial visualization of anatomical details. We reviewed the available literature and analysed the different printing technologies, the required procedural steps for 3D prototyping, the used cardiac imaging, the available materials and the clinical implications. We have highlighted different materials used to replicate aortic and mitral valves, vessels and myocardial properties. 3D printing allows a heuristic approach to investigate complex cardiovascular diseases, and it is a unique patient-specific technology providing enhanced understanding and tactile representation of cardiovascular anatomies for the procedural planning and decision-making process. 3D printing may also be used for medical education and surgical/transcatheter training. Communication between doctors and patients can also benefit from 3D models by improving the patient understanding of pathologies. Furthermore, medical device development and testing can be performed with rapid 3D prototyping. Additionally, widespread application of 3D printing in the cardiovascular field combined with tissue engineering will pave the way to 3D-bioprinted tissues for regenerative medicinal applications and 3D-printed organs.
(© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Summary: Here, we present a highly efficient R-package seqminer2 for querying and retrieving sequence variants from biobank scale datasets of millions of individuals and hundreds of millions of genetic variants. Seqminer2 implements a novel variant-based index for querying VCF/BCF files. It improves the speed of query and retrieval by several magnitudes compared to the state-of-the-art tools based upon tabix. It also reimplements support for BGEN and PLINK format, which improves speed over alternative implementations. The improved efficiency and comprehensive support for popular file formats will facilitate method development, software prototyping and data analysis of biobank scale sequence datasets in R.
Availability and Implementation: The seqminer2 R package is available from https://github.com/zhanxw/seqminer. Scripts used for the benchmarks are available in https://github.com/yang-lina/seqminer/blob/master/seqminer2%20benchmark%20script.txt.
Supplementary Information: Supplementary data are available at Bioinformatics online.
(© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The study sought to understand the potential roles of a future artificial intelligence (AI) documentation assistant in primary care consultations and to identify implications for doctors, patients, healthcare system, and technology design from the perspective of general practitioners.
Materials and Methods: Co-design workshops with general practitioners were conducted. The workshops focused on (1) understanding the current consultation context and identifying existing problems, (2) ideating future solutions to these problems, and (3) discussing future roles for AI in primary care. The workshop activities included affinity diagramming, brainwriting, and video prototyping methods. The workshops were audio-recorded and transcribed verbatim. Inductive thematic analysis of the transcripts of conversations was performed.
Results: Two researchers facilitated 3 co-design workshops with 16 general practitioners. Three main themes emerged: professional autonomy, human-AI collaboration, and new models of care. Major implications identified within these themes included (1) concerns with medico-legal aspects arising from constant recording and accessibility of full consultation records, (2) future consultations taking place out of the exam rooms in a distributed system involving empowered patients, (3) human conversation and empathy remaining the core tasks of doctors in any future AI-enabled consultations, and (4) questioning the current focus of AI initiatives on improved efficiency as opposed to patient care.
Conclusions: AI documentation assistants will likely to be integral to the future primary care consultations. However, these technologies will still need to be supervised by a human until strong evidence for reliable autonomous performance is available. Therefore, different human-AI collaboration models will need to be designed and evaluated to ensure patient safety, quality of care, doctor safety, and doctor autonomy.
(© The Author(s) 2020. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Cell-free protein synthesis (CFPS) systems enable the production of protein without the use of living, intact cells. An emerging area of interest is to use CFPS systems to characterize individual elements for genetic programs [e.g. promoters, ribosome binding sites (RBS)]. To enable this research area, robust CFPS systems must be developed from new chassis organisms. One such chassis is the Gram-negative Pseudomonas bacteria, which have been studied extensively for their diverse metabolism with promises in the field of bioremediation and biosynthesis. Here, we report the development and optimization of a high-yielding (198 ± 5.9 µg/ml) batch CFPS system from Pseudomonas putida ATCC 12633. Importantly, both circular and linear DNA templates can be applied directly to the CFPS reaction to program protein synthesis. Therefore, it is possible to prepare hundreds or even thousands of DNA templates without time-consuming cloning work. This opens the possibility to rapidly assess and validate genetic part performance in vitro before performing experiments in cells. To validate the P. putida CFPS system as a platform for prototyping genetic parts, we designed and constructed a library consisting of 15 different RBSs upstream of the reporter protein sfGFP, which covered an order of magnitude range in expression. Looking forward, our P. putida CFPS platform will not only expand the protein synthesis toolkit for synthetic biology but also serve as a platform in expediting the screening and prototyping of gene regulatory elements.
(© The Author(s) 2018. Published by Oxford University Press.)