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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2018

Dynamic load balancing enables large-scale flux variability analysis

Genome-scale metabolic models (GSMMs) of living organisms are used in a wide variety of applications pertaining to health and bioengineering. They are formulated as linear programs (LP) that are often under-determined. Flux Variability Analysis (FVA) characterizes the alternate optimal solution (AOS) space enabling thereby the assessment of the robustness of the solution. fastFVA (FFVA), the C implementation of MATLAB FVA, allowed to gain substantial speed up, although, the parallelism was managed through MATLAB. Here veryfastFVA (VFFVA) is presented, which is a pure C implementation of FVA, that relies on lower level management of parallelism through a hybrid MPI/OpenMP. The flexibility of VFFVA allowed to gain a threefold speedup factor and to decrease memory usage 14 fold in comparison to FFVA. Finally, VFFVA allows processing a higher number of GSMMs in faster times accelerating thereby biomedical modeling and simulation. VFFVA is available online at https://github.com/marouenbg/VFFVA.

bioinformatics↗

bioRxiv2018

Identification of a simple and novel cut-point based CSF and MRI signature for predicting Alzheimer disease progression that reinforces the 2018 NIA-AA research framework

The 2018 NIA-AA research framework proposes a classification system with beta-Amyloid deposition, pathologic Tau, and neurodegeneration (ATN) for the diagnosis and staging of Alzheimers Disease (AD). Data from the ADNI (AD neuroimaging initiative) database can be utilized to identify diagnostic signatures for predicting AD progression, and to determine the utility of this NIA-AA research framework. Profiles of 320 peptides from baseline cerebrospinal fluid (CSF) samples of 287 normal, mild cognitive impairment (MCI) and AD subjects followed over a 3-10 year period were measured via multiple reaction monitoring (MRM) mass spectrometry. CSF A{beta}42, total-Tau (tTau), phosphorylated-Tau (pTau-181) and hippocampal volume were also measured. From these candidate markers, optimal diagnostic signatures with decision thresholds to separate AD and normal subjects were first identified via unbiased regression and tree-based algorithms. The best performing signature determined via cross-validation was then tested in an independent group of MCI subjects to predict future progression. This multivariate analysis yielded a simple diagnostic signature comprising CSF pTau-181 to A{beta}42 ratio, MRI hippocampal volume and a novel PTPRN peptide, with a decision threshold on each marker. When applied to a separate MCI group at baseline, subjects meeting this signature criteria experience 4.3-fold faster progression to AD compared to a 2.2-fold faster progression using only conventional markers. This novel 4-marker signature represents an advance over the current diagnostics based on widely used marker, and is much easier to use in practice than recently published complex signatures. In addition, this signature reinforces the ATN construct from the 2018 NIA-AA research framework.\n\nDisclosuresViswanath Devanarayan is an employee of Charles River Laboratories, and as such owns equity in, receives salary and other compensation from Charles River Laboratories.\n\nData collection and sharing for this project was funded by the Alzheimers Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimers Association; Alzheimers Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.;Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimers Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

neuroscience↗

bioRxiv2013

Ordered, Random, Monotonic, and Non-Monotonic Digital Nanodot Gradients

Cell navigation is directed by inhomogeneous distributions of extracellular cues. It is well known that noise plays a key role in biology and is present in naturally occurring gradients at the micro- and nanoscale, yet it has not been studied with gradients in vitro. Here, we introduce novel algorithms to produce ordered and random gradients of discrete nanodots - called digital nanodot gradients (DNGs) - according to monotonic and non-monotonic density functions. The algorithms generate continuous DNGs, with dot spacing changing in two dimensions along the gradient direction according to arbitrary mathematical functions, with densities ranging from 0.02% to 44.44%. The random gradient algorithm compensates for random nanodot overlap, and the randomness and spatial homogeneity of the DNGs were confirmed with Ripleys K function. An array of 100 DNGs, each 400 x 400 {micro}m2, comprising a total of 57 million 200 x 200 nm2 dots was designed and patterned into silicon using electron-beam lithography, then patterned as fluorescently labeled IgGs on glass using lift-off nanocontact printing. DNGs will facilitate the study of the effects of noise and randomness at the micro- and nanoscales on cell migration and growth.

Bioengineering↗

bioRxiv2014

An Analysis of Cochlear Implant Distortion from a User’s Perspective

We describe our first-hand experience with a cochlear implant (CI), being both a recent recipient and a hearing researcher. We note the promising loudness, but very unpleasant distortion, which makes understanding speech difficult in many environments, including in noise, on the phone or through the radio. We also discuss the extreme unpleasantness of music, which makes recognizing familiar melodies very difficult. We investigate the causes of the above problems through mathematical analysis and computer simulations of sound mixtures, and find that surprisingly, the culprit appears to be non-biological in origin, but primarily due to the envelope-based signal processing algorithms currently used. This distortion is generated before the signal even enters the cochlea. Hence, the long-held belief that inter-electrode interference or current spreading is the cause, appears incorrect. We explain that envelope processing may have been originally instituted based on an inaccurate understanding of the role of place coding vs. temporal coding, or alternatively, because of an incorrect analogy to radio modulation theory. On the basis of our analysis, we suggest immediate concrete steps, some possibly in firmware alone, that may lead to a much improved experience.

Bioengineering↗

bioRxiv2014

A Tandem Cell for Nanopore-based DNA Sequencing with Exonuclease

A tandem cell is proposed for DNA sequencing in which an exonuclease enzyme cleaves bases (mononucleotides) from a strand of DNA for identification inside a nanopore. It has two nanopores and three compartments with the structure [cis1, upstream nanopore (UNP), trans1 = cis2, downstream nanopore (DNP), trans2]. The exonuclease is attached to the exit side of UNP in trans1/cis2. A cleaved base cannot regress into cis1 because of the remaining DNA strand in UNP. A profiled electric field over DNP with positive and negative components slows down base translocation through DNP. The proposed structure is modeled with a Fokker-Planck equation and a piecewise solution presented. Results from the model indicate that with probability approaching 1 bases enter DNP in their natural order, are detected without any loss, and do not regress into DNP after progressing into trans2. Sequencing efficiency with a tandem cell would then be determined solely by the level of discrimination among the base types inside DNP.

Bioengineering↗

bioRxiv2014

In Silico Design of Self-Optimizing Integrated Metabolic and Gene Regulatory Networks

Biological organisms acclimatize to varying environmental conditions via active self-regulation of internal gene regulatory networks, metabolic networks, and protein signaling networks. While much work has been done to elucidate the topologies of individual networks in isolation, understanding of inter-network regulatory mechanisms remains limited. This shortcoming is of particular relevance to synthetic biology. Synthetic biological circuits tend to lose their engineered functionality over generational time, primarily due to the deleterious stress that they exert on their host organisms. To reduce this stress (and thus minimize loss of functionality) synthetic circuits must be sensitive to the health of the host organism. Development of integrated regulatory systems is therefore essential to robust synthetic biological systems. The aim of this study was to develop integrated gene-regulatory and metabolic networks which self-optimize in response to varying environmental conditions. We performed in silico evolution to develop such networks using a two-step approach: (1) We optimized metabolic networks given a constrained amount of available enzyme. Here, we found that a proportional relationship between flux control coefficients and enzyme mass holds in all linear sub-networks of branched networks, except those sub-networks which contain allosteric regulators. Network optimization was performed by iteratively redistributing enzyme until flux through the network was maximized. Optimization was performed for a range of boundary metabolite conditions to develop a profile of optimal enzyme distributions as a function of environmental conditions. (2) We generated and evolved randomized gene regulatory networks to modulate the enzymes of a target metabolic pathway. The objective of the gene regulatory networks was to produce the optimal distribution of metabolic network enzymes given specific boundary metabolite conditions of the target network. Competitive evolutionary algorithms were applied to optimize the specific structures and kinetic parameters of the gene regulatory networks. With this method, we demonstrate the possibility of algorithmic development of integrated adaptive gene and metabolic regulatory networks which dynamically self-optimize in response to changing environmental conditions.

Bioengineering↗

bioRxiv2014

Division of Labor in Hand Usage Is Associated with Higher Hand Performance in Free-Ranging Bonnet Macaques, Macaca radiate

A practical approach to understanding lateral asymmetries in body, brain, and cognition would be to examine the performance advantages/disadvantages associated with the corresponding functions and behavior. In the present study, we examined whether the division of labor in hand usage, marked by the preferential usage of the two hands across manual operations requiring maneuvering in three-dimensional space (e.g., reaching for food, grooming, and hitting an opponent) and those requiring physical strength (e.g., climbing), is associated with higher hand performance in free-ranging bonnet macaques, Macaca radiata. We determined the extent to which the macaques exhibit laterality in hand usage in an experimental unimanual and a bimanual food-reaching task, and the extent to which manual laterality is associated with hand performance in an experimental hand-performance-differentiation task. We observed negative relationships between (a) the latency in food extraction by the preferred hand in the hand-performance-differentiation task (wherein, lower latency implies higher performance), the preferred hand determined using the bimanual food-reaching task, and the normalized difference between the performance of the two hands, and (b) the normalized difference between the performance of the two hands and the absolute difference between the laterality in hand usage in the unimanual and the bimanual food-reaching tasks (wherein, lesser difference implies higher manual specialization). Collectively, these observations demonstrate that the division of labor between the two hands is associated with higher hand performance.

Bioengineering↗

bioRxiv2014

Practice of Cardiac Auscultation:Clinical perspectives and its implications on computer aided diagnosis

Study of the disease demographics in human population indicates that cardiac ailments are the primary cause of premature death, and a need for emergent technologies is felt to address the rising trend. However, development of automated heart sound analysis system and its usage at the grassroot levels for cardiac pre-screening have been hindered by the lack proper understanding of the intrinsic characteristics of cardiac auscultation. In this article we present an investigatory report based on a nationwide survey conducted on the practice of cardiac auscultation for determination of its effectiveness in diagnosis. The aims are to achieve better validation of heart sound acquisition methods and use the clinical feedback from cardiologists for improvements in the classification of the cardiac abnormalities. Results obtained from six different classifiers used in the study are illustrated, which show a remarkable specificity using an improvised classification hierarchy, derived based on clinical recommendations. The study addresses the needs for better understanding of the relevancy of heart sound signal parameters, recording transducers, recording location and the inherent complexity associated in interpretation of heart sounds, specially in noisy environments of out-patient departments and primary healthcare centers. Further, the inter-relationship between heart sound and other advance medical imaging modalities, and the need for more focused training in cardiac auscultation among the medical and paramedical staff is investigated.

Bioengineering↗

bioRxiv2015

Efficient Assembly and Verification of ZFNs and TALENs for Modifying Porcine ApoE gene

Zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) are powerful tools for genome engineering. These synthetic nucleases are assembled with programmable, sequence-specific DNA-binding domain and a non-specific FokI cleavage domain. Apolipoprotein E (ApoE) gene polymorphism is associated with cardiovascular outcomes, including ischaemic stroke and coronary heart disease (CHD). So the objective of this study is to create mutations of AopE gene by ZFNs and TALENs technology. Here, we used the Context-dependent assembly (CoDA) method to design and screen ZFNs specifically targeting with ApoE gene. The targeted cleavage capacity of these ZFNs was validated in yeast system and HEK 293T cells. Meanwhile, an efficient assembled TALENs to target ApoE gene in HEK 293T cells was as a control. The results showed that both ZFNs and TALENs worked on ApoE gene with similar high-efficiency cleavage capability. The result would provide efficient methods for genome editing, so as to get disease model for gene therapy for the further study.

Bioengineering↗

bioRxiv2015

Extracorporeal Photoimmunotherapy for Circulating Tumor Cells

It is believed that metastasis through the cardiovascular system is primarily caused by circulating tumor cells (CTCs). We report an approach to eliminate circulating tumor cells from the blood stream by flowing the blood though an extracorporeal tube and applying photodynamic therapy (PDT). Chlorin e6 (Ce6), a photosensizer, was conjugated to antibody CD44 in order to target PC-3, a prostate cancer cell line. PC-3 cells were successfully stained by the Ce6-CD44 antibody conjugate. PDT was performed on whole blood spiked with stained PC-3 cells. As the blood circulated through a transparent medical tube, it was exposed to light of a specific wavelength generated by an LED array. A 2 minute exposure was sufficient to achieve selective cancer cell necrosis. Control studies showed no cell death.

Bioengineering↗

bioRxiv2015

Peptide sequencing in an electrolytic cell with two nanopores in tandem and exopeptidase

A nanopore-based approach to peptide sequencing without labels or immobilization is considered. It is based on a tandem cell (RSC Adv., 2015, 5, 167-171) with the structure [cis1, upstream pore (UNP), trans1/cis2, downstream pore (DNP), trans2]. An amino or carboxyl exopeptidase attached to the downstream side of UNP cleaves successive leading residues in a peptide threading from cis1 through UNP. A cleaved residue translocates to and through DNP where it is identified. A Fokker-Planck model is used to compute translocation statistics for each amino acid type. Multiple discriminators, including a variant of the current blockade level and translocation times through trans1/cis2 and DNP, identify a residue. Calculations show the 20 amino acids to be grouped by charge (+, -, neutral) and ordered within each group (which makes error correction easier). The minimum cleaving interval required of the exopeptidase, the sample size (number of copies of the peptide to sequence or runs with one copy) to identify a residue with a given confidence level, and confidence levels for a given sample size are calculated. The results suggest that if the exopeptidase cleaves each and every residue and does so in a reasonable time, peptide sequencing with acceptable (and correctable) errors may be feasible. If validated experimentally the proposed device could be an alternative to mass spectrometry and gel electrophoresis. Implementation-related issues are discussed.

Bioengineering↗

bioRxiv2015

Ff-nano, Short Functionalized Nanorods Derived from Ff (f1, fd or M13) Filamentous Bacteriophage

F-specific filamentous phage of Escherichia coli (Ff: f1, M13 or fd) are long thin filaments (860 nm x 6 nm). They have been a major workhorse in display technologies and bionanotechnology; however, some applications are limited by the high length-to-diameter ratio of Ff. Furthermore, use of functionalized Ff outside of laboratory containment is in part hampered by the fact that they are genetically modified viruses. We have now developed a system for production and purification of very short functionalized Ff-phage-derived nanorods, named Ff-nano, that are only 50 nm in length. In contrast to standard Ff-derived vectors that replicate in E. coli and contain antibiotic-resistance genes, Ff-nano are protein-DNA complexes that cannot replicate on their own and do not contain any coding sequences. These nanorods show an increased resistance to heating at 70 {degrees}C in 1 % SDS in comparison to the full-length Ff phage of the same coat composition. We demonstrate that functionalized Ff-nano particles are suitable for application as detection particles in sensitive and quantitative \"dipstick\" lateral flow diagnostic assay for human plasma fibronectin.

Bioengineering↗

bioRxiv2015

On the Optimal Use of Isotherm Models for the Characterization of Biosorption of Lead Onto Algae

In this study the experimental isotherm data of biosorption of Pb(II) onto algae was modeled using several models. These models are: Langmuir, Hill-Sips, Brouers-Sotolongo, Brouers-Gaspard, and Redlich-Peterson models. The coefficients of each model were determined by non-linear fitting using Mathematica9 program. The maximum Pb(II) removal rate increased with the increase of temperature and reached the maximum value (98%) at the temperature of 40 {degrees}C. Even if the R2 error quantity is not the unique and always the best measure for nonlinear fitting, the Brouers-Sotolongo model gives in all cases the best fit and is definitely the most suitable one to satisfactorily describe bioisorption of Pb(II) on the algal biomass. In addition, this study shows that a complete set of data is necessary to have a good representation of the isotherm.

Bioengineering↗

bioRxiv2015

A quasi-digital approach to peptide sequencing using tandem nanopores with endo- and exo-peptidases

A method of sequencing peptides using tandem cells (RSC Adv., 2015, 5, 167-171; RSC Adv., 2015, 5, 30694-30700) and peptidases is considered. A double tandem cell (two tandem cells in tandem) has three nanopores in series, an amino-acid-specific endopeptidase attached downstream of the first pore, and an exopeptidase attached downstream of the second pore. The endopeptidase cleaves a peptide threaded through the first pore into fragments that are well separated in time. Fragments pass through the second pore and are each cleaved by the exopeptidase into a series of single residues; the latter pass through the third pore and cause separate current blockades that can be counted. This leads to an ordered list of integers corresponding to the number of residues in each fragment. With 20 cells, one per amino acid type, and 20 peptide copies, the resulting 20 lists of integers are used by a simple algorithm to assemble the sequence. This is a quasi-digital process that uses the lengths of subsequences to sequence the peptide, it differs from conventional analog methods which seek to identify monomers in a polymer via differences in blockade levels, residence times, or transverse currents. Several implementation issues are discussed. In particular the problem of fast analyte translocation, widely considered intransigent, may be resolved through the use of a sufficiently long (40-60 nm) third pore. This translates to a required bandwidth of 1-2 MHz, which is within the range of currently available CMOS circuits.

Bioengineering↗

bioRxiv2015

Evaluating different passive optical clearing protocols for two-photon deep tissue imaging in adult intact visceral and neuronal organs

Imaging cellular activities in an entire intact whole organ with light is a grand challenge in optical microscopy. To date, most passive clearing techniques were shown to transform brain, neuronal and embryo tissue into near transparent state for deep tissue imaging. Here, we expand these passive clearing protocols from neuronal tissue (brain and spinal cord) to other visceral organs such as liver and colon and further evaluate their \"depth-clearing performance\" based on image contrast of endogenous fluorescence structures. We found that SeeDB achieves the highest depth in brain, 3DISCO is adept at clearing liver and spinal cord and ScaleViewA2 in colon. Overall, 3DISCO clears more rapidly than other agents but at a higher cost, while ScaleViewA2 is the most economical however at a slower rate. This study, for the first time, provide a direct evaluation of imaging depth, cost and time amongst passive tissue clearing protocols for different intact organs. In addition, we discuss the possible roles of tissue composition in clearing.

Bioengineering↗

bioRxiv2015

Surface-driven registration method for the structure-informed segmentation of diffusion MR images

Current methods for processing diffusion MRI (dMRI) to map the connectivity of the human brain require precise delineations of anatomical structures. This requirement has been approached either segmenting the data in native dMRI space or mapping the structural information from T1-weighted (T1w) images. The characteristic features of diffusion data in terms of signal-to-noise ratio, resolution, as well as the geometrical distortions caused by the inhomogeneity of magnetic susceptibility across tissues hinder both solutions. Unifying the two approaches, we propose regseg, a surface-to-volume nonlinear registration method that segments homogeneous regions within multivariate images by mapping a set of nested reference-surfaces. Accurate surfaces are extracted from a T1w image of the subject, using as target image the bivariate volume comprehending the fractional anisotropy (FA) and the apparent diffusion coefficient (ADC) maps derived from the dMRI dataset. We first verify the accuracy of regseg on a general context using digital phantoms. Then we establish an evaluation framework using undistorted dMRI data from the Human Connectome Project (HCP) and known deformations derived from real inhomogeneity fieldmaps. We analyze the performance of regseg computing the misregistration error of the surfaces estimated after being mapped with regseg onto 16 datasets from the HCP. The distribution of errors shows a 95% CI of 0.56-0.66 mm, that is below the dMRI resolution (1.25 mm, isotropic). Finally, we cross-compare the proposed tool against a nonlinear b0-to-T2w registration method, thereby obtaining a significantly lower misregistration error with regseg. Therefore, we demonstrate that regseg allows the accurate mapping of structural information in dMRI space, enabling the application of new structure-informed techniques in the connectome extraction.

Bioengineering↗

bioRxiv2015

Two-Dimensional Mapping of 3D Data from Confocal Microscopy

Confocal microscopy has been experimentally proven for decades to provide high-quality images for biological research. Its unique property of blocking out-of-focus light enables 3D rendering from planar stacks and visualization of internal features. However, visualizing 3D data on a flat display is not intuitive, and would lead to occasional distortion. In this study, a novel, easy-to-implement, and computationally fast solution is provided to reconstruct a confocal stack to true 3D data and subsequently map the information correctly with size and shape consistency to a 2D space for visualization and image analysis purposes.

Bioengineering↗

bioRxiv2015

Single Cells of Pseudomonas aeruginosa Exhibit Electrotaxis and Durotaxis Behaviours

Pseudomonas aeruginosa is frequently associated with nosocomial infections, including polymicrobial wound infections and the complex biofilm communities that reside within the cystic fibrosis lung. P. aeruginosa utilizes flagellum-mediated motility to approach, attach to, and spread across a surface using a combination of swimming, swarming and twitching (type IV pili extension and retraction) motility. We report an innovative approach to study the motility of single P. aeruginosa cells in microfluidic channels possessing different structural geometry, all with the flexibility of being able to manipulate stiffness gradients and electric fields to investigate changes in motility in response to specific stimuli. P. aeruginosa cells exhibit restricted motility in reduced microchannel spaces, with preferential migration toward a stiffer region in a rigidness gradient of substrate medium and preferential migration toward a positive electrode in presence of a pulsed or successive electric field. This single-cue environmental study using microfluidic technology lays the groundwork for multi-cue experimentation to more faithfully mimic conditions in vivo, demonstrating just some of the advantages of this technique. This study is designed to examine the interplay between surface rigidity, mechanical, and electrical cues to pave the way for improvements in the design of anti-fouling surfaces for biomedical applications and to identify new ways to inhibit bacterial biofilm growth through motility restriction.

Bioengineering↗