Delayed-interval BNT162b2 mRNA COVID-19 vaccination enhances humoral immunity and induces robust T cell responses.

Delayed dosing intervals are a strategy to immunize a greater proportion of the population. In an observational study, we compared humoral and cellular responses in health care workers receiving two doses of BNT162b2 (Pfizer-BioNTech) vaccine at standard (3- to 6-week) and delayed (8- to 16-week) intervals. In the delayed-interval group, anti-receptor-binding domain antibody titers were significantly enhanced compared to the standard-interval group. The 50% plaque reduction neutralization test (PRNT50) and PRNT90 titers against wild-type (ancestral) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Alpha, Beta and Delta variants were higher in the delayed-interval group. Spike-specific polyfunctional CD4+ and CD8+ T cells expressing interferon-γ and interleukin-2 were comparable between the two groups. Here, we show that the strategy of delaying second doses of mRNA vaccination may lead to enhanced humoral immune responses, including improved virus neutralization against wild-type and variant SARS-CoV-2 viruses. This finding has potentially important implications as vaccine implementation continues across a greater proportion of the global population.

Distinctive transcriptomic and epigenomic signatures of bone marrow-derived myeloid cells and microglia in CNS autoimmunity.

In the context of autoimmunity, myeloid cells of the central nervous system (CNS) constitute an ontogenically heterogeneous population that includes yolk sac-derived microglia and infiltrating bone marrow-derived cells (BMC). We previously identified a myeloid cell subset in the brain and spinal cord that expresses the surface markers CD88 and CD317 and is associated with the onset and persistence of clinical disease in the murine model of the human CNS autoimmune disorder, experimental autoimmune encephalomyelitis (EAE). We employed an experimental platform utilizing single-cell transcriptomic and epigenomic profiling of bone marrow-chimeric mice to categorically distinguish BMC from microglia during CNS autoimmunity. Analysis of gene expression and chromosomal accessibility identified CD88+CD317+ myeloid cells in the CNS of EAE mice as originating from BMC and microglia. Interestingly, each cell lineage exhibited overlapping and unique gene expression patterns and transcription factor motifs that allowed their segregation. Our observations will facilitate determining pathogenic contributions of BMC and microglia in CNS autoimmune disease. Ultimately, this agnostic characterization of myeloid cells will be required for devising disease stage-specific and tissue-specific interventions for CNS inflammatory and neurodegenerative disorders.

Hepatic glutamine synthetase controls N5-methylglutamine in homeostasis and cancer.

Glutamine synthetase (GS) activity is conserved from prokaryotes to humans, where the ATP-dependent production of glutamine from glutamate and ammonia is essential for neurotransmission and ammonia detoxification. Here, we show that mammalian GS uses glutamate and methylamine to produce a methylated glutamine analog, N5-methylglutamine. Untargeted metabolomics revealed that liver-specific GS deletion and its pharmacological inhibition in mice suppress hepatic and circulating levels of N5-methylglutamine. This alternative activity of GS was confirmed in human recombinant enzyme and cells, where a pathogenic mutation in the active site (R324C) promoted the synthesis of N5-methylglutamine over glutamine. N5-methylglutamine is detected in the circulation, and its levels are sustained by the microbiome, as demonstrated by using germ-free mice. Finally, we show that urine levels of N5-methylglutamine correlate with tumor burden and GS expression in a ß-catenin-driven model of liver cancer, highlighting the translational potential of this uncharacterized metabolite.

When Social Media Empowers Analytical Chemists to Explore Millions of Spectra Derived from a Complex Sample.

Analytical chemistry has never yielded such a wealth of experimental data as it does today, and this exponential trend shows no sign of abating. We continually advance the capabilities of our instruments and conceive innovative concepts, all in a concerted effort to naturally push the boundaries of our understanding regarding intricate sample matrices. Spectroscopic imaging, in the broadest sense, is certainly the field where we observe this acceleration even more pronouncedly. Analytical chemistry swiftly grasped the significance of processing acquired data for comprehensive exploration through utilization of chemometrics or machine learning tools. One can assert today that chemometrics undeniably constitutes an integral facet in the advancement of an analytical approach. However, we are now faced with a new challenge, as the experimental data accumulated for certain analytical techniques are so vast and massive that exploring them with such tools has become unfeasible, and this is by no means a computational capacity issue. Analytical chemistry is far from being the sole field affected by this issue, and one could argue that others have grappled with it long before us, such as, for instance, social media, to name just one. The purpose of this paper is to demonstrate that such a domain, which may initially seem distant from our concerns, can offer novel tools capable of overcoming these barriers, even though we are not necessarily dealing with the same objects. More specifically, we delve into the clustering of over 10 million LIBS spectra acquired as part of an imaging experiment aimed at exploring a singular rock sample. This will serve to demonstrate that an open-source library developed by Meta (formerly known as Facebook) can enable us to conduct a comprehensive exploration of this sample, a feat deemed impossible with conventional data analysis approaches.

Enhancing Diagnostic Capabilities for Occupational Lung Diseases Using LIBS Imaging on Biopsy Tissue.

Laser-induced breakdown spectroscopy (LIBS) imaging continues to gain strength as an influential bioanalytical technique, showing intriguing potential in the field of clinical analysis. This is because hyperspectral LIBS imaging allows for rapid, comprehensive elemental analysis, covering elements from major to trace levels consistently year after year. In this study, we estimated the potential of a multivariate spectral data treatment approach based on a so-called convex envelope method to detect exotic elements (whether they are minor or in trace amounts) in biopsy tissues of patients with occupational exposure-related diseases. More precisely, we have developed an approach called Interesting Features Finder (IFF), which initially allowed us to identify unexpected elements without any preconceptions, considering only the set of spectra contained in a LIBS hyperspectral data cube. This task is, in fact, almost impossible with conventional chemometric tools, as it entails identifying a few exotic spectra among several hundred thousand others. Once this detection was performed, a second approach based on correlation was used to locate their distribution in the biopsies. Through this unique data analysis pipeline to processing massive LIBS spectroscopic data, it was possible to detect and locate exotic elements such as tin and rhodium in a patient's tissue section, ultimately leading to a possible reclassification of their lung condition as an occupational disease. This review will thus demonstrate the potential of this new diagnostic tool based on LIBS imaging in addressing the shortcomings of approaches developed thus far. The proposed data processing approach naturally transcends this specific framework and can be leveraged across various domains of analytical chemistry, where the detection of rare events is concealed within extensive data sets.

Profiles of interferon-stimulated genes in multiple tissues and circulating pregnancy-associated glycoproteins and their association with pregnancy loss in dairy cows†.

Pregnancy loss (PL) in lactating dairy cows disrupts reproductive and productive efficiency. We evaluated the expression of interferon-stimulated genes (ISG) in blood leukocytes, vaginal and cervical epithelial cells, luteolysis-related genes, progesterone, and pregnancy-associated glycoprotein (PAG) profiles in lactating dairy cows (n = 86) to gain insight about PL. Expression of ISG on d17, d19, and d21 was greater in cows that maintained the pregnancy (P33) compared to nonpregnant with no PL (NP). Greater ISG differences between groups were observed in the cervix (96.7-fold) than vagina (31.0-fold), and least in blood leukocytes (5.6-fold). Based on individual profiles of ISG and PAG, PL was determined to occur either before (~13%) or after (~25%) d22. For cows with PL before d22, ISG expression was similar on d17 but by d21 was lower and OXTR was greater than P33 cows and similar to NP; timing of luteolysis was similar compared to NP cows suggesting embryonic failure to promote luteal maintenance and to attach to the endometrium (no increase in PAG). For cows with PL after d22, ISG expression was similar to P33 cows on d17, d19, and d21 and luteolysis, when it occurred, was later than NP cows; delayed increase in PAG suggested later or inadequate embryonic attachment. In conclusion, PL before d22 occurred due to embryonic demise/failure to signal for luteal maintenance, as reflected in reduced ISG expression by d21. Alternatively, embryos with PL between d22 and 33 adequately signaled for luteal maintenance (ISG) but had delayed/inadequate embryonic attachment and/or inappropriate luteolysis causing PL.

Assessing the in vivo impact of novel ß-lactamase inhibitors on the efficacy of their partner ß-lactams against serine carbapenemase-producing Pseudomonas aeruginosa using human-simulated exposures.

OBJECTIVES: To evaluate the efficacy of human-simulated regimens (HSRs) of ceftazidime, ceftazidime/avibactam, imipenem, imipenem/relebactam, meropenem and meropenem/vaborbactam in a murine thigh infection model against serine carbapenemase-producing Pseudomonas aeruginosa. METHODS: Nine P. aeruginosa clinical isolates harbouring GES-5 (n = 1), GES-20 (n = 1), GES-5/20 (n = 1), GES-19, GES-20 (n = 3) and KPC (n = 3) were evaluated. Six mice were administered HSRs of ceftazidime 2 g q8h (2 h infusion), ceftazidime/avibactam 2.5 g q8h (2 h infusion), meropenem 2 g q8h (3 h infusion), imipenem 0.5 g q6h (0.5 h infusion), imipenem/relebactam 1.25 g q6h (0.5 h infusion) and meropenem/vaborbactam 4 g q8h (3 h infusion). Change in bacterial burden relative to baseline and the percent of isolates meeting the 1 log10 kill endpoint were assessed. RESULTS: The addition of avibactam to ceftazidime increased the percentage of isolates meeting 1 log10 kill from 33% to 100% of GES- or KPC-harbouring isolates. Imipenem/relebactam HSR produced ≥1 log10 of kill against 83% and 100% of GES- and KPC-harbouring isolates, respectively, while imipenem alone failed to reach 1 log10 kill for any isolates. Vaborbactam resulted in variable restoration of meropenem activity as 1 log10 kill was achieved in only 33% and 66% of GES- and KPC-harbouring isolates, respectively, compared with no isolates for meropenem alone. CONCLUSIONS: Ceftazidime/avibactam and imipenem/relebactam were active against 100% and 89% of KPC- or GES-harbouring isolates tested in vivo. The activity of meropenem/vaborbactam was variable, suggesting this may be an inferior treatment option in this setting. Further studies to evaluate clinical outcomes in GES- and KPC-producing P. aeruginosa are warranted given their increasing prevalence worldwide.

Trends and challenges in microfluidic methods for protein manipulation-A review.

Proteins are important molecules involved in an immensely large number of biological processes. Being capable of manipulating proteins is critical for developing reliable and affordable techniques to analyze and/or detect them. Such techniques would enable the production of therapeutic agents for the treatment of diseases or other biotechnological applications (e.g., bioreactors or biocatalysis). Microfluidic technology represents a potential solution to protein manipulation challenges because of the diverse phenomena that can be exploited to achieve micro- and nanoparticle manipulation. In this review, we discuss recent contributions made in the field of protein manipulation in microfluidic systems using different physicochemical principles and techniques, some of which are miniaturized versions of already established macro-scale techniques.

Finite element modeling with patient-specific geometry to assess clinical risks of percutaneous pulmonary valve implantation.

BACKGROUND: Percutaneous pulmonary valve implantation (PPVI) is a non-surgical treatment for right ventricular outflow tract (RVOT) dysfunction. During PPVI, a stented valve, delivered via catheter, replaces the dysfunctional pulmonary valve. Stent oversizing allows valve anchoring within the RVOT, but overexpansion can intrude on the surrounding structures. Potentially dangerous outcomes include aortic valve insufficiency (AVI) from aortic root (AR) distortion and myocardial ischemia from coronary artery (CA) compression. Currently, risks are evaluated via balloon angioplasty/sizing before stent deployment. Patient-specific finite element (FE) analysis frameworks can improve pre-procedural risk assessment, but current methods require hundreds of hours of high-performance computation. METHODS: We created a simplified method to simulate the procedure using patient-specific FE models for accurate, efficient pre-procedural PPVI (using balloon expandable valves) risk assessment. The methodology was tested by retrospectively evaluating the clinical outcome of 12 PPVI candidates. RESULTS: Of 12 patients (median age 14.5 years) with dysfunctional RVOT, 7 had native RVOT and 5 had RV-PA conduits. Seven patients had undergone successful RVOT stent/valve placement, three had significant AVI on balloon testing, one had left CA compression, and one had both AVI and left CA compression. A model-calculated change of more than 20% in lumen diameter of the AR or coronary arteries correctly predicted aortic valve sufficiency and/or CA compression in all the patients. CONCLUSION: Agreement between FE results and clinical outcomes is excellent. Additionally, these models run in 2-6 min on a desktop computer, demonstrating potential use of FE analysis for pre-procedural risk assessment of PPVI in a clinically relevant timeframe.

Zeta Potential and Size Analysis of Zeolitic Imidazolate Framework-8 Nanocrystals Prepared by Surfactant-Assisted Synthesis.

The crystal nucleation and growth mechanism of monodispersed metal-organic framework nanoparticles were studied using time-resolved light dynamic, electrokinetic, and powder X-ray diffraction methods. We confirmed that zeolitic imidazolate framework-8 (ZIF-8) nanocrystals follow a nonclassical crystal growth pathway, where a fast nucleation occurs with dense liquid clusters or nanocrystals forming spontaneously when two precursors are mixed. We also explored the zeta potential and solvodynamic size changes of ZIF-8 prepared by a surfactant-assisted synthesis. Three modulators, including 1-methylimidazole (1-mIm), tris(hydroxymethyl)aminomethane (THAM), and (1-hexadecyl)trimethylammonium bromide (CTAB), were studied. We found that 1-mIm dramatically increases the rate of nucleation of ZIF-8. With an increasing amount of 1-mIm, which functions as a coordination modulator, the size increases, and the zeta potential of ZIF-8 decreases. Whereas THAM, as both a coordination and a deprotonation modulator, increases the size and zeta potential of ZIF-8 simultaneously, CTAB, as a long alkyl cationic surfactant, mainly adsorbs on the surface of ZIF-8, and the zeta potential of the formed ZIF-8 is controlled by the amount of CTAB in solution compared with its critical micelle concentration. Overall, we reveal that the modulator type and concentration can be used to control the size and zeta potential of the dispersed ZIF-8 nanocrystals in a colloid system. The experiments also enable identification of the nucleation and crystal growth processes of ZIF-8. The findings will be applicable to other nanocrystals in colloid systems, which are used for heterogeneous catalysis and guest molecular loadings.

Long-term survivorship care after CAR-T cell therapy.

While cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome are well-recognized acute toxicities of chimeric antigen receptor (CAR) T cell therapy, these complications have become increasingly manageable by protocolized treatment algorithms incorporating the early administration of tocilizumab and corticosteroids. As CAR-T cell therapy expands to new disease indications and the number of long-term survivors steadily increases, there is growing recognition of the need to appropriately evaluate and manage the late effects of CAR-T cell therapy, including late-onset or persistent neurotoxicity, prolonged cytopenias, delayed immune reconstitution and infections, subsequent malignancies, organ dysfunction, psychological distress, and fertility implications. In this review, we provide a practical approach to the long-term survivorship care of the CAR-T cell recipient, with a focus on the optimal strategies to address the common and challenging late complications affecting this unique population.

Manipulating the insulating post arrangement in DC-biased AC-iEK devices to improve microparticle separations.

There is a growing interest in the advancement of microscale electrokinetic (EK) systems for biomedical and clinical applications, as these systems offer attractive characteristics such as portability, robustness, low sample requirements and short response time. The present work is focused on manipulating the characteristics of the insulating post arrangement in insulator-based EK (iEK) systems for separating a binary mixture of spherical microparticles with same diameter (5.1 µm), same shape, made from the same substrate material and only differing in their zeta potential by ∼14 mV. This study presents a combination of mathematical modeling and experimental separations performed by applying a low-frequency alternating current (AC) voltage in iEK systems with 12 distinct post arrangements. These iEK devices were used to systematically study the effect of three spatial characteristics of the insulating post array on particle separations: the horizontal separation and the vertical separation between posts, and introducing an offset to the posts arrangement. Through normalization of the spatial separation between the insulating posts with respect to particle diameter, guidelines to improve separation resolution for different particle mixtures possessing similar characteristics were successfully identified. The results indicated that by carefully designing the spatial arrangement of the post array, separation resolution values in the range of 1.4-2.8 can be obtained, illustrating the importance and effect of the arrangement of insulating posts on improving particle separations. This study demonstrates that iEK devices, with effectively designed spatial arrangement of the insulating post arrays, have the capabilities to perform discriminatory separations of microparticles of similar characteristics.

Enabling the characterization of the nonlinear electrokinetic properties of particles using low voltage.

Insulator-based electrokinetically driven microfluidic devices stimulated with direct current (DC) voltages are an attractive solution for particle separation, concentration, or isolation. However, to design successful particle manipulation protocols, it is mandatory to know the mobilities of electroosmosis, and linear and nonlinear electrophoresis of the microchannel/liquid/particle system. Several techniques exist to characterize the mobilities of electroosmosis and linear electrophoresis. However, only one method to characterize the mobility of nonlinear electrophoresis has been thoroughly assessed, which generally requires DC voltages larger than 1000 V and measuring particle velocity in a straight microchannel. Under such conditions, Joule heating, electrolysis, and the DC power source cost become a concern. Also, measuring particle velocity at high voltages is noisy, limiting characterization quality. Here we present a protocol-tested on 2 µm polystyrene particles-for characterizing the mobility of nonlinear electrophoresis of the liquid/particle system using a DC voltage of only 30 V and visual inspection of particle dynamics in a microchannel featuring insulating obstacles. Multiphysics numerical modelling was used to guide microchannel design and to correlate particle location during an experiment with electric field intensity. The method was validated against the conventional characterization protocol, exhibiting excellent agreement while significantly reducing measurement noise and experimental complexity.

Estimation and probabilistic projection of age- and sex-specific mortality rates across Brazilian municipalities between 2010 and 2030.

BACKGROUND: Mortality rate estimation in small areas can be difficult due the low number of events/exposure (i.e. stochastic error). If the death records are not completed, it adds a systematic uncertainty on the mortality estimates. Previous studies in Brazil have combined demographic and statistical methods to partially overcome these issues. We estimated age- and sex-specific mortality rates for all 5,565 Brazilian municipalities in 2010 and forecasted probabilistic mortality rates and life expectancy between 2010 and 2030. METHODS: We used a combination of the Tool for Projecting Age-Specific Rates Using Linear Splines (TOPALS), Bayesian Model, Spatial Smoothing Model and an ad-hoc procedure to estimate age- and sex-specific mortality rates for all Brazilian municipalities for 2010. Then we adapted the Lee-Carter model to forecast mortality rates by age and sex in all municipalities between 2010 and 2030. RESULTS: The adjusted sex- and age-specific mortality rates for all Brazilian municipalities in 2010 reveal a distinct regional pattern, showcasing a decrease in life expectancy in less socioeconomically developed municipalities when compared to estimates without adjustments. The forecasted mortality rates indicate varying regional improvements, leading to a convergence in life expectancy at birth among small areas in Brazil. Consequently, a reduction in the variability of age at death across Brazil's municipalities was observed, with a persistent sex differential. CONCLUSION: Mortality rates at a small-area level were successfully estimated and forecasted, with associated uncertainty estimates also generated for future life tables. Our approach could be applied across countries with data quality issues to improve public policy planning.

Rational Design of Molecularly Imprinted Polymers for Curcuminoids Binding: Computational and Experimental Approaches for the Selection of Functional Monomers.

Molecularly imprinted polymers (MIPs) have emerged as bespoke materials with versatile molecular applications. In this study, we propose a proof of concept for a methodology employing molecular dynamics (MD) simulations to guide the selection of functional monomers for curcuminoid binding in MIPs. Curcumin, demethoxycurcumin, and bisdemethoxycurcumin are phenolic compounds widely employed as spices, pigments, additives, and therapeutic agents, representing the three main curcuminoids of interest. Through MD simulations, we investigated prepolymerization mixtures composed of various functional monomers, including acrylamide (ACA), acrylic acid (AA), methacrylic acid (MAA), and N-vinylpyrrolidone (NVP), with ethylene glycol dimethacrylate (EGDMA) as the cross-linker and acetonitrile as the solvent. Curcumin was selected as the template molecule due to its structural similarity to the other curcuminoids. Notably, the prepolymerization mixture containing NVP as the functional monomer demonstrated superior molecular recognition capabilities toward curcumin. This observation was supported by higher functional monomer molecules surrounding the template, a lower total nonbonded energy between the template and monomer, and a greater number of hydrogen bonds in the aggregate. These findings suggest a stronger affinity between the functional monomer NVP and the template. We synthesized, characterized, and conducted binding tests on the MIPs to validate the MD simulation results. The experimental binding tests confirmed that the MIP-NVP exhibited higher binding capacity. Consequently, based on MD simulations, our computational methodology effectively guided the selection of the functional monomer, leading to MIPs with binding capacity for curcuminoids. The outcomes of this study provide a valuable reference for the rational design of MIPs through MD simulations, facilitating the selection of components for MIPs. This computational approach holds the potential for extension to other templates, establishing a robust methodology for the rational design of MIPs.

Measures of contextuality in cyclic systems and the negative probabilities measure CNT3.

Several principled measures of contextuality have been proposed for general systems of random variables (i.e. inconsistently connected systems). One such measure is based on quasi-couplings using negative probabilities (here denoted by [Formula: see text], Dzhafarov & Kujala, 2016 Quantum interaction). Dzhafarov & Kujala (Dzhafarov & Kujala 2019 Phil. Trans. R. Soc. A 377, 20190149. (doi:10.1098/rsta.2019.0149)) introduced a measure of contextuality, [Formula: see text], that naturally generalizes to a measure of non-contextuality. Dzhafarov & Kujala (Dzhafarov & Kujala 2019 Phil. Trans. R. Soc. A 377, 20190149. (doi:10.1098/rsta.2019.0149)) additionally conjectured that in the class of cyclic systems these two measures are proportional. Here we prove that conjecture is correct. Recently, Cervantes (Cervantes 2023 J. Math. Psychol. 112, 102726. (doi:10.1016/j.jmp.2022.102726)) showed the proportionality of [Formula: see text] and the Contextual Fraction measure introduced by Abramsky & Brandenburger (Abramsky & Brandenburger 2011 New J. Phys. 13, 113036. (doi:10.1088/1367-2630/13/11/113036)). The present proof completes the description of the interrelations of all contextuality measures proposed within or translated into the Contextuality-by-Default framework so far as they pertain to cyclic systems. This article is part of the theme issue 'Quantum contextuality, causality and freedom of choice'.

Manifestation of site energy landscapes for ion transport in borate glasses.

The potential energy landscape of lithium borate glass of composition Li3B7O12 has been investigated by the charge attachment induced transport (CAIT) technique. Here, native lithium ions have been replaced by foreign alkali ions, M+ = K+, Rb+, Cs+. All experiments exhibit a pronounced decrease of native ion diffusion coefficients over more than 4 orders of magnitude with decreasing local population of Li+. The energy landscape is modelled by a site energy distribution (SED) with a concentration dependent Fermi energy of the native Li+ ions. The width of the populated part of the SED is found to be 250 meV (FWHM). The conclusion is made possible by a combination of a macroscopic ion replacement experiment with a Nernst-Planck-Poisson modelling of concentration depth profiles measured by secondary ion mass spectrometry (SIMS). Possible generalizations of macroscopic transport theory to match an Onsager ansatz are discussed.

Harnessing carboxymethyl cellulose and Moringa oleifera seed husks for sustainable treatment of a multi-metal real waste.

This study aimed to evaluate effective treatment strategies for laboratory waste with an initial pH of 1.0, containing Cr6+, Mn2+, Co2+, Fe3+, Ni2+, Cu2+, Zn2+, Sr2+, Hg2+, and Pb2+ ions, focusing on flocculation, precipitation, and adsorption techniques. The study utilized microparticles derived from Moringa oleifera seed husks (MS), cryogels of carboxymethyl cellulose (CMC), and hybrid cryogels combining CMC and MS (CMC-MS25 and CMC-MS50) as adsorbents. The optimal strategy involved raising the pH to 7 using NH4OH, leading to the partial precipitation of metal ions. The remaining supernatant was then passed through columns packed with the aforementioned adsorbents. Utilizing CMC-MS25 and CMC-MS50 adsorbents resulted in the simultaneous removal of over 90% of the targeted metal ions. The adsorption of Cu2+ ions onto the adsorbents was facilitated by electrostatic interactions between Cu2+ ions and carboxylate groups, as well as Cu-OH chelation, as confirmed by X-ray photoelectron spectroscopy. Under optimized conditions, the fixed-bed column adsorption capacity was determined as 88.2 mg g-1. The CMC-MS25 adsorbents proved reusable at least 5 times, with the recovered Cu2+ ions potentially suitable for other processes. The scalability and feasibility of producing these novel adsorbents suggest a promising, cost-effective solution for treating complex matrices and recovering high-value metals, as copper.

An Approach to Quantify Anisotropic Multiaxial Failure of the Annulus Fibrosus.

Tears in the annulus fibrosus (AF) of the intervertebral disk (IVD) occur due to multiaxial loading on the spine. However, most existing AF failure studies measure uniaxial stress, not the multiaxial stress at failure. Delamination theory, which requires advanced structural knowledge and knowledge about the interactions between the AF fibers and matrix, has historically been used to understand and predict AF failure. Alternatively, a simple method, the Tsai-Hill yield criteria, could describe multiaxial failure of the AF. This yield criteria uses the known tissue fiber orientation and an equation to establish the multiaxial failure stresses that cause failure. This paper presents a method to test the multiaxial failure stress of the AF experimentally and evaluate the potential for the Tsai-Hill model to predict these failure stresses. Porcine AF was cut into a dogbone shape at three distinct angles relative to the primary lamella direction (parallel, transverse, and oblique). Then, each dogbone was pulled to complete rupture. The Cauchy stress in the material's fiber coordinates was calculated. These multiaxial stress parameters were used to optimize the coefficients of the Tsai-Hill yield. The coefficients obtained for the Tsai-Hill model vary by an order of magnitude between the fiber and transverse directions, and these coefficients provide a good description of the AF multiaxial failure stress. These results establish both an experimental approach and the use of the Tsai-Hill model to explain the anisotropic failure behavior of the tissue.

A Graphical Approach to Visualize and Interpret Biochemically Coupled Biomechanical Models.

The last decade has seen the emergence of progressively more complex mechanobiological models, often coupling biochemical and biomechanical components. The complexity of these models makes interpretation difficult, and although computational tools can solve model equations, there is considerable potential value in a simple method to explore the interplay between different model components. Pump and system performance curves, long utilized in centrifugal pump selection and design, inspire the development of a graphical technique to depict visually the performance of biochemically-coupled mechanical models. Our approach is based on a biochemical performance curve (analogous to the classical pump curve) and a biomechanical performance curve (analogous to the system curve). Upon construction of the two curves, their intersection, or lack thereof, describes the coupled model's equilibrium state(s). One can also observe graphically how an applied perturbation shifts one or both curves, and thus how the other component will respond, without rerunning the full model. While the upfront cost of generating the performance curve graphic varies with the efficiency of the model components, the easily interpretable visual depiction of what would otherwise be nonintuitive model behavior is valuable. Herein, we outline how performance curves can be constructed and interpreted for biochemically-coupled biomechanical models and apply the technique to two independent models in the cardiovascular space. The performance curve approach can illustrate and help identify weaknesses in model construction, inform user-applied perturbations and fitting procedures to generate intended behaviors, and improve the efficiency of the model generation and application process.