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We consider a general mathematical model for protein subunit vaccine with a focus on the MF59-adjuvanted spike glycoprotein-clamp vaccine for SARS-CoV-2, and use the model to study immunological outcomes in the humoral and cell-mediated arms of the immune response from vaccination. The mathematical model is fit to vaccine clinical trial data. We elucidate the role of Interferon-𝛾 and Interleukin-4 in stimulating the immune response of the host. Model results, and results from a sensitivity analysis, show that a balance between the T𝐻 1 and T𝐻 2 arms of the immune response is struck, with the T𝐻 1 response being dominant. The model predicts that two-doses of the vaccine at 28 days apart will result in approximately 85% humoral immunity loss relative to peak immunity approximately 6 months post dose 1.

Human monkeypox virus (mpox) is a viral zoonosis belonging to the Orthopoxvirus genus of the Poxviridae family that presents with similar symptoms as seen previously in human smallpox patients. mpox is a growing concern internationally with over 80000 cases in non-endemic countries as of December 2022. In this review, we briefly cover the history and origins of mpox and describe its basic virology, noting key differences in mpox viral fitness traits pre and post-2022. We then summarize and critique current knowledge from epidemiological mathematical models, within-host models, and between-host transmission models. We distinguish between models that focus on immunity from vaccination, as well as geography, climatic variables, and animal models. We report various epidemiological parameters, such as the reproduction number R0, in a condensed format for ease of comparison between studies. We focus specifically on how mathematical modelling studies have led to novel mechanistic insight into Monkeypox transmission and pathogenesis. As mpox continues to emerge and is predicted to continue to form subsequent peaks in many historically non-endemic countries, mpox mathematical modelling studies can provide rapid actionable insight into viral dynamics to guide public health measures and mitigation strategies.

A compartment model for an in-host liquid nanoparticle delivered mRNA vaccine is presented. Through non-dimensionalisation, five timescales are identified that dictate the lifetime of the vaccine in-host: decay of interferon gamma, antibody priming, autocatalytic growth, antibody peak and decay, and interleukin cessation. Through asymptotic analysis we are able to obtain semi-analytical solutions in each of the time regimes which allows us to predict maximal concentrations and better understand parameter dependence in the model. We compare our model to 22 data sets for the BNT162b2 and mRNA-1273 mRNA vaccines demonstrating good agreement. Using our analysis, we estimate the values for each of the five timescales in each data set and predict maximal concentrations of plasma B-cells, antibody, and interleukin. Through our comparison, we do not observe any discernible differences between vaccine candidates and sex. However, we do identify an age dependence, specifically that vaccine activation takes longer and that peak antibody occurs sooner in patients aged 55 and greater.

Study question What is the thyroid disease rate in IVF patients and how does it affect their IVF outcome? Summary answer The thyroid disease rate was 19,5%, mostly of inflammatory origin. IVF outcome in these patients was similar to controls, but coexisting endometriosis rate was higher. What is known already Thyroid disease is the most common endocrine disorder in females of reproductive age. It is estimated that 20% of infertile females has history of thyroid disease. Thyroid hormones importantly impact fertility, acting directly on oocytes, sperm and embryo during fertilization, implantation and placentation, regulating estrogen and androgen metabolism as well as the menstrual cycle. The most common causes of thyroid disfunction are autoimmune disorders. The prevalence of thyroid autoimmunity among women undergoing IVF treatment is higher compared to the general population. Women with thyroid autoimmunity have higher risk of miscarriage, preterm birth and it may impact the IVF-ET outcome. Study design, size, duration It was a single center trial at the Division of Obstetrics and Gynecology, Department of Human Reproduction in the University Medical Centre of Ljubljana, Slovenia. The study included women undergoing their first IVF treatment in a one-year period. Participants/materials, setting, methods A total of 226 women undergoing their first IVF treatment were included. In the first part of our study, Patient characteristics and IVF outcome according to different TSH serum levels (< 0,59 mE/L, 0,59 - 2,5 mE/L, 2,5 - 4,23 mE/L ter > 4,23 mE/L) were analysed. In the second part of the study, we compared patient characteristics and IVF outcome in patients with and without thyroid disease. Main results and the role of chance The average age was 33 ± 4,7 years, the average BMI was 24±4,9 kg/m2. Three percent of women had TSH levels 4,23 mE/L. The obesity rate (BMI>30 kg/m2) was significantly different in all four groups of patients with the highest rate in the group of TSH 2,5-4,23 mE/L. Thyroid disease was found in 19,5% of patients (thyroid autoimmunity 18%, Hashimoto's thyroiditis 7,5% of patients). The thyroid disease rate was significantly different in all four groups with highest rate in group having TSH >4,23 mE/L and the lowest rate in group having TSH 0,59-2,5 mE/L. Endometriosis was diagnosed in 22% of patients with highest rate in patients having highest TSH levels. There was no correlation between patient characteristics and reproductive history (age, irregular menstrual cycle, dysmenorrhea, pregnancy, spontaneous abortion, recurrent abortion, FSH and LH serum levels) and TSH levels or preexisting thyroid disease. There were no significant differences in the IVF outcome (numbers of retrieved oocytes, immature oocytes and number of embryos) according to TSH levels or preexisting thyroid disease. Thyroid disease rate was significantly higher in patients with endometriosis. Limitations, reasons for caution Our study limitation is a smaller sample size that may affect our results, specifically the differences in the IVF outcome. There was no statistical difference in miscarriage and recurrent miscarriage rate in women with thyroid disease and women with normal thyroid function. Wider implications of the findings Our study gives an insight to the characteristics of women with thyroid disease undergoing IVF treatment in our facility, although the differences were statistically insignificant. As a secondary outcome we discovered a statistically significant correlation of endometriosis and inflammatory thyroid disease, which is rarely mentioed in the literature. Trial registration number not applicable

Within-host SARS-CoV-2 modelling studies have been published throughout the COVID-19 pandemic. These studies contain highly variable numbers of individuals and capture varying timescales of pathogen dynamics; some studies capture the time of disease onset, the peak viral load and subsequent heterogeneity in clearance dynamics across individuals, while others capture late-time post-peak dynamics. In this study, we curate multiple previously published SARS-CoV-2 viral load data sets, fit these data with a consistent modelling approach, and estimate the variability of in-host parameters including the basic reproduction number, R0. We find that fitted dynamics can be highly variable across data sets, and highly variable within data sets, particularly when key components of the dynamic trajectories (e.g. peak viral load) are not represented in the data. Further, we investigated the role of the eclipse phase time distribution in fitting SARS-CoV-2 viral load data. By varying the shape parameter of an Erlang distribution, we demonstrate that models with either no eclipse phase, or with an exponentially-distributed eclipse phase, offer significantly worse fits to these data, whereas models with less dispersion around the mean eclipse time (shape parameter two or more) offered the best fits to the available data.

Cellular-mediated immunity is critical for long-term protection against most viral infections, including coronaviruses. We studied 23 SARS-CoV-2-infected survivors over a one year post symptom onset (PSO) interval by ex vivo cytokine ELISpot assay. All subjects demonstrated SARS-CoV-2-specific IFN-γ, IL-2, and Granzyme B (GzmB) T cell responses at presentation, with greater frequencies in severe disease. Cytokines, mainly produced by CD4+ T cells, targeted all structural proteins (Nucleocapsid, Membrane, Spike) except Envelope, with GzmB > IL-2 > IFN-γ. Mathematical modeling predicted that: 1) cytokine responses peaked at 6 days for IFN-γ, 36 days for IL-2, and 7 days for GzmB, 2) severe illness was associated with reduced IFN-γ and GzmB, but increased IL-2 production rates, 3) males displayed greater production of IFN-γ, whereas females produced more GzmB. Ex vivo responses declined over time with persistence of IL-2 in 86% and of IFN-γ and GzmB in 70% of subjects at a median of 336 days PSO. The average half-life of SARS-CoV-2-specific cytokine-producing cells was modelled to be 139 days (∼4.6 months). Potent T cell proliferative responses persisted throughout observation, were CD4 dominant, and were capable of producing all 3 cytokines. Several immunodominant CD4 and CD8 epitopes identified in this study were shared by seasonal coronaviruses or SARS-CoV-1 in the Nucleocapsid and Membrane regions. Both SARS-CoV-2-specific CD4+ and CD8+ T cell clones were able to kill target cells, though CD8 tended to be more potent.ImportanceOur findings highlight the relative importance of SARS-CoV-2-specific GzmB-producing T cell responses in SARS-CoV-2 control, shared CD4 and CD8 immunodominant epitopes in seasonal coronaviruses or SARS-CoV-1, and indicate robust persistence of T cell memory at least one year after infection. Our findings should inform future strategies to induce T cell vaccines against SARS-CoV-2 and other coronaviruses.

SummaryBackgroundThe lipid nanoparticle (LNP)-formulated mRNA vaccines are a widely adopted two-dose vaccination public health strategy to manage the COVID-19 pandemic. Clinical trial data has described the immunogeneicity of the vaccine, albeit within a limited study time frame. Our aims were to use a within-host mathematical model for LNP-formulated mRNA vaccines, informed by available clinical trial data, to project a longer term understanding of humoral immunity as a function of vaccine type, dosage amount, age, and sex.MethodsWe developed a mathematical model describing the immunization process of LNP-formulated mRNA vaccines, and fit our model to twenty-two clinical humoral and cytokine BNT162b2 or mRNA-1273 human two-dose vaccination data sets. We incorporated multi-dose effects in our model to specify whether the dosage is standard or low-dose. We further specify the age groups 18-55, 56-70, and 70+ in our fits for two-standard doses of mRNA-1273, and sex in our fits for two-standard doses of BNT162b2. We used non-linear mixed effect models to fit to all similar data types (e.g. standard two-dose BNT162b2 or mRNA-1273, or two low-dose mRNA-1273). Therefore, in our fits all estimated parameters are statistically correlated, which allowed us to determine the underlying ‘population-dynamics’ structure common to a data type. We therefore made accurate long-term predictions informed by all clinical data used in this study.FindingsWe estimate that two standard doses of either mRNA-1273 or BNT162b2, with dosage times separated by the company-mandated intervals, results in individuals loosing more than 99% humoral immunity relative to peak immunity by eight months following the second dose. We predict that within an eight month period following dose two (corresponding to the CDC time-frame for administration of a third dose), there exists a period of time longer than one month where an individual has less then 99% humoral immunity relative to peak immunity, regardless of which vaccine was administered. We further find that age has a strong influence in maintaining humoral immunity; by eight months following dose two we predict that individuals aged 18-55 have a four-fold humoral advantage compared to aged 56-70 and 70+ individuals. We find that sex has little effect on the vaccine uptake and long-term IgG counts. Finally, we find that humoral immunity generated from two low doses of mRNA-1273 decays substantially slower relative to peak immunity gained than compared to two standard doses of either mRNA-1273 or BNT162b2.InterpretationFor the two dose mRNA vaccines, our predictions highlight the importance of the recommended third booster dose in order to maintain elevated levels of antibodies. We further show that age plays a critical role in determining the antibody levels. Hence, a third booster dose may confer an immuno-protective advantage in older individuals.FundingThis research is supported by NSERC Discovery Grant (RGPIN-2018-04546), NSERC COVID-19 Alliance Grant ALLRP 554923-20, CIHR-Fields COVID Immunity Task Force, NRC Pandemic Response Challenge Program Grant No. PR016-1.

Inspired by molecular motors in biology, there has been significant progress in building artificial molecular motors, using a number of quite distinct approaches. As the constructs become more sophisticated, there is also an increasing need to directly observe the motion of artificial motors at the nanoscale and to characterize their performance. Here, we review the most used methods that tackle those tasks. We aim to help experimentalists with an overview of the available tools used for different types of synthetic motors and to choose the method most suited for the size of a motor and the desired measurements, such as the generated force or distances in the moving system. Furthermore, for many envisioned applications of synthetic motors, it will be a requirement to guide and control directed motions. We therefore also provide a perspective on how motors can be observed on structures that allow for directional guidance, such as nanowires and microchannels. Thus, this Review facilitates the future research on synthetic molecular motors, where observations at a single-motor level and a detailed characterization of motion will promote applications.

Nature has evolved many mechanisms for achieving directed motion on the subcellular level. The burnt-bridges ratchet (BBR) is one mechanism used to achieve superdiffusive molecular motion over long distances through the successive cleavage of surface-bound energy-rich substrate sites. This mechanism has been associated with both nanoscale and microscale movement, with the latter accomplished through polyvalent interactions between a large hub (e.g. influenza virus) and substrate (e.g. cell surface receptors). Experimental successes in achieving superdiffusive motion by synthetic polyvalent BBRs have raised questions about the dynamics of their motility, including whether rolling or translation is better able to direct motion of microscale spherical hubs. Here we simulate the three-dimensional dynamics of a polyvalent sphere moving on and cleaving an elastic substrate. We find that substrate stiffness plays an important role in controlling both the motor's mode of motility and its directional persistence. As we tune lateral substrate stiffness from soft to stiff we find there exists an intermediate value that optimizes rolling behaviour. We also find that there is an optimal substrate stiffness for maximizing persistence length, while stiffness does not influence as strongly the superdiffusive dynamics of the particle. Lastly, we examine the effect of substrate density, and show that softer landscapes are better able to buffer against decreases in substrate occupancy, with the spherical motor maintaining superdiffusive motion more on softer landscapes than on stiff landscapes as occupancy drops. Our results highlight the importance of surface in controlling the motion of polyvalent BBRs.

The mean-squared displacement (MSD) is an averaged quantity widely used to assess anomalous diffusion. In many cases, such as molecular motors with finite processivity, dynamics of the system of interest produce trajectories of varying duration. Here we explore the effects of finite processivity on different measures of the MSD. We do so by investigating a deceptively simple dynamical system: a one-dimensional random walk (with equidistant jump lengths, symmetric move probabilities, and constant step duration) with an origin-directed detachment bias. By tuning the time dependence of the detachment bias, we find through analytical calculations and trajectory simulations that the system can exhibit a broad range of anomalous diffusion, extending beyond conventional diffusion to superdiffusion and even superballistic motion. We analytically determine that protocols with a time-increasing detachment lead to an ensemble-averaged velocity increasing in time, thereby providing the effective acceleration that is required to push the system above the ballistic threshold. MSD analysis of burnt-bridges ratchets similarly reveals superballistic behavior. Because superdiffusive MSDs are often used to infer biased, motor-like dynamics, these findings provide a cautionary tale for dynamical interpretation.

Two approaches to using optical floating zone (OFZ) technique for single crystal growth of the perovskite Pr1−xLaxAlO3 are discussed, along with the influence on the physical properties of the resulting single crystals due to oxidizing and reducing post anneals. In method one (M1) we used pre-reduced Pr2O3 powder starting material, while in the other method, M2, we employed an argon 5% hydrogen reducing environment during the floating zone single crystal growth. Magnetic susceptibility of the low temperature monoclinic phase of Pr0.2La0.8AlO3 is shown to be sensitive to the precise annealing protocol followed. For the post-growth reduced single crystal the magnetic susceptibility is flat across the R-3c to C2/m structural transition, whereas the oxidized and as-grown samples display a sharp upturn and downturn, respectively. We attribute the low temperature susceptibility differences to relative proportions of Pr3+ and Pr4+.

Many experiments and applications require the chemical coupling of target molecules to surfaces, during which the elimination of nonspecific interactions presents a difficult challenge. We report on a technologically accessible surface passivation and chemical conjugation method based on an NHS end-labeled F127 Pluronic block copolymer (F127-NHS). To quantify interactions between the F127-NHS surface and magnetic microspheres, we developed a simple assay: the microsphere adhesion by gravity, inversion, then counting, or "MAGIC" assay. To improve blocking of microspheres while maintaining the ability to chemically couple additional molecules, we implemented a pH-dependent two-step chemical modification process for amine microspheres. This process achieves an extremely high level of blocking nonspecific interactions (less than 2% nonspecific adhesion) for a variety of microsphere surface charges and chemical functionalities. We also demonstrate the ability to specifically tether magnetic microspheres to an F127-NHS surface, using single DNA molecules. Using the DNA microspheres, we establish the applicability of the surface for force spectroscopy (stable with an applied load >30 pN) via the massively parallel technique of centrifuge force microscopy. Finally, we demonstrate that the surface can be used in fluorescence studies with a fluorogenic peptide cleavage assay, with high levels of blocking achieved for both the fluorogenic peptide and trypsin. These results suggest applications including, but not limited to, single-molecule force spectroscopy and fluorescence, biosensors, medical implants, and anti-biofouling, which could make use of the F127-NHS surface.

The burnt-bridges ratchet (BBR) mechanism is a model for biased molecular motion whereby the construct destroys track binding sites as it progresses, and therefore acts as a diffusing forager, seeking new substrate sites. Using Monte Carlo simulations that implement the Gillespie algorithm, we investigate the kinetic characteristics of simple polyvalent BBRs as they move on tracks of increasing width. We find that as the track width is increased the BBRs remain nearly ballistic for considerable track widths proportional to the span (leg length) of the polyvalent walker, before transitioning to near-conventional diffusion on two-dimensional tracks. We find there exists a tradeoff in BBR track association time and superdiffusivity in the BBR design parameter space of span, polyvalency and track width. Furthermore, we develop an analytical model to describe the ensembleaverage motion on the track and find it is in good agreement with our Gillespie simulation results. This work offers insights into design criteria for de novo BBRs and their associated tracks, where experimentalists seek to optimize directionality and track association time., Includes SI, but not supporting movies

This paper describes the results of a research program to evaluate the effect of lowering zinc dithiophosphate (ZDDP) content on engine oil performance. The automative industry is concerned that engine oil composition may have an adverse effect on exhaust catalytic converter efficiency and has therefore called for more research to develop engine oils that will promote catlyst/engine oil compatibility. An apparently simple solution is to reduce ZDDP content to a level that allows satisfactory catalyst efficiency. The effects of lowering the ZDDP content have been evaluated in terms of wear, oxidation and bearing corrosion performance. It has been demonstrated that in laboratory engines and rig tests by quantifying the influence of lubricant composition on performance, engine oils can be formulated at lower phosphorous levels (0.08% wt) to meet the performance needs of modern passenger cars in the United States, Europe and Japan.