Acquisition vs. Memorization Trade-Offs Are Modulated by Walking Distance and Pattern Complexity in a Large-Scale Copying Paradigm

In a “block-copying paradigm”, subjects were required to copy a configuration of colored blocks from a model area to a distant work area, using additional blocks provided at an equally distant resource area. Experimental conditions varied between the inter-area separation (walking distance) and the complexity of the block patterns to be copied. Two major behavioral strategies were identified: in the memory-intensive strategy, subjects memorize large parts of the pattern and rebuild them without intermediate visits at the model area. In the acquisition-intensive strategy, subjects memorize one block at a time and return to the model after having placed this block. Results show that the frequency of the memory-intensive strategy is increased for larger inter-area separations (larger walking distances) and for simpler block patterns. This strategy-shift can be interpreted as the result of an optimization process or trade-off, minimizing combined, condition-dependent costs of the two strategies. Combined costs correlate with overall response time. We present evidence that for the memory-intensive strategy, costs correlate with model visit duration, while for the acquisition-intensive strategy, costs correlate with inter-area transition (i.e., walking) times

Montelukast medicines of today and tomorrow: from molecular pharmaceutics to technological formulations

Montelukast sodium is a leukotriene antagonist of growing interest as an alternative therapy for asthma across different age groups due to its bronchoprotective, anti-inflammatory and anti-allergic properties. Currently, montelukast is commercialized only in oral solid dosage forms, which are the favorite of adult patients but may pose challenges in administration to children of young age or patients suffering from dysphagia. This review presents a comprehensive revision of scientific reports and patents on emerging strategies for the delivery of montelukast. A common ground to these reports is the pursue of an enhanced montelukast performance, by increasing its bioavailability and physico-chemical stability. A wide variety of strategies can be found, from the formation of supramolecular adducts with cyclodextrins to encapsulation in nanoparticles and liposomes. The new dosage forms for montelukast are designed for non-enteric absorption, some for absorption in the oral cavity and another two being for local action in the nasal mucosa or in the pulmonary epithelium. The review describes the emerging delivery strategies to circumvent the current limitations to the use of montelukast that are expected to ultimately lead to the development of more patient-compliant dosage forms

Measuring routine childhood vaccination coverage in 204 countries and territories, 1980-2019: a systematic analysis for the Global Burden of Disease Study 2020, Release 1

Background: Measuring routine childhood vaccination is crucial to inform global vaccine policies and programme implementation, and to track progress towards targets set by the Global Vaccine Action Plan (GVAP) and Immunization Agenda 2030. Robust estimates of routine vaccine coverage are needed to identify past successes and persistent vulnerabilities. Drawing from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020, Release 1, we did a systematic analysis of global, regional, and national vaccine coverage trends using a statistical framework, by vaccine and over time. // Methods: For this analysis we collated 55 326 country-specific, cohort-specific, year-specific, vaccine-specific, and dose-specific observations of routine childhood vaccination coverage between 1980 and 2019. Using spatiotemporal Gaussian process regression, we produced location-specific and year-specific estimates of 11 routine childhood vaccine coverage indicators for 204 countries and territories from 1980 to 2019, adjusting for biases in country-reported data and reflecting reported stockouts and supply disruptions. We analysed global and regional trends in coverage and numbers of zero-dose children (defined as those who never received a diphtheria-tetanus-pertussis [DTP] vaccine dose), progress towards GVAP targets, and the relationship between vaccine coverage and sociodemographic development. // Findings: By 2019, global coverage of third-dose DTP (DTP3; 81·6% [95% uncertainty interval 80·4–82·7]) more than doubled from levels estimated in 1980 (39·9% [37·5–42·1]), as did global coverage of the first-dose measles-containing vaccine (MCV1; from 38·5% [35·4–41·3] in 1980 to 83·6% [82·3–84·8] in 2019). Third-dose polio vaccine (Pol3) coverage also increased, from 42·6% (41·4–44·1) in 1980 to 79·8% (78·4–81·1) in 2019, and global coverage of newer vaccines increased rapidly between 2000 and 2019. The global number of zero-dose children fell by nearly 75% between 1980 and 2019, from 56·8 million (52·6–60·9) to 14·5 million (13·4–15·9). However, over the past decade, global vaccine coverage broadly plateaued; 94 countries and territories recorded decreasing DTP3 coverage since 2010. Only 11 countries and territories were estimated to have reached the national GVAP target of at least 90% coverage for all assessed vaccines in 2019. // Interpretation: After achieving large gains in childhood vaccine coverage worldwide, in much of the world this progress was stalled or reversed from 2010 to 2019. These findings underscore the importance of revisiting routine immunisation strategies and programmatic approaches, recentring service delivery around equity and underserved populations. Strengthening vaccine data and monitoring systems is crucial to these pursuits, now and through to 2030, to ensure that all children have access to, and can benefit from, lifesaving vaccines

The genetic epidemiology of joint shape and the development of osteoarthritis

Congruent, low-friction relative movement between the articulating elements of a synovial joint is an essential pre-requisite for sustained, efficient, function. Where disorders of joint formation or maintenance exist, mechanical overloading and osteoarthritis (OA) follow. The heritable component of OA accounts for ~ 50% of susceptible risk. Although almost 100 genetic risk loci for OA have now been identified, and the epidemiological relationship between joint development, joint shape and osteoarthritis is well established, we still have only a limited understanding of the contribution that genetic variation makes to joint shape and how this modulates OA risk. In this article, a brief overview of synovial joint development and its genetic regulation is followed by a review of current knowledge on the genetic epidemiology of established joint shape disorders and common shape variation. A summary of current genetic epidemiology of OA is also given, together with current evidence on the genetic overlap between shape variation and OA. Finally, the established genetic risk loci for both joint shape and osteoarthritis are discussed

Influence of cell spreading and contractility on stiffness measurements using AFM

Atomic Force Microscopy (AFM) is widely used for measuring mechanical properties of cells, and to understand how cells respond to their mechanical environments. A standard method for obtaining cell stiffness from experimental force-indentation curves is based on the simplified Hertz theory developed for studying the indentation of a semi-infinite elastic body by a spherical punch, assumptions that do not hold for biological cells. The modified Hertz theory developed by Dimitriadis et al., which takes the finite sample height into account, is widely used by experimentalists for greater accuracy. However, neither of these two models account for the finite lateral spread of the cells and cellular contractility. In this paper, we address the influence of cell geometry, cell pre-stress, and nuclear properties on cell stiffness measurements by modeling indentation of a cell of prescribed geometry with a spherical AFM probe using the finite element method. Using parametric studies, we develop scaling relationships between the effective stiffness probed by AFM and the bulk cell stiffness, taking cell and tip geometry into account. Taken together, our results demonstrate the need to take cell geometry into account while estimating the cell stiffness and provide simple expressions for doing so

Cellular mechanoadaptation to substrate mechanical properties: contributions of substrate stiffness and thickness to cell stiffness measurements using AFM

Mechanosensing by adherent cells is usually studied by quantifying cell responses on hydrogels that are covalently linked to a rigid substrate. Atomic force microscopy (AFM) represents a convenient way of characterizing the mechanoadaptation response of adherent cells on hydrogels of varying stiffness and thickness. Since AFM measurements reflect the effective cell stiffness, therefore, in addition to measuring real cytoskeletal alterations across different conditions, these measurements might also be influenced by the geometry and physical properties of the substrate itself. To better understand how the physical attributes of the gel influence AFM stiffness measurements of cells, we have used finite element analysis to simulate the indentation of cells of various spreads resting on hydrogels of varying stiffness and thickness. Consistent with experimental results, our simulation results indicate that for well spread cells, stiffness values are significantly over-estimated when experiments are performed on cells cultured on soft and thin gels. Using parametric studies, we have developed scaling relationships between the effective stiffness probed by AFM and the bulk cell stiffness, taking cell and tip geometry, hydrogel properties, nuclear stiffness and cell contractility into account. Finally, using simulated mechanoadaptation responses, we have demonstrated that a cell stiffening response may arise purely due to the substrate properties. Collectively, our results demonstrate the need to take hydrogel properties into account while estimating cell stiffness using AFM indentation

Force generation and step-size fluctuations in a dynein motor

Molecular motors such as dynein are known to move by taking steps of different sizes, depending on the load. Here, we develop a simple, discrete, minimal ratchet model for a motor that can take steps of sizes delta(o) and 2 delta(o) in order to provide a bare-bones description of dynein. We obtain the force-velocity curves and diffusivity for this motor for different concentrations of ATP. We also study the mechano-chemical energy transduction and thermodynamic efficiency of the motor. Further, by investigating the statistics of step sizes for the motor, we show that the average step size and fluctuation in step sizes have a non-monotonic force dependence. We develop closed-form analytical expressions for all our results, which despite the simplicity of the model give a reasonable match with the known experiments and simulations on dynein

Investigation of the internal stress effects on static and dynamic characteristics of an electrostatically actuated beam for MEMS and NEMS application

Internal stress is often encountered in fixed-fixed beam based devices with micron or sub-micron length scales during device fabrication or operation. In this paper, we have investigated the effects of internal stress on static and dynamic characteristics of an electrostatically actuated cylindrical beam. The beam has been modelled using Euler-Bernoulli theory including the nonlinearities due to beam stretching and electrostatic forcing. The analysis has been carried out by solving the governing differential equations using a Galerkin based multi-modal reduced order modelling technique. A standard collocation based numerical scheme has also been used to confirm the results of the reduced order method. Our study shows that internal stress significantly influences the static and dynamic characteristics of the beam. We also find that, when compressive internal stress is high, it is important to include higher modes in the reduced order model. A design technique to achieve high resonant frequency stability under temperature variation, for electrostatically actuated beam oscillators, has also been proposed as a result of this investigation