Optimizing anisotropic transport on bioinspired sawtooth surfaces.

Species ranging from butterflies and other insects, to cactuses and lotus plants have evolved to use geometrically patterned surfaces to influence the transport of water droplets. While this phenomenon is well known, an ideal geometry has yet to be discovered. To determine the impact of surface geometry on droplet transport, we have studied the contact angle and droplet motion across anisotropically wetting patterned surfaces. The surface geometries tested were sawtooth patterns with angles (8.62-26.70°) and lengths (0.56-1.67 µm). The droplet contact angles were measured on 45° angled surfaces to simulate the droplet in motion. Velocities were measured using a high-speed camera shooting at 500 frames per second and the tailing edges of the droplets were hand tracked over 18 frames. It was found that travel along the sawtooth ridges is significantly faster than travel against the ridges for geometries with shallow angles. The optimal geometry was determined to be α = 8.62° and b = 1.67 µm and was replicated using nanoimprint lithography using materials with different surface energies. When replicated with acrylate resins and PDMS, the contact angles remained high, regardless of wettability, but we find that the overall velocity and velocity hysteresis depends on the hydrophobicity. More hydrophobic surfaces have overall higher hysteresis. The ability to tune imprinted surfaces to achieve ideal wetting characteristics using geometry will lead to interesting anisotropic material design.

Effect of Polymer Gel Elasticity on Complex Coacervate Phase Behavior.

Gels are key materials in biological systems such as tissues and may control biocondensate formation and structure. To further understand the effects of elastic environments on biomacromolecular assembly, we have investigated the phase behavior and radii of complex coacervate droplets in polyacrylamide (PAM) networks as a function of gel modulus. Poly-l-lysine (PLL) and sodium hyaluronate (HA) complex coacervate phases were prepared in PAM gels with moduli varying from 0.035 to 15.0 kPa. The size of the complex coacervate droplets is reported from bright-field microscopy and confocal fluorescence microscopy. Overall, the complex coacervate droplet volume decreases inversely with the modulus. Fluorescence microscopy is also used to determine the phase behavior and concentration of fluorescently tagged HA in the complex coacervate phases as a function of ionic strength (100-270 mM). We find that the critical ionic strength and complex coacervate stability are nonmonotonic as a function of the network modulus and that the local gel concentration can be used to control phase behavior and complex coacervate droplet size scale. By understanding how elastic environments influence simple electrostatic assembly, we can further understand how biomacromolecules exist in complex, crowded, and elastic cellular environments.

Ionic environment effects on collagen type II persistence length and assembly.

Collagen type II is a main structural protein in cartilage and forms fibrils. The radius of the fibrils ranges from 50 nm to a few hundred nm, and previous theoretical studies point to electrostatics and collagen elasticity (measured as the persistence length, lp) as the main origin for the self-limiting size scales. In this study, we have investigated the collagen triple helical structure and fibril size scales in pH 2 solutions with varying NaCl concentrations from 10-4 to 100 mM, at which collagen is positively charged, and in pH 7.4 solutions, with varying ionic strengths from 100 to 250 mM, at which collagen is both positively and negatively charged. Using static and dynamic light scattering, the radius of gyration (Rg), hydrodynamic radius (Rh), and second virial coefficient (A2) of collagen triple helices are determined, and lp is calculated. With increasing ionic strength, triple helical lp decreases in pH 2 solutions and increases in pH 7.4 solutions. The value ranges from 60 to 100 nm depending on the ionic environment, but at the salt concentration at which A2 is near zero, there are no net backbone interactions in solution, and the intrinsic collagen triple helix lp is determined to be 90-95 nm. Electron microscopy is used to determine the diameter of fibrils assembled in pH 7.4 conditions, and we compare lp of the collagen triple helices and fibril diameter using recent theory on fibril assembly. By better understanding collagen lp and fibril assembly, we can further understand mechanisms of biomacromolecule self-assembly.

Effects of Molecular Weight and Surface Interactions on Polymer Diffusion in Confinement.

Understanding the transport and thermodynamics of polymers in confined spaces is helpful for many separation processes like water purification, drug delivery, and oil recovery. Specifically, for water purification, dextran has been used as a "model" foulant. Uncovering how these polymers interact in confinement can reduce the fouling of organic membranes and will lead to better separation processes overall. We have determined the diffusion coefficient, D, of dextran and sodium polyacrylate in convex lens-induced confinement using differential dynamic microscopy. In this setup, the gap height ranges continuously from 0.077-21.8 µm. It was found that polymer diffusion becomes slower in higher confinement, which is consistent with a change in the increase of the hydrodynamic resistance to macromolecule motion and depends on the surface properties. These findings indicate that dextran diffusion changes in confinement and can lead to a better understanding of separation processes.

Persistence length of α-helical poly-L-lysine.

The α-helix has a significant role in protein function and structure because of its rigidity. In this study, we investigate the persistence length, lp, of α-helical poly-L-lysine, PLL, for two molecular weights. PLL experiences a random coil-helix transition as the pH is raised from 7 to 12. Using light scattering experiments to determine the radius of gyration (Rg), hydrodynamic radius, (Rh), the shape factor (Rg/Rh), and second virial coefficient (A2), and circular dichroism to determine the helical content, we find the structure and lp of PLL as a function of pH (7.4-11.4) and ionic strength (100-166 mM). With increasing pH, we find an increase in lp from 2 nm to 15-21 nm because of α-helix formation. We performed dissipative particle dynamics (DPD) simulations and found a similar increase in lp. While this lp is less than that predicted by molecular dynamics simulations, it is consistent with other experimental results, which quantify the mechanics of α-helices. By determining the mechanics of helical polypeptides like PLL, we can further understand their implications to protein function.

Spatially-Resolved Network Dynamics of Poly(vinyl alcohol) Gels Measured with Dynamic Small Angle Light Scattering.

Hydrogels are cross-linked polymer networks swollen in water. The large solvent content enables hydrogels to have unique physical properties and allows them to be used in diverse applications such as tissue engineering, drug delivery, and absorbents. Gel properties are linked to internal dynamics. While bulk gel dynamics have been studied extensively, how gel networks respond locally to deformation has yet to be understood. Here, poly(vinyl alcohol) (PVA) gels have been stretched to study the effects of deformation on gel dynamics parallel and perpendicular to the stretching direction using dynamic small angle light scattering (DSALS). The implementation of DSALS is described and compared to traditional DLS for PVA gels with different crosslink densities, ranging from 0.75-2%. Despite the orders of magnitude difference in the scattering vector, q, range of the techniques, the dynamics match, and the apparent elastic diffusion coefficient, DA increases linearly with the crosslink density for unstretched gels at a constant 2 wt% concentration. We observe that the elastic motion depends on the direction of stretch, decreasing perpendicular to stretching and increasing at parallel direction. Using DSALS can therefore be an effective tool to evaluate local hydrogel response to deformation.

How statistics became a "forbidden trick" for Soviet psychologists.

This study reconstructs the process by which quantitative methods were gradually displaced from Russian psychology in the early Soviet period. By the early 1930s, there was a decline in the importance of mathematical methods in psychological disciplines. It was accompanied by the rejection of some mathematical methods and the ideologization of the description of quantitative methodology. After the Central Committee's decree "O pedologicheskikh izvrashcheniyakh v sisteme Narkomprosov" ("On Pedological Perversions in the System of Narkomproses") of 1936 was published in the pages of national newspapers, statistical practice was completely discredited. At the same time, textbooks on statistics in psychological disciplines were withdrawn from circulation. Scientists' attempts to defend the neutrality of scientific methods were unsuccessful and were publicly criticized. As a result, statistical practice almost completely disappeared from psychological disciplines after 1936, although there was no outright ban on the use of statistics. There are two possible reasons for this. First, psychologists may have abandoned statistical practices as a result of ideological pressure. Second, owing to the elimination of mathematical methods, internal disciplinary contradictions-in particular, those characteristic of pedology-were eliminated. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Diffusive dynamics of charged nanoparticles in convex lens-induced confinement.

Transport through heterogeneous confined geometries is encountered in many processes and applications such as filtration, drug delivery, and enhanced oil recovery. We have used differential dynamic microscopy (DDM) and particle tracking to investigate dynamics of 36 nm negatively-charged polystyrene particles in convex lens-induced confinement (CLiC). The confinement gap height was controlled from 0.085 µm to 3.6 mm by sandwiching the aqueous particle solution between a glass coverslip and a convex lens using a homemade sample holder. With an inverted fluorescence microscope, sequences of micrographs were taken at various radial positions and gap heights for five particle concentrations (i.e. φ = 0.5 × 10-5, 1 × 10-5, 5 × 10-5, 10 × 10-5, 50 × 10-5) and ionic strengths ranging from 10-3 to 150 mM. The resulting image structure functions were fitted with a simple exponential model to extract the ensemble-averaged diffusive dynamics. It was found that particle diffusion was more hindered as a function of increased confinement. In addition, the ensemble-averaged diffusion coefficient was found to depend on the bulk concentration, and the concentration dependence increased as a function of confinement. Increasing particle and salt concentration led to confinement-dependent adsorption onto the geometry surface. Overall, we show that CLiC devices are simple and effective and can be used to study dynamics in continuous confinement from sub 100 nm to 100's of µm. These findings could lead to better understanding of separations and interactions in confining devices.

Electrostatic effects in collagen fibril formation.

Using light scattering and Atomic Force Microscopy techniques, we have studied the kinetics and equilibrium scattering intensity of collagen association, which is pertinent to the vitreous of the human eye. Specifically, we have characterized fibrillization dependence on pH, temperature, and ionic strength. At higher and lower pH, collagen triple helices remain stable in solution without fibrillization. At physiological pH, fibrillization occurs and the fibril growth is slowed upon either an increase in ionic strength or a decrease in temperature. The total light scattering with respect to ionic strength is non-monotonic in these conditions as a result of a competing dependence of fibril concentration and size on ionic strength. Fibril concentration is the highest at lower ionic strengths and rapidly decays for higher ionic strengths. On the other hand, fibril size is larger in solutions with higher ionic strength. We present a theoretical model, based on dipolar interactions in solutions, to describe the observed electrostatic nature of collagen assembly. At extreme pH values, either very low or very high, collagen triple helices carry a large net charge of the same sign preventing their assembly into fibrils. At intermediate pH values, fluctuations in the charge distribution of the collagen triple helices around roughly zero net charge lead to fibrillization. The growth kinetics of fibrils in this regime can be adequately described by dipolar interactions arising from charge fluctuations.

Gelation, Phase Separation, and Fibril Formation in Aqueous Hydroxypropylmethylcellulose Solutions.

The thermoresponsive behavior of a hydroxypropylmethylcellulose (HPMC) sample in aqueous solutions has been studied by a powerful combination of characterization tools, including rheology, turbidimetry, cryogenic transmission electron microscopy (cryoTEM), light scattering, small-angle neutron scattering (SANS), and small-angle X-ray scattering (SAXS). Consistent with prior literature, solutions with concentrations ranging from 0.3 to 3 wt % exhibit a sharp drop in the dynamic viscoelastic moduli G' and G″ upon heating near 57 °C. The drop in moduli is accompanied by an abrupt increase in turbidity. All the evidence is consistent with this corresponding to liquid-liquid phase separation, leading to polymer-rich droplets in a polymer-depleted matrix. Upon further heating, the moduli increase, and G' exceeds G″, corresponding to gelation. CryoTEM in dilute solutions reveals that HPMC forms fibrils at the same temperature range where the moduli increase. SANS and SAXS confirm the appearance of fibrils over a range of concentration, and that their average diameter is ca. 18 nm; thus gelation is attributable to formation of a sample-spanning network of fibrils. These results are compared in detail with the closely related and well-studied methylcellulose (MC). The HPMC fibrils are generally shorter, more flexible, and contain more water than with MC, and the resulting gel at high temperatures has a much lower modulus. In addition to the differences in fibril structure, the key distinction between HPMC and MC is that the former undergoes liquid-liquid phase separation prior to forming fibrils and associated gelation, whereas the latter forms fibrils first. These results and their interpretation are compared with the prior literature, in light of the relatively recent discovery of the propensity of MC and HPMC to self-assemble into fibrils on heating.

Extensional Flow Behavior of Methylcellulose Solutions Containing Fibrils.

The extensional properties of semidilute aqueous methylcellulose (MC) solutions have been characterized. Pure aqueous MC solutions are shear-thinning liquids at room temperature. With the addition of 8 wt % NaCl, a fraction of MC self-assembles into long fibrils, which modify the rheological properties of the original MC solution. Capillary Breakup Extensional Rheometry (CaBER) was used to characterize salt-free and 8 wt % NaCl solutions of MC at room temperature. The salt-free solutions exhibit only power-law behavior whereas solutions with NaCl exhibit both power-law and elastic regimes. As MC concentration increases, the extensional relaxation time also increases strongly, from 0.04 s at 0.5 wt % to 4 s at 1 wt %. In addition, the apparent extensional viscosity rapidly increases as a function of increasing MC concentration, from 40 Pa·s at 0.5 wt % to 1300 Pa·s at 1 wt %. This behavior is attributed to the presence of fibrils in the MC solutions containing NaCl.

Effectiveness of betahistine (48 mg/day) in patients with vestibular vertigo during routine practice: The VIRTUOSO study.

BACKGROUND: Vestibular vertigo is associated with substantially reduced quality of life. Betahistine is effective in improving vertigo-associated symptoms, with longer treatment periods leading to greater improvements; however, it is not known whether these effects persist after treatment cessation. METHODS: VIRTUOSO was a prospective, multinational, non-comparative, post-marketing observational programme investigating the effectiveness of betahistine (48 mg/day) and the course of vertigo after the discontinuation of treatment. Patients with vestibular vertigo who were prescribed 48 mg/day betahistine were enrolled in Russia and Ukraine. Treatment duration was up to 2 months, and patients were followed up for 2 months after discontinuation of betahistine. Efficacy endpoints included clinical response (assessed by change in vertigo severity), monthly attack frequency, and physician and patient grading of overall clinical response and improvement of vertigo-associated symptoms. RESULTS: Overall, 309 patients were enrolled and 305 completed the study. Clinical response was rated as good, very good or excellent in 74.1% of patients at end of treatment, with vertigo severity significantly decreased from baseline (p < 0.001). Monthly vertigo attack frequency decreased significantly during the 2 months of treatment (p < 0.001 from baseline) and further decreased during the 2-month follow-up (p < 0.001 from end of treatment). Overall, clinical response was graded as good or excellent by 94.4% of physicians and 95.4% of patients. Clinical improvement was considered either good or excellent by 82.6-90.5% of physicians and patients for nausea, vomiting and faintness. Only one adverse event was reported, with no serious adverse events. CONCLUSION: Our findings suggest that betahistine (48 mg/day) therapy is effective in treating vertigo in routine clinical settings. The observed effects persisted for 2 months after treatment cessation, suggesting that betahistine may facilitate lasting vestibular compensation.

Conformation of Methylcellulose as a Function of Poly(ethylene glycol) Graft Density.

Low molecular weight thiol-terminated poly(ethylene glycol) (PEG) (M ≈ 800) has been grafted onto a high molecular weight methylcellulose (MC, Mw ≈ 150000) by a facile thiol-ene click reaction; graft densities varied from 0.7% to 33% (grafts per anhydroglucose unit). Static and dynamic light scattering reveals that the overall radius of the chain increases systematically with graft density, in a manner in excellent agreement with theory. As the contour length remains unchanged, it is apparent that grafting leads to an increase in the persistence length of this semiflexible copolymer, by as much as a factor of 4. These results represent the first experimental verification of the excluded volume theory at low grafting densities, and demonstrate a promising synthetic platform for systematically increasing the persistence length of a model semiflexible, water-soluble polymer.

Effects and safety profile of betahistine in patients in the Russian contingent of OSVaLD, an open-label observational study in vestibular vertigo.

BACKGROUND: We report here data from the >200 patients recruited in Russia to take part in OSVaLD, a 12-week, open-label, post-marketing surveillance study of the response to betahistine 48 mg/day in vertigo of peripheral vestibular origin carried out in a total of 13 countries. METHODS: The primary efficacy endpoint was change in the Dizziness Handicap Inventory (DHI; 100-point scale). Changes in Hospital Anxiety and Depression Scale (HADS) and Medical Outcomes Study Short-Form 36, version 2 (SF-36v2(®)) scores were a priori secondary Outcomes. RESULTS: Total DHI score improved by 43 points during betahistine treatment. This aggregate improvement was equally distributed across the three domains of the DHI (physical, emotional, and functional; P<0.0001 for main and subscore changes from baseline). Statistically significant improvements versus baseline were also observed in mean HADS scores for anxiety and depression (both P<0.0001), and in the Physical Component Summary and Mental Component Summary scores of the SF-36v2 (both P<0.0001 versus baseline). Only one suspected adverse drug reaction was recorded in the Russian safety population (n=204), indicating that betahistine was well tolerated in those patients. CONCLUSION: Betahistine 48 mg/day was associated with clear improvements in well-configured and widely validated measures of health-related quality of life and an encouraging tolerability profile in patients in Russia who took part in OSVaLD.

Active and passive stabilization of body pitch in insect flight.

Flying insects have evolved sophisticated sensory-motor systems, and here we argue that such systems are used to keep upright against intrinsic flight instabilities. We describe a theory that predicts the instability growth rate in body pitch from flapping-wing aerodynamics and reveals two ways of achieving balanced flight: active control with sufficiently rapid reactions and passive stabilization with high body drag. By glueing magnets to fruit flies and perturbing their flight using magnetic impulses, we show that these insects employ active control that is indeed fast relative to the instability. Moreover, we find that fruit flies with their control sensors disabled can keep upright if high-drag fibres are also attached to their bodies, an observation consistent with our prediction for the passive stability condition. Finally, we extend this framework to unify the control strategies used by hovering animals and also furnish criteria for achieving pitch stability in flapping-wing robots.

Drug discovery and development for spinal muscular atrophy: lessons from screening approaches and future challenges for clinical development.

Spinal muscular atrophy (SMA) is a progressive pediatric neuromuscular disease. Because disease severity is related to survival motor neuron (SMN) protein levels, increasing SMN production from the SMN2 gene has been a major SMA drug-discovery strategy. Cell-based assays using neuronal cell lines and cells from SMA patients have identified compounds that can increase SMN protein expression. Our experience of using such an assay signaled potential risks to be avoided through the use of appropriate secondary assays. In addition to the 'SMN2' approach, compensating for decreased SMN protein or neuroprotection are also potential SMA drug-discovery strategies. SMA clinical trials are now a reality; however, trial design in a slowly progressing rare disease such as SMA will present an interesting future challenge.

Argon protects hypoxia-, cisplatin- and gentamycin-exposed hair cells in the newborn rat's organ of Corti.

During the last few years, an important protective effect of the noble gas xenon against neuronal hypoxic damage was observed. However, argon (Ar), a gas from the same chemical group, but less expensive and without anesthetic effect at normobaric pressure, has not been studied in terms of possible biological effects on cell protection. Ar was tested for its ability to protect organotypic cultures of the organ of Corti from 3-5 day old rats against hypoxia, cisplatin, and gentamycin toxicity. Cultures were exposed to nitrogen hypoxia (5% CO2, 95% N2), Ar hypoxia (5% CO2, 95% Ar) or normoxia for 30 h. Ar protected the hair cells from hypoxia-induced damage by about 25%. Ar-oxygen (O2) mixtures (21% O2, 5% CO2, 74% Ar) had no effect on the hair cell survival. Cisplatin (7.5-25 microM) and gentamycin (5-40 microM) exposed in medium under air damaged the hair cells in a dose-dependent manner. The exposure of cisplatin- and gentamycin-treated cultures to the Ar-O2 atmosphere significantly reduced the hair cell damage by up to 25%. This protective effect of Ar might provide a new protective approach against ototoxic processes.

[Cholesterol metabolism modulators in future drug therapy for atherosclerosis]. / Modulateurs du métabolisme du cholestérol et avenir du traitement de l'athérosclérose.

Atherosclerosis is a disease characterized by lipid accumulation in the vascular wall leading to myocardial infarction or stroke. Hypercholesterolemia is an important risk factor and current treatments are largely based on cholesterol lowering. In spite of proven efficacy of existing drugs, like statins, cardiovascular diseases still remain the most common cause of death in industrialised countries. Many new molecular targets are being studied to improve atherosclerosis treatment and reduce the number of deaths. The action on these targets could lead to a decrease of blood cholesterol levels or produce a direct anti-atherosclerotic effect on the vascular wall. A cholesterol lowering effect could be achieved by reducing cholesterol synthesis (squalene synthase inhibitors), intestinal cholesterol absorption as well as intestinal and liver lipoprotein secretion (microsomal transfer protein inhibitors, acyl-coenzyme A-cholesterol acyltransferase inhibitors) or by increasing fecal excretion of bile acids (ileal sodium-dependent bile acid transporter inhibitors). An anti-atherosclerotic effect on the vascular wall could be achieved by reducing the inflammation via activation of peroxisome proliferator activated receptors, or, more particularly, could consist of decreased expression of adhesion molecules and chemoattractant proteins. Increasing the adenosine triphosphate-binding cassette A1 protein and inhibiting acylcoenzyme A:cholesterol acyltransferase 1 activity could slow down formation of foam cells, which are a hallmark of atherosclerosis. Finally, the cholesterol fraction carried by high density lipoproteins, which is inversely correlated to cardiovascular risk, could be increased by cholesterol ester transfer protein inhibitors. All of these new classes of compounds are currently studied by pharmaceutical companies and are in different phases of development (preclinical or clinical).

[Cholesterol metabolism modulators and the future of atherosclerosis therapy]. / Modulateurs du métabolisme du cholestérol et avenir du traitement de l'athérosclérose.

Atherosclerosis is a disease characterized by lipid accumulation in the vascular wall leading to myocardial infarction or stroke. Hypercholesterolemia is an important risk factor and current treatments are largely based on cholesterol lowering. In spite of proven efficacy of existing drugs, like statins, cardiovascular diseases still remain the most common cause of death in industrialised countries. Many new molecular targets are being studied to improve atherosclerosis treatment and reduce the number of deaths. The action on these targets could lead to a decrease of blood cholesterol levels or produce a direct anti-atherosclerotic effect on the vascular wall. A cholesterol lowering effect could be achieved by reducing cholesterol synthesis (squalene synthase inhibitors), intestinal cholesterol absorption as well as intestinal and liver lipoprotein secretion (microsomal transfer protein inhibitors, acyl-coenzyme A-cholesterol acyltransferase inhibitors) or by increasing fecal excretion of bile acids (ileal sodium-dependent bile acid transporter inhibitors). An anti-atherosclerotic effect on the vascular wall could be achieved by reducing the inflammation via activation of peroxisome proliferator activated receptors, or, more particularly, could consist of decreased expression of adhesion molecules and chemoattractant proteins. Increasing the adenosine triphosphate-binding cassette A1 protein and inhibiting acyl-coenzyme A :cholesterol acyltransferase 1 activity could slow down formation of foam cells, which are a hallmark of atherosclerosis. Finally, the cholesterol fraction carried by high density lipoproteins, which is inversely correlated to cardiovascular risk, could be increased by cholesterol ester transfer protein inhibitors. All of these new classes of compounds are currently studied by pharmaceutical companies and are in different phases of development (preclinical or clinical).