Regularized Bennett and Zwanzig free energy estimators.

We consider the problem of free energy estimation from the general perspective of regularization and Bayes estimation theory. We try to take advantage of an assumed a priori knowledge of the free energy. We reformulate the original Bennett acceptance ratio method, in this perspective, devise a numerical algorithm to solve it, and give a closed formula to estimate the confidence in the prior. Finally, we test the derived estimators by applying them to a toy model.

Optimal Transport for Free Energy Estimation.

Optimal transport theory is a growing field of mathematics, which has recently found many applications. Here we take advantage of optimal transport for computational free energy estimation. We show analytically, and then via simulation, that this approach is effective in terms of optimizing the barriers of an alchemical transformation.

Modified haemagglutination inhibition assay for the detection of canine parvovirus type 2 antibodies in dog sera.

Canine parvovirus type 2 (CPV-2) infection is associated with severe gastroenteritis in puppies. Quantification of CPV-2 specific antibodies before vaccination can reveal the presence of interfering maternal-derived immunity and facilitate timing of effective immunisation. Inhibition of haemagglutination (HI) is commonly used to measure CPV-2-specific antibody levels in serum. However, the presence of nonspecific agglutinins in canine serum and artefactual precipitation of red blood cells (RBC) are both limitations of the assay. In this study, we compared the standard HI protocol with a refined HI protocol, in which canine serum was pre-incubated with porcine RBC for 12 h to remove nonspecific agglutinins and a lower concentration (0.1% vs. 0.8%) of porcine RBC suspensions was used to limit artefactual precipitation of RBC. A panel of canine sera, collected from 80 dogs of different ages and with different neutralising antibody titres, was analysed. Nonspecific agglutinins were identified in most (97%) serum samples from puppies <4 months of age and in only 7% dogs 6 months old. Pre-treatment of serum samples was effective in removing nonspecific agglutinins from all samples and artefactual precipitation of RBCs was not noted when 0.1% RBC suspensions were used. Refinement of the HI protocol has increased the accuracy of interpretation and reduced the interference of nonspecific agglutinins, primarily seen in puppies. This reduces the likelihood of incorrect assessment of passive or active immunity in puppies when deciding whether to administer or defer vaccination, which could potentially leave them susceptible to CPV-2 infection.

Computational analysis of the effect of [Tea][Ms] and [Tea][H2PO4] ionic liquids on the structure and stability of Aß(17-42) amyloid fibrils.

Experimental studies have reported the possibility of affecting the growth/dissolution of amyloid fibres by the addition of organic salts of the room-temperature ionic-liquid family, raising the tantalizing prospect of controlling these processes under physiological conditions. The effect of [Tea][Ms] and [Tea][H2PO4] at various concentrations on the structure and stability of a simple model of Aß42 fibrils has been investigated by computational means. Free energy computations show that both [Tea][Ms] and [Tea][H2PO4] decrease the stability of fibrils with respect to isolated peptides in solution, and the effect is significantly stronger for [Tea][Ms]. The secondary structure of fibrils is not much affected, but single peptides in solution show a marked decrease in their ß-strand character and an increase in α-propensity, again especially for [Tea][Ms]. These observations, consistent with the experimental picture, can be traced to two primary effects, i.e., the difference in the ionicity of the [Tea][Ms] and [Tea][H2PO4] water solutions and the remarkable affinity of peptides for [Ms]- anions, due to the multiplicity of H-bonds.

Solubility Advantage of Amorphous Ketoprofen. Thermodynamic and Kinetic Aspects by Molecular Dynamics and Free Energy Approaches.

Thermodynamic and kinetic aspects of crystalline (c-KTP) and amorphous (a-KTP) ketoprofen dissolution in water have been investigated by molecular dynamics simulation focusing on free energy properties. Absolute free energies of all relevant species and phases have been determined by thermodynamic integration on a novel path, first connecting the harmonic to the anharmonic system Hamiltonian at low T and then extending the result to the temperature of interest. The free energy required to transfer one ketoprofen molecule from the crystal to the solution is in fair agreement with the experimental value. The absolute free energy of the amorphous form is 19.58 kJ/mol higher than for the crystal, greatly enhancing the ketoprofen concentration in water, although as a metastable species in supersaturated solution. The kinetics of the dissolution process has been analyzed by computing the free energy profile along a reaction coordinate bringing one ketoprofen molecule from the crystal or amorphous phase to the solvated state. This computation confirms that, compared to the crystal form, the dissolution rate is nearly 7 orders of magnitude faster for the amorphous form, providing one further advantage to the latter in terms of bioavailability. The problem of drug solubility, of great practical importance, is used here as a test bed for a refined method to compute absolute free energies, which could be of great interest in biophysics and drug discovery in particular.

Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532).

BACKGROUND: Cell entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) depends on binding of the viral spike (S) proteins to angiotensin-converting enzyme 2 and on S protein priming by TMPRSS2. Inhibition of TMPRSS2 may work to block or decrease the severity of SARS-CoV-2 infections. Intriguingly, TMPRSS2 is an androgen-regulated gene that is up-regulated in prostate cancer where it supports tumor progression and is involved in a frequent genetic translocation with the ERG gene. First- or second-generation androgen-deprivation therapies (ADTs) decrease the levels of TMPRSS2. Here we put forward the hypothesis that ADTs may protect patients affected by prostate cancer from SARS-CoV-2 infections. MATERIALS AND METHODS: We extracted data regarding 9280 patients (4532 males) with laboratory-confirmed SARS-CoV-2 infection from 68 hospitals in Veneto, one of the Italian regions that was most affected by the coronavirus disease 2019 (COVID-19) pandemic. The parameters used for each COVID-19-positive patient were sex, hospitalization, admission to intensive care unit, death, tumor diagnosis, prostate cancer diagnosis, and ADT. RESULTS: There were evaluable 9280 SARS-CoV-2-positive patients in Veneto on 1 April 2020. Overall, males developed more severe complications, were more frequently hospitalized, and had a worse clinical outcome than females. Considering only the Veneto male population (2.4 million men), 0.2% and 0.3% of non-cancer and cancer patients, respectively, tested positive for SARS-CoV-2. Comparing the total number of SARS-CoV-2-positive cases, prostate cancer patients receiving ADT had a significantly lower risk of SARS-CoV-2 infection compared with patients who did not receive ADT (OR 4.05; 95% CI 1.55-10.59). A greater difference was found comparing prostate cancer patients receiving ADT with patients with any other type of cancer (OR 4.86; 95% CI 1.88-12.56). CONCLUSION: Our data suggest that cancer patients have an increased risk of SARS-CoV-2 infections compared with non-cancer patients. However, prostate cancer patients receiving ADT appear to be partially protected from SARS-CoV-2 infections.

Oral administration of modified live canine parvovirus type 2b induces systemic immune response.

Different strategies have been proposed to overcome maternally derived antibody (MDA) interference with canine parvovirus type 2 (CPV-2) immunisation, including intranasal vaccination, which presents some practical limitations. In the present study, the results of the oral administration of a commercial CPV-2b modified live virus (MLV) vaccine in pups with MDA are reported. The CPV-2b vaccine was orally administered to 14 6-week-old pups with a bait. Blood samples and rectal swabs were collected at different days post-vaccination (dpv) to determine CPV-2 antibody titres and DNA loads. Thirteen pups were positive to serological and virological tests after the first vaccination and one pup became positive after the second vaccine administration. The findings of this study suggest that systemic immunity against CPV-2 may be achieved by the use of an MLV CPV-2b vaccine administered orally even in the presence of MDA titres that usually interfere with vaccination.

In vitro virucidal activity of sodium hypochlorite against canine parvovirus type 2.

Canine parvovirosis is a very contagious, severe and often lethal infectious disease of dogs caused by canine parvovirus type 2 (CPV-2). Parvoviruses are very resistant to several disinfectants while are sensitive to halogens such as sodium hypochlorite which is often used for decontamination of veterinary clinics and animal housing facilities due to its broad spectrum of activity. If compliance with vaccination programmes and with proper disinfection plans is ensured, there should be no continuous, nor frequent, CPV-2 outbreaks in kennels and veterinary clinics. However, a continuous spread of CPV-2 infections is observed, even in kennels where an appropriate vaccination programme is applied, and this imposes a re-evaluation of disinfection protocols using sodium hypochlorite. The aim of the present study was to determine the effect of concentration, contact time and presence of organic matter on the virucidal activity of sodium hypochlorite against several CPV-2 strains. A sensitive in vitro assay capable of measuring the infectivity of CPV-2 was employed to determine the efficacy of three different concentrations of sodium hypochlorite. The data indicate that using a 0.75% sodium hypochlorite solution for a short contact time (1 min) can reduce significantly the CPV-2 titres and that even lower concentrations, i.e. 0.37%, can efficiently inactivate the viruses provided that the contact time is extended to 15 min. Results also confirm the importance of cleaning before disinfection since the presence of organic matter totally abrogated the virucidal activity of sodium hypochlorite solutions against the three CPV-2 strains.

Safety and efficacy of lithium in children and adolescents: A systematic review in bipolar illness.

INTRODUCTION: Many clinicians are reluctant to use traditional mood-stabilizing agents, especially lithium, in children and adolescents. This review examined the evidence for lithium's safety and efficacy in this population. METHODS: A systematic review was conducted on the use of lithium in children and adolescents with bipolar disorder (BD). Relevant papers published through June 30th 2018 were identified searching the electronic databases MEDLINE, Embase, PsycINFO and the Cochrane Library. RESULTS: 30 articles met inclusion criteria, including 12 randomized controlled trials (RCTs). Findings from RCTs demonstrate efficacy for acute mania in up to 50% of patients, and evidence of long-term maintenance efficacy. Lithium was generally safe, at least in the short term, with most common side effects being gastrointestinal, polyuria, or headache. Only a minority of patients experienced hypothyroidism. No cases of acute kidney injury or chronic kidney disease were reported. CONCLUSIONS: Though the available literature is mostly short-term, there is evidence that lithium monotherapy is reasonably safe and effective in children and adolescents, specifically for acute mania and for prevention of mood episodes.

Factors associated with Brazilian adolescents' satisfaction with oral health.

OBJECTIVE: To identify the sociodemographic, clinical and self-reported indicators of oral health associated with Brazilian adolescents' satisfaction with oral health. METHODS: Secondary data were used following the examination of 4,231 adolescents, aged 15 to 19 years, participating in a national oral health survey (SBBrasil 2010). The independent variables were grouped into demographics, predisposition/facilitation, oral health conditions and perceived dental treatment need. Satisfaction with oral health was considered the dependent variable. Ordinal logistic (multiple) regression models tested the variables in sequence (hierarchical), as per the conceptual model, assuming p≤0.05 as the criterion for remaining in the model (Wald test). Adjustment of the model was evaluated with the Akaike information criterion (AIC) and -2 Log L. RESULTS: Participants with perceived treatment need (OR=2.36, 95% CI = 2.14-2.61), toothache (OR=1.18, 1.10-1.28), presence of oral impacts on daily performance (OIDP) (OR= 1.55, 1.44-1.68), severe and very severe dental aesthetic index (DAI) (OR=1.17, 1.08-1.27), were female (OR=1.16, 1.10-1.23), were of black/brown ethnicity (OR=1.10, 1.04-1.17), and had caries in anterior (OR=1.20, 1.08-1.32) and posterior teeth (OR=1.22, 1.13-1.32) presented lower satisfaction with oral health. CONCLUSION: Satisfaction with oral health in Brazilian adolescents is linked to a multidimensional structure of factors that include demographic aspects, such as gender and ethnic group, self-perception aspects, such as perceived treatment need and oral health impact on daily activities, and clinical aspects, such as the presence of toothache, severe malocclusion and caries in anterior and posterior teeth.

Effective Surface Passivation of InP Nanowires by Atomic-Layer-Deposited Al2O3 with POx Interlayer.

III/V semiconductor nanostructures have significant potential in device applications, but effective surface passivation is critical due to their large surface-to-volume ratio. For InP such passivation has proven particularly difficult, with substantial depassivation generally observed following dielectric deposition on InP surfaces. We present a novel approach based on passivation with a phosphorus-rich interfacial oxide deposited using a low-temperature process, which is critical to avoid P-desorption. For this purpose we have chosen a POx layer deposited in a plasma-assisted atomic layer deposition (ALD) system at room temperature. Since POx is known to be hygroscopic and therefore unstable in atmosphere, we encapsulate this layer with a thin ALD Al2O3 capping layer to form a POx/Al2O3 stack. This passivation scheme is capable of improving the photoluminescence (PL) efficiency of our state-of-the-art wurtzite (WZ) InP nanowires by a factor of ∼20 at low excitation. If we apply the rate equation analysis advocated by some authors, we derive a PL internal quantum efficiency (IQE) of 75% for our passivated wires at high excitation. Our results indicate that it is more reliable to calculate the IQE as the ratio of the integrated PL intensity at room temperature to that at 10 K. By this means we derive an IQE of 27% for the passivated wires at high excitation (>10 kW cm-2), which constitutes an unprecedented level of performance for undoped InP nanowires. This conclusion is supported by time-resolved PL decay lifetimes, which are also shown to be significantly higher than previously reported for similar wires. The passivation scheme displays excellent long-term stability (>7 months) and is additionally shown to substantially improve the thermal stability of InP surfaces (>300 °C), significantly expanding the temperature window for device processing. Such effective surface passivation is a key enabling technology for InP nanowire devices such as nanolasers and solar cells.

Protein-ligand (un)binding kinetics as a new paradigm for drug discovery at the crossroad between experiments and modelling.

In the last three decades, protein and nucleic acid structure determination and comprehension of the mechanisms, leading to their physiological and pathological functions, have become a cornerstone of biomedical sciences. A deep understanding of the principles governing the fates of cells and tissue at the molecular level has been gained over the years, offering a solid basis for the rational design of drugs aimed at the pharmacological treatment of numerous diseases. Historically, affinity indicators (i.e. Kd and IC50/EC50) have been assumed to be valid indicators of the in vivo efficacy of a drug. However, recent studies pointed out that the kinetics of the drug-receptor binding process could be as important or even more important than affinity in determining the drug efficacy. This eventually led to a growing interest in the characterisation and prediction of the rate constants of protein-ligand association and dissociation. For instance, a drug with a longer residence time can kinetically select a given receptor over another, even if the affinity for both receptors is comparable, thus increasing its therapeutic index. Therefore, understanding the molecular features underlying binding and unbinding processes is of central interest towards the rational control of drug binding kinetics. In this review, we report the theoretical framework behind protein-ligand association and highlight the latest advances in the experimental and computational approaches exploited to investigate the binding kinetics.

Atom-by-Atom Analysis of Semiconductor Nanowires with Parts Per Million Sensitivity.

The functionality of semiconductor devices is determined by the incorporation of dopants at concentrations down to the parts per million (ppm) level and below. Optimization of intentional and unintentional impurity doping relies on methods to detect and map the level of impurities. Detecting such low concentrations of impurities in nanostructures is however challenging to date as on the one hand methods used for macroscopic samples cannot be applied due to the inherent small volumes or faceted surfaces and on the other hand conventional microscopic analysis techniques are not sufficiently sensitive. Here, we show that we can detect and map impurities at the ppm level in semiconductor nanowires using atom probe tomography. We develop a method applicable to a wide variety of nanowires relevant for electronic and optical devices. We expect that it will contribute significantly to the further optimization of the synthesis of nanowires, nanostructures and devices based on these structures.

Analytic model for the electrowetting properties of oil-water-solid systems.

The competitive wetting of oil and aqueous electrolytes on solid surfaces depends strongly on the surface charge of the solid-water and the water-oil interface. This charge density is generally not known a priori but changes as ions adsorb or desorb from or to the interfaces, depending on the composition of the fluid and the thickness of thin films of the aqueous phase that frequently arise on hydrophilic surfaces, such as minerals. We analyze the wettability of such systems by coupling standard Derjaguin-Landau-Verwey-Overbeek theory to a linearized charge regulation model. The latter is found to play an important role. By linearizing electrostatic interactions as well, we obtain a fully analytic description of transitions between different wetting scenarios as a function of the surface potentials at infinite separation and the charge regulation parameters of the two interfaces. Depending on the specific values of the regulation parameters, charge regulation is found to extend the parameter range of partial wetting and complete wetting at the expense of pseudopartial wetting and metastable wetting configurations, respectively. A specific implementation of the model is discussed for mica-water-alkane systems that was investigated in recent experiments.

Numerical simulation of astigmatic liquid lenses tuned by a stripe electrode.

We propose a new design for tuning the astigmatism of liquid micro-lenses using electric field and hydrostatic pressure as control parameters. We explore the feasibility and operating range of the lens with a self-consistent numerical calculation of the electric field distribution and the shape of the two-phase interface. Equilibrium shapes, including surface profiles parallel and perpendicular to a stripe electrode, are extracted to determine the astigmatism. The wavefronts are decomposed into Zernike polynomials under zero defocus conditions using a commercial ray-tracing software. We observe that the global curvature of the lens is primarily controlled by the hydrostatic pressure, while asphericity and astigmatism are controlled by the electric field. For optimized electrode geometries and simultaneous control of pressure and electric fields the astigmatism can be tuned from Z6 = 0…0.38 µm with minor changes in the focal length.

Diameter dependence of the thermal conductivity of InAs nanowires.

The diameter dependence of the thermal conductivity of InAs nanowires in the range of 40-1500 nm has been measured. We demonstrate a reduction in thermal conductivity of 80% for 40 nm nanowires, opening the way for further design strategies for nanoscaled thermoelectric materials. Furthermore, we investigate the effect of thermal contact in the most common measurement method for nanoscale thermal conductivity. Our study allows for the determination of the thermal contact using existing measurement setups. The thermal contact resistance is found to be comparable to the wire thermal resistance for wires with a diameter of 90 nm and higher.

On the shape of a droplet in a wedge: new insight from electrowetting.

The equilibrium morphology of liquid drops exposed to geometric constraints can be rather complex. Even for simple geometries, analytical solutions are scarce. Here, we investigate the equilibrium shape and position of liquid drops confined in the wedge between two solid surfaces at an angle α. Using electrowetting, we control the contact angle and thereby manipulate the shape and the equilibrium position of aqueous drops in ambient oil. In the absence of contact angle hysteresis and buoyancy, we find that the equilibrium shape is given by a truncated sphere, at a position that is determined by the drop volume and the contact angle. At this position, the net normal force between drop and the surfaces vanishes. The effect of buoyancy gives rise to substantial deviations from this equilibrium configuration which we discuss here as well. We eventually show how the geometric constraint and electrowetting can be used to position droplets inside a wedge in a controlled way, without mechanical actuation.

Post-resistance exercise hemodynamic and autonomic responses: Comparison between normotensive and hypertensive men.

To compare post-resistance exercise hypotension (PREH) and its mechanisms in normotensive and hypertensive individuals, 14 normotensives and 12 hypertensives underwent two experimental sessions: control (rest) and exercise (seven exercises, three sets, 50% of one repetition maximum). Hemodynamic and autonomic clinic measurements were taken before (Pre) and at two moments post-interventions (Post 1: between 30 and 60 min; Post 2: after 7 h). Ambulatory blood pressure (BP) was monitored for 24 h. At Post 1, exercise decreased systolic BP similarly in normotensives and hypertensives (-8 ± 2 vs -13 ± 2 mmHg, P > 0.05), whereas diastolic BP decreased more in hypertensives (-4 ± 1 vs -9 ± 1 mmHg, P < 0.05). Cardiac output and systemic vascular resistance did not change in normotensives and hypertensives (0.0 ± 0.3 vs 0.0 ± 0.3 L/min; -1 ± 1 vs -2 ± 2 U, P > 0.05). After exercise, heart rate (+13 ± 3 vs +13 ± 2 bpm) and its variability (low- to high-frequency components ratio, 1.9 ± 0.4 vs +1.4 ± 0.3) increased whereas stroke volume (-14 ± 5 vs -11 ± 5 mL) decreased similarly in normotensives and hypertensives (all, P > 0.05). At Post 2, all variables returned to pre-intervention, and ambulatory data were similar between sessions. Thus, a session of resistance exercise promoted PREH in normotensives and hypertensives. Although this PREH was greater in hypertensives, it did not last during the ambulatory period, which limits its clinical relevance. In addition, the mechanisms of PREH were similar in hypertensives and normotensives.

Kinetic characterization of fragment binding in AmpC ß-lactamase by high-throughput molecular simulations.

Small molecules used in fragment-based drug discovery form multiple, promiscuous binding complexes difficult to capture experimentally. Here, we identify such binding poses and their associated energetics and kinetics using molecular dynamics simulations on AmpC ß-lactamase. Only one of the crystallographic binding poses was found to be thermodynamically favorable; however, the ligand shows several binding poses within the pocket. This study demonstrates free-binding molecular simulations in the context of fragment-to-lead development and its potential application in drug design.

Computational methods in the discovery and design of BACE-1 inhibitors.

BACE-1 is a membrane associated aspartyl protease and is one of the enzymes responsible for the hydrolysis of the amyloid precursor protein. Due to its central role in the generation of the amyloid-ß peptide, it is considered as a primary drug target for Alzheimer's disease. BACE-1 has been the focus of many drug discovery programs aimed at identifying inhibitors that effectively block this enzyme and trigger the sought therapeutic effects. Thanks to the availability of a large number of crystal structures of the catalytic domain of this enzyme, computational methods, ranging from molecular dynamics simulations, quantum mechanical calculations and ligand docking, have played a fundamental role in almost every hit discovery and hit optimization campaign performed on this target. The present article reviews the latest computational modeling and drug discovery efforts that have been carried out on this target.