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Herein, we report the synthesis of graphene quantum dots (GQDs) functionalized with 1,5-diphenylcarbazone for the selective quantification of Fe in wine, via front-face fluorescence. Crystalline GQDs are obtained via a clean and relatively size-controlled synthesis based on the electrochemical exfoliation from a graphene foam. The product of the synthesis was later functionalized to solely detect Fe3+ amongst various other ions present within the sample. The detection is based on quenching the fluorescence emission from the functionalized nanomaterial in the presence of the analyte, which follows a linear relationship with the concentration of the analyte, consistent with the Stern-Volmer model. Diverse parameters involved in the measurements, including the pH and excitation wavelength, were optimized, giving place to limits of detection (LOD) of 0.014 mg L−1 and 0.11 mg L−1 in waters and white wines, respectively. A soft UV-based digestion and a profound analysis of interferences were key factors to achieve such LODs. Furthermore, front-face fluorescence measurements improved the applicability of the method by avoiding the commonly occurring matrix shielding effects. We believe that the sensitive, selective, and fast detection of Fe3+ within real (i.e.; wine) samples represents a major step forward in the field.

Complex thermo-kinetic interactions during metal additive manufacturing reduce the homogeneity of the microstructure of the produced samples. Understanding the effect of processing parameters over the resulting mechanical properties is essential for adopting and popularizing this technology. The present work is focused on the effect of laser power, scanning speed, and hatch spacing on the relative density, microhardness, and microstructure of 316L stainless steel processed by laser powder bed fusion. Several characterization techniques were used to study the microstructure and mechanical properties: optical, electron microscopies, and spectrometry. A full-factorial design of experiments was employed for relative density and microhardness evaluation. The results derived from the experimental work were subjected to statistical analysis, including the use of analysis of variance (ANOVA) to determine both the main effects and the interaction between the processing parameters, as well as to observe the contribution of each factor on the mechanical properties. The results show that the scanning speed is the most statistically significant parameter influencing densification and microhardness. Ensuring the amount of volumetric energy density (125 J/mm3) used to melt the powder bed is paramount; maximum densification (99.7%) is achieved with high laser power and low scanning speed, while hatch spacing is not statistically significant.

Abstract The promise of precision medicine has been limited by the pervasive resistance to many targeted therapies for cancer. Inferring the timing (i.e., pre-existing or acquired) and mechanism (i.e., drug-induced) of such resistance is crucial for designing effective new therapeutics. This paper studies cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) using tumor volume data obtained from patient-derived tumor xenografts. We ask if resistance mechanisms can be determined from this data alone, and if not, what data would be needed to deduce the underlying mode(s) of resistance. To answer these questions, we propose a family of mathematical models, with each member of the family assuming a different timing and mechanism of resistance. We present a method for fitting these models to individual volumetric data, and utilize model selection and parameter sensitivity analyses to ask: which member(s) of the family of models best describes HNSCC response to cetuximab, and what does that tell us about the timing and mechanisms driving resistance? We find that along with time-course volumetric data to a single dose of cetuximab, the initial resistance fraction and, in some instances, dose escalation volumetric data are required to distinguish among the family of models and thereby infer the mechanisms of resistance. These findings can inform future experimental design so that we can best leverage the synergy of wet laboratory experimentation and mathematical modeling in the study of novel targeted cancer therapeutics.

Sustainable corn starch nanoparticles were prepared using media milling to stabilize omega-3-rich Pickering emulsions based on chia oil. The milling conditions were as follows: 24 h (milling time), 0.4–0.6 mm (bead diameter), 1600 rpm (impeller speed), 30% (volume occupied by the grinding media), 7% w/v (starch concentration), and 0, 0.07 and 1% w/v of sodium dodecyl sulfate (SDS). Nanosuspensions containing 7% w/v of starch and the three concentrations of SDS were filtered, centrifuged, homogenized, and spray-dried to obtain redispersible powders. The particle size ranges were 2288 ± 211, 385 ± 21, and 278 ± 11 nm with 0, 0.07 and 1% w/v of SDS, respectively. The most stable backscattering profiles obtained during a period of one week were observed with 0.07 and 1% w/v of SDS. Therefore, the surface dilatational rheology of these particles adsorbed at chia oil/water interfaces was studied. A rapid decrease in the interfacial tension within 1 h was obtained with 1% w/v of SDS (down to 3 mN/m). Moreover, the most stable particle size after redispersion was obtained with the highest concentration of SDS. Finally, Pickering emulsions were prepared, and significant coalescence was observed with 0 and 0.07% w/v of SDS (within a few minutes). Nonetheless, in the presence of 1% w/v of SDS, oil droplets showed mean diameters and polydispersity indexes of 280.13 ± 4.60 nm and 0.35 ± 0.02, respectively, with no significant variations during storage for around 1 month. The results show that wet-stirred media milling can be applied to produce sustainable, new food-grade starch nanoparticles able to deliver bioactive compounds from chia oil.

Erica Cedeño,1 Ambar Cruz,1 Joaris Cortés,2 Kyle Melin,1 Luis Roman,3 Angel Gonzalez,3 Jorge Duconge,4 Darlene Santiago4 1Department of Pharmacy Practice, School of Pharmacy, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico; 2Department of Chemistry, Rio Piedras Campus, University of Puerto Rico, San Juan, Puerto Rico; 3SANOS Corporation, Caguas, Puerto Rico; 4Department of Pharmaceutical Sciences, School of Pharmacy, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto RicoCorrespondence: Darlene SantiagoDepartment of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico, Medical Sciences Campus, PO Box 365067, San Juan, 00936-5067, Puerto RicoTel +1 787-758-2525 ext. 5313Email darlene.santiago@upr.eduPurpose: Differences in the suppression of withdrawal symptoms have been observed in opioid-use-disorder (OUD) patients who were switched from Suboxone (the brand name of buprenorphine/naloxone sublingual films) to either 1 of 2 generic versions. These descriptive observations evidence the need to further assess the use of these generics and its impact on the adherence to and outcomes of OUD treatments. The objective of this case series was to describe patient and provider experiences, perceptions, and preferences when said patients were abruptly switched from Suboxone to one of the generic versions manufactured by Sandoz or Alvogen.Patients and Methods: A retrospective chart review of 24 Suboxone-maintained OUD patients from a single clinic who were forced to switch to a generic was performed to collect withdrawal and craving symptoms that occurred after the switch, as well as toxicology results and changes in dose (documented by the provider).Results: The medical records of 9 (37.5%) of the 24 patients showed that they were suffering from withdrawal symptoms and/or cravings, had had their doses adjusted, and/or had had a positive urine toxicology screen. All 9 subjects communicated a preference for the brand formulation over that of either of the generic versions; few expressed a preference for one generic formulation over the other. None of patients were able to switch back to the brand formulation, nor were any of them able to choose the generic that worked best for them. Insomnia, muscle pain, and gooseflesh skin were the most common withdrawal symptoms reported by the patients using the generics. Better outcomes were observed in patients who received a buprenorphine dose increase (2 mg) to suppress the withdrawal symptoms experienced while using the generics.Conclusion: Our study serves as a reference to prescribers regarding approaches (eg, a small dose adjustment) that may potentially encourage OUD treatment adherence and even improve outcomes in patients who appear to be decompensating after the brand-to-generic switch.Keywords: buprenorphine, buprenorphine generics, opioid-use disorder, withdrawal symptoms, relapse, cravings, brand-to-generic switch, Suboxone

Parvini, Cartagena and Solares introduce an iterative viscoelastic approach based on the generalized Maxwell and Kelvin-Voigt models. The results showed that metastatic melanoma cells had lower elasticity than normal fibroblasts and melanoma cells were less viscous than the fibroblasts over a large frequency range, enhancing the understanding of cellular responses at different frequencies.

Abstract Organic field‐effect transistors (OFETs) are considered almost purely interfacial devices with charge current mainly confined in the first two semiconducting layers in contact with the dielectric with no active role of the film thickness exceeding six to eight monolayers (MLs). By a combined electronic, morphological, structural, and theoretical investigation, it is demonstrated that the charge mobility and source–drain current in 2,20‐(2,20‐bithiophene‐5,50‐diyl)bis(5‐butyl‐5H‐thieno[2,3‐c]pyrrole‐4,6)‐dione (NT4N) organic transistors directly correlate with the out‐of‐plane domain size and crystallite orientation in the vertical direction, well beyond the dielectric interfacial layers. Polycrystalline films with thickness as high as 75 nm (≈30 MLs) and 3D molecular architecture provide the best electrical and optoelectronic OFET characteristics, highlighting that the molecular orientational order in the bulk of the film is the key‐enabling factor for optimum device performance. X‐ray scattering analysis and multiscale simulations reveal the functional correlation between the thickness‐dependent molecular packing, electron mobility, and vertical charge distribution. These results call for a broader view of the fundamental mechanisms that govern field‐effect charge transport in OFETs beyond the interfacial 2D paradigm and demonstrate the unexpected role of the out‐of‐plane domain size and crystallite orientation in polycrystalline films to achieve optimum electronic and optoelectronic properties in organic transistors.

Summary: Strategies targeting methane (CH4) and nitrous oxide (N2O) emissions are critical to meeting global climate targets. Existing literature estimates the emissions of these gases from specific sectors, but this knowledge must be synthesized to prioritize and incentivize CH4 and N2O mitigation. Accordingly, we review emissions sources and mitigation strategies in all key sectors (fuel extraction and combustion, landfilling, agriculture, wastewater treatment, and chemical industry) and the role of carbon markets in reducing emissions. The most accessible reduction opportunities are in the hydrocarbon extraction and waste sectors, where half (>3 Gt-CO2e/year) of the emissions in these sectors could be mitigated at no net cost. In total, 60% of CH4 emissions can be mitigated at less than $50/t-CO2. Expanding the scope of carbon markets to include these emissions could provide cost-effective decarbonization through 2050. We provide recommendations for carbon markets to improve emissions reductions and set prices to appropriately incentivize mitigation.

Viscoelastic characterization of materials at the micro- and the nanoscale is commonly performed with the aid of force–distance relationships acquired using atomic force microscopy (AFM). The general strategy for existing methods is to fit the observed material behavior to specific viscoelastic models, such as generalized viscoelastic models or power-law rheology models, among others. Here we propose a new method to invert and obtain the viscoelastic properties of a material through the use of the Z-transform, without using a model. We present the rheological viscoelastic relations in their classical derivation and their z-domain correspondence. We illustrate the proposed technique on a model experiment involving a traditional ramp-shaped force–distance AFM curve, demonstrating good agreement between the viscoelastic characteristics extracted from the simulated experiment and the theoretical expectations. We also provide a path for calculating standard viscoelastic responses from the extracted material characteristics. The new technique based on the Z-transform is complementary to previous model-based viscoelastic analyses and can be advantageous with respect to Fourier techniques due to its generality. Additionally, it can handle the unbounded inputs traditionally used to acquire force–distance relationships in AFM, such as ramp functions, in which the cantilever position is displaced linearly with time for a finite period of time.

Objectives: Excessive daytime sleepiness (EDS) is a highly prevalent symptom that increases the risk of traffic accidents and deteriorates the quality of life. The diagnosis of EDS is difficult because of the complex infrastructure that is required. The new test here proposed assesses the ability of a simple test of simplify the detection of daytime sleepiness compared with the OSLER test. Material and Methods: In the new test, during 20 minute subjects were asked to pass a finger by a groove in response to a light emitting diode, inside dark glasses, which was lit for 1s in every three, with headphones that reduce the ambient noise and was compared with the OSLER test on each subject in random order. Results: The proposed method showed a sensitivity of 100% and a specificity of 61%, with a positive predictive value of 67% and negative predictive value of 100% when compared with the OSLER test. The value of area under the ROC curve was 0.81 (0.62-0.99), p=0.013. In a Bland-Altman plot, most of the latency times differences are in the 95% agreement interval (p=0.05). In addition, the confidence interval of the mean and most of the positive results are above the zero line. The Cohens Kappa coefficient obtained is 0.58 (95% CI 0.29-0.88). Conclusion: In this sample of patients, the proposed method detects EDS in a similar way as OSLER test and can be performed in different environments without requiring special infrastructure or expert personnel.

ObjectivesTo determine the stance duration and ground reaction forces (GRF) of horses with deep digital flexor (DDF) tendinopathy at the level of the foot and compare the stance duration and GRF to those of clinically sound horses.DesignProspective clinical study.AnimalsSixteen horses (seven horses with bilateral forelimb lameness, four horses with unilateral forelimb lameness, and five horses with no lameness).ProceduresAnalyses of kinetic variables were performed on both forelimbs from sound horses and horses diagnosed with chronic DDF tendinopathy. Stance duration and longitudinal and vertical components of the GRF were determined for the limbs of clinically sound horses and limbs of horses with DDF tendinopathy. Separate Spearman correlation analyses were used to assess potential association within groups (combined left and right forelimbs of clinically sound horses, lamest limbs of horses with DDF tendinopathy, and contralateral limbs of horses with DDF tendinopathy) and with the set of kinetic variables. Analysis of variance on mean ranks of tied values was used to determine differences in kinetic variables between groups (PROC GLIMMIX) using the kinetic values of the clinically sound horses as the reference group.ResultsThere were a total of 11 lame horses. Seven horses had bilateral forelimb lameness and four had unilateral lameness. Of the 11 horses, there were 15 DDF tendinopathies. There were eight dorsal border DDF tendinopathies, five core DDF tendinopathies, and two sagittal/parasagittal splits DDF tendinopathies. The most lame limbs of horses with DDF tendinopathy had significantly smaller values for peak vertical force and time of peak braking force than did forelimbs of clinically sound horses. Also, the most lame limbs of horses with DDF tendinopathy had significantly larger values for the time of peak vertical force than did forelimbs of clinically sound horses.Conclusions and Clinical RelevanceHorses with chronic DDF tendinopathies develop certain alterations of GRF parameters. This information can be used in future studies to determine if particular kinetic variable changes in horses with DDF tendinopathies differ from those of horses with other pathologies within the foot and therefore could be diagnostic.

Atomic force microscopy (AFM) is a widely use technique to acquire topographical, mechanical, or electromagnetic properties of surfaces, as well as to induce surface modifications at the micrometer and nanometer scale. Viscoelastic materials, examples of which include many polymers and biological materials, are an important class of systems, the mechanical response of which depends on the rate of application of the stresses imparted by the AFM tip. The mechanical response of these materials thus depends strongly on the frequency at which the characterization is performed, so much so that important aspects of behavior may be missed if one chooses an arbitrary characterization frequency regardless of the materials properties. In this paper we present a linear viscoelastic analysis of intermittent-contact, nearly resonant dynamic AFM characterization of such materials, considering the possibility of multiple characteristic times. We describe some of the intricacies observed in their mechanical response and alert the reader about situations where mischaracterization may occur as a result of probing the material at frequency ranges or with probes that preclude observation of its viscoelastic behavior. While we do not offer a solution to the formidable problem of inverting the frequency-dependent viscoelastic behavior of a material from dynamic AFM observables, we suggest that a partial solution is offered by recently developed quasi-static force–distance characterization techniques, which incorporate viscoelastic models with multiple characteristic times and can help inform dynamic AFM characterization.

Atomic force microscopy (AFM) techniques have provided and continue to provide increasingly important insights into surface morphology, mechanics, and other critical material characteristics at the nanoscale. One attractive implementation involves extracting meaningful material properties, which demands physically accurate models specifically designed for AFM experimentation and simulation. The AFM community has pursued the precise quantification and extraction of rate-dependent material properties, in particular, for a significant period of time, attempting to describe the standard viscoelastic response of materials. AFM static force spectroscopy (SFS) is one approach commonly used in pursuit of this goal. It is capable of acquiring rich temporal insight into the behavior of a sample. During AFM-SFS experiments the cantilever base approaches samples with a nearly constant velocity, which is manipulated to investigate different timescales of the mechanical response. This manuscript seeks to build upon our previous work and presents an approach to extracting useful linear viscoelastic information from AFM-SFS experiments. In addition, the basis for selecting and restricting the model parameters for fitting is discussed from the perspective of applying this technique on a practical level. This work begins with a guided discussion that develops a fit function from fundamental laws, continues with conditioning a raw SFS experimental dataset, and concludes with the fit and prediction of viscoelastic response parameters such as storage modulus, loss modulus, loss angle, and compliance. These steps constitute a complete guide to leveraging AFM-SFS data to estimate key material parameters, with a series of detailed insights into both the methodology and supporting analytical choices.

Atomic force microscopy (AFM) is an important tool for measuring a variety of nanoscale surface properties, such as topography, viscoelasticity, electrical potential and conductivity. Some of these properties are measured using contact methods (static contact or intermittent contact), while others are measured using noncontact methods. Some properties can be measured using different approaches. Conductivity, in particular, is mapped using the contact-mode method. However, this modality can be destructive to delicate samples, since it involves continuously dragging the cantilever tip on the surface during the raster scan, while a constant tip–sample force is applied. In this paper we discuss a possible approach to develop an intermittent-contact conductive AFM mode based on Fourier analysis, whereby the measured current response consists of higher harmonics of the cantilever oscillation frequency. Such an approach may enable the characterization of soft samples with less damage than contact-mode imaging. To explore its feasibility, we derive the analytical form of the tip–sample current that would be obtained for attractive (noncontact) and repulsive (intermittent-contact) dynamic AFM characterization, and compare it with results obtained from numerical simulations. Although significant instrumentation challenges are anticipated, the modelling results are promising and suggest that Fourier-based higher-harmonics current measurement may enable the development of a reliable intermittent-contact conductive AFM method.

Polyphenols comprise a number of natural substances, such as flavonoids, that show interesting biological effects. Among these substances is naringin, a naturally occurring flavanone glycoside found in citrus fruits and Chinese medicinal herbs. Several studies have shown that naringin has numerous biological properties, including cardioprotective, cholesterol-lowering, anti-Alzheimer’s, nephroprotective, antiageing, antihyperglycemic, antiosteoporotic and gastroprotective, anti-inflammatory, antioxidant, antiapoptotic, anticancer and antiulcer effects. Despite its multiple benefits, the clinical application of naringin is severely restricted due to its susceptibility to oxidation, poor water solubility, and dissolution rate. In addition, naringin shows instability at acidic pH, is enzymatically metabolized by β-glycosidase in the stomach and is degraded in the bloodstream when administered intravenously. These limitations, however, have been overcome thanks to the development of naringin nanoformulations. This review summarizes recent research carried out on strategies designed to improve naringin’s bioactivity for potential therapeutic applications.

Abstract Currently, biological drug therapy for ocular angiogenesis treatment is based on the administration of anti‐VEGF agents via intravitreal route. The molecules approved with this purpose for ocular use include pegaptanib, ranibizumab, and aflibercept, whereas bevacizumab is commonly off‐label used in the clinical practice. The schedule dosage involves repeated intravitreal injections of anti‐VEGF agents to achieve and maintain effective concentrations in retina and choroids, which are administrated as solutions form. In this review article, we describe the features of different anti‐VEGF agents, major challenges for their ocular delivery and the nanoparticles in development as delivery system of them. In this way, several polymeric and lipid nanoparticles are explored to load anti‐VEGF agents with the aim of achieving sustained drug release and thus, minimize the number of intravitreal injections required. The main challenges were focused in the loading the molecules that maintain their bioactivity after their release from nanoparticulate system, followed the evaluation of them through studies of formulation stability, pharmacokinetic, and efficacy in in vitro and in vivo models. The analysis was based on the information published in peer‐reviewed published papers relevant to anti‐VEGF treatments and nanoparticles developed as ocular anti‐VEGF delivery system.

Abstract Scanning probe microscopy has enabled nanoscale mapping of mechanical properties in important technological materials, such as tissues, biomaterials, polymers, nanointerfaces of composite materials, to name only a few. To improve and widen the measurement of nanoscale mechanical properties, a number of methods have been proposed to overcome the widely used force-displacement mode, that is inherently slow and limited to a quasi-static regime, mainly using multiple sinusoidal excitations of the sample base or of the cantilever. Here, a different approach is put forward. It exploits the unique capabilities of the wavelet transform analysis to harness the information encoded in a short duration spectroscopy experiment. It is based on an impulsive excitation of the cantilever and a single impact of the tip with the sample. It performs well in highly damped environments, which are often seen as problematic in other standard dynamic methods. Our results are very promising in terms of viscoelastic property discrimination. Their potential is oriented (but not limited) to samples that demand imaging in liquid native environments and also to highly vulnerable samples whose compositional mapping cannot be obtained through standard tapping imaging techniques.

Kelvin probe force microscopy (KPFM) has been used for the characterization of metals, insulators, and semiconducting materials on the nanometer scale. Especially in semiconductors, the charge dynamics are of high interest. Recently, several techniques for time-resolved measurements with time resolution down to picoseconds have been developed, many times using a modulated excitation signal, e.g., light modulation or bias modulation that induces changes in the charge carrier distribution. For fast modulation frequencies, the KPFM controller measures an average surface potential, which contains information about the involved charge carrier dynamics. Here, we show that such measurements are prone to artifacts due to frequency mixing, by performing numerical dynamics simulations of the cantilever oscillation in KPFM subjected to a bias-modulated signal. For square bias pulses, the resulting time-dependent electrostatic forces are very complex and result in intricate mixing of frequencies that may, in some cases, have a component at the detection frequency, leading to falsified KPFM measurements. Additionally, we performed fast Fourier transform (FFT) analyses that match the results of the numerical dynamics simulations. Small differences are observed that can be attributed to transients and higher-order Fourier components, as a consequence of the intricate nature of the cantilever driving forces. These results are corroborated by experimental measurements on a model system. In the experimental case, additional artifacts are observed due to constructive or destructive interference of the bias modulation with the cantilever oscillation. Also, in the case of light modulation, we demonstrate artifacts due to unwanted illumination of the photodetector of the beam deflection detection system. Finally, guidelines for avoiding such artifacts are given.

In this short paper we explore the use of higher eigenmodes in single-eigenmode amplitude-modulation atomic force microscopy (AFM) for the small-indentation imaging of soft viscoelastic materials. In viscoelastic materials, whose response depends on the deformation rate, the tip–sample forces generated as a result of sample deformation increase as the tip velocity increases. Since the eigenfrequencies in a cantilever increase with eigenmode order, and since higher oscillation frequencies lead to higher tip velocities for a given amplitude (in viscoelastic materials), the sample indentation can in some cases be reduced by using higher eigenmodes of the cantilever. This effect competes with the lower sensitivity of higher eigenmodes, due to their larger force constant, which for elastic materials leads to greater indentation for similar amplitudes, compared with lower eigenmodes. We offer a short theoretical discussion of the key underlying concepts, along with numerical simulations and experiments to illustrate a simple recipe for imaging soft viscoelastic matter with reduced indentation.

The purpose of this study was to design, for the first time, a co-loaded liposomal formulation (CLL) for treatment of glaucoma including timolol maleate (TM) in the lipid bilayer and acetazolamide (Acz)-(2-hydroxy)propyl β-cyclodextrin (HPβCD) complexes (AczHP) solubilized in the aqueous core of liposomes. Formulations with TM (TM-L) and AczHP (AczHP-L), separately, were also prepared and characterized. A preliminary study comprising the Acz/HPβCD complexes and their interaction with cholesterol (a component of the lipid bilayer) was realized. Then, a screening study on formulation factors affecting the quality of the product was carried out following the design of the experiment methodology. In addition, in vitro release and permeation studies and in vivo lowering intraocular pressure (IOP) studies were performed. The results of the inclusion complexation behavior, characterization, and binding ability of Acz with HPβCD showed that HPβCD could enhance the water solubility of Acz despite the weak binding ability of the complex. Ch disturbed the stability and solubility parameters of Acz due to the fact of its competence by CD; thus, Chems (steroid derivative) was selected for further liposome formulation studies. The optimization of the lipid bilayer composition (DDAB, 0.0173 mmol and no double loading) and the extrusion as methods to reduce vesicle size were crucial for improving the physico-chemical properties and encapsulation efficiency of both drugs. In vitro release and permeation studies demonstrated that the CLL formulation showed improvement in in vitro drug release and permeation compared to the liposomal formulations with a single drug (TM-L and AczHP-L) and the standard solutions (TM-S and AczHP-S). CLL showed high efficacy in reducing and prolonging IOP, suggesting that the synergistic effect of TM and Acz on aqueous humor retention and the presence of this cyclodextrin and liposomes as permeation enhancers are responsible for the success of this strategy of co-loading for glaucoma therapy.

We explore the contact problem of a flat-end indenter penetrating intermittently a generalized viscoelastic surface, containing multiple characteristic times. This problem is especially relevant for nanoprobing of viscoelastic surfaces with the highly popular tapping-mode AFM imaging technique. By focusing on the material perspective and employing a rigorous rheological approach, we deliver analytical closed-form solutions that provide physical insight into the viscoelastic sources of repulsive forces, tip–sample dissipation and virial of the interaction. We also offer a systematic comparison to the well-established standard harmonic excitation, which is the case relevant for dynamic mechanical analysis (DMA) and for AFM techniques where tip–sample sinusoidal interaction is permanent. This comparison highlights the substantial complexity added by the intermittent-contact nature of the interaction, which precludes the derivation of straightforward equations as is the case for the well-known harmonic excitations. The derivations offered have been thoroughly validated through numerical simulations. Despite the complexities inherent to the intermittent-contact nature of the technique, the analytical findings highlight the potential feasibility of extracting meaningful viscoelastic properties with this imaging method.

Bioinspired design has been central in the development of hierarchical nanocomposites. Particularly, the nacre-mimetic brick-and-mortar structure has shown excellent mechanical properties, as well as gas-barrier properties and optical transparency. Along with these intrinsic properties, the layered structure has also been utilized in sensing devices. Here we extend the multifunctionality of nacre-mimetics by designing an optically transparent and electron conductive coating based on PEDOT:PSS and nanoclays Laponite RD and Cloisite Na+. We carry out extensive characterization of the nanocomposite using transmittance spectra (transparency), conductive atomic force microscopy (conductivity), contact-resonance force microscopy (mechanical properties), and SEM combined with a variety of stress-strain AFM experiments and AFM numerical simulations (internal structure). We further study the nanoclay’s response to the application of pressure with multifrequency AFM and conductive AFM, whereby increases and decreases in conductivity can occur for the Laponite RD composites. We offer a possible mechanism to explain the changes in conductivity by modeling the coating as a 1-dimensional multibarrier potential for electron transport, and show that conductivity can change when the separation between the barriers changes under the application of pressure, and that the direction of the change depends on the energy of the electrons. We did not observe changes in conductivity under the application of pressure with AFM for the Cloisite Na+ nanocomposite, which has a large platelet size compared with the AFM probe diameter. No pressure-induced changes in conductivity were observed in the clay-free polymer either.

Organic photovoltaic systems comprising donor polymers and acceptor fullerene derivatives are attractive for inexpensive energy harvesting. Extensive research on polymer solar cells has provided insight into the factors governing device-level efficiency and stability. However, the detailed investigation of nanoscale structures is still challenging. Here we demonstrate the analysis and modification of unidentified surface aggregates. The aggregates are characterized electrically by Kelvin probe force microscopy and conductive atomic force microscopy (C-AFM), whereby the correlation between local electrical potential and current confirms a defective charge transport. Bimodal AFM modification confirms that the aggregates exist on top of the solar cell structure, and is used to remove them and to reveal the underlying active layer. The systematic analysis of the surface aggregates suggests that the structure consists of PCBM molecules.

This study addresses a high resolution model for the synchronization of traffic lights on transport networks. A hybrid heuristic algorithm optimizes the mixed integer linear model, referred as MAXBAND, seeking to achieve maximal bandwidth by setting arterial signals. The assessed algorithm corresponds to a hybrid metaheuristic which combines Tabu Search and Variable Neighborhood Search. The algorithm uses a memory structure within an iterative local search, allowing a broader diversity of solutions. In addition, some adjustments were incorporated to the MAXBAND such as the revision of the constraints of the mixed integer linear model, including those that describe all the cyclic routes in the graph, and some bounds were generalized for integer variables. Extensive computational experiments were carried out evidencing a competitive performance for large instances.

Ecuadorian páramo ecosystems (EPEs) function as water sources, contain large soil carbon stores and high levels of biodiversity, and support human populations. The EPEs are mainly herbaceous páramo (HP). To inform policy and management and help drive ecological science toward a better understanding of the HP ecosystem, and the relationships among its multiple ecosystem services, we asked: (1) What is the state of the HP regarding its land use/land cover (LULC)?; and (2) Is the HP being pushed away from its natural state or it is regenerating? To answer these questions, we assessed the LULC in central EPEs using Landsat 8 imagery, Object-Based Image Analysis (OBIA) and a Classification and Regression Trees (CART) algorithm. Results show that two-fifths of the paramo ecosystem remain as native HP (NHP) and two-fifths as anthropogenic HP (AHP). Although the anthropic alteration of the pedogenesis of young paramo soil leads to the establishment of AHP, we found evidence of regeneration and resilience of the NHP. The results of this study will be useful to scientists and decision-makers with interest in páramo ecosystems in central Ecuador. The proposed methodology is simple, fast, and could be implemented in other landscapes to establish comprehensive monitoring systems useful in landscape assessment and planning.

The aim of this paper is to analyze the set of contributions of A. Duarte Gomes to the journal Psychologica. Specifically, his co-authors, the impact of his publications on other researchers, and the topics that have been the subject of his interest are analyzed. The search resulted in a total of 17 articles, published between 1991 and 2016, signed by him and in co-authorship. In this journal, A. Duarte Gomes reaches the highest levels of visibility in 2005, with a total of five articles of various kinds. The largest number of publications co-authored in Psychologica was with Leonor Pais and Teresa Rebelo, with five collaborations, and with Carla Carvalho, with four. Focusing on the topics covered in the different articles, it can be observed that A. Duarte Gomes’ scientific interest has focused on the organizational level of analysis, with the most relevant topic being that of organizational culture. The total number of citations received by the analyzed papers is 123, which means 7.2 citations per paper. Four of the articles have been cited in five articles published in JCR/SJR journals. The results have allowed us to empirically verify the role of A. Duarte Gomes building the work and organizational, and personnel psychology in Portugal.

Significant progress has been accomplished in the development of experimental contact-mode and dynamic-mode atomic force microscopy (AFM) methods designed to measure surface material properties. However, current methods are based on one-dimensional (1D) descriptions of the tip–sample interaction forces, thus neglecting the intricacies involved in the material behavior of complex samples (such as soft viscoelastic materials) as well as the differences in material response between the surface and the bulk. In order to begin to address this gap, a computational study is presented where the sample is simulated using an enhanced version of a recently introduced model that treats the surface as a collection of standard-linear-solid viscoelastic elements. The enhanced model introduces in-plane surface elastic forces that can be approximately related to a two-dimensional (2D) Young’s modulus. Relevant cases are discussed for single- and multifrequency intermittent-contact AFM imaging, with focus on the calculated surface indentation profiles and tip–sample interaction force curves, as well as their implications with regards to experimental interpretation. A variety of phenomena are examined in detail, which highlight the need for further development of more physically accurate sample models that are specifically designed for AFM simulation. A multifrequency AFM simulation tool based on the above sample model is provided as supporting information.

There is a need for new vaccine adjuvant strategies that offer both vigorous antibody and T-cell mediated protection to combat difficult intracellular pathogens and cancer. To this aim, we formulated class-B synthetic oligodeoxynucleotide containing unmethylated cytosine-guanine motifs (CpG-ODN) with a nanostructure (Coa-ASC16 or coagel) formed by self-assembly of 6-0-ascorbyl palmitate ester. Our previous results demonstrated that mice immunized with ovalbumin (OVA) and CpG-ODN formulated with Coa-ASC16 (OVA/CpG-ODN/Coa-ASC16) elicited strong antibodies (IgG1 and IgG2a) and Th1/Th17 cellular responses without toxic systemic effects. These responses were superior to those induced by a solution of OVA with CpG-ODN or OVA/CpG-ODN formulated with aluminum salts. In this study, we investigated the capacity of this adjuvant strategy (CpG-ODN/Coa-ASC16) to elicit CD8+ T-cell response and some of the underlying cellular and molecular mechanisms involved in adaptive response. We also analyzed whether this adjuvant strategy allows a switch from an immunization scheme of three-doses to one of single-dose. Our results demonstrated that vaccination with OVA/CpG-ODN/Coa-ASC16 elicited an antigen-specific long-lasting humoral response and importantly-high quality CD8+ T-cell immunity with a single-dose immunization. Moreover, Coa-ASC16 promoted co-uptake of OVA and CpG-ODN by dendritic cells. The CD8+ T-cell response induced by OVA/CpG-ODN/Coa-ASC16 was dependent of type I interferons and independent of CD4+ T-cells, and showed polyfunctionality and efficiency against an intracellular pathogen. Furthermore, the cellular and humoral responses elicited by the nanostructured formulation were IL-6-independent. This system provides a simple and inexpensive adjuvant strategy with great potential for future rationally designed vaccines.

The first challenge in the 2014 competition launched by the Teach-Discover-Treat (TDT) initiative asked for the development of a tutorial for ligand-based virtual screening, based on data from a primary phenotypic high-throughput screen (HTS) against malaria. The resulting Workflows were applied to select compounds from a commercial database, and a subset of those were purchased and tested experimentally for anti-malaria activity. Here, we present the two most successful Workflows, both using machine-learning approaches, and report the results for the 114 compounds tested in the follow-up screen. Excluding the two known anti-malarials quinidine and amodiaquine and 31 compounds already present in the primary HTS, a high hit rate of 57% was found.

This paper introduces a quasi-3-dimensional (Q3D) viscoelastic model and software tool for use in atomic force microscopy (AFM) simulations. The model is based on a 2-dimensional array of standard linear solid (SLS) model elements. The well-known 1-dimensional SLS model is a textbook example in viscoelastic theory but is relatively new in AFM simulation. It is the simplest model that offers a qualitatively correct description of the most fundamental viscoelastic behaviors, namely stress relaxation and creep. However, this simple model does not reflect the correct curvature in the repulsive portion of the force curve, so its application in the quantitative interpretation of AFM experiments is relatively limited. In the proposed Q3D model the use of an array of SLS elements leads to force curves that have the typical upward curvature in the repulsive region, while still offering a very low computational cost. Furthermore, the use of a multidimensional model allows for the study of AFM tips having non-ideal geometries, which can be extremely useful in practice. Examples of typical force curves are provided for single- and multifrequency tapping-mode imaging, for both of which the force curves exhibit the expected features. Finally, a software tool to simulate amplitude and phase spectroscopy curves is provided, which can be easily modified to implement other controls schemes in order to aid in the interpretation of AFM experiments.

The first challenge in the 2014 competition launched by the Teach-Discover-Treat (TDT) initiative asked for the development of a tutorial for ligand-based virtual screening, based on data from a primary phenotypic high-throughput screen (HTS) against malaria. The resulting Workflows were applied to select compounds from a commercial database, and a subset of those were purchased and tested experimentally for anti-malaria activity. Here, we present the two most successful Workflows, both using machine-learning approaches, and report the results for the 114 compounds tested in the follow-up screen. Excluding the two known anti-malarials quinidine and amodiaquine and 31 compounds already present in the primary HTS, a high hit rate of 57% was found.

We examine different approaches to model viscoelasticity within atomic force microscopy (AFM) simulation. Our study ranges from very simple linear spring–dashpot models to more sophisticated nonlinear systems that are able to reproduce fundamental properties of viscoelastic surfaces, including creep, stress relaxation and the presence of multiple relaxation times. Some of the models examined have been previously used in AFM simulation, but their applicability to different situations has not yet been examined in detail. The behavior of each model is analyzed here in terms of force–distance curves, dissipated energy and any inherent unphysical artifacts. We focus in this paper on single-eigenmode tip–sample impacts, but the models and results can also be useful in the context of multifrequency AFM, in which the tip trajectories are very complex and there is a wider range of sample deformation frequencies (descriptions of tip–sample model behaviors in the context of multifrequency AFM require detailed studies and are beyond the scope of this work).

We present an exploratory study of multimodal tapping-mode atomic force microscopy driving more than three cantilever eigenmodes. We present tetramodal (4-eigenmode) imaging experiments conducted on a thin polytetrafluoroethylene (PTFE) film and computational simulations of pentamodal (5-eigenmode) cantilever dynamics and spectroscopy, focusing on the case of large amplitude ratios between the fundamental eigenmode and the higher eigenmodes. We discuss the dynamic complexities of the tip response in time and frequency space, as well as the average amplitude and phase response. We also illustrate typical images and spectroscopy curves and provide a very brief description of the observed contrast. Overall, our findings are promising in that they help to open the door to increasing sophistication and greater versatility in multi-frequency AFM through the incorporation of a larger number of driven eigenmodes, and in highlighting specific future research opportunities.

This paper presents computational simulations of single-mode and bimodal atomic force microscopy (AFM) with particular focus on the viscoelastic interactions occurring during tip–sample impact. The surface is modeled by using a standard linear solid model, which is the simplest system that can reproduce creep compliance and stress relaxation, which are fundamental behaviors exhibited by viscoelastic surfaces. The relaxation of the surface in combination with the complexities of bimodal tip–sample impacts gives rise to unique dynamic behaviors that have important consequences with regards to the acquisition of quantitative relationships between the sample properties and the AFM observables. The physics of the tip–sample interactions and its effect on the observables are illustrated and discussed, and a brief research outlook on viscoelasticity measurement with intermittent-contact AFM is provided.

This paper presents experiments on Nafion® proton exchange membranes and numerical simulations illustrating the trade-offs between the optimization of compositional contrast and the modulation of tip indentation depth in bimodal atomic force microscopy (AFM). We focus on the original bimodal AFM method, which uses amplitude modulation to acquire the topography through the first cantilever eigenmode, and drives a higher eigenmode in open-loop to perform compositional mapping. This method is attractive due to its relative simplicity, robustness and commercial availability. We show that this technique offers the capability to modulate tip indentation depth, in addition to providing sample topography and material property contrast, although there are important competing effects between the optimization of sensitivity and the control of indentation depth, both of which strongly influence the contrast quality. Furthermore, we demonstrate that the two eigenmodes can be highly coupled in practice, especially when highly repulsive imaging conditions are used. Finally, we also offer a comparison with a previously reported trimodal AFM method, where the above competing effects are minimized.

The resonance frequency, amplitude, and phase response of the first two eigenmodes of two contact-resonance atomic force microscopy (CR-AFM) configurations, which differ in the method used to excite the system (cantilever base vs sample excitation), are analyzed in this work. Similarities and differences in the observables of the cantilever dynamics, as well as the different effect of the tip–sample contact properties on those observables in each configuration are discussed. Finally, the expected accuracy of CR-AFM using phase-locked loop detection is investigated and quantification of the typical errors incurred during measurements is provided.

This paper illustrates through numerical simulation the complexities encountered in high-damping AFM imaging, as in liquid enviroments, within the specific context of multifrequency atomic force microscopy (AFM). The focus is primarily on (i) the amplitude and phase relaxation of driven higher eigenmodes between successive tip–sample impacts, (ii) the momentary excitation of non-driven higher eigenmodes and (iii) base excitation artifacts. The results and discussion are mostly applicable to the cases where higher eigenmodes are driven in open loop and frequency modulation within bimodal schemes, but some concepts are also applicable to other types of multifrequency operations and to single-eigenmode amplitude and frequency modulation methods.

We present an overview of the bimodal amplitude–frequency-modulation (AM-FM) imaging mode of atomic force microscopy (AFM), whereby the fundamental eigenmode is driven by using the amplitude-modulation technique (AM-AFM) while a higher eigenmode is driven by using either the constant-excitation or the constant-amplitude variant of the frequency-modulation (FM-AFM) technique. We also offer a comparison to the original bimodal AFM method, in which the higher eigenmode is driven with constant frequency and constant excitation amplitude. General as well as particular characteristics of the different driving schemes are highlighted from theoretical and experimental points of view, revealing the advantages and disadvantages of each. This study provides information and guidelines that can be useful in selecting the most appropriate operation mode to characterize different samples in the most efficient and reliable way.

We introduce a novel and potentially powerful, yet relatively simple extension of the spectral inversion method, which offers the possibility of carrying out 4-dimensional (4D) atomic force spectroscopy. With the extended spectral inversion method it is theoretically possible to measure the tip–sample forces as a function of the three Cartesian coordinates in the scanning volume (x, y and z) and the vertical velocity of the tip, through a single 2-dimensional (2D) surface scan. Although signal-to-noise ratio limitations can currently prevent the accurate experimental implementation of the 4D method, and the extraction of rate-dependent material properties from the force maps is a formidable challenge, the spectral inversion method is a promising approach due to its dynamic nature, robustness, relative simplicity and previous successes.

Solid dispersions (SDx) containing Indomethacin (IND), a poorly water-soluble drug, and the disintegrant excipient sodium croscarmellose (SC) were prepared by a co-drying method and characterized by Infrared spectroscopy (FT-IR), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). An FT-IR analysis performed on IND-SC solid dispersion and their physical mixtures indicated that IND does not interact with SC in the solid state. An analysis of the information produced by DSC, XRD, and SEM confirmed that the crystalline α-form of IND was homogeneously incorporated into SDx. IND release from SDx was significantly greater than that from its corresponding physical mixtures with the high homogeneous molecular dispersion and the crystalline modification of IND appearing to be the cause. This behavior may have a beneficial effect on the biopharmaceutical performance of this drug.

Un modelo integrado de motivación en el trabajo (ASH-Mot) se puso a prueba en una muestra multicultural mediante el análisis de la validez de constructo y convergente. Este modelo integra, dentro de una red de relaciones, varios constructos motivacionales que operan a distintos niveles: necesidades, instrumentalidad, creencias de auto-eficacia, equidad y estados psicológicos críticos (conocimiento de los resultados, responsabilidad y significado). Dos estudios transversales se llevaron a cabo. En el primero participaron cuatro muestras diferentes de Chile, España, Inglaterra y Portugal. La validez de constructo de los instrumentos de medición se estudió por medio del AFC. En el segundo estudio, participó una muestra de México; se analizó la convergencia entre la medida de motivación propuesto por el ASH-Mot y otras medidas de motivación. Los resultados fueron positivos; reveló altos índices de ajuste entre los datos y el modelo teórico (valores superiores a 0,90 y residuos inferiores a 0,08), así como una alta convergencia entre las diferentes medidas de motivación (correlaciones superiores a 0,6). El modelo de ASH-Mot muestra unos valores adecuados de validez de sus herramientas y, más importante, proporciona información clave para la adaptación de las intervenciones una vez que los bajos niveles de motivación han sido detectados.

An study of temporal organization of the cycle-to-cycle variability (CCV) in spark ignition engines fueled with gasoline–hydrogen blends is presented. First, long time series are generated by means of a quasi-dimensional model incorporating the key chemical and physical components, leading to variability in the time evolution of energetic functions. The alterations in the combustion process, for instance the composition of reactants, may lead to quantitative changes in the time evolution of the main engine variables. It has been observed that the presence of hydrogen in the fuel mixture leads to an increased laminar flame speed, with a corresponding decrease in CCV dispersion. Here, the effects of different hydrogen concentrations in the fuel are considered. First, it is observed that return maps of heat release sequences exhibit different patterns for different hydrogen concentrations and fuel–air ratios. Second, a symbolic analysis is used to characterize time series. The symbolic method is based on the probability of occurrence of consecutive states (a word) in a symbolic sequence histogram (SSH). Modified Shannon entropy is computed in order to determine the adequate word length. Results reveal the presence of non-random patterns in the sequences and soft transitions between states. Moreover, the general behavior of CCV simulations results and three types of synthetic noises: white, log-normal, and a noisy logistic map, are compared. This analysis reveals that the non-random features observed in heat release sequences are quite different from synthetic noises.