Tobramycin nanoformulation for chronic pulmonary infections: From drug product definition to scale-up for preclinical evaluation.

Cystic fibrosis (CF) is characterized by abnormal mucus hydration due to a defective CF Transmembrane Regulator (CFTR) protein, leading to the production of difficult-to-clear mucus. This causes airflow obstruction, recurrent infections, and respiratory complications. Chronic lung infections are the leading cause of death for CF patients and inhaled tobramycin is the first-in-line antibiotic treatment against these infections, mainly caused by Pseudomonas aeruginosa in adult patients.

activity of novel apramycin-dextran nanoparticles and free apramycin against selected Dutch and Pakistani isolates.

are bacteria associated with respiratory tract infections and are increasingly becoming resistant to antibiotics, including carbapenems. Apramycin is a veterinary antibiotic that may have the potential to be re-purposed for use in human health, for example, for the treatment of respiratory tract infections after coupling to inhalable nanoparticles. In the present study, the antibiotic apramycin was formulated with single chain polymeric nanoparticles and tested in free and formulated forms against a set of 13 isolates (from the Netherlands and Pakistan) expressing different aminoglycoside resistance phenotypes.

Poly-l-glutamic acid modification modulates the bio-nano interface of a therapeutic anti-IGF-1R antibody in prostate cancer.

Modifying biological agents with polymers such as polyethylene glycol (PEG) has demonstrated clinical benefits; however, post-market surveillance of PEGylated derivatives has revealed PEG-associated toxicity issues, prompting the search for alternatives. We explore how conjugating a poly-l-glutamic acid (PGA) to an anti-insulin growth factor 1 receptor antibody (AVE1642) modulates the bio-nano interface and anti-tumor activity in preclinical prostate cancer models. Native and PGA-modified AVE1642 display similar anti-tumor activity in vitro; however, AVE1642 prompts IGF-1R internalization while PGA conjugation prompts higher affinity IGF-1R binding, thereby inhibiting IGF-1R internalization and altering cell trafficking.

Neutralization of ionic interactions by dextran-based single-chain nanoparticles improves tobramycin diffusion into a mature biofilm.

The extracellular matrix protects biofilm cells by reducing diffusion of antimicrobials. Tobramycin is an antibiotic used extensively to treat P. aeruginosa biofilms, but it is sequestered in the biofilm periphery by the extracellular negative charge matrix and loses its efficacy significantly.

Polyacetal-Based Combination Therapy for the Treatment of Prostate Cancer.

The high incidence of prostate carcinogenesis has prompted the search for novel effective treatment approaches. We have employed curcumin (Curc) and diethylstilbestrol (DES) to synthesize a series of polyacetal (PA)-based combination conjugates for prostate cancer (PCa) treatment. Given their bihydroxyl functionalities, Curc and DES molecules were incorporated into a PA mainchain using a one-pot reaction between diols and divinyl ethers.

HIF-1α inhibition by diethylstilbestrol and its polyacetal conjugate in hypoxic prostate tumour cells: insights from NMR metabolomics.

In this study, we have employed H NMR metabolomics to assess the metabolic responses of PC3 prostate tumour cells to hypoxia and to pharmacological HIF-1α inhibition by DES or its polyacetal conjugate tert-DES. Oxygen deprivation prompted a number of changes in intracellular composition and metabolic activity, mainly reflecting upregulated glycolysis, amino acid catabolism and other compensatory mechanisms used by hypoxic cells to deal with oxidative imbalance and energy deficit. Cell treatment with a non-cytotoxic concentration of DES, under hypoxia, triggered significant changes in 17 metabolites.

Near-infrared activatable phthalocyanine-poly-L-glutamic acid conjugate: increased cellular uptake and light-dark toxicity ratio toward an effective photodynamic cancer therapy.

In photodynamic therapy (PDT), the low absorptivity of photosensitizers in an aqueous environment reduces singlet oxygen generation efficiency and thereby decreases photosensitizing efficacy in biological conditions. To circumvent this problem, we designed a phthalocyanine-poly-L-glutamic acid conjugate (1-PG) made from a new phthalocyanine (Pc 1) monofunctionalized to allow adequate conjugation to PGA. The resulting 1-PG conjugate retained high absorptivity in the near-infrared (NIR) region at its λ 675nm in an aqueous environment.

Using Optimal Control to Disambiguate the Effect of Depression on Sensorimotor, Motivational and Goal-Setting Functions.

Differentiating the ability from the motivation to act is of central importance to psychiatric disorders in general and depression in particular. However, it has been difficult to develop quantitative approaches to relate depression to poor motor performance in goal-directed tasks. Here, we use an inverse optimal control approach to provide a computational framework that can be used to infer and factorize performance deficits into three components: sensorimotor speed, goal setting and motivation.

The Influence of Depression on Cognitive Control: Disambiguating Approach and Avoidance Tendencies.

Dysfunctions of approach and avoidance motivation play an important role in depression, which in turn may affect cognitive control, i.e., the ability to regulate thoughts and action to achieve internal goals.

Infants Time Their Smiles to Make Their Moms Smile.

One of the earliest forms of interaction between mothers and infants is smiling games. While the temporal dynamics of these games have been extensively studied, they are still not well understood. Why do mothers and infants time their smiles the way they do? To answer this question we applied methods from control theory, an approach frequently used in robotics, to analyze and synthesize goal-oriented behavior.

Smart branched polymer drug conjugates as nano-sized drug delivery systems.

Polymer-drug conjugates represent excellent nanopharmaceutical candidates, as they offer multiple advantages related to their intrinsic characteristics. Many of the said characteristics are provided by the covalent bonding between the drug and the polymer. However, their clinical development has been slow and only one polymer-drug conjugate has reached the market, thus there remains an urgent need for the development of new and smart polymeric systems.

Facial Video-Based Photoplethysmography to Detect HRV at Rest.

Our aim is to demonstrate the usefulness of photoplethysmography (PPG) for analyzing heart rate variability (HRV) using a standard 5-min test at rest with paced breathing, comparing the results with real RR intervals and testing supine and sitting positions. Simultaneous recordings of R-R intervals were conducted with a Polar system and a non-contact PPG, based on facial video recording on 20 individuals. Data analysis and editing were performed with individually designated software for each instrument.

New Ionic bis-MPA and PAMAM Dendrimers: A Study of Their Biocompatibility and DNA-Complexation.

Herein, the synthesis of five novel ionic dendrimers and their evaluation as biological carriers is reported. The compounds include an ionic bis-MPA dendrimer and four PAMAM dendrimers of different generations decorated with negatively charged hydrophilic chains of 2-[2-(2-methoxyethoxy)ethoxy]acetic acid as counter ions in order to increase their biocompatibility. The ionic dendrimers derived from bis-MPA have a low cytotoxicity at 0.

Amphiphilic dendritic derivatives as nanocarriers for the targeted delivery of antimalarial drugs.

It can be foreseen that in a future scenario of malaria eradication, a varied armamentarium will be required, including strategies for the targeted administration of antimalarial compounds. The development of nanovectors capable of encapsulating drugs and of delivering them to Plasmodium-infected cells with high specificity and efficacy and at an affordable cost is of particular interest. With this objective, dendritic derivatives based on 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) and Pluronic(®) polymers have been herein explored.

HRV based health&sport markers using video from the face.

Heart Rate Variability (HRV) is an indicator of health status in the general population and of adaptation to stress in athletes. In this paper we compare the performance of two systems to measure HRV: (1) A commercial system based on recording the physiological cardiac signal with (2) A computer vision system that uses a standard video images of the face to estimate RR from changes in skin color of the face. We show that the computer vision system performs surprisingly well.

Synthesis and evaluation as biodegradable herbicides of halogenated analogs of L-meta-tyrosine.

L-meta-tyrosine is an herbicidal nonprotein amino acid isolated some years ago from fine fescue grasses and characterized by its almost immediate microbial degradation in soil (half-life <24 h). Nine monohalogenated or dihalogenated analogs of this allelochemical have been obtained through a seven-step stereoselective synthesis from commercial halogenated phenols. Bioassays showed a large range of biological responses, from a growth root inhibition of lettuce seedling similar to that noted with m-tyrosine [2-amino-3-(2-chloro-5-hydroxyphenyl)propanoic acid or compound 8b] to an increase of the primary root growth concomitant with a delay of secondary root initiation [2-amino-3-[2-fluoro-5-hydroxy-3-(trifluoromethyl)phenyl]propanoic acid or compound 8h].

Multilayer Architectures for Facial Action Unit Recognition.

In expression recognition and many other computer vision applications, the recognition performance is greatly improved by adding a layer of nonlinear texture filters between the raw input pixels and the classifier. The function of this layer is typically known as feature extraction. Popular filter types for this layer are Gabor energy filters (GEFs) and local binary patterns (LBPs).

When a robot is social: spatial arrangements and multimodal semiotic engagement in the practice of social robotics.

Social roboticists design their robots to function as social agents in interaction with humans and other robots. Although we do not deny that the robot's design features are crucial for attaining this aim, we point to the relevance of spatial organization and coordination between the robot and the humans who interact with it. We recover these interactions through an observational study of a social robotics laboratory and examine them by applying a multimodal interactional analysis to two moments of robotics practice.

Detecting contingencies: an infomax approach.

The ability to detect social contingencies plays an important role in the social and emotional development of infants. Analyzing this problem from a computational perspective may provide important clues for understanding social development, as well as for the synthesis of social behavior in robots. In this paper, we show that the turn-taking behaviors observed in infants during contingency detection situations are tuned to optimally gather information as to whether a person is responsive to them.

Tracking motion, deformation, and texture using conditionally gaussian processes.

We present a generative model and inference algorithm for 3D nonrigid object tracking. The model, which we call G-flow, enables the joint inference of 3D position, orientation, and nonrigid deformations, as well as object texture and background texture. Optimal inference under G-flow reduces to a conditionally Gaussian stochastic filtering problem.

Toward practical smile detection.

Machine learning approaches have produced some of the highest reported performances for facial expression recognition. However, to date, nearly all automatic facial expression recognition research has focused on optimizing performance on a few databases that were collected under controlled lighting conditions on a relatively small number of subjects. This paper explores whether current machine learning methods can be used to develop an expression recognition system that operates reliably in more realistic conditions.

Foundations for a new science of learning.

Human learning is distinguished by the range and complexity of skills that can be learned and the degree of abstraction that can be achieved compared with those of other species. Homo sapiens is also the only species that has developed formal ways to enhance learning: teachers, schools, and curricula. Human infants have an intense interest in people and their behavior and possess powerful implicit learning mechanisms that are affected by social interaction.

Contrastive divergence in gaussian diffusions.

This letter presents an analysis of the contrastive divergence (CD) learning algorithm when applied to continuous-time linear stochastic neural networks. For this case, powerful techniques exist that allow a detailed analysis of the behavior of CD. The analysis shows that CD converges to maximum likelihood solutions only when the network structure is such that it can match the first moments of the desired distribution.