Carbohydrate-derived amphiphilic macromolecules: a biophysical structural characterization and analysis of binding behaviors to model membranes.

The design and synthesis of enhanced membrane-intercalating biomaterials for drug delivery or vascular membrane targeting is currently challenged by the lack of screening and prediction tools. The present work demonstrates the generation of a Quantitative Structural Activity Relationship model (QSAR) to make a priori predictions. Amphiphilic macromolecules (AMs) "stealth lipids" built on aldaric and uronic acids frameworks attached to poly(ethylene glycol) (PEG) polymer tails were developed to form self-assembling micelles. In the present study, a defined set of novel AM structures were investigated in terms of their binding to lipid membrane bilayers using Quartz Crystal Microbalance with Dissipation (QCM-D) experiments coupled with computational coarse-grained molecular dynamics (CG MD) and all-atom MD (AA MD) simulations. The CG MD simulations capture the insertion dynamics of the AM lipophilic backbones into the lipid bilayer with the PEGylated tail directed into bulk water. QCM-D measurements with Voigt viscoelastic model analysis enabled the quantitation of the mass gain and rate of interaction between the AM and the lipid bilayer surface. Thus, this study yielded insights about variations in the functional activity of AM materials with minute compositional or stereochemical differences based on membrane binding, which has translational potential for transplanting these materials in vivo. More broadly, it demonstrates an integrated computational-experimental approach, which can offer a promising strategy for the in silico design and screening of therapeutic candidate materials

Cardiac involvement in children with paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS): data from a prospective nationwide surveillance study.

BACKGROUND Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) may occur 4 to 8 weeks after SARS-CoV-2 infection. The acute presentation of PIMS-TS has been well described, but data on longer-term outcomes, particularly cardiac, is scarce. METHODS This prospective nationwide surveillance study included children and adolescents less than 18 years of age who were hospitalised with PIMS-TS in Switzerland between March 2020 and March 2022. Data was collected from all 29 paediatric hospitals through the Swiss Paediatric Surveillance Unit (SPSU) during hospitalisation and approximately six weeks after discharge. The data was analysed after categorising the participants into three groups based on their admission status to the intensive care unit (ICU) (non-ICU, ICU-moderate) and the requirement for invasive ventilatory and/or inotropic support (ICU-severe). RESULTS Overall, 204 children were included of whom 194 (95.1%) had follow-up data recorded. Median age was 9.0 years (interquartile range [IQR] 6.0-11.5) and 142 (69.6%) were male. In total, 105/204 (51.5%) required ICU admission, of whom 55/105 (52.4%) received inotropic support and 14/105 (13.3%) mechanical ventilation (ICU-severe group). Echocardiography was performed in 201/204 (98.5%) children; 132 (64.7%) had a cardiac abnormality including left ventricular systolic dysfunction (73 [36.3%]), a coronary artery abnormality (45 [22.4%]), pericardial effusion (50 [24.9%]) and mitral valve regurgitation (60 [29.9%]). Left ventricular systolic dysfunction was present at admission in 62/201 (30.8%) children and appeared during hospitalisation in 11 (5.5%) children. A coronary artery abnormality was detected at admission in 29/201 (14.2%) children and developed during hospitalisation or at follow-up in 13 (6.5%) and 3 (1.5%) children, respectively. None of the children had left ventricular systolic dysfunction at follow-up, but a coronary abnormality and pericardial effusion were found in 12 (6.6%) and 3 (1.7%) children, respectively. School absenteeism at the time of follow-up was more frequent in children who had been admitted to the ICU (2.5% in the non-ICU group compared to 10.4% and 17.6% in the ICU-moderate and ICU-severe group, respectively) (p = 0.011). CONCLUSION Cardiac complications in children presenting with PIMS-TS are common and may worsen during the hospitalisation. Irrespective of initial severity, resolution of left ventricular systolic dysfunction is observed, often occurring rapidly during the hospitalisation. Most of the coronary artery abnormalities regress; however, some are still present at follow-up, emphasising the need for prolonged cardiac evaluation after PIMS-TS

Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points

Interfacial interactions of nanoparticles with surfactants and polymers: a computational approach to target biomedical and pharmaceutical systems

Nanotechnology is an emerging field with the promise for new materials and applications, particularly in the medical field for diagnosis and treatment of disease. The high surface area to volume ratio of nanoparticles gives rise to useful material properties such as enhanced solubility and dissolution for drug nanoparticles as well as superparamagnetism in the case of magnetic nanoparticles. Often, nanoparticle interactions with surfactants and polymers arise in a variety of scenarios: the production and stabilization to reduce particle agglomeration, to aid in nanoparticle delivery to specific areas of the body, increase bioavailability by avoiding body clearance mechanisms, add desired functionality, and finally the biological targets of nanoparticles are often the surfactants (lipids of the cell membrane) or polymers (proteins) of the body. Understanding the interfacial interactions of nanoparticles with polymers or surfactants is therefore crucial in proceeding ahead with nanoparticles as viable options for medical treatments. In this dissertation, a series of computational techniques are employed to elucidate the interfacial interactions at the molecular level between surfactants, polymers, ii and nanoparticles in three different case studies. First, Molecular Dynamics and Dissipative Particle Dynamics simulation methods are used to study the stability of a model cell membrane to an applied stress in order to mimic the interactions that occur in magnetic fluid hyperthermia, a nanoparticle-based treatment for cancerous tumors. Here, the aim is to determine if magnetic nanoparticles are capable of generating mechanical forces sufficient to rupture a cell membrane. Secondly, coarse-grained Molecular Dynamics is utilized to explore the interaction of micelle-forming amphiphilic molecules interacting with the human scavenger receptor A for use in preventing uptake of oxidized low-density lipoproteins. Finally, Monte Carlo simulations are developed to study nanocrystal nucleation from solution in the presence of polymers to determine factors that act to promote or inhibit nucleation. iiiPh. D.Includes bibliographical referencesIncludes vitaby Michael D. Tomasin

Candidate targets for Multilocus Sequence Typing of Trypanosoma cruzi: validation using parasite stocks from the Chaco Region and a set of reference strains.

A Multilocus Sequence Typing (MLST) scheme was designed and applied to a set of 20 Trypanosoma cruzi stocks belonging to three main discrete typing units (T. cruzi I, V and VI) from a geographically restricted Chagas disease endemic area in Argentina, 12 reference strains comprising two from each of the six main discrete typing units of the parasite (T. cruzi I-VI), and one T. cruzi marinkellei strain. DNA fragments (≅400-bp) from 10 housekeeping genes were sequenced. A total of 4178 bp were analyzed for each stock. In all, 154 polymorphic sites were identified. Ninety-five sites were heterozygous in at least one analyzed stock. Seventeen diploid sequence types were identified from 32 studied T. cruzi stocks (including the reference strains). All stocks were correctly assigned to their corresponding discrete typing units. We propose this MLST scheme as provisional, with scope for improvement by studying new gene targets on a more diverse sample of stocks, in order to define an optimized MLST scheme for T. cruzi. This approach is an excellent candidate to become the gold standard for T. cruzi genetic typing. We suggest that MLST will have a strong impact on molecular epidemiological studies of Chagas disease and the phylogenetics of its causative agent

Assessing spatial patterns of phylogenetic diversity of Mexican mammals for biodiversity conservation

Phylogenetic diversity is a biodiversity measurement that describes the amount of evolutionary history contained by the taxonomic units in a region. It has proven to be an important metric for determining conservation priorities. Mammalian phylogenetic diversity patterns have been suggested as potential surrogates of biodiversity for establishing priority areas for conservation. This study aims to identify areas of high mammalian phylogenetic diversity in Mexico, a megadiverse country with high mammalian richness, and to assess how well protected areas encompass the phylogenetic diversity. IUCN distribution data for 479 Mexican mammals were used to estimate species richness. Data for the molecular markers cytB, 12S and COI, was gathered from GenBank and from laboratory extractions for reconstructing a maximum-likelihood phylogenetic tree. Spatial patterns in phylogenetic diversity were estimated by summing the branch lengths of the phylogenetic tree representing species presence across grid cells. The results were compared with the distribution of protected areas in Mexico in order to assess if phylogenetic diversity is effectively conserved. The southeastern part of Mexico was found to be the most diverse. The breadth of the phylogenetic tree was well represented within the protected areas. Beta-diversity analyses showed that the species composition between protected and unprotected areas is very similar. Protected areas group based on the phylogenetic composition of mammal species into three clusters corresponding to the Nearctic, Neotropical, and Mexican Transition Zone biogeographical regions, which suggests that protected areas could be managed based on these clusters