Can Mesoporous Silica Speed Up Degradation of Benzodiazepines? Hints from Quantum Mechanical Investigations

This work reports for the first time a quantum mechanical study of the interactions of a model benzodiazepine drug, i.e., nitrazepam, with various models of amorphous silica surfaces, differing in structural and interface properties. The interest in these systems is related to the use of mesoporous silica as carrier in drug delivery. The adopted computational procedure has been chosen to investigate whether silica–drug interactions favor the drug degradation mechanism or not, hindering the beneficial pharmaceutical effect. Computed structural, energetics, and vibrational properties represent a relevant comparison for future experiments. Our simulations demonstrate that adsorption of nitrazepam on amorphous silica is a strongly exothermic process in which a partial proton transfer from the surface to the drug is observed, highlighting a possible catalytic role of silica in the degradation reaction of benzodiazepines

Mature adults becoming teachers : sailing toward Ithaka.

My research was an eighteen-month study of how mature, college-educated adults (age range 24-56, professional experience diverse) transformed themselves from the men and women who entered a small, independent, field-based teacher preparation program in August into effective, state-certified teachers by the following June. The study continued into the next school year, tracing further development of each of the originally selected nine intern teachers, seven in their own classrooms, two, finally, in other chosen roles. The research was an interpretive study, combining the use of questionnaires, classroom observation, selections from journals, and in-depth interview/discussions with each of the nine participants at four times during the eighteen months. The interns\u27 own assessments of the time in different classroom settings with children/young adults and experienced mentor teachers, were that the extensive daily experiences were pivotal in moving them toward a perception of self as teacher. This perception represents an aspect of human development described by Piaget as decalage, by Kegan as the whole becoming a part of a new whole, by Perry as commitment in relativism. Learning of this depth and human development are synonymous. Analysis of reflective comments of participants revealed how each mature intern teacher wove knowledge, attitudes, materials, educational theory, support from his/her mentor teacher, and personality into the unique teacher she/he was becoming. The intensity of the intern experience led the majority of the interns, by the middle of the second semester, to know the kind of teacher each would be, to be articulate in discussing her/his approach to teaching in both theoretical and practical terminology, and to display effective leadership in the classroom. The route to this knowing I call an epistemology of learning. This is a study of individuals who know what they have learned in such a deep, meaningful sense that they are confident in their useable knowledge. The route to this knowing is interactive and collaborative, experiential and theoretical; the resultant learning is deeply meaningful in that it incorporates intellect and emotion as the whole person develops dynamically (Kegan), works through the imbalance of transition to a more inclusive view of the world (Perry), and senses the ego-integrity of a generative self (Erikson)

Reconstructing reactivity in dynamic host-guest systems at atomistic resolution: amide hydrolysis under confinement in the cavity of a coordination cage

Spatial confinement is widely employed by nature to attain unique efficiency in controlling chemical reactions. Notable examples are enzymes, which selectively bind reactants and exquisitely regulate their conversion into products. In an attempt to mimic natural catalytic systems, supramolecular metal-organic cages capable of encapsulating guests in their cavity and of controlling/accelerating chemical reactions under confinement are attracting increasing interest. However, the complex nature of these systems, where reactants/products continuously exchange in-and-out of the host, makes it often difficult to elucidate the factors controlling the reactivity in dynamic regimes. As a case study, here we focus on a coordination cage that can encapsulate amide guests and enhance their hydrolysis by favoring their mechanical twisting towards reactive molecular configurations under confinement. We designed an advanced multiscale simulation approach that allows us to reconstruct the reactivity in such host-guest systems in dynamic regimes. In this way, we can characterize amide encapsulation/expulsion in/out of the cage cavity (thermodynamics and kinetics), coupling such host-guest dynamic equilibrium with characteristic hydrolysis reaction constants. All computed kinetic/thermodynamic data are then combined, obtaining a statistical estimation of reaction acceleration in the host-guest system that is found in optimal agreement with the available experimental trends. This shows how, to understand the key factors controlling accelerations/variations in the reaction under confinement, it is necessary to take into account all dynamic processes that occur as intimately entangled in such host-guest systems. This also provides us with a flexible computational framework, useful to build structure-dynamics-property relationships for a variety of reactive host-guest systems

Measuring Ultrasonic Characterisation to Determine the Impact of Toc and the Stress Field on Shale Gas Anisotropy

While the majority of natural gas is produced from conventional sources, there is significant growth from unconventional sources, including shale-gas reservoirs. To produce gas economically, candidate shale typically requires a range of characteristics, including a relatively high total organic carbon (TOC) content, and it must be gas mature. Mechanical and dynamic elastic properties are also important shale characteristics that are not well understood as there have been a limited number of investigations of well-preserved samples. In this study, the elastic properties of shale samples are determined by measuring wave velocities. Arrays of ultrasonic transducers are used to measure five independent wave velocities, which are used to calculate the elastic properties of the shale. The results indicated that for the shale examined in this research, P- and S-wave velocities vary depending on the isotropic stress conditions with respect to the fabric and TOC content. It was shown that the isotropic stress significantly impacts velocity. In addition, S-wave anisotropy was significantly affected by increasing stress anisotropy. Stress orientation, with respect to fabric orientation, was found to be an important influence on the degree of anisotropy of the dynamic elastic properties in the shale. Furthermore, the relationship between acoustic impedance (AI) and TOC was established for all the samples

Rapid detection of copy number variations and point mutations in BRCA1/2 genes using a single workflow by ion semiconductor sequencing pipeline

Molecular analysis of BRCA1 (MIM# 604370) and BRCA2 (MIM #600185) genes is essential for familial breast and ovarian cancer prevention and treatment. An efficient, rapid, cost-effective accurate strategy for the detection of pathogenic variants is crucial. Mutations detection of BRCA1/2 genes includes screening for single nucleotide variants (SNVs), small insertions or deletions (indels), and Copy Number Variations (CNVs). Sanger sequencing is unable to identify CNVs and therefore Multiplex Ligation Probe amplification (MLPA) or Multiplex Amplicon Quantification (MAQ) is used to complete the BRCA1/2 genes analysis. The rapid evolution of Next Generation Sequencing (NGS) technologies allows the search for point mutations and CNVs with a single platform and workflow. In this study we test the possibilities of NGS technology to simultaneously detect point mutations and CNVs in BRCA1/2 genes, using the OncomineTM BRCA Research Assay on Personal Genome Machine (PGM) Platform with Ion Reporter Software for sequencing data analysis (Thermo Fisher Scientific). Comparison between the NGS-CNVs, MLPA and MAQ results shows how the NGS approach is the most complete and fast method for the simultaneous detection of all BRCA mutations, avoiding the usual time consuming multistep approach in the routine diagnostic testing of hereditary breast and ovarian cancers

Estimation of Carbonate Elastic Properties Using Nanoindentation and Digital Images

Petrophysical properties of carbonate reservoirs are less predictable than the properties of silisiclastic reservoirs. The main reason for that is chemical interaction of carbonate rocks with percolating fluids, ion exchange and recrystallization in geological time. Quantification of the elastic variability of carbonate grains on the microscale is the first step to constrain models and to obtain more realistic predictions of practically important rock properties of carbonate reservoirs. In this study we present elastic moduli of an oolite sample from the Pleistocene Dampier Formation of Southern Carnarvon Basin, Western Australia obtained by the nanoindentation technique.Young moduli of this highly heterogeneous sample are measured at 49 points regularly distributed in a 70x70micrometer rectangular grid on the surface. The frequency diagram shows bimodal distribution of the Young moduli that correspond to dense calcite phase and rare (dissolved) calcite phase. These two solid phases are apparent in the high resolution scanning electron microscope images. We used the obtained moduli of the dense and rare phases for numerical modelling of elastic properties of the carbonate sample from micro-CT images. The results of the numerical modelling using finite element code are compared with the elastic moduli obtained from acoustic velocities measured by ultrasonic technique

On the interactions of melatonin/β-cyclodextrin inclusion complex: A novel approach combining efficient semiempirical extended tight-binding (xtb) results with ab initio methods

Melatonin (MT) is a molecule of paramount importance in all living organisms, due to its presence in many biological activities, such as circadian (sleep–wake cycle) and seasonal rhythms (reproduction, fattening, molting, etc.). Unfortunately, it suffers from poor solubility and, to be used as a drug, an appropriate transport vehicle has to be developed, in order to optimize its release in the human tissues. As a possible drug-delivery system, β-cyclodextrin (βCD) represents a promising scaffold which can encapsulate the melatonin, releasing when needed. In this work, we present a computational study supported by experimental IR spectra on inclusion MT/βCD complexes. The aim is to provide a robust, accurate and, at the same time, low-cost methodology to investigate these inclusion complexes both with static and dynamic simulations, in order to study the main actors that drive the interactions of melatonin with β-cyclodextrin and, therefore, to understand its release mechanism

On the interactions of melatonin/β-cyclodextrin inclusion complex: A novel approach combining efficient semiempirical extended tight-binding (xtb) results with ab initio methods

Melatonin (MT) is a molecule of paramount importance in all living organisms, due to its presence in many biological activities, such as circadian (sleep–wake cycle) and seasonal rhythms (reproduction, fattening, molting, etc.). Unfortunately, it suffers from poor solubility and, to be used as a drug, an appropriate transport vehicle has to be developed, in order to optimize its release in the human tissues. As a possible drug-delivery system, β-cyclodextrin (βCD) represents a promising scaffold which can encapsulate the melatonin, releasing when needed. In this work, we present a computational study supported by experimental IR spectra on inclusion MT/βCD complexes. The aim is to provide a robust, accurate and, at the same time, low-cost methodology to investigate these inclusion complexes both with static and dynamic simulations, in order to study the main actors that drive the interactions of melatonin with β-cyclodextrin and, therefore, to understand its release mechanism

Innate dynamics and identity crisis of a metal surface unveiled by machine learning of atomic environments

Metals are traditionally considered hard matter. However, it is well known that their atomic lattices may become dynamic and undergo reconfigurations even well below the melting temperature. The innate atomic dynamics of metals is directly related to their bulk and surface properties. Understanding their complex structural dynamics is, thus, important for many applications but is not easy. Here, we report deep-potential molecular dynamics simulations allowing to resolve at an atomic resolution the complex dynamics of various types of copper (Cu) surfaces, used as an example, near the Hüttig (∼1/3 of melting) temperature. The development of deep neural network potential trained on density functional theory calculations provides a dynamically accurate force field that we use to simulate large atomistic models of different Cu surface types. A combination of high-dimensional structural descriptors and unsupervized machine learning allows identifying and tracking all the atomic environments (AEs) emerging in the surfaces at finite temperatures. We can directly observe how AEs that are non-native in a specific (ideal) surface, but that are, instead, typical of other surface types, continuously emerge/disappear in that surface in relevant regimes in dynamic equilibrium with the native ones. Our analyses allow estimating the lifetime of all the AEs populating these Cu surfaces and to reconstruct their dynamic interconversions networks. This reveals the elusive identity of these metal surfaces, which preserve their identity only in part and in part transform into something else under relevant conditions. This also proposes a concept of “statistical identity” for metal surfaces, which is key to understanding their behaviors and properties

Ataxia with oculomotor apraxia type 2: a clinical, pathologic, and genetic study

BACKGROUND: Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset between age 10 and 22 years, cerebellar atrophy, peripheral neuropathy, oculomotor apraxia (OMA), and elevated serum alpha-fetoprotein (AFP) levels. Recessive mutations in SETX have been described in AOA2 patients. OBJECTIVE: To describe the clinical features of AOA2 and to identify the SETX mutations in 10 patients from four Italian families. METHODS: The patients underwent clinical examination, routine laboratory tests, nerve conduction studies, sural nerve biopsy, and brain MRI. All were screened for SETX mutations. RESULTS: All the patients had cerebellar features, including limb and truncal ataxia, and slurred speech. OMA was observed in two patients, extrapyramidal symptoms in two, and mental impairment in three. High serum AFP levels, motor and sensory axonal neuropathy, and marked cerebellar atrophy on MRI were detected in all the patients who underwent these examinations. Sural nerve biopsy revealed a severe depletion of large myelinated fibers in one patient, and both large and small myelinated fibers in another. Postmortem findings are also reported in one of the patients. Four different homozygous SETX mutations were found (a large-scale deletion, a missense change, a single-base deletion, and a splice-site mutation). CONCLUSIONS: The clinical phenotype of oculomotor apraxia type 2 is fairly homogeneous, showing only subtle intrafamilial variability. OMA is an inconstant finding. The identification of new mutations expands the array of SETX variants, and the finding of a missense change outside the helicase domain suggests the existence of at least one more functional region in the N-terminus of senataxin