First-Principles Study of the Electronic and Magnetic Properties of Defects in Carbon Nanostructures

Understanding the magnetic properties of graphenic nanostructures is instrumental in future spintronics applications. These magnetic properties are known to depend crucially on the presence of defects. Here we review our recent theoretical studies using density functional calculations on two types of defects in carbon nanostructures: Substitutional doping with transition metals, and sp$^3$-type defects created by covalent functionalization with organic and inorganic molecules. We focus on such defects because they can be used to create and control magnetism in graphene-based materials. Our main results are summarized as follows: i)Substitutional metal impurities are fully understood using a model based on the hybridization between the $d$ states of the metal atom and the defect levels associated with an unreconstructed D$_{3h}$ carbon vacancy. We identify three different regimes, associated with the occupation of distinct hybridization levels, which determine the magnetic properties obtained with this type of doping; ii) A spin moment of 1.0 $\mu_B$ is always induced by chemical functionalization when a molecule chemisorbs on a graphene layer via a single C-C (or other weakly polar) covalent bond. The magnetic coupling between adsorbates shows a key dependence on the sublattice adsorption site. This effect is similar to that of H adsorption, however, with universal character; iii) The spin moment of substitutional metal impurities can be controlled using strain. In particular, we show that although Ni substitutionals are non-magnetic in flat and unstrained graphene, the magnetism of these defects can be activated by applying either uniaxial strain or curvature to the graphene layer. All these results provide key information about formation and control of defect-induced magnetism in graphene and related materials.

Interplay of Defects, Magnetism, Ripples and Strain in Graphene

We present a comprehensive study based on first-principles calculations about the interplay of four important ingredients on the electronic structure of graphene: defects + magnetism + ripples + strain. So far they have not been taken into account simultaneously in a set of ab initio calculations. Furthermore, we focus on the strain dependence of the properties of carbon monovacancies, with special attention to magnetic spin moments. We demonstrated that such defects show a very rich structural and spin phase-diagram with many spin solutions as function of strain. At zero strain the vacancy shows a spin moment of 1.5 Bohrs that increases up to 2 Bohrs with stretching. Changes are more dramatic under compression: the vacancy becomes non-magnetic under a compression larger than 2%. This transition is linked to the structural modifications associated with the formation of ripples in the graphene layer. Our results suggest that such interplay could have important implications for the design of future spintronics devices based on graphene derivatives, as for example a spin-strain switch based on vacancies.

Proliferative Defects and Formation of a Double Cortex in Mice Lacking Mltt4 and Cdh2 in the Dorsal Telencephalon

Radial glial cells (RGCs) in the ventricular neuroepithelium of the dorsal telencephalon are the progenitor cells for neocortical projection neurons and astrocytes. Here we showthatthe adherens junction proteins afadin and CDH2 are criticalforthe control of cell proliferation in the dorsal telencephalon and for the formation of its normal laminar structure. Inactivation of afadin or CDH2 in the dorsal telenceph-alon leads to a phenotype resembling subcortical band heterotopia, also known as “double cortex,” a brain malformation in which heterotopic gray matter is interposed between zones of white matter. Adherens junctions between RGCs are disrupted in the mutants, progenitor cells are widely dispersed throughout the developing neocortex, and their proliferation is dramatically increased. Major subtypes of neocortical projection neurons are generated, but their integration into cell layers is disrupted. Our findings suggest that defects in adherens junctions components in mice massively affects progenitor cell proliferation and leads to a double cortex-like phenotype.

Microstructure and tensile properties of carbon-epoxy laminates produced by automated fibre placement: Influence of a caul plate on the effects of gap and overlap embedded defects

Automated fibre placement (AFP) enables the trajectory of unidirectional composite tape to be optimized, but laying down complex shapes with this technology can result in the introduction of defects. The aim of this experimental study is to investigate the influence of gaps and overlaps on the microstructure and tensile properties of carbon-epoxy laminates. First, a comparison between a hand-layup and AFP layup, draped and cured under the same conditions, shows equivalent microstructures and tensile properties. This provides the reference values for the study. Then, gap and overlap embedded defects (more or less severe) are introduced during manufacturing, on two cross-ply layups [(0°/(90°)5/0°] and [(90°/0°)2/90°]. Autoclave cure without a caul plate results in local thickness variation and microstructural changes which depend on the defect type. This has a strong influence on mechanical performance. Use of a caul plate avoids these variations and in this case embedded defects hardly affect tensile properties.

Proliferative Defects and Formation of a Double Cortex in Mice Lacking Mltt4 and Cdh2 in the Dorsal Telencephalon

Radial glial cells (RGCs) in the ventricular neuroepithelium of the dorsal telencephalon are the progenitor cells for neocortical projection neurons and astrocytes. Here we showthatthe adherens junction proteins afadin and CDH2 are criticalforthe control of cell proliferation in the dorsal telencephalon and for the formation of its normal laminar structure. Inactivation of afadin or CDH2 in the dorsal telenceph-alon leads to a phenotype resembling subcortical band heterotopia, also known as “double cortex,” a brain malformation in which heterotopic gray matter is interposed between zones of white matter. Adherens junctions between RGCs are disrupted in the mutants, progenitor cells are widely dispersed throughout the developing neocortex, and their proliferation is dramatically increased. Major subtypes of neocortical projection neurons are generated, but their integration into cell layers is disrupted. Our findings suggest that defects in adherens junctions components in mice massively affects progenitor cell proliferation and leads to a double cortex-like phenotype.

Transcatheter Closure of Atrial Septal Defects in a Center With Limited Resources: Outcomes and Short Term Follow-Up

Background: Transcatheter closure of atrial septal defects (ASD) has been accepted world-wide as an alternative to surgical closure with excellent results. This interventional, non-surgical technique plays an important role in the treatment of ASD mostly in the developing world where resources are limited. Objectives: To report the outcomes and short term follow-up of transcatheter closure of ASD over a 12-year period at our institution with limited resources. Patients and Methods: This retrospective study included all patients with the diagnosis of secundum ASD and significant shunting (Qp/Qs > 1.5:1) as well as dilated right atrium and right ventricle who had transcatheter closure at Integrated Cardiovascular Center (PJT), Dr. Cipto Mangunkusumo Hospital between October 2002 and October 2014. One hundred fifty-two patients enrolled in this study were candidates for device closure. Right and left heart cardiac catheterization was performed before the procedure. All patients underwent physical examination, ECG, chest X-ray and transthoracal echocardiography (TTE) prior to device implantation. Results: A total of 152 patients with significant ASD underwent device implantation. Subjects’ age ranged from 0.63 to 69.6 years, with median 9.36 years and mean 16.30 years. They consisted of 33 (21.7%) males and 119 (78.3%) females, with mean body weight of 29.9 kg (range 8 to 75; SD 18.2). The device was successfully implanted in 150 patients where the majority of cases received the Amplatzer septal occluder (147/150; 98%) and the others received the Heart Lifetech ASD occluder (3/150, 2%), whereas two other cases were not suitable for device closure and we decided for surgical closure. The mean ASD size was 19.75 (range 14 - 25) mm. During the procedure, 5 (4.9%) patients had bradycardia and 3 (2.9%) patients had supraventricular tachycardia (SVT), all of which resolved. Conclusions: In our center with limited facilities and manpower, transcatheter closure of atrial septal defect was effective and safe as an alternative treatment to surgery. The outcome and short-term follow-up revealed excellent results, but long-term follow-up is needed.

Syndromic scalp defects : genotype-phenotype studies in Johanson-Blizzard syndrome and Adams-Oliver syndrome

Otto-von-Guericke-Universität Magdeburg, Fakultät für Naturwissenschaften, Dissertation, 2016

Convergent bioenergetic defects in Coenzyme Q10 depleted cells by pharmacological inhibition of coq2 enzyme (p-hydroxybenzoate polyprenyl transferase) and by genome editing technology targeting the encoding gene (COQ2)

Primary CoQ10 deficiency diseases encompass a heterogeneous spectrum of clinical phenotypes. Among these, defect or mutation on COQ2 gene, encoding a para-hydroxybenzoate polyprenyl transferase, have been associated with different diseases. Understanding the functional and metabolic impact of COQ2 mutation and the consequent CoQ10 deficiency is still a matter of debate. To date the aetiology of the neurological phenotypes correlated to CoQ10 deficiency does not present a clear genotype-phenotype association. In addition to the metabolic alterations due to Coenzyme Q depletion, the impairment of mitochondrial function, associated with the reduced CoQ level, could play a significant role in the metabolic flexibility of cancer. This study aimed to characterize the effect of varying degrees of CoQ10 deficiency and investigate the multifaceted aspect of CoQ10 depletion and its impact on cell metabolism. To induced CoQ10 depletion, different cell models were used, employing a chemical and genome editing approach. In T67 and MCF-7 CoQ10 depletion was achieved by a competitive inhibitor of the enzyme, 4-nitrobenzoate (4-NB), whereas in SH-SY5Y the COQ2 gene was edited via CRISPR-Cas9 cutting edge technology.

Novel biomaterials for regeneration of periapical bone defects in endodontic and implant therapy

Endodontic-related periapical bone defects are a common occurrence in the global populations. Considering the number of root canal treatments performed annually, new strategies and new biomaterials for the management of these bone defects will be important and highlight the need for continued research and development in endodontic field. The present PhD thesis have several objectives and is divided into two main sections: one focused on in vitro and laboratory research and the other on clinical in vivo investigations. The first part, focused on laboratory and in vitro research, investigated 2 main topics: • the microbial communities of apical periodontitis to evaluate the predominant bacterial using 16sr DNA-targeted Nanopore sequencing; • the physical-chemical properties of innovative premixed calcium-silicate based bioceramic sealers for endodontic therapy; The second part, focused on in vivo clinical studies, investigated 2 main topics: • the clinical application of premixed calcium-silicate-based sealers. Ethical committee approval was obtained in 2 separate in vivo studies. The first one is a prospective cohort study with a two-year follow-up where the test group was compared with a control group (considered the gold standard). The second is a pilot prospective cohort study with a 12-month follow-up which set the foundation for a subsequent randomized investigation. Thanks to these investigations, we validated a new technique that innovatively associates a warm obturation technique with calcium-silicate-based sealers. Historically, these sealers were only used with cold techniques. This investigation highlights the possibility for wider utilization and improvements in endodontic techniques. • The outcome of 2 different types of implants characterized by different surface treatments and placed with different techniques. The marginal bone level and periodontal parameters were evaluated with a follow-up of 4 and 10 years. This Ph.D thesis is based on a compilation of published papers I have done during my three-year PhD program.

Impaired Incretin Secretion And Pancreatic Dysfunction With Older Age And Diabetes.

To estimate the impact of aging and diabetes on insulin sensitivity, beta-cell function, adipocytokines, and incretin production. Hyperglycemic clamps, arginine tests and meal tolerance tests were performed in 50 non-obese subjects to measure insulin sensitivity (IS) and insulin secretion as well as plasma levels of glucagon, GLP-1 and GIP. Patients with diabetes and healthy control subjects were divided into the following groups: middle-aged type 2 diabetes (MA-DM), aged Type 2 diabetes (A-DM) and middle-aged or aged subjects with normal glucose tolerance (MA-NGT or A-NGT). IS, as determined by the homeostasis model assessment, glucose infusion rate, and oral glucose insulin sensitivity, was reduced in the aged and DM groups compared with MA-NGT, but it was similar in the MA-DM and A-DM groups. Insulinogenic index, first and second phase insulin secretion and the disposition indices, but not insulin response to arginine, were reduced in the aged and DM groups. Postprandial glucagon production was higher in MA-DM compared to MA-NGT. Whereas the GLP-1 production was reduced in A-DM, no differences between groups were observed in GIP production. In non-obese subjects, diabetes and aging impair insulin sensitivity. Insulin production is reduced by aging, and diabetes exacerbates this condition. Aging associated defects superimposed diabetic physiopathology, particularly regarding GLP-1 production. On the other hand, the glucose-independent secretion of insulin was preserved. Knowledge of the complex relationship between aging and diabetes could support the development of physiopathological and pharmacological based therapies.

Defective Apoptosis In Intestinal And Mesenteric Adipose Tissue Of Crohn's Disease Patients.

Crohn's disease (CD) is associated with complex pathogenic pathways involving defects in apoptosis mechanisms. Recently, mesenteric adipose tissue (MAT) has been associated with CD ethiopathology, since adipose thickening is detected close to the affected intestinal area. However, the potential role of altered apoptosis in MAT of CD has not been addressed. To evaluate apoptosis in the intestinal mucosa and MAT of patients with CD. Samples of intestinal mucosa and MAT from patients with ileocecal CD and from non-inflammatory bowel diseases patients (controls) were studied. Apoptosis was assessed by TUNEL assay and correlated with the adipocytes histological morphometric analysis. The transcriptional and protein analysis of selected genes and proteins related to apoptosis were determined. TUNEL assay showed fewer apoptotic cells in CD, when compared to the control groups, both in the intestinal mucosa and in MAT. In addition, the number of apoptotic cells (TUNEL) correlated significantly with the area and perimeter of the adipose cells in MAT. Transcriptomic and proteomic analysis reveal a significantly lower transcript and protein levels of Bax in the intestinal mucosa of CD, compared to the controls; low protein levels of Bax were found localized in the lamina propria and not in the epithelium of this tissue. Furthermore, higher level of Bcl-2 and low level of Caspase 3 were seen in the MAT of CD patients. The defective apoptosis in MAT may explain the singular morphological characteristics of this tissue in CD, which may be implicated in the pathophysiology of the disease.

Changes In Chromatin Structure In Nih 3t3 Cells Induced By Valproic Acid And Trichostatin A.

Valproic acid (VPA) and trichostatin A (TSA) are known histone deacetylase inhibitors (HDACIs) with epigenetic activity that affect chromatin supra-organization, nuclear architecture, and cellular proliferation, particularly in tumor cells. In this study, chromatin remodeling with effects extending to heterochromatic areas was investigated by image analysis in non-transformed NIH 3T3 cells treated for different periods with different doses of VPA and TSA under conditions that indicated no loss of cell viability. Image analysis revealed chromatin decondensation that affected not only euchromatin but also heterochromatin, concomitant with a decreased activity of histone deacetylases and a general increase in histone H3 acetylation. Heterochromatin protein 1-α (HP1-α), identified immunocytochemically, was depleted from the pericentromeric heterochromatin following exposure to both HDACIs. Drastic changes affecting cell proliferation and micronucleation but not alteration in CCND2 expression and in ratios of Bcl-2/Bax expression and cell death occurred following a 48-h exposure of the NIH 3T3 cells particularly in response to higher doses of VPA. Our results demonstrated that even low doses of VPA (0.05 mM) and TSA (10 ng/ml) treatments for 1 h can affect chromatin structure, including that of the heterochromatin areas, in non-transformed cells. HP1-α depletion, probably related to histone demethylation at H3K9me3, in addition to the effect of VPA and TSA on histone H3 acetylation, is induced on NIH 3T3 cells. Despite these facts, alterations in cell proliferation and micronucleation, possibly depending on mitotic spindle defects, require a longer exposure to higher doses of VPA and TSA.

Paired Evaluation Of Calvarial Reconstruction With Prototyped Titanium Implants With And Without Ceramic Coating.

To investigate the osseointegration properties of prototyped implants with tridimensionally interconnected pores made of the Ti6Al4V alloy and the influence of a thin calcium phosphate coating. Bilateral critical size calvarial defects were created in thirty Wistar rats and filled with coated and uncoated implants in a randomized fashion. The animals were kept for 15, 45 and 90 days. Implant mechanical integration was evaluated with a push-out test. Bone-implant interface was analyzed using scanning electron microscopy. The maximum force to produce initial displacement of the implants increased during the study period, reaching values around 100N for both types of implants. Intimate contact between bone and implant was present, with progressive bone growth into the pores. No significant differences were seen between coated and uncoated implants. Adequate osseointegration can be achieved in calvarial reconstructions using prototyped Ti6Al4V Implants with the described characteristics of surface and porosity.

Enhanced Glucose-induced Intracellular Signaling Promotes Insulin Hypersecretion: Pancreatic Beta-cell Functional Adaptations In A Model Of Genetic Obesity And Prediabetes.

Obesity is associated with insulin resistance and is known to be a risk factor for type-2 diabetes. In obese individuals, pancreatic beta-cells try to compensate for the increased insulin demand in order to maintain euglycemia. Most studies have reported that this adaptation is due to morphological changes. However, the involvement of beta-cell functional adaptations in this process needs to be clarified. For this purpose, we evaluated different key steps in the glucose-stimulated insulin secretion (GSIS) in intact islets from female ob/ob obese mice and lean controls. Obese mice showed increased body weight, insulin resistance, hyperinsulinemia, glucose intolerance and fed hyperglycemia. Islets from ob/ob mice exhibited increased glucose-induced mitochondrial activity, reflected by enhanced NAD(P)H production and mitochondrial membrane potential hyperpolarization. Perforated patch-clamp examination of beta-cells within intact islets revealed several alterations in the electrical activity such as increased firing frequency and higher sensitivity to low glucose concentrations. A higher intracellular Ca(2+) mobilization in response to glucose was also found in ob/ob islets. Additionally, they displayed a change in the oscillatory pattern and Ca(2+) signals at low glucose levels. Capacitance experiments in intact islets revealed increased exocytosis in individual ob/ob beta-cells. All these up-regulated processes led to increased GSIS. In contrast, we found a lack of beta-cell Ca(2+) signal coupling, which could be a manifestation of early defects that lead to beta-cell malfunction in the progression to diabetes. These findings indicate that beta-cell functional adaptations are an important process in the compensatory response to obesity.