Publications by authors named "Stefan Stefanov"

26 Publications

  • Page 1 of 1

Lipid Nanoparticulate Drug Delivery Systems: Recent Advances in the Treatment of Skin Disorders.

Pharmaceuticals (Basel) 2021 Oct 26;14(11). Epub 2021 Oct 26.

Department of Pharmaceutical Technologies, Faculty of Pharmacy, Medical University of Varna, 9002 Varna, Bulgaria.

The multifunctional role of the human skin is well known. It acts as a sensory and immune organ that protects the human body from harmful environmental impacts such as chemical, mechanical, and physical threats, reduces UV radiation effects, prevents moisture loss, and helps thermoregulation. In this regard, skin disorders related to skin integrity require adequate treatment. Lipid nanoparticles (LN) are recognized as promising drug delivery systems (DDS) in treating skin disorders. Solid lipid nanoparticles (SLN) together with nanostructured lipid carriers (NLC) exhibit excellent tolerability as these are produced from physiological and biodegradable lipids. Moreover, LN applied to the skin can improve stability, drug targeting, occlusion, penetration enhancement, and increased skin hydration compared with other drug nanocarriers. Furthermore, the features of LN can be enhanced by inclusion in suitable bases such as creams, ointments, gels (i.e., hydrogel, emulgel, bigel), lotions, etc. This review focuses on recent developments in lipid nanoparticle systems and their application to treating skin diseases. We point out and consider the reasons for their creation, pay attention to their advantages and disadvantages, list the main production techniques for obtaining them, and examine the place assigned to them in solving the problems caused by skin disorders.
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http://dx.doi.org/10.3390/ph14111083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619682PMC
October 2021

Low-dose rivaroxaban plus aspirin in older patients with peripheral artery disease undergoing acute limb revascularization: insights from the VOYAGER PAD trial.

Eur Heart J 2021 10;42(39):4040-4048

CPC Clinical Research, 2115 N Scranton Street, Suite 2040, Aurora, CO, USA.

Aims: In this secondary analysis of the VOYAGER trial, rivaroxaban 2.5 mg twice/day plus aspirin 100 mg/day was assessed in older adults. Advanced age is associated with elevated bleeding risk and unfavourable net benefit for dual antiplatelet therapy in chronic coronary artery disease. The risk-benefit of low-dose rivaroxaban in patients ≥75 years with peripheral artery disease (PAD) after lower extremity revascularization (LER) has not been described.

Methods And Results: The primary endpoint was a composite of acute limb ischaemia, major amputation, myocardial infarction, ischaemic stroke, or cardiovascular death. The principal safety outcome was thrombolysis in myocardial infarction (TIMI) major bleeding analysed by the pre-specified age cut-off of 75 years. Of 6564 patients randomized, 1330 (20%) were >75 years. Absolute 3-year Kaplan-Meier cumulative incidence rates for primary efficacy (23.4% vs. 19.0%) and safety (3.5% vs. 1.5%) endpoints were higher in elderly vs. non-elderly patients. Efficacy of rivaroxaban (P-interaction 0.83) and safety (P-interaction 0.38) was consistent irrespective of age. The combination of intracranial and fatal bleeding was not increased in patients >75 years (2 rivaroxaban vs. 8 placebo). Overall, benefits (absolute risk reduction 3.8%, number needed to treat 26 for the primary endpoint) exceeded risks (absolute risk increase 0.81%, number needed to harm 123 for TIMI major bleeding).

Conclusion: Patients ≥75 years with PAD are at both heightened ischaemic and bleeding risk after LER. No excess harm with respect to major, intracranial or fatal bleeding was seen in older patients yet numerically greater absolute benefits were observed. This suggests that low-dose rivaroxaban combined with aspirin should be considered in PAD after LER regardless of age.
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http://dx.doi.org/10.1093/eurheartj/ehab408DOI Listing
October 2021

Natural Lipids as Structural Components of Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for Topical Delivery.

Curr Pharm Des 2020 ;26(36):4524-4535

Department of Pharmaceutical Technologies, Faculty of Pharmacy, Medical University of Varna, Varna, Bulgaria.

Background: Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) are useful drug delivery systems for dermal application. Thanks to their biocompatible and biodegradable profile, these carriers offer many advantages such as enhanced bioavailability, low toxicity, viable drug targeting and controlled release. SLN and NLC are composed of well-tolerated lipids, including natural fats and oils that are successfully used in the pharmaceutical and cosmetic dermal formulation.

Objective: This article presents an overview of the benefits of selecting natural fats and oils as structural components of SLN and NLC for topical application.

Methods: This review is based on data published over the past 20 years about the development of stable and nontoxic lipid nanoparticles with natural lipids. We shed light on the role of natural fats in skin restoration, as well as on the contributed penetration and occlusive properties of SLN and NLC.

Results: The deliberate selection of excipients (type and lipid ratio) influences the quality of the final dermal formulation. Natural lipids show good compatibility with different active molecules and are able to create stable lipid matrices that facilitate the biopharmaceutical properties of lipid nanoparticles. Patents involving natural fats and oils in SLN and NLC composition are listed, yet it is important to note that the approved marketed formulations are mainly cosmetic, not pharmaceutical, products.

Conclusion: Natural lipids can enhance topical drug delivery by adding their ability of improving skin penetration and hydration to the permeation and occlusion properties of SLN and NLC.
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http://dx.doi.org/10.2174/1381612826666200514221649DOI Listing
March 2021

Comparison of Vitreomacular Interface Changes in Myopic Foveoschisis and Idiopathic Epiretinal Membrane Foveoschisis.

Am J Ophthalmol 2020 09 29;217:152-161. Epub 2020 Apr 29.

Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany.

Purpose: To compare characteristics of the vitreomacular interface (VMI) in myopic foveoschisis (mFS) and idiopathic epiretinal membrane foveoschisis (iERM-FS), and to correlate with optical coherence tomography and clinical data.

Design: Clinicopathologic study.

Methods: Epiretinal membrane and internal limiting membrane (ILM) specimens were removed from eyes with mFS (5 eyes) and iERM-FS (5 eyes). Harvested tissue was processed for immunocytochemistry and prepared by ultrathin series sectioning for transmission electron microscopy. Cell and collagen compositions were compared and correlated with clinical data.

Results: All eyes presented fibrocellular membranes irrespective if associated with mFS or iERM-FS. Cell and collagen types and distribution on the vitreal side of the ILM were similar in both groups, consistent with presence of tractional membranes on optical coherence tomography images. Immunostaining of all specimens were positive for glial cells, microglia, and hyalocytes. Electron microscopy revealed evidence of epiretinal cell multilayers with masses of vitreous collagen and signs of vitreous remodeling in both groups. Three eyes with mFS but none of the eyes with iERM-FS showed massive thinning of the ILM with prominent retinal undulations and presence of retinal nerve fiber layer fragments.

Conclusion: Whereas fibrocellular components of premacular tissue in mFS are similar to iERM-FS, pathologic abnormalities of the ILM were exclusively present in high myopia. Although peeling of the ILM appears important to completely remove tractional components of the VMI, histopathologic findings emphasize the risk for retinal damage in these highly myopic eyes, indicating that individual preoperative assessment and modification of surgical techniques require further investigation.
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http://dx.doi.org/10.1016/j.ajo.2020.04.023DOI Listing
September 2020

Knocking out C9ORF72 Exacerbates Axonal Trafficking Defects Associated with Hexanucleotide Repeat Expansion and Reduces Levels of Heat Shock Proteins.

Stem Cell Reports 2020 03 20;14(3):390-405. Epub 2020 Feb 20.

Technische Universität Dresden, Center for Regenerative Therapies TU Dresden (CRTD), 01307 Dresden, Germany. Electronic address:

In amyotrophic lateral sclerosis (ALS) motor neurons (MNs) undergo dying-back, where the distal axon degenerates before the soma. The hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of ALS, but the mechanism of pathogenesis is largely unknown with both gain- and loss-of-function mechanisms being proposed. To better understand C9ORF72-ALS pathogenesis, we generated isogenic induced pluripotent stem cells. MNs with HRE in C9ORF72 showed decreased axonal trafficking compared with gene corrected MNs. However, knocking out C9ORF72 did not recapitulate these changes in MNs from healthy controls, suggesting a gain-of-function mechanism. In contrast, knocking out C9ORF72 in MNs with HRE exacerbated axonal trafficking defects and increased apoptosis as well as decreased levels of HSP70 and HSP40, and inhibition of HSPs exacerbated ALS phenotypes in MNs with HRE. Therefore, we propose that the HRE in C9ORF72 induces ALS pathogenesis via a combination of gain- and loss-of-function mechanisms.
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http://dx.doi.org/10.1016/j.stemcr.2020.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066330PMC
March 2020

Arthritis in Two Patients With Partial Recombination Activating Gene Deficiency.

Front Pediatr 2019 5;7:235. Epub 2019 Jul 5.

Division of Pediatric Allergy and Immunology, Department of Pediatrics, University of South Florida, St. Petersburg, FL, United States.

Autoimmunity is becoming an increasingly recognized complication in patients with primary immunodeficiencies (PIDs), including a variety of combined immune deficiencies such as Recombination Activating Gene (RAG) defects. The approach to treating autoimmunity in PID patients is complex, requiring a balance between immunosuppression and susceptibility to infection. Inflammatory arthritis is a feature of immune dysregulation in many PIDs, and the optimal treatment may differ from first line therapies that usually consist of disease-modifying anti rheumatic drugs (DMARDs). An example of mechanism-based therapy of arthritis in PID uses blockade of IL-6 signaling with tocilizumab for patients with STAT 3 gain-of-function (GOF) mutation and augmented IL-6 pathway. Herein, we describe two PID cases with arthritis who were found to have defects in RAG. One patient with refractory inflammatory arthritis experienced remarkable improvement in symptoms with tocilizumab therapy. Arthritis can be a clinical feature of immune dysregulation in RAG deficiency, and tocilizumab therapy has been suggested to have utility in treatment of arthritis in RAG deficiency.
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http://dx.doi.org/10.3389/fped.2019.00235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625222PMC
July 2019

Endoscopic Interhemispheric Disconnection for Intractable Multifocal Epilepsy: Surgical Technique and Functional Neuroanatomy.

Oper Neurosurg (Hagerstown) 2020 02;18(2):145-157

Department of Neurosurgery, University Hospital of Lausanne, Lausanne, Switzerland.

Background: Callosotomy represents a palliative procedure for intractable multifocal epilepsy. The extent of callosotomy and the benefits of adding anterior and posterior commissurotomy are debated.

Objective: To describe a new technique of a purely endoscopic procedure to disconnect the corpus callosum, the anterior, posterior, and habenular commissures through the use of a single burr hole via a transfrontal transventricular route.

Methods: Our surgical series was retrospectively reviewed in terms of seizure control (Engel's class) and complication rate. Five cadaveric specimens were used to demonstrate the surgical anatomy of commissural fibers and third ventricle.

Results: The procedure may be divided into 3 steps: (1) endoscopic transventricular transforaminal anterior commissure disconnection; (2) disconnection of posterior and habenular commissures; and (3) total callosotomy. Fifty-seven patients were included in the analysis. A favorable outcome in terms of epilepsy control (Engel class 1 to 3) was found in 71.4% of patients undergoing callosotomy coupled with anterior, posterior, and habenular commissure disconnection against 53% of patients with isolated callosotomy (P = .26). Patients with drop attacks had better epilepsy outcome independently from the surgical procedure used.

Conclusion: The full endoscopic callosotomy coupled with disconnection of anterior, posterior and habenular commissures is a safe alternative to treat multifocal refractory epilepsy. A gain in seizure outcome might be present in this cohort of patients treated with total interhemispheric disconnection when compared with isolated callosotomy. Larger studies are required to confirm these findings.
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http://dx.doi.org/10.1093/ons/opz121DOI Listing
February 2020

Gas Mixing and Final Mixture Composition Control in Simple Geometry Micro-mixers via DSMC Analysis.

Micromachines (Basel) 2019 Mar 7;10(3). Epub 2019 Mar 7.

Department of Mechanical Engineering, University of Thessaly-Pedion Areos, 38334 Volos, Greece.

The mixing process of two pressure driven steady-state rarefied gas streams flowing between two parallel plates was investigated via DSMC (Direct Simulation Monte Carlo) for different combinations of gases. The distance from the inlet, where the associated relative density difference of each species is minimized and the associated mixture homogeneity is optimized, is the so-called mixing length. In general, gas mixing progressed very rapidly. The type of gas surface interaction was clearly the most important parameter affecting gas mixing. As the reflection became more specular, the mixing length significantly increased. The mixing lengths of the HS (hard sphere) and VHS (variable hard sphere) collision models were higher than those of the VSS (variable soft sphere) model, while the corresponding relative density differences were negligible. In addition, the molecular mass ratio of the two components had a minor effect on the mixing length and a more important effect on the relative density difference. The mixture became less homogenous as the molecular mass ratio reduced. Finally, varying the channel length and/or the wall temperature had a minor effect. Furthermore, it was proposed to control the output mixture composition by adding in the mixing zone, the so-called splitter, separating the downstream flow into two outlet mainstreams. Based on intensive simulation data with the splitter, simple approximate expressions were derived, capable of providing, once the desired outlet mixture composition was specified, the correct position of the splitter, without performing time consuming simulations. The mixing analysis performed and the proposed approach for controlling gas mixing may support corresponding experimental work, as well as the design of gas micro-mixers.
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http://dx.doi.org/10.3390/mi10030178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472011PMC
March 2019

Transcriptional dynamics of microRNAs and their targets during Drosophila neurogenesis.

RNA Biol 2019 01 20;16(1):69-81. Epub 2019 Jan 20.

a Berlin Institute for Molecular and Systems Biology , Max Delbrück Center for Molecular Medicine , Berlin , Germany.

During Drosophila melanogaster embryogenesis, tight regulation of gene expression in time and space is required for the orderly emergence of specific cell types. While the general importance of microRNAs in regulating eukaryotic gene expression has been well-established, their role in early neurogenesis remains to be addressed. In this survey, we investigate the transcriptional dynamics of microRNAs and their target transcripts during neurogenesis of Drosophila melanogaster. To this end, we use the recently developed DIV-MARIS protocol, a method for enriching specific cell types from the Drosophila embryo in vivo, to sequence cell type-specific transcriptomes. We generate dedicated small and total RNA-seq libraries for neuroblasts, neurons and glia cells at early (6-8 h after egg laying (AEL)) and late (18-22 h AEL) stage. This allows us to directly compare these transcriptomes and investigate the potential functional roles of individual microRNAs with spatiotemporal resolution genome-wide, which is beyond the capabilities of existing in situ hybridization methods. Overall, we identify 74 microRNAs that are significantly differentially expressed between the three cell types and the two developmental stages. In all cell types, predicted target genes of down-regulated microRNAs show a significant enrichment of Gene Ontology terms related to neurogenesis. We also investigate how microRNAs regulate the transcriptome by targeting transcription factors and find many candidate microRNAs with putative roles in neurogenesis. Our survey highlights the roles of microRNAs as regulators of differentiation and glioneurognesis in the fruit fly and provides distinct starting points for dedicated functional follow-up studies.
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http://dx.doi.org/10.1080/15476286.2018.1558907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380339PMC
January 2019

Ballistic and Collisional Flow Contributions to Anti-Fourier Heat Transfer in Rarefied Cavity Flow.

Sci Rep 2018 Sep 10;8(1):13533. Epub 2018 Sep 10.

Institute of Mechanics, Bulgarian Academy of Science, Acad. G. Bontchev Str., 1113, Sofia, Bulgaria.

This paper investigates anti-Fourier heat transfer phenomenon in a rarefied gas confined within a lid-driven cavity using a novel flow decomposition technique in the direct simulation Monte Carlo (DSMC) method proposed by Stefanov and co-workers. An isothermal cavity with different degrees of flow rarefaction from near continuum to mid transition regimes was considered to investigate cold-to-hot heat transfer from ballistic/collision flow decomposition viewpoint. A new cold-to-hot heat transfer indicator in the form of a scalar product of normalized heat flow vector and normalized temperature gradient vector has been introduced for the overall, ballistic and collision parts of these vectors. Using the new indicator, contributions of ballistic and collision flow parts to temperature and heat flux components was investigated with a specific emphasis on the cold-to-hot heat transfer phenomenon. We demonstrated that both ballistic and collision flow parts contribute to the occurrence of cold-to-hot heat transfer. However, it was found out that considered separately both ballistic and collision parts of heat transfer, when related to corresponding ballistic and collision temperature fields, they are ever hot-to-cold for all degrees of flow rarefaction. Thus, cold-to-hot heat transfer is a result of a subtle interplay between ballistic and collision parts in the slip and transition Knudsen regimes.
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http://dx.doi.org/10.1038/s41598-018-31827-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131268PMC
September 2018

The Bulgarian version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

Rheumatol Int 2018 Apr 7;38(Suppl 1):75-82. Epub 2018 Apr 7.

Clinica Pediatrica e Reumatologia, Paediatric Rheumatology International Trials Organisation (PRINTO), Istituto Giannina Gaslini, Via Gaslini 5, 16147, Genoa, Italy.

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Bulgarian language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data, and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the 3 Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity). A total of 183 JIA patients (12% systemic, 53.6% oligoarticular, 23.5% RF negative polyarthritis, 10.9% other categories) and 100 healthy children were enrolled in two centres. The JAMAR components discriminated well healthy subjects from JIA patients. Notably, there is no significant difference between the healthy subjects and their affected peers in the school-related problems variable. All JAMAR components revealed good psychometric performances. In conclusion, the Bulgarian version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.
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http://dx.doi.org/10.1007/s00296-018-3940-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893711PMC
April 2018

Growth and characterization of SiGeSn quantum well photodiodes.

Opt Express 2015 Sep;23(19):25048-57

We report on the fabrication and electro-optical characterization of SiGeSn multi-quantum well PIN diodes. Two types of PIN diodes, in which two and four quantum wells with well and barrier thicknesses of 10 nm each are sandwiched between B- and Sb-doped Ge-regions, were fabricated as single-mesa devices, using a low-temperature fabrication process. We discuss measurements of the diode characteristics, optical responsivity and room-temperature electroluminescence and compare with theoretical predictions from band structure calculations.
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http://dx.doi.org/10.1364/OE.23.025048DOI Listing
September 2015

Predicting the Knudsen paradox in long capillaries by decomposing the flow into ballistic and collision parts.

Phys Rev E Stat Nonlin Soft Matter Phys 2015 Jun 10;91(6):061001. Epub 2015 Jun 10.

Department of Mechanical Engineering, University of Thessaly, Volos, Greece.

The well-known Knudsen paradox observed in pressure driven rarefied gas flows through long capillaries is quantitatively explored by decomposing the particle distribution function into its ballistic and collision parts. The classical channel, tube, and duct Poiseuille flows are considered. The solution is obtained by a typical direct simulation Monte Carlo algorithm supplemented by a suitable particle decomposition indexation process. It is computationally confirmed that in the free-molecular and early transition regimes the reduction rate of the ballistic flow is larger than the increase rate of the collision flow deducing the Knudsen minimum of the overall flow. This description interprets in a precise, quantitative manner the appearance of the Knudsen minimum and verifies previously reported qualitative physical arguments.
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http://dx.doi.org/10.1103/PhysRevE.91.061001DOI Listing
June 2015

Endovascular treatment of posttraumatic pseudoaneurysm of the common carotid artery.

Case Rep Vasc Med 2015 31;2015:427040. Epub 2015 Mar 31.

Department of Vascular Surgery, La Paz University Hospital, 28046 Madrid, Spain.

Carotid artery injuries with pseudoaneurysm are uncommon but associated with central neurologic dysfunction. We present a case of posttraumatic pseudoaneurysm of the right common carotid artery treated by implantation of a covered stent. A 44-year-old woman with multiple injuries after fall from height presents a small dissection flap of the right common carotid artery (RCCA) on the initial computed tomography angiography (CTA). Fifteen days later a 10 mm pseudoaneurysm is observed on control CTA. We decided endovascular treatment. Through right femoral access with a long introducer sheath placed in the innominate artery, we implanted a covered stent Advanta V12 9 × 38 mm in the RCCA. The patient was discharged from the hospital with antiplatelet therapy without any neurological dysfunction and complete exclusion of the pseudoaneurysm. Use of covered stents has emerged as a safe and effective alternative to surgical repair of carotid injuries.
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http://dx.doi.org/10.1155/2015/427040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396546PMC
April 2015

Role of surface shape on boundary slip and velocity defect.

Phys Rev E Stat Nonlin Soft Matter Phys 2012 Jul 13;86(1 Pt 2):016314. Epub 2012 Jul 13.

Centre for Microfluidics and Microsystems Modelling, STFC Daresbury Laboratory, Warrington WA4 4AD, United Kingdom.

Although many gas-phase microfluidic devices contain curved surfaces, relatively little research has been conducted on the degree of slip over nonplanar surfaces. The present study demonstrates the influence of the surface shape (i.e., convex/concave) on the velocity slip and formation of the Knudsen layer. In addition, the study reveals that there is a simple relationship between the shear stress exerted on the surface and the velocity defect in the Knudsen layer.
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http://dx.doi.org/10.1103/PhysRevE.86.016314DOI Listing
July 2012

Thermal and second-law analysis of a micro- or nanocavity using direct-simulation Monte Carlo.

Phys Rev E Stat Nonlin Soft Matter Phys 2012 May 23;85(5 Pt 2):056310. Epub 2012 May 23.

Department of Mechanical Engineering, Faculty of Engineering, Ferdowsi University of Mashhad, Iran.

In this study the direct-simulation Monte Carlo (DSMC) method is utilized to investigate thermal characteristics of micro- or nanocavity flow. The rarefied cavity flow shows unconventional behaviors which cannot be predicted by the Fourier law, the constitutive relation for the continuum heat transfer. Our analysis in this study confirms some recent observations and shows that the gaseous flow near the top-left corner of the cavity is in a strong nonequilibrium state even within the early slip regime, Kn=0.005. As we obtained slip velocity and temperature jump on the driven lid of the cavity, we reported meaningful discrepancies between the direct and macroscopic sampling of rarefied flow properties in the DSMC method due to existence of nonequilibrium effects in the corners of cavity. The existence of unconventional nonequilibrium heat transfer mechanisms in the middle of slip regime, Kn=0.05, results in the appearance of cold-to-hot heat transfer in the microcavity. In the current study we demonstrate that existence of such unconventional heat transfer is strongly dependent on the Reynolds number and it vanishes in the large values of the lid velocity. As we compared DSMC solution with the results of regularized 13 moments (R13) equations, we showed that the thermal characteristic of the microcavity obtained by the R13 method coincides with the DSMC prediction. Our investigation also includes the analysis of molecular entropy in the microcavity to explain the heat transfer mechanism with the aid of the second law of thermodynamics. To this aim, we obtained the two-dimensional velocity distribution functions to report the molecular-based entropy distribution, and show that the cold-to-hot heat transfer in the cavity is well in accordance with the second law of thermodynamics and takes place in the direction of increasing entropy. At the end we introduce the entropy density for the rarefied flow and show that it can accurately illustrate departure from the equilibrium state.
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http://dx.doi.org/10.1103/PhysRevE.85.056310DOI Listing
May 2012

A reevaluation of rice mitochondrial evolution based on the complete sequence of male-fertile and male-sterile mitochondrial genomes.

Plant Physiol 2012 Feb 29;158(2):996-1017. Epub 2011 Nov 29.

Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA.

Plant mitochondrial genomes have features that distinguish them radically from their animal counterparts: a high rate of rearrangement, of uptake and loss of DNA sequences, and an extremely low point mutation rate. Perhaps the most unique structural feature of plant mitochondrial DNAs is the presence of large repeated sequences involved in intramolecular and intermolecular recombination. In addition, rare recombination events can occur across shorter repeats, creating rearrangements that result in aberrant phenotypes, including pollen abortion, which is known as cytoplasmic male sterility (CMS). Using next-generation sequencing, we pyrosequenced two rice (Oryza sativa) mitochondrial genomes that belong to the indica subspecies. One genome is normal, while the other carries the wild abortive-CMS. We find that numerous rearrangements in the rice mitochondrial genome occur even between close cytotypes during rice evolution. Unlike maize (Zea mays), a closely related species also belonging to the grass family, integration of plastid sequences did not play a role in the sequence divergence between rice cytotypes. This study also uncovered an excellent candidate for the wild abortive-CMS-encoding gene; like most of the CMS-associated open reading frames that are known in other species, this candidate was created via a rearrangement, is chimeric in structure, possesses predicted transmembrane domains, and coopted the promoter of a genuine mitochondrial gene. Our data give new insights into rice mitochondrial evolution, correcting previous reports.
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http://dx.doi.org/10.1104/pp.111.190231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271784PMC
February 2012

An analysis pipeline for genome-wide association studies.

Cancer Inform 2008 24;6:455-61. Epub 2008 Sep 24.

Human Genetics Section, Laboratory of Experimental Immunology, National Cancer Institute at Frederick, Frederick, MD 21702, USA.

We developed an efficient pipeline to analyze genome-wide association study single nucleotide polymorphism scan results. Purl scripts were used to convert genotypes called using the BRLMM algorithm into a modified PB format. We computed summary statistics characteristic of our case and control populations including allele counts, missing values, heterozygosity, measures of compliance with Hardy-Weinberg equilibrium, and several population difference statistics. In addition, we computed association tests, including exact tests of association for genotypes, alleles, the Cochran-Armitage linear trend test, and dominant, recessive, and over dominant models at every single nucleotide polymorphism (SNP). In addition, pairwise linkage disequilibrium statistics were elaborated, using the command line version of HaploView, which was possible by writing a reformatting script. Additional Perl scripts permit loading the results into a MySQL database conjoined with a Generic Genome Browser (gbrowse) for comprehensive visualization. This browser incorporates a download feature that provides actual case and control genotypes to users in associated genomic regions. Thus, re-analysis "on the fly" is possible for casual browser users from anywhere on the Internet.
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http://dx.doi.org/10.4137/cin.s966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2603547PMC
May 2010

Long-term results of femoro-femoral crossover bypass after endovascular aortouniiliac repair of abdominal aortic and aortoiliac aneurysms.

Vasc Endovascular Surg 2008 Oct-Nov;42(5):420-6. Epub 2008 Jun 25.

Department of Angiology and Vascular Surgery, Hospital Universitario La Paz, Madrid, Spain.

Aortouniiliac stent grafts allow the endovascular treatment of complex anatomy aortoiliac aneurysms. The main drawback is the need for femoro-femoral crossover bypass, with its complications and its patency limitations. However, some authors have shown good results of femoro-femoral crossover bypass in aneurysmal disease. In this article, initial and long-term results of our experience in femoro-femoral crossover bypass revascularization after endovascular aortouniiliac stent grafts repair of aortoiliac aneurysms is reported. Prospective collection, intention-to-treat, and retrospective analysis maintained database. Femoro-femoral crossover bypass patency assessment of all patients treated between January 1999 and September 2002, compared patients with or without associated occlusive arterial disease. Urgent indications were excluded. In total of 52 patients, with a mean age 72.6 years, 30.8% of patients were identified with associated occlusive arterial disease. Initial systemic and local, access site, complications were 7.7% and 7.7%, respectively, no early thrombosis or death is reported. Primary patency was 90.9% at 54 months, 66 months assisted primary and secondary patency were 97.7% and 100%, respectively. The 48-month survival rate was 84.2%. No significant differences between patients with or without associated occlusive arterial disease were found. Femoro-femoral crossover bypass after aortouniiliac stent grafts treatment of aortoiliac aneurysms shows excellent initial and long-term patency and low complication rate.
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http://dx.doi.org/10.1177/1538574408318008DOI Listing
January 2009

Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33.

Proc Natl Acad Sci U S A 2008 Mar 7;105(11):4340-5. Epub 2008 Mar 7.

Laboratory of Genomic Diversity, Human Genetics Section, National Cancer Institute-Frederick, Frederick, MD 21702, USA.

We performed a three-phase genome-wide association study (GWAS) using cases and controls from a genetically isolated population, Ashkenazi Jews (AJ), to identify loci associated with breast cancer risk. In the first phase, we compared allele frequencies of 150,080 SNPs in 249 high-risk, BRCA1/2 mutation-negative AJ familial cases and 299 cancer-free AJ controls using chi(2) and the Cochran-Armitage trend tests. In the second phase, we genotyped 343 SNPs from 123 regions most significantly associated from stage 1, including 4 SNPs from the FGFR2 region, in 950 consecutive AJ breast cancer cases and 979 age-matched AJ controls. We replicated major associations in a third independent set of 243 AJ cases and 187 controls. We obtained a significant allele P value of association with AJ breast cancer in the FGFR2 region (P = 1.5 x 10(-5), odds ratio (OR) 1.26, 95% confidence interval (CI) 1.13-1.40 at rs1078806 for all phases combined). In addition, we found a risk locus in a region of chromosome 6q22.33 (P = 2.9 x 10(-8), OR 1.41, 95% CI 1.25-1.59 at rs2180341). Using several SNPs at each implicated locus, we were able to verify associations and impute haplotypes. The major haplotype at the 6q22.33 locus conferred protection from disease, whereas the minor haplotype conferred risk. Candidate genes in the 6q22.33 region include ECHDC1, which encodes a protein involved in mitochondrial fatty acid oxidation, and also RNF146, which encodes a ubiquitin protein ligase, both known pathways in breast cancer pathogenesis.
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http://dx.doi.org/10.1073/pnas.0800441105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2393811PMC
March 2008

Analysis of genetic variation in Ashkenazi Jews by high density SNP genotyping.

BMC Genet 2008 Feb 5;9:14. Epub 2008 Feb 5.

Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Background: Genetic isolates such as the Ashkenazi Jews (AJ) potentially offer advantages in mapping novel loci in whole genome disease association studies. To analyze patterns of genetic variation in AJ, genotypes of 101 healthy individuals were determined using the Affymetrix EAv3 500 K SNP array and compared to 60 CEPH-derived HapMap (CEU) individuals. 435,632 SNPs overlapped and met annotation criteria in the two groups.

Results: A small but significant global difference in allele frequencies between AJ and CEU was demonstrated by a mean FST of 0.009 (P < 0.001); large regions that differed were found on chromosomes 2 and 6. Haplotype blocks inferred from pairwise linkage disequilibrium (LD) statistics (Haploview) as well as by expectation-maximization haplotype phase inference (HAP) showed a greater number of haplotype blocks in AJ compared to CEU by Haploview (50,397 vs. 44,169) or by HAP (59,269 vs. 54,457). Average haplotype blocks were smaller in AJ compared to CEU (e.g., 36.8 kb vs. 40.5 kb HAP). Analysis of global patterns of local LD decay for closely-spaced SNPs in CEU demonstrated more LD, while for SNPs further apart, LD was slightly greater in the AJ. A likelihood ratio approach showed that runs of homozygous SNPs were approximately 20% longer in AJ. A principal components analysis was sufficient to completely resolve the CEU from the AJ.

Conclusion: LD in the AJ versus was lower than expected by some measures and higher by others. Any putative advantage in whole genome association mapping using the AJ population will be highly dependent on regional LD structure.
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http://dx.doi.org/10.1186/1471-2156-9-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2259380PMC
February 2008

The genetic study of three population microisolates in South Tyrol (MICROS): study design and epidemiological perspectives.

BMC Med Genet 2007 Jun 5;8:29. Epub 2007 Jun 5.

Institute of Genetic Medicine, European Academy, Bolzano, Italy.

Background: There is increasing evidence of the important role that small, isolated populations could play in finding genes involved in the etiology of diseases. For historical and political reasons, South Tyrol, the northern most Italian region, includes several villages of small dimensions which remained isolated over the centuries.

Methods: The MICROS study is a population-based survey on three small, isolated villages, characterized by: old settlement; small number of founders; high endogamy rates; slow/null population expansion. During the stage-1 (2002/03) genealogical data, screening questionnaires, clinical measurements, blood and urine samples, and DNA were collected for 1175 adult volunteers. Stage-2, concerning trait diagnoses, linkage analysis and association studies, is ongoing. The selection of the traits is being driven by expert clinicians. Preliminary, descriptive statistics were obtained. Power simulations for finding linkage on a quantitative trait locus (QTL) were undertaken.

Results: Starting from participants, genealogies were reconstructed for 50,037 subjects, going back to the early 1600s. Within the last five generations, subjects were clustered in one pedigree of 7049 subjects plus 178 smaller pedigrees (3 to 85 subjects each). A significant probability of familial clustering was assessed for many traits, especially among the cardiovascular, neurological and respiratory traits. Simulations showed that the MICROS pedigree has a substantial power to detect a LOD score > or = 3 when the QTL specific heritability is > or = 20%.

Conclusion: The MICROS study is an extensive, ongoing, two-stage survey aimed at characterizing the genetic epidemiology of Mendelian and complex diseases. Our approach, involving different scientific disciplines, is an advantageous strategy to define and to study population isolates. The isolation of the Alpine populations, together with the extensive data collected so far, make the MICROS study a powerful resource for the study of diseases in many fields of medicine. Recent successes and simulation studies give us confidence that our pedigrees can be valuable both in finding new candidates loci and to confirm existing candidate genes.
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http://dx.doi.org/10.1186/1471-2350-8-29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1913911PMC
June 2007

Genetic structure in contemporary south Tyrolean isolated populations revealed by analysis of Y-chromosome, mtDNA, and Alu polymorphisms.

Hum Biol 2006 Aug;78(4):441-64

Institute of Genetic Medicine, European Academy of Bolzano, Viale Druso 1, 39100 Bolzano-Bozen, Italy.

Most of the inhabitants of South Tyrol in the eastern Italian Alps can be considered isolated populations because of their physical separation by mountain barriers and their sociocultural heritage. We analyzed the genetic structure of South Tyrolean populations using three types of genetic markers: Y-chromosome, mitochondrial DNA (mtDNA), and autosomal Alu markers. Using random samples taken from the populations of Val Venosta, Val Pusteria, Val Isarco, Val Badia, and Val Gardena, we calculated genetic diversity within and among the populations. Microsatellite diversity and unique event polymorphism diversity (on the Y chromosome) were substantially lower in the Ladin-speaking population of Val Badia compared to the neighboring German-speaking populations. In contrast, the genetic diversity of mtDNA haplotypes was lowest for the upper Val Venosta and Val Pusteria. These data suggest a low effective population size, or little admixture, for the gene pool of the Ladin-speaking population from Val Badia. Interestingly, this is more pronounced for Ladin males than for Ladin females. For the pattern of genetic Alu variation, both Ladin samples (Val Gardena and Val Badia) are among the samples with the lowest diversity. An admixture analysis of one German-speaking valley (Val Venosta) indicates a relatively high genetic contribution of Ladin origin. The reduced genetic diversity and a high genetic differentiation in the Rhaetoroman- and German-speaking South Tyrolean populations may constitute an important basis for future medical genetic research and gene mapping studies in South Tyrol.
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http://dx.doi.org/10.1353/hub.2006.0057DOI Listing
August 2006

Long homopurine*homopyrimidine sequences are characteristic of genes expressed in brain and the pseudoautosomal region.

Nucleic Acids Res 2006 19;34(9):2663-75. Epub 2006 May 19.

Institute of Biosciences and Technology, Center for Genome Research, Texas A&M University System Health Science Center, Texas Medical Center, 2121 West Holcombe Blvd, Houston, TX 77030, USA.

Homo(purine*pyrimidine) sequences (R*Y tracts) with mirror repeat symmetries form stable triplexes that block replication and transcription and promote genetic rearrangements. A systematic search was conducted to map the location of the longest R*Y tracts in the human genome in order to assess their potential function(s). The 814 R*Y tracts with > or =250 uninterrupted base pairs were preferentially clustered in the pseudoautosomal region of the sex chromosomes and located in the introns of 228 annotated genes whose protein products were associated with functions at the cell membrane. These genes were highly expressed in the brain and particularly in genes associated with susceptibility to mental disorders, such as schizophrenia. The set of 1957 genes harboring the 2886 R*Y tracts with > or =100 uninterrupted base pairs was additionally enriched in proteins associated with phosphorylation, signal transduction, development and morphogenesis. Comparisons of the > or =250 bp R*Y tracts in the mouse and chimpanzee genomes indicated that these sequences have mutated faster than the surrounding regions and are longer in humans than in chimpanzees. These results support a role for long R*Y tracts in promoting recombination and genome diversity during evolution through destabilization of chromosomal DNA, thereby inducing repair and mutation.
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http://dx.doi.org/10.1093/nar/gkl354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1464109PMC
May 2006

Evolution of the vertebrate ABC gene family: analysis of gene birth and death.

Genomics 2006 Jul 2;88(1):1-11. Epub 2006 May 2.

Laboratory of Genomic Diversity, Building 560, Room 21-18, NCI-Frederick, Frederick, MD 21702, USA.

Vertebrate evolution has been largely driven by the duplication of genes that allow for the acquisition of new functions. The ATP-binding cassette (ABC) proteins constitute a large and functionally diverse family of membrane transporters. The members of this multigene family are found in all cellular organisms, most often engaged in the translocation of a wide variety of substrates across lipid membranes. Because of the diverse function of these genes, their large size, and the large number of orthologs, ABC genes represent an excellent tool to study gene family evolution. We have identified ABC proteins from the sea squirt (Ciona intestinalis), zebrafish (Danio rerio), and chicken (Gallus gallus) and, using phylogenetic analysis, identified those genes with a one-to-one orthologous relationship to human ABC proteins. All ABC protein subfamilies found in Ciona and zebrafish correspond to the human subfamilies, with the exception of a single ABCH subfamily gene found only in zebrafish. Multiple gene duplication and deletion events were identified in different lineages, indicating an ongoing process of gene evolution. As many ABC genes are involved in human genetic diseases, and important drug transport phenotypes, the understanding of ABC gene evolution is important to the development of animal models and functional studies.
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http://dx.doi.org/10.1016/j.ygeno.2006.03.001DOI Listing
July 2006
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