Impact of Geo-mechanical Properties on the Fracture Treatment of Utica Shale

Unconventional gas reservoirs become one of the most important energy sources in United States and all over the world. The Appalachian basin has very organic rich shale formations; it contains Marcellus and Utica shale formations with billions of cubic feet of natural gas as reserve. The development in hydraulic fracturing technology with horizontal drilling for thousands of lateral feet increase the recoverable gas from the shale formations and challenges the researchers to understand the fracturing mechanism and to study the relation between operation parameters and formation properties with the fracturing treatment outcome.;The main objective of this thesis was to study the impact of formation geo-mechanical properties such as horizontal stress level, Young\u27s modulus and Poison\u27s ratio on the fracturing treatment outcome and also on the complex fracture growth. More precisely, the impact of these properties on the growth of discrete fracture network (DFN). A single horizontal well model was built using commercial software to simulate the fracturing treatment. This model built based on Utica shale properties obtained from different sources.;In this thesis, we investigated the impact of horizontal stress level, Young\u27s modulus, Poison\u27s ratio and the leak-off coefficient. The results showed that the horizontal stress level plays a significant role in controlling the fracture orientation and growth, also affects the stimulated reservoir volume (SRV). The Young\u27s modulus and the Leak-off coefficient also impact the fracture and the discrete fracture network. It has been determined that the formations with high Young\u27s modulus generated high SRV. The Poison\u27s ratio had negligible impact on the fracturing treatment outcome

Cancer Stem Cell-Related Markers in Normal and Neoplastic Oral Mucosa. A study on human samples and experimental models

The existence of cancer stem cells (CSCs) in solid cancers is still a controversial issue. Several markers were successfully used to enrich for cells with stem cell-like properties in oral squamous cell carcinoma (OSCC). Among these, ALDH1 was reported in both OSCC and several other human cancers. The aim of this study was to investigate the pattern of expression of several CSC-related markers including ALDH1 and the normal oral keratinocyte stem cell marker p75NTR relative to each other in patient samples and OSCC-derived cells, and the potential of p75NTR to identify and isolate CSCs in OSCC. To simultaneously detect several CSC-related markers in patient samples, a multiple IHC protocol engaging three un-conjugated monoclonal primary antibodies from the same Ig subclass was first developed, based on previously reported protocols. Compared to other methods, stripping of the preceding reaction by microwave heating, combined with additional suppression of enzyme activity, has enabled specific detection of all three reactions by using the same detection system, with no detectable cross reactivity. Archival formalin-fixed paraffin embedded tissues from OSCC (n=177), oral dysplasia (OD, n=10), and normal human oral mucosa from healthy donors (NHOM, n=31) have been subjected to the developed multiple IHC protocol, while keratinocytes derived from OSCC, OD and NHOM were subjected to multiple fluorescent activated cell sorting (FACS). The findings of the two approaches showed a wider range of variability in the level of expression and localization of the CSCrelated markers in OSCC and OD as compared to NHOM. In addition, the data also indicated a functional difference between different cellular phenotypes positive for either p75NTR or ALDH1A1. Firstly, higher proliferation (Ki67) was observed in p75NTR+ cells in comparison to ALDH1+ or p75NTR+ALDH1+ cells. Secondly, the frequency of p75NTR+ cells was higher in OSCCs of small size (T1 & T2) and OSCCs with poor to moderate differentiation grade, and correlated with poor survival of patients clinically deemed as of better prognosis. High frequency of ALDH1+ cells was found to be associated with lymph node metastasis. No statistically significant association was found between any of the clinical variables investigated and the frequency of the co-localization of CSC-related markers. Thirdly, OSCC cells sorted for p75NTR and ALDH1 displayed different expression profile of several CSC-EMT related genes. OSCC-derived cells sorted for p75NTR expression were compared for stem cell properties using both in vivo and in vitro assays. Statistically significant higher stem cell properties were found for the p75NTRHigh cells than for the p75NTRLow cells in all assays performed. This suggested that p75NTR can be used for isolating a subpopulation enriched for cells with stem cell–like properties in OSCC. Nevertheless, the p75NTRLow subpopulation did also exhibit some stem cell features, but to a lesser extent. Propagation of p75NTRLow cells for several passages in culture showed that the expression of p75NTR could rise spontaneously. This finding was also supported by the similar expression of p75NTR by the xenografts generated by both subpopulations in NOD\SCID IL2R null mice. Similar spontaneous generation of ALDH1High cells by propagation of ALDH1Low cells was observed, although with a different kinetic. Taken together, the data from this study showed high inter-patient variability in the expression of the CSC markers investigated, and high intra-tumor heterogeneity of the CSC subpopulation. The results presented here suggest also that some OSCC might have several distinct CSC phenotypes, each with impact on different clinical aspects, while other OSCC might completely lack a hierarchical organization. De novo generation of p75NTRHigh or ALDH1High cells from their negative counterparts might indicate the existence of a dynamic equilibrium between cancer cells with different degrees of differentiation

Study of High Pressure Heaters and Its Influence on Operation Cost in Power Plants: Case Study Garri -4

Electricity is one of the most important achievements that modern sciences have given to mankind. It became a part of modern life and one cannot think of a world without it. It has many uses in our daily life. Recently, in Sudan, there are some problems related to its continuity and availability of electrical and thermal power generation. This paper presents a part of the solution for the generation of thermal power for Garri-4. The characteristics of electrical energy are sustainability, easy transmission, and easy utilization. All these factors make electrical energy desirable. The main problem of electrical power is the high cost of production due to the high cost of fuel. Through the centuries, there is a lot of work done to reduce the energy cost, by rising up the efficiency and increase the performance of the systems. This paper shows the effect of high-pressure (HP) heaters out of service in the Garri-4 power plant. It aims to investigate the influence of HP heaters on the power plant's overall performance. The mathematical modeling is used through thermodynamic and heat transfer equations to study the efficiency and the operation cost for the power plant. The paper concludes that HP heaters have a clear influence on the power plant performance by increasing the overall power plant efficiency and reduce the operation cost. It also makes it less harmful to the environment through less emission due to less fuel consumption. There is an increase the overall power plant efficiency by 3.78% , 1.03%., and 2.56%, from 27.67%, for different cases studied in this paper

The Effect of Primary Open Angle Glucoma on Progression of Diabetic Retinopathy in Type 2 Diabetic Patients in Alsayem Eye Hospital

Background: Diabetic retinopathy is a serious complication of diabetes. Five percent of patients of type 2 diabetes (NIDDM) have signs of eye problems when diabetes is diagnosed.Control of blood sugar, blood pressure and cessation of smoking, have an important role in slowing the progression of retinopathy and other eye problems caused by diabetes.  Objectives: To determine whether there is a difference in progression of diabetic retinopathy among patients with and without primary open angle glucoma (POAG). Design: comparative cross –sectional study.  Participants: 160 patients who were on regular follow up and treatment in both retina and glaucoma clinics in Al-Sayem Eye Hospital were enrolled in the study. Patients were divided into 2 groups, the study group: included 80 patients who were type 2 diabetics with POAG (group A) .The control group were having type 2 diabetes without POAG (group B).The patients were compared for the grade of diabetic retinopathy according to international clinical diabetic retinopathy disease severity scale. For maculopathy patients were also classified according to international clinical diabetic macular edema disease severity scale. Risk factors for both groups were studied as follow: age, duration of DM, control of DM, systemic hypertension and smoking. Results: In multivariate analyses adjusting for above risk factors and examination for both groups. Diabetic retinopathy was not found in the study group (100%), compared to patients in the control group (patients without POAG) in which no diabetic retinopathy was found in only 8.8%. Mild NPDR was found in 14 patients (43.7%), moderate non prolifrative diabetic retinopathy(NPDR) was observed in 70 patients (32.5%), and severe NPDR in 24 patients (15%). Mild maculopathy was observed in only 4 patients in the study group (5%), all of them were poorly controlled with duration of diabetes of >11 years.In the control group, the majority of patients had no diabetic macular edema(DME) (65%). Mild DME was found in 48 patients (30%). Eight patients only in the control group had moderate DME. Conclusion: POAG and increased cup disc ratio are associated with a lower risk of DR, particularly vision-threatening retinopathy.&nbsp

Establishment of Hematological Reference intervals for healthy Children in Elobied City, Sudan

Hemogram Reference intervals are established since a healthy population is critical to accurately interpret laboratory tests, which include Hemoglobin estimation, Red blood cells count and indices, White blood cells count and differential in addition to Platelets count. This study aims to establish the reference interval of the complete hemogram amongst healthy Sudanese children in Elobied city, Sudan. A descriptive cross-sectional study  included 354 healthy children, aged between 3 to 17 years, who were categorized into three groups according to age. A questionnaire was fulfilled, EDTA anti-coagulated venous blood sample was collected from each child then the complete hemogram was performed automated hematological analyzer (Sysmex Xp 300), Finally, Data was analyzed by a software program (SPSS version 21). The hematological reference intervals for healthy children [Hb g/dl, HCT%, RBCs count x106μL, MCV/fL ,MCH /pg., MCHC g/dl ,WBCs count x10³/μL, Neutrophil count%, Eosinophil count %, Basophile count %, lymphocyte count ,Monocytes count%, RDW CV and PLTs count×10³/μL] are [(12.4±1.2),(37±4),(5.0 ±0.4), (82±5.0), (26±3.0), (32±3.0) ,(7.0±2.0) (47±10), (1±0.1) ,(0±0),(45± 10),(7 ± 4), (13±1.8) &(227±91)] respectively. The hematological RI for healthy children in Elobied was established in this study to be representative of this population, there was a significant gender-based difference in all the evaluated hematological parameters, they were found to be higher in males than in females except for basophil (%). Finally, the results of this study would shed a light on the importance of establishing RI for the children population in Elobied

Glomerular proteomic profiling of kidney biopsies with hypertensive nephropathy reveals a signature of disease progression

Hypertensive nephropathy (HN) requires a kidney biopsy as diagnostic gold-standard but histological findings are unspecific and specific prognostic markers are missing. We aimed at identifying candidate prognostic markers based on glomerular protein signatures. We studied adult patients (n = 17) with eGFR >30 ml/min/1.73m(2) and proteinuria = 1.5, pPeer reviewe

Axl-inhibitor bemcentinib alleviates mitochondrial dysfunction in the unilateral ureter obstruction murine model

Renal fibrosis is a progressive histological manifestation leading to chronic kidney disease (CKD) and associated with mitochondrial dysfunction. In previous work, we showed that Bemcentinib, an Axl receptor tyrosine kinase inhibitor, reduced fibrosis development. In this study, to investigate its effects on mitochondrial dysfunction in renal fibrosis, we analysed genome-wide transcriptomics data from a unilateral ureter obstruction (UUO) murine model in the presence or absence of bemcentinib (n = 6 per group) and SHAM-operated (n = 4) mice. Kidney ligation resulted in dysregulation of mitochondria-related pathways, with a significant reduction in the expression of oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), citric acid cycle (TCA), response to reactive oxygen species and amino acid metabolism-related genes. Bemcentinib treatment increased the expression of these genes. In contrast, AKT/PI3K signalling pathway genes were up-regulated upon UUO, but bemcentinib largely inhibited their expression. At the functional level, ligation reduced mitochondrial biomass, which was increased upon bemcentinib treatment. Serum metabolomics analysis also showed a normalizing amino acid profile in UUO, compared with SHAM-operated mice following bemcentinib treatment. Our data suggest that mitochondria and mitochondria-related pathways are dramatically affected by UUO surgery and treatment with Axl-inhibitor bemcentinib partially reverses these effects.publishedVersio

Characterization of glomerular extracellular matrix in IgA nephropathy by proteomic analysis of laser-captured microdissected glomeruli

Background IgA nephropathy (IgAN) involves mesangial matrix expansion, but the proteomic composition of this matrix is unknown. The present study aimed to characterize changes in extracellular matrix in IgAN. Methods In the present study we used mass spectrometry-based proteomics in order to quantitatively compare protein abundance between glomeruli of patients with IgAN (n = 25) and controls with normal biopsy findings (n = 15). Results Using a previously published paper by Lennon et al. and cross-referencing with the Matrisome database we identified 179 extracellular matrix proteins. In the comparison between IgAN and controls, IgAN glomeruli showed significantly higher abundance of extracellular matrix structural proteins (e.g periostin, vitronectin, and extracellular matrix protein 1) and extracellular matrix associated proteins (e.g. azurocidin, myeloperoxidase, neutrophil elastase, matrix metalloproteinase-9 and matrix metalloproteinase 2). Periostin (fold change 3.3) and azurocidin (3.0) had the strongest fold change between IgAN and controls; periostin was also higher in IgAN patients who progressed to ESRD as compared to patients who did not. Conclusion IgAN is associated with widespread changes of the glomerular extracellular matrix proteome. Proteins important in glomerular sclerosis or inflammation seem to be most strongly increased and periostin might be an important marker of glomerular damage in IgAN.publishedVersio

AXL targeting reduces fibrosis development in experimental unilateral ureteral obstruction

The AXL receptor tyrosine kinase (RTK) is involved in partial epithelial-tomesenchymal transition (EMT) and inflammation – both main promoters of renal fibrosis development. The study aim was to investigate the role of AXL inhibition in kidney fibrosis due to unilateral ureteral obstruction (UUO). Eight weeks old male C57BL/6 mice underwent UUO and were treated with oral AXL inhibitor bemcentinib (n = 22), Angiotensin-converting enzyme inhibitor (ACEI, n = 10), ACEI and bemcentinib (n = 10) or vehicle alone (n = 22). Mice were sacrificed after 7 or 15 days and kidney tissues were analyzed by immunohistochemistry (IHC), western blot, ELISA, Sirius Red (SR) staining, and hydroxyproline (Hyp) quantification. RNA was extracted from frozen kidney tissues and sequenced on an Illumina HiSeq4000 platform. After 15 days the ligated bemcentinib-treated kidneys showed less fibrosis compared to the ligated vehicle-treated kidneys in SR analyses and Hyp quantification. Reduced IHC staining for Vimentin (VIM) and alpha smooth muscle actin (aSMA), as well as reduced mRNA abundance of key regulators of fibrosis such as transforming growth factor (Tgfb), matrix metalloproteinase 2 (Mmp2), Smad2, Smad4, myofibroblast activation (Aldh1a2, Crlf1), and EMT (Snai1,2, Twist), in ligated bemcentinib-treated kidneys was compatible with reduced (partial) EMT induction. Furthermore, less F4/80 positive cells, less activity of pathways related to the immune system and lower abundance of MCP1, MCP3, MCP5, and TARC in ligated bemcentinib-treated kidneys was compatible with reduction in inflammatory infiltrates by bemcentinib treatment. The AXL RTK pathway represents a promising target for pharmacologic therapy of kidney fibrosis.publishedVersio

Systems analyses of the Fabry kidney transcriptome and its response to enzyme replacement therapy identified and cross-validated enzyme replacement therapy-resistant targets amenable to drug repurposing

Fabry disease is a rare disorder caused by variations in the alpha-galactosidase gene. To a degree, Fabry disease is manageable via enzyme replacement therapy (ERT). By understanding the molecular basis of Fabry nephropathy (FN) and ERT's long-term impact, here we aimed to provide a framework for selection of potential disease biomarkers and drug targets. We obtained biopsies from eight control individuals and two independent FN cohorts comprising 16 individuals taken prior to and after up to ten years of ERT, and performed RNAseq analysis. Combining pathway-centered analyses with network-science allowed computation of transcriptional landscapes from four nephron compartments and their integration with existing proteome and drug-target interactome data. Comparing these transcriptional landscapes revealed high inter-cohort heterogeneity. Kidney compartment transcriptional landscapes comprehensively reflected differences in FN cohort characteristics. With exception of a few aspects, in particular arteries, early ERT in patients with classical Fabry could lastingly revert FN gene expression patterns to closely match that of control individuals. Pathways nonetheless consistently altered in both FN cohorts pre-ERT were mostly in glomeruli and arteries and related to the same biological themes. While keratinization-related processes in glomeruli were sensitive to ERT, a majority of alterations, such as transporter activity and responses to stimuli, remained dysregulated or reemerged despite ERT. Inferring an ERT-resistant genetic module of expressed genes identified 69 drugs for potential repurposing matching the proteins encoded by 12 genes. Thus, we identified and cross-validated ERT-resistant gene product modules that, when leveraged with external data, allowed estimating their suitability as biomarkers to potentially track disease course or treatment efficacy and potential targets for adjunct pharmaceutical treatment