Differential import of proteins across the mitochondrial inner membrane via the TIM23 Complex

Mitochondrial precursor proteins differ in their structure, destination and signal, which facilitates the import process across membranes through translocase complexes. The outer and inner membrane translocase complex, TOM-TIM23 complex imports presequence and sorting signal carrying precursor proteins into the matrix and integrated into the inner membrane, respectively. Matrix import of presequence carrying precursor proteins are performed by the interaction of TIM23 complex and presequence translocase-associated import motor (PAM). Membrane insertion of hydrophobic segments of the precursor proteins via stop-transfer mechanism is supported by the direct physical interaction of Mgr2 to the incoming precursor protein. Various studies are focused on the biogenesis, substrate recognition, import behavior, of the TIM23 complex, whereas comparatively less is explored about the regulatory unit, Tim17. Site-specific photo-crosslinking data suggest that Tim17 and Mgr2 differentially interact with hydrophilic and hydrophobic precursor protein segments within the TIM23 complex. In this study, Tim17 temperature-sensitive (ts) mutants are used to understand how Tim17 and Mgr2 cooperate in the decoding of inner membrane sorting signals and the release of precursor proteins into the phospholipid bilayer. In vitro import experiments performed with radiolabelled precursor proteins are used to observe differential sorting behavior of Tim17. The study shows that Tim17 is involved in the lateral sorting of precursor proteins along with Mgr2. Mgr2 provides stability and rescues the import defect of Tim17 and together opens analogously as a channel towards the inner membrane only for hydrophobic sorting signal carrying precursor proteins. In the second part, cst6 mutants are used to observe import kinetics in response to upregulation of Tim23. The cst6 is one of the transcriptional factors of Tim23, which endures mutation to support the allotropic expression of the mitochondrial gene, ATP9. It is observed that the overexpression of Tim23 displays increased import of mitochondrial precursor proteins as the gain of function mutations.Mitochondriale Vorläuferproteine unterscheiden sich in ihrer Struktur, ihrem Ziel und ihrem Signal, was den Importprozess über Membranen durch Translokasekomplexe erleichtert. Der Translokasekomplex der äußeren und inneren Membran, TOM-TIM23 Complex, importiert Präsequenz- und Sortiersignale, die Vorläuferprotein tragen, in die Matrix und wird in die innere Membran integriert. Der Matriximport von Präsequenz tragendem Vorläuferprotein wird durch die Wechselwirkung von TIM23 Complex und Präsequenztranslokase-assoziiertem Importmotor (PAM) durchgeführt. Die Membraninsertion von hydrophoben Segmenten des Vorläuferproteins über den Stop-Transfer-Mechanismus wird durch die direkte physikalische Wechselwirkung von Mgr2 mit dem ankommenden Vorläuferprotein unterstützt. Verschiedene Studien konzentrieren sich auf die Biogenese, Substraterkennung und das Importverhalten des TIM23-Komplexes, während vergleichsweise weniger über die regulatorische Einheit Tim17 untersucht wird. Ortsspezifische Photovernetzungsdaten legen nahe, dass Tim17 und Mgr2 unterschiedlich mit hydrophilen und hydrophoben Vorläuferproteinsegmenten innerhalb des TIM23-Komplexes interagieren. In dieser Studie werden temperaturempfindliche (ts) Tim17-Mutanten verwendet, um zu verstehen, wie Tim17 und Mgr2 bei der Decodierung von Sortiersignalen der inneren Membran und der Freisetzung von Vorläuferprotein in die Phospholipid-Doppelschicht zusammenarbeiten. In-vitro-Importversuche mit radioaktiv markierten Vorläuferproteinen werden verwendet, um das unterschiedliche Sortierverhalten von Tim17 zu beobachten. Die Studie zeigt, dass Tim17 zusammen mit Mgr2 an der lateralen Sortierung des Vorläuferproteins beteiligt ist. Das Mgr2 bietet Stabilität und rettet den Importdefekt von Tim17 und öffnet sich zusammen analog als Kanal zur inneren Membran nur für das hydrophobe Sortiersignal, das das Vorläuferprotein trägt. Im zweiten Teil werden cst6-Mutanten verwendet, um die Importkinetik als Reaktion auf die Hochregulation von Tim23 zu beobachten. Das cst6 ist einer der Transkriptionsfaktoren von Tim23, der eine Mutation aushält, um die allotrope Expression des mitochondrialen Gens ATP9 zu unterstützen. Es wird beobachtet, dass die Überexpression von Tim23 einen erhöhten Import von mitochondrialem Vorläuferprotein als Gewinn von Funktionsmutationen zeigt.IRTG 183

Rising Costs of Insulin and Effects of Self-Management in Type 1 Diabetes

Background Type 1 diabetes, also known as juvenile diabetes or insulin-dependent diabetes is a chronic condition where the pancreas may not be able to produce little to no insulin. This type of diabetes can be attributed to some factors such as age, family history, environmental factors or types of viruses. It is seen more often in children or adolescence but can develop in adults, averaging approximately 5-10% of the population. Insulin is a type of hormone produced in the pancreas naturally or can be manufactured in the laboratory. People with Type 1 Diabetes need insulin from an exogenous source to survive. Due to the increased need for insulin and the ability to mass produce multiple types of insulin, there is a rising cost in the United States. Since pharmaceutical manufacturers do not have price limitations or direct competition in the insulin market, they can price their products at any desired level. In equivalent, costs of diabetes medication costs have increased following the insulin influx demand. Objective This thesis will explore ways to reach, educate the population and provide cost effective insulin and medications for diabetics. Establishing accessibility would aid in an increase of safety and self-management of the disease process and possibly decrease rates of deaths associated with diabetes. Summary of Findings Through review of different research types, there were common trends regarding the major inflation of insulin costs to difficulty of accessibility of goods. Difficulty of accessibility can also be attributed to poor health literacy, communication or if there were disagreements with healthcare goals of the patient. In addition, an underlying strength of all these studies was participation of varied ages, genders, races and socioeconomic standing. Proposal We want to examine the impact of the rising costs of insulin on patients’ ability to manage their Type 1 diabetes, specifically looking at the effects it has on lower socioeconomic regions. **This piece will divulge into a thesis and literature review with provided researc

Experimental Verification of Effect of Different Fluid Properties on the Vibration Response of a Cantilever Rotor

The current analysis is an effort to obtain the vibration characteristics of the cantilever rotor shaft with an extra mass added at the free end of the rotor shaft partially immersed in the viscous medium. This work is concentrated on the theoretical analysis of the natural frequency and amplitude of the spinning cantilever rotor shaft with addition mass using the influence coefficient method. The influence of fluid forces is studied using the Navier-Stoke’s equation. The gap ratio (ratio of the fluid-filled container radius to the shaft radius) and viscosity of the fluid are taken as the main variable parameters. MATLAB programming is used to obtaining vibration behavior from the theoretical expressions. Аn obtained result from the numerical analysis is validated by the comparison of the results of experimental analysis.Запропонований аналіз має метою отримати характеристики коливань валу консольного ротора з додатковою масою на вільному кінці валу, частково зануреного у в'язке середовище. Увага зосереджена на теоретичному аналізі власних частот та амплітуд обертового консольного валу з додатковою масою з використанням методу коефіцієнта впливу. Вплив сил рідини вивчається за допомогою рівняння Нав'є-Стокса. Коефіцієнт зазору (відношення радіуса ємності, наповненої рідиною, до радіуса валу) та в'язкість рідини приймаються за основні змінні параметри. Для отримання вібраційної поведінки з теоретичних виразів використовується програмування MATLAB. Отриманий результат чисельного аналізу підтверджується порівнянням з результатами експериментального аналізу

Dynamic Analysis of Cracked Rotor in Viscous Medium and its Crack Diagnosis Using Intelligent Techniques

Fatigue cracks have high potential to cause catastrophic failures in the rotor which can lead to catastrophic failure if undetected properly and in time. This fault may interrupt smooth, effective and efficient operation and performance of the machines. Thereby the importance of identification of crack in the rotor is not only for leading safe operation but also to prevent the loss of economy and lives.The condition monitoring of the engineering systems is attracted by the researchers and scientists very much to invent the automated fault diagnosis mechanism using the change in dynamic response before and after damage. When the rotor with transverse crack immersed in the viscous fluid, analysis of cracked rotor is difficult and complex. The analysis of cracked rotor partially submerged in the viscous fluid is widely used in various engineering systems such as long spinning shaft used drilling the seabed for the extracting the oil, high-speed turbine rotors, and analysis of centrifuges in a fluid medium. Therefore, dynamic analysis of cracked rotor partially submerged in the viscous medium have been presented in the current study. The theoretical analysis has been performed to measure the vibration signatures (Natural Frequencies and Amplitude) of multiple cracked mild steel rotor partially submerged in the viscous medium. The presence of the crack in rotor generates an additional flexibility. That is evaluated by strain energy release rate given by linear fracture mechanics. The additional flexibility alters the dynamic characteristics of cracked rotor in a viscous fluid. The local stiffness matrix has been calculated by the inverse of local dimensionless compliance matrix. The finite element analysis has been carried out to measure the vibration characteristics of cracked rotor partially submerged in the viscous medium using commercially available finite element software package ANSYS. It is observed from the current analysis, the various factors such as the viscosity of fluid, depth and position of the cracks affect the performance of the rotor and effectiveness of crack detection techniques. Various Artificial Intelligent (AI) techniques such as fuzzy logic, hybrid BPNN-RBFNN neural network, MANFIS and hybrid fuzzy-rule base controller based multiple faults diagnosis systems are developed using the dynamic response of rotating cracked rotor in a viscous medium to monitor the presence of crack. Experiments have been conducted to authenticate the performance and accuracy of proposed methods. Good agreement is observed between the results

Smooth Muscle Cell Mitochondrial Respiration – Effects of Aerobic Training and Type I Diabetes

Cardiovascular disease is the leading cause of death among diabetic patients, due mostly to mitochondrial dysfunction and resulting oxidative stress. Endurance exercise has been firmly established as a way to reduce diabetes and cardiovascular disease morbidity and mortality. The importance of mitochondria for both training performance and health underlies the significance of better understanding the factors that regulate exercise-induced adaptations in mitochondrial network dynamics. The effects on mitochondrial skeletal and cardiac muscle have already been well documented in the past. However, the specific impact of aerobic training on respiratory capacity in the vasculature remain to be established. Furthermore, the relationship between aerobic exercise and mitochondrial function in diabetic patients has yet to be investigated. We hypothesized that a long-term aerobic exercise intervention would enhance mitochondrial respiratory capacity in vascular smooth muscle cells. First, we investigated the effects of training in the vasculature of healthy mice (C57BL/6) and compared them to their sedentary counterparts. We found that exercise stimulates a rise in vascular mitochondrial content and respiratory capacity, especially complex I respiration (p < 0.05). However, when comparing diabetic trained mice to diabetic sedentary controls, it was found that aerobic training induced a downregulation in mitochondrial protein expression as well as a decrease in complex I respiration. In these experiments, our findings suggest that despite the demonstrated benefits of exercise, careful measures should be taken when exposing diabetic models that carry an inherently high risk of cardiovascular disease to prolonged exercise

Subpatent Plasmodium with mutant pfmdr1, pfcrt, and pvmdr1 alleles from endemic provinces in Mindanao, the Philippines: implications for local malaria elimination

Objectives This study was performed to identify and characterize circulating Plasmodium species in three provinces of Mindanao approaching malaria elimination. Methods Rapid diagnostic tests (RDT), microscopic examination, and PCR were used to detect malaria parasites. PCR-positive isolates were genotyped for polymorphisms in loci of interest. Results A total of 2639 participants were surveyed in Mindanao between 2010 and 2013. Malaria prevalence by PCR was 3.8% (95% confidence interval (CI): 2.7-5.2%) in Sarangani, 10% (95% CI: 7.7-12.7%) in South Cotabato, and 4.2% (95% CI: 3.2-5.6%) in Tawi-Tawi. P. falciparum and P. vivax were identified in all three provinces, and there was one case of P. malariae in South Cotabato. RDT was inferior to PCR for detecting asymptomatic P. falciparum and P. vivax. In Tawi-Tawi, microscopy failed to identify 46 PCR-positive malaria infections. The presence of pfcrt haplotypes CVMNK, CVIET, and SMNT (codons 72-76), pfmdr1 haplotype NFSND (codons 86, 184, 1034, 1042, 1246), and pvmdr1 haplotype NFL (codons 91, 976, 1076) was confirmed in Mindanao. Conclusions Asymptomatic Plasmodium infections persisted in local communities between 2010 and 2013. PCR successfully identified subpatent malaria infections, and can better characterize malaria epidemiology in communities seeking malaria control and elimination at the local level

Advancing social equity in and through marine conservation

Substantial efforts and investments are being made to increase the scale and improve the effectiveness of marine conservation globally. Though it is mandated by international law and central to conservation policy, less attention has been given to how to operationalize social equity in and through the pursuit of marine conservation. In this article, we aim to bring greater attention to this topic through reviewing how social equity can be better integrated in marine conservation policy and practice. Advancing social equity in marine conservation requires directing attention to: recognition through acknowledgment and respect for diverse peoples and perspectives; fair distribution of impacts through maximizing benefits and minimizing burdens; procedures through fostering participation in decision-making and good governance; management through championing and supporting local involvement and leadership; the environment through ensuring the efficacy of conservation actions and adequacy of management to ensure benefits to nature and people; and the structural barriers to and institutional roots of inequity in conservation. We then discuss the role of various conservation organizations in advancing social equity in marine conservation and identify the capacities these organizations need to build. We urge the marine conservation community, including governments, non-governmental organizations and donors, to commit to the pursuit of socially equitable conservation

How to Learn to Love the Hustle: When living your Maine dream means working four jobs, you can get discouraged or you can get to work. And you might learn something about yourself

Story about a writer who moved to Maine in 2007 who had to learn the value of hard work and to piece odd jobs together to survive while living in Maine. The difficulties of questioning skills, abilities and the writer\u27s identity are described although her tenacity outweighed all

Sustainable Waste Management for Hawaii’s Correctional Facilities: Barriers to Implementation

M.S

Three manuscripts on the role of entrepreneurial ecosystems in supporting the resiliency and growth of military veteran-owned firms in the rural United States.

Entrepreneurship can be a pathway of opportunity for military veterans, as well as provide economic growth for rural communities. However, because of public data limitations, there is no research on the relationship between veteran-owned firms and rural entrepreneurial ecosystems. The resiliency and growth of military veteran-owned firms in rural America may be predicated on the conditions of their local entrepreneurial ecosystem. Using the available public data, this dissertation sets the conditions for future work. To the extent available identification will be made of ecosystem conditions that are conducive to veteran-owned firm growth, resiliency, and death. Quantifiable characteristics include individual, spatial, cultural, policy, and temporal factors. Ultimately, this product will drive future efforts with restricted federal microdata below the state or commuting zone level in the Texas Federal Statistical Research Data Center, United States Census Bureau. I address the relationship between a military veteran and their entrepreneurial ecosystem with three project outcomes that will be addressed in three linked manuscripts. These manuscripts will use descriptive statistics and visualization, logistic regression, ordinary least squares (OLS) regression, hierarchical linear modeling (HLM), and spatial econometrics. The use of HLM and spatial econometrics takes into consideration the nuances of local conditions that are traditionally lost in high-level aggregation. In this way, I will statistically simulate the effect of an entrepreneurial culture as well as geographic space and time. These variables include traditional measures of an entrepreneurial ecosystem (such as percent self-employed or industry agglomeration), as well as new measures that are relevant to veteran-owned firms and are created through data mining (like the presence of veteran service organizations or locally oriented community banks). The contribution of this dissertation is new knowledge for community development stakeholders to assess the local entrepreneurial ecosystem, as well as facilitate community support for benchmarked factors that, if present, will assist in the growth and resiliency of veteran-owned firms. This dissertation is also an initial foray into the effect of space on military veteran reintegration after service. Ultimately, targeted research on this subgroup will improve research on inclusive economic development for other subgroups. Sustainability of this dissertation is fortified by a) publishing new knowledge in peer-reviewed academic journals, b) informing the data-driven development of a localized curriculum for Cooperative Extension agents to utilize, c) supporting NGO stakeholders in helping individuals attain economic independence through entrepreneurial success, and d) using information gained to develop future models of entrepreneurial ecosystems