Biophysical characterization of the plakin family

The desmosome is an inter-cellular complex required for strong cell-cell adhesion in skin and heart tissue. The plakin family of proteins is important to the desmosome as their main function is to act as linkers between the cell surface and cytoskeleton. The structures, dynamics, impact of heart disease causing mutations and interactions of these component domains have remained largely unknown. In order to better understand this, biophysical techniques were used to shed light into the specific effects of pathological mutations using complementary techniques including nuclear magnetic resonance spectroscopy, small angle X-ray scattering and X-ray crystallography. Novel insights included the modular organization and flexibility of serial spectrin repeat constructs in the N-terminal plakin domain was established. Biophysical characterization of a variety of plakin family C-terminal tail constructs was successfully conducted in addition to understanding the molecular consequences of disease causing point mutations linked to Arryhthmogenic Right Ventricular Cardiomyopathy. Together this provides a better understanding of the specific roles of the plakin family’s N- and C- termini in linking the desmosomal machinery on the cell membrane to the intermediate filaments

Theory And Practice In Capital Budgeting: Evidence From Kuwait

Capital budgeting is an important tool in corporate finance, which is supported with numerous methods. Previous researches in this field shows that simple methods of capital budgeting are preferred over complex methods. With an objective to adopt relevant modification in the academic sector this paper evaluates the preferred capital budgeting practices in Kuwait, one of the strongest economy in the world, through a structured questionnaire distributed among 100 firms. The study also reveals the significance of demographic factors on real life capital budgeting practices as well as it probes in to the significance of the subjects; introductory finance, financial management and risk management. The results of the study are consistent with the previous researches in this field, that majority of the respondents use the NPV.  Furthermore, age, educational qualification, managerial levels, years of experience, company size, among others all have significant effects on most capital budgeting methods

KFAED

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Civil and Environmental Engineering, 2005."September 2005."Includes bibliographical references (leaves 148-150).This thesis examines the record of the Kuwait Fund for Arab Economic Development (KFAED) in light of changing fashions regarding the proper role and management of such funds in the development finance process. The key questions addressed are whether its concessional aid is allocated according to Donor Interest (DI) or Recipient Needs (RN), what precisely is the grant element in KFAED loans, whether this grant allocation is consistent with the fund's stated policy and if it is linked to one or more of the currently held views regarding how aid should be allocated in order to be most effective - to overcome the "two gaps," to strengthen institutions and governance or to reward/incentivize effective macroeconomic management. The KFAED is an interesting and important subject of study for many reasons. After Saudi Arabia, Kuwait is the second largest Arab aid donor, having contributed a total of more than $18.5 billion between 1960 and 2002. It was the first to officially establish a bilateral aid institution: KFAED, which purports to be free of mercantilist motives as its aid is not tied to procurement, as is the case with most developed countries' aid institutions. The thesis consists of three mutually dependent sections. The first surveys the domain of theoretical and empirical development economics since World War II. It reviews its evolution over time, linking successes and failures in development aid to the refinement of macroeconomic points of view among various schools of thought. Since the implementation of any economic policy is highly sensitive to the political goals of the policy makers, we show that the evolution of macroeconomic theory is not, in itself, able to account for Kuwait Foundation for the Advancement of the Science's partial funding of this research, under grant 2005-12-01, is acknowledged. changes in the pattern of development aid. "Fashions" in such aid reflect not only the past history of aid itself, but also the histories of the donor nations or their multi-lateral vehicles. Our specific interest in regional Arab geopolitical development is contextualized in order to trace the effects of development theory evolution on the Middle Eastern region.(cont.) The second section studies the aid allocation of the KFAED. It seeks to determine, among other things, whether the allocation of aid reflects recipient needs or donor interest. We modeled the allocation decision as a two-stage process: selection and allocation. The empirical analysis demonstrates that income, ethnicity, religion and politics are all factors in the selection stage. Arab, Muslims countries and more populous countries receive a higher share of the total aid allocated (allocation stage). The third section extends the second by adding the third stage: grant element determination. It addresses two questions: how grant element is calculated and what factors influence its allocations. In addressing the first question, we offer a rationale for an adjusted discount rate in calculating grant element--the percentages of subsidy embedded in the loan. When this rate is applied, the results point to consistent overestimation of the traditionally published grant element statistics. We then examine the grant element allocation. We find that the actual allocation is quite different than that implied by the stated policy of the KFAED. Chief among the sources of variation are political factors, income and sectors. Finally, we test to see if the current grant element allocation is in line with any of the three views regarding how aid should be allocated: the two gap, macroeconomic management, and governance and institutions building. We find that it is weakly related to the two-gap view, but appears to bear no relation to the other two.by Sulaiman Ahmed Al-Jassar.Ph.D

Numerical And Approximate- Analytical Solution Of Fuzzy Initial Value Problems

Persamaan pembezaan kabur ( FDEs ) digunakan untuk memodel masalah tertentu dalam bidang sains dan kejuruteraan dan telah dikaji oleh ramai penyelidik . Masalah tertentu memerlukan penyelesaian FDEs yang memenuhi keadaan awal kabur menimbulkan masalah awal kabur ( FIVPs ). Contoh masalah seperti ini boleh didapati dalam fizik, kejuruteraan, model penduduk, dinamik reaktor nuklear, masalah perubatan, rangkaian neural dan teori kawalan. Walau bagaimanapun, kebanyakan masalah nilai awal kabur tidak boleh diselesaikan dengan tepat. Tambahan pula, penyelesaian analisis tepat yang diperoleh juga mungkin begitu sukar untuk dinilai dan oleh itu kaedah berangka dan analisis hampiran perlu untuk memperoleh penyelesaian. Fuzzy differential equations (FDEs) are used for the modeling of some problems in science and engineering and have been studied by many researchers. Certain problems require the solution of FDEs which satisfy fuzzy initial conditions giving rise to fuzzy initial problems (FIVPs). Examples of such problems can be found in physics, engineering, population models, nuclear reactor dynamics, medical problems, neural networks and control theory. However, most fuzzy initial value problems cannot be solved exactly. Furthermore, exact analytical solutions obtained may also be so difficult to evaluate and therefore numerical and approximate- analytical methods may be necessary to evaluate the solution

Mechanistic basis of desmosome-targeted diseases

Desmosomes are dynamic junctions between cells that maintain the structural integrity of skin and heart tissues by withstanding shear forces. Mutations in component genes cause life-threatening conditions including arrhythmogenic right ventricular cardiomyopathy, and desmosomal proteins are targeted by pathogenic autoantibodies in skin blistering diseases such as pemphigus. Here, we review a set of newly discovered pathogenic alterations and discuss the structural repercussions of debilitating mutations on desmosomal proteins. The architectures of native desmosomal assemblies have been visualized by cryo-electron microscopy and cryo-electron tomography, and the network of protein domain interactions is becoming apparent. Plakophilin and desmoplakin mutations have been discovered to alter binding interfaces, structures, and stabilities of folded domains that have been resolved by X-ray crystallography and NMR spectroscopy. The flexibility within desmoplakin has been revealed by small-angle X-ray scattering and fluorescence assays, explaining how mechanical stresses are accommodated. These studies have shown that the structural and functional consequences of desmosomal mutations can now begin to be understood at multiple levels of spatial and temporal resolution. This review discusses the recent structural insights and raises the possibility of using modeling for mechanism-based diagnosis of how deleterious mutations alter the integrity of solid tissues

Sequence-specific 1H, 13C and 15N backbone resonance assignments of the plakin repeat domain of human envoplakin

The plakin repeat domain is a distinctive hallmark of the plakin superfamily of proteins, which are found within all epithelial tissues. Plakin repeat domains mediate the interactions of these proteins with the cell cytoskeleton and are critical for the maintenance of tissue integrity. Despite their biological importance, no solution state resonance assignments are available for any homologue. Here we report the essentially complete (1)H, (13)C and (15)N backbone chemical shift assignments of the singular 22 kDa plakin repeat domain of human envoplakin, providing the means to investigate its interactions with ligands including intermediate filaments

Disease-Associated Mutations in CEP120 Destabilize the Protein and Impair Ciliogenesis.

Ciliopathies are a group of genetic disorders caused by a failure to form functional cilia. Due to a lack of structural information, it is currently poorly understood how ciliopathic mutations affect protein functionality to give rise to the underlying disease. Using X-ray crystallography, we show that the ciliopathy-associated centriolar protein CEP120 contains three C2 domains. The point mutations V194A and A199P, which cause Joubert syndrome (JS) and Jeune asphyxiating thoracic dystrophy (JATD), respectively, both reduce the thermostability of the second C2 domain by targeting residues that point toward its hydrophobic core. Genome-engineered cells homozygous for these mutations have largely normal centriole numbers but show reduced CEP120 levels, compromised recruitment of distal centriole markers, and deficient cilia formation. Our results provide insight into the disease mechanism of two ciliopathic mutations in CEP120, identify putative binding partners of CEP120 C2B, and suggest a complex genotype-phenotype relation of the CEP120 ciliopathy alleles

Cosmic ray short burst observed with the Global Muon Detector Network (GMDN) on June 22, 2015

We analyze the short cosmic ray intensity increase ("cosmic ray burst": CRB) on June 22, 2015 utilizing a global network of muon detectors and derive the global anisotropy of cosmic ray intensity and the density (i.e. the omnidirectional intensity) with 10-minute time resolution. We find that the CRB was caused by a local density maximum and an enhanced anisotropy of cosmic rays both of which appeared in association with Earth's crossing of the heliospheric current sheet (HCS). This enhanced anisotropy was normal to the HCS and consistent with a diamagnetic drift arising from the spatial gradient of cosmic ray density, which indicates that cosmic rays were drifting along the HCS from the north of Earth. We also find a significant anisotropy along the HCS, lasting a few hours after the HCS crossing, indicating that cosmic rays penetrated into the inner heliosphere along the HCS. Based on the latest geomagnetic field model, we quantitatively evaluate the reduction of the geomagnetic cut-off rigidity and the variation of the asymptotic viewing direction of cosmic rays due to a major geomagnetic storm which occurred during the CRB and conclude that the CRB is not caused by the geomagnetic storm, but by a rapid change in the cosmic ray anisotropy and density outside the magnetosphere.Comment: accepted for the publication in the Astrophysical Journa

Mechanism of intermediate filament recognition by plakin repeat domains revealed by envoplakin targeting of vimentin

Plakin proteins form critical connections between cell junctions and the cytoskeleton; their disruption within epithelial and cardiac muscle cells cause skin-blistering diseases and cardiomyopathies. Envoplakin has a single plakin repeat domain (PRD) which recognizes intermediate filaments through an unresolved mechanism. Herein we report the crystal structure of envoplakin's complete PRD fold, revealing binding determinants within its electropositive binding groove. Four of its five internal repeats recognize negatively charged patches within vimentin via five basic determinants that are identified by nuclear magnetic resonance spectroscopy. Mutations of the Lys1901 or Arg1914 binding determinants delocalize heterodimeric envoplakin from intracellular vimentin and keratin filaments in cultured cells. Recognition of vimentin is abolished when its residues Asp112 or Asp119 are mutated. The latter slot intermediate filament rods into basic PRD domain grooves through electrosteric complementarity in a widely applicable mechanism. Together this reveals how plakin family members form dynamic linkages with cytoskeletal frameworks