Papaya as a Medicinal Plant

Papaya has been used medicinally to treat an extremely broad range of ailments including intestinal worms, dengue fever, diabetes, hypertension, wound repair, and as an abortion agent. Although papaya is most commonly consumed as a ripe fruit, the plant tissues used as curatives are mainly derived from the seeds, young leaves, latex, or green immature fruit. The agents responsible for action have not been conclusively identified for all uses, but there is increasing evidence that activity may be attributable to benzyl isothiocyanate (BITC) in the case of anthelmintic and abortifacient action, and to the protease papain, and possibly chymopapain, in relation to wound repair. The location of these compounds in papaya tissues is likely to explain why different tissues are used for different ailments. Seeds, young leaves, and latex are good sources of BITC and are consequently used as a curative for intestinal worms. Immature green fruit is a good source of protease and is used as a topical application for burn wounds to accelerate tissue repair. The type of papaya tissue used may therefore provide a clue as to the active agent in ailments where papaya extracts have exhibited some activity (diabetes, hypertension, dengue fever). However, the compound(s) responsible for action remains to be identified. Modes of action of papaya extracts vary, but may include lowering blood glucose levels (diabetes), vascular muscle relaxation (hypertension), increasing blood cell count (dengue fever), stimulation of cell proliferation (wound healing), spasmodic contraction of uterine muscles (abortion), and induction of phase 2 enzymes (cancer chemoprevention). Although there has been increased study over the last decade into the physiological mode of action of papaya extracts, further increase in the knowledge of the compounds responsible for curative action will help to transfer the use of papaya from folklore remedies to mainstream medicinal use.

Influence of dingoes on sheep distribution in Australia

Objective To describe the influence of the dingo (Canis lupus dingo) on the past, present and future distributions of sheep in Australia. Design The role of the dingo in the rise and fall of sheep numbers is reviewed, revised data are provided on the present distribution and density of sheep and dingoes, and historical patterns of sheep distribution are used to explore the future of rangeland sheep grazing. Results Dingoes are a critical causal factor in the distribution of sheep at the national, regional and local levels. Dingo predation contributed substantially to the historical contraction of the sheep industry to its present-day distribution, which is almost exclusively confined to areas within fenced dingo exclusion zones. Dingo populations and/or their influence are now present and increasing in all sheep production zones of Australia, inclusive of areas that were once dingo free'. Conclusions Rangeland production of wool and sheep meat is predicted to disappear within 30-40 years if the present rate of contraction of the industry continues unabated. Understanding the influence of dingoes on sheep production may help refine disease response strategies and help predict the future distribution of sheep and their diseases.

Magmatic evolution of topaz-bearing granite stocks within the Wiborg rapakivi granite batholith

This study brings new insights into the magmatic evolution of natural F-enriched peraluminous granitic systems. The Artjärvi, Sääskjärvi and Kymi granite stocks within the 1.64 Ga Wiborg rapakivi granite batholith have been investigated by petrographic, geochemical, experimental and melt inclusion methods. These stocks represent late-stage leucocratic and weakly peraluminous intrusive phases typical of rapakivi granites worldwide. The Artjärvi and Sääskjärvi stocks are multiphase intrusions in which the most evolved phase is topaz granite. The Kymi stock contains topaz throughout and has a well-developed zoned structure, from the rim to the center: stockscheider pegmatite equigranular topaz granite porphyritic topaz granite. Geochemically the topaz granites are enriched in F, Li, Be, Ga, Rb, Sn and Nb and depleted in Mg, Fe, Ti, Ba, Sr, Zr and Eu. The anomalous geochemistry and mineralogy of the topaz granites are essentially magmatic in origin; postmagmatic reactions have only slightly modified the compositions. The Kymi equigranular topaz granite shows the most evolved character, and the topaz granites at Artjärvi and Sääskjärvi resemble the less evolved porphyritic topaz granite of the Kymi stock. Stockscheiders are found at the roof contacts of the Artjärvi and Kymi stocks. The stockscheider at Artjärvi is composed of biotite-rich schlieren and pegmatite layers parallel to the contact. The schlieren layering is considered to have formed by velocity-gradient sorting mechanism parallel to the flow, which led to the accumulation of mafic minerals along the upper contact of the topaz granite. Cooling and contraction of the topaz granite formed fractures parallel to the roof contact and residual pegmatite magmas were injected along the fractures and formed the pegmatite layers. The zoned structure of the Kymi stock is the result of intrusion of highly evolved residual melt from deeper parts of the magma chamber along the fractured contact between the porphyritic granite crystal mush and country rock. The equigranular topaz granite and marginal pegmatite (stockscheider) crystallized from this evolved melt. Phase relations of the Kymi equigranular topaz granite have been investigated utilizing crystallization experiments at 100 to 500 MPa as a function of water activity and F content. Fluorite and topaz can crystallize as liquidus phases in F-rich peraluminous systems, but the F content of the melt should exceed 2.5 - 3.0 wt % to facilitate crystallization of topaz. In peraluminous F-bearing melts containing more than 1 wt % F, topaz and muscovite are expected to be the first F-bearing phases to crystallize at high pressure, whereas fluorite and topaz should crystallize first at low pressure. Overall, the saturation of fluorite and topaz follows the reaction: CaAl2Si2O8 (plagioclase) + 2[AlF3]melt = CaF2 (fluorite) + 2Al2SiO4F2 (topaz). The obtained partition coefficient for F between biotite and glass D(F)Bt/glass is 1.89 to 0.80 (average 1.29) and can be used as an empirical fluormeter to determine the F content of coexisting melts. In order to study the magmatic evolution of the Kymi stock, crystallized melt inclusions in quartz and topaz grains in the porphyritic and the equigranular topaz granites and the marginal pegmatite were rehomogenized and analyzed. The homogenization conditions for the melt inclusions from the granites were 700 °C, 300 MPa, and 24 h, and for melt inclusions from the pegmatite, 700 °C, 100 MPa, and 24/96 h. The majority of the melt inclusions is chemically similar to the bulk rocks (excluding H2O content), but a few melt inclusions in the equigranular granite show clearly higher F and low K2O contents (on average 11.6 wt % F, 0.65 wt % K2O). The melt inclusion compositions indicate coexistence of two melt fractions, a prevailing peraluminous and a very volatile-rich, possibly peralkaline. Combined petrological, experimental and melt inclusion studies of the Kymi equigranular topaz granite indicate that plagioclase was the liquidus phase at nearly water-saturated (fluid-saturated) conditions and that the F content of the melt was at least 2 wt %. The early crystallization of biotite and the presence of muscovite in crystallization experiments at 200 MPa contrasts with the late-stage crystallization of biotite and the absence of muscovite in the equigranular granite, indicating that crystallization pressure may have been lower than 200 MPa for the granite.

Pressure and alloying effects on the metal to insulator transition in NiS2-xSex studied by infrared spectroscopy

The metal to insulator transition in the charge-transfer NiS2-xSex compound has been investigated through infrared reflectivity. Measurements performed by applying pressure to pure NiS2 (lattice contraction) and by Se alloying (lattice expansion) reveal that in both cases an anomalous metallic state is obtained. We find that optical results are not compatible with the linear Se-alloying vs pressure-scaling relation previously established through transport, thus pointing out the substantially different microscopic origin of the two transitions.

Dependence Logic: Investigations into Higher-Order Semantics Defined on Teams

This thesis is a study of a rather new logic called dependence logic and its closure under classical negation, team logic. In this thesis, dependence logic is investigated from several aspects. Some rules are presented for quantifier swapping in dependence logic and team logic. Such rules are among the basic tools one must be familiar with in order to gain the required intuition for using the logic for practical purposes. The thesis compares Ehrenfeucht-Fraïssé (EF) games of first order logic and dependence logic and defines a third EF game that characterises a mixed case where first order formulas are measured in the formula rank of dependence logic. The thesis contains detailed proofs of several translations between dependence logic, team logic, second order logic and its existential fragment. Translations are useful for showing relationships between the expressive powers of logics. Also, by inspecting the form of the translated formulas, one can see how an aspect of one logic can be expressed in the other logic. The thesis makes preliminary investigations into proof theory of dependence logic. Attempts focus on finding a complete proof system for a modest yet nontrivial fragment of dependence logic. A key problem is identified and addressed in adapting a known proof system of classical propositional logic to become a proof system for the fragment, namely that the rule of contraction is needed but is unsound in its unrestricted form. A proof system is suggested for the fragment and its completeness conjectured. Finally, the thesis investigates the very foundation of dependence logic. An alternative semantics called 1-semantics is suggested for the syntax of dependence logic. There are several key differences between 1-semantics and other semantics of dependence logic. 1-semantics is derived from first order semantics by a natural type shift. Therefore 1-semantics reflects an established semantics in a coherent manner. Negation in 1-semantics is a semantic operation and satisfies the law of excluded middle. A translation is provided from unrestricted formulas of existential second order logic into 1-semantics. Also game theoretic semantics are considerd in the light of 1-semantics.

Mathematical models on the impact of noise and dyadic molecular structures on the properties of a cardiac myocyte

In cardiac myocytes (heart muscle cells), coupling of electric signal known as the action potential to contraction of the heart depends crucially on calcium-induced calcium release (CICR) in a microdomain known as the dyad. During CICR, the peak number of free calcium ions (Ca) present in the dyad is small, typically estimated to be within range 1-100. Since the free Ca ions mediate CICR, noise in Ca signaling due to the small number of free calcium ions influences Excitation-Contraction (EC) coupling gain. Noise in Ca signaling is only one noise type influencing cardiac myocytes, e.g., ion channels playing a central role in action potential propagation are stochastic machines, each of which gates more or less randomly, which produces gating noise present in membrane currents. How various noise sources influence macroscopic properties of a myocyte, how noise is attenuated and taken advantage of are largely open questions. In this thesis, the impact of noise on CICR, EC coupling and, more generally, macroscopic properties of a cardiac myocyte is investigated at multiple levels of detail using mathematical models. Complementarily to the investigation of the impact of noise on CICR, computationally-efficient yet spatially-detailed models of CICR are developed. The results of this thesis show that (1) gating noise due to the high-activity mode of L-type calcium channels playing a major role in CICR may induce early after-depolarizations associated with polymorphic tachycardia, which is a frequent precursor to sudden cardiac death in heart failure patients; (2) an increased level of voltage noise typically increases action potential duration and it skews distribution of action potential durations toward long durations in cardiac myocytes; and that (3) while a small number of Ca ions mediate CICR, Excitation-Contraction coupling is robust against this noise source, partly due to the shape of ryanodine receptor protein structures present in the cardiac dyad.

Studies on Unsteady Shock Interactions Near a Generic Scramjet Inlet

An experimental and numerical study is presented to show the effect of cowl length and angle on the ramp/cowl shock interaction phenomena fora two-dimensional planar scramjet inlet model. Experiments areconducted in a hypersonic shock tunnel, at Mach 8, at four lengths of owl and three cowl angles. Investigations include schlieren flow Visualization near the cowl region and static pressure and heat transfer rate measurement inside the inlet chamber. Various ramp/cowl shock interaction processes resulted for different cowl configurations have been visualized using a high-speed camera. Edney type-II interference pattern is observed for 131 and 141-mm cowl lengths,whereas it is an Edney type-I interference pattern in case of a 151 mm cowl with all their typical features resulting because of the ramp/cowl shock interaction. Experiments with a cowl configuration other than 0deg show the flow to he established through the inlet because or the reduced contraction ratio. Heat transfer peaks can be observed for the10 and 20-deg cowl cases where flow through the inlet is found to be established. These may serve as the possible locations of fuel injection.

Changes in CO2 emissions over business cycle recessions and expansions in the United States: A decomposition analysis

This paper examines the asymmetry of changes in CO2 emissions over business cycle recessions and expansions using yearly data from 1949 and monthly data from 1973 for the United States (US). In addition, decomposition analysis is applied to investigate the relative roles of various proximate contributing factors to observed changes in total and per capita CO2 emissions and emissions intensity, over business cycle phases. The results suggest, inter alia, that aggregate emissions and emissions intensity reduce much faster in contractions than they increase in expansions. In addition, unlike the three previous expansions, in the most recent post-GFC US expansion, emissions per capita have continued to decline, and at a rate very similar to the rate of reduction in preceding contractions. This suggests the real possibility that the most recent contraction may have had an ongoing impact on the path of per capita emissions well beyond the immediate impact experienced during the contraction itself.

Response of the anterior sclera to accommodation in myopes and emmetropes

• The biomechanical properties of the sclera are documented to be altered in eyes with myopia, with the myopic sclera thought to be more susceptible to deformation from otherwise normal ocular forces. • The close anatomical and functional relationship between the ciliary body and sclera suggests that ciliary muscle contraction during accommodation may influence the overlying sclera. • This study aimed to characterise the changes occurring in anterior scleral thickness with accommodation using anterior segment optical coherence tomography (AS-OCT) in young adult myopes and emmetropes.

Thyroid Hormone Control of Cardiac Substrate Metabolism

Thyroid hormone (TH) plays an important role in maintaining a homeostasis in all the cells of our body. It also has significant cardiovascular effects, and abnormalities of its concentration can cause cardiovascular disease and even morbidity. Especially development of heart failure has been connected to low levels of thyroid hormone. A decrease in TH levels or TH-receptor binding adversely effects cardiac function. Although, this occurs in part through alterations in excitation-contraction and transport proteins, recent data from our laboratory indicate that TH also mediates changes in myocardial energy metabolism. Thyroid dysfunction may limit the heart s ability to shift substrate pathways and provide adequate energy supply during stress responses. Our goals of these studies were to determine substrate oxidation pattern in systemic and cardiac specific hypothyroidism at rest and at higher rates of oxygen demand. Additionally we investigated the TH mediated mechanisms in myocardial substrate selection and established the metabolic phenotype caused by a thyroid receptor dysfunction. We measured cardiac metabolism in an isolated heart model using 13Carbon isotopomer analyses with MR spectroscopy to determine function, oxygen consumption, fluxes and fractional contribution of acetyl-CoA to the citric acid cycle (CAC). Molecular pathways for changes in cardiac function and substrate shifts occurring during stress through thyroid receptor abnormalities were determined by protein analyses. Our results show that TH modifies substrate selection through nuclear-mediated and rapid posttranscriptional mechanisms. It modifies substrate selection differentially at rest and at higher rates of oxygen demand. Chronic TH deficiency depresses total CAC flux and selectively fatty acid flux, whereas acute TH supplementation decreases lactate oxidation. Insertion of a dominant negative thyroid receptor (Δ337T) alters metabolic phenotype and contractive efficiency in heart. The capability of the Δ337T heart to increase carbohydrate oxidation in response to stress seems to be limited. These studies provided a clearer understanding of the TH role in heart disease and shed light to identification of the molecular mechanisms that will facilitate in finding targets for heart failure prevention and treatment.

Actin Dynamics in Muscle Cells

In every cell, actin is a key component involved in migration, cytokinesis, endocytosis and generation of contraction. In non-muscle cells, actin filaments are very dynamic and regulated by an array of proteins that interact with actin filaments and/or monomeric actin. Interestingly, in non-muscle cells the barbed ends of the filaments are the predominant assembly place, whereas in muscle cells actin dynamics was reported to predominate at the pointed ends of thin filaments. The actin-based thin filament pointed (slow growing) ends extend towards the middle of the sarcomere's M-line where they interact with the thick filaments to generate contraction. The actin filaments in muscle cells are organized into a nearly crystalline array and are believed to be significantly less dynamic than the ones in other cell types. However, the exact mechanisms of the sarcomere assembly and turnover are largely unknown. Interestingly, although sarcomeric actin structures are believed to be relatively non-dynamic, many proteins promoting actin dynamics are expressed also in muscle cells (e.g ADF/cofilin, cyclase-associated protein and twinfilin). Thus, it is possible that the muscle-specific isoforms of these proteins promote actin dynamics differently from their non-muscle counterparts, or that actin filaments in muscle cells are more dynamic than previously thought. To study protein dynamics in live muscle cells, I used primary cell cultures of rat cardiomyocytes. My studies revealed that a subset of actin filaments in cardiomyocyte sarcomeres displays rapid turnover. Importantly, I discovered that the turnover of actin filaments depends on contractility of the cardiomyocytes and that the contractility-induced actin dynamics plays an important role in sarcomere maturation. Together with previous studies those findings suggest that sarcomeres undergo two types of actin dynamics: (1) contractility-dependent turnover of whole filaments and (2) regulatory pointed end monomer exchange to maintain correct thin filament length. Studies involving an actin polymerization inhibitor suggest that the dynamic actin filament pool identified here is composed of filaments that do not contribute to contractility. Additionally, I provided evidence that ADF/cofilins, together with myosin-induced contractility, are required to disassemble non-productive filaments in developing cardiomyocytes. In addition, during these studies we learned that isoforms of actin monomer binding protein twinfilin, Twf-1 and Twf-2a localise to myofibrils in cardiomyocytes and may thus contribute to actin dynamics in myofibrils. Finally, in collaboration with Roberto Dominguez s laboratory we characterized a new actin nucleator in muscle cells - leiomodin (Lmod). Lmod localises towards actin filament pointed ends and its depletion by siRNA leads to severe sarcomere abnormalities in cardiomyocytes. The actin filament nucleation activity of Lmod is enhanced by interactions with tropomyosin. We also revealed that Lmod expression correlates with the maturation of myofibrils, and that it associates with sarcomeres only at relatively late stages of myofibrillogenesis. Thus, Lmod is unlikely to play an important role in myofibril formation, but rather might be involved in the second step of the filament arrangement and/or maintenance through its ability to promote tropomyosin-induced actin filament nucleation occurring at the filament pointed ends. The results of these studies provide valuable new information about the molecular mechanisms underlying muscle sarcomere assembly and turnover. These data offer important clues to understanding certain physiological and pathological behaviours of muscle cells. Better understanding of the processes occurring in muscles might help to find strategies for determining, diagnosis, prognosis and therapy in heart and skeletal muscles diseases.

On the Structure of Contractible Edges in k-connected Partial k-trees

Contraction of an edge e merges its end points into a new single vertex, and each neighbor of one of the end points of e is a neighbor of the new vertex. An edge in a k-connected graph is contractible if its contraction does not result in a graph with lesser connectivity; otherwise the edge is called non-contractible. In this paper, we present results on the structure of contractible edges in k-trees and k-connected partial k-trees. Firstly, we show that an edge e in a k-tree is contractible if and only if e belongs to exactly one (k + 1) clique. We use this characterization to show that the graph formed by contractible edges is a 2-connected graph. We also show that there are at least |V(G)| + k - 2 contractible edges in a k-tree. Secondly, we show that if an edge e in a partial k-tree is contractible then e is contractible in any k-tree which contains the partial k-tree as an edge subgraph. We also construct a class of contraction critical 2k-connected partial 2k-trees.

Spiral-Wave Turbulence and Its Control in the Presence of Inhomogeneities in Four Mathematical Models of Cardiac Tissue

Regular electrical activation waves in cardiac tissue lead to the rhythmic contraction and expansion of the heart that ensures blood supply to the whole body. Irregularities in the propagation of these activation waves can result in cardiac arrhythmias, like ventricular tachycardia (VT) and ventricular fibrillation (VF), which are major causes of death in the industrialised world. Indeed there is growing consensus that spiral or scroll waves of electrical activation in cardiac tissue are associated with VT, whereas, when these waves break to yield spiral- or scroll-wave turbulence, VT develops into life-threatening VF: in the absence of medical intervention, this makes the heart incapable of pumping blood and a patient dies in roughly two-and-a-half minutes after the initiation of VF. Thus studies of spiral- and scroll-wave dynamics in cardiac tissue pose important challenges for in vivo and in vitro experimental studies and for in silico numerical studies of mathematical models for cardiac tissue. A major goal here is to develop low-amplitude defibrillation schemes for the elimination of VT and VF, especially in the presence of inhomogeneities that occur commonly in cardiac tissue. We present a detailed and systematic study of spiral- and scroll-wave turbulence and spatiotemporal chaos in four mathematical models for cardiac tissue, namely, the Panfilov, Luo-Rudy phase 1 (LRI), reduced Priebe-Beuckelmann (RPB) models, and the model of ten Tusscher, Noble, Noble, and Panfilov (TNNP). In particular, we use extensive numerical simulations to elucidate the interaction of spiral and scroll waves in these models with conduction and ionic inhomogeneities; we also examine the suppression of spiral- and scroll-wave turbulence by low-amplitude control pulses. Our central qualitative result is that, in all these models, the dynamics of such spiral waves depends very sensitively on such inhomogeneities. We also study two types of control chemes that have been suggested for the control of spiral turbulence, via low amplitude current pulses, in such mathematical models for cardiac tissue; our investigations here are designed to examine the efficacy of such control schemes in the presence of inhomogeneities. We find that a local pulsing scheme does not suppress spiral turbulence in the presence of inhomogeneities; but a scheme that uses control pulses on a spatially extended mesh is more successful in the elimination of spiral turbulence. We discuss the theoretical and experimental implications of our study that have a direct bearing on defibrillation, the control of life-threatening cardiac arrhythmias such as ventricular fibrillation.

Third post-Newtonian angular momentum flux and the secular evolution of orbital elements for inspiralling compact binaries in quasi-elliptical orbits

The angular-momentum flux from an inspiralling binary system of compact objects moving in quasi-elliptical orbits is computed at the third post-Newtonian (3PN) order using the multipolar post-Minkowskian wave generation formalism. The 3PN angular-momentum flux involves the instantaneous, tail, and tail-of-tails contributions as for the 3PN energy flux, and in addition a contribution due to nonlinear memory. We average the angular-momentum flux over the binary's orbit using the 3PN quasi-Keplerian representation of elliptical orbits. The averaged angular-momentum flux provides the final input needed for gravitational-wave phasing of binaries moving in quasi-elliptical orbits. We obtain the evolution of orbital elements under 3PN gravitational radiation reaction in the quasi-elliptic case. For small eccentricities, we give simpler limiting expressions relevant for phasing up to order e(2). This work is important for the construction of templates for quasi-eccentric binaries, and for the comparison of post-Newtonian results with the numerical relativity simulations of the plunge and merger of eccentric binaries.

Long-term outcome and extraintestinal manifestations in congenital chloride diarrhea

The rare autosomal recessive disease congenital chloride diarrhea (CLD) is caused by mutations in the solute carrier family 26 member 3 (SLC26A3) gene on chromosome 7q22.3-31.1. SLC26A3 encodes for an apical epithelial chloride-bicarbonate exchanger, the intestinal loss of which leads to profuse chloride-rich diarrhea, and a tendency to hypochloremic and hypokalemic metabolic alkalosis. Although untreated CLD is usually lethal in early infancy, the development of salt substitution therapy with NaCl and KCl in the late 1960s made the disease treatable. While the salt substitution allows normal childhood growth and development in CLD, data on long-term outcome have remained unclarified. One of the world s highest incidences of CLD 1:30 000 to 1:40 000 occurs in Finland, and CLD is part of the Finnish disease heritage. We utilized a unique sample of Finnish patients to characterize the long-term outcome of CLD. Another purpose of this study was to search for novel manifestations of CLD based on the extraintestinal expression of the SLC26A3 gene. This study on a sample of 36 patients (ages 10-38) shows that the long-term outcome of treated CLD is favorable. In untreated or poorly treated cases, however, chronic contraction and metabolic imbalance may lead to renal injury and even to renal transplantation. Our results demonstrate a low-level expression of SLC26A3 in the human kidney. Although SLC26A3 may play a minor role in homeostasis, post-transplant recurrence of renal changes shows the unlikelihood of direct transporter modulation in the pathogenesis of CLD-related renal injury. Options to resolve the diarrheal symptoms of CLD have been limited. Unfortunately, our pilot trial indicated the inefficacy of oral butyrate as well. This study reveals novel manifestations of CLD. These include an increased risk for hyperuricemia, inguinal hernias, and probably for intestinal inflammation. The most notable finding of this study is CLD-associated male subfertility. This involves a low concentration of poorly motile spermatozoa with abnormal morphology, high seminal plasma chloride with a low pH, and a tendency to form spermatoceles. That SLC26A3 immunoexpression appeared at multiple sites of the male reproductive tract in part together with the main interacting proteins cystic fibrosis transmembrane conductance regulator (CFTR) and sodium-hydrogen exchanger 3 (NHE3) suggests novel sites for the cooperation of these proteins. As evidence of the cooperation, defects occurring in any of these transporters are associated with reduced male fertility. Together with a finding of high sweat chloride in CLD, this study provides novel data on extraintestinal actions of the SLC26A3 gene both in the male reproductive tract and in the sweat gland. These results provide the basis for future studies regarding the role of SLC26A3 in different tissues, especially in the male reproductive tract. Fortunately, normal spermatogenesis in CLD is likely to make artificial reproductive technologies to treat infertility and even make unassisted reproduction possible.