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The National Cohesion and Integration Commission (NCIC) was set up to facilitate and promote equality of opportunity, good relations, harmony and peaceful coexistence between persons of the different ethnic and racial communities of Kenya, and to advise the Government on all aspects thereof after the violence that followed the December 2007 elections. In Kenya, Bridging Ethnic Divides: A Commissioner's Experience on Cohesion and Integration, Commissioner Alice Wairimu Nderitu looks behind the scenes at the NCIC's efforts to ensure peaceful co-existence. Such as, working with elders, mediating confidentially between political leaders at the highest levels and co-founding and working as first Co-Chair of Uwiano Platform for Peace, a conflict prevention agency largely credited with leading efforts in ensuring peaceful processes during the 2010 Constitutional referendum and 2013 General elections. The book tells of NCIC's efforts in grappling with the seemingly intractable problem of managing the negative consequence of ethnic differences on questions such as: Why is Kenya so ethnically polarised? Why is an ethnic group the key defining factor in Kenyan politics? What hope is there for an inclusive Kenya? The book shows that positive policies and intra- and inter-ethnic spaces can be used to counter negative influences that lead to fear, exclusion and violence. The diversity of Kenya's ethnicities and races need not be a pretext for conflict, but a source of truly national identity. It proves that dialogue on understanding differences and commonalities leads to improved relationships and understanding on societal dynamics. This in turn, contributes to preventing and transforming conflicts through appropriate inclusion policies, identifying entry points for change as well as opportunities to tackle the norms and behaviours that underpin structural disparities.
Very few countries hide or obscure the significance of their most important historical achievements. Kenya has managed to do so without any regrets or even a thought about the implication of such a major oversight in connection with Mau Mau Resistance. The reason for this underplay is not difficult to understand. The government that came to power at independence was not only not part of the Mau Mau movement which fought for land and freedom for working people, but actively opposed it. It sought and was given by the departing colonial power state power, land and freedom for its class, thereby sidelining the radical resistance movement and its activists. This elite then used its state power to ensure that the nation forgets its radical history which would have alerted future generations to the theft of their inheritance and country. This book provides essential facts about Mau Mau. It seeks to give voice to the Mau Mau resistance fighters. It is aimed at young people who were born after independence and who have been deprived of their historical heritage; it is also a tribute to those who played a part in the war of independence and in Mau Mau without whose contribution independence would have remained a dream. It seeks to restore Kenyas working class history of resistance to colonialism and imperialism. The Kenya Resists Series covers different aspects of resistance by people of Kenya to colonialism and imperialism. It reproduces material from books, unpublished reports, research and oral or visual testimonies. The three aspects chosen for the first three publications in the Series Mau Mau, Trade Unions and Peoples Resistance make up the three pillars of resistance of the people of Kenya.
Temperature- and field-dependent 1H-, 19F-, and 79,81Br-NMR measurements together with zero - field 79,81Br-NQR measurements on polycrystalline samples of barlowite, Cu4(OH)6FBr are conducted to study the magnetism and possible structural distortions on a microscopic level. The temperature dependence of the 79,81Br-NMR spin-lattice relaxation rates 1/T1 indicate a phase transition at TN ≃ 15 K which is of magnetic origin, but with an unusually weak slowing down of fluctuations below TN. Moreover, 1/T1T scales linear with the bulk susceptibility which indicates persisting spin fluctuations down to 2 K. Quadupolare resonance (NQR) studies reveal a pair of zero-field NQR- lines associated with the two isotopes of Br with the nuclear spins of I = 3/2. Quadrupole coupling constants of vQ ≃ 28.5 MHz and 24.7 MHz for 79Br- and 81Br-nuclei are determined from Br-NMR and the asymmetry parameter of the electric field gradient was estimated to η ≃ 0.2. The Br-NQR lines are consistent with our findings from Br-NMR and they are relatively broad, even above TN. This broadening and the relative large η value suggests a symmetry reduction at the Br- site reflecting the presence of a local distortion in the lattice. Our density-functional calculations show that the displacements of Cu2 atoms located between the kagome planes do not account for this relatively large η. On the other hand, full structural relaxation, including the deformation of kagome planes, leads to a better agreement with the experiment.
Damaged mitochondria are selectively eliminated by mitophagy. Parkin and PINK1, gene products mutated in familial Parkinson’s disease, play essential roles in mitophagy through ubiquitination of mitochondria. Cargo ubiquitination by E3 ubiquitin ligase Parkin is important to trigger selective autophagy. Although autophagy receptors recruit LC3-labeled autophagic membranes onto damaged mitochondria, how other essential autophagy units such as ATG9A-integrated vesicles are recruited remains unclear. Here, using mammalian cultured cells, we demonstrate that RABGEF1, the upstream factor of the endosomal Rab GTPase cascade, is recruited to damaged mitochondria via ubiquitin binding downstream of Parkin. RABGEF1 directs the downstream Rab proteins, RAB5 and RAB7A, to damaged mitochondria, whose associations are further regulated by mitochondrial Rab-GAPs. Furthermore, depletion of RAB7A inhibited ATG9A vesicle assembly and subsequent encapsulation of the mitochondria by autophagic membranes. These results strongly suggest that endosomal Rab cycles on damaged mitochondria are a crucial regulator of mitophagy through assembling ATG9A vesicles.
A necessary requirement for a pharmacological effect is that a drug molecule tightly interacts with its disease relevant target molecule in the patient. Kinases are regulatory, signal transmitting enzymes and are a large protein family that belongs to the most frequent targets of pharmaceutical industry, as deregulation of kinases has been associated with the development of a variety of diseases, including cancer. In drug discovery, equilibrium binding metrics such as the affinity (Ki, KD) or potency (IC50, EC50) are usually applied for the systematic profiling for potent and selective drug candidates. In recent years, dynamic binding parameters, the drugs association (kon) and dissociation (koff) rates for desired primary-targets and undesired off-targets, were discussed to be better predictors than steady-state affinity per se (KD = koff / kon) for the onset and duration of the drug-target complex in the open in vivo environment and thereby for the therapeutic effect and safety of the drug. It is yet unclear whether and when the binding kinetics parameters can influence drug action in the complex context of pharmacokinetics and pharmacodynamics and how the kinetic rate constants can be optimized rationally. One major obstacle for providing proof for the hypothesis that drug binding kinetics is of importance for drug action is the generation of large and comparable binding kinetic datasets.
The aim of this thesis was the comprehensive analysis of the binding kinetic and affinity parameters of a diverse spectrum of 270 small-molecule kinase inhibitors against a panel of pharmacologically relevant kinases to study the role played by binding kinetics for drug discovery: The generated dataset was utilized to assess the effect of chemical properties on drug binding kinetics, and to evaluate the impact of kinetic rate constants on the success of compounds in the drug discovery pipeline.
Large scale profiling was made possible by a recently developed “kinetic Probe Competition Assay” (kPCA), whose evaluation is based on Motulsky’s and Mahan’s “kinetics of competitive binding” theory. Monte Carlo analyses performed in this dissertation widened the theoretical knowledge of this theory, provided new insights into its limitations and allowed to derive recommendations about how to best design assays. It was demonstrated that kPCA is indeed high-throughput compatible and that it is comparable to other biochemical and biophysical assay formats in terms of precision and accuracy.
Multivariable linear regression for the description of the determined kinase inhibitors’ target binding characteristics (kon or koff or KD) using molecular properties and/or particular kinase-inhibitor interactions as descriptors supported the assumption that molecular properties of compounds might affect binding kinetics, generated new hypothesis about molecular determinants influencing binding kinetic parameters and provided a rational basis for following structure-kinetic relationship studies. Remarkably, the binding kinetic rate constants were better described by the established models than binding affinities.
Interestingly, the systematic, quantitative analysis of kinase inhibitors’ target binding kinetics indicated that a slow dissociation rate for the main target is a feature which is more frequently observed in inhibitors that reached approval or late stage clinical testing than in earlier phases of clinical development. In addition, it was demonstrated that binding kinetics of kinase inhibitors is a better predictor for the time course of target engagement in cells as compared to affinity per se. Furthermore, in some study cases simulations using a standard pharmacokinetics model and a modified model considering the inhibitors binding kinetics lead to different in vivo kinase occupancy time profiles. It was illustrated by simulations how the concept of kinetic selectivity can be applied to turn an unselective compound in equilibrium conditions into a more selective compound in the open in vivo situation, where the thermodynamic equilibrium of drug-target binding is not necessarily reached.
Thus the generated data and models provide evidence for the importance of binding kinetics in drug discovery and represent a valuable resource for future studies in this field.
The genus Disparalona Fryer, 1968 comprises a well-defined species complex, the hamatagroup, which might have sibling species in South America. This hamata-group needs urgent revision. Besides that, a complete morphological evaluation of the endemic species D. leptorhyncha (Daday, 1905) is lacking. Thus, the aim of the present study is to revise populations of species of the hamatagroup in South America and to redescribe D. leptorhyncha. Our findings pointed to an occurrence of species which are part of the Disparalona (Mixopleuroxus) linage. Currently, the Neotropics have the highest diversity to the genus, with three species of the hamata-complex – D. (M.) hamata (Birge, 1879), D. (M.) lucianae sp. nov., D. (M.) tenuispina sp. nov. – in addition to D. (M.) leptorhyncha. These species can be differentiated from each other by the morphology of their rostrum, labrum, and postabdomen.
This thesis is concerned with systematic investigations of electronic noise in novel condensed matter systems. Although fluctuations are frequently considered a nuisance, that is, a disturbance limiting the accuracy of scientific measurements, in many cases they can reveal fundamental information about the inherent system dynamics. During the past decades, the study of electronic fluctuations has evolved into an indispensable tool in condensed matter physics.
The focus of the present work lies both in a further development of the fluctuation spectroscopy technique and in the study of materials of current interest. In particular, a comprehensive study of the charge carrier dynamics in the archetypal diluted magnetic semiconductors (Ga,Mn)As and (Ga,Mn)P was performed. In spite of extensive research work carried out during the last years, there still exists no theoretical consensus on the precise mechanism of ferromagnetic order and the electronic structure in these materials. Moreover, disorder and correlation effects complicate the understanding of these compounds.
Fluctuation spectroscopy experiments presented in this work provide strong evidence that a percolation transition is observed in samples with localized charge carriers, since the normalized resistance noise magnitude displays a significant enhancement around the Curie temperature. In addition, this quantity exhibits a power law scaling behavior as a function of the resistance, which is in good agreement with theoretical models of percolating systems.
By contrast, it was found that the resistance noise in metallic samples is mainly dominated by the physics of defects such as manganese interstitials and arsenic antisites. Furthermore, first noise studies were carried out on hafnia- and yttria-based resistive random access memories. In these memristor devices, the rupture and re-formation of oxygen deficient conducting filaments caused by the electric field and Joule heating driven motion of mobile anions lead to an unusual resistance switching behavior. For the first time, comparative noise measurements on oxygen deficient and stoichiometric hafnium oxide devices, as well as on novel yttrium oxide based devices were performed in this work. Finally, new strategies for noise measurements of highly insulating and extremely low-resistive samples were developed and realized. In detail, an experimental setup for the measurements of dielectric polarization fluctuations in insulating systems was designed and successfully tested. Here, the polarization noise of a sample is measured as current or voltage fluctuations produced within a capacitance cell. The study of dielectric polarization noise allows for conclusions to be drawn regarding equilibrium structural dynamics in insulators such as relaxor ferroelectrics. On the other hand, as successfully demonstrated for a heavy-fermion compound, focused ion beam etching enables to introduce a meander-shaped geometry in single crystal platelets, in order to strongly enhance the sample resistance and thus make resistance noise measurements possible. First results indicate a connection of the noise properties with the Kondo effect in the investigated material.
In Christian history spiritual awakenings are a recurring and important phenomenon. The Blantyre Spiritual Awakening was characterized by an overt evangelistic fervour among bands of people that belonged to an ever growing Born Again Movement in the city, from 1974 into the 1980s. This history covers The Blantyre Awakening which revived Evangelical Christianity in Malawi and prepared the way for the emerging Charismatic Movement.
This book is a collection of essays written in the early 1990s. Some are an attempt to think theologically about the social and political changes and challenges that Malawi was navigating during those years. Others are critically reflecting on the nature and content of the Christian faith as it was coming to expression in an African context. The essays are a plea for relevancy and contextuality in Christian praxis and theological reflection in Malawi and, indeed, in Africa as a whole.
Sangaya
(2018)
Possibly the most outstanding Malawian church leader of the 1960s and 1970s was the Very Reverend Jonathan Sangaya, General Secretary of the Church of Central Africa Presbyterian (CCAP) Synod of Blantyre. To him fell the task of guiding his church into the post-missionary era and his dynamic leadership was a major factor in the success with which that transition was completed. This vivid biography offers many insights into the history of the church and society during his lifetime. It is a welcome addition to the literature covering the transition from mission to church in African Christianity, and will enable many readers to become acquainted with a great Malawian of a former generation.