10,860 research outputs found
The role of Umkhonto we Sizwe (MK) in the national liberation struggle in South Africa with reference to the rural far northern Transvaal, 1976-1990
No full textIncludes bibliographical references (leaves 250-275)
Experiencing the armed struggle : the Soweto generation and after
No full textIncludes bibliographical references (p. 354-369).This study explores the experiences of the rank-and-file soldiers of Umkhonto we Sizwe and the Azanian People's Liberation Anny. Extensive interviews by the author and other researchers reveal the voices of the soldiers themselves. The African National Congress and Pan African Congress archives at the University of the Western Cape and the University of Fort Hare supplement and verify these oral testimonies, as do some published sources. Most previously published materials about the armed struggle against apartheid have already focused on diplomacy, strategy and tactics, operations, leadership, and human rights abuses to the neglect of the soldiers' actual experiences. This study complements these with significant new oral history materials from the Soweto generation of soldiers and their successors. When dealing with MK, many authors have documented issues of the camp structure in Angola, and operations inside South Africa, so much of this detail is only addressed briefly, leaving space to explore the soldiers' experiences. In the case of APLA, very little has been written on its history, and more detail is provided on these subjects. This study therefore deals with the soldiers' politicisation and motivation for joining the armed struggle, their experiences in leaving South Africa and training in exile, the crises in exile which limited their effectiveness for a time, their return to fight in South Africa, and their difficulties in the "new" South Africa. These materials reveal that vast problems remain facing these veterans of the struggle against apartheid, and that they have the potential, if properly supported and employed, to contribute substantially to the development of present day South Africa. Conversely, if their neglect continues, they also have the potential to bring vast harm to the country. Further use of the investigative tools of oral history, especially if extended to the former soldiers' vernacular languages, is necessary to augment the history of South Africa, and these soldiers' contributions
Interview with MK Ajay, Executive Vice President of Human Resources, Colgate-Palmolive (India)
No full textColgate-Palmolive is a well-known American multinational corporation. It is well regarded as a very reputable, ethical, admired and sustainable company that values employee diversity. In this interview with the Head of HR of Colgate India, we can find some unique features in its management team, style and organisational culture. The interview explores the alignment and dynamics between business and HR strategies, long-term sustainable perspective on leadership at all levels, and building harmony in industrial relations.Full Tex
MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology
No full textThe
emergence and evolution of new immunological cancer therapies has
sparked a rapidly growing interest in discovering novel pathways to
treat cancer. Toward this aim, a novel series of pyrrolidine derivatives
(compound 5) were identified as potent inhibitors of
ERK1/2 with excellent kinase selectivity and dual mechanism of action
but suffered from poor pharmacokinetics (PK). The challenge of PK
was overcome by the discovery of a novel 3(S)-thiomethyl
pyrrolidine analog 7. Lead optimization through focused
structure–activity relationship led to the discovery of a clinical
candidate MK-8353 suitable for twice daily oral dosing
as a potential new cancer therapeutic
Genetic dissection of the phosphoinositide cycle in Drosophila photoreceptors
No full textPhototransduction in Drosophila is mediated by phospholipase C-dependent hydrolysis of PIP2, and is an important model for phosphoinositide signalling. Although generally assumed to operate by generic machinery conserved from yeast to mammals, some key elements of the phosphoinositide cycle have yet to be identified in Drosophila photoreceptors. Here, we used transgenic flies expressing fluorescently tagged probes (P4M and Tb-R332H), which allow in vivo quantitative measurements of PI4P and PIP2 dynamics in photoreceptors of intact living flies. Using mutants and RNA interference for candidate genes potentially involved in phosphoinositide turnover, we identified Drosophila PI4KIII alpha (CG10260) as the PI4-kinase responsible for PI4P synthesis in the photoreceptor membrane. Our results also indicate that PI4KIII alpha activity requires rbo (the Drosophila orthologue of Efr3) and CG8325 (orthologue of YPP1), both of which are implicated as scaffolding proteins necessary for PI4KIII alpha activity in yeast and mammals. However, our evidence indicates that the recently reported central role of dPIP5K598 (CG3682) in PIP2 synthesis in the rhabdomeres should be re-evaluated; although PIP2 resynthesis was suppressed by RNAi directed against dPIP5K598, little or no defect was detected in a reportedly null mutant (dPlP5K(18))
Differential effects of ketamine and MK-801 on the induction of long-term potentiation
No full textKetamine and MK-801 are phencyclidine (PCP)-like noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor that produce a use-dependent blockade of the NMDA receptor-coupled channel. Recent studies have suggested that the binding properties of these drugs to the NMDA receptor in-vitro are different. In the present study, the effects of ketamine and MK-801 on the induction of long-term potentiation (LTP) were compared at perforant path--granule cell synapses in anaesthetized rats. LTP was observed in animals treated with either saline or MK-801, but not in those treated with ketamine. These results reveal that ketamine and MK-801 differentially modulate the induction of LTP, and we propose that this differential modulation may be related to the different binding properties of the drugs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56198/1/marenNREP91.pd
New Oral Pcsk9 Inhibitor: “Mk-0616”
No full textMK-0616, a novel oral macrocyclic peptide inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9), represents a significant advancement in the treatment of hypercholesterolemia. Unlike current PCSK9 inhibitors, which are injectable monoclonal antibodies and siRNA molecules, MK-0616 offers a patient-friendly alternative. The development of MK-0616 involved innovative synthetic chemistry and in vitro mRNA display technology. This cutting-edge approach led to the creation of an orally administered peptide with the ability to cover a larger portion of PCSK9 compared to smaller, linear peptides. Phase 1 and 2b clinical trials have demonstrated MK-0616’s safety, efficacy, and pharmacokinetics. These trials indicate the drug’s dose-dependent systemic absorption and long half-life. Notably, MK-0616 has exhibited comparable low-density lipoprotein cholesterol-lowering effects to currently available PCSK9 inhibitors, all while maintaining good tolerability in diverse patient populations, including those concurrently on statin therapy. As MK-0616 advances to Phase 3 trials, its lipid-lowering potential for heterozygous familial hypercholesterolemia and its impact on reducing the time to adverse cardiac events will be evaluated in a broad and diverse population, including underrepresented groups. The results achieved so far are promising for individuals with hypercholesterolemia, as they offer a potential solution for effectively lowering low-density lipoprotein cholesterol in patients on statin therapy and mitigating the risk of cardiovascular events. Ongoing research and monitoring will be critical to establish its long-term safety and efficacy, but MK-0616 may emerge as a valuable addition to the array of lipid-lowering therapies available to patients
Dawn Aerospace Mk-III Spaceplane Aerothermodynamic Analysis
No full textDawn Aerospace is developing a horizontal take-off and landing two stage to orbit partially-reusable launcher concept. The re-usable first stage spaceplane operates on a return to launch site trajectory and integrates into the existing airspace, flying as an UAV. For any re-entry vehicle the design needs to account for aerothermodynamic behaviour around the vehicle, to ensure the structure can survive the re-entry temperatures. The unique mission of the Mk-III means the thermal design considerations are unique and provide a new engineering challenge and research topic. This thesis investigates the aerothermodynamic behaviour of the Mk-III flow and structure. A loosely coupled model was created for this purpose, which couples engineering methods to predict the aerothermodynamics and the thermal behaviour of the structure. The coupling is done by transferring the external skin temperature and convective heat flux between the two simulations. The primary research question for this thesis is “What thermal protection systems have potential to be implemented on the Dawn Aerospace Mk-III spaceplane for a range of different design trajectories.” Two thermal protection systems (TPS) and material choices have been identified as potential solutions. The first is a fully titanium structure, which can handle the temperature experienced by the Mk-III for all trajectories at every point along the vehicle. The second is a combined titanium and BMI CF structure with an insulation layer on the BMI CF. The titanium is required for the temperatures experienced on the vehicle’s leading edges, while the BMI CF has been identified as suitable in areas away from the leading edge if protected by an insulation TPS. A benefit this option produces is that the insulation layer can be changed in thickness to lighten the vehicle for lower design trajectories, therefore creating different vehicles for different trajectories. However, combining a metal with a composite could pose manufacturing issues such as cost for different manufacturing processes and joining problems. This thesis could not properly trade-off between these two options due to it being outside the scope of this thesis and due to limitations in detailed structural knowledge. These two material choices were chosen from four materials analysed in the thesis and four different TPS. Other TPS were not suitable at decreasing the structural temperature for the Mk-III mission or had an unjustifiable weight penalty. The other material choices would have been suitable in certain situations but were heavier than the current proposed options and might have required a TPS. This thesis provides valuable insight in what suitable material and TPS choices could be for the Mk-III mission. It also shows that for any future material and TPS choice to be made, a comprehensive structural analysis is required. Mass is a key trade-off parameter between the two proposed solutions and a better structural analysis is required for any further trade-off.Aerospace Engineerin
On the determinant of Up on Mk(p,χ)
No full textIn this work, for p a prime, we compute the absolute value of the determinant of the UpUp-operator on the vector space Mk(p,χ)Mk(p,χ) of holomorphic modular forms of weight k and level Γ0(p)Γ0(p) with character χχ. As an implication, we confirm a number of conjectures of the second author
Influence of melatonin on the testicular regression induced by subcutaneous testosterone pellets in male rats kept in long or short photoperiod.
No full textDaily afternoon injections of 25 micrograms melatonin for 12 weeks had no effect on testicular weights of male rats kept in long photoperiod (14L:10D); similarly, exposure of rats to short photoperiod (2L:22D) had no effect on gonadal weight. However, rats maintained in a long or short photoperiod and implanted every 2 weeks with a 15 mm Silastic pellet containing testosterone showed a significant reduction in testicular weight; this effect was more pronounced in rats exposed to a short photoperiod. Melatonin injections in testosterone-treated rats in a long photoperiod exacerbated the inhibitory effects of testosterone alone. Subcutaneous 2-weekly implants of a beeswax pellet containing 1 mg melatonin reversed the effects of the melatonin injections on relative testicular weights but not those due to short photoperiod exposure. Testosterone implants significantly reduced pituitary LH values in long and short photoperiod-exposed animals, more particularly in those exposed to short photoperiod. Melatonin injections alone or in combination with melatonin pellets did not further exaggerate the depression in pituitary LH due to testosterone alone in long photoperiod-exposed animals; similarly melatonin pellets did not reverse the depression in pituitary LH observed. No significant differences in plasma prolactin concentrations or in thyroxine concentrations or free thyroxine index were observed after any combination of treatments. We therefore suggest that the effects observed with short photoperiod may be due to melatonin
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