Strategic Aid: Explaining The Motives And Choices Of International Donors

Foreign aid, as one of the most “baffling” concepts of international politics according to Hans Morgenthau, is studied by scholars from various fields without a conclusive consensus on its causes. This dissertation project aims to understand and explain foreign aid motivation and distribution of major donor countries. As a multipurpose foreign policy tool, foreign aid is often associated with negative consequences at the recipient end such as causing corruption, sustaining authoritarian leaders in power and prolonging civil wars. However, in reality we observe more and more countries starting their own development assistance programs with increasing funds. It is this puzzle between negative findings associated with foreign aid in scholar works and positive approach of donor governments that this project is addressing. There is a need to understand the actual motives of donors in order to make sense of their foreign aid policies. In this dissertation, I use a mixed method approach that combines a quantitative study of foreign aid motivation and distribution of thirty donor countries with highest aid budgets from 2002 to 2013 and a case study of Turkey with in-depth analysis of its foreign aid policy. A sound theoretical categorization of major donor countries is a gap in the literature. I address this gap by creating an eclectic typology of donors based on their power index and regime type. This typology enables me to categorize donors as (i) major powers, (ii) emerging major powers, (iii) middle powers, and (iv) regional middle powers. The findings support the argument that foreign aid is a function of security and economic interest for major power while emerging major powers mainly emphasize economic interest. Middle powers consider needs of the recipients more than any other category. Regional middle powers’ motivation is mainly related to their targeted soft power policies. While regional middle powers distribute their foreign aid regionally, all other donor categories distribute aid globally. The case study of Turkey as a regional middle power suggests that Turkey uses foreign aid together with other foreign policy tools in order to increase its soft power in targeted regions

Effect of context and process on success of international mediation: a comparative study of mediation efforts in Cyprus and Northern Ireland conflicts

The aim of the thesis is to explore the determinants of success in international mediation. While trying to answer the question of "what determinants affected the success or failure of international mediation in Cyprus and Northern Ireland conflicts?" a comparative case study method was used. George Mitchell's mediation effort in Northern Ireland as a success and Kofi Annan's mediation effort in Cyprus as a failure were compared under the Contingency Model of Mediation. Eight hypotheses which were put forward by Jacob Bercovitch and his colleagues after their quantitative study of 284 international mediation attempts were tested on these two cases. While making this comparative case study research, a triangulated data collection method was used. Firstly, various forms of documentary information were analyzed which include academic articles, evaluations of the same topic, books written on the topic. Secondly, focused interviews were conducted with NGO representatives, academics, policy makers and other experts on the issues. Lastly, two field trips were made to Cyprus and Northern Ireland during which direct observations were made for a better understanding of historical and behavioral factors affecting the process. The findings show that both of the cases meet the highest possibility of success only on three of the variables (out of eight) which are regime types, issues and strategies of the mediator. According to this conclusion, theoretically both of the mediation attempts are expected to be unsuccessful. However, in reality, one of them was successful while the other was not. Therefore, the determinants of success put forward by Bercovitch were not enough to explain the success of George Mitchell and failure of Kofi Annan. In last part of the thesis, additional determinants which were potentially affected the outcome of the mediation attempts in these two cases were listed. More research is needed to understand whether or not these additional determinants are effective on outcome of other international mediation efforts

Phospho-regulation of the spindle assembly checkpoint

Mitosis is a highly regulated process by which a cell duplicates and distributes its chromosomal DNA into two identical daughter cells equally. Equal distribution of the chromosomes is crucial for accurate propagation of genetic information. This is essential for maintaining viability and preventing genomic instability that can potentially lead to cancer. In order to avoid unequal distribution of chromosomes, cells employ a surveillance mechanism called the spindle assembly checkpoint (SAC). The SAC is an inhibitory signalling network, which delays segregation of chromosomes, until they have stably attached to spindle microtubules through their multi-protein platforms, known as kinetochores. The main target of the SAC is the anaphase promoter complex/ cyclosome (APC/C), an E3 ubiquitin ligase. Specifically APC/C and its activator Cdc20 are inhibited by the main effector of the SAC, called the mitotic checkpoint complex (MCC). The MCC consists of Cdc20, Mad2, Mad3 and Bub3 (except S. pombe) proteins, which are recruited to the unattached kinetochores to promote MCC assembly. Once the chromosomes stably attach to the spindle, the SAC is turned off, MCC disassembles, and APC/CCdc20 is released from the inhibition. Activated APC/CCdc20 then targets its two main substrates, securin and cyclin B, for proteasomal degradation, and thereby triggers anaphase onset and mitotic exit. SAC signalling involves many protein components, whose activities are essentially regulated by direct protein-protein interactions and/ or post-translational modifications. One of these major modifications is phosphorylation, which is mediated by the SAC kinases such as Aurora B, Mps1 and Bub1. A number of studies have characterised SAC related substrates of Aurora B and Mps1 kinases in several model organisms. On the other hand, Bub1 kinase activity has been thought to play a key role in chromosome bi-orientation and more of an auxiliary role in SAC activation. The aim of this study is to investigate the importance of Bub1 kinase activity for SAC response in fission yeast Schizosaccharomyces pombe (S. pombe). SAC activation assays, using various degrees of spindle perturbation, have demonstrated that Bub1 kinase activity plays an important role in SAC maintenance. In order to examine the pathways downstream of Bub1, we set out to indicate Bub1 substrates which may be involved in SAC signalling. According to studies in various species, Cdc20 appears to be a prominent candidate, whose phosphorylation by Cdk1 and Bub1 kinases has been reported to regulate its mitotic activity. To investigate whether Cdc20 is phosphorylated by Bub1 in vitro, we purified recombinant S. pombe proteins from insect cells. Subsequent kinase assays identified Cdc20 as an in vitro substrate of Bub1, and the phosphorylated sites in Cdc20 were mapped by mass spectrometry. To address if this phospho-modification is involved in SAC regulation, phosphorylation mutants of Cdc20 were analysed in terms of their abilities to activate and silence SAC in vivo. Results show that phosphorylation of Cdc20 C-terminus promotes SAC maintenance in response to spindle damage. Furthermore, the mutations mimicking Bub1-mediated phosphorylation of Cdc20 Cterminus restore the SAC defects in the absence of Bub1 kinase activity. In addition, we purified S. pombe mitotic checkpoint complex (MCC) from insect cells, and analysed the interactions between its components (Cdc20, Mad2 and Mad3) by cross-linking mass spectrometry. Crystal structure of S.pombe MCC has been determined recently, which lacks Mad3 C-terminus and flexible C-terminal tail of Cdc20. Using an MCC with full length Mad3, we identified novel interactions between the C-terminal tails Mad3 and Cdc20, which are in close proximity to the identified Cdc20 phosphorylation sites. Briefly, in this study we confirm the previously known roles of Bub1 kinase activity (chromosome bi-orientation). Moreover, we propose a new pathway (in addition to the well-established H2A pathway) mediated by Cdc20, that may be important to maintain the SAC response

The live cell DNA stain SiR-Hoechst induces DNA damage responses and impairs cell cycle progression

AbstractSiR-Hoechst (SiR-DNA) is a far-red fluorescent DNA probe being used widely for time-lapse imaging of living cells that is reported to be minimally toxic at concentrations as high as 10–25 µM. However, measuring nuclear import of Cyclin B1, inhibition of mitotic entry, and the induction of γH2AX foci in cultured human cells reveals that SiR-Hoechst induces DNA damage responses and G2 arrest at concentrations well below 1 µM. SiR-Hoechst is useful for live cell imaging, but it should be used with caution and at the lowest practicable concentration.</jats:p

Distinct Postsurgical Management in Young and Elderly Breast Cancer Patients Results in Equal Survival Rates

Background: Although breast cancer (BC) is one of the most common malignant diseases in women, the majority of the studies describing the characteristics of BC in elderly patients have been limited to survival assessments or tumor features, without using younger BC patients as a reference group. The aim of our study was to describe and compare tumor characteristics and management patterns in elderly versus younger breast cancer patients in Turkey. Materials and Methods: We retrospectively analyzed 152 patients with invasive breast cancer who underwent surgery in our institution between 2002 and 2012. Patients were divided into 2 groups according to age at the time of diagnosis. Results: There were 62 patients in the elderly group (>= 65 years) and 90 patients in the younger group (0.001). There were no significant differences regarding histology, localization, lymph node involvement, or types of surgical procedures between the 2 groups. Comorbidities were more common in elderly patients (p<0.001). In addition, elderly patients were more likely to receive hormonal therapy (p<0.001) and less likely to receive radiotherapy (p=0.08) and chemotherapy (p=0.003). There was no difference in survival and locoregional recurrence rates between the groups. Conclusions: The results of this study demonstrate that breast cancer in elderly patients has more favorable tumor features, warranting less aggressive treatment regimens after surgery

Kinetochore life histories reveal an Aurora-B-dependent error correction mechanism in anaphase

Chromosome mis-segregation during mitosis leads to aneuploidy, which is a hallmark of cancer and linked to cancer genome evolution. Errors can manifest as "lagging chromosomes" in anaphase, although their mechanistic origins and likelihood of correction are incompletely understood. Here, we combine lattice light-sheet microscopy, endogenous protein labeling, and computational analysis to define the life history of >10 kinetochores. By defining the "laziness" of kinetochores in anaphase, we reveal that chromosomes are at a considerable risk of mis-segregation. We show that the majority of lazy kinetochores are corrected rapidly in anaphase by Aurora B; if uncorrected, they result in a higher rate of micronuclei formation. Quantitative analyses of the kinetochore life histories reveal a dynamic signature of metaphase kinetochore oscillations that forecasts their anaphase fate. We propose that in diploid human cells chromosome segregation is fundamentally error prone, with an additional layer of anaphase error correction required for stable karyotype propagation

The relationship between glycemic control and BNP levels in diabetic patients

Background: Glycemic control affects cardiovascular risk factors positively. The purpose of this study was to assess B-type natriuretic peptide (BNP) levels in patients with poorly controlled diabetes before and after glycemic regulation was achieved.Methods: The study was performed in a prospective design. The study population consisted of 79 consecutive diabetic patients with poor glycemic control. All subjects underwent transthoracic echocardiography. Levels of fasting plasma glucose, glycosylated hemoglobin (HbA1c), lipid parameters, and BNP were measured before the onset of the treatment and after glycemic regulation was achieved.Results: A significant decrease in BNP (95.0 [4.0–1807] ng/L vs. 52.0 [2.1–987.0] ng/L, p &lt; 0.001) levels were observed, after improving glycemic control. The decrease in BNP levels was positively correlated with the decrease in HbA1c (r = 0.345, p = 0.003) and fasting plasma glucose (r = 0.366, p = 0.002). There was no correlation between the decrease in BNP levels and lipid parameters (p = NS).Conclusions: We conclude that poor glycemic control may cause high levels of BNP which maylead to overdiagnosis of congestive heart failure. We suggest that HbA1c and fasting plasma glucose should be checked in patients with high levels of BNP

Evidence for a HURP/EB free mixed-nucleotide zone in kinetochore-microtubules

Current models infer that the microtubule-based mitotic spindle is built from GDP-tubulin with small GTP caps at microtubule plus-ends, including those that attach to kinetochores, forming the kinetochore-fibres. Here we reveal that kinetochore-fibres additionally contain a dynamic mixed-nucleotide zone that reaches several microns in length. This zone becomes visible in cells expressing fluorescently labelled end-binding proteins, a known marker for GTP-tubulin, and endogenously-labelled HURP - a protein which we show to preferentially bind the GDP microtubule lattice in vitro and in vivo. We find that in mitotic cells HURP accumulates on the kinetochore-proximal region of depolymerising kinetochore-fibres, whilst avoiding recruitment to nascent polymerising K-fibres, giving rise to a growing “HURP-gap”. The absence of end-binding proteins in the HURP-gaps leads us to postulate that they reflect a mixed-nucleotide zone. We generate a minimal quantitative model based on the preferential binding of HURP to GDP-tubulin to show that such a mixed-nucleotide zone is sufficient to recapitulate the observed in vivo dynamics of HURP-gaps

Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers

We address whether combinations with a pan-RAF inhibitor (RAFi) would be effective in KRAS mutant pancreatic ductal adenocarcinoma (PDAC). Chemical library and CRISPR genetic screens identify combinations causing apoptotic anti-tumor activity. The most potent combination, concurrent inhibition of RAF (RAFi) and ERK (ERKi), is highly synergistic at low doses in cell line, organoid, and rat models of PDAC, whereas each inhibitor alone is only cytostatic. Comprehensive mechanistic signaling studies using reverse phase protein array (RPPA) pathway mapping and RNA sequencing (RNA-seq) show that RAFi/ERKi induced insensitivity to loss of negative feedback and system failures including loss of ERK signaling, FOSL1, and MYC; shutdown of the MYC transcriptome; and induction of mesenchymal-to-epithelial transition. We conclude that low-dose vertical inhibition of the RAF-MEK-ERK cascade is an effective therapeutic strategy for KRAS mutant PDAC.Peer reviewe