Analysis of the functional repertoire of a mutant form of survivin, K129E, which has been linked to lung cancer

Background Survivin is a protein that is normally present only in G2 and M-phases in somatic cells, however, in cancer cells, it is expressed throughout the cell cycle. A prosurvival factor, survivin is both an inhibitor of apoptosis and an essential mitotic protein, thus it has attracted much attention as a target for new oncotherapies. Despite its prevalence in cancer, reports of survivin mutations have mostly been restricted to loci within its promoter, which increase the abundance of the protein. To date the only published mutation within the coding sequence is an adenine > guanine substitution in exon 4. This polymorphism, which was found in a cohort of Korean lung cancer patients, causes a lysine > glutamic acid mutation (K129E) in the protein. However, whether it plays a causative role in cancer has not been addressed. Methods Using site directed mutagenesis we recapitulate K129E expression in cultured human cells and assess its anti-apoptotic and mitotic activities. Results K129E retains its anti-apoptotic activity, but causes errors in mitosis and cytokinesis, which may be linked to its reduced affinity for borealin. Conclusion K129E expression can induce genomic instability by introducing mitotic aberrations, thus it may play a causative role in cancer

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

A system-theoretic approach to global and local regulation in neuron morphologies

Synaptic plasticity is a crucial neuronal mechanism for learning and memory. It allows synapses to change their strength over time. This dissertation focuses on a particular form of synaptic plasticity called synaptic scaling, a homeostatic mechanism that preserves relative synaptic strengths in an activity-dependent manner. Synaptic scaling is fundamental for neuronal stability, regulating other plasticity mechanisms like Hebbian plasticity or long-term potentiation (LTP). The aims of this dissertation are to explore the implications of synaptic scaling (and other forms of plasticity, such as structural plasticity) on the overall behavior of neurons. This is done using system-theoretic tools and feedback control. We first formulate a biophysical closed loop model of synaptic scaling. We then study how synaptic scaling affect neurons’ behavior in both abstract and reconstructed morphologies. This study reveals important tradeoffs between robustness, convergence rate, and accuracy of scaling. We first look at synaptic scaling as a “global control action” whose main role is to guarantee a steady level of neural activity. We then consider activity-dependent degradation as a “local control action” whose role is to assist the neuron in fine-tuning different desirable spatial concentration profiles. We show that, in extreme scenarios, it can promote a level of competition between synapses that has a destabilizing effect on the overall behavior. At the methodological level, we use compartmental modeling and we focus on the in- teraction between feedback and transport, in linear and nonlinear settings. Using classical system-theoretic tools like Bode and Nyquist analysis and singular perturbation arguments, and more recent tools like contraction and dominance theory, we derive parameter ranges under which synaptic scaling is stable and well-behaved (slow regulation), stable and oscilla- tory (aggressive regulation), and unstable (pathological regulation). We also study the system robustness against static and dynamics uncertainties. Finally, to understand how different plasticity mechanisms simultaneously affect the neuron behavior, we study synaptic scaling in the presence of activity-dependent growth (mimicking a structural plasticity mechanism). This is a third layer of control action shaping the neuron morphology. We find that activity-dependent growth improves the neuron’s performance when synaptic scaling is insufficient

Qualitative behavior and robustness of dendritic trafficking

The paper studies homeostatic ion channel trafficking in neurons. We derive a nonlinear closed-loop model that captures active transport with degradation, channel insertion, average membrane potential activity, and integral control. We study the model via dominance theory and differential dissipativity to show when steady regulation gives way to pathological oscillations. We provide quantitative results on the robustness of the closed loop behavior to static and dynamic uncertainties, which allows us to understand how cell growth interacts with ion channel regulation

Ca-substituted, A-site deficient perovskite La_0.2Sr_0.7TiO₃ as a potential anode material for SOFCs

Samples from across the solid solution series La0.2Sr0.7-xCaxTiO3, were successfully synthesised by solid state reaction. Structural properties were determined at room temperature using X-ray powder diffraction and conductivity measurements were performed using the four probe DC and van der Pauw techniques at different temperatures and atmospheres. On increasing x, the perovskite phase lattice symmetry changes from cubic Pm (3) over barm to tetragonal I4/mcm at x = 0.05 and tetragonal to orthorhombic Pbnm at x = 0.425. The lattice also shrinks as x increases. Samples showed only a slight 0.3% increase in lattice volume after reduction at 900 degrees C in 5% H-2. On increasing calcium doping, conductivity in reduced samples and equilibrated at 900 degrees C in 5%H-2 increased markedly reaching 27.53 S cm(-1) at x = 0.45, but decreased as x increased further.</p

Dendritic trafficking: synaptic scaling and structural plasticity

Neuronal circuits internally regulate electrical signaling via a host of homeostatic mechanisms. Two prominent mechanisms, synaptic scaling and structural plasticity, are believed to maintain average activity within an operating range by modifying the strength and spatial extent of network connectivity using negative feedback. However, both mechanisms operate on relatively slow timescales and thus face fundamental limits due to delays. We show that these mechanisms fulfill complementary roles in maintaining stability in a large network. In particular, even relatively, slow growth dynamics improves performance significantly beyond synaptic scaling alone