Role of reactive oxygen species in protein degradation in murine myotubes induced by proteolysis-inducing factor and angiotensin II

The antioxidants butylated hydroxytoluene (BHT, 1 mM) and d-α-tocopherol (10 μM) completely attenuated protein degradation in murine myotubes in response to both proteolysis-inducing factor (PIF) and angiotensin II (Ang II), suggesting that the formation of reactive oxygen species (ROS) plays an important role in this process. Both PIF and Ang II induced a rapid and transient increase in ROS formation in myotubes, which followed a parabolic dose-response curve, similar to that for total protein degradation. Antioxidant treatment attenuated the increase in expression and activity of the ubiquitin-proteasome proteolytic pathway by PIF and Ang II, by preventing the activation of the transcription factor nuclear factor-κB (NF-κB), through inhibition of phosphorylation of the NF-κB inhibitor protein (I-κB) and its subsequent degradation. ROS formation by both PIF and Ang II was attenuated by diphenyleneiodonium (10 μM), suggesting that it was mediated through the NADPH oxidase system. ROS formation was also attenuated by trifluoroacetyl arachidonic acid (10 μM), a specific inhibitor of cytosolic phospholipase A2, U-73122 (5 μM) and D609 (200 μM), inhibitors of phospholipase C and calphostin C (300 nM), a highly specific inhibitor of protein kinase C (PKC), all known activators of NADPH oxidase. Myotubes containing a dominant-negative mutant of PKC did not show an increase in ROS formation in response to either PIF or Ang II. The two Rac1 inhibitors W56 (200 μM) and NSC23766 (10 μM) also attenuated both ROS formation and protein degradation induced by both PIF and Ang II. Rac1 is known to mediate signalling between the phosphatidylinositol-3 kinase (PI-3K) product and NADPH oxidase, and treatment with LY24002 (10 μM), a highly selective inhibitor of PI-3K, completely attenuated ROS production in response to both PIF and Ang II, and inhibited total protein degradation, while the inactive analogue LY303511 (100 μM) had no effect. ROS formation appears to be important in muscle atrophy in cancer cachexia, since treatment of weight losing mice bearing the MAC16 tumour with d-α-tocopherol (1 mg kg- 1) attenuated protein degradation and increased protein synthesis in skeletal muscle. © 2007 Elsevier Inc. All rights reserved.

Polymer degradation and stability

This edition of Polymer Degradation and Stability is dedicated to papers which were presented in the session on ‘Chemical Modification’ at the Third International Conference on Modification Degradation and Stabilisation of Polymers (MoDeSt) held in Lyon in August 2004. This was the third meeting of the MoDeSt Society which was set up in the year 2000 under the chairmanship of Professor Franco LaMantia; the earlier meetings were held in Palermo (2000) and Budapest (2002). The overall goal of the MoDeSt Society is to promote the latest research carried out in University laboratories, in public organisations and in industry through publications, and organisation of biannual scientific conferences and workshops that act as forums for scientific developments and for promoting networking between academics and industrialists from across the field of polymer modification, degradation and stabilisation. In September 2004, Professor Norman Billingham was elected as Chairman of the Society. The conference was organised by Dr Alain Michel and Veronique Bounor-Legare of the University Claude Bernard, Lyon 1, attracting over 250 delegates with the ‘Chemical Modification’ Session alone enjoying 54 oral presentations and many more poster presentations. We are all very grateful to the organisers for running such a successful and enjoyable meeting. I wish to thank my co-editors, Professors Philippe Dubois and Domenico Acierno and Dr Alain Michel, for their cooperation in the editorial task of the papers published in this special issue. On behalf of the editors of this issue, I wish to express our appreciation to the Editor-in-Chief of Polymer Degradation and Stability, Professor Norman Billingham, for the support and help received during the preparation of this special issue.

Novel sol–gel preparation of (P2O5)0.4–(CaO)0.25–(Na2O)X–(TiO2)(0.35−X) bioresorbable glasses (X = 0.05, 0.1, and 0.15)

Quaternary phosphate-based glasses in the P2O5–CaO–Na2O–TiO2 system with a fixed P2O5 and CaO content of 40 and 25 mol% respectively have been successfully synthesised via sol–gel method and bulk, transparent samples were obtained. The structure, elemental proportion, and thermal properties of stabilised sol–gel glasses have been characterised using X-ray diffraction (XRD), energy dispersive X-ray spectroscopy (EDX), 31P nuclear magnetic resonance (31P NMR), titanium K-edge X-ray absorption near-edge structure (XANES), fourier transform infrared (FTIR) spectroscopy, and differential thermal analysis (DTA). The XRD results confirmed the amorphous nature for all stabilized sol–gel derived glasses. The EDX result shows the relatively low loss of phosphorus during the sol–gel process and Ti K-edge XANES confirmed titanium in the glass structure is in mainly six-fold coordination environment. The 31P NMR and FTIR results revealed that the glass structure consist of mainly Q1 and Q2 phosphate units and the Ti4+ cation was acting as a cross-linking between phosphate units. In addition DTA results confirmed a decrease in the glass transition and crystallisation temperature with increasing Na2O content. Ion release studies also demonstrated a decrease in degradation rates with increasing TiO2 content therefore supporting the use of these glasses for biomedical applications that require a degree of control over glass degradation. These sol–gel glasses also offer the potential to incorporate proactive molecules for drug delivery application due to the low synthesis temperature employed.

Review of industrial temperature measurement technologies and research priorities for the thermal characterisation of the factories of the future

As the largest source of dimensional measurement uncertainty, addressing the challenges of thermal variation is vital to ensure product and equipment integrity in the factories of the future. While it is possible to closely control room temperature, this is often not practical or economical to realise in all cases where inspection is required. This article reviews recent progress and trends in seven key commercially available industrial temperature measurement sensor technologies primarily in the range of 0 °C–50 °C for invasive, semi-invasive and non-invasive measurement. These sensors will ultimately be used to measure and model thermal variation in the assembly, test and integration environment. The intended applications for these technologies are presented alongside some consideration of measurement uncertainty requirements with regard to the thermal expansion of common materials. Research priorities are identified and discussed for each of the technologies as well as temperature measurement at large. Future developments are briefly discussed to provide some insight into which direction the development and application of temperature measurement technologies are likely to head.

Synthesis and characterisation of interfacial layers in organic solar cells

The quest for renewable energy sources has led to growing attention in the research of organic photovoltaics (OPVs), as a promising alternative to fossil fuels, since these devices have low manufacturing costs and attractive end-user qualities, such as ease of installation and maintenance. Wide application of OPVs is majorly limited by the devices lifetime. With the development of new encapsulation materials, some degradation factors, such as water and oxygen ingress, can almost be excluded, whereas the thermal degradation of the devices remains a major issue. Two aspects have to be addressed to solve the problem of thermal instability: bulk effects in the photoactive layer and interfacial effects at the photoactive layer/charge-transporting layers. In this work, the interface between photoactive layer and electron-transporting zinc oxide (ZnO) in devices with inverted architecture was engineered by introducing polymeric interlayers, based on zinc-binding ligands, such as 3,4-dihydroxybenzene and 8-hydroxyquinoline. Also, a cross-linkable layer of poly(3,4-dimethoxystyrene) and its fullerene derivative were studied. At first, controlled reversible addition-fragmentation chain transfer (RAFT) polymerisation was employed to achieve well-defined polymers in a range of molar masses, all bearing a chain-end functionality for further modifications. Resulting polymers have been fully characterised, including their thermal and optical properties, and introduced as interlayers to study their effect on the initial device performance and thermal stability. Poly(3,4-dihydroxystyrene) and its fullerene derivative were found unsuitable for application in devices as they increased the work function of ZnO and created a barrier for electron extraction. On the other hand, their parental polymer, poly(3,4-dimethoxystyrene), and its fullerene derivative, upon cross-linking, resulted in enhanced efficiency and stability of devices, if compared to control. Polymers based on 8-hydroxyquinoline ligand had a negative effect on the initial stability of the devices, but increased the lifetime of the cells under accelerated thermal stress. Comprehensive studies of the key mechanisms, determining efficiency, such as charge generation and extraction, were performed by using time-resolved electrical and spectroscopic techniques, in order to understand in detail the effect of the interlayers on the device performance. Obtained results allow deeper insight into mechanisms of degradation that limit the lifetime of devices and prompt the design of better materials for the interface stabilisation.

A facilities maintenance management process based on degradation prediction using sensed data

Energy efficiency and user comfort have recently become priorities in the Facility Management (FM) sector. This has resulted in the use of innovative building components, such as thermal solar panels, heat pumps, etc., as they have potential to provide better performance, energy savings and increased user comfort. However, as the complexity of components increases, the requirement for maintenance management also increases. The standard routine for building maintenance is inspection which results in repairs or replacement when a fault is found. This routine leads to unnecessary inspections which have a cost with respect to downtime of a component and work hours. This research proposes an alternative routine: performing building maintenance at the point in time when the component is degrading and requires maintenance, thus reducing the frequency of unnecessary inspections. This thesis demonstrates that statistical techniques can be used as part of a maintenance management methodology to invoke maintenance before failure occurs. The proposed FM process is presented through a scenario utilising current Building Information Modelling (BIM) technology and innovative contractual and organisational models. This FM scenario supports a Degradation based Maintenance (DbM) scheduling methodology, implemented using two statistical techniques, Particle Filters (PFs) and Gaussian Processes (GPs). DbM consists of extracting and tracking a degradation metric for a component. Limits for the degradation metric are identified based on one of a number of proposed processes. These processes determine the limits based on the maturity of the historical information available. DbM is implemented for three case study components: a heat exchanger; a heat pump; and a set of bearings. The identified degradation points for each case study, from a PF, a GP and a hybrid (PF and GP combined) DbM implementation are assessed against known degradation points. The GP implementations are successful for all components. For the PF implementations, the results presented in this thesis find that the extracted metrics and limits identify degradation occurrences accurately for components which are in continuous operation. For components which have seasonal operational periods, the PF may wrongly identify degradation. The GP performs more robustly than the PF, but the PF, on average, results in fewer false positives. The hybrid implementations, which are a combination of GP and PF results, are successful for 2 of 3 case studies and are not affected by seasonal data. Overall, DbM is effectively applied for the three case study components. The accuracy of the implementations is dependant on the relationships modelled by the PF and GP, and on the type and quantity of data available. This novel maintenance process can improve equipment performance and reduce energy wastage from BSCs operation.

Soil organic carbon storage and soil properties for 50 soil profiles in the Lena River Delta including land form description and map

To project the future development of the soil organic carbon (SOC) storage in permafrost environments, the spatial and vertical distribution of key soil properties and their landscape controls needs to be understood. This article reports findings from the Arctic Lena River Delta where we sampled 50 soil pedons. These were classified according to the U.S.D.A. Soil Taxonomy and fall mostly into the Gelisol soil order used for permafrost-affected soils. Soil profiles have been sampled for the active layer (mean depth 58±10 cm) and the upper permafrost to one meter depth. We analyze SOC stocks and key soil properties, i.e. C%, N%, C/N, bulk density, visible ice and water content. These are compared for different landscape groupings of pedons according to geomorphology, soil and land cover and for different vertical depth increments. High vertical resolution plots are used to understand soil development. These show that SOC storage can be highly variable with depth. We recommend the treatment of permafrost-affected soils according to subdivisions into: the surface organic layer, mineral subsoil in the active layer, organic enriched cryoturbated or buried horizons and the mineral subsoil in the permafrost. The major geomorphological units of a subregion of the Lena River Delta were mapped with a land form classification using a data-fusion approach of optical satellite imagery and digital elevation data to upscale SOC storage. Landscape mean SOC storage is estimated to 19.2±2.0 kg C/m**2. Our results show that the geomorphological setting explains more soil variability than soil taxonomy classes or vegetation cover. The soils from the oldest, Pleistocene aged, unit of the delta store the highest amount of SOC per m**2 followed by the Holocene river terrace. The Pleistocene terrace affected by thermal-degradation, the recent floodplain and bare alluvial sediments store considerably less SOC in descending order.

Fossilization and degradation of archaeal intact polar tetraether lipids in ODP Site 201-1229 sediments

Glycerol dibiphytanyl glycerol tetraether (GDGT) lipids are part of the cellular membranes of Thaumarchaeota, an archaeal phylum composed of aerobic ammonia oxidizers, and are used in the paleotemperature proxy TEX86. GDGTs in live cells possess polar head groups and are called intact polar lipids (IPL-GDGTs). Their transformation to core lipids (CL) by cleavage of the head group was assumed to proceed rapidly after cell death but it has been suggested that some of these IPL-GDGTs can, just like the CL-GDGTs, be preserved over geological timescales. Here, we examined IPL-GDGTs in deeply buried (0.2-186 mbsf, ~2.5 Myr) sediments from the Peru Margin. Direct measurements of the most abundant IPL-GDGT, IPL-crenarchaeol, specific for Thaumarchaeota, revealed depth profiles which differed per head group. Shallow sediments (<1 mbsf) contained IPL-crenarchaeol with both glycosidic- and phosphate headgroups, as also observed in thaumarchaeal enrichment cultures, marine suspended particulate matter and marine surface sediments. However, hexose, phosphohexose-crenarchaeol is not detected anymore below 6 mbsf (~7 kyr), suggesting a high lability. In contrast, IPL-crenarchaeol with glycosidic head groups is preserved over time scales of Myr. This agrees with previous analyses of deeply buried (>1 m) marine sediments, which only reported glycosidic and no phosphate-containing IPL-GDGTs. TEX86 values of CL-GDGTs did not markedly change with depth, and the TEX86 of IPL-derived GDGTs decreased only when the proportions of monohexose- to dihexose-GDGTs changed, likely due to the enhanced preservation of the monohexose GDGTs. Our results support the hypothesis that in situ GDGT production and differential IPL degradation in sediments is not substantially affecting TEX86 paleotemperature estimations based on CL GDGTs and indicate that likely only a small amount of IPL-GDGTs present in deeply buried sediments is part of cell membranes of active Archaea. The amount of archaeal biomass in the deep biosphere based on these IPLs may have been substantially overestimated.

THE MICROSTRUCTURES OF ZR-EXCEL ALLOY: EFFECTS OF HEAVY ION IRRADIATION, PLASTIC DEFORMATION, THERMAL TREATMENT AND IN-SITU HEATING

Zr-Excel alloy (Zr-3.5Sn-0.8Nb-0.8Mo) is a dual phase (α + β) alloy in the as-received pressure tube condition. It has been proposed to be the pressure tube candidate material for the Generation-IV CANDU-Supercritical Water Reactor (CANDU-SCWR). In this dissertation, the effects of heavy ion irradiation, deformation and heat treatment on the microstructures of the alloy were investigated to enable us to have a better understanding of the potential in-reactor performance of this alloy. In-situ heavy ion (1 MeV) irradiation was performed to study the nucleation and evolution of dislocation loops in both α- and β-Zr. Small and dense type dislocation loops form under irradiation between 80 and 450 °C. The number density tends to saturate at ~ 0.1 dpa. Compared with the α-Zr, the defect yield is much lower in β-Zr. The stabilities of the metastable phases (β-Zr and ω-Zr) and the thermal-dynamically equilibrium phase, fcc Zr(Mo, Nb)2, under irradiation were also studied at different temperatures. Chemi-STEM elemental mapping was carried out to study the elemental redistribution caused by irradiation. The stability of these phases and the elemental redistribution are strongly dependent on irradiation temperature. In-situ time-of-flight neutron diffraction tensile and compressive tests were carried out at different temperatures to monitor lattice strain evolutions of individual grain families during these tests. The β-Zr is the strengthening phase in this alloy in the as-received plate material. Load is transferred to the β-Zr after yielding of the α-Zr grains. The temperature dependence of static strain aging and the yielding sequence of the individual grain families were discussed. Strong tensile/compressive asymmetry was observed in the {0002} grain family at room temperature. The microstructures of the sample deformed at 400 °C and the samples only subjected to heat treatment at the same temperature were characterized with TEM. Concentration of β phase stabilizers in the β grain and the morphology of β grain have significant effect on the stability of β- and ω-Zr under thermal treatment. Applied stress/strain enhances the decomposition of isothermal ω phase but suppresses α precipitation inside the β grains at high temperature. An α → ω/ZrO phase transformation was observed in the thin foils of Zr-Excel alloy and pure Zr during in-situ heating at 700 °C in TEM.

Asymmetric hydrogen flame in a heated micro-channel: role of Darrieus-Landau and thermal-diffusive instabilities

Present work examines numerically the asymmetric behavior of hydrogen/air flame in a micro-channel subjected to a non-uniform wall temperature distribution. A high resolution (with cell size of 25 μm × 25 μm) of two-dimensional transient Navier–Stokes simulation is conducted in the low-Mach number formulation using detailed chemistry evolving 9 chemical species and 21 elementary reactions. Firstly, effects of hydrodynamic and diffusive-thermal instabilities are studied by performing the computations for different Lewis numbers. Then, the effects of preferential diffusion of heat and mass transfer on the asymmetric behavior of the hydrogen flame are analyzed for different inlet velocities and equivalence ratios. Results show that for the flames in micro-channels, interactions between thermal diffusion and molecular diffusion play major role in evolution of a symmetric flame into an asymmetric one. Furthermore, the role of Darrieus–Landau instability found to be minor. It is also found that in symmetric flames, the Lewis number decreases behind the flame front. This is related to the curvature of flame which leads to the inclination of thermal and mass fluxes. The mass diffusion vectors point toward the walls and the thermal diffusion vectors point toward the centerline. Asymmetric flame is observed when the length of flame front is about 1.1–1.15 times of the channel width.

Oxidative stress and its haemodynamic consequences in chronic kidney disease

Chronic kidney disease (CKD) is associated with increased cardiovascular risk in comparison with the general population. This can be observed even in the early stages of CKD, and rises in proportion to the degree of renal impairment. Not only is cardiovascular disease (CVD) more prevalent in CKD, but its nature differs too, with an excess of morbidity and mortality associated with congestive cardiac failure, arrhythmia and sudden death, as well as the accelerated atherosclerosis which is also observed. Conventional cardiovascular risk factors such as hypertension, dyslipidaemia, obesity, glycaemia and smoking, are highly prevalent amongst patients with CKD, although in many of these examples the interaction between risk factor and disease differs from that which exists in normal renal function. Nevertheless, the extent of CVD cannot be fully explained by these conventional risk factors, and non-conventional factors specific to CKD are now recognised to contribute to the burden of CVD. Oxidative stress is a state characterised by excessive production of reactive oxygen species (ROS) and other radical species, a reduction in the capacity of antioxidant systems, and disturbance in normal redox homeostasis with depletion of protective vascular signalling molecules such as nitric oxide (NO). This results in oxidative damage to macromolecules such as lipids, proteins and DNA which can alter their functionality. Moreover, many enzymes are sensitive to redox regulation such that oxidative modification to cysteine thiol groups results in activation of signalling cascades which result in adverse cardiovascular effects such as vascular and endothelial dysfunction. Endothelial dysfunction and oxidative stress are present in association with many conventional cardiovascular risk factors, and can be observed even prior to the development of overt, clinical, vascular pathology, suggesting that these phenomena represent the earliest stages of CVD. In the presence of CKD, there is increased ROS production due to upregulated NADPH oxidase (NOX), increase in a circulating asymmetric dimethylarginine (ADMA), uncoupling of endothelial nitric oxide synthase (eNOS) as well as other mechanisms. There is also depletion in exogenous antioxidants such as ascorbic acid and tocopherol, and a reduction in activity of endogenous antioxidant systems regulated by the master gene regulator Nrf-2. In previous studies, circulating markers of oxidative stress have been shown to be increased in CKD, together with a reduction in endothelial function in a stepwise fashion relating to the severity of renal impairment. Not only is CVD linked to oxidative stress, but the progression of CKD itself is also in part dependent on redox sensitive mechanisms. For example, administration of the ROS scavenger tempol attenuates renal injury and reduces renal fibrosis seen on biopsy in a mouse model of CKD, whilst conversely, supplementation with the NOS inhibitor L-NAME causes proteinuria and renal impairment. Previous human studies examining the effect of antioxidant administration on vascular and renal function have been conflicting however. The work contained in this thesis therefore examines the effect of antioxidant administration on vascular and endothelial function in CKD. Firstly, 30 patients with CKD stages 3 – 5, and 20 matched hypertensive controls were recruited. Participants with CKD had lower ascorbic acid, higher TAP and ADMA, together with higher augmentation index and pulse wave velocity. There was no difference in baseline flow mediated dilatation (FMD) between groups. Intravenous ascorbic acid increased TAP and O2-, and reduced central BP and augmentation index in both groups, and lowered ADMA in the CKD group only. No effect on FMD was observed. The effects of ascorbic acid on kidney function was then investigated, however this was hindered by the inherent drawbacks of existing methods of non-invasively measuring kidney function. Arterial spin labelling MRI is an emerging imaging technique which allows measurement of renal perfusion without administration of an exogenous contrast agent. The technique relies upon application of an inversion pulse to blood within the vasculature proximal to the kidneys, which magnetically labels protons allowing measurement upon transit to the kidney. At the outset of this project local experience using ASL MRI was limited and there ensued a prolonged pre-clinical phase of testing with the aim of optimising imaging strategy. A study was then designed to investigate the repeatability of ASL MRI in a group of 12 healthy volunteers with normal renal function. The measured T1 longitudinal relaxation times and ASL MRI perfusion values were in keeping with those found in the literature; T1 time was 1376 ms in the cortex and 1491 ms in the whole kidney ROI, whilst perfusion was 321 mL/min/100g in the cortex, and 228 mL/min/100g in the whole kidney ROI. There was good reproducibility demonstrated on Bland Altman analysis, with a CVws was 9.2% for cortical perfusion and 7.1% for whole kidney perfusion. Subsequently, in a study of 17 patients with CKD and 24 healthy volunteers, the effects of ascorbic acid on renal perfusion was investigated. Although no change in renal perfusion was found following ascorbic acid, it was found that ASL MRI demonstrated significant differences between those with normal renal function and participants with CKD stages 3 – 5, with increased cortical and whole kidney T1, and reduced cortical and whole kidney perfusion. Interestingly, absolute perfusion showed a weak but significant correlation with progression of kidney disease over the preceding year. Ascorbic acid was therefore shown to have a significant effect on vascular biology both in CKD and in those with normal renal function, and to reduce ADMA only in patients with CKD. ASL MRI has shown promise as a non-invasive investigation of renal function and as a biomarker to identify individuals at high risk of progressive renal impairment.

Impact of weight loss on oxidative stress and inflammatory cytokines in obese type 2 diabetic patients.

Background: Type 2 diabetes mellitus is associated with abnormal markers of inflammatory cytokines and oxidative stress markers. Although, these abnormalities could be modulated with weight reduction; there is limitation in clinical studies that have addressed the beneficial effects of weight reduction in modulating biomarkers of inflammatory cytokines and oxidative stress for obesity associated with type 2 diabetes mellitus. Objective: This study was designed to detect the effects of weight loss on the inflammatory cytokines, oxidative stress markers in obese type 2 diabetic patients. Material and Methods: Eighty obese patients with type 2 diabetes mellitus, their age ranged from 35-57 years and their body mass index ranged from 31-35 kg/m2 were equally assigned into 2 groups: the weight reduction group received aerobic exercises, diet regimen, where as the control group received medical treatment only for 12 weeks. Results: The mean values of body mass index (BMI), tumor necrosis factor–alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein (sCRP), conjugated dienes (CD) and malondialdehyde (MDA) were significantly decreased, while the mean values of glutathione peroxidase (GPx), superoxide dismutase (SOD) and glutathione (GSH) were significantly increased in patients of group (A), while changes were not significant in group (B). Also, there were significant differences between mean levels of the investigated parameters in group (A) and group (B) at the end of the study. Conclusion: Weight loss ameliorates inflammatory cytokines and oxidative stress markers in obese type 2 diabetic patients.

Physical Design Methodologies for Low Power and Reliable 3D ICs

As the semiconductor industry struggles to maintain its momentum down the path following the Moore's Law, three dimensional integrated circuit (3D IC) technology has emerged as a promising solution to achieve higher integration density, better performance, and lower power consumption. However, despite its significant improvement in electrical performance, 3D IC presents several serious physical design challenges. In this dissertation, we investigate physical design methodologies for 3D ICs with primary focus on two areas: low power 3D clock tree design, and reliability degradation modeling and management. Clock trees are essential parts for digital system which dissipate a large amount of power due to high capacitive loads. The majority of existing 3D clock tree designs focus on minimizing the total wire length, which produces sub-optimal results for power optimization. In this dissertation, we formulate a 3D clock tree design flow which directly optimizes for clock power. Besides, we also investigate the design methodology for clock gating a 3D clock tree, which uses shutdown gates to selectively turn off unnecessary clock activities. Different from the common assumption in 2D ICs that shutdown gates are cheap thus can be applied at every clock node, shutdown gates in 3D ICs introduce additional control TSVs, which compete with clock TSVs for placement resources. We explore the design methodologies to produce the optimal allocation and placement for clock and control TSVs so that the clock power is minimized. We show that the proposed synthesis flow saves significant clock power while accounting for available TSV placement area. Vertical integration also brings new reliability challenges including TSV's electromigration (EM) and several other reliability loss mechanisms caused by TSV-induced stress. These reliability loss models involve complex inter-dependencies between electrical and thermal conditions, which have not been investigated in the past. In this dissertation we set up an electrical/thermal/reliability co-simulation framework to capture the transient of reliability loss in 3D ICs. We further derive and validate an analytical reliability objective function that can be integrated into the 3D placement design flow. The reliability aware placement scheme enables co-design and co-optimization of both the electrical and reliability property, thus improves both the circuit's performance and its lifetime. Our electrical/reliability co-design scheme avoids unnecessary design cycles or application of ad-hoc fixes that lead to sub-optimal performance. Vertical integration also enables stacking DRAM on top of CPU, providing high bandwidth and short latency. However, non-uniform voltage fluctuation and local thermal hotspot in CPU layers are coupled into DRAM layers, causing a non-uniform bit-cell leakage (thereby bit flip) distribution. We propose a performance-power-resilience simulation framework to capture DRAM soft error in 3D multi-core CPU systems. In addition, a dynamic resilience management (DRM) scheme is investigated, which adaptively tunes CPU's operating points to adjust DRAM's voltage noise and thermal condition during runtime. The DRM uses dynamic frequency scaling to achieve a resilience borrow-in strategy, which effectively enhances DRAM's resilience without sacrificing performance. The proposed physical design methodologies should act as important building blocks for 3D ICs and push 3D ICs toward mainstream acceptance in the near future.

An Evaluation of Oxidative Status in Serum and Breast Milk of Mothers Giving Birth Prematurely and at Full-Term

Background: Burning fat and carbohydrates to provide energy in biological systems causes the formation of free oxygen species. Objectives: This study aimed to evaluate the oxidative status of serum and breast milk of mothers giving birth prematurely and at full-term. Materials and Methods: The study comprised 50 mothers who gave birth at full-term at more than 38 weeks and 43 mothers who gave birth pre-term at below 32 weeks. On the postnatal 5th day, samples of the mother’s milk and serum were taken and stored at -80°C until the study day. On the study day, the total oxidant and total antioxidant levels were measured using the Erel method and the oxidative stress index (OSI) was calculated. Results: While the total oxidant level and total antioxidant level values of the milk of the premature birth mothers were found to be significantly high compared to those of the full-term birth mothers (P = 0.001), no statistically significant difference was found in the oxidative stress index values (P > 0.05). No statistically significant difference was found in the total oxidant level and oxidative stress index values of the serum of the premature birth mothers compared to those of the full-term birth mothers, while the total antioxidant level was found to be significantly low (P = 0.04). Conclusions: The oxidants and antioxidants in the milk of mothers giving birth prematurely were found to be significantly higher than those of full-term birth mothers. This can be evaluated as the milk of the premature birth mothers providing increased antioxidant defense to protect the infant.