The image of authoritarian figures and leaders inspired many of Francis Bacon's paintings. Among these, his interpretation of the Portrait of Pope Innocent X (1650) by Velázquez represents an exemplary way of revealing the complex dilemmas incorporated within a leader. However, whereas in Velázquez's portrait the Pope appeared regal, serene and inquisitive, Bacon's Study after Velázquez's Portrait of Pope Innocent X (1953) seems to explore the isolation conferred by his authority. The obsession of Bacon with this painting may suggest a wider challenge to contemporary organizational mythology — top managers, businessmen, politicians, CEOs, bankers, etc. — experiencing a sort of leadership crisis, in a moment when their public image is being questioned and their social status threatened. Is it, then, possible to visualize how our contemporary images of power may become transfigured, challenged and contorted? The dialogue between these two representations of Innocent X inspires questions about the representation and re-interpretation of authority and leadership and it aims at responding the question of What do images of leaders as depicted by portraiture contribute to our understanding of leading and leadership? This paper follows the analytical framework proposed by Guthey and Jackson (2005, 2008) concerning a 'visual genealogy' (Schroeder and Zwick, 2004) of images of leaders. The notion of establishing a 'genealogy' of representations of leadership draws upon the work of Michel Foucault, concerning the ways through which Western culture creates subjects and, most specifically, how images of leadership are created through portraiture and art. The interest in the Pope acknowledges the significance of his figure as leader of the Catholic Church, one of the most important institutions in European history; here, however, the intention is to establish a dialogue between Bacon's view on leadership in the figure of Innocent X, on the one hand, and on the other the original portrait by Velázquez, both seen in the context of contemporary discussions about leadership and charisma. Here, portraiture is approached as an aesthetic expression that can be used as a means of enquiring into certain aspects of leadership (Taylor and Hansen, 2005). Both perceptions coincided in their interpretation of leadership as focused on the charismatic individual; yet each of these two representations evidences a rupture, a questioning of this view. Velázquez, in a troppo vero (too real) depiction of the Pope, shows an efficient and cruel leader while offering his personal interpretation of the politics of his time. Bacon's interpretation goes further, by representing a powerful yet isolated leader, whose excessive individuality has produced a cage in which he remains trapped. Separated from his subjects, this view resembles the excessive attention that the individual is given when understanding leadership and its potential problems. This paper adds to the exploration of aesthetic expressions as a means of enquiring into organizational and social issues, for example, the case of leadership. It evidences the potentialities of considering specific artistic expressions, such as portraiture, as heuristic devices towards understanding some of the processes through which leadership is socially constructed, and the mechanisms promoting one notion or another of leadership in different historical periods.


Among the unwelcome legacies of the past century are a group of conflicts, both intrastate and interstate, that seem destined never to end. From Kashmir to Nagorno-Karabakh, Colombia to Sudan, the Korean Peninsula to the Middle East, these deeply entrenched, intermittently violent conflicts have so far resisted all outside efforts to resolve them.What lessons aside from the apparent futility of mediation can such dismal situations possibly offer? As the distinguished contributors to "Grasping the Nettle" make plain, this is not a rhetorical question. Unyielding conflicts offer numerous insights not only about the sources of intractability but also about such facets of mediation and conflict management as how to gain leverage, when to engage and disengage, how to balance competing goals, and who to enlist to play supporting roles.The first part of this eye-opening volume identifies and analyzes the defining characteristics and underlying dynamics of intractable conflicts. The second part turns the spotlight on no fewer than eight current cases, in each instance chronicling the conflict's evolution, evaluating the internal and external factors that have conspired to prevent a settlement, and assessing whether past peacemaking initiatives have in fact only aggravated the conflict. The conclusion makes the point that even intractable conflicts eventually end and highlights the strategic approaches and tactical steps that have yielded success in the past for mediators and conflict managers from governments, international organizations, and NGOs."


This paper addresses the question: how might those engaged in the mission of training secondary Speech-education teachers create a "pedagogy of authentic civic action" in light of current standards legislation that functions more to perpetuate a liberal republic than it does to vivify (and articulate) an authentic democracy? The arena of K-12 education in the U.S. (including Speech education) is in the midst of an extensive standardization movement. State standards increasingly cast both the practices of secondary Speech-education and the training of Speech teachers. Relevant here is that Speech-education standards lack any mention of democracy or civic participation, a decision that, in essence, impedes teachers from engaging these projects. In contrast, it is noteworthy that the formal genesis of democracy and education theory is directly coupled to the birth of rhetoric (or Speech). Concurrently, Civics standards employ the language of rhetoric, yet ignore its discipline and its pedagogy. The work argues that current standards, while valuable in many ways, limit the vision of civics and democracy to the extent that they embrace a set of sterilized Speech standards. The piece calls for a revised set of rhetoric-based benchmarks designed to invigorate an authentic democracy model of education. A contrast between existing standards and an alternative civics-as-rhetoric curriculum is outlined. Finally, an initial theory of a "pedagogy of strong democracy" based in the study and practices of Speech (or rhetoric) is proposed. (Contains 20 references.) (Author/RS) Reproductions supplied by EDRS are the best that can be made from the original document.


Restriction fragment length polymorphism (RFLP) analysis of mitochondrial DNA was used to examine the regional population structure of a species of gecko (Oedura reticulata) in vegetation remnants within the Western Australian wheatbelt. The species exhibited considerable polymorphism within and between populations with 22 haplotypes recognized among 12 populations. Phylogenetic analysis of haplotypes and clustering of nucleotide divergence among populations demonstrated little regional structure within the species with several haplotypes present in all three regions surveyed. This contrasted markedly with variation in haplotype frequency among populations which showed a high degree of independence between populations indicating that current levels of maternal gene flow are low and that the populations are too small to prevent genetic drift. This conclusion is supported by generally lower numbers of haplotypes in remnant populations than in nearby nature reserves. These findings, combined with demographic data from a previous study, suggest that post‐fragmentation populations of O. reticulata are unable to form a metapopulation structure in the habitat that remains and that stochastic extinction forces alone will be sufficient to severely reduce the regional distribution of this species. This study demonstrates that mtDNA is a useful tool for detecting contemporary population phenomena and can provide qualitative information of practical importance to wildlife managers.


Wet Ag/AgCl electrodes, although very popular in clinical diagnosis, are not appropriate for expanding applications of wearable biopotential recording systems which are used repetitively and for a long time. Here, the development of a low-cost and low-noise active dry electrode is presented. The performance of the new electrodes was assessed for recording electrocardiogram (ECG) and electroencephalogram (EEG) in comparison with that of typical gel-based electrodes in a series of long-term recording experiments. The ECG signal recorded by these electrodes was well comparable with usual Ag/AgCl electrodes with a correlation up to 99.5% and mean power line noise below 6.0 μVRMS. The active electrodes were also used to measure alpha wave and steady state visual evoked potential by recording EEG. The recorded signals were comparable in quality with signals recorded by standard gel electrodes, suggesting that the designed electrodes can be employed in EEG-based rehabilitation systems and brain-computer interface applications. The mean power line noise in EEG signals recorded by the active electrodes (1.3 μVRMS) was statistically lower than when conventional gold cup electrodes were used (2.0 μVRMS) with a significant level of 0.05, and the new electrodes appeared to be more resistant to the electromagnetic interferences. These results suggest that the developed low-cost electrodes can be used to develop wearable monitoring systems for long-term biopotential recording.


Person re-identification is an important task in video surveillance that aims to associate people across camera views at different locations and time. View variability is always a challenging problem seriously degrading person re-identification performance. Most of the existing methods either focus on how to learn view invariant feature or how to combine viewwise features. In this paper, we mainly focus on how to learn view-independent features by getting rid of view specific information through a view confusion learning mechanism. Specifically, we propose an end-to-end trainable framework, called View Confusion Feature Learning (VCFL), for person Re-ID across cameras. To the best of our knowledge, VCFL is originally proposed to learn view-independent identity-wise features, and it's a kind of combination of view-generic and view-specific methods. Furthermore, we extract sift-guided features by using bag-of-words model to help supervise the training of deep networks and enhance the view invariance of features. In experiments, our approach is validated on three benchmark datasets including CUHK01, CUHK03, and MARKET1501, which show the superiority of the proposed method over several state-of-the-art approaches.


Abstract From newt testes we cloned by reverse transcription-polymerase chain reaction (RT-PCR) activin βA and βB subunit genes, each encoding the mature region of the peptides. A single form for each of the subunit genes was isolated. Newt βA and βB share 80 and 98% protein sequence similarity with the human subunits, respectively. Northern blot analysis showed that βA subunit mRNA is approximately 7 kilobases in length and is expressed during spermatogenesis in stages from spermatogonial to spermatid, but activin βB subunit mRNA is barely detectable during these stages. We also isolated a cDNA clone containing the entire coding region of βA subunit and performed in situ hybridization with its cRNA probe. Newt activin βA subunit mRNA was detected in Sertoli cells, but not in germ cells or pericystic cells. These findings suggest that activin A plays an important role in newt spermatogenesis.


We use a spherical shell elastic finite element analysis to characterize intraplate stresses and plate-driving forces in the Philippine Sea Plate. Our finite element mesh is comprised of 489 nodes and 914 elements, and provide a spatial resolution of about 1°. The Philippine Sea Plate is unusual in that it does not have large numbers of seismic or tectonic stress indicators, and there are no midplate borehole stress data which can be used as constraints in this finite element study. However, it does possess a unique boundary configuration which potentially can lend more insight to plate forces and stresses than can similar studies on plates with more seismically active interiors. Because the plate's boundary consists primarily of subduction zones with roughly equal proportions of boundary on the overlying and downgoing sides of trench, the resultant plate stress field is very sensitive to subduction-related forces. As a result, borehole stress measurements in certain parts of the plate would be useful in further constraining these forces. We find that trench pull forces can explain a large component of the velocity of the Philippine Sea Plate. However, trench pull has somewhat less overall effect on the stresses across the plate than do the lateral density and topographic variations within the plate (i.e., gravitational or potential energy force), and trench suction forces are probably about an order of magnitude smaller than the net trench pull forces. Collisional forces may dominate the stress fields near Taiwan and the Izu Peninsula, but they are of only secondary importance in determining the motion and deformation of the Philippine Sea Plate. The forces that generate stress orientations most closely matching the observed stress indicators produce a lithospheric stress field across the plate that averages about 15 MPa over a 70 km thick lithosphere, scaling inversely with lithosphere thickness. Values up to four times as great are produced locally.


How hard is it to solve a system of bilinear equations? No solutions are presented in this report, but the problem is posed and some preliminary remarks are made. In particular, solving a system of bilinear equations is reduced by a suitable transformation of its columns to solving a homogeneous system of bilinear equations. In turn, the latter has a nontrivial solution if and only if there exist two invertible matrices that, when applied to the tensor of the coefficients of the system, zero its first column. Matlab code is given to manipulate three-dimensional tensors, including a procedure that finds one solution to a bilinear system often, but not always.


Hormone-dependent cancers depend largely on folding and regulation by a chaperone-steroid receptor complex. The final stage of the receptor-chaperone complex consists of a receptor, a heat shock protein 90 (Hsp90) dimer, p23, and an immunophilin. Hormone-dependent prostate cancer progresses due to key interactions between the androgen receptor complex and the ligand dihydrotestosterone. While current treatments block androgen receptor-ligand interactions, these therapies are no longer effective in advanced stage, hormone independent prostate cancer (HRPC), when the receptor is activated even in miniscule levels of hormone. Therefore, we are interested in targeting other members of the androgen receptor complex and signaling cascade, namely the immunophilin FK506 binding protein (FKBP52) and the Wnt cell signaling protein β-catenin. FKBP52 has the ability to potentiate activity of the androgen, progesterone, and glucocorticoid receptors and is a prostate cancer biomarker. β-catenin is a member of the cellular adhesion complex with E-cadherin in healthy cells, but in aberrant situations, β-catenin actively promotes progression and invasion in a number of cancers. Our data from FKBP52 knockout mouse embryonic fibroblast cell lines suggests that FKBP52 and β-catenin work in tandem to synergize androgen receptor (AR) transcriptional activity with the probasin promoter. When AR, FKBP52, and β-catenin are co-transfected, a synergistic up-regulation of AR signaling is observed, as assessed by luciferase reporter assays. According to pull down assays, FKBP52 and β-catenin can interact in the absence of other proteins. Luciferase assays of mutant FKBP52 proteins suggest that FKBP529s binding to β-catenin involves the FKBP52 proline-rich loop and may act independently of Hsp90 binding. Interestingly, it appears that this synergistic effect is promoter-specific, suggesting that regulation by these proteins occurs at the transcriptional level. We have successfully abrogated the synergism of these proteins using the FKBP52-specific inhibitor MJC13, a small molecule developed for use in our laboratory. According to surface plasmon resonance studies, this molecule binds the androgen receptor at the BF-3 regulatory surface, the interaction surface for FKBP52 regulation of receptor. According to recent findings, AR, Wnt, and Human Epidermal Growth Factor Receptor 2 signaling pathways are linked in molecular apocrine breast cancer progression. We therefore hypothesize that our findings could be relevant to breast cancer as well as prostate cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-07-02.


One class anomaly detection on high-dimensional data is one of the critical issue in both fundamental machine learning research area and manufacturing applications. A good anomaly detection should accurately discriminate anomalies from normal data. Although most previous anomaly detection methods achieve good performances, they do not perform well on high-dimensional imbalanced dataset 1) with a limited amount of data; 2) multi-modal distribution; 3) few anomaly data. In this paper, we develop a multi-modal one-class generative adversarial network based detector (MMOC-GAN) to distinguish anomalies from normal data (products). Apart from a domain-specific feature extractor, our model leverage a generative adversarial network(GAN). The generator takes in a modified noise vector using a pseudo latent prior and generate samples at the low-density area of the given normal data to simulate the anomalies. The discriminator then is trained to distinguish the generate samples from the normal samples. Since the generated samples simulate the low density area for each modal, the discriminator could directly detect anomalies from normal data. Experiments demonstrate that our model outperforms the state-of-the-art one-class classification models and other anomaly detection methods on both normal data and anomalies accuracy, as well as the F1 score. Also, the generated samples can fully capture the low density area of different types of products.


We introduce Breadth-First Pipeline Parallelism, a novel training schedule which optimizes the combination of pipeline and data parallelism. Breadth-First Pipeline Parallelism lowers training time, cost and memory usage by combining a high GPU utilization with a small batch size per GPU, and by making use of fully sharded data parallelism. Experimentally, we observed an increase of up to 43% in training throughput for a 52 billion-parameter model using a small batch size per GPU compared to Megatron-LM, which would reduce the training time and cost by the same amount on a large GPU cluster.


This work is motivated by an attempt to explain the origins of syringomyelia. This serious disease is characterized by the appearance of cavities, called syrinxes, in the central canal of the spinal cord resulting in partial or complete paralysis. The causes of syringomyelia are unknown but pressure propagation is probably implicated. Pressure pulses, caused by coughing, sneezing and similar activities, propagate up the cerebrospinal fluid (CSF) in the spinal subarachnoid space. Williams (1990) suggested a possible cause of syrinx formation is that when such pressure pulses encounter a partial or total blockage a large pressure rise would be generated in the spinal central canal. Our theoretical model modeling was undertaken to investigate Williams' hypothesis.
Essentially, we model the spinal system as a channel separated into two parts by a flexible diaphragm representing the spinal cord. The upper part (A) represents the subarachnoid space while the lower part (B), which has a much smaller cross-sectional area, represents the central canal. A theory for pressure wave propagation in such a two-chamber system is described. It has been used to study the wave characteristics of the two-chamber system. In this way it has been found that the leading edge of a pressure pulse/wall bulge tends to steepen into a shock-like wave or elastic jump. When such a pressure pulse is incident on a blockage in the subarachnoid space, a large pressure rise is generated in its vicinity. We showed that this pressure rise could be momentary or permanent depending on whether the pressure pulse bulge is positive or negative. This provides a possible mechanism for the formation of the syrinxes.

An experimental rig has also been built in order to qualitatively confirm some theoretical results. The experimental wave speed agreed with the wave speed defined in the theoretical model. We were also able to confirm that the reflection of a pressure pulse from a blockage placed in the upper part A (subarachnoid space) leads to high pressure in the vicinity of the blockage.


The role of the vagus nerve in the somnogenic and pyrogenic effects of lipopolysaccharide (LPS) was studied in rats. Control rats ( n= 8) and rats subjected to bilateral subdiaphragmal vagotomy (VX; n = 9) were injected with 100 μg/kg ip LPS at the beginning of the dark period. Sleep and brain temperature (Tbr) were recorded for 23 h after the injections. LPS caused increases in non-rapid eye movement sleep (NREMS) for 12 h after the injection in control rats. Sleep intensity, as indicated by the slow-wave activity (SWA) of the electroencephalogram during NREMS, was suppressed. LPS elicited biphasic Tbr responses: an initial hypothermia was followed by increases in Tbr that lasted for ∼20 h. In vagotomized rats, the NREMS responses to LPS were blunted. The magnitude of the LPS-induced NREMS increases was about one-half of that seen in control rats, and these sleep responses lasted only for 6 h. LPS did not affect SWA in VX animals. VX completely abolished the hypothermic responses to LPS and shortened the duration of the hyperthermia. The results suggest that the subdiaphragmal vagi play an important, but not exclusive, role in the somnogenic and pyrogenic actions of intraperitoneally injected LPS.


Conductive EMI noise analysis for switched reluctance machine (SRM), including noise diagnosing by the separator and noise suppression, are presented in this paper. Firstly, the CM and DM noise current loops in SRM's power converter are discussed, and the noise separator based on 0°/180° splitter is employed for noise diagnosis. Then, the EMI filer design and the radiator-ungrounded method are proposed for SRM noise suppression. Experimental results show that the noise diagnose method is valid and reliable for EMI filter design, and the AC input of SRM influence the total noise greatly. Moreover, the proposed EMI filter technique is verified to satisfy EMC standards, and its noise decline rate reaches to 30%. The radiator-ungrounded method is testified to be effective against CM noise.


Porous metal frameworks offer potentially useful applications for the aerospace, automotive and bio-medical industries. They can be used as electrodes, actuators, or as selective membrane films. The versatility of the physical features (pore size, pore depth, overall porosity and pore surface coverage) as well as the large range of surface chemistries for both metal oxides and pure noble metals offers scope to functionalise metal nano-particles and networks of nano-porous metal structures. As well as traditional routes to producing metal structures, such as metal sintering or foaming, novel high-throughput techniques have recently been investigated. Nanoparticle self-assembly, metal ion reduction and deposition as well as metal alloy de-alloying were identified as sustainable routes to produce large surface areas of such nano-porous metal frameworks. The main limitations of the current fabrication techniques include the difficulty to process stable and homogeneous arrays of nano-scale pores and the control of their morphology due to the high reactivity of nano-structured metal structures. This paper aims at critically reviewing the various fabrication techniques and surface functionalization routes used to produce advanced functional porous metal frameworks. The limitations and advantages of the different fabrication techniques will be discussed in light of the final material properties and targeted applications.


ABSTRACT The involvement of propofol and circular RNAs (circRNAs) in lung cancer progression has been identified. However, the relationship between propofol and circRNAs as well as the underlying molecular mechanisms on lung cancer development remain unclear. Cell viability, migration and invasion were measured by cell counting kit-8 assay, 5-bromo-2-deoxyuridine (BrdU) and transwell assay. Glycolytic metabolism was calculated by measuring the glucose consumption, lactate production and extracellular acidification. Western blot was used to detect the protein of glucose transporter 1 (GLUT1), glycolysis enzymes, and forkhead box M1 (FOXM1). The expression of circRNA transcriptional adaptor 2A (circTADA2A), microRNA (miR)-455-3p and FOXM1 mRNA was detected by quantitative real-time polymerase chain reaction. The interaction between miR-455-3p and circTADA2A or FOXM1 was analyzed using the dual-luciferase reporter assay. Murine xenograft model was established to perform in vivo experiments. We found propofol treatment alleviated lung cancer cell proliferation, migration, invasion and aerobic glycolysis in vitro as well as inhibited tumor growth in vivo. Propofol decreased the level of circTADA2A and exerted anti-tumor effects by regulating circTADA2A. MiR-455-3p directly interacted with circTADA2A and FOXM1 in lung cancer cells, and circTADA2A could regulate FOXM1 expression by binding to miR-455-3p. Subsequently, rescue assay showed that propofol inhibited cell proliferation, migration, invasion and aerobic glycolysis by regulating circTADA2A/miR-455-3p/FOXM1 axis in lung cancer. Collectively, propofol suppressed cell carcinogenesis and aerobic glycolysis by regulating circTADA2A/miR-455-3p/FOXM1 axis in lung cancer, providing an effective clinical implication for propofol to prevent the development of lung cancer.


A three-wheeled amphibian vehicle comprises a hull 2, body 3, front steered wheels 11, 11', and rear wheel 9. Each steered wheel is connected to the amphibian by a retractable suspension assembly 10, 10'. Upper and lower suspension arms 14 and 15 have pivotal connections 17 and 18 to inner upright arm 16. Retraction rams 28 are connected to body 3, and can retract the wheels for use on water and protract them for use on land. Wheels 11, 11' also lean on cornering. The pivotal connections 17, 18 for wheel retraction are also used to facilitate leaning. This may be allowed through rotation of drop link 31 around pivot 32. A motor and gearbox assembly 30 may be attached to body 3 to provide controlled lean when cornering, and to keep the amphibian upright when stationary. Leaning may be powered, or user initiated. Powered lean correction may be provided.


The calculation of J-integrals for cases with rotational effects using the finite or boundary elements needs special treatment. In this work, an attempt is made to derive the J-integral expressions for cases with rotational loading conditions. New useful ideas for reducing domain integrals to boundary integrals and improving the accuracy of J-integrals are developed. The new ideas are implemented in finite and boundary element programs which were developed and validated in this work by taking a case study of central-cracked rotating disc with known analytical solution. The results of the developed programs show good agreements with the analytical solution.


From the moment they met at a pub in London, drink was the most conspicuous part of the lives of Caitlin and her 'genius poet', Dylan Thomas. It fuelled their sexual adventures, lessened their shyness and enriched their social life. This searing book is Caitlin's story of the passions, the rage and the tragic humour of those years of drink and the toll it took on the lives of two talented people, leaving one of them dead at the age of thirty-nine, and the other alone, penniless and an alcoholic. It is also the memoir of a woman not always likeable, but consistently energetic and honest and possessing an indomitable spirit.


The ability to access and use water sanitation and hygiene (WASH) facilities is a fundamental human right. Increasingly, government and non-governmental organizations (NGOs) are supporting the implementation of WASH projects in the developing world. However, the specific challenges faced by persons with disabilities (PWD) are not widely included in the design process of WASH facilities. Additionally, PWD are often excluded from the implementation and decision-making processes of WASH projects. It is the objective of this briefing paper to describe the findings, recommendations and guidelines for inclusive WASH development gleaned from experience with the Africa WASH & Disabilities Study (AWDS). The AWDS seeks to facilitate access to WASH installations through modifications of existing WASH installations (e.g. hand-pumps, pump superstructures, latrines and laundry aprons) as well as through the development of simple, low-cost assistive WASH technologies (e.g. latrine seats and chairs).


A total of 1,024 barrows (each initially 157 lb, PIC L337 x C22) were used in a 28-d study to evaluate the effects of increased crystalline amino acids (none versus 4.5 lb/ton of L-lysine HCl plus L-threonine to maintain the proper ratio relative to lysine) and added dietary fat (none, 3 or 6% choice white grease) on finishing pig growth performance. All experimental diets were formulated with a constant true ileal digestible lysine:ME ratio based on NRC, (1998) ingredient values for ME. A minimum true ileal digestible threonine:lysine ratio of 68% and a minimum true ileal digestible methionine + cystine:lysine ratio of 55% were used in diet formulation. There was no synthetic amino acid by added fat interactions. Increasing added fat increased (linear, P<0.01) ADG and improved F/G. Replacing soybean meal with crystalline amino acids had no affect on growth performance. This indicates that the increased amounts of L-lysine HCl and added Lthreonine were used as efficiently as amino acids provided from soybean meal. Neither adding fat nor crystalline lysine affected feed cost/lb of gain using current ingredient prices. However, margin over feed cost (profit) increased as added fat increased because of the increased pig weight due to improved ADG. In summary, these results confirm the improved ADG and F/G when adding fat to finishing pig diets. Furthermore, 4.5 lb/ton of Llysine HCl and L-threonine can effectively replace soybean meal without negatively affecting growth performance of pigs from 157 to 217 lb.


Systematic consideration of environmental aspects within the early stages of product development (PD) can be considered highly significant in order for the overall environmental performance of the product to be improved. Many methods and tools have been developed aiming to enable this consideration and provide the properties that need to be considered and improved. This article provides an overview of some well-known and more applicable tools and methods that have been developed and are available today. The identified tools are generally classified in two groups: Guidelines and Analytical tools. The limitations and barriers of current tools are assessed and categorized and two areas for work are proposed in order to address current limitations in the existing literature. One of the areas is followed and a scoring model is proposed as a new tool for sustainable PD.


The electrokinetic process seems to be interesting to the earthwork portion on the construction of buildings, and transportation projects since this simple, fast, yet reliable technique could expedite dehydrating of soil and reduce delays in the construction schedule. This paper examined the technical feasibility and a brief cost analysis of using plastic electrodes for electrokinetically dehydrating clayey soils with high moisture content were also carried out. The results from the experimental program carried out on a marine clayey soil with copper and plastic electrodes showed a great deal of soil improvement since positive changes in undrained shear strength occur due to the free water dehydration process induced by electroosmosis and to the adsorbed water dehydration process induced by electromigration. It was also observed that values of the undrained shear strength remained stable at the final stages of the electrokinetic process indicating a permanent soil improvement. Finally, it was noticed that dehydrating could be achieved at lower costs by employing plastic electrodes.


: Acute symptomatic biliary tract disease in the elderly is usually associated with a tenfold increase in operative morbidity and mortality when compared to the disease in non-elderly patients. Over a 10-year period 118 elderly patients with a mean age of 77.2 years (range 65 to 98 years) were operated on for benign biliary tract disease. Acute cholecystitis was found at operation in 33 patients (28%), empyema in nine (7.6%), gangrene of the gallbladder in three (2.5%), and 24 patients (20.3%) were found to have common bile duct stones. Seventy-three patients had chronic cholecystitis. Complications occurred in 29 patients (24.6%), with pneumonia and wound infection as the two most common. Fifteen patients died, making the overall mortality rate 12.7 per cent. The mean age of the patients who died was 81.5 years. Two patients died following elective operations (mortality rate 1.7%), while the remainder died after emergent or urgent operations (11%). Elective biliary tract surgery in the elderly for symptomatic disease is safe and will reduce postoperative morbidity and mortality.


We present in this paper an extension of the message-driven confidence-driven framework that we developed for onboard guarded software upgrading. The purpose of this work is to provide the framework with the capability of protecting distributed software upgrades that involve message-passing interface changes. To achieve this goal, we propose an approach to clustering the components involved in software upgrades and those involved in message-passing interface changes, such that from outside the cluster all those components can be perceived collectively as one virtual low-confidence component. Moreover, we develop a confidence-driven mechanism that enables combined use of sender- and receiver-side message logging for efficient, fine-grained error containment and recovery. The paper provides a detailed algorithm description.


An attempt has been made to clad Mg alloy with Al by twin-roll casting. This was done by inserting an Al sheet between the roll and the Mg alloy melt during twin-roll casting. Microstructural investigation across the transverse section of the as-cast Al-clad Mg alloy sheet reveals a very good interfacial bonding between Al and the base Mg alloy. Annealing of the Al-clad Mg alloy sheet results in the formation of layers of various intermetallic phases along the Mg/Al interface. Subsequent rolling of the as-annealed sheet significantly improves the formability of the reaction zone, as evidenced by the cracking of the base Mg alloy before the cracking of the reaction zone.


Energy generation sites are increasingly being constructed in coastal and marine spaces and the rate of implementation is likely to increase in coming decades, due to a combination of increasing energy demand and international targets to reduce greenhouse gas emissions. In many cases the installation of energy generation structures greatly reduces or entirely prevents other potentially damaging industries, such as fishing and mining, from operating in surrounding areas. These sites also provide hard substratum and complex habitat in what are commonly soft-sediment environments. As such, they have been associated with high rates of colonisation by marine life, increased biodiversity and increased productivity. However, energy generation sites also have the potential to damage and fragment habitats and associated communities, and increase noise and/or chemical pollution in the marine environment. As competition for marine space grows, an emerging literature is increasingly considering whether conservation objectives and energy generation can be colocated. We synthesise available literature from around the world to consider what the potential conservation benefits of marine energy generation sites are. We discuss whether such sites are compatible with marine protected area designation, and examine this argument both from a biodiversity and policy perspective.


Objective: The objective of present study is to evaluate the potential of liquisolid (LS) technology to enhance the dissolution characteristics of a combination of two poorly soluble drugs formulated as a single tablet. Materials and Methods: LS compacts have been prepared using compositions with varying ratios of propylene glycol (as water miscible non-volatile vehicle), lactose, and microcrystalline cellulose PH 102 (MCC PH 102) (as carriers), while Syloid® 244FP silica as a coating material. To evaluate the role of additives on various parameters such as loading factor, powder flow, disintegration, and dissolution profile of prepared LS formulations, number of additives such as Kollidon® 30, hydroxy propyl methyl cellulose-low viscosity, polyethylene glycol 4000, Kollidon® VA64, and low-substituted hydroxypropyl cellulose-LH-11 were added to the formulation. Results and Discussion: Among the tested carriers, MCC PH 102 was found to enhance drug release considerably. Addition of additives was found to further enhance powder flow and provide faster release of drugs from formulations. Among all the LS formulations prepared, LS - 18 demonstrated the fastest disintegration time (1.02 min) and fastest dissolution rate (84.6% in 10 min for glipizide and 44.6% for atorvastatin) with 100% drug release. Conclusion: The study demonstrated that LS technology can lead to suitable coformulation of two poorly soluble drugs for antidiabetic-antihyperlipidemic cotherapy of metabolic syndrome with enhanced dissolution.


ABSTRACT Supporting patients with acute respiratory distress syndrome (ARDS), using a protective mechanical ventilation strategy characterizedby low tidal volume and limitation of positive end-expiratory pressure (PEEP) is a standard practice in the intensive care unit.However, these strategies can promote lung de-recruitment, leading to the cyclic closing and reopening of collapsed alveoli and smallairways. Recruitment maneuvers (RM) can be used to augment other methods, like positive end-expiratory pressure and positioning,to improve aerated lung volume. Clinical practice varies widely, and the optimal method and patient selection for recruitmentmaneuvers have not been determined, considerable uncertainty remaining regarding the appropriateness of RM. This review aimsto discuss recent findings about the available types of RM, and compare the effectiveness, indications and adverse effects amongthem, as well as their impact on morbidity and mortality in ARDS patients. Recent developments include experimental and clinicalevidence that a stepwise extended recruitment maneuver may cause an improvement in aerated lung volume and decrease thebiological impact seen with the traditionally used sustained inflation, with less adverse effects. Prone positioning can reduce mortalityin severe ARDS patients and may be an useful adjunct to recruitment maneuvers and advanced ventilatory strategies, such noisyventilation and BIVENT, which have been useful in providing lung recruitment.Key words: Valsava Maneuver. Positive-Pressure Respiration. Respiratory Distress Syndrome, Adult. Respiration, Artificial. PronePosition.


Background: Rhabdomyolysis is a clinical and biochemical syndrome that occurs when skeletal muscle cells disrupt and release creatine phosphokinase and myoglobin into the interstitial space and plasma. The causes of rhabdomyolysis are legion, but the most important and the classical form is the crush syndrome. Acute kidney injury occurs in 33-50% of patients with rhabdomyolysis. Here we report nine cases with acute kidney injury due to crush injury with rhabdomyolysis after the Al-Aema bridge catastrophe in Baghdad, in September 2005. Methods: Nine patients presented to the nephrology department of the Baghdad Teaching Hospital with a suggestive history of crush and laboratory evidence of rhabdomyolysis and acute kidney injury within the first three weeks of this tragic event. All patients were treated initially with aggressive fluid resuscitation with isotonic normal saline and bicarbonate. However, eight patients required acute peritoneal dialysis that was followed by intermittent hemodialysis, while only one received watchful conservative treatment with intravenous fluid support. Results: All patients achieved complete recovery of their clinical status and renal function and discharged within a period of 8 to 30 days. Conclusion: Crush syndrome is common. Early detection, aggressive fluid support still the main aspect of management. Correction of electrolytes abnormalities beside the judicious decision of dialysis initiation are also important in the management of this potentially life threatening situation.


Castle Hangnail needs a new master or mistress to boss around the minions and terrorize the realm, but those minions aren't convinced that twelve-year-old sweetheart Molly is the right one for the job, even if she is carrying one of their invitations. It turns out that she stole it, though that fact isn't revealed until well after she has already completed most of the tasks required to get the castle up to snuff, and after the staff has already fallen in love with her. What Molly lacks in true evil, she makes up for with her sharp wit, cleverness, and willingness to see bad guys get their due; these traits ably compensate for her youth and for her core of goodness, which startles the minions who were pretty certain up until now that if they aren't being tormented, then they weren't doing their jobs. The plot neatly gets the parents out of the way, giving Molly free and unsupervised rein and allowing readers to live vicariously through a girl who is pampered by minotaurs, animated armor, and various other cool, slightly spooky characters. The drafty castle is carefully described in ways that highlight the personality and mystery such a location can offer, becoming a character in itself that creaks and sighs, houses bats and moles and misfits, and serves as a true icon of magic for the area. Frequent black and white illustrations mostly add humor, keeping the scarier elements tolerable for skittish readers. Fans of Ibbotson and Vande Velde will be right at home with this novel, and all readers will likely hope that Molly returns for more adventures now that she's truly earned her place. AS


Cystic fibrosis (CF) is a fatal genetic disease that affects 1/2500 people in the UK. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause dehydration of mucosal membranes, leading to mucus obstruction of the small airways. The CF lungs are susceptible to recurrent infection promoting chronic neutrophilic inflammation. Neutrophils recruited to the CF lungs become dysfunctional and are ineffective at clearing pathogens, perpetuating inflammation. Neutrophil serine proteases (NSPs) released by neutrophils collaterally remodel the airway, reducing lung function and causing mortality.
The complement anaphylatoxins (C5a and C3a) are important mediators of inflammation. C5a and C3a are chemotactic for monocytes and granulocytes, they also stimulate degranulation and the generation of reactive oxygen species (ROS). C5a is particularly potent towards neutrophils and is critical for orchestrating their response towards pathogens. C5a and C3a are elevated in the CF airway. Furthermore, in addition to complement activation these anaphylatoxins can be generated by non-complement proteases including NSPs. The mechanisms by which C5a and C3a promote chronic neutrophilic inflammation in the CF airways are not fully understood.
In my study I show that C5a and C3a correlate with markers of neutrophilic inflammation (neutrophil count and CXCL8) in bronchoalveolar lavage (BAL) fluid from paediatric CF patients. I further characterise the generation of functionally active C5a-like and C3a-like forms by NSPs. Moreover, I demonstrate that atypical C5a production by NSPs cannot be prevented by therapeutic complement inhibitors. I show for the first time that NSP-generated C5a-like fragments are resistant to inactivation by carboxypeptidase B, an important regulator of C5a activity.
I also further characterise the interaction between C5a and soluble glycosaminoglycans (GAGs), these are abundant during chronic neutrophilic inflammation of the CF airway. Additionally, I show that GAG interaction influences C5a activity. In conclusion, the CF airway environment modifies C5a function; these mechanisms could promote chronic neutrophilic inflammation.


Abstract The pre-Cenozoic kinematic and tectonic history of the Arctic Alaska Chukotka (AAC) terrane is not well known. The difficulties in assessing the history of the AAC terrane are predominantly due to a lack of comprehensive knowledge about the composition and age of its basement. During the Mesozoic, the AAC terrane was involved in crustal shortening, followed by magmatism and extension with localized high-grade metamorphism and partial melting, all of which obscured its pre-orogenic geological relationships. New zircon geochronology and isotope geochemistry results from Wrangel Island and western Chukotka basement rocks establish and strengthen intra- and inter-terrane lithological and tectonic correlations of the AAC terrane. Zircon U–Pb ages of five granitic and one volcanic sample from greenschist facies rocks on Wrangel Island range between 620±6 and 711±4 Ma, whereas two samples from the migmatitic basement of the Velitkenay massif near the Arctic coast of Chukotka yield 612±7 and 661±11 Ma ages. The age spectrum (0.95–2.0 Ga with a peak at 1.1 Ga and minor 2.5–2.7 Ga) and trace element geochemistry of inherited detrital zircons in a 703±5 Ma granodiorite on Wrangel Island suggests a Grenville–Sveconorwegian provenance for metasedimentary strata in the Wrangel Complex basement and correlates with the detrital zircon spectra of strata from Arctic Alaska and Pearya. Temporal patterns of zircon inheritance and O–Hf isotopes are consistent with Cryogenian–Ediacaran AAC magmatism in a peripheral/external orogenic setting (i.e. a fringing arc on rifted continental margin crust).


A new polymorph of oxindole (termed as "δ-form") has been found and characterized by single-crystal X-ray diffraction. Its structural properties were compared with those of the previously reported polymorphs (the α-, β- and γ-forms). This polymorphic form was crystallized for the first time but could not be reproduced. Thus, the δ-form can serve as an example of a "disappearing polymorph". As a result, the three previously reported α-, β- and γ-forms have now been characterized by powder X-ray diffraction, vibrational spectroscopy (infrared and Raman) and calorimetry (differential scanning calorimetry). In the structures of the earlier known α- and β-forms, N–H⋯O hydrogen bonds connect the molecules into dimers, while the crystals of the γ- and δ-forms contain hydrogen-bonded chains of associated molecules. An analysis of the Hirshfeld surfaces and fingerprint plots has also been performed to study the intermolecular interactions in the crystal network of each polymorph. The spectroscopic and thermal investigations showed that the polymorphs convert into the α-form, which indicates that the α-form is the most stable at ambient temperature. Additionally, the α- and β-forms are enantiotropically-related phases, whereas the γ-form is monotropically related to the α-form. Unexpectedly, the β- and γ-forms were found to be unstable under Cu Kα radiation and both gradually transformed into the α-form with the γ-phase being more stable.


This letter presents the outage performance analysis for a cognitive relay network (CRN) with imperfect channel knowledge estimations. Under the condition of imperfect channel state information (CSI) estimations of interference links between primary and secondary systems, especially the links from both secondary transmitter and secondary relays to primary users, the exact outage probability is derived over Rayleigh fading channels and is verified through simulations. The simulation results show that: 1) increasing the number of relays is an effective approach to mitigate the outage performance degradation caused by the imperfect CSI; 2) the imperfect CSI of the secondary transmitter-primary user (PU) link has a greater impact on the outage performance than that of the secondary relay-PU link.


ABSTRACT Vancomycin taper regimens are commonly used for the treatment of recurrent Clostridium difficile infections. One rationale for tapering and pulsing of the dose at the end of therapy is to reduce the selective pressure of vancomycin on the indigenous intestinal microbiota. Here, we used a mouse model to test the hypothesis that the indigenous microbiota that provide colonization resistance against C. difficile and vancomycin-resistant enterococci (VRE) is repopulated during tapering courses of vancomycin. Mice were treated orally with vancomycin daily for 10 days, vancomycin in a tapering dose for 42 days, fidaxomicin for 10 days, or saline. To assess colonization resistance, subsets of mice were challenged with 104 CFU of C. difficile or VRE at multiple time points during and after completion of treatment. The impact of the treatments on the microbiome was measured by cultures, real-time PCR for selected anaerobic bacteria, and deep sequencing. Vancomycin taper-treated mice developed alterations of the microbiota and disruption of colonization resistance that was persistent 18 days after treatment. In contrast, mice treated with a 10-day course of vancomycin exhibited recovery of the microbiota and of colonization resistance by 15 days after treatment, and fidaxomicin-treated mice maintained intact colonization resistance. These findings demonstrate that alteration of the indigenous microbiota responsible for colonization resistance to C. difficile and VRE persist during and after completion of tapering courses of vancomycin.


The field of assisted reproduction has been developed to treat infertility in women, companion animals, and endangered species. In the horse, assisted reproduction also allows for the production of embryos from high performers without interrupting their sports career and contributes to an increase in the number of foals from mares of high genetic value. The present manuscript describes the procedures used for collecting immature and mature oocytes from horse ovaries using ovum pick-up (OPU). These oocytes were then used to investigate the incidence of aneuploidy by adapting a protocol previously developed in mice. Specifically, the chromosomes and the centromeres of metaphase II (MII) oocytes were fluorescently labeled and counted on sequential focal plans after confocal laser microscope scanning. This analysis revealed a higher incidence in the aneuploidy rate when immature oocytes were collected from the follicles and matured in vitro compared to in vivo. Immunostaining for tubulin and the acetylated form of histone four at specific lysine residues also revealed differences in the morphology of the meiotic spindle and in the global pattern of histone acetylation. Finally, the expression of mRNAs coding for histone deacetylases (HDACs) and acetyl-transferases (HATs) was investigated by reverse transcription and quantitative-PCR (q-PCR). No differences in the relative expression of transcripts were observed between in vitro and in vivo matured oocytes. In agreement with a general silencing of the transcriptional activity during oocyte maturation, the analysis of the total transcript amount can only reveal mRNA stability or degradation. Therefore, these findings indicate that other translational and post-translational regulations might be affected. Overall, the present study describes an experimental approach to morphologically and biochemically characterize the horse oocyte, a cell type that is extremely challenging to study due to low sample availability. However, it can expand our knowledge on the reproductive biology and infertility in monovulatory species.


MOS capacitors are fabricated with ultrathin (equivalent oxide thickness, EOT=2.1 nm) atomic layer deposited (ALD) Si-nitride/SiO/sub 2/ stack gate dielectrics annealed in NH/sub 3/ at a moderate temperature of 550/spl deg/C. Excellent performances in the reduction of leakage currents and electrical stress induced degradations are exhibited by these capacitors. An interesting feature of suppressed soft breakdown events is observed in ramped voltage stressing experiments and constant electric field induced time-dependent dielectric breakdown measurements. The capacitors also exhibited excellent interface quality, lower bulk trap density, lower trap generation rate and higher reliability in comparison with the capacitors fabricated with conventional thermal SiO/sub 2/ dielectrics as well as with ALD Si-nitride/SiO/sub 2/ stack dielectrics without NH/sub 3/ annealing. The proposed stack gate dielectric appears to be very promising for ULSI devices.


We consider the problem of controlling an unstable linear plant with Gaussian disturbances over an additive white Gaussian noise channel with an average transmit power constraint, where the signaling rate of communication may be different from the sampling rate of the underlying plant. Such a situation is quite common since sampling is done at a rate that captures the dynamics of the plant and that is often lower than the signaling rate of the communication channel. This rate mismatch offers the opportunity of improving the system performance by using coding over multiple channel uses to convey a single control action. In a traditional, separation-based approach to source and channel coding, the analog message is first quantized down to a few bits and then mapped to a channel codeword whose length is commensurate with the number of channel uses per sampled message. Applying the separation-based approach to control meets its challenges: first, the quantizer needs to be capable of zooming in and out to be able to track unbounded system disturbances, and second, the channel code must be capable of improving its estimates of the past transmissions exponentially with time, a characteristic known as anytime reliability. We implement a separated scheme by leveraging recently developed techniques for control over quantized-feedback channels and for efficient decoding of anytime-reliable codes. We further propose an alternative, namely, to perform analog joint source–channel coding, by this avoiding the digital domain altogether. For the case where the communication signaling rate is twice the sampling rate, we employ analog linear repetition as well as Shannon–Kotel'nikov maps to show a significant improvement in stability margins and linear-quadratic costs over separation-based schemes. We conclude that such analog coding performs better than separation, and can stabilize all moments as well as guarantee almost-sure stability.


Line-field confocal optical coherence tomography (LC-OCT) is a non-invasive optical imaging technique based on a combination of the optical principles of optical coherence tomography and reflectance confocal microscopy with line-field illumination, which can generate cell-resolved images of the skin, in vivo, in vertical section, horizontal section and in three dimensions. This article reviews the optical principles of LC-OCT, including low coherence interferometry, confocal filtering and line-field arrangement. The optical setup allowing for the acquisition of color images of the skin surface in parallel with LC-OCT images, without compromising LC-OCT performance, is also presented. Practical use of LC-OCT is demonstrated through an overview of the workflow of examining a patient using a commercial handheld LC-OCT probe (deepLive™, DAMAE Medical), from creating the patient record in the software, acquiring the images, to reviewing and interpreting the images. LC-OCT can generate a significant amount of data, making automated deep learning algorithms particularly relevant for assisting in the analysis of LC-OCT images. A review of algorithms developed for skin layer segmentation, keratinocyte nuclei segmentation, and automatic detection of atypical keratinocyte nuclei is provided.


The pilot's task in commercial aircraft operations has changed from flying the aircraft by means of manual control, to increased monitoring of the cockpit. The increase of automation provides a high level of stability and reduces variations and disturbances, leaving crews with little exposure to surprise. Current training programs are similarly focused on dealing with anticipated problems and pre-determined responses, provide little opportunity to prepare for the unexpected and unforeseen. In this paper we frame the research agenda for investigating how pilots cope with surprise and confusion in modern aircraft. An interview study with pilots has been carried out, identifying areas for further investigation regarding manual control, procedure applicability, system knowledge and training for unexpected events. A crew-aircraft control model has been developed to frame the functions and processes to be further investigated.1


Cassia fistula is used in Indian traditional medicine as a remedy for various diseases including tumours. The present study has investigated the chemopreventive efficacy of Cassia fistula bark extracts in 7, 12–dimethyl benz(a)anthracene (DMBA) induced hamster buccal pouch carcinogenesis. The mechanistic pathway for its chemopreventive potential was assessed by measuring the status of lipid peroxidation by-products, antioxidants and detoxification enzyme activities in the circulation and tissues of tumour bearing animals. Oral squamous cell carcinoma was developed in buccal pouches of hamsters by painting with 0.5% DMBA, three times a week for 14 weeks. We observed 100% tumour formation in DMBA alone painted animals. Oral administration of Cassia fistula bark extract to DMBA painted animals completely prevented the formation of oral squamous cell carcinoma. The bark extract also restored the status of lipid peroxidation by-products, antioxidants and detoxification enzymes in DMBA painted animals. These results suggest that Cassia fistula bark extract has prominent chemopreventive effect during DMBA induced oral carcinogenesis, which is probably due to the presence of one or more potent anticarcinogenic principles and their synergistic effect. The chemopreventive potential of Cassia fistula may also be due to its antilipid peroxidative, antioxidative and modulation of detoxification agents during DMBA induced oral carcinogenesis.


Unmanned aerial vehicle (UAV) network is a promising technology for assisting Internet-of-Things (IoT), where a UAV can use its limited service coverage to harvest and disseminate data from IoT devices with low transmission abilities. The existing UAV-assisted data harvesting and dissemination schemes largely require UAVs to frequently fly between the IoTs and access points, resulting in extra energy and time costs. To reduce both energy and time costs, a key way is to enhance the transmission performance of IoT and UAVs. In this work, we introduce collaborative beamforming into IoTs and UAVs simultaneously to achieve energy and time-efficient data harvesting and dissemination from multiple IoT clusters to remote base stations (BSs). Except for reducing these costs, another non-ignorable threat lies in the existence of the potential eavesdroppers, whereas the handling of eavesdroppers often increases the energy and time costs, resulting in a conflict with the minimization of the costs. Moreover, the importance of these goals may vary relatively in different applications. Thus, we formulate a multi-objective optimization problem (MOP) to simultaneously minimize the mission completion time, signal strength towards the eavesdropper, and total energy cost of the UAVs. We prove that the formulated MOP is an NP-hard, mixed-variable optimization, and large-scale optimization problem. Thus, we propose a swarm intelligence-based algorithm to find a set of candidate solutions with different trade-offs which can meet various requirements in a low computational complexity. We also show that swarm intelligence methods need to enhance solution initialization, solution update, and algorithm parameter update phases when dealing with mixed-variable optimization and large-scale problems. Simulation results demonstrate the proposed algorithm outperforms state-of-the-art swarm intelligence algorithms.


We extend the existing theoretical model for determining the characteristic features of magnetic deflagration in nanomagnet crystals. For the first time, all energy levels are accounted for calculation of the the Zeeman energy, the deflagration velocity, and other parameters. It reduces the final temperature and significantly changes the propagation velocity of the spin-flipping front. We also consider the effect of a strong transverse magnetic field, and show that the latter significantly modifies the spin-state structure, leading to an uncertainty concerning the activation energy of the spin flipping. Our front velocity prediction for a crystal of Mn-12 acetate in a longitudinal magnetic field is in much better agreement with experimental data than the previous reduced-model results.


With the increasing availability of spatially referenced health data over long period of times, it urges different methods to detect missing opportunities contained in them can be utlised to learn more about epidemiology of diseases. This thesis presents different methods of spatiotemporal analysis over health data and considers three different datasets. The three main parts of this thesis covers different applications of spatiotemporal analyses on three major health datasets: official tuberculosis data in Portugal, Surveillance, Epidemiology and End Results Program data and National Health Service open prescribing data. All statistical inferences are mainly based on the Bayesian framework including both exact and approximating methods. The first main contribution uncovered the sub-regional epidemiology of tuberculosis from 2000-2013 in Lisbon and Oporto Metropolitan Areas in Portugal. The analysis provided a Poisson mixed effect model approach on tuberculosis in Portugal at a finer geographical scale compared to past researches. Such model includes both spatial and temporal correlated effects, interaction terms and unstructured random effects. The inference is based on the Integrated Nested Laplace Approximation method. The analysis revealed that having adjusted to known risk factors based on previous research, there are still spatial clusters in both Metropolitan areas with similar but not identical temporal trends. High incidences are more focused around poverty zones which are not necessarily high population density areas. The second interest of this thesis falls in the area of survival studies. A two-way Bayesian spatiotemporal hazard model is introduced in the second main part of this thesis. This is a novel extension which resolves the ignorance of real calendar time when subjects enter the study by including it as a secondary timescale, on top of random effects. In many previous studies, the main interest focuses on the survival duration of study subjects and the time of entry is often eliminated, especially in hazard models. This is not always a suitable assumption when the study is carried over an extended period of time, e.g. decades. Such two-way spatial survival model knits the problem into a 3-dimensional one where both timescales and spatial random effects are considered at the same time. Even though the application of the model over breast cancer in New Mexico from the Surveillance, Epidemiology and End Results program did not present as satisfying results. Supported by simulation studies, the two-way spatial survival model does respect the fact that data are accumulated over time and in that sense, treats the data in a more natural way. It should still provide a different and more natural way to approach long-term data and allow comparisons of different behaviours between; for example population-based cancer registries. The last contribution of this thesis concentrates on the modelling of general practice (GP) open prescribing data. This source of data constitutes a rich time series covering drugs prescribed by all general practitioners across England. The full potential of such a source of data has not been exploited. The ultimate goal for this project is to detect missing opportunities in such open-source data to learn about the epidemiology of a disease. In this part of the thesis, we focused on the pregabalin prescribing data at both GP and Clinical Commissioning Group(CCG)-level across England. The work demonstrated a clear North-South divide in behaviour of pregabalin prescriptions adjusting for spatial effects and deprivation at units of milligrams. This shows that the cause of higher prescribing rate of pregabalin in the North is not just caused by higher deprivation rate. Temporal trend developed differently within each CCG and among GPs, some of which showed an increasing trend.


The need for antiviral drugs is real and relevant. Broad spectrum antiviral drugs have a particular advantage when dealing with rapid disease outbreaks, such as the current COVID-19 pandemic. Since viruses are completely dependent on internal cell mechanisms, they must cross cell membranes during their lifecycle, creating a dependence on processes involving membrane dynamics. Thus, in this study we examined whether the synthesis of glycosphingolipids, biologically active components of cell membranes, can serve as an antiviral therapeutic target. We examined the antiviral effect of two specific inhibitors of GlucosylCeramide synthase (GCS); (i) Genz-123346, an analogue of the FDA-approved drug Cerdelga®, (ii) GENZ-667161, an analogue of venglustat which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit the replication of four different enveloped RNA viruses of different genus, organ-target and transmission route: (i) Neuroinvasive Sindbis virus (SVNI), (ii) West Nile virus (WNV), (iii) Influenza A virus, and (iv) SARS-CoV-2. Moreover, GCS inhibitors significantly increase the survival rate of SVNI-infected mice. Our data suggest that GCS inhibitors can potentially serve as a broad-spectrum antiviral therapy and should be further examined in preclinical and clinical trial. Analogues of the specific compounds tested have already been studied clinically, implying they can be fast-tracked for public use. With the current COVID-19 pandemic, this may be particularly relevant to SARS-CoV-2 infection. One Sentence Summary An analogue of Cerdelga®, an FDA-approved drug, is effective against a broad range of RNA-viruses including the newly emerging SARS-CoV-2.


The signal transducer and activator of transcription (STAT) 5b is a universal transcription factor that plays key biological roles in allergic diseases, immunodeficiencies, autoimmunities, cancers, hematological diseases, growth disorders, and lung diseases. The identification of distinct pathological manifestations of STAT5b deficiency in humans has highlighted the critical role of the STAT5b pathway. Proper gene transcription at IL-2R α, FOXP3, Bcl-2, and growth hormone (GH) associated loci are thought to be associated with normal STAT5b transcriptional activity. These genes are thought to play important roles in allergy/autoimmunity, immunodeficiency, cancer/anemia, and growth, respectively. The STAT5A and STAT5B genes are collocated on 17q11. Although these two monomeric proteins exhibit peptide sequence similarities of >90%, it is known through observations of STAT5b deficient subjects that STAT5a and STAT5b are not fully redundant in humans. Patients with STAT5b deficiency have decreased numbers of regulatory CD4+CD25high T cell (Treg) despite their STAT5a levels being normal. Prior studies on STAT5b deficient subjects have revealed immunological aberrations associated with the following disease phenotype: modest lymphopenia and decreased populations of Treg, γ−δ T cells, and natural killer (NK) cells. Most subjects with STAT5b deficiency show severe eczema, and autoimmune disease (juvenile idiopathic arthritis, autoimmune thyroiditis, idiopathic thrombocytic purpura) which are thought to be associated with Treg dysfunction. We will review the likely pathophysiological mechanisms associated with STAT5b deficiency.


Two Fagus sylvatica L. stands with different Leaf Area Index and similar planophile Leaf Angle Distribution were created with L-systems based plant growth software and rendered using both Lambertian and Bousquet's model leaf Bidirectional Reflectance Distribution Function (BRDF) assumption. During the simulation process the sun was positioned at three different zenith angles, namely 10°, 30°, and 60°. The sensor azimuth angles, for each case, ranged from 0° to 315° in 45° increments while the view zenith angles were 0°, 20° and 40°. The forest stands were rendered with the Physically Based Ray Tracer (PBRT) algorithm introducing in each case the Lambertian or the Bousquet BRDF approximation. This set-up enabled a direct reflectance comparison of the two approximations. It was found that the common assumption of Lambertian leaf BRDF input in a global canopy illumination scenario overestimated the reflectance in the visible part of the electromagnetic spectrum. However, in the infrared part we can assume that the Lambertian approximation of leaf BRDF can accurately simulate the light reflectance in a canopy stand. Similarly in this case study both rendering approaches provided equal values for the Normalized Difference Vegetation Index (NDVI) while differed greatly for the Photochemical Reflectance index (PRI).


We show that viewing graphs as sets of node features and incorporating structural and positional information into a transformer architecture is able to outperform representations learned with classical graph neural networks (GNNs). Our model, GraphiT, encodes such information by (i) leveraging relative positional encoding strategies in self-attention scores based on positive definite kernels on graphs, and (ii) enumerating and encoding local sub-structures such as paths of short length. We thoroughly evaluate these two ideas on many classification and regression tasks, demonstrating the effectiveness of each of them independently, as well as their combination. In addition to performing well on standard benchmarks, our model also admits natural visualization mechanisms for interpreting graph motifs explaining the predictions, making it a potentially strong candidate for scientific applications where interpretation is important. Code available at https://github.com/inria-thoth/GraphiT.


A set of fundamental cognitive processes of the brain is formally described in this paper. The cognitive processes defined at the meta cognitive level of the layered reference mode of the brain (LRMB) encompass those of object identification, concept establishment, categorization, comparison, qualification, quantification, selection, and search. Real-time process algebra (RTPA) is adopted as the denotational mathematical means for rigorous modeling and describing the meta cognitive processes. The mathematical model of each meta process is created and modeled in RTPA. All cognitive models and processes are explained on the basis of the object- attribute-relation (OAR) model for internal information and knowledge representation and manipulation.


Abstract Knowledge about how the type, timing, and arrangement of cultural practices influence weed species composition is important for understanding the ecological results of control strategies and designing alternative crop management systems. We evaluated weed seed density, diversity, and community composition from 1997 to 1999 in a 35-yr-old study comparing cropping sequences (continuous corn, corn–soybean, corn–oat–hay) and tillage systems (conventional, minimum, and no-tillage) in Wooster, OH. Weed seedbank diversity, as measured by species richness (S), evenness (J), and the Shannon–Weiner index (H′), was influenced by crop diversity; mean values for each of the indices were generally higher for all combinations of the three-crop sequence than for the corn monoculture or the corn–soybean rotation. Except for 1998, mean seed density (to a depth of 10 cm) was higher in continuous corn (x̄ = 5,220 m−2) than in corn and soybean rotations (x̄ = 2,360 m−2). Species richness and seed density were also affected by tillage. Mean values for S (x̄ = 10.8 species) and mean germinable seeds (x̄ = 5,960 m−2) were greatest in the no-tillage system, where the soil was disturbed only by the coulter units of the planter. Differences in weed seedbank community composition among tillage and rotation treatments were examined using two multivariate analyses. Using a multiresponse permutation procedure and canonical discriminant analysis, results suggest that the weed seed community in a corn–oat–hay rotational system differs in structure and composition from communities associated with continuous corn and corn–soybean systems. Additionally, germinable weed seed communities in no-tillage differed in composition from those in conventional and minimum tillage. Crop sequence and tillage system influenced weed species density and diversity and therefore community structure. Manipulation of these factors could help reduce the negative impact of weeds on crop production. Nomenclature: Oat, Avena sativa L.; soybean Glycine max L. Merr.; alfalfa, Medicago sativa L.; corn, Zea mays L.


The study of women's historiography worldwide, historically, was largely neglected until the feminist movement advocated for the inclusion of women's contributions to world history. The inclusion of 'women and gender' studies in Egyptology commenced in the late 1980's, however, the predominance of literature pertains to the Pharaonic period. To date, little concentrated analysis dedicated to the women of Early Dynastic period (3150 – 2890 BC) has been undertaken. The thesis investigates the roles of the women in the early Egyptian society, through the examination of the biographic details recorded on their funerary monuments. The multi-disciplinary investigation combines a textual, and a new sociological approach, to the women's titles recovered from the cemeteries of Abydos, Abu Rawash and Helwan. The evaluation into the previous scholarship regarding the titles uncovers androcentric characterisation of the women as concubines associated with the harem, which has masked the women's participation in the society. The textual analysis re-evaluates the titles objectively and situates the women's involvement contextually, providing new insight into the society of Early Dynastic Egypt. The study offers an anthology of the women's Early Dynastic stelae that provides a framework for the developments and changes to women's roles throughout the different period of Egyptian history.


Cohort analysis of life span in a uniform LIO rat population established a correlation between death cause and age-related death force parameters. It also demonstrated certain sex-related differences involved. The life span of males which had tumors at the time of death, whatever the real cause of death, was significantly longer than that in tumor-free animals. The life span of tumor-free females and those which died from cancer was shorter while the longest-surviving group bore non-fatal tumors. It is suggested that prognosis of individual survival be based on a combination of traditional procedures of mathematical evaluation of population mortality rates and complex assessment of individual health. This approach envisages formation of cohorts characterized by maximum differences in aging dynamics.


Abstract At high temperature, coarse-grained (bulk) rutile is well established as the stable phase of TiO2, and nanophase anatase, thermodynamically stable relative to nanophase rutile, transforms irreversibly to rutile as it coarsens. The lack of experimental heat-capacity data for bulk anatase below 52 K lends uncertainty to its standard entropy and leaves open a slight possibility that anatase may have a thermodynamic stability field at low temperature, as suggested by some theoretical calculations. In the present study, the molar heat capacities of rutile and anatase were measured from 0.5 K to about 380 K. These data were combined with previously measured high-temperature heat capacities, and fits of the resulting data set were used to generate CP°,m, Δ0TSm°, Δ0THm°, and Δ0TGm° values at smoothed temperatures between 0.5 and 1300 K for anatase and 0.5 and 1800 K for rutile. Using these new data and the enthalpy of transformation between anatase and rutile at 298 K, the change in Gibbs free energy for the transition between anatase and rutile from 0 to 1300 K was calculated. These calculations reveal that the transformation from bulk anatase to bulk rutile is thermodynamically favorable at all temperatures between 0 and 1300 K, confirming that bulk anatase does not have a thermodynamic stability field. Implications for the natural occurrence of these two minerals in terrestrial, lunar, and planetary settings are discussed. In particular, anatase requires low-temperature aqueous conditions for its formation and may be a reliable indicator of such conditions in both terrestrial and extraterrestrial settings.


Wireless Sensor Networks with Mobile Sinks (WSN-MSs) are considered a viable alternative to the heavy cost of deployment of traditional wireless sensing infrastructures at scale. However, current state-of-the-art approaches perform poorly in practice due to their requirement of mobility prediction and specific assumptions on network topology. In this paper, we focus on low-delay and high-throughput opportunistic data collection in WSN-MSs with general network topologies and arbitrary numbers of mobile sinks. We first propose a novel routing metric, Contact-Aware ETX (CA-ETX), to estimate the packet transmission delay caused by both packet retransmissions and intermittent connectivity. By implementing CA-ETX in the defacto TinyOS routing standard CTP and the IETF IPv6 routing protocol RPL, we demonstrate that CA-ETX can work seamlessly with ETX. This means that current ETX-based routing protocols for static WSNs can be easily extended to WSN-MSs with minimal modification by using CA-ETX. Further, by combing CA-ETX with the dynamic backpressure routing, we present a throughput-optimal scheme Opportunistic Backpressure Collection (OBC). Both CA-ETX and OBC are lightweight, easy to implement, and require no mobility prediction. Through test-bed experiments and extensive simulations, we show that the proposed schemes significantly outperform current approaches in terms of packet transmission delay, communication overhead, storage overheads, reliability, and scalability.


Results of no-choice and choice feeding tests against Bandicota bengalensis showed that bromethalin is highly toxic and efficacious rodenticide. However, its susceptibility differed between sexes. In no-choice test minimum time of cent-percent mortality was 1.2 days (range 1-2). The amount of toxicant consumed per rat resulting in complete mortality was 4.92±0.78 and 5.09±0.22 mg/kg in female and male rats respectively. In choice tests, mean days to death was 2.1 (range 1-4 days) and the amount of toxicant consumed per rat averaged 5.56±0.30 mg/kg. The latency period exceeded 210 minutes of the poisoning.


Abstract
In mid-1969 a regional outbreak of bacillary dysentery extended into El Salvador from neighboring Guatemala and Honduras. The etiologic agent was Shigella dysenteriae type 1; epidemic strains from El Salvador had antibiotic-resistance patterns identical to those of strains previously isolated in Guatemala. The areas first affected were the Departments of Ahuachapan, which is contiguous with Guatemala to the northwest, and Chalatenango, which borders Honduras to the north. Subsequently, cases of severe dysentery developed in all 14 departments of El Salvador with a general pattern of spread from north to south along main routes of commerce. The continued increase in cases late in 1969 and early in 1970 indicated that the epidemic would continue, since such contributing factors as overcrowding and poor sanitation remained unchanged. Infants seemed to be at greatest risk of severe illness and death. Similarly high attack rates in older children and adults suggest that the population was uniformly susceptible to this organism. Confusion about the etiology contributed to the high mortality rate: treatment at first was limited to antiamebic therapy and ineffective antimicrobial agents. The case-fatality ratio dropped wherever adequate antibiotic and fluid therapy were employed.


The study of technology and societal challenges is a growing area in information systems research. This paper explores how social movements can use virtual worlds to raise awareness or create safe spaces for their members. As social movements move into virtual worlds, the technical environment becomes more important. This paper presents an interpretive field study using netnographic research and empirical data from a study of a lesbian, gay, bisexual, and transgender social movement in World of Warcraft. This paper takes the position that an understanding of affordances is required for users to be able to create convivial outcomes to shape the use of virtual worlds for their own goals and intentions. The paper presents the concept of convivial affordances, which brings together the theories of affordances and conviviality, and suggests that social users can shape IT artefacts through a creative combination of affordances for their specific goals, and with community involvement.


Temperature plays a vital role in the machining industry today. A Nickel-Chrome versus Nickel-Silicon thin-film thermocouple system has been established for measuring instantaneous workpiece temperature in chemical explosive material machining. The NiCr/NiSi thin-film thermocouples have been deposited inside high speed steel cutters by magnetron sputtering. The typical deposition conditions are summarized. Static and dynamic calibrations of the NiCr/NiSi thin-film thermocouples are presented. The Seebeck coefficient of the TFTC is 40.4 μV/°C which is almost the same as that of NiCr/NiSi wire thermocouple. The response time is about 0.42ms. The testing results indicate that the developed NiCr/NiSi thin-film thermocouple sensors can respond fast enough to catch the very short temperature pulse and perform excellently when machining chemical explosive material in situ.


Computer-assisted text coding can facilitate the analysis of large text collections. To evaluate the functionality of providing an analyst with a ranked list of suggestions for suitable text codes, we used a data set of discussion posts, which had been manually coded for reasons given for taking a stance on the topic of vaccination. We trained a logistic regression classifier to rank these reasons according to the probability that they would be present in the post. The approach was evaluated for its ability to include the expected reasons among the n top-ranked reasons, using an n between 1 and 6. The logistic regression-based ranking was more effective than the baseline, which ranked reasons according to their frequency in the training data. Providing such a list of possible codes, ranked by logistic regression, could therefore be a useful feature in a tool for text coding.


While the range of systemic complications causing death after aortic surgery is well documented, the incidence is not. A study was undertaken to determine the incidence of systemic postoperative complications and the operative mortality of patients undergoing elective aortic surgery in a hospital that caters to a homogeneous population group. Records of 557 patients who had undergone aortic bypass or aneurysm replacement surgery over an 8-year period were studied at Addington Hospital, Durban. All had placement of a prosthetic fabric graft, 188 (33%) for aortic aneurysm replacement. Men made up 56% of the patients and the average age was 66 years. Standard selection criteria and peri-operative management were employed in all cases. All patients were classified according to the Goldman scoring system. There were significant systemic complications in 48 patients (8.6%), with 23 (4%) deaths. Respiratory complications were the most frequent (2.9%) followed by gastro-intestinal complications. (2.9%) followed by gastro-intestinal complications. The most frequent causes of death were cardiac arrest (20%) and gastro-intestinal malfunction, mainly bowel infarction. Only 3 patients developed acute renal failure in isolation but all died. When age was analysed as a factor in the causation of morbidity, there was an appreciably lower complication rate in patients under 50 years, but this reached a plateau in the 6th decade. The overall mortality and morbidity rates were acceptable. It would appear that age is weighted too heavily in the Goldman scoring system, although these criteria have reduced the incidence of cardiac complications.


Food's place on the urban, municipal agenda has become an increasing focus in the emergent fields of food policy and food planning, whose leaders argue that food needs to be more explicitly added to the urban agenda. Yet, public food markets are a food system activity that municipal governments have been long engaged in. Reports from leading health, planning, and food organizations assert that farmers markets—the dominant form of public retail food markets in the US today—should be explicitly included in zoning and other municipal codes to ensure that they can be created and sustained. Despite their popularity as a local sustainable food system and healthy food access strategy, it is unclear whether markets have been codified through municipalities' planning and policy instruments, and research has largely not addressed this topic. This study aims to elicit whether markets have been codified into law, focusing on US municipal charters, codes and zoning ordinances, using Michigan, an upper Midwest state, as a case. After analyzing municipal documents to determine whether and where markets have been codified into law in ninety Michigan cities, this study concludes that markets are highly underrepresented in municipal policy, rarely defined in code, and mostly absent from zoning ordinances, even among those cities with currently operating markets. Market presence in code is, however, associated with the presence of historically operated markets. These findings raise questions about why markets are missing from codified food policy and what risks this poses to the future of markets. They also highlight the need to better document the market sector and underline the importance of including historic perspectives when examining the efficacy of current food policy efforts.


Creativity: a word often associated with fun, colour and play, a sentiment reflected in companies attempting to recreate it for profit. Exhibitions like the Wondr Experience litter their spaces with similar childlike aesthetics, with the superficial goal of fostering creativity, but resulting in the true aim of an endless stream of identical Instagram posts and more ticket sales. This paper reveals a darker and more authentic side to creativity, proposing that discomfort is an essential ingredient. Juxtaposing the cute spaces for 'plandids' and the bean bags and beer fridges of office spaces jumping on the hype, the study reveals that to engage in creative thought you have to be in a state of apprehension. Graphic designers often follow the security of grids designed by the likes of Josef Müller-Brockman, however the piece suggests that this kind of work is within the realms of comfort. This tendency for playing it safe is possibly because of the consumerist society we live in – not many designers can afford to take risks because failure means no paycheck. In this way, the paper ends with the suggestion that due to the culture we are in, creativity is observed as an act of rebellion.


Aspects of electronic part-cooling techniques applicable to 300-500°C equipments are presented. Contrary to some beliefs, the minimization of thermal resistance at these temperatures is as important as at lower temperatures. The significant shifts in the natural modes of heat transfer which occur with high-temperature electronic parts are outlined, together with some recommended methods of cooling high-temperature parts and assemblies.


Groups of nymphal Rhipicephalus appendiculatus Muguga, having a mean of 1 or 9 Theileria parva Muguga-infected salivary gland acini per tick, were kept under quasi-natural conditions at an altitude of 1950 m or 20°C at a relative humidity of 85% in the laboratory and their survival and infection prevalence and abundance determined over time. Theileria parva infections for both categories of ticks survived in the nymphal ticks for 50 or 26 weeks post salivary gland infection under quasi-natural or laboratory conditions respectively. There was a distinct decline in infections in the more heavily infected nymphae under both conditions of exposure, reflecting an apparent density dependence in parasite survival. Nymphal ticks having an average infection level of 1 infected salivary gland acinus per tick, survived for up to 69 or 65 weeks post-repletion under quasi-natural or the laboratory conditions respectively. Nymphae having an average infection level of 9 infected salivary gland acini per tick survived for a similar duration under each of the 2 conditions. The infection level of 9 infected salivary gland acini per tick did not seem to significantly affect the survival of the tick vector compared to those having an average of 1 infected salivary gland acinus per tick.


Breast cancer is the second leading cause of cancer death among women. One in eight women will be diagnosed with breast cancer in their life period .There are several risk factors for progress of carcinogen cell. Zinc and lead have crucial role in oxidative stress and changes in their level can enhance progress of carcinogen cells. The purpose of this study is to discover the level of zinc and lead in plasma of breast cancer patients. One hundred numbers with breast carcinoma diagnosis was confirmed by pathological samples and the results were compared with standard values and amount of these elements was observed in the blood by atomic absorption.  Zinc plasma level in patients was found to be 50.59 + 4.72 (μg/dl) with p value of p=0.003 which is lower than standard value (80 μg/dl). On the other hand, the plasma lead level was identified to be 6.24 + 1.173(μg/dl) in patients and zero in the standard value. According to the observation, breast cancer patients had a higher lead level than standard value and lower zinc level.  Zinc acts as an important free-radical scavenger to protect cells and deficiency of that can increases progress of carcinogen cells. Therefore, use of trace elements and also the chelators of heavy metals are necessary to prevent breast cancer in high risk individuals.


1) Smooth pursuit eye movements (SPEM) were recorded in 18 normal, 20 schizophrenic and 50 epileptic subjects. Most of the schizophrenic and epileptic subjects were under medication, antipsychotic drugs in the former and antiepileptic drugs in the latter. 2) In schizophrenics and epileptics, rate of the saccadic component in SPEM was higher than that of normal controls. The rate of large amplitude saccades was higher in epileptics than in schizophrenics. 3) Though small amplitude saccades were usually superimposed on SPEM in schizophrenic patients, both large and small amplitude saccades superimposed irregularly on the smooth tracking curve were observed in epileptics, and overshoots or undershoots were also seen frequently. 4) SPEM disorder in epileptics was observed in more than half of patients receiving antiepileptic medication, especially in patients with a long period of treatment. SPEM disorder in epileptics tended to occur frequently in patients who received phenytoin in doses higher than a certain level; i.e. approximately 150 mg per day for a long period of time. 5) It is conceivable that the SPEM disorder represents a latent or subclinical cerebellar dysfunction due to phenytoin medication. It is suggested that the SPEM measurement is a useful tool to find out subclinical side effects of antiepileptic drug in the treatment of epilepsy.


Bromodomain inhibitors have been reported to activate HIV-1 transcription in vitro, but their effect on activation of HIV-1 reservoirs during cART in vivo is unclear. We found that BETi (I-BET151) treatment reactivated HIV-1 gene expression in humanized mice during suppressive cART. Interestingly, I-BET151 preferentially reactivated HIV-1 gene expression in monocytic cells, but not in CD4 T cells, in cART-treated mice. Furthermore, I-BET151 significantly increased HIV-1 transcription in monocytic cells, but not in HIV-1-infected CD4 T cells, via CDK2-dependent mechanisms. Our findings suggest that BETi can preferentially activate monocytic HIV-1 reservoir cells and that a combination of reservoir activation agents targeting different cell types and pathways is needed to achieve reactivation of different HIV-1 reservoir cells during cART. ABSTRACT Combination antiretroviral therapy (cART) effectively suppresses HIV-1 replication and enables HIV‑infected individuals to live long, productive lives. However, the persistence of HIV-1 reservoirs of both T and myeloid cells with latent or low-replicating HIV-1 in patients under cART makes HIV-1 infection an incurable disease. Recent studies have focused on the development of strategies to activate and purge these reservoirs. Bromodomain and extraterminal domain proteins (BETs) are epigenetic readers involved in modulating gene expression. Several bromodomain inhibitors (BETi) are reported to activate viral transcription in vitro in HIV-1 latency cell lines in a P-TEFb (CDK9/cyclin T1)-dependent manner. Little is known about BETi efficacy in activating HIV-1 reservoir cells under cART in vivo. Here we report that a BETi (I-BET151) efficiently activated HIV-1 reservoirs under effective cART in humanized mice in vivo. Interestingly, I-BET151 during suppressive cART in vivo activated HIV-1 gene expression only in monocytic cells and not in CD4+ T cells. We further demonstrate that BETi preferentially enhanced HIV-1 gene expression in monocytic cells rather than in T cells and that whereas CDK9 was involved in activating HIV-1 by I-BET151 in both monocytic and T cells, CDK2 enhanced HIV-1 transcription in monocytic cells but inhibited it in T cells. Our findings reveal a role for CDK2 in differential modulation of HIV-1 gene expression in myeloid cells and in T cells and provide a novel strategy to reactivate monocytic reservoirs with BETi during cART. IMPORTANCE Bromodomain inhibitors have been reported to activate HIV-1 transcription in vitro, but their effect on activation of HIV-1 reservoirs during cART in vivo is unclear. We found that BETi (I-BET151) treatment reactivated HIV-1 gene expression in humanized mice during suppressive cART. Interestingly, I-BET151 preferentially reactivated HIV-1 gene expression in monocytic cells, but not in CD4 T cells, in cART-treated mice. Furthermore, I-BET151 significantly increased HIV-1 transcription in monocytic cells, but not in HIV-1-infected CD4 T cells, via CDK2-dependent mechanisms. Our findings suggest that BETi can preferentially activate monocytic HIV-1 reservoir cells and that a combination of reservoir activation agents targeting different cell types and pathways is needed to achieve reactivation of different HIV-1 reservoir cells during cART.


The concentration of the sand inside the flowlines can directly affect the magnitude of erosion in various pipelines and pipe fittings components. The erosion models available in the literature suggest that the relationship between erosion and sand concentration is linear. Furthermore, some authors believe that for a volume concentration of sand approximately below 0.75% by volume (corresponding to about 2% by mass in liquid), the effects of sand concentration on the rate of erosion are minimal. However, one could ask how this limitation on the amount of sand concentration varies in various geometries as the local concentration at the location where the sand particles are impacting can change within a flow geometry and how this can affect the maximum local erosion rates. Therefore, the sand concentration distributions inside a vertical pipe and two elbows in series for liquid-solid and liquid-gas-solid flows are examined in this investigation by CFD simulations and experimentally. Experiments are performed in a facility with two vertical pipe sections (101.6 mm reducing to a 50.8 mm inner pipe diameters) and immediately after the first and second elbows (50.8 mm inner pipe diameter) from the inner to the outer diameter of the elbows. The concentration distributions are associated with erosion measurement results in both the first and the second elbows. Finally, the CFD simulations of the corresponding experiments in liquid-sand and liquid-gas-sand flows are conducted and compared with the experimental erosion patterns and magnitude as well as various concentration distributions.