In Turkey, canine hepatozoonosis is an emerging infection with a large number of cases detected during the past five years. In the present study, serum zinc, copper and iron concentrations of dogs infected with Hepatozoon canis were measured for the first time. Compared to the controls (n = 10), serum zinc and iron concentrations in infected animals (n = 14) decreased significantly (p < 0.05 and p < 0.01, respectively), whereas the concentrations of copper in diseased animals increased significantly (p < 0.05). In conclusion, the results of the present study indicate that Hepatozoon canis infection may cause alterations in serum zinc iron and copper concentrations. Furthermore, in the treatment of infected animals addition of zinc and iron to the ration of infected animals should be taken into consideration. Hepatozoonozis, dog, trace minerals


Background : The inverse relationship between low to moderate alcohol consumption and several favorable health outcomes has been well established in many epidemiological studies and meta-analyses. However, several questions still remain controversial. Aims : To discuss a number of open questions relating to the healthy effect of a moderate intake of alcohol (especially wine) on cardiovascular disease and total mortality. This will be based on findings from the literature, with a particular emphasis on meta-analyses. Results and Conclusion : The role of different alcoholic beverages, age and sex, confounding, former drinkers and study design has been discussed. Whether wine is better than beer or spirits, though suggestive, remains to be established. Cardiovascular morbidity and total mortality is significantly reduced both in men and women who are regular drinkers of low amounts of alcohol; however, the predicted protection in women disappears at lower doses than in men. The primary protection of alcohol decreases after adjustment for known variables, thus confirming the importance of confounding in assessing drinking effects, but it remains significant and of undoubted public health value. As the cardiovascular protection by moderate alcohol consumption might have been unduly overestimated by inclusion in control groups of former drinkers, we compared studies that used as a reference group the category of no alcohol intake and/or formally excluded former drinkers with studies which did not: the protection was indeed somewhat lower in the former than in the latter studies, but was still statistically significant. We conclude that the dose-response relationship between alcohol intake and cardiovascular risk or total mortality, consistently described by J-shaped curves, can be reasonably attributed to a combination of both real beneficial (at lower doses) and harmful (at higher doses) effects of alcohol or wine consumption.


OBJECTIVE
To determine whether triamcinolone acetonide diffuses from the distal interphalangeal joint (DIPJ) to the navicular bursa, diffusion is direct or systemic, and addition of sodium hyaluronan has an effect on diffusion in horses.

ANIMALS
11 adult horses without forelimb lameness.

PROCEDURES
1 randomly chosen forelimb DIPJ of each horse received an injection of 10 mg of triamcinolone acetonide plus 20 mg of sodium hyaluronan (group 1), and the contralateral forelimb DIPJ received an injection of 10 mg of triamcinolone acetonide plus 2 mL of lactated Ringer's solution (group 2). Synovial fluid samples were taken from both forelimb navicular bursae and 1 hind limb navicular bursa (systemic control group) at 6 hours. Triamcinolone acetonide concentrations in synovial fluid were quantified by use of high-performance liquid chromatography plus tandem mass spectrometry. Data were logarithmically transformed, and contrast analysis was performed on the 3 groups.

RESULTS
Triamcinolone acetonide was detected in navicular bursal samples in all groups. Groups 1 and 2 had significantly greater concentrations of triamcinolone acetonide than the systemic control group. There was no significant difference between groups 1 and 2.

CONCLUSIONS AND CLINICAL RELEVANCE
Triamcinolone acetonide diffused directly from the DIPJ into the navicular bursa in clinically normal horses, and diffusion was not affected by addition of hyaluronan. Injection into the DIPJ with triamcinolone acetonide or a triamcinolone acetonide-hyaluronan combination can potentially be used for treatment of navicular syndrome, but further studies are needed to determine whether triamcinolone acetonide diffuses similarly in horses with navicular syndrome.


Abstract Internalized oppression is the primary means by which all of us hold on to, 'agree' and re-enact our unresolved and repressed difficulties. This paper will examine this particular phenomenon with specific regard to black and white relations in workplace contexts. The reality of prevailing external and internal issues will be fully discussed to highlight factors relating to racial oppression, capacity for resilience and their deleterious effects on black identity development.


Two studies were conducted to evaluate the correlation between growth performance of chicks fed full fat soybean (FFSB) extruded at 145, 155 and o 165 and laboratory quality tests. In biological study, one hundred and forty four d-old male broiler chicks were divided into 12 groups including 3 treatments with 4 replicates of 12 chicks each and fed three diets containing 15 % FFSB extruded at 145, 155 and 165 o C from 0 to 21 d of age. Feed intake (FI), weight gain (WG) and feed conversion ratio (FCR) of chicks were not affected with increasing FFSB extrusion temperatures during 0-21 d of age. For evaluation the quality tests, the urea activity index (UA) was obtained as 0.11, 0.09 and 0.05 for FFSB extruded at 145, 155 and 165 °C, respectively. The correlation between UA with WG and FCR of chicks were 88 and 85 percent, respectively. The protein solubility in KOH (PSKOH) of FFSB extruded at 145, 155 and 165 °C, were 80.2, 78.1 and 72.4, respectively. The correlation between PSKOH with WG and FCR of chicks were 81and 88 percent, respectively. The protein dispersibility index (PDI) were 21.5, 20.8 and 16.5 for FFSB extruded at 145, 155 and 165 °C, respectively. The correlation of PDI with WG and FCR of chicks were 92 and 89 percent, respectively. It is concluded that the laboratory quality tests of FFSB were extruded at 145, 155 and 165 °C were in optimum range for broiler nutrition. Also the PDI had higher correlation with growth rate of chickens as compared to UA and PSKOH and could be the best quality index for estimating the growth rate of broiler chickens fed EFFSB.


Background: In 2012, the American Association for the Study of Liver Diseases published practice guidelines for the management of patients with ascites caused by cirrhosis, using data from randomized controlled trials (RCTs) and observational studies. We reexamined the strength of these RCTs by calculating the fragility index (FI), a novel metric proposed for evaluating the robustness of RCTs. Methods: We screened all RCTs referenced in the guidelines for specific criteria. We calculated the FI and fragility quotient (FQ), and analyzed the correlation between FI and several variables. Results: Twenty-one RCTs were included. The median (25th, 75th) FI and FQ were 1 (interquartile range [IQR] 0.5-6) and 0.070 (IQR 0.008-0.166), respectively. For studies that reported the number of patients lost to follow up (12 RCTs), the median of patients lost was 2 (IQR 0-6.5). There was no significant correlation between FI and sample size (rs=0.357), P-value (rs=-0.299), number lost to follow up (rs=0.355), Science Citation Index (rs=0.347), year of publication (rs=-0.085), blinding (rpb=-0.18) or number of centers (rpb=0.10). However, a significant correlation was seen between FI and number needed to treat (rs=-0.549; P=0.015). Conclusions: RCTs in the field of cirrhosis-related ascites are fragile. Of the 21 trials analyzed, 13 had an FI of 3 or below and these trials influenced 13 of the 49 recommendations in the guidelines. We recommend the incorporation of FI and FQ in addition to P-value to better understand the meaning of the results in gastroenterological studies.


Henderson, B. J., Mitha, A. S., le Roux, B. T., and Gotsman, M. S. (1973).Thorax, 28, 488-491. Haemolysis related to mitral valve replacement with the Beall valve prothesis. Experience of valve replacement with the Beall compressed Teflon disc valve in 59 patients confirms that the incidence of clinically significant late red cell destruction is high. An apparently previously unrecorded high incidence of early haemolysis, so severe in one patient as to be directly the cause of death, is reported. In 29 patients there was massive haemolysis in early convalescence, not recognized in urine from some hours after the end of bypass and never encountered with other designs of prosthetic valve or homograft valve.


Previous research in sport psychology has shown a connection between fan support of sport teams and overall team success by focusing on factors that influence the frequency of fan attendance. The present study examined the impact of fan identification as another determinant of fan support that may operate independent of structural factors such as win-loss record or actual fan attendance. College undergraduates (N=120) completed a survey of student activities that contained measures of collective esteem and ingroup identification in terms of their university affiliation. Subjects indicated the number of games attended and provided evaluations of the university's basketball and football teams. Results indicated that aspects of collective group identity significantly predict fan support in terms of attendance and overall evaluation of both sport teams. Also, level of group identification predicted attitudinal support of teams regardless of actual fan attendance. Implications for the connection of fan identit...


Objective. Obsessive-compulsive disorder (OCD) is a frequent and disabling neuropsychiatric disorder with a lifetime prevalence of 3%. About 40% to 60% of patients show no or just partial symptom improvement to treatment with a first-line drug and cognitive behavior therapy. Ten percent of patients remain treatment refractory despite several treatments. For these patients, repetitive Transcranial Magnetic Stimulation (rTMS) has been suggested as a treatment option. Method. We investigated the efficacy of rTMS on the Supplementary Motor Area (SMA) in 16 right handed pharmaco-resistant OCD patients in an outpatient setting. The patients have been diagnosed with OCD by two psychiatrists and referred for rTMS intervention. Patients received 16 sessions of low frequency (0.5 HZ) rTMS on SMA,100% motor threshold, 1200 stimuli/day for 40 minutes every other day. OCD, depression, and anxiety symptoms were measured at baseline, 2, 6, and 12 weeks by Yale-Brown Obsessive Compulsive Scale(Y-BOCS) and Hamilton Depressive and Anxiety rating scales (HAM-D and HAM-A). We assessed the side effects of rTMS by a self-administrative questionnaire. Results. Patients' scores in Y-BOCS, HAM-D, and HAM-A were significantly decreased following rTMS treatment. The baseline and 12 weeks scores of Y-BOCS were 28.94 and 18.31 (P-value < 0.01), HAM-D were 14.69 and 7.94 (P-value <0.01) and HAM-A were 16.38 and 6.94 (P- value < 0.01), respectively. The patients reported no serious side effects of rTMS except two case that reported light headach. Conclusion. This study showed that low-frequency rTMS on SMA improved OCD, anxiety, and depression symptoms after 16 sessions.


Abstarct. The phenomenon of the Aksi Bela Islam (ABI) shows a strong solidarity among the people. Hundreds of thousands and even millions of Muslims simultaneously went to Jakarta to demonstrate with the aim of reducing and imprisoning Governor Basuki Tjahaja Purnama (Ahok). Borrowing the term Vedi R. Hadiz, the ABI movement can be regarded as a populist Islamic movement. This paper shows that the emergence of a populist Islamic movement became a new landscape to see Indonesian Muslims. By using position warfare, the ABI movement won its victory. Therefore, to see Indonesian Muslims as a reference not only from the Nahdlatul Ulama or Muhammadiyah organizations but also from populist Islam born from the ABI.


INTRODUCTION
We found no comprehensive studies on the location of transnational tobacco and leaf company (TTLC) subsidiaries (business entities they control) or the consequences of their presence for health policy. Here we assess (1) the global reach of TTLCs by mapping their tobacco growing and manufacturing subsidiaries and (2) the relationship between in-country presence of the tobacco industry and their power and interference.

METHODS
Data on subsidiaries were collated through systematic searching for countries' supply chain activities in documents and webpages. Cross-sectional multiple regression analysis was used to assess the association between the number of agricultural and manufacturing TTLCs and the Tobacco Industry Interference score, and the degree to which these were mediated by tobacco control, good governance, and economic importance of tobacco.

RESULTS
TTLC supply chain activity had global reach. As the number of TTLCs with tobacco growing and manufacturing activities rose, interference increased significantly. Interference was associated with poorer tobacco control. The association with more TTLCs undertaking final product manufacturing was related to higher value tobacco exports but was not related to tobacco making a bigger contribution to the economy.

CONCLUSIONS
TTLCs continue to control the global tobacco supply chain through their globe-spanning subsidiaries. The presence of TTLCs in a country is associated with political interference. Countries should consider their participation in the tobacco supply chain alongside the understanding that they are likely to cede political power to TTLCs, potentially undermining the health of their populations.

STUDY IMPLICATIONS
Tobacco control research has traditionally concentrated on the demand side of tobacco. Our results lend support to calls for more research on the supply of tobacco. Governments should require tobacco companies to provide detailed, up-to-date information in an easily accessible format on in-country supply chain activities. Policymakers should take the likelihood of political interference in health and environmental policy into account when making decisions about foreign direct investment offered by the tobacco industry.


The process of out-migration has significantly been associated with the welfare of the households at origin across the world. The process of migration is mainly initiated from Pakistan with a prime objective to elevate the social position as there are only a few opportunities left for the people to work and earn for livings. The overall size of international migrants from Sindh province is a handful (approximately .9 million) and the majority of these migrants moved to the Gulf region but some also moved to the rest of the world particularly in Europe and the US. The impact of migration can be seen on many aspects of households of migrants but for the current research, it is focused only on female children's education in the case of Khairpur (Mir's) district in the province of Sindh, Pakistan. The selection of the respondents was made by using purposive sampling technique. The data was collected from 120 households of migrants who at least had one member living abroad and sending remittances regularly. The focus of the current research was on two major aspects; (a) out-migration and inflow of remittances and (b) educational outcomes of the female children studying at primary school level. It is perceived that migration of father and subsequently the inflow of remittances can make a huge difference for the educational outcomes of female children. In some cases, the inflow of remittances leads toward the improvement in the educational performance of the female children.


The oil and gas industry has been focusing on enhancing safety, reliability, and reducing costs associated with subsea surveillance and inspections. Emerging robotic and sensing systems, as enabling technologies, are being adopted and adapted by ExxonMobil in various applications. This paper presents multiple use cases where ExxonMobil has utilized these systems to address the challenges within our operations, more specifically, miniature remotely operated vehicles (mini-ROVs) and shallow-water autonomous underwater vehicles (AUVs), along with the learnings from these applications and proposed future systems.
 Mini-ROVs equipped with optical and acoustic sensors are currently being used by ExxonMobil for the inspection of hulls, platforms, and mooring chains. After achieving favorable results with miniature systems that are remotely operated, there was a natural shift towards autonomy. Low-logistics shallow-water AUVs equipped with sidescan sonar, multibeam sonar, and optical cameras are now being utilized by ExxonMobil for pipeline inspections and environmental surveys. The successful experiences from both robotic systems have built a strong foundation for ExxonMobil as the industry's interest in subsea resident systems increases.
 Successful pilot tests by ExxonMobil conducted in the past couple of years have demonstrated that a large support vessel and extensive human intervention can be eliminated. The utilization of emerging robotic and sensing systems for subsea surveillance and inspections has proven to enhance safety and reduce cost by an order of magnitude when compared to conventional techniques.


With the recent Google v. Spain decision by the European Court of Justice and the Delfi v. Estonia case before theGrand Chamber of the European Court of Human Rights (ECtHR), the position of internet intermediaries is at the center of attention once again. In Google v. Spain, the ECJ decided that Google must be seen as the controller of the information it indexes. Hence, all legal obligations specified in the Data Protection Directive should be respected by Google and other internet intermediaries like it. In the Delfi v. Estonia, the ECtHR ruled that internet platforms running on User Generated Content and user comments can rely on the freedom of speech, protected under article 10 ECHR. Still, this right may be curtailed if the rights of others are infringed through, for example, defamatory user comments. It is interesting to see that these two regimes are now applied to internet providers, while originally, the e-Commerce Directive from 2000 was meant to be the main juridical framework under which to judge the liability of internet intermediaries for actions conducted by their users through their networks.


A number of studies (mainly in vitro and in vivo animal models) have examined the interaction of trace elements with DNA. Normal dietary levels of various trace elements are required to prevent the occurrence of oxidative damage, and deficiency may increase susceptibility. Conversely, overload of some trace elements, including copper and iron, has been demonstrated to result in adverse effects. However, under normal physiological conditions, such overloads are unlikely to occur.


Ultrasound detection of capillary blood flow is difficult as capillary blood flow provides a weak backscattered signal with a small Doppler shift. To aid in the detection of such signals, a new algorithm is introduced exploiting two powerful ideas. First, the receiver is developed by creating subspaces corresponding to expected flow and clutter signals. It then exploits the fact that some of the basis vectors in the flow and clutter subspaces are very nearly perpendicular. By projecting the input data onto the perpendicular components of the flow subspace a very sensitive detector can be realized. Secondly, the detector coherently sums inputs from several angles. In vitro ultrasound data is collected and applied to the detector. The algorithm utilizing multiple angles is shown to be sensitive detecting flow in the experimental data down to 5 mm/sec in a 6 mm diameter channel.


The research described in this paper was conducted at the University of Debrecen, Farm and Regional Research Institute in its Botanical and Exhibition Garden, Hungary. The aim was to investigate the influence of plant biostimulants on the morphological parameters of three lettuce varieties (May King, Kobak and Great Lakes). Willow bark extract and Bistep were used through irrigation and spray onto the plant leaves with the amount of 5% Willow and 0,5% Bistep. Vegetative parameters like head structure (1….10), head weight (g head-1), head closing (1….10), number of leaves, head diameter (cm), internal stem size (cm) and root weight (g head-1) were measured in 2019 and 2020. According to our results, vegetative parameters are significantly affected by plant varieties and treatments. In the experiment of 2019, important vegetative parameters were influenced by the Willow extract, while in the season of 2020 the most influenced parameters were under the impact of Bistep biostimulants followed by Willow+Bistep. However, the most favourable vegetative growth was recorded in the Kobak variety in the season of 2019 followed by May King and Great Lakes varieties in the season of 2020. On the other hand, the interaction effect of plant varieties and plant biostimulants on the vegetative parameters were varied from seasons. For example, for the season 2019, significantly the highest vegetative value was recorded for the interaction of May King variety treated with Willow extract, whereas in 2020, significantly the most influenced vegetative parameters were under the influence of the interaction of Bistep and May King variety followed by the interaction of Willow+Bistep and Kobak variety.


A high triplet energy level (ET) and balanced carrier mobility are critical factors for host materials in efficient blue phosphorescent organic light-emitting diodes (PHOLEDs). Herein, we report a facile synthesis of four compounds, dicarbazolylphenylphosphine (DCPP), dicarbazolylphenylphosphine oxide (DCPPO), tricarbazolylphosphine (TCP), and tricarbazolylphosphine oxide (TCPO), and their application as host materials in a classic blue phosphorescent emitter bis[2-(4,6-difluorophenyl)pyridinato-C2,N](picolinato)iridium(III) (FIrpic). The four compounds show a high ET of up to 3.0 eV and tunable mobilities. We fabricated four OLEDs with a device structure of ITO/MoO3 (1 nm)/N,N′-dicarbazolyl-3,5-benzene (mCP):MoO3 (20 wt%, 10 nm)/mCP (30 nm)/Host:FIrpic (7 wt%, 20 nm)/1,3,5-tri(m-pyrid-3-yl-phenyl) benzene (TmPyPB, 40 nm)/LiF (1 nm)/Al (100 nm), all of which display maximum external quantum efficiencies (EQEs) exceeding 20%. The DCPPO-based device reaches the highest EQE of 27.5%, the maximum luminance of 14 070 cd m−2, and the lowest efficiency roll-off of 22.2% from 1 to 10 mA cm−2, which is among the best-performing FIrpic-based PHOLEDs without using any light extraction method.


We present a new measurement of the linear bias of radio loud active galactic nuclei (RLAGN) at $z\approx0.3$ and $L_{\rm 1.4GHz}>10^{23}\,{\rm W\,Hz^{-1}}$ selected from the Best & Heckman (2012) sample, made by cross-correlating the RLAGN surface density with a map of the convergence of the weak lensing field of the cosmic microwave background from Planck. We detect the cross-power signal at a significance of $3\sigma$ and use the amplitude of the cross-power spectrum to estimate the linear bias of RLAGN, $b=2.5 \pm 0.8$, corresponding to a typical dark matter halo mass of $\log_{10}(M_{\rm h} /h^{-1} M_\odot)=14.0^{+0.3}_{-0.5}$. When RLAGN associated with optically-selected clusters are removed we measure a lower bias corresponding to $\log_{10}(M_{\rm h} /h^{-1} M_\odot)=13.7^{+0.4}_{-1.0}$. These observations support the view that powerful RLAGN typically inhabit rich group and cluster environments.


This study carries out a comparative analysis of primary mathematics curricula put into practice during Turkish Republican period. The data for this study are composed of official curricula documents which are examined in terms of teaching principles. The study adopts a qualitative approach and employs document analysis method. The official documents are examined via content analysis technique. The analysis distinguishes a set of teaching principles envisioned to achieve effective mathematics instruction. A historical comparison of the principles indicates certain variations in the prescriptions of curricula documents as well as several features that remain unchanged throughout the Republican period. The importance of these principles for an effective mathematics teaching is discussed and certain suggestions for future curriculum development efforts have been presented.


Stepped care is increasingly seen as an appropriate model for efficient and cost-effective provision of needs-based mental healthcare services, and is now recommended by bodies such as the National Institute for Clinical Excellence. In this paper we examine how the stepped care model can provide a useful framework for thinking about new mental health technologies. Consideration of each level and intensity of care can suggest provision of specific technological support. Furthermore technology can potentially support transitions between levels of care and improve continuity of care. While it does not provide a complete framework for design – and can be criticised as being service-centred rather than client-centred – it can nonetheless provide a useful part of the analytic frame of the designer.


Development of a local area network (LAN) needs a network cable such as UTP twisted pair especially for connecting hardware like personal computer with CCTV. The connection should be on the basis of IP address which is connected with switch, and then the data eventually is sent to server. Generally, in the field, a hardware network has two main connection; first, connections to electricity for switching on the software by using an electricity cable which is suitable to the need of electrical capacity; second, connection to UTP twisted network for sending the data to the server. This process can be simplified by using network cable both for sending the data to server and for electrical pathway. Some pairs of network cable which are not used for sending data to server can be occupied to convey electrical wave to switch on and to operate the hardware. In order to use network cable for multiple purposes, it needs electrical configuration such as power of ethernet (PoE). The PoE is a system to utilize the UTP twisted pair cable to transmit unoccupied power for electrical pathway so that it can increase the efficiency of system.


It is not easy to design and run Convolutional Neural Networks (CNNs) due to: 1) finding the optimal number of filters (i.e., the width) at each layer is tricky, given an architecture; and 2) the computational intensity of CNNs impedes the deployment on computationally limited devices. Oracle Pruning is designed to remove the unimportant filters from a well-trained CNN, which estimates the filters' importance by ablating them in turn and evaluating the model, thus delivers high accuracy but suffers from intolerable time complexity, and requires a given resulting width but cannot automatically find it. To address these problems, we propose Approximated Oracle Filter Pruning (AOFP), which keeps searching for the least important filters in a binary search manner, makes pruning attempts by masking out filters randomly, accumulates the resulting errors, and finetunes the model via a multi-path framework. As AOFP enables simultaneous pruning on multiple layers, we can prune an existing very deep CNN with acceptable time cost, negligible accuracy drop, and no heuristic knowledge, or re-design a model which exerts higher accuracy and faster inference


In this paper we propose a synthetic indicator for evaluating Italian universities' scientific research using the Scimago Institutions Ranking (SIR) 2014 data. Starting from some indicators computed by SIR, after having analysed the distribution shape, fitted parameters of some statistical models, calculated an appropriate standardization, we aggregate the indicators to get a Synthetic Indicator (from now, SI) of research evaluation. The obtained synthetic indicator has been used to rank Italian Higher Education Institutions (from now, HEIs). This ranking has been compared firstly with the ranking of National Agency for the Evaluation of Universities and Research Institutes (ANVUR), based on the Evaluation of Research Quality (VRQ 2004-2010) results, in terms of standardized mark, and then with the ranking based on the assignments of the competitive allocation model (research share of FFO) yearly attributed to the Italian HEIs by the Ministry of University and Research (MIUR). The results of the analysis show a moderate positive correlation between SI and the VQR 2004-2010 indicators (r=0,543), and between SI and FFO per capita  (r=0,487).The paper's original contribution deals with a Synthetic Indicator with a Gaussian distribution summarizing the SIR variables and with the highlighting of a convergence between Italian ANVUR evaluation, based on peer to peer and bibliometric analysis, but using only few publications, and the analysis proposed in this paper, based on Scopus bibliometric data, and related to all the publications in the same period.


A micro-electro-mechanical system (MEMS) trenched piezoelectric energy harvester based on a cantilever structure has been proposed. The trenched piezoelectric layer has increased the output voltage and the generated power. It also provides three additional design parameters such as the trench position, depth and length. A particle swarm approach has been used for optimisation of the piezoelectric energy harvester geometry with the aim of finding the optimum design which transfers the maximum harvested power to a definite load. The optimisations and comparisons have been made for unimorph, bimorph, trenched and non-trenched cantilever beams. The results are quite revealing that the generated power for a trenched bimorph energy harvester is much larger than other structures. The optimum design found by particle swarm optimisation algorithm has asymmetric trenches in the top and bottom piezoelectric layers and can generate much more power than the unoptimised structure.


A record high current density of 580 μA/μm is achieved for long-channel, few-layer black phosphorus transistors with scandium contacts after 400 K vacuum annealing. The annealing effectively improves the on-state current and Ion/Ioff ratio by 1 order of magnitude and the subthreshold swing by ∼2.5×, whereas Al2O3 capping significantly degrades transistor performances, resulting in 5× lower on-state current and 3× lower Ion/Ioff ratio. The influences of moisture on black phosphorus metal contacts are elucidated by analyzing the hysteresis of 3-20 nm thick black phosphorus transistors with scandium and gold contacts under different conditions: as-fabricated, after vacuum annealing, and after Al2O3 capping. The optimal black phosphorus film thickness for transistors with scandium contacts is found to be ∼10 nm. Moreover, p-type performance is shown in all transistors with scandium contacts, suggesting that the Fermi level is pinned closer to the valence band regardless of the flake thickness.


Classifying functions according to some common properties into libraries of functions is an important step in many logic synthesis and technology mapping algorithms used in FPGA design flows. NPN classification is one of the frequently used classifications. Existing algorithms for NPN classification perform a sequence of steps to derive the resulting NPN class, but discard the intermediate results produced at the end of each step. The hierarchical method introduced in this paper uses the same sequence of steps, but it saves the intermediate results at each step and reuses them when classifying other functions. It is, on average, 3.7 times faster compared to a state-of-the-art non-hierarchical method, at the cost of a modest increase in memory needed to save the class hierarchy. The hierarchical approach enables a rapid exact NPN classification for functions up to 10 inputs-it exactly classifies one million 6-input functions in the same time as the heuristic state-of-the-art algorithm.


Simulation is the key to scaling up validation and verification for robotic systems such as autonomous vehicles. Despite advances in high-fidelity physics and sensor simulation, a critical gap remains in simulating realistic behaviors of road users. This is because devising first principle models for human-like behaviors is generally infeasible. In this work, we take a data-driven approach to generate traffic behaviors from real-world driving logs. The method achieves high sample efficiency and behavior diversity by exploiting the bi-level hierarchy of high-level intent inference and low-level driving behavior imitation. The method also incorporates a planning module to obtain stable long-horizon behaviors. We empirically validate our method with scenarios from two large-scale driving datasets and show our method achieves balanced traffic simulation performance in realism, diversity, and long-horizon stability. We also explore ways to evaluate behavior realism and introduce a suite of evaluation metrics for traffic simulation. Finally, as part of our core contributions, we develop and open source a software tool that unifies data formats across different driving datasets and converts scenes from existing datasets into interactive simulation environments. For video results and code release, see https://bit.ly/3L9uzj3.


A robotic cell-a manufacturing system widely used in industry-contains two or more robot-served machines, repetitively producing a number of part types. In this paper, we consider scheduling of operations in a bufferless dual-gripper robotic cell processing multiple part types. The processing constraints specify the cell to be a flowshop. The objective is to determine the robot move sequence and the sequence in which parts are to be processed so as to maximize the long-run average throughput rate for repetitive production of parts. We provide a framework to study the problem, and address the issues of problem complexity and solvability. Focusing on a particular class of robot move sequences, we identify all potentially optimal robot move sequences for the part-sequencing problem in a two-machine dual-gripper robot cell. In the case when the gripper switching time is sufficiently small, we specify the best robot move sequence in the class. We prove the problem of finding an optimal part sequence to be strongly NP-hard, even when the robot move sequence is specified. We provide a heuristic approach to solve the general two-machine problem and evaluate its performance on the set of randomly generated problem instances. We perform computations to estimate the productivity gain of using a dual-gripper robot in place of a single-gripper robot. Finally, we extend our results for the two-machine cell to solve an m -machine problem.


This article presents findings from a case study related to the risks associated with the choice of traditional, tenure track faculty to teach online. Education offered at a distance via the World Wide Web is on the rise; so too is the demand for university faculty members who will teach those courses. While traditional academic and professional expectations remain unchanged, the new medium presents a new context in which these faculty members live, work, and balance personal and professional decisions. This study provided a multi-dimensional perspective on one college of education's faculty and administrators as they seek to negotiate this emerging environment. Interviews with faculty, administrators, and faculty peer reviewers were conducted to provide a more complete, triangulated picture of the case.


We study the phase-space distribution of satellite galaxies associated with late-type galaxies in the GIMIC suite of simulations. GIMIC consists of resimulations of five cosmologically representative regions from the Millennium Simulation, which have higher resolution and incorporate baryonic physics. Whilst the disc of the galaxy is well aligned with the inner regions (r ∼ 0.1r200) of the dark matter halo, both in shape and angular momentum, there can be substantial misalignments at larger radii (r ∼r200). Misalignments of >45 ◦ are seen in ∼30 per cent of our sample. We find that the satellite population aligns with the shape (and angular momentum) of the outer dark matter halo. However, the alignment with the galaxy is weak owing to the mismatch between the disc and dark matter halo. Roughly 20 per cent of the satellite systems with 10 bright galaxies within r200 exhibit a polar spatial alignment with respect to the galaxy – an orientation reminiscent of the classical satellites of the Milky Way. We find that a small fraction (∼10 per cent) of satellite systems show evidence for rotational support which we attribute to group infall. There is a bias towards satellites on prograde orbits relative to the spin of the dark matter halo (and to a lesser extent with the angular momentum of the disc). This preference towards co-rotation is stronger in the inner regions of the halo where the most massive satellites accreted at relatively early times are located. We attribute the anisotropic spatial distribution and angular momentum bias of the satellites at z = 0 to their directional accretion along the major axes of the dark matter halo. The satellite galaxies have been accreted relatively recently compared to the dark matter mass and have experienced less phase-mixing and relaxation – the memory of their accretion history can remain intact to z = 0. Understanding the phase-space distribution of the z = 0 satellite population is key for studies that estimate the host halo mass from the line-of-sight velocities and projected positions of satellite galaxies. We quantify the effects of such systematics in estimates of the host halo mass from the satellite population.


Genomic DNA is highly compacted in the nucleus of eukaryotic cells as a nucleoprotein assembly called chromatin1. The basic unit of chromatin is the nucleosome, where ∼146 base pair increments of the genome are wrapped and compacted around the core histone proteins2,3. Further genomic organization and compaction occur through higher order assembly of nucleosomes4. This organization regulates many nuclear processes, and is controlled in part by histone post-transtranslational modifications and chromatin-binding proteins. Mechanisms that regulate the assembly and compaction of the genome remain unclear5,6. Here we show that in the presence of physiologic concentrations of mono- and divalent salts, histone tail-driven interactions drive liquid-liquid phase separation (LLPS) of nucleosome arrays, resulting in substantial condensation. Phase separation of nucleosomal arrays is inhibited by histone acetylation, whereas histone H1 promotes phase separation, further compaction, and decreased dynamics within droplets, mirroring the relationship between these modulators and the accessibility of the genome in cells7-10. These results indicate that under physiologically relevant conditions, LLPS is an intrinsic behavior of the chromatin polymer, and suggest a model in which the condensed phase reflects a genomic "ground state" that can produce chromatin organization and compaction in vivo. The dynamic nature of this state could enable known modulators of chromatin structure, such as post-translational modifications and chromatin binding proteins, to act upon it and consequently control nuclear processes such as transcription and DNA repair. Our data suggest an important role for LLPS of chromatin in the organization of the eukaryotic genome.


HISTONE SYNTHESIS AND DEPOSITION The DNA of all eukaryotic genomes is organized into a nucleoprotein complex called chromatin. Chromatin is essential for compacting genomic DNA and plays a primary role in governing DNA accessibility and gene expression. The composition of chromatin is modulated during all DNA transactions, including DNA replication, transcription, repair, and recombination. Therefore, the formation, maintenance, and alterations of chromatin structures are of central importance to eukaryotic molecular biology. Nucleosomes are the fundamental, repeating subunits of chromatin. Nucleosomes contain an octamer of core histone proteins, two molecules each of histones H2A, H2B, H3, and H4, around which 146 bp of DNA wraps 1.7 times (Luger et al. 1997). When the genomic DNA is duplicated during each S phase of the cell cycle, metazoan cells must make millions of new nucleosomes to accommodate the new DNA. Histone deposition occurs almost immediately onto newly synthesized DNA (for review, see Franco and Kaufman 2004; Loyola and Almouzni 2004; Gunjan et al. 2005). This coordination between DNA synthesis and nucleosome formation during S phase is essential for eukaryotic organisms to avoid DNA damage and replication fork collapse (Hoek and Stillman 2003; Ye et al. 2003; Franco et al. 2005; Groth et al. 2005). However, not all nucleosome formation occurs in concert with replication; histones are mobilized and/or evicted from DNA during many other chromosomal transactions, including transcription and DNA repair. Therefore, histone deposition onto DNA must occur both during and outside of S phase, and both these processes affect genome stability. Regulation...


The uncontrolled exploitation of Earth's resources has resulted in irreversible changes in the environment generally and the climate in particular. Therefore, a global and immediate policy response is urgently required to reduce greenhouse gas emissions and mitigate climate change. There is compelling evidence that climate change is the greatest and widest-ranging market failure ever seen. To combat the resultant market failure and externalities, there is a need to tackle climate change through economics. The paper aims at portraying the certainty associated with the economic approaches, rather than the policy approaches for combating climate change. A carbon tax seems to be a potent mitigation policy, other policies being cap and trade, renewable portfolio standards, feed-in tariffs, production tax credits. If these policies are implemented exclusive of each other, irrespective weaknesses may cause hurdles, however, if harmonised internationally, they can be effective in promoting clean energy and thereby helping combat climate change. We compare these policies in different countries with a view to comprehensively analysing their respective roles in combating climate change.


The thesis on Van Dun is that there is a conflict between freedom and property rights, and that libertarians ought to side with the former. If not, people, many people, will likely starve to death by being trapped in their houses, unable to get out of them, or, caught outside of them, without the ability to return home. This is unjust, and hence unlibertarian, since such people will in effect be imprisoned, without being found guilty of any crime, indeed, without even having been accused of perpetrating any illegal action. This sad state of affairs will come about (VD) asserts, if the libertarian emphasis on private property rights is fully implemented. How so? If the non-aggression principle (NAP) of libertarianism is adhered to, private road owners will be able to charge the veritable "arm and a leg" to homeowners for access and egress. These capitalists will thus be empowered to trap individuals in their homes, prevent them from returning there unless they pay large fees, and/or forbid such movement outright. The highway corporations would have every right to impinge upon the freedom to travel of their clients, since, in the libertarian society, all property, including roads, would be privately owned, and the proprietors of these vehicular passageways would have every right to charge price they wished, up to and including an infinite price, which would be equivalent to out right prohibition. They could engage in this sort of encirclement, or as I (Block, 2008) have characterized this problem, as "entrapment."


Companies frequently need to redesign their software infrastructures in response to marketplace changes, but they must do so carefully so that the new architecture will not disrupt existing operations or increase operating costs unnecessarily. To support these goals, system architects have long recognized the need to build a repository of information about all of their company's systems and their interfaces. Using this information, architects create system interface diagrams to help them study the existing architecture. The authors discuss their system, Enterprise Navigator, which lets users make ad hoc queries about an enterprise software architecture and then automatically generate the corresponding system interface diagram in real time on the Web.


The Ohio Archivist is the semi-annual newsletter of the Society of Ohio Archivists. It is published every spring and fall prior to the regularly scheduled meetings of the society.


This paper is a critical commentary on the article "Adaptation Processes Affecting Performance in Elite Sport" (Schinke, Battochio, Lidor, Tenenbaum, Dube, & Lane, 2012). We review relevant literature and highlight theoretical and conceptual concerns regarding Schinke et al.'s model, particularly regarding their characterization of adaptation as a process versus an outcome, and the role of appraisals, emotions, emotional regulation, coping, and Fiske's (2004) core motives within their model of adaptation. Adaptation or adjustment among elite athletes is a valuable area of research in sport psychology; however, Schinke et al.'s model oversimplifies the adaptation process and has limited utility among sport psychology researchers and practitioners.


The feasibility of an effective two-year-minimum operational Windsat lidar mission using a CO2 TEA laser and heterodyne detection on board a (free-flying) modified Advanced Tiros-N (ATN) meteorological satellite is described. The lidar instrument design employed results from the lightweighting of previous designs through the use of current technology and from some projected laser-engineering development. The Windsat system design and mission requirements are described, and the ATN reconfiguration and subsystem modifications are detailed. The weight (without propellant) and the operational power load of the integrated spacecraft are estimated at 1182 kg and 760–790 W, respectively.


The Monte Carlo method is implemented to solve the direct bioheat transfer problems, which are often encountered in the treatment planning of cancer hyperthermia. Several algorithms were developed to solve for the temperature transients inside the biological bodies with various time or space-dependent boundary conditions, blood perfusion, metabolic rate, and volumetric heat source for the tissues. The computer code thus compiled was validated through comparison with a theoretical solution. To illustrate the applications of the present numerical strategy, heat transfer in several three-dimensional cases was particularly studied. Parametric calculations were performed to test the technical adaptability of the present Monte Carlo algorithms. Some mathematical issues thus raised are discussed.


. Symmetry in optimization has been known to wreak havoc in optimization algorithms. Often, some of the hardest instances are highly symmetric. This is not the case in linear programming, as symmetry allows one to reduce the size of the problem, possibly dramatically, while still maintaining the same optimal objective value. This is done by aggregating symmetric variables. However, this aggregation, when disag-gregated, will necessarily be on the center of the optimal face. Similar to interior point methods, a crossover routine has to be used to convert that solution to a vertex solution. In this work, we use a generalization of symmetries, equitable partitions, to aggregate and solve a linear program. Then, using the partition as a guide, we show how to effectively convert the disaggretated solution as a vertex. This allows us to not just solve, but arrive at a vertex solution, to otherwise difficult highly symmetric problems.


Introduction: Mandibular Symphysis (MS) is one of the most important regions of craniofacial complex. Understanding its morphology is important both for differential diagnosis and orthodontic treatment planning. Hence the purpose of this study was to measure symphysis morphological traits of patients with deficient mandibles versus that of normal mandible patients. Material and Methods: It was a cross-sectional study that was carried out in Out Patient's Department of Margalla Institute of Health Sciences. The duration of this study was six months from June 2015 to January 2016. Thirty four normal angle patients with MMA in the range of 25.5° ± 5.3° were included in the study. McNamara analysis was done to divide them into two groups, first group of patients with short mandible and the second group of patients with normal mandible. On cephalogram, angle B-PogMe, angle B-B1-Gn and perpendicular distance from Pog to B-Me line were measured for all patients. The readings were compared for the two groups of patients. Results: The angle B-B1-Gn (symphysis vertical dimension) and anterior prominence of MS (perpendicular distance between Pogonion and B-Me line) showed no significant differences between the two groups (P>0.05). The angle B-Pog-Me (symphysis convexity) was found to be greater in short mandible group of patients. This parameter showed statistically significant difference between the two groups (P<0.05). Conclusions: Patients with short mandible have different symphyseal morphology than patients with normal mandible. Anterior prominence of symphysis and its vertical dimensions are increased in long mandible patients. But symphyseal convexity is increased in short mandible patients showing statistically significant difference between the two groups.


The German skill formation system has been undergoing significant changes over the last two decades and most recently we observed massive expansion of higher education vis-à-vis the 'traditional' dual vocational training, which stands in contrast with the notion of equilibrium that has accompanied the German skill formation system in the literature. Yet, while the institutional underpinnings of the traditional model have been subject to comprehensive scrutiny and theorisation – including analyses of recent patterns of change – it remains unclear what arrangements have become institutionalised as skill formation 'moves up' from the dual vocational training to the university system. The article suggests that a (dominant) pattern of state coordination co-exist with a segmentalist pattern: the state mobilized resources and coordinated the provision of high skill formation to the benefit of all companies and in particular of small and medium sized enterprises that have relatively fewer resources and capacity to train; in parallel, large firms, with more resources and a large internal labour market, met their high skill needs also without state-mediation, by establishing direct relationships with higher education institutions through dual study programmes.


Atherosclerosis is a multifactorial disease involving a lot of genes and proteins recruited throughout its manifestation. The present study aims to exploit bioinformatic tools in order to analyze microarray data of atherosclerotic aortic lesions of ApoE knockout mice, a model widely used in atherosclerosis research. In particular, a dynamic analysis was performed among young and aged animals, resulting in a list of 852 significantly altered genes. Pathway analysis indicated alterations in critical cellular processes related to cell communication and signal transduction, immune response, lipid transport, and metabolism. Cluster analysis partitioned the significantly differentiated genes in three major clusters of similar expression profile. Promoter analysis applied to functional related groups of the same cluster revealed shared putative cis-elements potentially contributing to a common regulatory mechanism. Finally, by reverse engineering the functional relevance of differentially expressed genes with specific cellular pathways, putative genes acting as hubs, were identified, linking functionally disparate cellular processes in the context of traditional molecular description.


Abstract Education and health are both capital investments in national development, often viewed as independent factors on a country's labor force supply and productivity. This study uses the 2010–2011 Third Integrated Household Survey in Malawi to propose an Education-enhanced Health Human Capital (EHHC) model where education influences labor force supply directly as well as indirectly through improvements in adult health. Relative to the Health Human Capital (HHC) model, the EHHC model better fits the available data, capturing the multiple effects of education. A national economic simulation of the 2013 age 13 cohort in Malawi confirms the importance of education as a tool for national development. Specifically, if the mean education of the age 13 cohort increased from the present national mean to the completion of secondary school, the total effects of education would lead to a predicted increase in annual tax revenue of 580 million Malawian Kwacha.


Stem rust (black rust) caused by Puccinia graminis f.sp.tritici is one of the most important air borne diseases of wheat (Triticum aestivum) in the central high lands of Ethiopia, including west and southwest Shewa zones. The pathogen is capable to produce new physiological races that attack resistant varieties and develop epidemic under favorable environmental conditions which results in a serious yield loss. However, information on the status of stem rust distribution and races in west and southwest Shewa zones is lacking. Therefore, the present studies were based on stem rust survey to compute the prevalence and intensity of disease; race analysis via inoculation of stem rust isolates and multiplication of single-pustule of the pathogen and race designation by inoculating on wheat differential lines. Eighty six wheat fields were assessed in 12 districts of west and south west Shewa zones with altitude ranges between1925-2915 m.a.s.l. Seventy five (87.2%) wheat fields infected with stem rust had the overall mean of 33% incidence and 10.8% severity. The mean prevalence of stem rust was 96.3% in southwest and 83.1% in west Shewa zones, whereas, the mean incidence was 34.7% and 31.2% in west and southwest Shewa zones, respectively. Similarly, mean severity was 14.5% in west and 7.1% in southwest Shewa zones. Forty five stem rust samples collected during the survey were analyzed on the twenty standard stem rust differentials and resulted in identification of 5 races (TTTTH, TTKSK, TKTTF, HKPPF & HKNTF). Of these, 88.4% of the isolates were TKTTF (Digalu race) followed by 4.7% of the isolates by TTKSK (Ug99). Among the five races, the most virulent, which made 18 Sr genes non-effective was TTTTH. TKTTF and TTKSK races were virulent on 85% of Sr genes. Differential host carrying Sr24 was an effective gene which confers resistance to all of the races identified in the area. On the other hand, the wheat differential hosts carrying the resistance genes Sr McN, Sr10, Sr9a, Sr30, Sr9g, Sr8a, Sr6, Sr7b and Sr21 were ineffective to 100% of the isolates tested. Hence, the Sr resistance gene Sr24 can be used as sources of resistance in wheat breeding program.


Parallel I/O is an indispensable part of scientific applications. The current stack of parallel I/O contains many tunable parameters. While changing these parameters can increase I/O performance many-fold, the application developers usually resort to default values because tuning is a cumbersome process and requires expertise. We propose two auto-tuning models, based on active learning that recommend a good set of parameter values (currently tested with Lustre parameters and MPI-IO hints) for an application on a given system. These models use Bayesian optimization to find the values of parameters by minimizing an objective function. The first model runs the application to determine these values, whereas, the second model uses an I/O prediction model for the same. Thus the training time is significantly reduced in comparison to the first model (e.g., from 800 seconds to 18 seconds). Also both the models provide flexibility to focus on improvement of either read or write performance. To keep the tuning process generic, we have focused on both read and write performance. We have validated our models using an I/O benchmark (IOR) and 3 scientific application I/O kernels (S3D-IO, BT-IO and GenericIO) on two supercomputers (HPC2010 and Cori). Using the two models, we achieve an increase in I/O bandwidth of up to 11× over the default parameters. We got up to 3× improvements for 37 TB writes, corresponding to 1 billion particles in GenericIO. We also achieved up to 3.2× higher bandwidth for 4.8 TB of noncontiguous I/O in BT-IO benchmark.


The aim of this paper is to define the structural geometry and kinematics of Neogene deformation of the Matese Massif in order to validate the applicability of either thin-skinned or thick-skinned compressive styles in the Apennines. The Matese structure appears as a single N-vergent thrust sheet above a low angle thrust fault, which was later deformed by footwall thrust sheets. The massif is composed mainly of Mesozoic carbonates of inner platform to by-pass and slope facies, separated within the thrust sheet by high angle faults with small component of reverse displacements. These faults acted as normal faults in the Mesozoic and Cenozoic and affected the carbonate facies distribution. During Neogene compression they were mildly reactivated and then passively truncated by the basal short-cut thrust fault that cut from pre-Triassic units to Jurassic dolostone towards the foreland. Finally, Quaternary extensional tectonics dissected the thrust sheet displacing it by up to 1000 m. This has resulted in the present-day structural setting of the Matese Massif as a horst bounded to the SW and NE by extensional basins filled with continental deposits.


Background Promoting healthcare access and reducing out-of-pocket (OOP) expenditure is an important health policy goal in a developing country including India. How far health insurance interventions have helped in achieving these objectives is examined in the present study. Objectives This paper examines the impact of health insurance in promoting access to healthcare use and providing financial risk protection during health emergency. This also evaluates the relative role of publically financed pro-poor health insurance-PFPHI (like, the Rashtriya Swasthya Bima Yojana-RSBY and state run health insurance scheme) schemes, employer insurers and private insurance companies in providing financial protection to meet health expenses. Methods This study has explored data at the household?s level from two National Sample Survey (60th: 2004–05 and 68th: 2011–12) rounds, provided by Government of India. The two-sample t-test, concentration curve and multivatiate regression analysis is used. Result We found that health insurance promotes access to healthcare use for inpatient cares and promote equity. The impact of health insurance in promoting healthcare use remained noticeable high among poorest, as the inpatient rates of poor insured persons found about 16.4% higher than poor uninsured persons. However, it appears that health insurance encourages people to switch to costlier/tertiary cares and sidetracking primary care providers and leading to demand-supply induce moral hazard problems. This in turn increases the cost per inpatient episode of care. Health insurances financial protection remained highly biased towards rich and urban, while limited to poor and rural residents. The publically financed pro-poor health insurance strategies turned effective in promoting healthcare access/use, in area where provider networks are fairly extensive spreading across regions, in failure, their likely impacts found to be low. The role of private insurers (with the increase in FDI caps in health insurance from 26% to 29%) however expected to grow in India but financial protection provided by them are found one of the lowest. The average amount of premium collected by them is one of the highest but reimbursement made is very low. Conclusion Findings suggest India needs to adopt both health insurance and tax-financing strategies with appropriate regulation of private providers and insurers markets.


This paper examines how identity is reconstructed in second language literacy of adult female refugees and immigrants, and how their prior literacy and language experience influences their current literacy usage which develops slowly due to a lack of suitable education for them in the United States, causing difficulties during their integration process. Responding to the low representation of immigrant women in research, three major research methods to collect the qualitative data were used: (1) prompted journal entries as narrative inquiries, (2) observations and field notes, and (3) semi-structured interviews to understand the participants' previous and current literacy development and identity construction. Through a detailed analysis, the results demonstrated a connection between the first language (L1) and the second language (L2) literacy development and how the upbringing, as well as religious literacy, influenced the participants' language learner identity and the identity as an immigrant. The findings shed light on the limited education services provided for adult women immigrating to the US and inform existing language programs by highlighting the unique lived experiences and related literacy needs of this population to voice their thoughts and stories that reconstruct their identities, as well as providing support for using the language in day to day encounters.


This research aims to examine the influence of institutional environment in the entrepreneurial context of Oman. It draws on the burgeoning literature that links entrepreneurship and institutions. Previous entrepreneurship literature has largely focused on the developed world, and assumed transferable findings to emerging economies regardless of the significant institutional differences, which warrants scholarly attention. In response, this research produces three papers that examine three interrelated phenomena within the entrepreneurial context of Oman, using institutional lens. The first paper examines the emergence of hidden entrepreneurs, an understudied phenomenon in the informal entrepreneurship literature, and its effects on the entrepreneurial ecosystem and the wider economy. Calling upon the weaknesses in the institutional environment that led to the emergence of hidden entrepreneurs, the second paper examines the role these institutional dynamics play in shaping the efficacy of entrepreneurial learning (EL) programmes. As the second paper showed a dominance of unfavourable institutions that undermine formal EL programmes, the third paper was inclined to examine the informal collaborative EL approaches that entrepreneurs follow by utilising prevailing coexisting institutional logics, mainly digitisation and social capital logics. Embedded in interpretive paradigm, the three papers followed qualitative approach using in-depth interviews with 44 entrepreneurs and stakeholders within the entrepreneurial ecosystem. The papers revealed an interplay between unique institutional elements that have given rise to different implications to entrepreneurship in Oman. These include: regulatory weaknesses despite the government's momentous efforts to develop entrepreneurship sector; the undue influence of the family in shaping individual endeavour; limited entrepreneurial mindset in the society; the emergence of digital social networks; the normative influence of wasta; and an Islamic value to knowledge sharing. The overall research offers theoretical, methodological, and contextual contributions as well as practical implications by providing multi-layered understanding of entrepreneurship phenomenon within an understudied context (i.e. Oman), which generated new insights at the intersection of entrepreneurship and institutional theory.


We use a database of approximately 200,000 modified Mercalli intensity (MMI) observations of California earthquakes collected from USGS "Did You Feel It?" (DYFI) reports, along with a comparable number of peak ground‐motion amplitudes from California seismic networks, to develop probabilistic relationships between MMI and peak ground velocity (PGV), peak ground acceleration (PGA), and 0.3‐s, 1‐s, and 3‐s 5% damped pseudospectral acceleration (PSA). After associating each ground‐motion observation with an MMI computed from all the DYFI responses within 2 km of the observation, we derived a joint probability distribution between MMI and ground motion. We then derived reversible relationships between MMI and each ground‐motion parameter by using a total least squares regression to fit a bilinear function to the median of the stacked probability distributions. Among the relationships, the fit to peak ground velocity has the smallest errors, though linear combinations of PGA and PGV give nominally better results. We also find that magnitude and distance terms reduce the overall residuals and are justifiable on an information theoretic basis. For intensities MMI≥5, our results are in close agreement with the relations of Wald, Quitoriano, Heaton, and Kanamori (1999); for lower intensities, our results fall midway between Wald, Quitoriano, Heaton, and Kanamori (1999) and those of Atkinson and Kaka (2007). The earthquakes in the study ranged in magnitude from 3.0 to 7.3, and the distances ranged from less than a kilometer to about 400 km from the source.

Online Material: Figures showing the relationship between 0.3 s, 1.0 s, and 3.0 s pseudospectral acceleration and MMI.


Background : Innovative work is being undertaken across Scotland to reshape delivery of care. Effective Anticipatory Care Planning (ACP) is key to ensuring optimal delivery of an appropriate and sustainable model of health and care. This is supported through the use of information sharing technology, the Key Information Summary (KIS), to communicate across the primary and acute care interface. The initiative is aligned with the NHS Quality Strategy for Scotland, the 2020 vision and the National Health and Wellbeing Outcomes supporting Health and Social Care integration. At a time of significant change and challenge within our healthcare system there is a need to ensure provision of safe, high quality services at home or in a homely setting for people with disabilities, long term conditions or multiple morbidities. This is achievable by developing a robust community infrastructure with capacity and capability to optimise care and quality of life and manage more people more independently out of hospital. ACP is a person-centred, proactive, "thinking ahead" approach, requiring services and professionals to work with individuals and their carers to set personal goals ensuring the right thing is done at the right time by the right person with the right outcome. ACP evolves reflecting the individual's situation and requires a supportive whole-system infrastructure to ensure delivery of positive outcomes. ACP provides opportunities to improve health literacy and understand personal health and care issues, circumstances and outcomes, enabling informed decision-making and expression of preferences. The work responds to the challenge of providing care for an ageing population with increasing prevalence of long term conditions and multiple morbidities. Currently, in Scotland, 80% of individuals admitted to hospital are over 75 years. 30% of admissions could potentially be avoided through mainstreaming an ACP approach supported by a model providing appropriate case management, interventions close to home, signposting, access to supported self management, local intermediate care, enablement and rehabilitation. Planning and improvement : A cross-sector *Anticipatory Care Planning Task and Finish Group* aligned with the *Living Well in Communities (LWIC)* initiative has developed a National Action Plan to support implementation of ACP principles across Scotland over two years to deliver best-model, person-centred care close to home with consequent reduction in avoidable hospital admissions and bed days. The National Action Plan : has been informed by continuous improvement work over the last decade to implement principles outlined by Kerr (2005) and learning from improvement through collaboration on reshaping care for long term conditions and multi-morbidities supported by local best practice initiatives. Population stratification estimates that 5-6% of the population could potentially benefit from ACP. Vulnerable individuals should be identified and offered interventions in a timely way to enable informed choice and ensure optimise outcomes. ACP triggers based on situation, condition and assessment support ACP initiation. Triggers include falls, which account for 10% of unplanned admissions, polypharmacy and dementia. 2% of the population, (high-resource individuals), utilise 77% of hospital inpatient days and 50% of combined prescribing resources. There is potential to improve efficiency through collaborative work for this group. Primary Drivers : The National ACP Action Plan focusses on 3 Primary Drivers (below) developed through extensive scoping work, improvement methodology informed by logic modelling and consultation with a wide range of stakeholders and service users. 1. Awareness-raising with public, services and organisations to embed ACP within each Locality to help those with multiple morbidities and ensure delivery of locally accessible services for those with most complex needs. 2. Carer support must be prioritised alongside ACP. 3. Provision of consistent ACP material to support individuals and appropriate information sharing between professionals to support collaborative work. The Key Information Summary (KIS) currently hosted on the GP IT system enables eACP access. Following successful pilot work, engagement with General Practice and Primary Care has been established by integrating KIS and ACP with the Quality and Safety Domain of the GP Contract QOF. In Year One, 151,641 individuals (3.2% of the population) had a KIS. Through partnership working KIS is accessible to unscheduled care services including NHS 24, Out of Hours, Emergency Department and hospital front door resulting in 3.32m KIS accesses/annum outside general practice. 81% KIS contain information considered valuable to informing appropriate interventions. Ongoing work is focussed on evolution of KIS to enable greater accessibility and cross sector working. Further improvement will also include an organisational scoping exercise, tests of change, learning needs analysis and developing an identifiable single "branded" Scottish ACP and national role out of a whole-system ACP model co-ordinated through a national ACP Partnership Network and communication strategy.


The recently established Garden Route National Park (GRNP) along the Cape south coast of South Africa occurs in a landscape where indigenous forests, fire-prone fynbos shrublands and fire-sensitive plantations of alien invasive trees are interspersed. We used the area as a case study in the challenges facing conservation managers in the achievement of biodiversity goals in a fire-prone environment. We explored the context within which fire management was practised during the past century by interviewing former catchment managers and reviewing forestry and catchment management policies. Mountain fynbos adjacent to plantations was subjected to burning regimes aimed at the protection of commercial timber resources rather than the preservation of fynbos biodiversity. Prescribed burning of fynbos adjacent to the plantations was typically done in multiple belt systems at rotations of about 4–8 years during spring, summer and autumn, to avoid the winter berg wind season. Such short-rotation and low-intensity fires favour resprouting graminoids over slow-maturing reseeders, and likely account for the compositional impoverishment observed in fynbos near plantations. Current and future challenges faced by the GRNP include (1) balancing conflicting fire management requirements for plantation safety against fynbos conservation; (2) the continual invasion of fynbos by fire-propagated alien pines sourced from plantations; (3) inadequate resources to redress the 'invasion debt' caused by the socio-economic legacy and past management neglect; and (4) fragmentation of land use between conservation and forestry threatening the sustainability of the region at large. We provide recommendations for management actions and research priorities to address these challenges.


Construction of building and other civil engineering structures on weak or soft soil is highly risky because such soil is susceptible to differential settlements, poor shear strength, and high compressibility.Organic soils are difficult to deal with due to their particular characteristics such as high compressibility and poor strength and, as a consequence, criteria based on common mineral soils may not generally be applied to them. The objective of this research is to investigate and assess adding different percentages of organic matters on soil stiffness, from laboratory experimental work, and to i nvestigate the effectiveness of animal disposals and plants pieces (leaves) ontwo soil types. Hence, in the present research, mixed organic materials have been used, and it was randomly included in to the soil at four different percentages of organic content, i.e. 5, 10, 15, and 20% by the weight of two main raw, silty soil and clayey soil. The research revealed from the laboratory tests that when organic mattersincreased the stiffness of both clayey and silty soil were reduced, and the reduction were from 16.5% to about 61% with 5 and 20% adding percentage of organic matter respectively. While the liquidity and plasticity increased from the reference soil (without organic materials) as well as the swelling index increasing for the two types of tested soils. Moreover the research indicates the percentage of organic contents played an important role in the development of the vertical displacement of the clayey and silty soil under loading.


Lower urinary tract symptoms (LUTS) have been considered as clinically prevalent symptom in women, and can be ameliorated by the change of abdominal muscles and pelvic floor muscle (PFM). This study investigated the efficacy of Pilates program using Oov and mat on the change of abdominal muscle thickness, PFM function, and LUTS clinical score. 53 women experiencing LUTS were randomly assigned to Oov Pilates exercise group (OPEG) (n=20), mat Pilates exercise group (MPEG) (n= 16), and symptomatic control group (SCG) (n=17), respectively, and two groups using Oov and mat participated in 8-week Pilates program. Thickness of abdominal muscle, functional movement of PFM, and LUTS clinical score were measured from all groups. Thickness of rectus abdominis, internal oblique abdominis, transversus abdominis was significantly improved in OPEG (P<0.05), however, MPEG showed a significant change only in transversus abdominis (P<0.05). In all abdominal muscles, OPEG had a significantly improved abdominal muscle thickness compared to SCG (P<0.05). Functional movement of PFM in OPEG was significantly decreased (P<0.005), but not in MPEG and SCG. In LUTS clinical score, OPEG and MPEG showed a significantly abated symptoms in degree of voiding-related symptoms and discomfort (P<0.005), but not in SCG. Our study highlighted that Pilates using Oov can be an effective intervention to ameliorate the quantitative quality of abdominal muscle thickness and PFM, which ultimately provides the satisfied self-clinical index in degree of voiding-related symptoms and discomfort.


Background: Long-term care nurses are in a pivotal position to be augmenting the quality of life for residents and improving the death and dying experience for residents, their family members and surrogate decision makers. Currently there is a paucity of literature that acknowledges the experiences of long-term care nurses and their involvement with end-of-life decision making and care. Purpose: To describe long-term care nurses' perceptions of factors that influence their communication with end-of-life surrogate decision makers and the kind of support they need to support this discussion. Method: A descriptive study using mixed-methods convergent design was used to obtain responses from a sample of 30 long-term care nurses. An online survey included questions to obtain quantitative data and open-ended questions for short responses. Results from both sets of data were brought together and compared during the analysis phase. Results: The findings of this study highlight the personal factors of the nurse, the characteristics of the surrogate decision maker, contextual factors, situational related inputs, and the support desired by long-term care nurses. Participants rated factors according to importance in their experiences of communicating with surrogate decision makers. Seven themes were inductively derived from the analysis: 1) selected or appointed as surrogate makes a difference, 2) strong trusting bond between nurse-resident and nurse-family, 3) being too close to see resident's wishes, 4) interdisciplinary team agreement, 5) living will as a communication roadmap, 6) peaceful environment, and 7) the need to create emotional distance. Long-term care nurses also identified the types of support they seek or need to be effective in communicating with end-of-life care surrogate decision makers. Conclusion: As the numbers of the older population continue to increase, the demand for nurses to develop expertise in caring for dying residents and communicating with them, their family members, and surrogate decision makers will increase. Understanding their experiences and providing support to long-term care nurses may strengthen their capacity to communicate about death and dying and their delivery of quality end-of-life care to residents.


Levoglucosan has been widely used to quantitatively assess biomass burning's contribution to ambient aerosols, but previous such assessments have not accounted for levoglucosan's degradation in the atmosphere. We develop the first global simulation of atmospheric levoglucosan, explicitly accounting for its chemical degradation, to evaluate the impacts on levoglucosan's use in quantitative aerosol source apportionment. Levoglucosan is emitted into the atmosphere from the burning of plant matter in open fires (1.7 Tg yr-1) and as biofuels (2.1 Tg yr-1). Sinks of atmospheric levoglucosan include aqueous-phase oxidation (2.9 Tg yr-1), heterogeneous oxidation (0.16 Tg yr-1), gas-phase oxidation (1.4 × 10-4 Tg yr-1), and dry and wet deposition (0.27 and 0.43 Tg yr -1). The global atmospheric burden of levoglucosan is 19 Gg with a lifetime of 1.8 days. Observations show a sharp decline in levoglucosan's concentrations and its relative abundance to organic carbon aerosol (OC) and particulate K+ from near-source to remote sites. We show that such features can only be reproduced when levoglucosan's chemical degradation is included in the model. Using model results, we develop statistical parametrizations to account for the atmospheric degradation in levoglucosan measurements, improving their use for quantitative aerosol source apportionment.


: During the last decennium it has become clear that the course of an inflammatory reaction is not only governed by the immune system. In this paper we describe which other organ systems than the immune system may influence chronic inflammatory responses such as observed in Juvenile Chronic Arthritis (JCA). Attention will be focussed on the role of glucocorticoids, catecholamines and of the neurotransmitter substance P.


In 2019 the European Economic Area Agreement (EEA) celebrated 25 years of promoting the European integration and cooperation in economic and many other relevant matters. Climate issues were, however, not included in the negotiations of the EEA Agreement. Combating climate change is thus not listed as one of the objectives of the EEA environmental law. Furthermore, the Main Part of the EEA Agreement has not been updated since its entry into force. Still, the Agreement is the most relevant platform for the European cooperation in combating climate change. This article sheds light on the EU/EEA climate law and policy from the perspective of Norway that due to its energy sector is quite unique in the context of the EU climate policy. Moreover, Norway not only participates in most of the EU initiatives, but also takes actions to strengthen the EU/EEA cooperation in climate action and promotes setting ambitious climate goals.


Classifying proteins into families and superfamilies allows identification of functionally important conserved domains. The motifs and scoring matrices derived from such conserved regions provide computational tools that recognize similar patterns in novel sequences, and thus enable the prediction of protein function for genomes. The eBLOCKs database enumerates a cascade of protein blocks with varied conservation levels for each functional domain. A biologically important region is most stringently conserved among a smaller family of highly similar proteins. The same region is often found in a larger group of more remotely related proteins with a reduced stringency. Through enumeration, highly specific signatures can be generated from blocks with more columns and fewer family members, while highly sensitive signatures can be derived from blocks with fewer columns and more members as in a superfamily. By applying PSI-BLAST and a modified K-means clustering algorithm, eBLOCKs automatically groups protein sequences according to different levels of similarity. Multiple sequence alignments are made and trimmed into a series of ungapped blocks. Motifs and position-specific scoring matrices were derived from eBLOCKs and made available for sequence search and annotation. The eBLOCKs database provides a tool for high-throughput genome annotation with maximal specificity and sensitivity. The eBLOCKs database is freely available on the World Wide Web at http://motif.stanford.edu/eblocks/ to all users for online usage. Academic and not-for-profit institutions wishing copies of the program may contact Douglas L. Brutlag (email@example.com). Commercial firms wishing copies of the program for internal installation may contact Jacqueline Tay at the Stanford Office of Technology Licensing (email@example.com; http://otl.stanford.edu/).


This article examines how scholarship on veterans has begun to incorporate gender as a relevant category of research. Drawing on feminist theory, it identifies different approaches to gender within the field of veterans studies and suggests avenues for advancing this aspect of research. The vast majority of gender research on veterans treats gender as a descriptive category or variable through a focus on female veterans or gender differences. This article argues that research on veterans can be enriched by employing gender as an analytical category. Focusing on gender norms, power and inequality based on gender, and the intersections of gender with other categories of social difference opens up new questions for gender research on veterans. This kind of broader, analytical conceptualization of gender reveals the ways in which gender shapes the transition to civilian life for all veterans and how veterans policies and programs impact gender relations.


You are given points on a graded scale for the best possible answer(s), and points are deducted for answers that would result in a poor outcome or delay your arriving at the right answer. Answers that have little or no impact receive zero points. On questions that focus on differential diagnoses, bonus points are awarded if you select the most likely diagnosis as your first choice. At the end of the exercise you will add up your points to obtain a total score.


The incidence and characteristics of ring sideroblastic and megaloblastic changes in bone marrow were studied in chronically ill, malnourished alcoholics and well-nourished alcoholics without complicating medical illness. A clear correlation of blood alcohol level with changes in serum pyridoxal-5-phosphate (PLP) values or with the incidence of ring sideroblasts could not be demonstrated. The appearance of ring sideroblasts was associated with dietary restrictions of pyridoxine and noticeable folic-acid-deficient megaloblastosis. The majority of subjects with ring sideroblasts were from the chronic, malnourished alcoholic group; the number of sideroblasts correlated with severity of marrow magaloblastic change. While low serum PLP levels were characteristic of the chronically ill alcoholic with ring sideroblasts, equally low levels were detected in the absence of the marrow abnormality. Thus, a low serum PLP value alone is not a certain indication of the presence of marrow ring sideroblasts.


The physiopathological mechanism of diarrhea with water and electrolyte disturbances is not fully clear. But it already appears that progress in our knowledge of the pathology goes together with progress in physiology. Work on cholera has clarified our knowledge of intestinal were not fully realised. In the short term one may foresee that our concept of the regulation of digestion of a meal will change.


With the continuous development of vehicle and electronic industry, SBW (Steering by Wire) is replacing the traditional steering device of vehicle. Firstly this paper introduces the principle and structure of SBW, then discusses how to model the kinetic equation of SBW and how to simplify the model reasonably, and then obtains the control model of SBW. To meet the system requirement of robust performance, this paper selects the control strategy based on H? algorithm. According to the further observation and study on the curve of S/T singular value in H? algorithm, put forward a method which constructs a closed loop function and then back-step the system controller on the basis of key parameter in system frequency. The analysis of the time domain and the frequency domain of SBW, the simulation result under the interference and parameter perturbation of the model show that the controller designed by this method is simple and effective, and the controller owns perfect robust stability and robust performance.


Abstract. We present an interactive image deformation method which preserves the local shapes of salient objects in the concerned image during the deformation. The proposed method falls into the moving least squares (MLS) framework, but notably differs from the original MLS deformation method. First, a saliency-related distance is developed to replace the original Euclidean distance in the weight definition. Second, the original affine matrix is decomposed into a single rotation matrix and a symmetric matrix by using a singular value decomposition, then the free parameters of these matrices are interpolated according to the saliency information. Furthermore, for the line-based MLS deformation, the closed-form solution of weight cannot be found directly when using the proposed saliency-based distance. To address this problem, we propose a method using an exponential transformation to regulate the weight where the regulation factor is also correlated to saliency information. All these revisions lead a saliency-sensitive mapping which creates a deformation change in the nonvital parts of image while preserving the local shapes of salient parts. Experimental results show that the proposed deformation outperforms the original MLS deformation in terms of visual performance.


Roots, cereal crowns, and stems growing beneath the soil surface provide important resistance to soil erosion. Understanding the amount and distribution of this material in the soil profile could provide insight into resistance to soil erosion by water and improve the performance of soil erosion models, such as the revised universal soil loss equation (RUSLE) and the water erosion prediction project (WEPP). Erosion models use built-in or external crop growth models to populate crop yield and live aboveground and associated belowground biomass databases. We examined two data sets from the dryland small grain production region in the Pacific Northwest of the United States to determine root:shoot ratios, the vertical distribution of root and attached belowground biomass, and incorporated residue from previously grown crops. Data were collected in 1993, 1994, 1995, and 2000 from short-term no-till and conventional tillage experiments conducted near Pendleton, Oregon, and Pullman, Washington, and in 1999 and 2000 from long-term experiments representative of farming practices near Pendleton, Oregon. The crops sampled in the short-term data set included soft white winter and spring wheat (Triticum aestivum L.; WW and SW, respectively), spring peas (Pisum sativum L.; SP), and winter canola (Brassica napus L.; WC). Crops sampled in the long-term study included WW, SW, and SP. Data were collected at harvest in both data sets and during three phenologic stages in each of the crops in the short-term data set. Soil samples were collected to a depth of 60 cm (23.6 in) in the short-term and 30 cm (11.9 in) in the long-term experiments. In both sets of measurements, we found greater than 70% of root mass is in the top 10 cm (3.9 in) of the soil profile with the exception of SP, which had 70% of root mass in the top 15 cm (5.9 in) of the soil profile. WC produced significantly more biomass near the soil surface than WW, SW, or SP. Root-to-shoot biomass ratios in mature wheat ranged from 0.13 to 0.17 in the top 30 cm (11.9 in) of the soil profile, substantially lower than values suggested for use in WEPP (0.25). In the long-term experiments, soil of the conventionally tilled continuous winter wheat (CWW) plots contained significantly greater biomass than soil of conventionally tilled winter wheat/fallow (CR) and no-till winter wheat/fallow (NT) treatments. There was no significant difference between CWW and conventionally tilled winter wheat/spring pea (WP); however, CWW returned more residue to the soil than WP because SP produced less residue and these residues were incorporated with a field cultivator rather than a moldboard plow. More accurate representation of root development, particularly in winter crops, could improve RUSLE and WEPP performance in the Pacific Northwest where winter conditions have proven difficult to model.


A pathological study was performed on the necropsy eyes of a 59-year old-woman who had suffered for nine years from multifocal posterior uveitis. The disease had been controlled by steroid therapy with good preservation of visual function. Extensive investigation did not reveal the aetiology. On macroscopic examination numerous focal lesions with various degrees of pigmentation were observed scattered across the fundi. These lesions were studied by light and electron microscopy and immunohistochemistry. There was ongoing chorioretinal inflammation in the foci, producing destruction of Bruch's membrane, the retinal pigment epithelium (RPE), and the outer retina. The focal scars showed migration of RPE and glial cells and neovascularisation. Capillary and venule endothelial cells were swollen at the inflammatory sites. Attempts to establish a cause for this condition were unsuccessful.


Micrometeorological flux towers provide spatially integrated estimates of net ecosystem production (NEP) of carbon over areas ranging from several hectares to several square kilometers, but they do so at the expense of spatially explicit information within the footprint of the tower. This finer-scale information is crucial for understanding how physical and biological factors interact and give rise to tower-measured fluxes in complex landscapes. We present a simple approach for quantifying and evaluating the spatial heterogeneity of cumulative growing season NEP for complex landscapes. Our method is based on spatially distributed information about physical and biological landscape variables and knowledge of functional relationships between constituent fluxes and these variables. We present a case study from a complex landscape in the Rocky Mountains of Montana (US) to demonstrate that the spatial distribution of cumulative growing season NEP is rather large and bears the imprint of the topographic and vegetation variables that characterize this complex landscape. Net carbon sources and net carbon sinks were distributed across the landscape in manner predictable by the intersection of these landscape variables. We simulated year-to-year climate variability and found that some portions of the landscape were consistently either carbon sinks or carbon sources, but other portions transitioned between sink and source. Our findings reveal that this emergent behavior is a unique characteristic of complex landscapes derived from the interaction of topography and vegetation. These findings offer new insight for interpreting spatially integrated carbon fluxes measured over complex landscapes.


1H MRS allows insight into the chemical composition of the central nervous system. However, as a result of technical challenges, it has rarely been applied to the spinal cord. In particular, the strong susceptibility changes around the spinal cord and the pulsatile flow of the cerebrospinal fluid lead to distinct B0 field distortions which often considerably degrade the spectral quality. Hence, B0 shimming is one of the main challenges in 1H MRS of the spinal cord. Electrocardiogram (ECG)‐triggered, higher order, projection‐based B0 shimming was introduced and compared with both conventional projection‐based B0 shimming and B0 shimming based on ECG‐triggered, three‐dimensional B0 field mapping. The linewidth of the unsuppressed water peak was used to evaluate the reproducibility and the potential improvement to B0 homogeneity. The use of ECG‐triggered projection‐based B0 shimming in combination with ECG triggering during preparation phases and triggering during acquisition of the spectra is the most robust method and thus helps to improve the spectral quality for MRS of the spinal cord. Copyright © 2012 John Wiley & Sons, Ltd.


3193 Methylation of DNA is an epigenetic modification that plays an important role in the regulation of gene expression in mammalian cells. Although DNA methylation is required for normal cell development and function, aberrant methylation and the resulting aberrant expression of genes, such as tumor suppressor genes and oncogenes, contribute to the development of malignancies. Interestingly, aberrant DNA methylation has recently emerged as one of the most frequent molecular alterations in hematologic malignancies, providing a powerful rationale to use inhibitors of DNA methylation as a novel means of targeting hematologic malignancies. VidazaTM [Pharmion Corporation] (5-azacytidine), an FDA approved drug for the treatment of myelodysplastic syndromes, is an inhibitor of DNA methylation. Multiple myeloma (MM) is currently an incurable hematological malignancy despite all the conventional and novel therapies, and we here examined the biological effects using VidazaTM on human MM cells. We demonstrate here that VidazaTM has significant cytotoxicity in both conventional therapy sensitive (MM1S, RPMI-8226) and resistant (MM1R, RPMI-Dox40, RPMI-LR5) MM cell lines, as well as freshly isolated patient MM tumor cells, with an IC50 of 1.25-4 μM at 72 hours in vitro. Importantly, no cytotoxic effects of VidazaTM were detected in peripheral blood mononuclear cells (PBMNC) obtained from healthy volunteers at ≤ 20 μM, suggesting a therapeutic index. Moreover, VidazaTM overcame the survival and growth advantages conferred by interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1), or by adherence of MM cells to bone marrow stromal cells (BMSC). VidazaTM induced apoptosis in MM cells, as determined by flow cytometric analysis using PI and Annexin V staining. VidazaTM-induced apoptosis was associated with PARP, caspase 8 and caspase 9 cleavage. Importantly, pan-caspase inhibitor zVAD-fmk, significantly, but only partially, inhibited apoptosis induced by VidazaTM, suggesting the involvement of both caspase dependent and independent pathways. Taken together, our studies therefore demonstrate that VidazaTM induces apoptosis and overcomes in vitro drug resistance in MM cells. Ongoing studies are delineating the mechanism of action of VidazaTM against MM cells to further provide the preclinical rationale for clinical evaluation of VidazaTM, alone or in combination with other agents, to improve patient outcome in MM.


In the conversion of bovine plasminogen to bovine plasmin not only the expected urokinase-catalysed cleavage of Arg-557-Val-558, and the following autocatalytic cleavage separating the N-terminal peptide 1-77 from the heavy chain of plasmin, but also a cleavage at Arg-342-Met-343 between kringles 3 and 4 is seen. Here, kinetic studies of the interaction of bovine alpha 2-antiplasmin with bovine plasmin were performed on isolated bovine midiplasmin (lacking kringles 1-3) and on bovine plasmin containing all of the activation products from the bovine plasminogen. A series of experiments using stopped-flow fluorescence fast kinetics as well as conventional techniques suggests a reaction model in accordance with the one known for the human system. First, a tight complex (K1 in the nanomolar range) is formed in a fast reaction step; and second, a tightening of this complex occurs in a slow reaction step. The final complex is indeed so tight (Ki < or = pM), that the reaction for many practical purposes is legitimately considered irreversible. The stopped-flow method allows for the determination of reliable values of the second-order rate constant for the fast association step. At pH 7.4 and 25 degrees C, k+1 = 1.7 x 10(6) M-1 s-1 was obtained in the absence and k+1 = 0.9 x 10(6) M-1.s-1 in the presence of the kringles 1-3 domain of bovine plasmin. In contrast to this, substantial reductions of k+1 were seen in the presence of concentrations of 6-amino-hexanoic acid corresponding to lysine-binding-site interactions and far too low to be attributed to active-site interactions with the bovine plasmins (for each, Ki = 42 mM). All in all, the data indicated that the lysine-binding site(s) not of kringle 1, but of midiplasmin (those of kringles 4 and 5) are regulating the inhibition reaction.