International guidelines suggest ultrasound surveillance for hepatocellular carcinoma (HCC) early diagnosis in liver cirrhosis (LC) patients, but 40% of nodules <2 cm escape detection. We investigated the existence of an ultrasound pattern indicating a higher risk of developing HCC in patients under surveillance. 359 patients with LC (Child-Pugh A-B8) underwent ultrasound screening (median follow-up 54 months, range 12–90 months), liver function tests, alpha-fetoprotein assay, and portal hypertension evaluation. Echo patterns were homogeneous, bright liver, coarse, coarse small nodular pattern, and coarse large nodular pattern. During follow-up 13.9% developed HCC. At multivariate analysis using Cox's model alpha-fetoprotein, coarse large nodular pattern, portal hypertension, and age were independent predictors of HCC development. Kaplan-Meier estimates of HCC cumulative risk in relation to the baseline echo patterns showed risk of 75% in coarse large nodular pattern patients, 23% coarse small nodular pattern, 21% coarse pattern, 0% homogeneous, and bright liver echo patterns (log-rank test = 23.6, P < 0.001). Coarse large nodular pattern indicates a major risk factor for HCC as 40.7% of patients with this pattern developed HCC. Homogeneous and bright liver echo patterns and the absence of portal hypertension were not related to HCC. This observation could raise the question of possibly modifying the follow-up timing in this subset of patients.


An interesting aspect of the many recent researches on the history of medicine in Korea is a concentration on oral histories, a trend that is sure to supplement the lack of medical documents and historical materials covering the modern period. This trend will also contribute to the invention of new approaches in the historiography of medicine. Although the fragments of oral testimony cannot be expected to give a perfect representation of historical reality, such "slices of life" help represent history from the viewpoint of ordinary people and members of the medical profession who are less often acknowledged. The recent researches that have taken oral testimony on the history of medicine in Korea have both racked up achievements as well as encountered limitations. First, many disciplines such as history, literature, cultural anthropology, folklore, sociology, and the history of medicine have used the technique of oral histories in the research approaches, and, especially since the start of the 2000s, have produced a variety of materials. The large amounts of raw materials published in these many disciplines are sure to bring even higher research achievements. Second, for the most part, oral history researches in the medical profession have concentrated on second-tier practitioners, such as midwives, apothecaries, and acupuncturists, and the experiences of such untypical sufferers as lepers and victims of germ and atomic warfare. While the oral history of more prominent medical figures tends to underline his or her story of success, the oral histories of minority participants in the medical profession and patients can reveal the truth that has remained veiled until now. It is especially meaningful that these oral histories enable researchers to reconstruct history from below, as it were. Third, the researches that take the oral history approach are intended to complement documentary records. Surprisingly, through being given the opportunity to tell their histories, the interviewees have frequently experienced the testimony as an act of self-healing. Formally, an oral history is not a medical practice, but in many cases the interviewee is able to realize his or her own identity and to affirm his or her own life's story. It is in this light that we need to pay attention to the possibilities of such a humanistic form of therapy. Finally, because the research achievements depend on oral materials, the objectivity and rationality of description take on an important research virtue. When conducting an oral history, the researcher partakes of a close relationship with interviewees through persistent contact and can often identify with them. Accordingly, the researcher needs to take care to maintain a critical view of oral materials and adopt an objective perspective over his or her own research object.


The Distribution of OpenCL Kernel Execution Across Multiple Devices Steven Gurfinkel Master of Applied Science Graduate Department of the Edward S. Rogers Sr. Department of Electrical and Computer Engineering University of Toronto 2014 Many computer systems now include both CPUs and programmable GPUs. OpenCL, a new programming framework, can program individual CPUs or GPUs; however, distributing a problem across multiple devices is more difficult. This thesis contributes three OpenCL runtimes that automatically distribute a problem across multiple devices: DualCL and m2sOpenCL, which distribute tasks across a single system's CPU and GPU, and DistCL, which distributes tasks across a cluster's GPUs. DualCL and DistCL run on existing hardware, m2sOpenCL runs in simulation. On a system with a discrete GPU and a system with integrated CPU and GPU devices, running programs from the Rodinia benchmark suite, DualCL improves performance over a single device, when host memory is used. Running similar benchmarks, m2sOpenCL shows that reducing the overheads present in current systems improves performance. DistCL accelerates unmodified compute intense OpenCL kernels, obtained from Rodinia, AMD samples and elsewhere, when distributing them across a cluster.


The purpose of this study was to assess the efficacy of intravenous iodinated contrast media pretesting and to determine whether pretesting can reduce the incidence of adverse reactions caused by administration of iodinated contrast media. We collected data on 3315 patients who had received injections of iodinated contrast media in our department from November 2005 to June 2006. The patients were divided into two groups: those in whom pretesting was performed and 1142 patients in whom pretesting was not performed. The incidence of adverse reactions after intravenous contrast media administration (including ionic and nonionic iodinated contrast media) was recorded and analyzed. In the 2173 patients with pretesting, 7 had adverse reactions during pretesting and only 1 proceeded to complete the study. This patient did not have an adverse reaction after the study. Adverse reactions occurred in 36 (1.66%) of the 2167 patients who underwent pretesting. In the 1142 patients without pretesting, adverse reactions occurred in 19 (1.66%) of these patients. The results showed no statistical difference between the two groups (p = 0.997). Pretesting patients for adverse reactions to intravenous iodinated contrast media does not decrease the incidence of peri- and postprocedure adverse reactions.


Three-dimensional modeling of building environments and indoor positioning is essential for emergency response in cities. Traditional ground-based measurement methods, such as geodetic astronomy, total stations, and global positioning system (GPS) receivers, cannot meet the demand for high precision positioning and it is therefore essential to conduct multiple-angle data-acquisition and establish three-dimensional spatial models. In this paper, a rapid modeling technology is introduced, which includes multiple-angle remote sensing image acquisition based on unmanned aerial vehicles (UAVs), an algorithm to remove linear and planar foregrounds before reconstructing the backgrounds, and a three-dimensional modeling (3DM) framework. Additionally, an indoor 3DM technology is introduced based on building design drawings, and an indoor positioning technology is developed using iBeacon technology. Finally, a prototype system of the indoor and outdoor positioning-service system in an urban firefighting rescue scenario is introduced to demonstrate the value of the method proposed in this paper.


The effects of androgens on human skin include growth and differentiation of sebaceous glands, terminal hair growth, epidermal barrier function, wound healing, and modification of the cutaneous microbiome. Androgens exert their activities via ligand formation with intracytoplasmic androgen receptors which can then translocate to the nucleus and interact with genetic androgen response elements to influence signaling cascades. Differences in tissue distribution and activities of enzymes that modify androgen synthesis and catabolism, variations related to gender and ethnicity/race, and genetic polymorphisms that affect androgen receptor functionality directly impact androgen physiology and the pathophysiology associated with a variety of disease states. This manuscript reviews the fundamentals of androgen physiology, androgen synthesis and catabolism in local skin tissue, androgen receptor activity, as well as the impact of genetic polymorphisms and gender. Emphasis is placed on the roles of androgenic activity in sebaceous gland development, sebum production, and the pathophysiology of acne vulgaris. J Drugs Dermatol. 2020;19(3 Suppl 1):s30-35.


[(35)S]Cystine-labelled immunoglobulin MOPC21 (IgG1) was prepared from myeloma cells in tissue culture. Carrier myeloma protein was added and the protein was digested with pepsin. The digest was fractionated on Sephadex G-50 into two fractions, further digested with trypsin and again fractionated on Sephadex. Disulphide-bridge peptides were purified by electrophoresis and chromatography and identified by radioautography. A peptide of 96 residues was isolated, which contains both the heavy-light interchain disulphide bridge and all the inter-heavy-chain disulphide bridges. Other peptides were isolated, accounting for all the intrachain disulphide bridges (which could be placed by homology with proteins of other species), except for the variable section of the light chain. Sequences describing this missing disulphide bridge were obtained from totally reduced and alkylated light chains. Peptides related to the interchain disulphide-bridge peptide were isolated from partially reduced and alkylated myeloma protein and from totally reduced heavy chain. The interchain disulphide-bridge peptide was placed at the C-terminal position of the F(ab')(2) fragment, prepared by digestion of the protein with pepsin at pH4.0. Sequences from the heavy-chain intrachain disulphide bridges of MOPC 21 immunoglobulin are compared with homologous sequences from mouse myeloma proteins of other subclasses and proteins of other species.


Aims The neuropsychological impact of sleep disordered breathing (SDB) is well recognised but identifying which children require intervention is a challenge due to the poor specificity of history and examination findings. Polysomnography is the gold standard but availability is limited. Oximetry is commonly used to screen for SDB but, despite good specificity, it lacks sensitivity. This study aims to assess the impact of using a multi-channel sleep system (MCSS) on detection and outcomes in SDB. Methods Data was collected prospectively on children with symptoms of SDB undergoing sleep studies between 08/2015–08/ 2016, following assessment in ENT or paediatric clinics at a district general hospital. Studies were performed using Stowood Scientific Instruments Visi-3 sleep systems incorporating audio, video, pulse transit time and oximetry data. Study findings were categorised as normal; primary snoring; upper airway resistance syndrome (UARS); obstructive sleep apnoea or 'abnormal other' and compared with standard oximetry criteria. Results (Figure 1 here) Abstract G438 Figure 1 The use of MCSS identified 69 more children with abnormalities than oximetry alone. Seven children with abnormal oximetry were found to have normal studies. There were 3 oximetry failures who were categorised normal; primary snoring and UARS using MCSS. The median age of children with positive studies was 4.78 years (range 0–17 years). (Figure 2 here) Data published by the Royal College of Surgeons show directly standardised tonsillectomy rates (SDB), for the 2 Clinical Commissioning Groups served by the Trust, of 12.56/1 00 000 and 17.76/1 00 000 population (mean 26.03/1 00 000 population; England).1 Conclusions Twice as many children with SDB were identified using MCSS compared with oximetry. Its use was associated with low adenotonsillectomy rates due to surgeons managing most children with normal studies conservatively. The need for inpatient stay increases the cost of MCSS but this is offset by fewer children undergoing surgery. Forty children with symptoms of SDB and recurrent tonsillitis, who had studies to stratify perioperative risk before tonsillectomy, could have been evaluated more cost-effectively with oximetry. If validated for use at home, MCSS would further reduce costs while detecting SDB with increased sensitivity and specificity. Reference Royal College of Surgeons, Procedure Explorer Tool http://rcs.methods.co.uk/pet.html


In a full-scale CCS, millions of tons of CO2 must be stored underground. Injection of dry or undersaturated (with respect to water) CO2 leads to dry-out of formation water and salt precipitation. Salt precipitation during CO2 injection into the geological formations causes reduced injectivity and negatively influences reservoir rock properties. It also may have the potential to block CO2 leakage pathways within the fractured caprocks. The present-day reservoir-scale models of salt precipitation consider mechanisms such as water evaporation into CO2 and capillary backflow of water into the dried zone. However, it has been suggested that salt precipitation due to these mechanisms fills only a fraction of the pore network and does not significantly impact the permeability. We report microfluidic experiments on glass-microchips and organic-rich shale specimens to provide insights into the physics and dynamics of salt precipitation at pore-scale and to find the possible explanations for the large-scale salt precipitation observed in the field operations. Moreover, we investigate whether salt crystals can partially or entirely clog fracture apertures and leaking pathways in the seal sequences. The experimental results introduce two interrelated phenomena –self-enhancing of salt growth and water film salt transport, which together remarkably intensify the rate and amount of precipitations. It is shown that salt crystals, although at different rates, grow in both aqueous and gas phases. The salt crystals precipitate in two distinct forms: (a) large single cubic halite crystals in the aqueous phase and (b) dense micrometer-sized halite crystals on the interface of rock and CO2 stream. The micrometer-sized crystals in the gas phase create a microporous medium with large capillarity that can strongly imbibe brine over long distances to the evaporation front via capillary connected water films. It is demonstrated that the CO2 phase states influence magnitude, distribution and precipitation patterns of salt accumulations.


With looming political tailwinds, consumer preference shifts, and such disruptive technologies as blockchain, the mortgage landscape will continue to be transformed in 2017 and beyond. Expect to see more innovation and consolidation as mortgage service companies place their bets for the coming "lift off" in e-mortgages.


The blockbuster hit of the year 2000 reached theaters less than six months before the contentious U.S. presidential election. Gladiator spoke directly to the issues that haunted the 2000 campaign, using the Roman empire of 180 C.E. to stand in for a contemporary America longing for moral leadership and republican values. But the restored Roman republic will presumably be utterly unlike the democracy promised by the film's Marcus Aurelius. Gladiator used allusions to the 1960 Spartacus in order to appear progressive before finally giving the people, a dull lot addicted to the violent entertainment of gladiatorial combat, the custodians they clearly need—good men in the aristocratic senate supported by a loyal military. This paper explores the parallels between the Republican strategies of 2000 and the republican sympathies of the film.


Abstract. Four evening events and one morning event of joint EISCAT/STARE observations during ~22h are considered and the differences between observed STARE line-of-sight (l-o-s) velocities and EISCAT electron drift velocities projected onto the STARE beams are studied. We demonstrate that the double-pulse technique, which is currently in use in the STARE routine data handling, typically underestimates the true phase velocity as inferred from the multi-pulse STARE data. We show that the STARE velocities are persistently smaller (1.5–2 times) than the EISCAT velocities, even for the multi-pulse data. The effect seems to be more pronounced in the evening sector when the Finland radar observes at large flow angles. We evaluate the performance of the ion-acoustic approach (IAA, Nielsen and Schlegel, 1985) and the off-orthogonal fluid approach (OOFA, Uspensky et al., 2003) techniques to predict the true electron drift velocity for the base event of 12 February 1999. The IAA technique predicts the convection reasonably well for enhanced flows of >~1000m/s, but not so well for slower ones. By considering the EISCAT N(h) profiles, we derive the effective aspect angle and effective altitude of backscatter, and use this information for application of the OOFA technique. We demonstrate that the OOFA predictions for the base event are superior over the IAA predictions and thus, we confirm that OOFA predicts the electron velocities reasonably well in the evening sector, in addition to the morning sector, as concluded by Uspensky et al. (2003). To check how "robust" the OOFA model is and how successful it is for convection estimates without the EISCAT support, we analysed three additional evening events and one additional morning event for which information on N(h) profiles was intentionally ignored. By accepting the mean STARE/EISCAT velocity ratio of 0.55 and the mean azimuth rotation of 9° (derived for the basic event), we show that the OOFA performs reasonably well for these additional events. Key words. Ionosphere (ionospheric irregularities, plasma waves and instabilities, auroral ionosphere)


The theory of large one-shot simultaneous-play games with a biosocial typology has been presented in both the individualized and distributionalized forms— large individualized games (LIG) and large distributionalized games (LDG), respectively. Using an example of an LDG with two actions and a single trait in which some Nash equilibrium distributions cannot be induced by the Nash equilibria of the representing LIG, this paper offers three equivalence results that delineate a relationship between the two game forms. Our analysis also reveals the different roles that the Lebesgue unit interval and a saturated space play in the theory.


The objective of this paper is to analyze the main geometric parameters which affecting the stiffness of anti-roll bar. Further these parameters are also affecting the body roll angle. By the optimization of these geometric parameters we can able to increase the stiffness of bar and which will help to reduce the body roll angle. To calculate the stiffness of anti-roll bar Finite Element software ANSYS is used. The deflection for the change in internal angle, arm length, moment of inertia, distance between bushes found by static analysis. To calculate the body roll angle equation used from the literature survey, however they haven't taken all the suspension characteristics in the calculation of moment caused by the suspended and non-suspended masses. The equilibrium condition is considered between the moments of the force acting on the suspended and non-suspended masses and moments of reaction of the springs and anti-roll bar used in suspensions. The comparison of different anti-roll bar is based on the basis of stiffness per weight. The anti-roll bar which having more ratio of stiffness per weight can be used in the vehicle. As it will improve the stiffness of bar with small increase in weight, which will result in the improving roll stability of the vehicle.


INTRODUCTION
Clinical judgment is necessary for clinical decision making and enhancing it in nursing students improves health care quality. Since clinical judgment is an interactive phenomenon and dependent on context and culture, it can be affected by many different factors.

AIM
To understand the experiences of Iranian nursing students and teachers about the factors influencing nursing students' clinical judgment.

MATERIALS AND METHODS
A qualitative study was conducted using a directed content analysis approach. In this study, purposive sampling and semi-structured interviews were applied with seven nursing students, six faculty member teachers and four clinical instructors from Guilan University of Medical Sciences, Gilan, Iran.

RESULTS
The factors influencing nursing students' clinical judgment consisted of five main categories including thoughtful behaviour, professional ethics, use of evidence based care, the context of learning environment and individual and professional features of clinical teachers.

CONCLUSION
Relying on the results of this research, teachers can create an appropriate educational condition and a safe psychological atmosphere, use instructional strategies strengthening deep thought processes, applying professional ethics and scientific evidence and principles to establish clinical judgment in nursing students.


Massive stars are rare but of paramount importance for their immediate environment and their host galaxies. They lose mass from their birth through strong stellar winds up to their spectacular end of their lives as supernovae. The mass loss changes as they evolve and in some phases it becomes episodic or displays outburst activity. One such phase is the Yellow Hypergiants, in which they experience outbursts due to their pulsations and atmosphere instabilities. This is depicted in photometry as a decrease in their apparent magnitude. The object ρ Cassiopeia (Cas) is a bright and well known variable star that has experienced four major outbursts over the last century, with the most recent one detected in 2013. We derived the light curves from both visual and digital observations and we show that with some processing and a small correction ( ∼ 0 . 2 mag) for the visual the two curves match. This highlights the importance of visual observations both because of the accuracy we can obtain and because they fully cover the historic activity (only the last two of the four outbursts are well covered by digital observations) with a homogeneous approach. By fitting the outburst profiles from visual observations we derive the duration of each outburst. We notice a decreasing trend in the duration, as well as shorter intervals between the outbursts. This activity indicates that ρ Cas may be preparing to pass to the next evolutionary phase.


In the present research Kuh-e Siah Section in the Northeast of Shiraz in the Interior Fars, was investigated to study microfacies, sequence stratigraphy, facies analysis and sedimentary environment of Fahliyan Formation. Generally, 345 meters of these sediments were studied by investigating 240 thin sections. In this study, the indicator microfacies were accurately identified which include Mudstone, Wackestone, Packstone and Grainstone. Besides, skeletal and non-skeletal grains of these microfacies are Intraclast, Bioclast, Exteraclast and Peloid. According to lithostratigraphic study, underneath limit of Fahliyan Formation with the Surmeh Formation and its upper contact with Gadvan Formation were in the gradual form (SB2) and included (TST-LST-Early HST-Late HST) system tracts. In general, there were two second-degree sequences in this section., According to the analysis of the sedimentary environment, the The lowermost of the Fahliyan Formaion is comprised of the Inner shelf deposit Which changes to Open marine sediments (with homoclinal type) And eventually terminates to outer shelf deposit. Based on the received micropaleontologic data, the age determination of the Fahliyan Formation Is assigned to Neocomian.


Abstract Two years experiment was carried out to compare the nutritional composition in bulbs of ten onion cultivars grown in the field conditions. Pyruvic acid, ascorbic acid and soluble sugars were determined in the edible part of onion bulbs. In most cultivars the content of pyruvate as the pungency index was ranged between 3-7 μmol g-1 fresh weight (medium pungency), however, three of them exceeded 7 μmol g-1 fresh weight (high pungency). A higher level of pyruvate corresponded in most cases with higher sugar content but was not correlated with that of ascorbic acid.


In everyday practice, dentists are confronted with an increasing number of patients with complex medical problems. There is divergence of opinion among dentists regarding how to obtain a thorough medical/social history. Purpose: The objective of this audit is to produce a standardised medical history in order to identify the medically compromised patient attending the general dental practitioner. At present in the Dublin Dental School and Hospital, there are three different methods: a verbal enquiry, and a written or an electronic questionnaire. This study was undertaken to identify any differences or discrepancies between each of the three methods in eliciting the medical history, and to determine whether one method was superior to the others. The results are used to recommend the most accurate method for obtaining a thorough health history for practitioners, both in a hospital and a general practice setting. Method: One hundred and fifty charts within the Dublin Dental School and Hospital of all new patients at a randomly chosen clinic were selected and then audited: 50 charts from the oral and maxillofacial surgery assessment clinics (written pro forma questionnaire), 50 from the oral medicine clinic (consultant verbal enquiry), and 50 from A&E (electronic questionnaire) were compared to determine if an adequate medical history was taken, and to detect differences and discrepancies in patients' medical histories. The records pertained to 91 females and 59 males. The age distribution was 5-87 years for females and 3-85 years for males. The mean age was 45 years for females and 42 years for males. Results: The written patient-administered pro forma questionnaire, combined with verbal verification by the clinician/consultant, proved to be the most useful and consistent method for detecting medical problems in dental patients. The consultant verbal enquiry alone showed more inconsistency than the other two methods. Based on these results, a modified questionnaire for use within all departments in the Dental Hospital has been proposed. This may also be suitable for use by general dental practitioners in their practice setting. Conclusion: It is incumbent on the clinician/dentist to evaluate each patient's general health prior to delivering treatment in order to avoid unnecessary and preventable complications. The use of written patient-administered pro forma questionnaires is beneficial but must be verified by the examining clinician/dentist and assessed at each new visit (6-12 monthly) to be contemporaneous. Journal of the Irish Dental Association 2011; 57 (1): 54-59. February/March 2011 54 : VOLUME 57 (1) Peer-reviewed JOURNAL OF THE IRISH DENTAL ASSOCIATION JIDA_FebruaryMarch2011_AW_JIDA 07/02/2011 10:30 Page 54


Despite the huge primary energy consumption associated with heating and cooling (H&C) demand in EU building stock, the share of installed renewable H&C solutions is still marginal (i.e. 5%). In order to speed up a transition towards the widespread application of renewable H&C in buildings, innovative solutions are designed to compete against traditional solutions. SunHorizon project aims to demonstrate the potential for a user-friendly and costeffective solution based on an optimized design and combination of commercial innovative solar technologies (thermal or/and PV) and Heat Pumps (HP). This paper presents how different technologies (two solar panels, three HPs and thermal storage) have been coupled in four different Technology Packages (TPs) to satisfy H&C demand of both residential and tertiary buildings. Preliminary thermo-economic TRNSYS simulation results are presented about four demo sites in Latvia, Germany and Spain, to demonstrate such innovative solutions able to cover up to 80% of H&C demand with a reduction of greenhouse gas (GHG) emissions up to 70%.


Walking through the spice markets of Tashkent or down the Champs-Elysees in search of something unique that I can't find at home, I am struck by two things: * Nothing has changed in hundreds of years. Marco Polo, Christopher Columbus and other explorers couldn't resist the urge to trade in goods that they could not find at home, such as precious metals, spices and silks. * Everything has changed. The world has become a much smaller place. It is more and more difficult to find things that are unique. I can explore the world's offerings and gather my trinkets via the Internet without ever leaving my living room. The globalization of the markets is not limited to trinkets. Multinational corporations of all sizes take advantage of the availability of raw materials and lower labor costs overseas to provide us with a wide array of goods and services at lower cost. Foreign companies in growing numbers routinely raise money in U.S. financial markets, and U.S. investors increasingly seek to diversify through foreign investments. As of April the 48 major world stock exchanges listed 39,152 companies, of which 2,648 were cross-border listings. The clients we serve, the companies we work for and the students we educate are all affected by the world economy. They will increasingly take advantage of the international opportunities that await them. There is no doubt this globalization of the world's markets has been enabled by technology, which allows us to reach millions of people around the world in a matter of seconds. That has created new opportunities for businesses and investors and new sources of capital for issuers. Is this a good thing? My answer is "yes." We need to embrace the world economy. It is a powerful force for raising living standards around the globe. The free flow of goods, labor and capital lowers costs as it increases investment and provides jobs. Higher living standards around the world would contribute to economic, political and social stability. Whether we like it or not, globalization is happening. The real question is: How can we take advantage of the opportunities? DISPELLING MYTHS It is a misconception that international opportunities are available only to large, multinational organizations or that access to large amounts of capital and global reach are necessary to be successful. In fact, smaller and more nimble organizations can do quite well in the international markets. They can act quickly and focus on niche markets--such as specialized computer software or equipment or one-of-a-kind consumer goods--that larger companies may overlook or not be interested in serving. Furthermore, the financing needed is often less than anticipated. We also need to remember that not all exports are physical goods. In fact, companies in the service industries make up the fastest-growing sector of the global economy, and the United States is the largest exporter of services. CPAs in public practice can advise clients interested in exporting the services they offer--and also can export their own services. The advantages to exporting are many, including increased profits and the chance to take advantage of idle capacity and certain tax incentives, as well as expand the company's market. But, of course, there are risks. Small and midsize businesses or practices considering going international need to hire advisers familiar with laws and regulations, trade restrictions, distribution requirements and other business practices and standards in the countries where they will be working. Depending on the country, the business environment can be quite different From our own. CONVERGENCE OF STANDARDS Here in the United States, we are accustomed to an infrastructure with national rules that reduce risks--giving us the confidence to enter into transactions--and contribute to a smoothly functioning economy within our borders. The global markets require a similar set of international rules to achieve a smooth functioning of the market economy. …


Diffusion magnetic resonance imaging (MRI) allows the probing of tissue microstructure in the brain non-invasively. The standard method for quantitatively analysing microstructure is diffusion tensor imaging (DTI) with a typical b-value of 1000 s/mm2. However, high b-value imaging (b > 2000 s/mm2) can increase the contrast between tissue types. The disadvantage of high b is the detrimental effect of decreased signal-to-noise-ratio (SNR) on diffusion models. This work begins by investigating the efficacy of exploiting the fitting error of DTI at b = 3000 s/mm2 to provide further information of brain microstructure using bootstrapped principal eigenvectors, µ1. This study revealed binomial distributions of µ1 with potential to be exploited to provide further information of the underlying microstructure.
Another factor affecting SNR in diffusion-weighted data is the magnetic field strength of the MRI scanner. Change in DTI measures with SNR by way of increasing b-value and at 1.5 versus 3 T was systematically assessed. Significant differences in DTI measures between field strengths were found suggesting careful comparison of DTI data when acquired at 1.5 and 3 T. The limitations of DTI in modelling the slow diffusion component (fitting between b = 2000 to 3000 s/mm2) were also demonstrated.
Other algorithms exist for modelling diffusion profiles without the assumption of diffusion following a Gaussian distribution. One such method is the recently developed multi-compartment model NODDI (Neurite Orientation Dispersion and Density Imaging). The final aim of this work is to further understand how this technique behaves with change in magnetic field strength and its within-subject reproducibility in relation to DTI. This investigation found significant field strength effect on NODDI estimates as well as reasonable white matter diffusion measurements in multi-fibre regions where DTI fails. However, given the complexity of NODDI, greater within- subject variability was found in white matter compared to the simpler tensor model.


Coronary artery disease (CAD) is intrinsically related to presence of atherosclerotic plaques. The rupture of this plaques is responsible for most acute coronary events. Intracoronary optical coherence tomography (IOCT) enables a detailed high-resolution visualization of micro-structural changes of the arterial wall in vivo. In this paper, we introduce a new way of identifying atherosclerotic plaques using 1D Convolutional Neural Networks (CNN) analyzing only the lumen contour. Training and test were performed with 1600 IOCT frames from in vivo patients. In our tests, we achieved f1-score of 95% for atherosclerotic plaque recognition. The results allow us to report an interesting correlation between the lumen contour geometry and the presence of plaques in the vascular wall observed through IOCT exams. The use of lumen contour for plaque detection opens two new perspectives: assisting specialists in the task of detecting plaques visually by paying special attention to the lumen and allowing methods to work in real time to detect plaques using efficient methods that use less information and deliver accurate results.


Objective: To describe the UK experience with Renal Denervation (RDN). Design and method: RDN may lower blood pressure (BP) in people with resistant hypertension. The UK Renal Denervation Affiliation is an independent, investigator-led initiative. Each centre had done >5 cases. A standardised dataset was collected retrospectively, anonymised and submitted to the coordinating centre for analysis. Results: Results from 246 cases from 16 centres are reported. Average cases per centre was 15. Five different ablation technologies were used: unipolar catheters in 198 and multipolar in 48. Mean age was 56.7 years, 53% female, 87% Caucasian and 27% diabetes. Previous stroke/TIA - 24%; myocardial infarction - 15%; proteinuria - 26%. Patients were screened by a mean of 1.6 specialists with an interest in hypertension. 86% attended specialist hypertension clinics. On average 4.7 drugs were used before RDN; 95% were on 3+ drugs; 90% were on RAS blockers, 90% diuretics and 56% aldosterone antagonists at time of RDN. Pre-RDN mean office BP was 186/102 mmHg. Ambulatory blood pressure monitoring (ABP) data were available for 179 patients (73%). Average pre-RDN ABP was: daytime - 170/98; night - 154/86. Average follow-up was 10.7 months. Mean Office BP post-RDN was 164/93, a fall of 22/9 mmHg (P < 0.001). In 24%, office SBP fell 40+ mmHg. On average, 0.8 drugs were withdrawn per patient and 0.3 drugs added between RDN and follow-up. Mean daytime ABP after RDN was 158/92 and nighttime ABP 145/81 - fall in daytime ABP was 12/6 (p < 0.001). 18% had a drop in day systolic ABP of >20 mmHg. A decrease in GFR >25% was seen at 10 months in 5% patients. Otherwise, no significant complications were seen. Conclusions: In a cohort of 246 patients from 16 UK centres who had undergone renal denervation, a significant fall in blood pressure was observed. Office BP fell by 22/9 mmHg. Daytime ambulatory BP fell by 12/6 mmHg. Carefully selected patients with resistant hypertension exhibited significant BP reduction following RDN. This was a group with severe hypertension who had been well characterised in specialist hypertension clinics. Drug additions/withdrawals did not appear to explain the BP fall.


Understanding the nanoparticle-cell interaction is critical for the safe development of nanomaterials. Herein, we explore the impact of three metal oxide nanoparticles, nonporous Stober SiO(2), mesoporous SiO(2), and nonporous anatase TiO(2) nanoparticles, on primary culture mast cells. Using transmission electron microscopy and inductively coupled plasma atomic emission spectroscopy, we demonstrate that each class of nanoparticle is internalized by the mast cells, localizing primarily in the secretory granules, with uptake efficiency increasing in the following order: nonporous SiO(2) < porous SiO(2) < nonporous TiO(2) nanoparticles. The influence of nanoparticle-laden granules was assessed using carbon-fiber microelectrode amperometry measurements that reveal functional changes in chemical messenger secretion from mast cell granules. Both nonporous and porous SiO(2) nanoparticles cause a decrease in the number of molecules released per granule, with nonporous SiO(2) also inducing a decrease in the amperometric spike frequency and, therefore, having a larger impact on cell function. As the two classes of SiO(2) nanoparticles vary only in their porosity, these results suggest that, while the mesoporous SiO(2) has a drastically larger total surface area due to the pores, the cell-contactable surface area, which is higher for the nonporous SiO(2), is more important in determining a nanoparticles' cellular impact. In comparison, exposure to nonporous TiO(2) slows the kinetics of secretion without altering the number of molecules released from the average granule. The varying immune cell response following exposure to nonporous SiO(2) and nonporous TiO(2) indicates that the nanoparticle-cell interactions are also modulated by surface chemistry.


Pertussis is a highly contagious infectious disease of the respiratory tract which is caused by Bordetella pertussis. Before widespread introduction of vaccination against pertussis, almost every child contracted pertussis. The disease is most severe in neonates and children under the age of 1. Introduction of mass vaccination reduced the number of pertussis cases significantly and resulted in a 10-fold decrease in pertussis mortality in the Netherlands in the late 1950s. Despite vaccination, pertussis remained endemic. A major epidemic occurred in the Netherlands in 1996. Since the 1996 outbreak, the Netherlands now has an epidemic pertussis cycle with peaks every 2 to 3 years during the last decade. Also in several other European countries, as well as Canada, The United States and Australia, a re-emergence of pertussis was observed. Several explanations were proposed for the sudden increase of pertussis in the Netherlands including waning immunity in adolescents and adults, increased reporting, improved diagnosis of the disease and the adaptation of the B. pertussis population. In the Netherlands, pathogen adaptation has probably played an important role in the resurgence of pertussis. Vaccine adapted strains showed polymorphisms in two proteins implicated in protective immunity: P.69 Prn and Ptx. The role of P.69 Prn in protective immunity has been well documented in both humans and in animal models. Furthermore, P.69 Prn is present in several of the currently most used ACVs.
Until recently, relatively little was known about the antibody response to P.69 Prn, the location of epitopes on P.69 Prn and the role of variation in Prn on immune evasion. Variation in the variable region1 was described to affect the Ab response to this region, but no direct evidence or a feasible mechanism for immune evasion was described. The goal of this thesis was to identify the location of (protective) epitopes to which human Abs are directed, and to investigate the role of variation in P.69 Prn and the implications for the anti-P.69 Prn Ab response.
Our results clearly indicate that Prn has evolved several ways to escape antibody and possibly phage binding. We showed that the N-terminus of P.69 Prn harbors important epitopes. Furthermore, our data suggests that the variable region1 has evolved to hide those important epitopes from immune recognition and possibly phage binding. In addition, Prn has several other flexible (and variable) loops that are employed to hide adjacent epitopes from the immune system (epitope masking). The N- and C-termini of P.69 Prn interact physically, which results in the masking of a part of Prn. Since the C-terminus has a linear structure that folds towards the N-terminus, it is likely that the Ab response to this region is less efficient then an Ab response directed to the conformational epitopes located in parts of the molecule that are covered by the C-terminus (conformational masking). The loops that are exposed, e.g. region1, region2, and several other loops, were shown to be highly variable (antigenic variation). We showed that deletion of the variable regions does not improve protection against infection. Apparently deletion of the decoy regions does not automatically skew the Ab response towards the conserved protective epitopes. However, we have shown that it is possible to employ synthetic peptides to induce a protective response towards conserved and protective epitopes.
The results presented in this thesis have shed new light on the mechanisms employed by bacteria, and B. pertussis in particular, to evade immune recognition. These results will facilitate the development of new, possibly synthetic, but mainly more effective vaccines.


The main objective of the study is to investigate the impact of globalization on the quality of life in the Asian countries. The panel data for Asian countries was analized for the period from 1995 to 2015. The Human Development Index (Proxy variable of quality of life) was used as dependent variable, and political, economic and social globalization were used as independent variables. The stationarity of variables was checked and we found that all variables (LPG, LEG, LSG, HDI, KOF, LGDP, and PR) were not stationary at level but at first difference all variables were stationary. Pedroni and Johansan co-integration tests were used to find the long-run relationship among the variables. Fully Modified OLS shows that there is a positive impact of political, economic and social globalization on the quality of life in the Asian countries in the long run. The results of this study show that globalization enhances the quality of life of their residents by improving Human Development Index of Asian countries. Not only KOF Index but its main aspects (political, economic and social globalization) also play a role in improving quality of life in the Asian countries.


&NA; Although habitual caffeine users ingest the drug repeatedly throughout each day, the persistence of caffeine's known cardiovascular effects with such repeated use has not been investigated. Blood pressure and heart rate were measured under resting conditions in 10 healthy, male coffee or tea drinkers for 2 hours following a pretreatment dose of caffeine (125 mg) on two separate days after overnight abstinence. Either a second caffeine dose or placebo was administered and measurements continued for 1.5 hours. Compared to placebo, the second dose of caffeine produced significant increases in heart rate and diastolic and mean arterial, but not systolic, blood pressures. The results suggest that the cardiovascular effects of caffeine may persist throughout the day with repeated administration of moderate amounts of caffeine. Habitual caffeine use does not necessarily lead to complete tolerance, which suggests that caffeine's cardiovascular effects could contribute to an increased risk of cardiovascular disease.


An important computational tool in drug design is target prediction where either for a given chemical structure the interacting biomolecules (e.g. proteins) must be identified. Chemical structures interact with different biomolecules if they have similar 3D structure. Thus, the outputs of the prediction are highly interdependent from each other. Furthermore, we have partially labelled molecules since not all training molecules are measured of being active on each biomolecule. The Merck Kaggle challenge on chemical compound activity was won by Hinton's group with deep networks. This indicates the high potential of deep learning in drug design and attracted the attention of big pharma. However, the unrealistically small scale of the Kaggle dataset does not allow to assess the value of deep learning in drug target prediction if applied to in-house data of pharmaceutical companies. Even a publicly available drug activity data base like ChEMBL is magnitudes larger than the Kaggle dataset. ChEMBL has 13 M compound descriptors, 1.3 M compounds, and 5 k drug targets, compared to the Kaggle dataset with 11 k descriptors, 164 k compounds, and 15 drug targets. On the ChEMBL database, we compared the performance of deep learning to seven target prediction methods, including two commercial predictors, three predictors deployed by pharma, and machine learning methods that we could scale to this dataset. Deep learning outperformed all other methods with respect to the area under ROC curve and was significantly better than all commercial products. Deep learning surpassed the threshold to make virtual compound screening possible and has the potential to become a standard tool in industrial drug design.


Parameter estimation of a nonlinear model based on maximizing the likelihood using gradient-based numerical optimization methods can often fail due to premature termination of the optimization algorithm. One reason for such failure is that these numerical optimization methods cannot distinguish between the minimum, maximum, and a saddle point; hence, the parameters found by these optimization algorithms can possibly be in any of these three stationary points on the likelihood surface. We have found that for maximization of the likelihood for nonlinear mixed effects models used in pharmaceutical development, the optimization algorithm Broyden–Fletcher–Goldfarb–Shanno (BFGS) often terminates in saddle points, and we propose an algorithm, saddle-reset, to avoid the termination at saddle points, based on the second partial derivative test. In this algorithm, we use the approximated Hessian matrix at the point where BFGS terminates, perturb the point in the direction of the eigenvector associated with the lowest eigenvalue, and restart the BFGS algorithm. We have implemented this algorithm in industry standard software for nonlinear mixed effects modeling (NONMEM, version 7.4 and up) and showed that it can be used to avoid termination of parameter estimation at saddle points, as well as unveil practical parameter non-identifiability. We demonstrate this using four published pharmacometric models and two models specifically designed to be practically non-identifiable.


Background Low participation rates in randomised controlled trials involving children are almost a universal problem, leading to high cost and low statistical power. Trial, parent/family, child, and physician factors have been reported to influence parental willingness to consent for paediatric trials. Purpose To identify modifiable and unmodifiable factors associated with parental consent. Methods Demographic and clinical characteristics of children and their families and physician characteristics associated with parental consent were evaluated in a recent randomised placebo-controlled trial of prophylactic antibiotics to prevent recurrent urinary tract infection. Results Of 1109 eligible children identified (mean age, 2.0 years), 412 parents (37.2%) consented. On a multivariate analysis, the only modifiable factor associated with consent was request for consent by a member of the research study team rather than by a member of the clinical team (risk ratio (RR) = 1.9, 95% confidence interval (CI): 1.2–2.9). The unmodifiable factors significantly associated with consent were age of the child (≥4 years) (RR = 1.2, 95% CI: 1.1–1.4), presence of vesicoureteric reflux (RR = 1.5, 95% CI: 1.3–1.8), inpatient management of the index infection (RR = 0.8, 95% CI: 0.7–0.9), and multiple (≥4) symptoms at presentation (RR = 1.3, 95% CI: 1.1–1.5). Limitations We have reported data from only one of the four participating centres in this trial. Data on non-consenters in other participating centres were not completely collected. Data on characteristics of the recruiting physician were limited. These findings are applicable for those considering a single randomised controlled trial. Conclusions Parent, child, and physician factors are associated with consent for trial participation, with most not being modifiable. Having a member of the research study team approach the parent for consent appears to be the only feasible strategy for increasing recruitment to randomised trials in this setting.


Hydro responded to demands from residents of farms and hamlets for a fair share of the "public power" that was being distributed to municipalities in southwestern Ontario in 1910. It extended its transmission lines along the back concessions of the region, developed new agrarian applications for electricity, and devised a rural rate schedule capable of attracting new customers and encouraging electrical consumption. Provincial government funds were allocated to Hydro for rural development in the 1920s and moderate growth was maintained until World War II interrupted the rural construction program. After the war, however, rural electrification in southern Ontario progressed rapidly until 1958 when provincial money for that region was substantially reduced and Hydro redirected its attention to the needs of the North. While Fleming shows that the public utility proved responsive to changing economic conditions, technological developments, and political considerations as it became a world leader in rural electrification, he also presents evidence of the policies and methods which have engendered negative sentiment toward Ontario Hydro. For example, he reveals that the "power at cost" policy was both a way to achieve price reduction and a strategy for price maintenance. In describing the various influences on Ontario Hydro's program of rural electrification, Fleming has drawn from an impressive array of archival and newspaper sources, including the Ontario Hydro Archives, the Ontario Archives of the Hydro-Electric Commission, and files in the office of the Ontario Premier. Power at Cost will become the standard reference on the subject of rural electrification in Ontario.


The main purpose of my thesis is to determine the current influence of credit rating downgrades and upgrades made by Moody's on the U.S. equity market. Previous literature has already talked about the effect of credit ratings on stock or bond price, however, my paper is different from previous works. I will focus on a single nationally recognized credit rating organization; I will talk about the both downgrade effect and the upgrade effect; I will do a case study of the credit rating effect on Ford, IBM, and Boeing. The results indicates that overall, Moody's rating announcements have an important effect on the stock abnormal returns as expected with more significant and sizable effect for upgrades based on the case study of three companies. In the future research it would be interesting to collect more data for companies in various industries and see if the effect is different. Influence of Moody's Rating Downgrade and Upgrade on the U.S. Equity Market: A Case Study of IBM, Ford, and Boeing 3


This paper investigates the relationship between output growth and employment growth in India for the period 1978–2010 at the aggregate and sectoral levels. Using a Kaldorian framework of endogenous productivity growth, we find that Kaldor–Verdoorn effects in the economy have become more predominant over time, especially in the post-reform (1994–2010) period. Our estimated Kaldor–Verdoorn coefficients, measured as the employment elasticity of output growth, for both formal sector and total employment have dropped dramatically over time, suggesting that India has leapfrogged into a high-productivity regime without the broad-based expansion of labour-intensive production that has been characteristic of fast-growing economies in East Asia. We examine some explanations for why these Kaldor–Verdoorn effects have become pronounced over time and are not convinced that wage pressure has been one of the reasons. A shift in the composition of demand towards higher-productivity sectors, however, does appear to be an important part of the explanation. We also find mixed evidence that forces of international competition have generated pressures to adopt more capital-intensive techniques of production.


Education is vital to the progression and sustainability of society. By developing effective learning programs, this creates numerous impacts and benefits for future generations to come. K-12 STEM Education: Breakthroughs in Research and Practice is a pivotal source of academic material on the latest trends, techniques, technological tools, and scholarly perspectives on STEM education in K-12 learning environments. Including a range of pertinent topics such as instructional design, online learning, and educational technologies, this book is an ideal reference source for teachers, teacher educators, professionals, students, researchers, and practitioners interested in the latest developments in K-12 STEM education.


The popularity of Taekwondo is ever increasing. This is apparent in the tens of millions of practitioners worldwide, and by the inclusion of Taekwondo in the summer Olympic Games. With all its popularity, it is paramount that the art be handed down in a clear, knowledgeable, and sustainable way - this book does just that. Originally published in 1983, this authoritative work has been the guide for thousands of Taekwondo Black Belts as they advanced in their training. Whether your training is for self-defense, forms competition, or for preparation for Olympic Games, this newly revised edition provides beginner/intermediate to advance level training to assist you on your journey in Taekwondo. The most popular part of this book is the Nine black belt forms which are required by the World Taekwondo Federation for promotion in ranking. Additional sections include the history, philosophy, and science of Taekwondo, along with an updated schedule of the official competition rules. Contents include: History, Philosophy, and Meditation; Hand and Foot Techniques; Sparring Techniques; Self-defense Techniques; Breaking Techniques; Nine Black Belt Forms - required for promotion by the World Taekwondo Federation, and used in sanctioned international Taekwondo competitions; Eight Taegeuk Forms - required for promotion of all color belts and 1st dan black belt, and used in sanctioned international Taekwondo competitions; and, Rules and regulations of the World Taekwondo Federation including sparring and poomsae competitions.


Bone continually adapts to meet changing physical and biological demands. Osteoblasts, osteoclasts, and osteocytes cooperate to integrate these physical and biochemical cues to maintain bone homeostasis. Although TGFβ acts on all three of these cell types to maintain bone homeostasis, the extent to which it participates in the adaptation of bone to mechanical load is unknown. Here, we investigated the role of the TGFβ pathway in load-induced bone formation and the regulation of Sclerostin, a mechanosensitive antagonist of bone anabolism. We found that mechanical load rapidly represses the net activity of the TGFβ pathway in osteocytes, resulting in reduced phosphorylation and activity of key downstream effectors, Smad2 and Smad3. Loss of TGFβ sensitivity compromises the anabolic response of bone to mechanical load, demonstrating that the mechanosensitive regulation of TGFβ signaling is essential for load-induced bone formation. Furthermore, sensitivity to TGFβ is required for the mechanosensitive regulation of Sclerostin, which is induced by TGFβ in a Smad3-dependent manner. Together, our results show that physical cues maintain bone homeostasis through the TGFβ pathway to regulate Sclerostin expression and the deposition of new bone.


The nuclear envelope (NE) subdivides eukaryotic cells into a nuclear and a cytoplasmic compartment, forcing material exchange between these two compartments to proceed through the nuclear pore complexes (NPCs). While proteins smaller than 30-40 kDa can passively diffuse through the NPCs, larger objects require nuclear transport receptors (NTRs) for efficient transport. NTRs have the privilege of facilitated NPC-passage; they bind transport cargoes and transfer them from one side of the NE to the other. NTRs can act as unidirectional cargo pumps, whereby they utilize the chemical potential of the nucleocytoplasmic RanGTP gradient with high nuclear and low cytoplasmic RanGTP levels.
CRM1 is a major, essential and highly conserved nuclear export receptor. It exports a great variety of cargoes from the nucleus to the cytoplasm. CRM1 also keeps e.g. several translation factors and RanGAP cytoplasmic. The latter is required for maintaining the nucleocytoplasmic RanGTP gradient. CRM1 recognizes many cargoes through so-called leucine-rich nuclear export signal (NES), sequences containing 4-5 hydrophobic residues in a 14-15 residues long stretch. Although NESs are described in the context of primary protein structure, a reliable NES prediction has been a challenge and failed, e.g. for eIF2β and Rna1p (S.pombe RanGAP).
Here we present a new NES prediction algorithm based on the recent crystal structures of different NES sequences with CRM1. We classified NES two PKI-type and REV-type with two different consensus definitions. PKI-type NES were graded for CRM1 binding strength and additional filtering was applied with disorder prediction. The REV-type NES was a novel classification based on Rev protein NES, and we show that there are several other examples of this type of NES. The estimation power of the new prediction algorithm was shown on prediction of already known NESs as control, and it also was able to predict the NESs of human eIF2β and S.pombe Rna1p, which was also confirmed experimentally.
Another challenge had been the question of how many different cargo species are actually transported by CRM1. To address this, we optimized affinity chromatography on immobilized CRM1 and used it to retrieve RanGTP-dependent cargoes from a cytoplasmic HeLa extract. This analysis revealed hundreds of new CRM1 cargo candidates, which were further group into functional protein categories. Most of the ribosomal proteins are found in our dataset. Besides them, we find serine threonine kinases, ATP dependent helicases, spliceosomal proteins, translation initiation factors, actin regulators, and E3 ubiquitin ligases. Proteins of metabolic pathways, cell adhesion, phagosome, and proteasome are excluded from the data set.


Objective: To compare the aesthetic outcome of cervical lymph node excision skin closure between Steri-Strips closure and simple interrupted sutures using Nylon 6-0.

Materials and Methods: The present study was a single-blinded randomized controlled trial of forty patients with cervical lymph node excision. They were randomized into two groups of twenty. The first group was allocated to close the skin by simple interrupted sutures with Nylon 6-0, the other group received the Steri-Strips for skin closure. Complications were observed at the first and second week. The aesthetic outcomes for skin closure were evaluated at 12 weeks postoperatively using the predetermined Sakka's cosmetic assessment criteria and scoring system.

Results: There was no statistically significant difference between the two groups in terms of gender, age, length of surgical wound, and pathology. The Steri-Strips group showed significantly lower Sakka's aesthetic score compared to the 6-0 Nylon sutures group (6.25±0.85 and 7.75 ±1.33, p<0.001). There was no significant difference in aesthetic outcomes between genders. Moreover, the operative time of the Steri-Strips group was significantly less than that of the 6-0 Nylon sutures group (2.2±0.41 and 4.75±0.44 minutes, p<0.001).

Conclusion: Skin closure with Steri-Strips gave better aesthetic outcomes compared to the 6-0 Nylon sutures (p<0.001). However, the aesthetic outcomes were assessed by physicians, so the patients'satisfaction could not be assessed.

Keywords: Lymph node biopsy; Hypertrophic scar; Keloid; Cosmetic outcome; Steri-strip


The European Commission published its new Digital Finance Strategy on 24 September 2020 (DFS 2020). One of the centerpieces of the Strategy is the draft regulation on a pilot regime for market infrastructures based on distributed ledger technology (known as PilotR).

The PilotR Proposal foresees a regulatory sandbox approach for the European Single Market, offering firms a set of exemptions from EU financial law allowing them to test distributed ledger technologies (DLTs) in certain activities related to trading, clearing, and settlement. Besides offering room for experiment, the PilotR Proposal supports the education of EU regulators about DLTs in this context, which may come to form the basis for foundational changes to EU law.

The PilotR Proposal constitutes a significant step towards a future-proof EU fintech framework. We appreciate the European scale of PilotR, with an 'EU Passport' and ongoing cooperation across competent authorities and the ESMA. PilotR is characterized by an innovative 'Business Plan Approach' where the DLT operator defines governance functions and liabilities of entities operating, and connected to, DLT. Through this Business Plan Approach, PilotR promotes innovation while demanding business-specific risk mitigation, avoiding one-size-fits-all approaches. This bold regulatory move, however, prompts legal questions regarding the enforceability of business-induced rules vis-a-vis the nodes that do not qualify as operators as well as third parties.

Furthermore, the PilotR Proposal would benefit from three amendments: First, EU legislators should articulate a clear link between the priorities laid down in the DFS 2020 and PilotR, along with an explanation of how PilotR fits into a broader set of measures to support innovation. Second, PilotR is characterized by a narrow scope with a relatively long timeline for testing, thereby the degree of mutual learning will be reduced. Third, being limited to authorized MiFID firms and CSDs only, regulatory leniency will be reserved for incumbents only – despite PilotR's expressed objective to benefit innovative start-ups.


This research was conducted to investigate whether negative brand associations attached to Russian hockey players impact their draft rankings during the National Hockey League (NHL) Entry Draft. A quantitative analysis based on various regression model specifications was used to test whether Russian players were drafted relatively equally to their counterparts in the NHL Entry Draft. The data consisted of the NHL draft picks between 1993 and 2013 and their performance statistics and physical characteristics. The results suggested that Russian players were drafted relatively equal to their counterparts from other countries. Meanwhile, Russian players who played in the CHL before the draft are actually drafted better than Canadians who played in the same league. Hence, the negative brand associations attached to Russians were unlikely to impact their draft rankings. This study redefined the so-called "Russian Factor" from a notion that allegedly damages Russian players' rankings to one that enhances their rankings.


Advances in the management of HIV infection have resulted in a growing population of older adults living with HIV. Both aging and HIV infection have been independently associated with central nervous system changes and corresponding declines in neurocognitive functioning. Poorer semantic verbal fluency output is also common in both HIV infection and healthy older adults, although, the possible additive effects of these risk factors are unknown. The present study aimed to examine the combined effects of aging and HIV on semantic verbal fluency and its component processes (i.e., clustering and switching), the neurocognitive correlates of clustering and switching in older HIV-infected adults, and the associations between clustering and switching and everyday functioning. Participants included 257 individuals across 4 demographically matched groups: Younger (i.e., <40 years) Healthy (n=93), Younger HIV-infected (n=50), Older (i.e., [greater than or equal to]50 years) Healthy (n=51), and Older HIV-infected (n=63) individuals. Participants were administered a standard semantic fluency protocol scored according to established clustering and switching guidelines (Troyer et al., 1997) and a selfreported assessment of everyday functioning as part of a comprehensive neuropsychological, medical, and psychological evaluation. Jonckheere-Terpstra tests revealed a significant stepwise additive effect between the groups for overall semantic fluency output (p = 0.004) and a trend for declining switching performance (p = 0.056), but not cluster size (p = 0.826), with greatest deficits evident in the Older HIV-infected participants. Results were not better explained by confounding psychiatric, medical, or HIV disease characteristics. Within the older HIV-infected adults, poorer switching was associated with deficits in learning and executive functioning and selfreported declines in everyday functioning. Results suggest that HIV infection and aging may confer adverse additive effects on the executive components of semantic fluency (i.e., switching), which was associated with poorer everyday functioning outcomes and may be driven by the combined frontostriatal neuropathological burden of these two conditions. This research provides preliminary insight into the cognitive architecture of HIV-associated neurocognitive disorders among older adults, and may ultimately guide rehabilitation efforts aimed at improving overall quality of life for the growing population of older adults living with HIV infection


The atrial activity of the human heart is normally visible in the ECG as a P-wave. In patients with intermittent atrial fibrilation, a different P-wave morphology can sometimes be seen, indicating atrial conduction defects. The purpose of this study was to develop a method to discriminate between such P-waves and normal ones. 20 recordings of each type were used in a classification which, based on impulse response analysis of the P-wave and linear discrimination between various parameters, produced a correct classification in 37 of the 40 recordings (sensitivity 95%, specificity 90%).


This guide provides a general introduction to Library and information resources for the study of Search tools, websites and gateways for Scandinavian studies.


An epidemiological survey was conducted to evaluate the prevalence of drug use among new entrants in Italian prisons. Overall, 1267 inmates were recruited by 9 prisons. Drug use before imprisonment was reported by 55.8% of the participants. Cocaine was the most commonly used drug (42%), followed by heroin (34%), marijuana/cannabis (33%), ecstasy (7%), hallucinogens (6%), amphetamines (5%); more than one drug was reported by 68% of abusers. Recent use (1 month before imprisonment) was admitted by up to 27% of inmates. Alcohol or tobacco use was reported by 38 and 77% of the inmates, respectively. Our findings indicate that a high proportion of inmates has ever used drugs; adequate intervention is needed to reduce the risk of addictive behaviour in this population group.


A key component of many reinforcement learning (RL) algorithms is the approximation of the value function. The design and selection of features for approximation in RL is crucial, and an ongoing area of research. One approach to the problem of feature selection is to apply sparsity-inducing techniques in learning the value function approximation; such sparse methods tend to select relevant features and ignore irrelevant features, thus automating the feature selection process. This dissertation describes three contributions in the area of sparse value function approximation for reinforcement learning.
One method for obtaining sparse linear approximations is the inclusion in the objective function of a penalty on the sum of the absolute values of the approximation weights. This L1 regularization approach was first applied to temporal difference learning in the LARS-inspired, batch learning algorithm LARS-TD. In our first contribution, we define an iterative update equation which has as its fixed point the L 1 regularized linear fixed point of LARS-TD. The iterative update gives rise naturally to an online stochastic approximation algorithm. We prove convergence of the online algorithm and show that the L1 regularized linear fixed point is an equilibrium fixed point of the algorithm. We demonstrate the ability of the algorithm to converge to the fixed point, yielding a sparse solution with modestly better performance than unregularized linear temporal difference learning.
Our second contribution extends LARS-TD to integrate policy optimization with sparse value learning. We extend the L1 regularized linear fixed point to include a maximum over policies, defining a new, "greedy" fixed point. The greedy fixed point adds a new invariant to the set which LARS-TD maintains as it traverses its homotopy path, giving rise to a new algorithm integrating sparse value learning and optimization. The new algorithm is demonstrated to be similar in performance with policy iteration using LARS-TD.
Finally, we consider another approach to sparse learning, that of using a simple algorithm that greedily adds new features. Such algorithms have many of the good properties of the L1 regularization methods, while also being extremely efficient and, in some cases, allowing theoretical guarantees on recovery of the true form of a sparse target function from sampled data. We consider variants of orthogonal matching pursuit (OMP) applied to RL. The resulting algorithms are analyzed and compared experimentally with existing L1 regularized approaches. We demonstrate that perhaps the most natural scenario in which one might hope to achieve sparse recovery fails; however, one variant provides promising theoretical guarantees under certain assumptions on the feature dictionary while another variant empirically outperforms prior methods both in approximation accuracy and efficiency on several benchmark problems.


One cut domain family member 2 (ONECUT2), also termed OC-2, is a newly discovered member of the ONECUT transcription factor family. As a transcription factor, ONECUT2 can widely regulate protein expression associated with cell proliferation, migration, adhesion, differentiation and cell material metabolism. Recent studies have revealed that ONECUT2 is associated with tumor cell proliferation, angiogenesis and metastasis; it is also associated with epithelial-mesenchymal transition in cancer cells. The present review examines the distribution and expression of ONECUT2 in a variety of tumors, its oncogenic role in tumor progression and the possible mechanisms of regulation. Given the emerging role of ONECUT2 in the development and progression of tumors, ONECUT2 might be a promising target for tumor therapy.


abstract:Prevailing models of social development for the southern Korean Iron Age (ca. 300 b.c.–a.d. 300) focus on contact with China as well as the dynamic interaction between local polities to explain the development of socio-political complexity but the nature of this contact has not been critically examined or its more granular processes explored. This article uses two prominent grave good types discovered in southeastern Korean burials to question these models as well as conceptions of archaeological cultures in the region more generally. These objects, Chinese bronze mirrors and iron objects decorated with bracken-like spiral designs, both indicate significant interaction with Han China via its administrative commanderies, but their production and diverse mortuary contexts do not conform to any current model of culture contact, acculturation, hybridity, or entanglement. The variable production processes, expression of exotic motifs through these objects, and the way these objects were interred in graves suggests that we should look for cultural unity and early indicators of socio-cultural complexity within regions where local groups were particularly active in expressing their differences within a set of agreed-upon parameters. I argue that the southern peninsula is best described as a set of interdependent local groups with a similar ritual vocabulary, but little to no political unity even directly prior to the appearance of the Three Kingdoms polities of Paekche, Silla, and Kaya.


In this paper, a new two-level bipartitioning algorithm TLP, combining a hybrid clustering technique with an iterative improvement based partitioning process, is proposed. The hybrid clustering algorithm consisting of a local bottom-up clustering technique to merge modules and a global top-down ratio-cut technique for decomposition can be used to reduce the partitioning complexity and improve the performance. To generate a high-quality partitioning solution, a module migration based partitioning algorithm MMP is also proposed as the base partitioner for the TLP algorithm. The MMP algorithm implicitly promotes the move of clusters during the module migration processes by paying more attention to the neighbors of moved modules, relaxing the size constraints temporarily during the migration process, and controlling the module migration direction. Experimental results obtained show that the TLP algorithm generates stable and high-quality partitioning results. The TLP algorithm improves the unstable property of module migration based algorithms such as FM and STABLE in terms of the average net cut value. On the other hand, TLP outperforms MELO, GFM/sub t/ and CDIP/sub LA3/ by 23%, 7%, and 10%, respectively and is competitive with hMetis, ML/sub c/ and LSR/MFFS which have generated better results than many recent state-of-the-art partitioning algorithms.


Two Monte Carlo simulation studies investigated the effectiveness of the mean adjusted χ2/df statistic proposed by Drasgow and colleagues and, because of problems with the method, a new approach for assessing the goodness of fit of an item response theory model was developed. It has been previously recommended that mean adjusted χ2/df values greater than 3 using a cross-validation data set indicate substantial misfit. The authors used simulations to examine this critical value across different test lengths (15, 30, 45) and sample sizes (500, 1,000, 1,500, 5,000). The one-, two- and three-parameter logistic models were fitted to data simulated from different logistic models, including unidimensional and multidimensional models. In general, a fixed cutoff value was insufficient to ascertain item response theory model–data fit. Consequently, the authors propose the use of the parametric bootstrap to investigate misfit and evaluated its performance. This new approach produced appropriate Type I error rates and had substantial power to detect misfit across simulated conditions. In a third study, the authors applied the parametric bootstrap approach to LSAT data to determine which dichomotous item response theory model produced the best fit. Future applications of the mean adjusted χ2/df statistic are discussed.


Purpose: To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888. Experimental Design:In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation. Results: ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with Kis of 5.2 and 2.9 nmol/L, respectively. The compound has good oral bioavailability and crosses the blood-brain barrier. ABT-888 strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model, temozolomide alone exhibited minimal efficacy, whereas ABT-888, when combined with temozolomide, significantly slowed tumor progression. In the MX-1 breast xenograft model (BRCA1 deletion and BRCA2 mutation), ABT-888 potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, ABT-888 potentiated radiation (2 Gy/d × 10) in an HCT-116 colon carcinoma model. In each model, ABT-888 did not display single-agent activity. Conclusions: ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.


In this paper, a novel path planning approach is proposed to generate porous structures with internal features. The interconnected and continuous deposition path is designed to control the internal material composition in a functionally graded manner. The proposed layer-based algorithmic solutions generate a bilayer pattern of zigzag and spiral toolpath consecutively to construct heterogeneous three-dimensional (3D) objects. The proposed strategy relies on constructing Voronoi diagrams for all bounding curves in each layer to decompose the geometric domain and discretizing the associated Voronoi regions with ruling lines between the boundaries of the associated Voronoi regions. To avoid interference among ruling lines, reorientation and relaxation techniques are introduced to establish matching for continuous zigzag path planning. In addition, arc fitting is used to reduce over-deposition, allowing nonstop deposition at sharp turns. Layer-by-layer deposition progresses through consecutive layers of a ruling-line-based zigzag pattern followed by a spiral path deposition. A biarc fitting technique is employed through isovalues of ruling lines to generate G1 continuity along the spiral deposition path plan. Functionally graded material properties are then mapped based on a parametric distance-based weighting technique. The proposed approach enables elimination or minimization of over-deposition of materials, nonuniformity on printed strands and discontinuities on the toolpath, which are shortcomings of traditional zigzag-based toolpath plan in additive manufacturing (AM). In addition, it provides a practical path for printing functionally graded materials.


Murine neural stem cell exosomes/microvesicles can work to reduce SARS-CoV-2, an effect that can be adaptively enhanced via viral RNA fragment stimulation, which requires the PIWI-piRNA system. Murine neural stem cells (NSCs) were recently shown to release piRNA-containing exosomes/microvesicles (Ex/Mv) for exerting antiviral immunity, but it remains unknown if these Ex/Mv could target SARS-CoV-2 and whether the PIWI-piRNA system is important for these antiviral actions. Here, using in vitro infection models, we show that hypothalamic NSCs (htNSCs) Ex/Mv provided an innate immunity protection against SARS-CoV-2. Importantly, enhanced antiviral actions were achieved by using induced Ex/Mv that were derived from induced htNSCs through twice being exposed to several RNA fragments of SARS-CoV-2 genome, a process that was designed not to involve protein translation of these RNA fragments. The increased antiviral effects of these induced Ex/Mv were associated with increased expression of piRNA species some of which could predictably target SARS-CoV-2 genome. Knockout of piRNA-interacting protein PIWIL2 in htNSCs led to reductions in both innate and induced antiviral effects of Ex/Mv in targeting SARS-CoV-2. Taken together, this study demonstrates a case suggesting Ex/Mv from certain cell types have innate and adaptive immunity against SARS-CoV-2, and the PIWI-piRNA system is important for these antiviral actions.


Inosine-5'-monophosphate dehydrogenase (IMPDH) is an attractive drug target for the control of parasitic infections. The enzyme catalyzes the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP), the committed step in de novo guanosine monophosphate (GMP) biosynthesis. We have determined the crystal structures of IMPDH from the protozoan parasite Tritrichomonas foetus in the apo form at 2.3 A resolution and the enzyme-XMP complex at 2.6 A resolution. Each monomer of this tetrameric enzyme is comprised of two domains, the largest of which includes an eight-stranded parallel beta/alpha-barrel that contains the enzyme active site at the C termini of the barrel beta-strands. A second domain, comprised of residues 102-220, is disordered in the crystal. IMPDH is expected to be active as a tetramer, since the active site cavity is formed by strands from adjacent subunits. An intrasubunit disulfide bond, seen in the crystal structure, may stabilize the protein in a less active form, as high concentrations of reducing agent have been shown to increase enzyme activity. Disorder at the active site suggests that a high degree of flexibility may be inherent in the catalytic function of IMPDH. Unlike IMPDH from other species, the T. foetus enzyme has a single arginine that is largely responsible for coordinating the substrate phosphate in the active site. This structural uniqueness may facilitate structure-based identification and design of compounds that specifically inhibit the parasite enzyme.


Within institutionalised educational activities one of, if not the, most important factor for students' learning is the teacher's manner of teaching. In this symposium we will present the framework and some of the results from a project where we are identifying teaching traditions – manners of teaching that many teachers use – within science education and physical education and analysing the pros and cons of each of the traditions regarding learning. In other words, the project focuses on the institutional dimension of learning, by identifying limits and possibilities for learning offered by different teaching traditions. The results of this research will then, from the perspective of cooperative engineering (Sensevy et al 2013), be tested in use together with practicing teachers in order to evaluate their potential for helping teachers cope with important didactic choices in planning, realizing and evaluating their teaching.The project builds on a comparative didactics approach (Caillot 2007; Mercier, Schubauer-Leoni & Sensevy 2002) in combination with a pragmatic perspective on teaching and learning. The ambition is to search for as many different teaching traditions as possible in order to optimize the possibility to find effective and fruitful teaching approaches. Therefore, the project includes participants from various contexts in three countries; France, Sweden and Switzerland.Teaching is only possible through the process of inclusion and exclusion of content (Englund 1986). The term privileging, coined by Wertsch (1998), explicate the fact that also the learning process includes choices (cf. Almqvist & Ostman 2006). The term draws attention to the fact that participants in the learning process valuate and judge certain artefacts, meetings, questions, and so forth, as reasonable and fruitful, while others, though fully conceivable, are ignored or disregarded.The privileging that takes place during meaning-making directs learning in a certain direction and toward certain content (i.e. Wickman & Ostman 2002) and is limited by the institutional "boundaries" in which knowledge, teaching and learning unfold. Focusing on the didactical aspects of education, we search for the connections between selective traditions (cf. Ostman 1996, Quennerstedt 2006), teachers' manners of teaching (cf. Lundqvist et al 2012) and students' privileging (cf. Almqvist & Ostman 2006). These three concepts deal with the fact that activities as education, teaching and learning are constituted by selection of content and teaching strategies.In our analyses we are interested to find out what role encounters with the teacher has for students' privileging and learning. Especially we are interested to find out which role the manner of teaching has for students' learning of habits of privileging and what effect certain habits have for the learning outcome. The learning of specific habits of privileging is occurring in the interplay between students' earlier knowledge and experiences, the interaction with peers and the manners of teaching (Lundqvist et al 2012).Studies in comparative didactics may be productive in that they contribute with knowledge about different ways of the teaching and learning of specific subject content (Caillot 2007). The differences and similarities identified in the studies will help to describe teaching learning in each school subject more precisely and thereby generate new knowledge about different school subjects. In order to maximize the finding of different teaching traditions we make i) investigations in four subjects – physics, chemistry, biology and physical education and health – in Sweden, France and Switzerland and ii) comparative investigations within these four subjects between the three countries and iii) comparative investigation between these four subjects and between countries.ReferencesAlmqvist, J., Ostman, L. (2006). Privileging and Artifacts: On the use of information technology in science education. Interchange, 37(3): 225-250Caillot, M. (2007). The Building of a New Academic Field: the case of French didactiques. European Educational Research Journal, 6(2), 125-130.Englund, T. (1986). Curriculum as a political problem. Changing educational conceptions, with special reference to citizenship education. Lund: Studentlitteratur/Chartwell-Bratt.Lundqvist, E., Almqvist, J., & Ostman, L. (2012). Institutional traditions in teachers' manners of teaching. Cultural Studies of Science Education, 7(1), 111-127.Mercier, A., Schubauer-Leoni, M. L., & Sensevy, Gerard. (2002). Vers une didactique comparee. Revue Francaise de Pedagogie, 141(Numero thematique), 5-16.Quennerstedt, M. (2006). Att lara sig halsa. Orebro Studies in Education 15.Sensevy, G., Forest, D., Quilio, S. & Morales, G. (2013). Cooperative engineering as a specific design-based research. ZDM, The International Journal on Mathematics Education, 45(7), 1031-1043Wertsch, J. V. (1998). Mind as action. New York, Oxford University Press. Wickman, P.-O., & Ostman, L. (2002). Learning as discourse change: A sociocultural mechanism. Science Education, 86; 601-623.Ostman, L. (1996). Discourse, discursive meanings and socialization in chemistry education. Journal of Curriculum Studies, 28 (1); 37-55.


In this study we have analysed the genetic variation and phylogeography in a global sample of the cellar fungus Coniophora puteana, which is an important destroyer of wooden materials indoor. Multilocus genealogies of three DNA regions (beta tubulin, nrDNA ITS and translation elongation factor 1α) revealed the occurrence of three cryptic species (PS1–3) in the morphotaxon C. puteana. One of the lineages (PS3) is apparently restricted to North America while the other two (PS1–2) have wider distributions on multiple continents. Interspecific hybridization has happened between two of the lineages (PS1 and PS3) in North America. In three dikaryotic isolates, two highly divergent beta tubulin alleles coexisted, one derived from PS1 and one from PS3. Furthermore, one isolate included a recombinant ITS sequence, where ITS1 resembled the ITS1 version of PS3 while ITS2 was identical to a frequent PS1 ITS2 version. This pattern must be due to hybridization succeeded by intralocus recombination in ITS. The results further indicated that introgression has happened between subgroups appearing in PS1. We hypothesize that the observed reticulate evolution is due to previous allopatric separation followed by more recent reoccurrence in sympatry, where barriers to gene flow have not yet evolved. A complex phylogeographical structure is observed in the morphotaxon C. puteana caused by (i) cryptic speciation; (ii) the interplay between natural migration and distribution patterns and probably more recent human mediated dispersal events; and (iii) hybridization and introgression.


Purpose Rods and cones convert light stimuli into signaling information for brain- mediated visual perception. Specific gene mutations primarily affecting both photoreceptor (PRs) types lead to retinal dystrophies, including rod-cone (retinitis pigmentosa) and cone-rod degeneration. Rods and cones are generated from common precursor cells and their differentiation program is strongly regulated by transcription factors (TFs) that control gene networks during development transitions and in the adult to maintain their identity and function.

The aim of this thesis was to investigate post-mitotic transcriptional regulation of rod- and cone-specific gene regulatory networks (GRNs). Specifically, retrieving transcription factor sets has biological relevance and may be instrumental for designing somatic gene transfer methodologies for both gene-based and regenerative therapeutic strategies.

Methods
We developed an Adeno-associated viral (AAV) vector-based transfer method to isolate rods and cones by fluorescence-based sorting. To isolate "pure" rod and cone populations from the same retinal samples we designed a double expression cassette ("double fluo") encoding mCherry under the transcriptional control of the human G-protein coupled receptor Kinase 1 (GRK1) gene rods and cones-specific promoter elements of, and eGFP under the transcriptional control of rod-specific human Guanine Nucleotide Binding Protein Alpha Transducing (GNAT1) promoter elements. Porcine (Sus scrofa) retinae were injected with AAV 2/8 GRK1-mCherry_hGNAT1-eGFP, at the dose of 1x1012 genome copies (GC) per eye (n=3). The animals were sacrificed 15 days after injection to evaluate fluorescence reporter based rod and cone photoreceptor identities by histological and FACS analysis. We evaluated, on sorted populations, rods and cone specific transcriptomes by RNA sequencing (RNA- seq) using Illumina Hiseq 1500 (n=3). Moreover, after overexpression of human Retina And Anterior Neural Fold Homeobox (RAX), using subretinal injection of AAV2/8 hGNAT1-hRAX2aeGFP at a dose of 5 x 1011gc/eye we studied the GRN associated with RAX, by a second round of RNA-seq. Electroretinography (ERG) was used to correlate RAX-specific GRN with retina function.

Results
Histological analysis showed unambiguous expression of both mCherry and eGFP in rods, whereas cones showed exclusive expression of mCherry. Furthermore, cone arrestin (CAR) showed exclusive co-localization with the mCherry signal (cones), which was absent in red-green cells (rods). Photoreceptors specifically labeled were positive for both mCherry and eGFP (rods) or mCherry-only (cones) expressing Rhodopsin (RHO), Neural retina leucin zipper (NRL), Guanine Nucleotide Binding Protein Alpha Transducine 1 (GNAT1) (rod markers) and Short wavelength cone opsin (S-opsin), Medium wavelength cone opsin (M-opsin), Guanine Nucleotide Binding Protein Alpha Transducing 2 (GNAT2) (cone markers), respectively.

RNA-seq differential expression analysis (DEA) showed 198 differential expressed genes (DEGs), of which 68 genes were up-regulated and 128 genes down-regulated in rod versus cone analysis. Furthermore, 8 TFs were found differentially expressed in rods and 8 in cones. In the cone-specific TFs set, out of 3 known TFs (Rax, Sall3 and Six6), Rax was selected for further analysis. Rax was ectopically expressed in rods (Rax-rod) to reconstruct its GRN. Differential expression analysis identified 386 DEGs, of which 224 genes (58%) were up- and 162 (42%) down regulated. Clustering for biological processes gene ontology (BP-GO), showed enrichment in action potential genes. Furthermore, ERG showed a different light response of the hRax-treated retina. In particular, a decrease of the mesopic (dark adapted) and an increase of the photopic (light adapted) responses were found.

Conclusion
We showed that the "double fluo" provided a robust method to isolate and cross-compare rod and cone photoreceptors in the adult porcine retina upon photoreceptor somatic gene transfer via AAV vectors. Furthermore, RNA-seq data set analysis showed that the cone and rod specific transcriptome differs quantitatively by about 200 transcripts and that 8 TFs are photoreceptor specific In addition, the data show that post-mitotic rods are able to express cone genes upon Rax ectopic expression. Furthermore the data support a role of Rax in controlling cone-specific action potential gene set.


We thank Pesta and Burtscher for their comments on our study. In this article, we have demonstrated, for the first time, that 4 months of resistance (RES) or aerobic (AER) training are equally effective in reducing hepatic fat content among sedentary type 2 diabetes subjects with nonalcoholic fatty liver disease (NAFLD). This study was a subproject of the RAED2 Study, a randomized, controlled trial aimed at comparing the metabolic effects of RES and AER training in diabetic patients. Pesta and Burtscher hypothesized that in untrained overweight/ obese subjects with little experience in exercise, RES training would be unable to induce the specific adaptations characteristic of this exercise modality, and that this, in turn, might explain why the results of AER and RES training were similar. We agree that, in untrained subjects, there may be some overlap between the effects of AER and RES training, and that the fullblown effects of these different exercise modalities can be only appreciated when sustained high-intensity training is performed, as occurs in athletes. Nonetheless, the latter would not be an appropriate model for assessing the effects of these training modalities on hepatic fat accumulation of sedentary subjects with type 2 diabetes, which was the aim of our study. Moreover, as reported previously, in our study, peak oxygen uptake improved after training in both groups, but to a greater extent in the AER group, whereas increased strength was found only in the RES group. In addition, lean mass of the limbs significantly increased in the RES group, but not in the AER group. These findings clearly indicate that the stimulus was quite different between the two protocols. These differences were guaranteed through a careful supervision of exercise sessions as well as a progressive increase of workload. In particular, as concerns the RES group, workload was gradually increased to 70%-80% 1-RM, with the weight being adjusted approximately every 2 weeks to match the progress of the subjects. With regard to baseline data, there were not statistically significant differences between groups. Overall, most type 2 diabetes patients are sedentary and have no experience with exercise programs. The clinical message that we were able to give is that exercise alone can provide benefit for NAFLD management in these patients, and that, after 4 months of training, RES exercise is as effective as AER exercise in reducing hepatic fat content in these subjects. Future research should address this important issue in the long term.


Due to the emissions of air pollutants, acid rain in southern China poses a great threat to terrestrial ecosystems. However, its influences on ecological processes such as litter decomposition and soil organic carbon (SOC) accumulation are still not clear. The aim of this study was to understand the potential mechanisms of carbon sequestration change in response to long-term acid rain in a subtropical forest. A field experiment with simulated acid rain (SAR) treatment was conducted in a monsoon evergreen broadleaf forest in southern China. Four levels of SAR treatment were implemented by irrigating the plots with water of different pH values (4.5 as a control, 4.0, 3.5, and 3.0). The results showed that the concentration of SOC and recalcitrant index for the SAR pH = 3.0 treatment were significantly higher compared to the control. Lignin fractions in litter residue layers were significantly increased, while soil microbial biomass carbon and soil ligninolytic enzyme activities were reduced under the SAR treatment. The concentration of SOC and recalcitrant index had positive relationships with the litter residue lignin fraction, but negative relationships with soil ligninolytic enzyme activity. These findings indicate that soil carbon accumulation could be enhanced with more stable lignin input under prolonged acid rain in forest ecosystems in southern China.