The accidental reentry of 38 Starlink satellites occurred in early February 2022, associated with the occurrence of moderate magnetic storms. A poorly understood structure of coronal mass ejections (CMEs) caused the magnetic storms at unexpected timing. Therefore, a better understanding of minor CME structures is necessary for the modern space weather forecast. During this event, the "up to 50%" enhancement of air drag force was observed at ~200 km altitude, preventing the satellites' safety operations. Although the mass density enhancement predicted by the NRLMSIS2.0 empirical model is less than 25 % under the present moderate magnetic storms, the real-time GAIA simulation showed a mass density enhancement of up to 50%. Further, the real-time GAIA simulation suggests that the actual thermospheric disturbances at 200 km altitude may occur with larger amplitude in a broader area than previously thought.


A 2-loop waste heat recovery system with Rankine steam cycles for the improvement of fuel efficiency of gasoline vehicles has been investigated. A high temperature loop(HT loop) is a system to recover the waste heat from the exhaust gas, a low temperature loop(LT loop) is for heat recovery from the engine coolant cold relatively. This paper has dealt with a layout of a LT loop system, the review of the working fluids, and the design of the cycle. The design point and the target heat recovery of the LT boiler, a core part of a LT loop, has been presented and analytically investigated. Considering the characteristics of the cycle, the basic concept of the LT boiler has been determined as a shell-and tube type counterflow heat exchanger, the performance characteristics for various design parameters were investigated.


Background: Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell diseases, accounting for < 5% of all hematologic malignancies in children. MDS is characterized by cytopenia, dysplasia in one or more of the major myeloid lineages, ineffective hematopoiesis, and recurrent genetic abnormalities. Approximately 30% of patients with MDS show progression to AML within a few months up to several years. This is an MDS case report in children who have undergone Acute Myeloid Leukaemia transformation with Myelodysplasia-Related Changes (AML-MRC). Case Report: A 16-year-old boy came to the Emergency Department of Sanglah General Hospital with a complaint of pain and swelling in both knees and joints since last month. Fatigue and fever happened a week before admission. Previously, he had been hospitalized twice with the same symptoms. Physical examination revealed pale conjunctiva with pancytopenia in the laboratory result. A blood smear showed normochromic normocytic anemia, neutropenia, and thrombocytopenia. Bone marrow aspiration morphology showed hypercellularity with blast presentation > 10% and multilineage dysplasia > 50% supporting MDS diagnosed transformation to Acute Myeloid Leukaemia with MyelodysplasiaRelated Changes (AML-MRC). Leukemia phenotyping showed positive results on CD 33, CD 36 and HLA-DR presenting Monocytic Lineage. Conclusion: High degree dysplasia and blast percentage in blood and bone marrow increase tendency to transform into acute myeloid leukemia (AML). The diagnose of MDS requires analysis of blood and bone marrow morphology and cytogenetic analysis as a recommendation by WHO classification.


Introduction Oesphageal SCC carries a poor prognosis. Squamous HGD is the precursor lesion to SCC. Risk of progression to SCC with HGD can be 65% at 5 years. RFA is a minimally invasive technique with proven efficacy for early neoplasia arising in Barrett's oesophagus. We present prospective data from 10 centres in the United Kingdom (UK) HALO registry. Methods Superficial lesions were removed by endoscopic mucosal resection (EMR) before RFA. Treatment consisted of a single ablation at 12J/cm2. Patients were followed up 3 months after treatment with biopsies. Those with residual dysplasia underwent further RFA until 12 months when they were assessed for treatment success or failure. Recurrent dysplasia was retreated with EMR/RFA. Primary outcomes were reversal of dysplasia (CR-D) at 12 months. Results 26 patients had RFA. Mean length mucosa ablated was 5.3 cm (1–14). 7/26 (27%) had EMR before RFA. Prior EMR did not confer benefit to outcome, nor did baseline disease length. Following first RFA, 6/26 patients (23%) progressed to invasive disease. Only one more patient progressed later in treatment course. CR-D was achieved in 50% at protocol end, mean 1.7 RFA treatments (1–4). 10/13 (77%) with successful RFA at 12 months remain disease free at most recent follow up (median 21 months). Kaplan Meier statistics show 2 years post treatment 68% patients are likely to remain in remission from dysplasia for those with successful outcome at 12 months. 5 patients (19%) required dilatations for oesophageal stricturing. Conclusion Squamous HGD & CIS are aggressive pathologies as evidenced by the fact that 23% patients in our cohort progressed to invasive disease despite RFA. However the majority who do not progress early (13/19 patients) achieve benefit & are more likely to have a successful & durable outcome. There is limited experience in the UK with RFA in these patients. Pre RFA EMR for visible lesions is limited in our series. As a result some patients may be under staged prior to RFA which may account for the high rate of progression after first treatment. Disclosure of Interest None Declared


Given a lack of consideration for the role and importance of stakeholders and the importance of stakeholders in the operation of biomass power plants in China, a comprehensive analysis oriented toward stakeholder risk management is needed to further develop the country's biomass energy industry. Accordingly, we analyzed institutional factors that contribute to or constrain progress in biomass power generation in China. Data were collected from 275 straw suppliers (farmers) living around a biomass power plant, 15 middlemen, five power plant managers, and five local government officers. Interviews were held with all the participants, but questionnaires were additionally administered to the straw suppliers. Results showed that: (1) risk transfer in the biomass supply chain is one of the reasons why farmers are unwilling to supply straw; (2) middlemen are vital intermediaries between biomass power plant managers and farmers as a middleman-based biomass supply system is necessary to guarantee the quantity of straw supply, and; (3) the institutional structure that underlies the Chinese biomass energy industry is immature.


Forecasting keyword/topic activities in social networking sites has been the subject of many recent studies, as such activities represent, in many cases, a direct estimate of the spreadth of real-world phenomena, it eg. box-office revenues or flu epidemies. Most of these studies rely on pointwise, regression-like prediction algorithms and focus on few, usually unambiguous, keywords/topics. We study different strategies to rank keyword activities through a comparison of pointwise and pairwise learning to rank approaches, as well as the impact of keyword ambiguity, keyword activity and keyword set size on the prediction results. It is the first time, to our knowledge, that such dimensions are evaluated in this framework. Our experiments are conducted on a large dataset built by monitoring Twitter over a year and including 1497 keywords.


Igor Gouzenko's defection might have been the first—and most famous—of the Cold War in Canada, but it was hardly the last. Recently opened after Access to Information Act requests made by the Canadian Foreign Intelligence History Project, a number of records cast brighter light on this aspect of Canada's intelligence history. This article offers an overview of how the Government of Canada established its policy to manage defection and those who defected. It offers a number of possible leads for future research projects, some, but not all, of which, will require the release of further material, whether under the Access to Information Act or a broader declassification framework from the Government of Canada.


This report concerns a clinical and histopathologic study of an eye containing two apparently independent malignant melanomata and showing, in addition, changes in the cornea consistent with the diagnosis of endothelial dystrophy. A review of the literature indicates the rarity of truly independent multiple malignant tumors in the same eye and reveals surprisingly few histopathologic studies of eyes with endothelial dystrophy. It would seem, therefore, that an eye with both conditions is worth reporting. The eye was made available through the courtesy of Dr. Harold G. Scheie. REPORT OF CASE A woman, age 59, was first seen on Aug. 3, 1948, complaining of progressive blurring of vision for five years. Her corrected visual acuity was 6/12−2 O. D. and 6/15+3 O. S. The central portions of both corneas appeared hazy. With the slit lamp, this clouding was found to result from typical changes of endothelial dystrophy with secondary epithelial edema.


Here we describe the first record of the turtle Chitracephalus dumonii Dollo, 1884 (syn. ?Salasemys pulcherrima Fuentes Vidarte et al., 2003) from Early Cretaceous (Berriasian) deposits in northwestern Germany. Several carapace remains have been found within the material collected by h. f. w. Grabbe in the the early 1880s, deposited in the Geoscience Centre of the Gottingen University, which show typical morphological characters of this species. It represents the stratigraphically oldest representative of Chitracephalus (syn. ?Salasemys). The supposed phylogenetic relationship of this species in the relation to the Late Jurassic Platycephalus oberndorferi wagner, 1853 (Platychelidae) and the modern Chelus fimbriatus Schneider, 1783 (Chelidae) is discussed.


Interior color design of educational spaces in traditional classrooms has been previously evidenced by research to have an impact on students' enjoyment and achievement from their learning sessions. However scarce research has been dedicated to investigate a comparable effect for interior colors of digitally designed 3D e-learning spaces in 3D Virtual Worlds (utilized as 3D Virtual Learning Environments) on students' satisfaction from their e-learning experiences. This study investigates students' contentment from being immersed in 3D e-learning spaces with a diverse range of colors by ranking the various color hues according to student satisfaction. Hence, this paper aims to shed light and issue recommendations on most and least preferred colors by learners to be used for architectural computer-aided color design of educational spaces in 3D virtual worlds and learning environments in an attempt to initialize guidelines for architectural design of digital educational facilities inside these 3D virtual web applications.


We report a method for direct generation of voltage programmable, arbitrarily shaped laser pulses of subpicosecond duration and roughly 100 fs resolution. A waveguide intensity modulator was fabricated and incorporated into a fiber‐grating pulse compressor to shape temporally the chirped pulse before compression. Optical pulses with sin(x)/x and square envelopes are synthesized to demonstrate the technique.


The Archipelago hosts very diverse and biogeographically unique fish communities. About 735 fish species in 109 families have been recorded from the Archipelago to date. Abundances and species diversity increase in East-West and South-North direction and the highest diversity at individual sites are found at Abd al-Kuri. Abundance-Frequency-Distributions and Occurrence- Frequency-Distributions reveal that many species have relatively small populations and occur at few sites only. Modelling of the archipelagic diversity of fish using incidence-based richness estimators such as Chao2, ICE, or Jacknife2 indicate that the actual diversity ranges between 830 and 890 species (excluding deep-dwelling species below 200 m depth). The islands are thus endowed with the highest diversity of marine fishes in the Arabian region and match up with other tropical island groups or even countries in the Indian Ocean. The diversity is especially striking in comparing Species-Area-Relationships across the surrounding eco-regions. For example, certain "reef" associated families and functional groups are as diverse, or even more diverse, than their respective groups in the entire Red Sea, even though the islands' coastline is approximately eight times less in length and supports considerably fewer biogenic reefs. Thus, other ecological determinants than the species-area relationship such as habitat heterogeneity, niche diversity, biogeographic nesting and productivity are more likely key factors. The impressive fish diversity is, for example, matched by high fish biomass productivity, with certain sites ranking among the most productive sites in the Indian Ocean, and the interplay between these parameters is currently a major line of our research. The Archipelago may thus well be considered a marine "micro continent" in terms of its ecological ichthyogeography.


OBJECTIVE
To observe the effects of modified Bazhen Decoction (BZD) in assistant with enteral nutrition (EN) on the growth hormone, the nutritional state, and the immune function in patients with gastric cancer after operation.

METHODS
The prospective, random, single-blinded, controlled clinical trial was adopted. 88 patients receiving gastric cancer operation were randomly assigned to the parenteral nutrition group (Group A, 27 cases), the EN group (Group B, 30 cases), and the comprehensive group (Group C, BZD in assistant with EN, 31 cases). Isocaloric and isonitrogenous parenteral nutritional support was given to patients in Group A from the operation day to the ninth day. Isocaloric and isonitrogenous EN was given to patients in Group B and C from the second day of operation till the ninth day. 100 mL BZD was nasal fed to patients in Group C during the second day to the ninth day after operation. The levels of the growth hormone, immune indices such as IgA, IgG, CD4+, CD8+, and CD4+/CD8+, etc., and nutritional indices such as serum albumin, prealbumin, transferrin, etc. were detected in the three groups one day before operation, on the 1st day after operation, and on the tenth day after operation.

RESULTS
The levels of IgA, IgG, CD4+, and CD4+/CD8+, serum albumin, prealbumin, transferrin decreased more than before operation in the three groups, with statistical difference (P<0.05). On the tenth day after operation, all indices in Group B and C were somewhat improved, showing statistical difference when compared with those in Group A (P<0.05). Besides, the aforesaid indices were higher in Group C than in Group B (P<0.05).

CONCLUSIONS
Modified BZD in assistant with EN could further promote the elevation of the growth hormone levels. Besides, it could further improve the nutrition state and the immune function.


Capacity reduction mainly caused by the shuttle effect and low conductivity restricts the commercial application of lithium-sulfur batteries (LSBs). Herein, we developed a method to overcome these two obstacles synchronously by designing nitrogenous carbon decorated hollow Co3-xMnxO4/C nanocages as hosts of sulfur. These hosts were derived from manganese doped ZIF-67 by a facile sintering method, which provided polar surface to anchor lithium polysulfides and considerable electronic conductivity. The polar material Co3-xMnxO4 and special hollow frame contribute to efficient synergistic sulfur-fixation, resulting in great cycling stabilities. The manganese elements ensure an efficient conversion among LSPs. At the same time, N-doped carbon provides excellent electrical conductivity, thereby leading to splendid rate performances. Thus, a battery with great stability and high capacity could be achieved. As a result, Co3-xMnxO4/C/S with 66 wt% sulfur content delivered a high initial capacity of 1082 mA h g-1 at 1C, together with a slow average capacity decay of 0.056% per cycle at 10C over 500 cycles. When the average sulfur loading is 1.3 mg cm-2, a capacity of 628 mA h g-1 can be maintained at 5C after 500 cycles.


Mobile technologies are increasingly rooted in society and, therefore, intuitively, teachers begin to take advantage of devices that students carry with them daily in a logic of 1:1 bring your own device (BYOD). In fact, it becomes crucial to use this media to promote/increase new pedagogical activities to motivate and challenge students to acquire and discover knowledge. This was the inspiration to create the MobiGeo, an Urban Game, for Geography teaching. The research question that guided the project was to understand whether the implementation of MobiGeo influence the process of learning geography in an outdoor education context. Data obtained allow the researchers to conclude that Urban Games are potential agents of motivation and interaction that predispose students to learn geography in informal learning environments. So, they suggest that the roles of teacher and student should not be abandoned but recycled and adapted to this new reality that requires more personalized and diverse activities of learning. KeywoRdS Informal Learning, Mobile Learning, Qr Codes, Outdoor Education, Urban games


Ad-hoc network is expected as a network in place of the cellular network, has been researched widely. The development of routing protocol is one of the problems in an ad-hoc network. Since the flooding packets cause decrease of performance of the network, wasteful communications should refrain. FORP(Flow Oriented Routing Protocol) is one of routing protocols in Ad-hoc network, which uses the mobility information(e.g. location, speed and direction), and chooses the longest expiration route for source and destination pairs. In the flooding of the route search, the packets explode, as the number of nodes increases in the service area. However, FORP doesn't take explosion-control. In this paper, we discuss the effect to the destruction of extra control packets in the route search using the mobility information.


The magnitude of biological response varies with different radiation types. Using Linear Energy Transfer (LET) to differentiate types of incident radiation beam, the Relative Biologic Effectiveness (RBE) as a function of LET (RBE-LET) was found to have a characteristic shape with a peak around LET values 100 - 200 eV/nm. This general feature is believed to be a property of the incident beam. Our systems engineering model, however, suggests that the shape of the RBE-LET curve is a cell trait, a property of the cell. Like any other trait, phenotypic variations result from interactions of the genes and their context. State-space block diagram of the differential equation model suggests the genes are those in the DNA double strand break (dsb) repair pathway; and the context is cellular stress responsing to DNA damage by both external stimuli and internal redox state. At a deeper level, the block diagram suggests cell using mathematical calculations in its decision-making when facing a stress signal. The MRN protein complex, in particular, may perform addition to count the degree of DNA twisting for the homeostatic regulation of DNA supercoiling. The ATM protein may act as a feedback amplifier.


We reviewed data collected from 1993 to 2004 as part of the routine activities of the national tuberculosis (TB) control programme (NTP) in Morocco. More than 1 million household TB contacts were identified in approximately 200,000 investigations. On average, 77% of identified contacts were screened every year; overall prevalence was 2.5%. The proportion of TB cases identified in household contacts of registered cases was 5.6%. This was significantly higher in children under 10 years and in patients registered and diagnosed with symptomatic primary complex. Performing TB contact investigations as part of the routine activities of NTP services is feasible in low-middle-income countries.


The use of renewable energy (RE) sources, primarily wind and solar generation, is poised to grow significantly within the Indian power system. The Government of India has established a target of 175 gigawatts (GW) of installed RE capacity by 2022, including 60 GW of wind and 100 GW of solar, up from 29 GW wind and 9 GW solar at the beginning of 2017. Thanks to advanced weather and power system modeling made for this project, the study team is able to explore operational impacts of meeting India's RE targets and identify actions that may be favorable for integration.


We present the design of miniaturized resonant inclusions to be employed in the practical realization of metamaterial samples with anomalous values of the real part of the permeability. Such inclusions, in fact, can be employed in the design of both mu-negative (MNG) materials and artificial magnetodielectrics (with negative and high-positive values of the real part of the permeability, respectively). The inclusions here considered are the multiple split-ring resonators (MSRRs), that represent a straightforward extension of the commonly used split-ring resonators (SRRs), and the spiral resonators (SRs), that enable a greater miniaturization rate. Some physical insights on the resonance mechanism and on the inherent saturation of the resonant frequency when increasing the number of the rings of the MSRRs and the number of the turns of the SRs are given in the paper. New and accurate analytical design formulas, based on a quasi-static model, for both MSRRs and SRs are derived and tested through a proper comparison with the existing formulas and full-wave numerical results. Both MSRRs and SRs are shown to be useful to reduce the electrical dimensions of the resonant inclusions when synthesizing artificial metamaterials.


Mr. Robert F. Ashby's article in the Autumn number on the provision of fiction in libraries encourages us, as consumers who are not librarians, to make a suggestion about the criteria used in selecting from one kind of popular fiction, crime stories. The element of something more than a puzzle and a story has always intrigued us in these books, and our interest in them is now almost exclusively in their discussion of this other factor. So we read crime fiction at random, from the local library; and recently we took the first six thrillers which neither of us had read from the Latest Additions shelf so as deliberately to consider them from this point of view.


The thermal behavior of semiconductor devices fabricated with a variety of different materials has been analyzed using the three-dimensional transmission-line matrix (TLM) method. This method can easily incorporate the temperature dependence of thermal parameters, is numerically stable, and compares favorably with other numerical techniques in computational expenditure and convenience in modeling complex geometries. As an example, a three-dimensional thermal analysis of a typical microwave power device structure is presented. The model demonstrates the effects of overlay metal and conductivity of the substrate material in limiting the temperature rise. Both the transient and steady-state thermal operation are quantitatively studied. The study shows that the TLM method has considerable potential in the thermal analysis and design of semiconductor devices. >


Enterohemorrhagic Escherichia coli (EHEC), a pathogenic subset of Shiga toxin-producing E. coli (STEC), is an important cause of hemorrhagic colitis and hemolytic–uremic syndrome (HUS), and a rare cause of urinary tract infections (UTIs) with associated HUS. EHEC strains attach intimately to intestinal epithelium with formation of actin pedestals (attaching-effacing (A/E) lesions); however, the mechanism of EHEC attachment to the uroepithelium is unknown. We conducted a retrospective study on archived urinary bladder specimens from gnotobiotic piglets that naturally developed cystitis associated with EHEC O157:H7 infection following oral inoculation and fecal shedding. Paraffin-embedded bladder tissues from three piglets with cystitis and immunohistochemical evidence of EHEC O157:H7 adherence to the uroepithelium were processed for and examined by transmission electron microscopy. EHEC O157:H7 bacteria were found in one of three piglets, intimately attached to pedestals on the apical surfaces of the superficial urothelium (umbrella cells). Cystitis was significantly associated with the length of survival of the piglets post-inoculation (p = 0.0339; estimated odds ratio = 2.6652). This is the first report of E. coli causing A/E-like lesions in the uroepithelium, and also evidence of the utility of the gnotobiotic piglet as a model for studies of the pathogenesis of EHEC UTIs.


prejudice of the other ministries in Whitehall, little planning or thought was given to what would happen when the war ended. Almost casually, and without developing his thought, Molesworth raises at one point the question of the role of the Army in independent India. After many years in North India, he was stationed in the south, and was greatly impressed by the radical differences between the two areas. Wondering how so diverse a country could be kept together, he was reminded of an old saying, "Whoever controls the Army, controls India." It occurred to him that the Indian Army, so proud of being nonpolitical, and so contemptuous of politicians, might be forced to become the dominant power in order to preserve the unity of India. While unfortunately his book does not help very much in explaining the phenomenon of the nonpolitical Indian Army in a world of political colonels, it does provide some understanding of the working of one of the unique institutions created by an imperial power.


This study was carried out to determine the effect of seed growing regions and loading speed on some mechanical properties of castor seed. These properties are used to design and improve related machines such as expeller that are used for extraction of oil from castor seed. Mechanical properties of castor seed were expressed in terms of rupture force and energy, bio-yield force, apparent modulus of elasticity and toughness using material testing machine. Factorial test with Completely Randomized Design (CRD) was used to study the effect of velocity (4 levels: 5, 15, 25, 35 mm min -1 ) and seed growing regions (Izeh, Dezfoul, Baghmalek, Shoushtar and Urmia). The results showed that the effect of seed growing region on force, modulus of elasticity, bio-yield force and rupture energy was significant. Izeh seed had the maximum rupture force (75.11 N) whereas Dezfoul and Shoushtar seed had the minimum amount of rupture force (approximately 42 N). Also, loading speed had a significant effect on modulus of elasticity and rupture energy. With the increase of loading speed modulus of elasticity of Baghmalek seed decreased significantly from 144 to 65.5 MPa. Finally, interaction effect of seed growing region and loading speed was significant for most properties. In this research work, an extrusion system was designed and fabricated for the extraction of castor oil.


Global climate change has led to range shifts in plants and animals, thus threatening biodiversity. Latitudinal shifts have been shown to be more pronounced than elevational shifts, implying that northern range edge margins may be more capable to keeping pace with warming than upper elevational limits. Additionally, global climate change is expected to disadvantage habitat specialists. In the Alps, climatic variation along the elevation gradient allows the coexistence of habitat specialists and generalists. Alpine species are anticipated to adapt their elevational ranges to the change of various climate variables caused by global climate change. Regional differences might buffer elevational shifts. Furthermore, distinct climate variables might differently affect the shifts of habitat specialists and generalists. To study the effect of climate change on Alpine species, we analysed hunting bag, climate and biogeographical data of two grouse species (Tetrao tetrix and Lagopus muta) and two hare species (Lepus timidus varronis and L. europaeus) in Grisons, Switzerland, over a period of 30 years. Our results based on 84,630 harvested specimens were as follows: (1) only three out of seven climate variables changed significantly within the study period. (2) The grouse species significantly shifted towards higher elevations, whereas the hare species only shifted in their minimum/maximum elevations. (3) Hunting elevation of habitat generalists increased more than in habitat specialists. (4) The elevational shifts were mostly related to the number of frost days. (5) Hunting elevation increased especially in the southern biogeographical region. To conclude, all four taxa respond to climate change but habitat generalists more rapidly than habitat specialists. The range shift to higher elevations due to global climate change will lead to a reduction in habitat availability for snow‐adapted species. Climate change is thus a serious threat to alpine biodiversity. Regions rich in alpine habitats will have an increased responsibility to conserve these species.


This paper presents several general properties of resistive nonlinear n -ports from a geometric point of view using recent tools from differential topology. The geometric approach is coordinate-free and hence the results of the paper do not depend on the particular choice of a tree, a loop matrix, a cutset matrix, a set of independent variables, etc. Firstiy, a classification is given of resistive n -ports into logical categories such as weakly regular n -ports, regular n -ports, completely regular n -ports, and universally regular n -ports, etc. Transversality of the internal resistor constitutive relations and the Kirchhoff space plays an important role in this paper. Secondly, a structural stability result is given. In this paper, structural stability means the persistence of the configuration space under small perturbations of the internal resistor constitutive relations. Essentially the result asserts that a resistive n -port is structurally stable if and only if the internal resistor constitutive relations are transversal to the Kirchhoff space. Thirdly, two basic perturbation techniques are given which guarantee the transversality of the internal resistor constitutive relations and the Kirchhoff space. The first technique involves element perturbations, i.e., perturbations of the internal resistor constitutive relations. The second technique involves network perturbations, i.e, by augmenting extra ports to an original n -port. Lastly, coordinate-free definitions of reciprocity and anti-receprocity are given in terms of exterior product and symmetric product of two tensors, respectively, and then some of their properties are investigated.


Dimensional variations across a girth weld undergoing reeling leads to strain concentrations close to the weld that have to be taken into consideration in crack growth evaluations. The aim of the present paper is to outline an analysis procedure for simulating the complex load history, and to illustrate the effect of material and wall thickness variations between the two joints on each side of the girth weld. Verification analyses are also made towards full-scale tests simulating the cyclic loading during the reeling process. The computer software ANSYS was applied with contact and plasticity formulation, and the load history through reel, aligner and straightener was modelled. A combination of beam and shell elements was applied for the pipe, ending up in an efficient tool for design analysis. The nonlinear material model included kinematic hardening and was based upon a Ramberg-Osgood type of stress-strain curve. The effect of kinematic hardening through cyclic loading was studied in an effort to define the material properties of the as-installed pipe. The numerical model also came out with contact pressures between the reel and the pipe, being of special interest for thermally coated pipes. Ovalisation of the pipe was available, and goes into the bending moment capacity for expansion control. A full-scale bending test of clad pipe around a girth weld was performed, simulating the load history through the reeling process. Measured strains and forces were compared with numerical results as a verification of the analysis model. A separate ANSYS model was created for the test case, based on the material models in the global model. The location of strain concentrations in the vicinity of the girth weld was given special attention in the comparison between tests and numerical simulation. Material tests for backing steel and clad, respectively, around the circumference of the as-tested pipe illustrate the strain hardening effect as basis for evaluation of the kinematic hardening parameters implemented in the numerical models. Analyses were then used for a parameter study on strain concentrations with yield stress and wall thickness variations across the girth weld. Also, the amplifying effect of local buckling during reeling is evaluated, as basis for defining needed back-tension.Copyright © 2010 by ASME


Helicobacter pylori are gram-negative bacteria that colonize the gastric epithelia of approximately 50% of the world's population. This infection is considered to be the leading known cause of chronic gastritis, peptic ulcers, gastric MALT and gastric cancer. In addition, there is evidence linking the bacteria to several extra- gastric diseases. The association of extra-gastric diseases with colon cancer and other colonic neoplasms has been the subject of much debate since it was first suggested. Although some studies have cast doubt on this association, others have sustained it. These include a recent meta-analysis and cross-sectional study of more than 150,000 patients which is the largest on this subject so far. In addition, there are numerous articles that support the biological plausibility of this association. In this article we review the available evidence regarding this association and the mechanisms of causality that have been proposed.


It is apparent from the foregoing discussion that carnitine plays an essential role in human intermediary metabolism. The question of a dietary requirement for carnitine, particularly for the human infant, is of significant theoretical and practical interest. Aberrant carnitine metabolism resulting from abnormal genetic or acquired conditions may have serious consequences for the affected individual. At present many of the treatment modalities for carnitine deficiency are empirical. Further clarification of the mechanisms by which carnitine depletion is manifest in these conditions is essential for designing treatment programs. Moreover, therapeutic use of carnitine in several human diseases not involving carnitine deficiency per se has been indicated. Before such treatment becomes generally accepted, we must determine precisely the role of this amino acid in the biochemical and physiological events that participate in the pathogenesis of each disease.


Several algorithms for gate-level sequential circuit optimization have been reported in the literature. They perform operations similar to those in the more mature multilevel combinational domain while taking relationships across several time periods into account. These techniques are heuristic and their application ad hoc: there is no guarantee of optimality. We present a technique for producing an optimum two-level acyclic sequential circuit. While the circuit restrictions and cost function are limiting, the guarantee of optimality is novel and illuminating. The technique presented herein is useful for optimizing sub-circuits of a multilevel sequential circuit just as two-level combinatorial techniques have been in the combinational domain. Furthermore, the algorithm can be used to detect precisely circuits in which logic sharing across latch boundaries is actually possible- a hitherto unsolved problem.<<ETX>>


The catalytic activity of histidase and the expression of the enzyme protein were investigated in rat hepatomas induced by diethylnitrosamine. The results indicated that the activities of histidase in the hepatomas were significantly diminished as compared with normal rat livers (P < 0.01). Western blot analysis revealed that enzyme protein levels in hepatomas were markedly reduced. It is thus inferred that some factors which control expression of histidase protein may be altered during carcinogenesis. These findings lay a foundation for studying the relationship between the regulation and expression of the histidase gene and hepato carcinogenesis.


Polygonatum verticillatum All. is used traditionally as an analgesic and plant diuretic. The methanol extract of aerial parts of Polygonatum verticillatum (PA) was assessed in various experimental paradigms. The pain threshold in the form of abdominal constriction induced by acetic acid was significantly (p < 0.01) inhibited by PA at test doses (50, 100 and 200 mg/kg). In the formalin test, PA elicited a significant (p < 0.01) analgesic activity in both phases and strongly attenuated the formalin‐induced flinching behaviour. The hot plate test was used to evaluate central involvement in the analgesic profile of PA. The PA significantly relieved thermal‐induced pain. From a mechanistic point of view, the central antihyperalgesic activity was tested for antagonism with naloxone, but no antagonism was observed. The current investigations suggest that the active constituent(s) in PA has an analgesic profile with predominant peripheral activity which is augmented by an opioid independent central effect. In the diuretic assay, PA (300 and 600 mg/kg) showed mild insignificant diuretic activity. Our study rationalized the traditional use of Polygonatum verticillatum in the treatment of painful conditions. Copyright © 2011 John Wiley & Sons, Ltd.


Nonfarm earnings from diverse sources account for a substantial and growing share of household income among smallholder farmers in many areas of Sub-Saharan Africa, but information about the effects of these earnings on farm investments is relatively sparse. This study focuses on fertilizer investments given the importance of soil fertility in raising crop productivity, the central role of fertilizer in most recommendations for managing soils, and the high cash cost of fertilizers. We use panel data from a sample of roughly 1200 smallholder farmers in Kenya to estimate input demand for fertilizer, testing the effects of off-farm income, as well as nonfarm income, income from labor on other farms, and all off-farm income combined. We compare effects among three types of crops: a major food staple (maize), and emerging cash crop (vegetables), and traditional export crops (coffee/tea). Demand functions are estimated with double hurdle regression, a Control Function approach to handle potential endogeneity of off-farm income, and Correlated Random Effects to treat time-invariant heterogeneity. We find that, holding prices, other crops grown, locational and relevant household characteristics constant, off-farm earnings have a negative impact on fertilizer use on both staple and emerging cash crops in Kenya, and a weak, positive effect on traditional cash crops. Nonfarm income explains most of this pattern, although the effects of labor on other farms are evident in the case of vegetables, which are relatively labor-intensive throughout the growing season. Results have implications for public investments in rural development as smallholders commercialize in Kenya.


Surface geology and gravity data suggest the presence of a major subsurface ramp zone in the Paris (Putnam) thrust beneath the mountain ranges south of Pocatello, Idaho. Immediately to the west a major thrust plate of mainly upper Paleozoic rocks (Hansel allochthon) overlies the Paris plate and conceals any evidence of the proposed ramp. Minor petroleum exploration work has been conducted in the general area of the ramp. At localities in the Bannock Range, Blue Spring Hills, and Deep Creek Mountains, surface geology may indicate the presence of a steep ramp on the underlying Paris thrust. Recent mapping at the north end of the Deep Creek Mountains suggests the presence of an anticline west of Bannock Peak that has been disrupted by Basin and Range faults. This anticline lies at the structural contact between the area of upper Paleozoic rocks to the west (Hansel plate) and the area underlain by lower Paleozoic and Precambrian strata to the east (Paris plate). A similar structural-stratigraphic relationship is present locally in the Bannock Range and Blue Spring Hills. Restored cross sections, which have Basin and Range fault offsets removed, show that inference of a ramp on the underlying decollement a each locality helps to explain the observed structural-stratigraphic associations. Preliminary analysis of gravity data supports the existence of a major thrust ramp beneath the mountain ranges south of Pocatello. A progressive eastward decrease in Bouguer anomaly values associated with pre-Tertiary rocks across the thrust belt begins in the Bannock Range, and may indicate that tectonic duplication of the sedimentary section has occurred as far west as the Bannock Range. The progressive eastward decrease in Bouguer values may reflect tectonic thickening associated with a significant ramp on the underling decollement. Limited petroleum exploration work has been conducted along the exposed western margin of the Paris thrust plate and in the adjacent Hansel plate. Although near-surface strata in the Paris plate in the Bannock Range area lack hydrocarbon potential, it is possible that favorable stratigraphic units exist beneath the thrust at depth. The Hansel plate deserves additional exploration attention in that potential reservoir facies of the thick upper Paleozoic sequence are present in folded structures in the Blue Spring Hills and Sublett Range. Furthermore, the Manning Canyon Shale, which is a possible hydrocarbon source, is widespread in the Hansel plate. Structural complexity and high heat flow in the area have been the main deterrents to hydrocarbon exploration. End_of_Article - Last_Page 1345------------


We prove a bilinear Strichartz type estimate for irrational tori via a decoupling type argument, \cite{bourgain2014proof}, recovering and generalizing the result of \cite{de2006global}. As a corollary, we derive a global well-posedness result for the cubic defocusing NLS on two dimensional irrational tori with data of infinite energy.


Long‐term streamflow reconstructions help characterize climate variability and extreme climatic events, such as droughts, which play a crucial role in water resource planning. Dendrohydrological reconstructions generally build on indirect associations between streamflow and radial tree growth, both of which depend on cool season precipitation in the Pacific Northwest. We develop a new approach that integrates a tree ring reconstruction of cool season precipitation with historical meteorological data and a physically based hydrologic model to reconstruct warm season streamflow and streamflow uncertainty. The Upper Yakima Basin in Washington state is used as a test case. We applied objective screening, principal components analysis, and multiple linear regression to reconstruct 366 years of basin‐average cool season precipitation. The reconstruction was integrated with five temporally and spatially distributed cool season precipitation patterns spanning the historical range of natural variability. These distributed meteorological reconstructions were used as inputs to the Variable Infiltration Capacity (VIC) hydrologic model over the Yakima basin to produce an ensemble of warm season streamflows for each reconstructed year. The resultant streamflow reconstruction retains dendroclimatic information and quantifies the inherent uncertainty in warm season streamflow associated with historical meteorology. Finally, the meteorological reconstructions were systematically perturbed and used to drive the VIC to examine the potential impacts of climate change on warm season streamflow over the 366‐year record. Despite projected wetter conditions in the future, less precipitation is stored as snowpack (due to warmer winter temperatures) and consequently warm season streamflow will be systematically reduced. The combination of long records of variability and systematic changes related to climate change provides useful information about the combined effects of natural variability and projected systematic changes in climate to support 21st‐century water planning.


This study is the first to demonstrate that ferroelectric R3c LiNbO3‐type ZnSnO3 nanowires (NWs), through the piezocatalysis and piezophototronic process, demonstrate a highly efficient hydrogen evolution reaction (HER). The polarization and electric field curves indicate that ZnSnO3 NWs exhibit typical ferroelectric hysteresis loops. Time‐resolved photoluminescence spectra reveal that the relaxation time increases with the increasing concentration of oxygen vacancies. Moderated 3H‐ZnSnO3 NWs (thermally annealed for 3 h in a hydrogen environment) have the longest extended carrier lifetime of approximately 8.3 ns. The piezoelectricity‐induced HER, via the piezocatalysis process (without light irradiation), reaches an optimal H2‐production rate of approximately 3453.1 µmol g−1 h−1. Through the synergistic piezophototronic process, the HER reaches approximately 6000 µmol g−1 in 7 h. Crucially, the mechanical force–induced spontaneous polarization functions as a carrier separator, driving the electron and hole in opposite directions in ferroelectric ZnSnO3 NWs; this separation reduces the recombination rate, enhancing the redox process. This theoretical analysis indicates that the photocatalytic and piezocatalytic effects can synergistically enhance piezophototronic performance through capitalizing on well‐modulated oxygen vacancies in ferroelectric semiconductors. This study demonstrates the essential role of this synergy in purifying water pollutants and converting water into hydrogen gas through the piezophototronic process.


This article reports on research commissioned to address the topic of domestic abuse against men in Scotland. The research addressed three key questions: (1) Why do male victims appear much more frequently in crime survey data than in recorded crime statistics? (2) Are there significant differences in the nature and frequency of domestic abuse experienced by men and women? (3) In what kinds of relationships does domestic abuse against men occur? The article explains that the relative absence of male victims in the domestic abuse statistics gathered by the Scottish police can be accounted for in terms of gender differences in experiences of victimisation and reporting patterns. Drawing upon in-depth interview material elicited from a sample of men originally counted as 'male victims' in the Scottish Crime Survey, the article also argues that statistics collated on the basis of crime survey data overstate men's experiences of domestic abuse. The article concludes with a discussion of the methodological and policy implications that should be drawn from this finding.


The first phylogenetic study of Portschinskia is presented based on 42 adult morphological characters scored for all 11 species, including four new species Portschinskia burmensis sp. nov., Portschinskia sichuanensis sp. nov., Portschinskia xizangensis sp. nov. and Portschinskia yunnanensis sp. nov.Portschinskia luliangensis is established as a junior synonym of Portschinskia magnifica. Monophyly of Portschinskia is strongly supported by nine non-homoplasious synapomorphies. All cladograms resolve P. yunnanensis as a basal taxon and a well-resolved Portschinskia gigas clade {P. gigas + ((Portschinskia bombiformis + (P. burmensis + (P. magnifica + P. xizangensis))) + (Portschinskia himalayana + (Portschinskia przewalskyi + P. sichuanensis)))}. The only topological difference is Portschinskia loewii and Portschinskia neugebaueri either being sister taxa or branching off successively at the base of the P. gigas clade. Three colour-pattern types are recognized, with the yellow-tailed pattern optimized as the ancestral state. Our data show that the modal colour pattern of Portschinskia species is the same as in bumblebees, and a regional correlation in species diversity and colour patterns can be detected between sympatric Portschinskia and Bombus species. As a result, we suggest that colour patterns of Portschinskia can be explained as Batesian mimicry tracking locally dominant bumblebees.


By considering momentum transfer in the Fermi constraint procedure, the stability of the initial nuclei and fragments produced in heavy-ion collisions can be further improved in the quantum molecular dynamics simulations. The case of the phase space occupation probability larger than one is effectively reduced with the proposed procedure. Simultaneously, the energy conservation can be better described for both individual nuclei and heavy-ion reactions. With the revised version of the improved quantum molecular dynamics (ImQMD) model, the fusion excitation functions of $^{16}$O+$^{186}$W and the central collisions of Au+Au at 35 AMeV are re-examined. The fusion cross sections at sub-barrier energies and the charge distribution of fragments are relatively better reproduced due to the reduction of spurious nucleon emission. The charge and isotope distribution of fragments in Xe+Sn, U+U and Zr+Sn at intermediate energies are also predicted. More unmeasured extremely neutron-rich fragments with $Z=16-28$ are observed in the central collisions of $^{238}$U+$^{238}$U than that of $^{96}$Zr+$^{124}$Sn, which indicates that multi-fragmentation of U+U may offer a fruitful pathway to new neutron-rich isotopes.


This paper discusses approaches to strengthen and monitor urban resilience through the use of indicators. Resilience is the capacity of a city or community to prepare for, respond to and adapt from dangerous and disruptive events, such as natural disasters, economic crises, demographic changes, health epidemics and others. Given that resilience is a multi-dimensional phenomenon, local authorities should design and implement strategies for urban resilience that integrate economic, social, environmental and institutional aspects. In order to monitor progress in becoming more resilient, local authorities should use indicators that measure resilience along these dimensions. The paper analyses different types of indicators and discusses the contexts in which they should be used. It provides recommendations on how local authorities can choose indicators tailored to their policy priorities and develops guidelines for the effective use of indicators in a broader governance framework.


Editor,—Lane and colleagues'1confidential inquiry into families with two siblings with cystic fibrosis was essentially to determine whether couples with one child were offered prenatal diagnosis before a second pregnancy. There are several misconceptions with reference to the Northern Ireland population. The statement "clinicians and/or clinical geneticists did not offer prenatal diagnosis to a significant proportion of the couples . . . 56% of those in Northern Ireland", does not reflect the actual situation. Since 1990 there has been a policy that when a child with cystic fibrosis is diagnosed, the paediatricians refer the family for genetic counselling. Most referrals are accepted and the genetic counselling session always includes information on prenatal diagnosis and appraisal of all possible reproductive options. When a couple embark on a further pregnancy, they can contact directly the regional genetics service responsible for coordinating the regional prenatal diagnostic clinics. These clinics, which are staffed by obstetricians and clinical geneticists, provide chorionic villus biopsy and early amniocentesis from 12 weeks' gestation.2 All obstetricians are aware of these clinics in Northern Ireland.

The statement that "the Abortion Act does not apply there and this may affect uptake of prenatal counselling" is incorrect. While the 1967 Abortion …


Sustainability, proposed as a concept and strategic solution to the contemporary crisis, poses several challenges for humanity, among which is the formation of individuals capable of facing the complexity of environmental problems, as well as of visualizing and developing a free society, fair and in balance.
In order to contribute to this challenge, the present work was proposed to investigate the contribution of Scenario Based Learning to the development of competencies for sustainability, both from a conceptual and practical point of view, designing an educational resource and carrying out a pilot test in students of the Autonomous University of San Luis Potosi. The specific objectives were: (1) Identify, select and formulate the systemic analysis of two cases, one in Mexico and one in Germany, to show the complexity of the relationship between sustainability dimensions and the challenges faced by the actors in the management of this and, (2) Design and test an educational resource around its contribution to the development of critical thinking and systemic thinking competencies.
The pilot test of the educational resource was carried out with a multidisciplinary group, integrating undergraduate students from: Communication Sciences, Environmental Sciences and Health, Agroindustrial Engineering, Psychology and Psychopedagogy.
Based on assessment interviews, it was concluded that scenario-based learning allowed to contribute to the development of competencies for sustainability. The two selected cases: Rio Rin and Rio Verde were effective in demonstrating complexity, and they also warned of the challenges that result from the management of the sustainability. Finally, it should be mentioned that the development of interpersonal competence (dialogue and collaboration mainly) that was not within the objectives of the thesis was evidenced.


We studied the vegetation development in the Pannonian salt steppes in SW Slovakia (class Festuco-Puccinellietea) for eight years on permanent plots. The saline grassland was ploughed in 2002 to cultivate wheat and barley, and after two years it was left fallow. An open vegetation structure was typical for the initial stages, dominated by the obligate halophyte Tripolium pannonicum, accompanied by Atriplex littoralis and other annuals. Species richness significantly increased in the subsequent years. From the fifth year of the study, a significant increase of facultative halophytes (e.g. Lotus tenuis, Tetragonolobus maritimus, Agrostis stolonifera) and colonization of some expansive species (Phragmites communis, Calamagrostis epigejos) was observed and accompanied by a decrease in the cover of obligate halophytes (T. pannonicum and Puccinellia distans). Plantago maritima exhibited an opposite trend, and it was the only halophyte that was able to increase its population after the disturbance, due to vegetative propagation by rhizomes which increased the competitiveness of the species. The declining presence of salt-demanding species indicates a strong degradation of the saline vegetation, which might be linked to gradual desalinization of the soil. We conclude that population fluxes after adverse human disturbance and subsequent abandonment are very high, and succession of halophytic communities after such a strong disturbance is very fast, leading to deterioration of the habitat.


Diabetic foot ulcers (DFUs) combined with necrotizing fasciitis (NF) has rapid onset, involves a wide range of lesions, is difficult to treat, and has a high mortality rate. It has become a clinically critical disease. DFU patients are at high risk for NF. The STAGE principles guide surgical intervention in the treatment of DFU wounds and emphasizes that "based on anatomical layers, the management focuses on blood supply and includes layer-by-layer incision to the infected area, maintenance of effective wound drainage, and step-by-step treatment of the wound." This work reports the application of the STAGE principles for the treatment of 9 cases of DFUs combined with NF in the lower leg (Wagner grade 3-5). The mean ankle-brachial index was 0.55 (0-0.91, standard deviation [SD] = 0.33), the mean years of smoking were 19.56 years (0-50, SD = 17.83), and the mean cigarette consumption was 9.11 cigarettes/day (0-20, SD = 7.77). The mean duration of ulcers was 45.56 days (3-103, SD = 35.44). Among the 9 patients, only patient no. 9 died, and the mean follow-up time for the other 8 patients was 12 months (3-36, SD = 13.42). In short, the STAGE principles are also applicable to the treatment of DFUs combined with NF in the lower leg.


As the design rule of lithography becomes smaller, printability of reticle defect to wafer is critical for the photomask manufacturing technology. In order to improve the controllability of reticle defects, inspection and repair systems are expanding their capability by continuously modifying hardware and software. This is a good solution to detect and review the defect but it is indirect approaching to reduce the defect in the photomask process. To produce the photomask of defect free or low defect density, effort is needed to improve the capability of defect control in the mask-making process and to evaluate the source of hard defect as well as soft defect. In this paper, we concern the defect source and the feature of printed defects in photomask manufacturing steps. We also discuss the efforts to eliminate the defect source and to control the mask-making process with low defect density. In order to eliminate the source of defects, we partition the mask-making process with defect inspection system, SLF27 TeraStar and Lasertec MD2000, and review a defect shape with CD SEM and AFM. And we compare printed defects, which exist in each process steps, after dry etching process.


Hypercarotenaemia is seen more frequently among young infants and children. This condition develops mainly due to excessive intake of carotenoid bearing foods. Evidence shows that, not all infants develop hypercarotenaemia due to excessive intake of carotenoid containing foods. The objective of this study was to study the prevalence of hypercarotenaemia among nursery/kindergarten children in the Western province of Sri Lanka and to correlate the food intake with development of hypercarotenaemia. The occurrence of hypercarotenaemia among their siblings fed similar diets was also observed. A self administrated questionnaire was given to the parents (n = 780) of nursery/kindergarten children (2-5 years) in the Western province to collect information on the intake of carotenoid rich foods and development of hypercarotenaemia among the children attending these nurseries and their siblings. Among all the subjects investigated twelve (n = 12) had developed hypercarotenaemia. Children fed with high carotenoid bearing food/fruits were categorized in to two groups depending on the whether they have received a vitamin A mega dose (n = 287) or not (n = 328). The prevalence of hypercarotenaemia among children fed high quantity of carotenoid foods (n = 615) was 2%, while the group fed with vitamin A mega dose and not fed vitamin A mega dose were 1.4% and 2.5% respectively. We suggest a genetic effect that is probably recessive, involved with absorption or the metabolism of carotenoids in children who develop hypercarotenaemia. In conclusion, the study showed the prevalence of hypercarotenaemia to be <2%, irrespective of the amount of carotenoids ingested and vitamin A mega dosing.


Objective This study aimed to evaluate the safety and necessity of tracheostomy after anterior cervical discectomy and fusion (ACDF) with plating, despite the close proximity of the two surgical skin incisions. Methods Sixty-three patients with traumatic cervical fractures or spinal cord injury (SCI) who underwent single-level ACDF and plating between January 2014 and June 2019 were included in this study. The patients included 45 men and 18 women, with a mean age of 48.5 years. A retrospective analysis of the patients' demographic data, level of injury, radiological findings, and neurological status was performed based on the American Spinal Injury Association (ASIA), open tracheostomy, and decannulation rate. Additionally, risk factors necessitating tracheostomy were statistically analyzed. Results Eighteen patients (28.5%) required subsequent open tracheostomy. Among them, 11 patients were successfully decannulated, four patients could not be decannulated during the follow-up period, and three patients died of unrelated complications. The median interval from ACDF with plating to open tracheostomy was 9.6 days (range, 5–23 days). On the basis of neurological status, ASIA A and B patients (p<0.001), high signal intensity on T2-weighted-magnetic resonance (MR) images (p=0.001), and major cervical fracture and dislocation were significant risk factors for tracheostomy (p=0.02). No patient showed evidence of significant soft tissue, bony infection, or nonunion during the follow-up period. Conclusion Independent tracheostomy did not increase the risk of infection or nonunion despite the close proximity of the two surgical skin incisions.


In multivariate spectral calibration by principal component regression (PCR), the principal components (PCs) are calculated from the response data measured at all employed instrument channels; however some channels are redundant and their responses do not possess useful information. Thus, the extracted PCs possess mixed information from both useful and redundant channels. In this work, we propose a segmentation approach based on unsupervised pattern recognition to identify the most informative spectral region and then to construct a stable multivariate calibration model by PCR. In this method, the instrument channels are clustered into different segments via Kohonen self‐organization map. The spectral data of each segment are then subjected to PCA and the derived PCs are used as input variables for an inverse least square (ILS) regression model employing stepwise selection of the informative PCs. The proposed method was evaluated by the analysis of four simulated and six experimental data sets. It was found that our proposed method can model the above data sets with prediction errors lower than conventional partial least squares (PLS) and PCR methods. In addition, the prediction ability of our method was better than the previously reported models for these data sets. Copyright © 2011 John Wiley & Sons, Ltd.


The article is dedicated to the 30th anniversary of the Russian Mass Media Law, adopted on December 27, 1991. This Law is proposed to be considered as innovative, which laid the foundation for a number of innovations in national legal science and legislative practice. Among these innovations are: the author's nature of drafting, consolidation of the thesaurus of the Law in a separate article of the Law, the establishment of a cumulative liability mechanism, etc. Over the next three decades, the Law has undergone numerous changes that have predetermined law enforcement practice. The article analyzes the trends of the ongoing transformation: the expansion of the concept of abuse of freedom of the media, expansion of diversity of types of mass media, etc. As part of considering the future prospects of the Law, the need is revealed to bring it into terminological compliance with the Constitution of the Russian Federation, the Civil and other codes, to eliminate legal and logical defects formed in the process of its creation and subsequent adjustment. The necessity of the Law transformation into the Mass Communications Law is substantiated.


Heterocyclic compounds are of very much interest in our daily life. They have high significance in our living system. Heterocyclic compounds have a wide range of applications in agrochemicals, pharmaceuticals, veterinary products etc. They are also used as starting material in the synthesis of organic compounds. These are also used in sanitizers, developers, anti-ordinates, corrosion inhibitors etc. Heterocyclic compounds are the cyclic compounds which contain one or more different atoms other than carbon in a ring structure. These compounds may be aromatic or anti-aromatic. Heterocyclic compounds widely found in nature, e.g. pyramiding and purine are the parts of DNA, vitamins and enzymes. Heterocyclic compounds are very important for human survival too. They are important information carrier. These are used in neurotransmitter and pyrimidines; nucleoside is a part of genetic material that transfers information from one generation to other. This review article focuses on the importance of heterocyclic compounds in our life in different ways.


Local reactivity descriptors, such as the condensed local softness and Fukui function, have been employed to investigate the intercluster reactivity of the metalloaromatic (Al4Li- and Al4Na-) and antiaromatic (Al4Li4 and Al4Na4) compounds. We have used the concept of group softness and group Fukui function to characterize the strength of the nucleophilicity (ability to donate electrons) of the Al4 unit in these compounds. The aim of this work is to understand the enhanced efficiency of the electron injection of the Al-Li cathode in the organic light emitting diode due to the formation of Al-Li clusters at the interface. Our analysis shows that the Al4 unit of the Al4Li- cluster has the highest nucleophilicity compared to the other clusters. Hence, we believe that the formation of the Al4Li- type of metalloaromatic clusters would be responsible for the increase in the efficiency of the electron injection of the Al-Li cathode.


A distributed expert system has been proposed for the bridge crane control. Its configuration is mainly based on the use of distributed nodes connected by means of a CAN network This type of systems allows the implementation of highly flexible control systems capable of adapting themselves to different situations. The expert system used is based on rule nets (RN), which are a formalism that seeks to express an automatism in a similar way to as would make it a human being:"IF antecedents THEN consequents". But at the same time rule nets are a tool for the design, analysis and implementation of rule based systems (RBS), and consist on a mathematic-logical structure which analytically reflects the set of rules that the human expert has designed. Additionally, the RN is able to take decisions concerning possible malfunctions and has bounded response time. In this paper the design of the proposed control system is shown with the methodology is presented. Satisfactory results have been obtained when the control system has been applied in a scale model assembly chain crane, important advantages being shown over previously implemented centralised knowledge-based systems.


Six mutants of Cryptococcus neoformans resistant to nystatin and pimaricin and three mutants resistant to amphotericin B were isolated by ultraviolet irradiation techniques from two wild-type strains. The major sterols of the wild-type strains were Δ7-ergosten-3β-ol and ergosterol. All six mutants resistant to nystatin and pimaricin showed either loss of ergosterol and concurrent production of Δ7, 22-ergostadien-3β-ol and Δ7-ergosten-3β-ol, or loss of both the wild-type sterols, with production of Δ8(9)-ergosten-3β-ol and Δ5, 8(9), 22-ergostatrien-3β-ol. The mutants producing Δ7, 22-ergostadien-3β-ol and Δ7-ergosten-3β-ol showed relatively low levels of resistance to nystatin and pimaricin, whereas the mutants producing Δ8(9)-ergosten-3β-ol and Δ5, 8(0), 22-ergostatrien-3β-ol showed a high level of resistance to either drug. Although highly resistant to amphotericin B, however, the three mutants produced sterol compositions identical to those of the wild types, indicating that the strains acquired resistance other than by alteration of the membrane sterols. The mutants producing Δ8(9) and Δ5, 8(9), 22 sterols were not virulent for mice, showed reduced growth rates at 25 C, and failed to grow at 37 C. The other mutants showed a slightly reduced rate of growth both at 25 and 37 C, and the virulence in mice was slightly reduced in comparison with that of the wild types. These comparisons were on gross observations and were not statistically analyzed.


Autobiography of an Archive is a collection of essays by Nicholas B. Dirks written since 1991, preceded by an autobiographical introduction. This review article discusses the collection in relation to Dirks's overall scholarship and the wider intellectual field in which history, anthropology, and colonialism intersect in the study of India. Dirks has written three books: The Hollow Crown (1987), an "ethnohistory" of a "little kingdom" in south India; Castes of Mind (2001), about colonialism, anthropology, and caste in India; and The Scandal of Empire (2006), which discusses the foundations of British imperial sovereignty. In The Hollow Crown and other writings, Dirks significantly contributed to the debate about the "rapprochement" between anthropology and history, which was prominent in the 1980s. But in the 1990s, Dirks thought, the rapprochement ground to a halt; the relationship between anthropology and colonialism then came to the fore, and Castes of Mind, as well as some of these essays, were influential critical studies of colonial anthropology. In recent essays, Dirks has examined the "politics of knowledge" and the postwar development of South Asian area studies in the United States. This article argues that although the relationship between anthropology and history is now rarely debated, historical anthropology has continued to develop since the 1980s. Moreover, anthropologists in general now recognize that history matters, and that colonialism crucially shaped modern society and culture in India, and other former colonial territories. Many of Dirks's conclusions about, for example, Indian kingdoms and caste in colonial discourse, have been criticized by other scholars. Nonetheless, anthropological writing, especially on India, is no longer unhistorical, as it once often was, and Dirks's scholarship has played a valuable part in bringing about this change.


Since 2002, the Kate Gleason College of Engineering (KGCOE) at the Rochester Institute of Technology (RIT) has seen its Multidisciplinary Senior Design (MSD) program grow from a small pilot project into a college-wide initiative involving four departments and almost 400 students annually. While subtle adjustments have been made each year, a major redesign effort was undertaken prior to the 2006 academic year to improve program alignment with departmental objectives, to improve delivery efficiency and effectiveness, and to improve student and faculty satisfaction. Coordination of related projects and sharing of information between approximately 60 design teams in a given year, and preserving continuity of information from one year to the next has proven to be a challenging hurdle. This paper addresses the project definition process, which was overhauled to focus on the definition of related projects within a set of disciplinary "tracks," consistent with academic programs and faculty interests. Emphasis was placed on the development of reusable and scalable platforms to lay the foundation for future project extensions, and to encourage cross-project and cross-department collaboration. The process by which project tracks, project families and individual projects were identified, screened, modified and ultimately selected will be discussed. The integral relationship between the Design Project Management course, which trains the future project managers and technical leaders of the multidisciplinary project teams, and the project definition process will be illustrated. The development of the Aerospace Systems and Technology Track, with particular emphasis on the Microsystems Engineering and Technology for the Future Exploration of Outer Space Regions (METEOR) family of projects will be used as a case example to illustrate the process.


We present a study of the peculiar Type Ia supernova 2001ay (SN 2001ay). The defining features of its peculiarity are high velocity, broad lines, and a fast rising light curve, combined with the slowest known rate of decline. It is one magnitude dimmer than would be predicted from its observed Δm15, and shows broad spectral features. We base our analysis on detailed calculations for the explosion, light curves, and spectra. We demonstrate that consistency is key for both validating the models and probing the underlying physics. We show that this SN can be understood within the physics underlying the Δm15 relation, and in the framework of pulsating delayed detonation models originating from a Chandrasekhar mass, MCh, white dwarf, but with a progenitor core composed of 80% carbon. We suggest a possible scenario for stellar evolution which leads to such a progenitor. We show that the unusual light curve decline can be understood with the same physics as has been used to understand the Δm15 relation for normal SNe Ia. The decline relation can be explained by a combination of the temperature dependence of the opacity and excess or deficit of the peak luminosity, α, measured relative to the instantaneous rate of radiative decay energy generation. What differentiates SN 2001ay from normal SNe Ia is a higher explosion energy which leads to a shift of the 56Ni distribution toward higher velocity and α < 1. This result is responsible for the fast rise and slow decline. We define a class of SN 2001ay-like SNe Ia, which will show an anti-Phillips relation.


Research was carried out at IT Sligo to determine travel modes, and views and preferences of commuter stakeholders on sustainable transport provision. Findings were planned to provide inputs into development of a workplace travel plan and targeted reduction in car travel to the Institute, due to a planning application and associated transport development control conditions relating to a major Institute building project. It was also considered that existing parking demand was excessive and unsustainable thereby the plan provided an opportunity to influence travel modes positively. Quantitative and qualitative survey methodologies were utilised in the initial stage of the study from November 2012 to February 2013. This included the identification of relevant stakeholder groups, the issuance of on-line questionnaires to determine modal choice and preferences of stakeholders, "live" interviews to gather real time journey characteristics, modal focus groups to determine concerns and attitudes, car parking accumulation surveys and comprehensive technical assessments of the Institute's transport infrastructure. An analysis of public transport services, usage and facilities was also performed. As part of the Institute's implementation of a Sustainable Workplace Travel plan under the Smarter Travel Campus programme, monitoring of travel modes and attitudes was instigated during November/December 2014. This included an extended on-line stakeholder survey based on the 2012/13 study with additional questions relating to sustainable travel facilities to increase cycling, walking and public transport uptake, and a technical review of transport facilities and services. It was found from the 2012/13 on-line (494 respondents/343 students) and 2012 live surveys (1346 interviewees) that the dominant travel mode to the Institute was by private car at 80% (60% for live survey), with car-sharing only occurring in 15% of trips (22% for live survey). It was determined that travel distance, convenience, public transport provision, and car sharing issues were the dominant factors affecting transport mode. Walking trips corresponded to a 27% modal share (on-line survey), compared with 36% ('live' survey). It was considered that a significant portion of walking commuters did not participate in the on-line survey. Inadequate lighting was also found to be a significant inhibitor to walking with security concerns highlighted. Parking availability influenced commuters' time of arrival negatively. The use of public transport services (private/public bus) from the 2012/13 surveys was low (2% live survey; 5% on-line survey) with lack of facilities on campus and poorly connected, infrequent services the main hindrances identified. Cycling trip (2% live survey; 7% on-line survey) rates were low with obstacles such as weather, inadequate cycling routes, commuting distance, and poor Institute facilities identified. The 2014 on-line questionnaire (210 respondents) findings strongly correlated with 2012/13 findings. Recent upgrades to Institute bus services had increased public transport bus mode share to 8%.Cycling modal share had also increased to 8% but awareness of new cyclist facilities and services was low amongst respondents. The 2014 survey also indicated that walking had also increased in popularity from 27% to 32% of respondents. It was concluded that insufficient awareness of new sustainable transport facilities had limited its potential.


This article focuses on the role of demand in the National System of Innovations: why it is so important, and how does it affect the dynamics of the system and the flow of inventions and innovations. To study the evolutions and the dynamics of the different systems a series of composite indicators will be build up. In the paper it will be argued that the system of innovation can be defined by four different dimensions: Social and Human Capital, Knowledge Creation, Innovation capacity of the Supply and Innovation from the Demand. The evolution of these dimensions is studied over a period of fifteen years and compared across fourteen European countries. This structure allows to study different dynamics, and evolution over time of different systems. The study highlights the weak links of the system, comparing each national system with the performance of the rest of the states members. The identification of the weakness and the evolution of the weakness over the time gives interesting policy conclusions. The aim of the paper is also to contribute to the theory of composite indicators by offering a new approach to select, after carrying out a sensitivity analysis, the best indicator.


This document (16 pages) describes the project objectives and methods and summarizes its key findings. A book presenting in detail the project findings is published in 2009 by Oxford University Press. The information in this summary must be considered preliminary.


A 57-yr-old female with corticotropinoma showing no Cushingoid stigmata is reported. Basal plasma levels of ACTH measured with immunoradiometric assay and beta-endorphin were high, 12.6-15.9 pmol/l and 3.5 pmol/l, respectively. Plasma cortisol level and urinary free cortisol excretion were normal, 303-359 nmol/l and 171-226 nmol/day, respectively. Plasma ACTH markedly increased to 70.5 pmol/l with intravenous administration of 100 microg CRH. Diurnal rhythm of plasma ACTH was seen, but its level in the night was still high. Plasma ACTH suppression with dexamethasone was insufficient. CRH stimulation after dexamethasone suppression increased plasma ACTH level from 4.4 to 13.7 pmol/l. Intravenous administration of 4 microg desmopressin increased plasma ACTH from 15.6 to 19.6 pmol/l. Oral administration of 16 mg lepramide insufficiently decreased plasma ACTH from 7.3 to 5.3 pmol/l. However, plasma cortisol responses in these conditions were normal. Postoperative pathological study revealed subtype 1 corticotropinoma immunohistochemically and electron-microscopically. Postoperative basal plasma ACTH decreased to 3.9 pmol/l, although plasma cortisol did not change. Diurnal rhythm and dexamethasone suppressibility of plasma ACTH became normal. Plasma sample was chromatographed on a Sephadex G-75 column. The elution profile showed two peaks of ACTH, one of which was compatible with 1-39 ACTH and another with higher molecular weight ACTH which was probably secreted from corticotropinoma. Anomaly in processing of proopiomelanocortin was suspected.


Inosine is a naturally occurring purine nucleoside, the effect of which was discovered only in recent decades. It has potential to prevent neuronal and glial death and can stimulate axonal outgrowth. This study evalu - ated the effect of inosine (400 mg per rat) administered orally two hours after experimental spinal cord injury and continuously daily for 12 days. We observed the effect of inosine on clinical and histological changes by means of measurement of recovery of hind leg motor function and urinary bladder function, frequency of spasms, neu - ronal profile and spinal cord tissue sparing. The rats were randomly divided into three groups, SCI-Aqua and SCI-Inosine, with daily administration of aqua for injection or inosine, and SCI-Sham group without spinal injury. The motor function of hind legs and urinary bladder function were evaluated daily for 12 days after the spinal cord injury. In the SCI-Inosine group we recorded lower incidence of spasms due to spinal cord irritation in the early postoperative period when compared to the SCI-Aqua group. We used immunohistochemistry with specific neuronal antibodies to determine the neuronal profiles and the Luxol fast blue staining method to detect the white and grey matter tissue sparing. In our study we recorded significant differences in recovery between the SCI-Aqua and SCI-Inosine group from eigth days after surgery. Moreover, the post mortem investigation of transverse spinal cord sections revealed significantly higher numbers in the SCI-Inosine group (more neurons, greater tissue spar - ing). According to our findings inosine accelerates the recovery of neurological functions.


The eigenmode propagation method is proposed to analyze the discontinuity problems in planar dielectric waveguides. This recursive algorithm is based on the numerical mode matching method, but it uses less computation time and computer memory, which makes the analysis of multiregion, vertically stratified media much more effective. With this algorithm, the required computer memory is independent of the number of regions in the problem, and the computation time is linearly proportional to the number of regions. Therefore, it is particularly suitable for the analysis of planar waveguide discontinuities and waveguide bends. Using this method, larger problems can be analyzed which are impractical with the finite element method. Numerical examples are given to demonstrate that the computation time is linearly proportional to the number of discontinuities, while the computer memory is almost a constant independent of the number of discontinuities. >


Anxiety is a common clinical presentation. Primary anxiety poses a significant problem in its management. Many among the current treatment options of anxiety are habit forming causing significant withdrawal symptoms. There are dose dependent responses often associated with drug adversities. Day time sedation is an undesired effect of many drugs used for anxiety management limiting its usage. Ayurveda recommends a bio- physical procedure to manage anxiety. Shirodhara , a dripping procedure is utilized as a front line therapy for anxiety in Ayurveda. Seeing the limitations of conventional biomedical management of anxiety requiring an improvement upon the existing protocols of managements, and also seeing the use of shirodhara for anxiety management in ayurvedic clinics, a pragmatic study to evaluate the effect of shirodhara in generalized anxiety disorder was done. This was a pragmatic study consisting of shirodhara with ksheer bala oil as an intervention upon generalized anxiety disorder patients. The study was conducted upon 13 patients and observations were done for six weeks. The responses observed through the changes in Hamilton Anxiety Scale were evaluated using paired t test to observe the pre-post significance.


Hypoglycemia is known to be intrinsic to the treatment of diabetes because insulin is a powerful glucose-lowering agent and sulfonylureas exert their effect through insulin release by the pancreatic β-cells. Hypoglycemia occurs in association with these two common modes of therapy and was previously accepted as a part of the treatment of this condition. With the arrival of other modes of diabetes treatment, such as metformin, thiazolidenediones, α2-glucosidase inhibitors, and incretins, which do not induce hypoglycemia except when administered in combination with insulin and sulfonylureas, the issue of hypoglycemia has to be assessed in the context of both the immediate risk related to neuroglycopenia and the possible long-term risk of diabetic vascular complications.

Vascular complications of hypoglycemia have to be tackled with greater urgency now because two recent trials of intensified diabetes treatment with insulin, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and Veteran's Affairs Diabetes Trial (VADT), did not demonstrate a reduction in cardiovascular events (1,2). In fact, the intensified insulin treatment arm of the ACCORD trial had to be halted because of an increase in overall mortality, despite a reduction in acute myocardial infarction. The rate of hypoglycemia in both trials was significantly increased with intensified insulin treatment. Although the analysis of the ACCORD data did not support the hypothesis that the increased mortality in the study was a result of hypoglycemia, the fact that hypoglycemia may often be asymptomatic leaves us with the possibility that it may be responsible.

The fact that hypoglycemia results in platelet hyperaggregability (3) and an increase in several factors involved …


Multi-hop wireless communication is playing a key role in today's communication networks. Despite several advancements in communication protocols and technologies, QoS provisioning is still a challenging issue in multi-hop wireless communications. In this paper, we propose a novel scheduling mechanism based on resource reservation for guaranteeing the QoS performance of real-time sessions (RTSNs) in IEEE 802.11e-based multi-hop wireless networks (MHWNs). Since RTSNs are sensitive to end-to-end delay in addition to their throughput requirements, our scheme defines a novel bandwidth reservation mechanism which guarantees resources to high priority services (i.e. RTSNs) for meeting both the delay and the throughput requirements. Moreover, the concurrent transmission (CT) mechanism implemented in the pre-configured contention-free period (CFP) further enhances the bandwidth utilization by means of letting chosen CT partners to transmit data simultaneously without collision. Simulation results show that the proposed scheduling mechanism significantly increases the efficiency of the bandwidth usage and successfully optimizes the QoS performance of RTSNs while providing fairness for other traffic sessions.


The various sperm cell types present in a simple ejaculate differ in their motility and morphology. However, little is known about the nuclear maturity of these sperm cells and their relationship with morphological and motile characteristics. Protamines are considered a good marker of sperm nuclear maturity since they are added to the DNA in the last stage of spermatogenesis. We have analyzed the P1/P2 ratio and the protamine content of subpopulations of human spermatozoa at different stages of maturation, isolated by density gradient centrifugation of ejaculated spermatozoa obtained from 3 groups of patients from our Assisted Reproduction Unit: 10 men of proven fertility, 12 oligozoospermic men, and 13 asthenozoospermic men. Four different fractions (F2-F5) were collected from the top to the bottom of the Percoll gradient. Differences in the motion and morphology were found between the fractions in each of the groups studied, with fraction F5 being the one with the best morphology and motility. However, no significant differences in the P1/P2 ratio were found between fractions within the same group of samples, indicating that the P1/P2 ratio and the amount of protamines are relatively independent of the morphology and motility of sperm cells. In contrast, statistically significant differences were found in the P1/P2 ratio and in the relative amount of protamines between the 3 groups.


OBJECTIVE
This study investigated the short-term subcutaneous tissue reaction and biomineralization ability of two epoxy-based root canal sealers containing calcium hydroxide (MBP and MBPc) and ProRoot MTA.

MATERIALS AND METHODS
Polyethylene tubes containing the materials were implanted into the dorsal connective tissue of Wistar rats (n = 52) for 7 or 30 days; empty implanted tubes served as controls. Specimens were stained with hematoxylin-eosin and von Kossa stain or left unstained for observation under polarized light. Qualitative and quantitative evaluations of all tissue reactions were performed. One-way anova and the Kruskal-Wallis test were used for statistical analysis (P < 0.05).

RESULTS
No significant differences were observed among the groups. All three materials induced mild-to-moderate tissue reactions at 7 days, which decreased over time. Dystrophic mineralization and birefringent structures were observed only in the ProRoot MTA (®) group.

CONCLUSION
Both MBP and MBPc appear to be biocompatible but do not stimulate biomineralization.


To analyze the factors that influence customer's online shopping satisfaction, quantitative research is used through a survey. Six factors are used as independent variables in this study, namely: security, information availability, shipping, quality, pricing and time. The study, conducted in Portugal, uses primary data in the form of a survey with a questionnaire as a research instrument, using a five-point Likert scale. The sampling technique in this study uses convenience sampling. The data (n=193) were analyzed using Confirmatory Factor Analysis and Multiple Regression. The analysis carried out reveals the main factors that influence specific online shopping satisfaction, in the Portuguese market. The obtained result analysis confirmed that quality, information availability, pricing, and shipping have a significant effect on online shopping customer satisfaction, while security have no significant effect on online shopping customer's satisfaction and time presented an unacceptable internal consistency, and so it was not possible to conclude about this factor.


Glucagon, insulin, somatostatin, and pancreatic polypeptide have been localized in the anolian pancreas using peroxidase-antiperoxidase immunocytochemistry. The most abundant endocrine cell type contains glucagon. Insulin-containing cells are the next most numerous. Somatostatin-immunoreactive cells tend to be localized at the periphery of the islet cords. Pancreatic polypeptide-containing cells are a minor endocrine component scattered throughout the exocrine pancreas and occasionally within the islet areas. No staining was observed after application of antigastrin serum.


[1] Six Ocean Drilling Program (ODP) sites, in the Northwest Atlantic have been used to investigate kinematic and chemical changes in the "Western Boundary Undercurrent" (WBUC) during the development of full glacial conditions across the Marine Isotope Stage 5a/4 boundary (~70,000 years ago). Sortable silt mean grain size SS¯ measurements are employed to examine changes in near bottom flow speeds, together with carbon isotopes measured in benthic foraminifera and % planktic foraminiferal fragmentation as proxies for changes in water-mass chemistry. A depth transect of cores, spanning 1.8–4.6 km depth, allows changes in both the strength and depth of the WBUC to be constrained across millennial scale events. SS¯ measurements reveal that the flow speed structure of the WBUC during warm intervals ("interstadials") was comparable to modern (Holocene) conditions. However, significant differences are observed during cold intervals, with higher relative flow speeds inferred for the shallow component of the WBUC (~2 km depth) during all cold "stadial" intervals (including Heinrich Stadial 6), and a substantial weakening of the deep component (~3–4 km) during full glacial conditions. Our results therefore reveal that the onset of full glacial conditions was associated with a regime shift to a shallower mode of circulation (involving Glacial North Atlantic Intermediate Water) that was quantitatively distinct from preceding cold stadial events. Furthermore, our chemical proxy data show that the physical response of the WBUC during the last glacial inception was probably coupled to basin-wide changes in the water-mass composition of the deep Northwest Atlantic.


Background: Young patients with osteoarthritic knees are a challenging population because of a combination of high functional demands and limited indication for joint replacement. Purpose: To analyze the potential of the cartilage regenerative approach by documenting the results and failures of matrix-assisted autologous chondrocyte transplantation (MACT) at midterm follow-up. Study Design: Case series; Level of evidence, 4. Methods: Forty-four patients affected by cartilage lesions in osteoarthritic knees underwent MACT as a salvage procedure. The mean age at surgery was 42 years (range, 20-58 years), and the average defect size was 4 cm2 (range, 1.5-9 cm2). Patients were prospectively evaluated with the subjective International Knee Documentation Committee (IKDC), EuroQol visual analog scale (EQ-VAS), and Tegner scores preoperatively; at 1, 2, and 5 years; and at a final assessment at 9 years' mean follow-up. Adverse events and failures were also reported. Results: A statistically significant improvement was observed in all scores from the initial evaluation to the final follow-up. The mean ± standard deviation IKDC subjective score improved from 38.0 ± 15.8 to 67.0 ± 18.3 at 2 years (P < .0005), with a subsequent decrease to 57.8 ± 20.6 at the final follow-up (P = .012). The same trend was confirmed by the EQ-VAS score. The activity level revealed by the Tegner score improved at all follow-ups but without achieving the preinjury level. The analysis of the influencing factors showed the importance of the meniscus condition, revealing a significantly inferior outcome in knees with previous or combined partial meniscectomy procedures. During the study period, 12 patients had failed results, producing a cumulative failure rate of 27.3%. At the last evaluation, half of the patients considered their condition not better than before the treatment, and 39% would not repeat the treatment considering the results obtained. Conclusion: Despite a statistically significant improvement, the clinical outcome was poor. A higher improvement could be obtained in patients who had not undergone previous or combined meniscectomies, but this was limited over time. The failure rate was also high, regardless of the degree of osteoarthritis. Tissue-engineered cartilage implantation is questionable for this indication, and the limits of this scaffold-based procedure have to be considered if it is used as a salvage procedure for young patients affected by knee osteoarthritis.


The multistep PROTAC (PROteolysis TArgeting Chimeras) degradation process poses challenges for their rational development, as rate limiting steps determining PROTAC efficiency remain largely unknown. Moreover, the slow throughput of currently used endpoint assays does not allow the comprehensive analysis of larger series of PROTACs. Here we developed cell-based assays using NanoLuciferase and HaloTags, that allow measuring PROTAC induced degradation and ternary complex formation kinetics and stability in cells. Using PROTACs developed for degradation of WDR5, the characterization of the mode of action of these PROTACs in the early degradation cascade revealed a key role of ternary complex formation and stability. Comparing a series of ternary complex crystal structures highlighted the importance of an efficient E3-target interface for ternary complex stability. The developed assays outline a strategy for the rational optimization of PROTACs using a series of live cell assays monitoring key steps of the early PROTAC induced degradation pathway. Significance The multistep PROTAC induced degradation process of a POI poses a significant challenge for the rational design of these bifunctional small molecules as critical steps that limit PROTAC efficacy cannot be easily assayed at required throughput. In addition, the cellular location of the POI may pose additional challenges as some cellular compartments, such as the nucleus, may not be easily reached by PROTAC molecules and the targeted E3 ligases may not be present in this cellular compartment. We propose therefore a comprehensive assay panel for PROTACs evaluation in cellular environments using a sensor system that allows continuous monitoring of the protein levels of the endogenous POI. We developed a cell line expressing WDR5 from its endogenous locus in fusion with a small sequence tag (HiBIT) that can be reconstituted to functional NanoLuciferase (NLuc). This system allowed continuous monitoring of endogenous WDR5 levels in cells and together with HaloTag system also the continuous monitoring of ternary complex (E3, WDR5 and PROTAC) formation. As this assay can be run at high throughput, we used this versatile system monitoring three diverse chemical series of WDR5 PROTACs that markedly differ in their degradation properties. Monitoring cell penetration, binary complex formation (PROTAC-WDR5 and PROTAC-VHL) as well as ternary complex formation we found that PROTAC efficiency highly correlated with synergy of ternary complex formation in cells. This study represents a first data set on diverse PROTACs studying this property in cellulo and it outlines a strategy for the rational optimization of PROTACs. It also provided kinetic data on ternary complex assembly and dissociation that may serve as a benchmark for future studies utilizing also kinetic properties for PROTAC development. Comparative structural studies revealed larger PROTAC mediated interaction surfaces for PROTACs that efficiently formed ternary complexes highlighting the utility of structure based optimization of PROTAC induced ternary complexes in the development process.