This paper examines the Italian ceramics industry and the deep changes which affected the international competitive scenario by pointing out the world production map which was rapidly redrawed with the entry in the market of the emergent competitors. It is particularly studied the ceramic district and its structural and competitive dynamics regarding transformations, dynamism factors, competition, international opening and the product and process innovation also with the change of the relation with the market, with the purpose to face the world competition.


Diabetic nephropathy (DN) is the most common cause of end-stage kidney disease worldwide, and is associated with increased morbidity and mortality in patients with both type 1 and type 2 diabetes. Increasing prevalence of diabetes has made the need for effective treatment of DN critical and thereby identifying new therapeutic targets to improve clinical management. Autophagy is a highly conserved 'self-eating' pathway by which cells degrade and recycle macromolecules and organelles. Autophagy serves as an essential mechanism to maintain homeostasis of glomeruli and tubules, and plays important roles in human health and diseases. Impairment of autophagy is implicated in the pathogenesis of DN. Emerging body of evidence suggests that targeting the autophagic pathway to activate and restore autophagy activity may be renoprotective. In this review, we examine current advances in our understanding of the roles of autophagy in diabetic kidney injury, focusing on studies in renal cells in culture, human kidney tissues, and experimental animal models of diabetes. We discuss the major nutrient-sensing signal pathways and diabetes-induced altered intracellular metabolism and cellular events, including accumulation of advanced glycation end-products, increased oxidative stress, endoplasmic reticulum stress, hypoxia, and activation of the renin-angiotensin system, which modulate autophagic activity and contribute to the development of DN. We also highlight recent studies of autophagy and transforming growth factor-β in renal fibrosis, the final common response to injury that ultimately leads to end-stage kidney failure in both type 1 and type 2 diabetes. These findings suggest the possibility that autophagy can be a therapeutic target against DN.


Recently, a local framework of Newton-type methods for constrained systems of equations has been developed which, applied to the solution of Karush-KuhnTucker (KKT) systems, enables local quadratic convergence under conditions that allow nonisolated and degenerate KKT points. This result is based on a reformulation of the KKT conditions as a constrained piecewise smooth system of equations. It is an open question whether a comparable result can be achieved for other (not piecewise smooth) reformulations. It will be shown that this is possible if the KKT system is reformulated by means of the Fischer-Burmeister complementarity function under conditions that allow degenerate KKT points and nonisolated Lagrange multipliers. To obtain this result, novel constrained Levenberg-Marquardt subproblems are introduced which allow significantly longer steps for updating the multipliers. Based on this, a convergence rate of at least 1.5 is shown.


. The study combined UV/TiO2 with ultrasonic procedure to degrade azo dye wastewater of Acid Yellow 17. The effects of factors including pH value, initial concentration of dye, and quantities of TiO2, Fe (II), and Fe (III) added on the removal efficiency of azo dye Acid Yellow 17 were investigated. Experimental results revealed significant additive effect attributed to the combination of two procedures under 13-watt UV irradiation and 10-watt ultrasound. Analysis of the catalyst properties indicated no evident changes in the appearance of crystal and TiO2 catalyst by UV/TiO2 combined with ultrasonic procedure. However, the specific surface area was increased by approximately 53%. No effective formation of hydrogen peroxide (ND  1 mg/L) proved that the addition of Fe (II) and Fe (III) failed to induce the Fenton-like reaction effectively. Nevertheless, the addition of Fe ions affected significantly the initial adsorption and the degradation rate of the dye. Moreover, the treatment efficiency of Fe (III) was found to be superior to that of Fe (II) under the same concentration.


Omalizumab is a recombinant humanized monoclonal anti-IgE antibody. Until now, the efficiency of omalizumab in chronic spontaneous urticaria has been demonstrated in several studies. However in the literature, data showing the efficiency of omalizumab in different phenotypes of H1-antihistamine-refractory chronic urticaria are limited. In this report, the success of treatment with omalizumab from the first dose is presented in three patients with chronic spontaneous urticaria, chronic autoimmune urticaria, and idiopathic angioedema, who were unresponsive to high-dose H1-antihistamine. The symptoms of all patients resolved with the first dose of omalizumab and no symptom recurrence developed during the follow-up period. In this case presentation, the effective treatment of different phenotypes of H1-antihistamine-refractory chronic urticaria is discussed with a review of the literature.


Negative pressure is the main control variable in scrap copper smelting process, the control of negative pressure is not only closely related with producing safely, but also produces a direct impact on the quality of the anode plate, it is also a key breakthrough in energy saving. This paper first analyses the characteristics of negative pressure control in scrap copper smelting process, aims to larger overshoot and longer regulation under conventional PID control method, and then utilizes fuzzy control to correct the PID parameters online, to achieve the optimization control of negative pressure. Simulation result shows that the adjustment process of optimized control of negative pressure is steady and rapid, usually no or slightly overshoot, and the settling time is also reduced significantly.


CONTEXT
The contribution of reproductive hormones to mood has been the focus of considerable research. Results from clinical and epidemiological studies have been inconsistent. It remains unclear whether alterations in serum hormone levels across the menopausal transition are linked to depressive symptoms.

OBJECTIVES
To evaluate the relationship between serum hormone levels and high depressive symptoms and whether hormone levels or their change might explain the association of menopausal status with depressive symptoms previously reported in a national sample of midlife women.

DESIGN
A longitudinal, community-based, multisite study of menopause. Data were collected at baseline and annually from December 1995 to January 2008 on a range of factors. Early follicular phase serum samples were assayed for levels of estradiol, follicle-stimulating hormone, testosterone, and dehydroepiandrosterone sulfate.

SETTING
Seven communities nationwide.

PARTICIPANTS
A community-based sample of 3302 multiethnic women, aged 42 to 52 years, still menstruating and not using exogenous reproductive hormones. Main Outcome Measure Depressive symptoms assessed with the Center for Epidemiological Studies Depression Scale (CES-D). The primary outcome was a CES-D score of 16 or higher.

RESULTS
In multivariable random-effects logistic regression models, log-transformed testosterone level was significantly positively associated with higher odds of a CES-D score of 16 or higher (odds ratio = 1.15; 95% confidence interval, 1.01-1.31) across 8 years, and a larger increase in log-transformed testosterone from baseline to each annual visit was significantly associated with increased odds of a CES-D score of 16 or higher (odds ratio = 1.23; 95% confidence interval, 1.04-1.45). Less education, being Hispanic, and vasomotor symptoms, stressful life events, and low social support at each visit were each independently associated with a CES-D score of 16 or higher. No other hormones were associated with a CES-D score of 16 or higher. Being perimenopausal or postmenopausal compared with being premenopausal remained significantly associated with a CES-D score of 16 or higher in all analyses.

CONCLUSIONS
Higher testosterone levels may contribute to higher depressive symptoms during the menopausal transition. This association is independent of menopausal status, which remains an independent predictor of higher depressive symptoms.


Bhusal, Prem. M.S., Department of Computer Science and Engineering, Wright State University, 2019. Scalable Clustering for Immune Repertoire Sequence Analysis. The development of the next-generation sequencing technology has enabled systems immunology researchers to conduct detailed immune repertoire analysis at the molecule level. Large sequence datasets (e.g., millions of sequences) are being collected to comprehensively understand how the immune system of a patient evolves over different stages of disease development. A recent study has shown that the hierarchical clustering (HC) algorithm gives the best results for B-cell clones analysis an important type of immune repertoire sequencing (IR-Seq) analysis. However, due to the inherent complexity, the classical hierarchical clustering algorithm does not scale well to large sequence datasets. Surprisingly, no algorithms have been developed to address this scalability issue for immunology research. In this thesis, we study two different strategies, aiming at finding the best scalable methods that can preserve the quality of hierarchical clustering structure. The two strategies include (1) non-Euclidean indexing methods for speeding up the classical hierarchical clustering(HC), (2) a new tree-based sequence summarization approach SCT that scans the large sequence dataset once and generates summaries for hierarchical clusters(HC). And we also experimented with the Spark based minimum-spanning-tree algorithm (SparkMST) that generates the equivalent result of single linkage hierarchical clustering (SLINK) for comparative analysis. We have implemented all these algorithms and experimented with real sequence datasets for B-cell clones analysis. The result shows that (1) the indexing-enhanced HC (e.g., using the Vantage-Point tree for indexing) preserves the clustering quality very well, while also significantly reducing the time complexity of the original HC; (2) SCT with HC is the fastest approximate HC method with slightly sacrificed quality; and (3) SparkMST scales out satisfactorily and gives significant performance gain with a large Spark cluster.


A behavioral test based on Kansei engineering was conducted in this paper to study the relationship between suit collar styles and the aesthetic of women's suits, as well as college students' perceptual cognition about women's closure collar suits from the cognitive psychology of consumers. Firstly, factors leading to style changes of collars were determined and classified, then series of pictures with different closure collars were drawn. 64 college students as subjects were tested by psychology software EPrime. SPSS was used in this research to analyze aesthetic evaluation difference between different closure collar types by variance analysis. Finally, a optional female closure collar suit was found, which was the most professional style that college students liked most. Consumers' perceptual cognition of suits which was always difficult to measure was quantified in this paper, so that it became more easy to understand and grasp the perceptual demands of consumers. Conclusions of this paper can provide references for designers and manufacturers to design and produce women's suits that really satisfy the mental needs of consumers


The field of nanotechnology is about research and development on materials whose at least one dimension is in the range of 1 to 100 nanometers. In recent years, the research activity for developing nano-materials has grown exponentially owing to the fact that they offer better solutions to the challenges faced by various fields such as energy, food, and environment. In this paper, the importance of transmission electron microscopy (TEM) based techniques is demonstrated for investigating the properties of nano-materials. Specifically the nano-materials that are investigated in this report include gold nano-particles (Au-NPs), silver atom-clusters (Ag-ACs), tantalum single-atoms (Ta-SAs), carbon materials functionalized with iron cobalt (Fe-Co) NPs and titania (TiO2) NPs, and platinum loaded Ceria (Pt-CeO2) Nano composite. TEM techniques that are employed to investigate nano-materials include aberration corrected bright-field TEM (BF-TEM), high-angle dark-field scanning TEM (HAADF-STEM), electron energy-loss spectroscopy (EELS), and BF-TEM electron tomography (ET). With the help presented of results in this report, it is proved herein that as many TEM techniques as available in a given instrument are essential for a comprehensive nano-scale analysis of nanomaterials.


Despite a paucity of material available from continental Africa, previous morphological and molecular phylogenetic studies have suggested that Angraecum , the largest genus of the angraecoid orchids, is polyphyletic. A recent study based on broad sampling from the region confirmed the monophyly of section Dolabrifolia and a clear delimitation of four of its five members, one of which represents a new species. Based on these results, a comprehensive taxonomic revision of Angraecum sect. Dolabrifolia is presented here. It includes an identification key and a detailed description of each species, along with color photographs, distribution maps, information on habitat and phenology, and a preliminary risk of extinction assessment according to the IUCN Red List categories and criteria. Species richness in the section is highest in Atlantic Central Africa and around the Albertine Rift. The new species, A. biteaui , is described and illustrated with line drawings. It most closely resembles A. aporoides in general aspect but differs in both foliar and floral characters, and is only known from lowland forests in Gabon.


In the present study different extracts of Acacia nilotica leaves were tested for total phenolic and flavonoid content, antioxidant activities. Extracts were also subjected to phytochemical analysis using GC-MS analytical techniques. Antioxidant potential was determined using DPPH free radical scavenging assay, hydrogen peroxide scavenging assay, metal chelating assay and β-carotene-linoleic acid assay. Methanol extract exhibited maximum antioxidant activity (94.3 %) followed by the ethyl acetate extract (90.7 %). Total phenolic content was highest in the methanol extract and total flavonoid content in ethyl acetate extract. Positive correlation was observed between the total phenolic content, total flavonoid content and antioxidant activities. Principle component analysis revealed correlation between different parameters. D-pinitol, catechol, N-2,4-dnp-L-arginine, squalene, R-limonene, 9-octadecen-12-ynoic acid, methyl ester, androst-5-en, 2(1-H)-quinolinone, heptacosane, 2-pentadecanone, 6,10,14-trimethyl, linoleic acid, γ-linoleic acid, palmitic acid, stearic acid were the main compounds present in different extracts of Acacia nilotica leaves and could serve as a possible source of natural antioxidants in food and pharmaceutical industry.


In the Greek New Testament, relative sentences that are introduced by relative pronouns alone, apart from the adverbial uses, are the most frequent subordinate sentence type. The research reported on in this paper aimed to investigate and describe a number of syntactic features of relative constructions in the Greek New Testament, taking account, among others, of some typological parameters that have been developed in the general linguistics literature for these constructions. The results indicate that relative constructions in the Greek New Testament have a variety of features, all of which have counterparts in some modern (or other ancient) languages, despite the differences. The relative sentence in the Greek New Testament is mostly postnominal, and the relative pronoun-type is used in those cases for encoding the role of the coreferential element in the relative sentence. Phrases expressing a variety of syntactic functions in a sentence (e.g. subject, direct object, etc.) are accessible to relativisation, that is, they can be represented by relative pronouns. Nominal elements serve mostly as antecedents of relative sentences, although sentences appear in that function as well. A variety of syntactic types of relative sentences can be distinguished, including the prenominal participial, postnominal finite/participial, circumnominal, free relative, adverbial, prejoined, postjoined, sentential and conjoined types. These can be linked in a systematic way to the four functions of relative sentences in the New Testament, i.e. identifying, appositive, adverbial and continuative. Relative sentences also play a role in communicative strategies. Prejoined relative sentences, for example, are most suitable for exposition and theme-building, especially in the correlative diptych construction. Keywords : Relative sentence, relative construction, syntax, Hellenistic Greek, New Testament


We consider a (sub) critical Galton-Watson process with neutral mutations (infinite alleles model), and decompose the entire population into clusters of individuals carrying the same allele. We specify the law of this allelic partition in terms of the distribution of the number of clone-children and the number of mutant-children of a typical individual. The approach combines an extension of Harris representation of Galton-Watson processes and a version of the ballot theorem. Some limit theorems related to the distribution of the allelic partition are also given.


The rice XA21 immune receptor kinase and the structurally related XA3 receptor, confer immunity to Xanthomonas oryzae pv. oryzae (Xoo), the causal agent of bacterial leaf blight. Here we report the isolation of OsSERK2 (rice somatic embryogenesis receptor kinase 2) and demonstrate that OsSERK2 positively regulates immunity mediated by XA21 and XA3 as well as the rice immune receptor FLS2 (OsFLS2). Rice plants silenced for OsSerk2 display altered morphology and reduced sensitivity to the hormone brassinolide. OsSERK2 interacts with the intracellular domains of each immune receptor in the yeast-two-hybrid system in a kinase activity dependent manner. OsSERK2 undergoes bidirectional trans-phosphorylation with XA21 in vitro and forms a constitutive complex with XA21 in vivo. Taken together, these results demonstrate an essential role for OsSERK2 in the function of three rice immune receptors and suggest that direct interaction with the rice immune receptors is critical for their function.


The combination of Monte-Carlo tree search (MCTS) with deep reinforcement learning has led to significant advances in artificial intelligence. However, AlphaZero, the current state-of-the-art MCTS algorithm, still relies on handcrafted heuristics that are only partially understood. In this paper, we show that AlphaZero's search heuristics, along with other common ones such as UCT, are an approximation to the solution of a specific regularized policy optimization problem. With this insight, we propose a variant of AlphaZero which uses the exact solution to this policy optimization problem, and show experimentally that it reliably outperforms the original algorithm in multiple domains.


NORMAL large elastic arteries are remarkably resistant to infection. 1,2 However, when congenital or acquired vascular abnormalities exist, this resistance may be compromised. For some unknown reason, enteric pathogens demonstrate a predilection for invasion of such abnormal vessels and members of the Salmonella group in particular are the most frequent offenders. Areas of arteriosclerotic change within large vessels are the usual site of bacterial invasion and aneurysmal rupture is the usual outcome. Prior to the advent of reconstructive vascular surgery, the ruptured abdominal aneurysm was largely a curiosity of academic interest. As vascular surgery was introduced it soon became apparent that infection was probably the gravest complication associated with reconstructive procedures. When infection exists prior to surgery, the chance of success is remote unless the infectious process can be eradicated. This report is prompted by a recent experience with a ruptured arteriosclerotic abdominal aortic aneurysm associated with salmonellosis. A review


Supervised ASR models have reached unprecedented levels of accuracy, thanks in part to ever-increasing amounts of labelled training data. However, in many applications and locales, only moderate amounts of data are available, which has led to a surge in semi- and weakly-supervised learning research. In this paper, we conduct a large-scale study evaluating the effectiveness of weakly-supervised learning for speech recognition by using loosely related contextual information as a surrogate for ground-truth labels. For weakly supervised training, we use 50k hours of public English social media videos along with their respective titles and post text to train an encoder-decoder transformer model. Our best encoder-decoder models achieve an average of 20.8% WER reduction over a 1000 hours supervised baseline, and an average of 13.4% WER reduction when using only the weakly supervised encoder for CTC fine-tuning. Our results show that our setup for weak supervision improved both the encoder acoustic representations as well as the decoder language generation abilities.


CdS(Cadmium sulfide)/PAMAM(polyamidoamine) Nanocomposites were in-situ prepared taking PAMAM dendrimers as stabilization in water. The prepared solution containing photoluminescent semiconductor CdS QDs(Quantum dots) was utilized for detection of aged fingermarks on adhesive tape strips. The fingermarks were aged for 1 d, 7 d and 30 d in nature light respectively. The results show that the latent aged fingermarks treated with CdS/PAMAM nanocomposites emit yellow luminescence under ultraviolet excitation of 365 nm in the dark. Aged fingermarks were detected successfully with better resolving rate comparing with existing nano-scale commercial TiO2 powder suspension.


The effect of hydrocortisone acetate on the maturity of male Labeo gonius was studied during spawning season. Maturation was inhibited and spermiation arrested. Reduction in the lobes of the testes, volume of the testes and gonadosomatic index were observed. The length of the testes was also reduced. The clumping of spermatozoa occurred in the middle part of the seminiferous lobules. The control group remained unchanged.


Nickel pincers as enzyme cofactors Organometallic nickel complexes long synthesized in the laboratory exist naturally in enzymes as well. Desguin et al. determined the structure and metal-binding residues of the Ni-containing active site in bacterial lactate racemase (see the Perspective by Zamble). A dithiodinicotinic acid mononucleotide derivative cofactor binds Ni through sulfur and carbon bonds, resembling synthetic nickel pincer complexes. Genes encoding accessory proteins involved in the synthesis of this cofactor are widely distributed in other bacteria, suggesting its involvement in other enzymes. Science, this issue p. 66; see also p. 35 The bacterial interconversion of lactic acid isomers requires an enzyme with a nickel pincer complex. [Also see Perspective by Zamble] Lactic acid racemization is involved in lactate metabolism and cell wall assembly of many microorganisms. Lactate racemase (Lar) requires nickel, but the nickel-binding site and the role of three accessory proteins required for its activation remain enigmatic. We combined mass spectrometry and x-ray crystallography to show that Lar from Lactobacillus plantarum possesses an organometallic nickel-containing prosthetic group. A nicotinic acid mononucleotide derivative is tethered to Lys184 and forms a tridentate pincer complex that coordinates nickel through one metal-carbon and two metal-sulfur bonds, with His200 as another ligand. Although similar complexes have been previously synthesized, there was no prior evidence for the existence of pincer cofactors in enzymes. The wide distribution of the accessory proteins without Lar suggests that it may play a role in other enzymes.


Social distancing is widely acknowledged as an effective public health policy combating the novel coronavirus. But extreme forms of social distancing like isolation and quarantine have costs and it is not clear how much social distancing is needed to achieve public health effects. In this article, we develop a design-based framework to test the causal null hypothesis and make inference about the dose-response relationship between reduction in social mobility and COVID-19 related public health outcomes. We first discuss how to embed observational data with a time-independent, continuous treatment dose into an approximate randomized experiment, and develop a randomization-based procedure that tests if a structured dose-response relationship fits the data. We then generalize the design and testing procedure to a longitudinal setting, and apply them to investigate the effect of social distancing during the first phased reopening in the United States on public health outcomes using data compiled from UnacastTM, the United States Census Bureau, and the County Health Rankings and Roadmaps Program. We rejected a primary analysis null hypothesis that stated the social distancing from April 27, 2020, to June 28, 2020, had no effect on the COVID-19-related death toll from June 29, 2020, to August 2, 2020 (p-value < 0.001), and found that it took more reduction in mobility to prevent exponential growth in case numbers for non-rural counties compared to rural counties.


While the wireless communication systems provide the means of connectivity nearly everywhere and all the time, communication security requires more attention. Even though current efforts provide solutions to specific problems under given circumstances, these methods are neither adaptive nor flexible enough to provide security under the dynamic conditions which make the security breaches an important concern. In this paper, a cognitive security (CS) concept for wireless communication systems in the physical layer is proposed with the aim of providing a comprehensive solution to wireless security problems. The proposed method will enable the comprehensive security to ensure a robust and reliable communication in the existence of adversaries by providing adaptive security solutions in the communication systems by exploiting the physical layer security from different perspective. The adaptiveness relies on the fact that radio adapts its propagation characteristics to satisfy secure communication based on specific conditions which are given as user density, application specific adaptation, and location within CS concept. Thus, instead of providing any type of new security mechanism, it is proposed that radio can take the necessary precautions based on these conditions before the attacks occur. Various access scenarios are investigated to enable the CS while considering these conditions.


In this paper, we will examine if the trickle-down effect has ever taken in rural Indonesia. One of the cases draws attention in economic development study is poverty and income gap from wealthiest people to the less fortunate larger group of people. The argument goes as trickle-down effect appears to be the best solution to eradicate poverty as well as to solve the income gap. Tourism has become a strategy targeted by the government to spread the trickle-down effect to the less fortunate larger group of people. The government believes by sustaining the growth in tourism would accelerate the trickle-down effect and brings a less fortunate group of people to better living. In its fundamental theory, the trickle-down effect has offered delusion where jobs would be created as the conditions are met. However, this paper argues that even in tourism the trickle-down effect strategy has served less for what it has promised. Through qualitative research in Ngadisari Village, a remote area, where Mount Bromo has been a tourism landmark globally, this paper finds that trickle-down effect has come with little benefit to uplift the living standard of the poor. Thus, the trickle-down effect has served only as delusions of growth government has ever aspired. Keywords: humanism, Mount Bromo, tourism economics, tourist destination, trickle-down economics.


Energy is far and wide regarded as a driving force behind manufacturing sector production. However, energy intensity is a measure of how efficiently energy is used in the manufacturing sector. This makes it crucial to examine energy efficiency and manufacturing sector performance in Nigeria from 1986-2017. Time series secondary data sourced from CBN Statistical Bulletin and International Energy Agency on manufacturing sector contribution to GDP as proxy for manufacturing sector performance was used as dependent variable, while energy efficiency proxy by energy intensity with labour and capital intensity as the independent variables. The study employed estimation techniques of ADF unit root test, Johansen co-integration test and Error Correction Model. The results based on Error Correction Model revealed that 65% of the deviation in the variables employed in the study would be restored in one year. It was also revealed that energy intensity, labour intensity and capital intensity had significant positive impact on manufacturing sector contribution to GDP in Nigeria within the study period. The study concluded that increased in energy intensity, labour intensity and capital intensity led to increase in manufacturing sector performance in Nigeria within the study period. Based on the findings, the study recommended that government should ensure there is increase in the amount of energy intensity so as to enhance manufacturing sector performance in Nigeria. Government and Non-Governmental organizations should also make sure that the amount of labour intensity is also increased in order to promote the performance of manufacturing sector in Nigeria. Finally, government should ensure that adequate provisions are made in the energy sector in order to increase the amount of capital intensity in the manufacturing sector so as to improve its performance in Nigeria.


Background The existence of psychotropic polypharmacy is well established and its detrimental effects on patients in long-term care are irrefutable. In 2009, 88% of long-term patients in the Royal Hospital Donnybrook were on at least one psychotropic medicine, with 59% on three or fewer and 25% on four or more. This level of consumption coupled with a high rate of observed adverse consequences was not conducive to optimum pharmaceutical care. Pharmacists have been shown to be an essential resource for optimum medicines use and safety and play a vital role in influencing prescribing. Consequently, a medicines review by the pharmacist has been implemented in collaboration with the prescribers. Purpose The objective was to modify psychotropic prescribing through pharmacist intervention via the clinical medicines review, in order to reduce patient morbidity and increase the quality of life. Materials and methods Clusters of patients were chosen for the medicines review sessions based on status decline or length of stay. The pharmacist acquired the patients' drug regimen prior to the meeting to facilitate preanalysis. The prescribers and clinical nurse manager then joined the pharmacist on the ward where medical notes and labs were reviewed. The pharmacist conducted a clinical review and made appropriate recommendations from evidence-based guidance such as NICE, STOPP-START and Beers Criteria. These were suggested and substantiated in an attempt to modify patient-specific psychotropic prescribing. Results Prescribers implemented the majority of recommendations and psychotropic polypharmacy reduced, which infers a tangible transformation in psychotropic prescribing practice. Anecdotal evidence has demonstrated an improvement in morbidity with positive changes in the physical status and behaviour of most patients. An audit revealed a significant reduction in the number of psychotropic drugs prescribed per patient (from 2.3 to 1.7, p<0.002) and also a decrease in the total number of medicines per patient (7.1 to 6.0, p<0.003) reflecting a decline in side effects suffered. The effect of the intervention has been reinforced by a reduction in the level of admissions to acute care. Conclusions The effect of pharmacist intervention on psychotropic prescribing through clinical medicines reviews have had an unambiguous impact on the medicines burden of long-term patients in this hospital. This initiative accentuates the value of the clinical pharmacist review and the effectiveness of pharmacist collaboration with prescribers in optimising pharmaceutical care.


Abstract Histone chaperones prevent promiscuous histone interactions before chromatin assembly. They guarantee faithful deposition of canonical histones and functionally specialized histone variants into chromatin in a spatial- and temporally-restricted manner. Here, we identify the binding partners of the primate-specific and H3.3-related histone variant H3.Y using several quantitative mass spectrometry approaches, and biochemical and cell biological assays. We find the HIRA, but not the DAXX/ATRX, complex to recognize H3.Y, explaining its presence in transcriptionally active euchromatic regions. Accordingly, H3.Y nucleosomes are enriched in the transcription-promoting FACT complex and depleted of repressive post-translational histone modifications. H3.Y mutational gain-of-function screens reveal an unexpected combinatorial amino acid sequence requirement for histone H3.3 interaction with DAXX but not HIRA, and for H3.3 recruitment to PML nuclear bodies. We demonstrate the importance and necessity of specific H3.3 core and C-terminal amino acids in discriminating between distinct chaperone complexes. Further, chromatin immunoprecipitation sequencing experiments reveal that in contrast to euchromatic HIRA-dependent deposition sites, human DAXX/ATRX-dependent regions of histone H3 variant incorporation are enriched in heterochromatic H3K9me3 and simple repeat sequences. These data demonstrate that H3.Y's unique amino acids allow a functional distinction between HIRA and DAXX binding and its consequent deposition into open chromatin.


Polyunsaturated fatty acid (PUFA) is an essential class of dietary fatty acids, because of the lack of endogenous enzymes for desaturation in humans. Previous research on n-3 PUFA has demonstrated several health benefits and antiatherogenic actions, but n-6 PUFA have not received much research attention. We investigated whether serum fatty acid composition, especially n-6 PUFAs and desaturase activity, is associated with obesity in type 2 diabetic patients. Subjects were 80 type 2 diabetic patients (age: 60.3±13.9 years) who had no EPA agent intake. They were divided into two groups: obese group (n=52) with a BMI more than 25 kg/m2 and non-obese group (n=28) with a BMI less than 25 kg/m2. Fatty acid levels in serum were measured using gas chromatography. The desaturase activity for n-6 PUFAs was calculated as the arachidonic acid/dihomo-gamma-linolenic acid (DGLA) ratio for Δ5 desaturase (D5D). The obese group revealed a higher saturated fatty acid (SFA) and DGLA levels than those in the non-obese group. No significant difference was observed in the serum n-3 PUFA levels between the two groups. The D5D index of the obese group was significantly lower than that of the non-obese group. Serum DGLA levels showed significant positive correlations with waist circumference, BMI, triglyceride, and hepatic AST and ALT levels. Moreover, SFA showed a significant positive correlation with BMI. The levels of D5D index showed a significant negative correlation with BMI. Increase in serum DGLA levels was related to the number of metabolic factors. These results suggest that type 2 diabetic patients with obesity had changes in their blood fatty acid profile, especially increased DGLA levels. The high levels of blood DGLA indicate downregulation of n-6 metabolism, probably caused by the decreased activity of D5D. The fat quality in the diet and changes in desaturase activity might contribute to the development of obesity. Disclosure M. Saito: None. M. Higa: None. T. Suzuki: None. M. Michishita: None. M. Hijikata: None. K. Yamashita: None. K. Ikehara: None. T. Ichijo: None.


The collaborative representation-based classifier (CRC) is proposed as an alternative to the sparse representation based classifier (SRC) for image face recognition. CRC solves an l2-regularized least squares formulation, with algebraic solution, while SRC optimizes over an I1-regularized least squares problem. As an extension of CRC, the weighted collaborative representation-based classifier (WCRC) is further proposed. The weights in WCRC are picked intuitively, it remains unclear why such choice of weights works and how we optimize those weights. In this paper, we propose a learned collaborative representation based classifier (LCRC) and attempt to answer the above questions. Our learning technique is based on the fixed point theorem and we use a weights formulation similar to WCRC as the starting point. Through extensive experiments on face datasets we show that the learning procedure is stable and convergent, and that LCRC is able to improve in performance over CRC and WCRC, while keeping the same computational efficiency at test.


The present work aims to propose a framework for modelling, analysing and synthesising information on nuclear safeguards with various uncertainties. After a hierarchical analysis of states' nuclear activities on the basis of the International Atomic Energy Agency (IAEA) Physical Model, the multilayer structure of the evaluation model for states' nuclear activities is outlined. Special emphasis is given to the synthesis and evaluation of the Physical Model indicator information by using a newly developed belief rule- based inference methodology (RIMER), which handles hybrid uncertain information in nuclear safeguards' evaluation process. RIMER is developed on the basis of the Dempster-Shafer theory of evidence, decision theory and fuzzy rule-based systems. In this methodology, various types of information from different sources can be transformed and used in the inference process. The new methodology can provide a flexible and effective procedure to deal with hybrid, uncertain assessment information to arrive at rational conclusions. The evaluation model framework illustrates and clarifies the inference and synthesis formalism from the given case study in this paper.


Results of our on-going development of biological warfare agents (BWA) detection systems based on spectral detection of ultraviolet (UV) laser induced fluorescence (LIF) are presented. A compact optical parametric oscillator (OPO) with intracavity sum-frequency mixing (SFM) to generate 293 nm UV laser irradiation was developed. The OPO/SFM device was pumped by a diode-pumped Nd:YAG laser (1064 nm), including subsequent second-harmonic generation (SHG) in an external periodically poled KTiOPO4 (PPKTP) crystal. The laser generated 1.8 ns pulses at 100 Hz with an average power of 44 mW at 532 nm. The whole system could be used to deliver approximately 30 µJ laser irradiation per pulse (100 Hz) at 293 nm. The spectral detection part of the system consists of a grating and a photomultiplier tube (PMT) array with 32 channels, which can measure fluorescence spectra in the wavelength band from 250 nm to 800 nm. The detector system was designed along with a trigger laser to enable measurement of fluorescence spectra from an individual aerosol particle of simulants for BWA upon excitation with a single nanosecond laser pulse. We demonstrate the successful detection and spectral characterization of simulants for BWA, i.e., Bacillus atrophaeus (BG), Bacillus thuringiensis (BT), and Ovalbumin (OA).


ABSTRACT Oritavancin, a lipoglycopeptide antibiotic in development, accumulates to high levels in the lysosomes of eukaryotic cells. We examined specific functions of macrophages (phagocytic capacity, lysosomal integrity, metabolic activity, and production of reactive oxygen species [ROS]) in correlation with the cellular accumulation of the drug, using J774 mouse macrophages and THP-1 human monocytes differentiated into macrophages using phorbol 12-myristate 13-acetate. Oritavancin did not affect Pseudomonas aeruginosa phagocytosis, lysosomal integrity, or metabolic activity in cells incubated for 3 h with extracellular concentrations ranging from 5 to 50 μg/ml. At extracellular concentrations of ≥25 μg/ml, oritavancin reduced latex bead phagocytosis by approximately 50% and doubled ROS production in J774 macrophages only. This may result from the fact that the cellular accumulation of oritavancin was 15 times higher in J774 cells than in activated THP-1 cells at 3 h. Human pharmacokinetic studies estimate that the concentration of oritavancin in alveolar macrophages could reach approximately 560 μg/ml after administration of a cumulative dose of 4 g, which is below the cellular concentration needed in the present study to impair latex bead phagocytosis (1,180 μg/ml) or to stimulate ROS production (15,000 μg/ml) by J774 cells. The data, therefore, suggest that, in spite of its substantial cellular accumulation, oritavancin is unlikely to markedly affect macrophage functions under the conditions of use investigated in current phase III trials (a single dose of 1,200 mg).


This paper investigates the relation between growth forecast errors and planned fiscal consolidation during the crisis. We find that, in advanced economies, stronger planned fiscal consolidation has been associated with lower growth than expected, with the relation being particularly strong, both statistically and economically, early in the crisis. A natural interpretation is that fiscal multipliers were substantially higher than implicitly assumed by forecasters. The weaker relation in more recent years may reflect in part learning by forecasters and in part smaller multipliers than in the early years of the crisis.


The semen quality of 479 men in infertile marriages, who attended the infertility clinic of OOUTH, Sagamu between May 2004 and April 2009 were analyzed. The semen samples were physically examined, microscopically analyzed and aerobically cultured. The result showed that out of 51.5% oligospermic cases recorded, 39.8% could be classified severe. Cryptozoospermia were diagnosed in 72 (15%) cases. Bacteriospermia and Necrozoospermia were found in 149 and 6 cases respectively. The predominant organism isolated was Staphylococcus aureus (50.32%) while Neisseria gonorrhoea was isolated in only 2 cases. Highest infection of 62.4% was noticed among the group with 1% - 19% motility. From the studied population, 8.8% were azoospermic. The commonest morphological defects were pin and ragged heads (48%). It is therefore obvious that the assessment of semen quality remains one of the important steps in infertility interventions.


Significance One of the most important technological advances by humans is the domestication of plant species for the production of food. We have used high-throughput sequencing to identify changes in DNA sequence and gene expression that differentiate cultivated tomato and its wild relatives. We also identify hundreds of candidate genes that have evolved new protein sequences or have changed expression levels in response to natural selection in wild tomato relatives. Taken together, our analyses provide a snapshot of genome evolution under artificial and natural conditions. Although applied over extremely short timescales, artificial selection has dramatically altered the form, physiology, and life history of cultivated plants. We have used RNAseq to define both gene sequence and expression divergence between cultivated tomato and five related wild species. Based on sequence differences, we detect footprints of positive selection in over 50 genes. We also document thousands of shifts in gene-expression level, many of which resulted from changes in selection pressure. These rapidly evolving genes are commonly associated with environmental response and stress tolerance. The importance of environmental inputs during evolution of gene expression is further highlighted by large-scale alteration of the light response coexpression network between wild and cultivated accessions. Human manipulation of the genome has heavily impacted the tomato transcriptome through directed admixture and by indirectly favoring nonsynonymous over synonymous substitutions. Taken together, our results shed light on the pervasive effects artificial and natural selection have had on the transcriptomes of tomato and its wild relatives.


Genetic diversity is the basis for present day diversified living systems and future genetic improvement needs. Within the framework of breed conservation, genetic characterization is important in guarding breeds and is a prerequisite for managing genetic resources. The objective of the present study is to estimate the genetic diversity and phylogenetic relationships among Egyptian horse breeds (Native and Arabian) and an exotic breed (Thoroughbred) using Random Amplified Polymorphic DNA – Polymerase Chain Reaction (RAPD) technique. Initially, 25 primers were screened among all the breeds of which 14 primers amplified the genomic DNA. Four primers generated reproducible and distinct RAPD profiles and were used for further analysis. A total of 40 loci were amplified, of which 37 were found polymorphic (92.5%), useful for genetic variation study between breeds. The genetic diversity had the highest value (0.2048) in Arabian and the lowest value (0.0116) in Native breed. The genetic distance was found highest between Arabian and Thoroughbred (D=0.5442) and lowest between Native and Arabian (D=0.3280). However, genetic identity was highest (I=0.7204) between Native and Arabian and lowest (I=0.5803) between Arabian and Thoroughbred. UPGMA dendrogram based on Neis genetic distance grouped the investigated horse breeds genotypes into two clusters. The first cluster includes Egyptian breeds (Native and Arabian) where as the second cluster include Thoroughbred which appeared to be most distant from the other breeds. In conclusion, these results indicated the effectiveness of RAPD in detecting polymorphism between horse populations and their applicability in population studies and establishing genetic relationships among the horse populations. [Nature and Science. 2010;8(5):90-99]. (ISSN: 1545-0740).


OBJECTIVES
To determine patterns in antilipidemic drug prescriptions among a group of patients covered by the General Social Security System (Sistema General de Seguridad Social) in Colombia.

METHODS
A descriptive, observational study was conducted of 41 580 hyperlipidemics of both sexes, who were over 20 years of age, undergoing treatment from at least April to June 2006, and were residents of one of 19 cities in Colombia. A database was created to track prescription data collected by the pharmaceutical company that dispenses medications to the patients.

RESULTS
The mean age was 58.4+/-13.5 years; 58.9% of the participants were women. Of the total number of patients, 95.6% were receiving monotherapy, while 4.4% were receiving two or more antilipidemics. Prescriptions were ranked as follows: statins (70.9%), fibrates (27.5%), bile acid sequestrant resins (0.9%), and others (0.7%), all at low dosage levels. The most common therapy combinations were lovastatin + gemfibrozil (n = 1 568), cholestyramine + gemfibrozil (n = 92), and cholestyramine + lovastatin (n = 78). Comedications most frequently prescribed were: antihypertensive (60.9%), antiinflammatory (56.5%), antiulcer (22.9%), and antidiabetes drugs (20.6%), and acetylsalicylic acid (ASA, 3.8%). Antianginals and ASA were being underused, while antiinflamatories and antiulcer drugs were being overused.

CONCLUSIONS
Dyslipidemia is a primary risk factor for developing coronary heart disease and stroke, frequent causes of morbidity and mortality in Colombia and the world. All of the antilipidemics are being used at lower-than-recommended dosage levels. Clearly there is a need for creating educational strategies to address these prescribing habits and for exploring clinical results of the pharmaceuticals studied.


Endometrial cancer exhibits a strong incidence in western developed countries mainly due to fat-rich diet and obesity. Processing of dietary lipids is triggered by bile acids, amphipathic detergents that are synthesized in the liver and stored in the gallbladder. In addition to their well-recognized role in dietary lipid absorption and cholesterol homeostasis, bile acids can also act as signaling molecules with systemic endocrine functions. In the present study we investigated the biological effects of the primary bile chenodeoxycholic acid (CDCA) on a human endometrial cancer cell line, Ishikawa. Low concentrations of CDCA are able to stimulate Ishikawa cell growth by inducing a significant increase in Cyclin D1 protein and mRNA expression through the activation of the membrane G protein-coupled receptor (TGR5)-dependent pathway. Dissecting the molecular mechanism underlying this effect by mutagenesis, EMSA and ChIP analysis revealed that CDCA-induced Cyclin D1 expression requires the enhanced recruitment of the transcription factor CREB on the cyclic AMP-responsive element motif within the Cyclin D1 gene proximal promoter. Our results suggest a novel molecular mechanism explaining the potential contribution of high-fat diet and obesity to endometrial cancer growth and progression opening the rationale for strategies to prevent the risk of this obesity-related cancer in women.


Short peripheral catheter (SPC) failure is an important clinical problem. The purpose of this study was to clarify the relationship between SPC failure and etiologies such as thrombus, subcutaneous edema, and catheter dislodgment using ultrasonography and to explore the risk factors associated with the etiologies. Two hundred catheters that were in use for infusion, excluding chemotherapy, were observed. Risk factors were examined by logistic regression analysis. Sixty catheters were removed as the result of SPC failure. Frequency of thrombus with subcutaneous edema in SPC failure cases was significantly greater than in those cases where therapy was completed without complications (P < .01). Multivariate analysis demonstrated that 2 or more insertion attempts were significantly associated with thrombus with subcutaneous edema. Results suggest that subsurface skin assessment for catheterization could prevent SPC failure.


During the past 7th Security Framework Program the European Commission funded a research project called CATO (CBRN Crisis management, Architectures, Technologies and Operational procedures) to develop a prototype decision support system for crisis management in addition to providing a suite of guidelines for first responders and incident commanders when dealing with chemical, biological, radiological or nuclear incidents. In order to derive these guidelines a proof-of-concept experiment was setup during which several passive agent (Stable CsCl) dispersions with improvised explosive devices and vehicle-borne improvised explosive devices were carried out. Each dispersion was thoroughly characterised by a number of monitoring devices, including high-volume air samplers and size-segregated air samplers. All environmental and forensic samples were collected by the UK counter terrorism police, following strict labelling and chain-of-custody protocols. The samples were analysed at the Belgian Nuclear Research Center suing the k0 method for instrumental neutron activation technique. A full consequence assessment analysis was carried out assuming that the observed concentration of Cs-133 in samples was Cs-137 instead and use was made of the specific activity of Cs-137. Due to the sensitivity of the information the European Commission classified this research. The resulted reported on in this work have been unclassified and are released to assist emergency planners and first responders to take the necessary precautions. The results indicate that, up to distances of 50 m from ground zero radiation levels will be considerable and therefore live-saving actions must be performed by fire/rescue wearing full protective gear. In addition, low-wind conditions will favor a long airborne residence time and therefore the use of full-face protective gear is a must. In order to protect first responders, a radiation protection specialist is to determine how long people can enter and remain in the contaminated area. The recovery of evidence in the case of a car-bomb will be hard or even impossible due to the high level of radioactive material remaining inside the vehicle.


Between 1999 and 2004 we undertook an ecological study of African lions (Panthera leo) in Hwange National Park, western Zimbabwe to measure the impact of sport-hunting beyond the park on the lion population within the park, using radio-telemetry and direct observation. 34 of 62 tagged lions died during the study (of which 24 were shot by sport hunters: 13 adult males, 5 adult females, 6 sub-adult males). Sport hunters in the safari areas surrounding the park killed 72% of tagged adult males from the study area. Over 30% of all males shot were sub-adult (<4 years). Hunting off-take of male lions doubled during 2001–2003 compared to levels in the three preceding years, which caused a decline in numbers of adult males in the population (from an adult sex ratio of 1:3 to 1:6 in favour of adult females). Home ranges made vacant by removal of adult males were filled by immigration of males from the park core. Infanticide was observed when new males entered prides. The proportion of male cubs increased between 1999 and 2004, which may have occurred to compensate for high adult male mortality. 2006 Elsevier Ltd. All rights reserved.


A federal district court judge who has sentenced more than 4000 defendants reflects on federal sentencing and its role in mass incarceration. The focus of the article is on federal sentencing in crack cocaine cases and policy disagreements with the United States Sentencing Guidelines (Guidelines) in drug trafficking cases. The article explores the U.S. Supreme Court cases in Kimbrough v. United States, United States v. Spears, and Pepper v. United States, the only U.S. Supreme Court cases that address sentencing judges' policy disagreements with the guidelines. Ironically, or perhaps serendipitously, the author was the sentencing judge in both Spears and Pepper, where he was reversed a whopping 5 times by the U.S. Court of Appeals for the Eighth Circuit (twice by an en banc court) before both defendants' sentencing positions were vindicated by the U.S. Supreme Court. The article takes exception to two Third Circuit judges who have argued in law review articles that federal sentencing judges should be concerned about "legislative backlash" if they sentence outside the now advisory guidelines. In the arc of the history of federal sentencing and its impact on mass incarceration, we are perched at a cresting point where the gravity of reason and our Nation's experience with mass incarceration hopefully will pull towards greater justice in sentencing.


Some of mutations in the tau gene, which were found in frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP‐17), affect alternative splicing of its exon 10 which encodes one of four microtubule‐binding motifs. To examine the molecular mechanisms responsible for aberrant splicing of the tau gene containing mutations linked to FTDP‐17, we performed Exon trapping and binding assay using tau exon 10 pre‐mRNA and nuclear extracts of neuroblastoma cell lines and in vitro splicing using dsx‐substrate. We determined that 5′ site of tau exon 10 (nucleotides 12–45) possesses exonic splicing enhancer (ESE) activities in vitro splicing and the FTDP‐17‐linked mutations affect the ESE activities and alter the splicing patterns of tau exon 10. Tra2β directly and ASF/SF2 indirectly associated with the ESE of wild tau exon 10. The binding amounts of these SR proteins to tau exon 10 bearing N279K mutation increased and they enhanced splicing the mutant tau exon 10. SRp30c also enhanced the splicing of tau exon 10. These results suggest that mutations in tau exon 10 that are linked to FTDP‐17 affect the ESE activities by altering the binding of some SR proteins to its pre‐mRNA.


Direct-to-consumer (DTC) prescription drug brand websites, as a form of DTC advertising, are receiving increasing attention due to the growing number and importance as an ad and a consumer information source. This study examined consumer trust in a DTC website as an important factor influencing consumers' attitude toward the website and behavioral intention. Applying the conceptual framework of website trust, the particular focus of investigation was the effect of the website trust cue factor on consumers' perceived DTC website trust and subsequent attitudinal and behavioral responses. Results show a significant relation between the website trust cue factor and consumers' perceived DTC website trust. Perceived DTC website trust, in turn, was found to be significantly associated with consumers' attitude toward the DTC website and behavioral intention.


This dissertation studies financial crises and sector-based analysis. Chapter 1 studies the balance of payments crisis in the euro area periphery countries preceded by significant private capital inflows from 1999 to 2007. With a detailed empirical investigation, I find that these capital inflows in the form of debt mainly financed the nontradable sector and the industries with weak forward linkages to the tradable sector. The model economy explains that domestic misallocation of the capital inflows in terms of inter-industry linkages can trigger the debt repayment problem which was experienced by PIIGS (Portugal, Italy, Ireland, Greece, and Spain). More precisely, it shows that the debt infows under the protection of implicit bailout-guarantee cannot be repaid in the case when they primarily nance the nontradable sector with weak forward linkage to the tradable sector. Chapter 2, which is co-authored with Aaron Tornell and Hyo Sang Kim, looks at the size distribution of economic distress (ED) events over the recent period of globalization (1970 - 2014) and the long historical period (1830 - 2013). We find that there exists a remarkable relation between the magnitude of economic distress events and the frequency with which they occur. We document that there is a threshold below which the size of ED events follows an exponential distribution, while a Pareto distribution (a power-law) applies for ED events larger than the threshold. To explain the empirical results, we present a wildre model in which the dynamics of an individual ED event is determined by the interaction of two opposing forces: (i) the natural stochastic growth of the ED, which is proportional to the size of the damage that has already occurred; and (ii) a policy that attempts to extinguish the economic distress. We then derive the steady-state cross-sectional distribution of the final size of the ED events. Chapter 3 studies a sector rotation strategy. I introduce a sector rotation model that generates forecasts of sector performance combining 4 factors which include price momentum, market sentiment, macroeconomic factors, and earnings expectations. The backtest results show that all 4 factors and the sector rotation model outperform its benchmark (Equal-Weight Basket). Moreover, macro factor as a single factor generates the highest risk-adjusted returns.


Cloud service for personal users has become more popular world-wide since Apple Inc. launched iCloud storage service in October, 2011. However, such cloud storage service was not new because many global telecom companies, usually called telcos, as well as many portals had already offered similar Internet-based online storage services at that time. As of now, there can be seen hundreds of diverse cloud storage and computing services for both personal and enterprise users in the global market. During last several years, Korean cloud service market has been led by three major telcos, who have launched more advanced and more diversified services competing with each other. Some questions may arise: What makes that happen and what kind of market dynamics affects on the evolution of cloud service offerings? This paper tries to answer these questions by categorizing and analysing 84 cloud services offered by three major telcos in Korea during last three years. As a research framework, Pessemier's new product classification scheme was employed and precedence relationships among differently positioned service categories were analyzed to figure out the competitive evolutionary dynamics of the market. From the empirical study, path dependency was observed and resource-based view of the market competition was validated. Also, it was found that a player's next move in service offering to a better position in Pessemier's product space is quite closely related with the competitive position as well as the company-owned competitive resources like technology competency and company-wide service scope.


Abstract With increasing globalization, transnational crime in general, and human trafficking in particular, a design of new legal framework is required in order to effectively operationalize interstate law enforcement operations and prosecutions. The development of a transnational criminal legal framework—or frameworks—can build on pre-existing transnational economic frameworks. There is also the need to extend the application of domestic law beyond national borders to influence transnational corporate behavior. Regulations based on reflexive law are one possible approach. Teubner's idea of reflexive law has been informing developments in this area. This approach uses traditional national law to inform corporate governance strategies in order to achieve effects on the market. A few jurisdictions have already adopted measures modeled on this approach to tackle human trafficking and slavery-like conditions in global supply chains. Weaknesses in the approaches adopted by the UK and the State of California have already been identified. If strengthened, this approach could be adopted in more jurisdictions—including the EU—and also to combat more areas of transnational crime—such as money laundering. This paper will examine the resulting challenges using human trafficking as a case study.


This is a report on two neonates suffering from a severe nasal obstruction with respiratory distress. The cause of dyspnoea was identified as an abnormal bony narrowing at the level of the apertura piriformis. The etiology of this anomaly remains obscure. Surgical treatment was mandatory and performed as a transnasal approach using the operating microscope and otosurgical instruments. A special stent was used (U-shaped custom-made Portex tube) for several weeks to prevent recurrent narrowing. The advantage of a transnasal approach compared to the sublabial route is described and discussed.


The aim of this paper is to analyse whether the functional diversity of the fungal community follows the environmental gradients as much as vascular plants. After determination of the Ellenberg's indicator values on the basis of 602 cormophyte species occurring in 110 permanent plots across Central Europe, the relation between soil fungi and the abiotic factors as defined by Ellenberg's indicators has been evaluated. The palynological assessment proves that not the fungal occurrence, but the concentration of fungal remains is the most appropriate tool to unravel causal links between the belowground microflora and the soil abiotic factors. The analyses show a striking dichotomy within the fungal community. First, the logarithms of fungal diversity and hyphal density show close but opposite relationships with light, moisture, soil reaction and nitrogen availability. Second, fungal functional groups show parallel, decreasing trends for soil reaction and nitrogen availability. Aside from the mycorrhizal network as a whole (ericoid, EM and AM), we demonstrate that the degree of ecological information supplied by the different trophic levels (litter-related fungi, fimicolous fungi, wood-related fungi and strictly ericoid mycorrhizal fungi) is much greater than expected from previous studies.


Mental health problems and parental anxiety in children with epilepsy were investigated. Parents of 83 children with epilepsy and 172 healthy children were asked to complete Strengths and Difficulties Questionnaire for their children and State-Trait Anxiety Inventory for themselves. In those with epilepsy, 39.8% (n: 33) were girls, 60.2% (n: 50) were boys and their mean age was 9.34 ± 3.99 years. Control group was more successful in school (p < 0.001). Emotional problems score in children with epilepsy was higher than control group (p < 0.001). Case group's behavior problems and attention deficit hyperactivity scores were higher (p < 0.001, p=0.009 respectively). Prosocial behavior scores of the control group were significantly higher (p=0.004). State (p=0.001) and trait (p=0.001) anxiety levels of parents of children with epilepsy were higher. Children with epilepsy have more neuro-behavioral problems; and their parents have greater anxiety levels. Physicians should be in contact with children with epilepsy for the psychological health of the family besides seizure control.


A 3-year-old intact female domestic shorthair cat was presented for the evaluation of a palpable intra-abdominal mass in the left caudal abdomen. The cat had a history of anorexia, depression and prolonged estrus over a period of about 1 month. Smears prepared from a fine needle aspirate of the mass revealed large round to oval cells arranged individually or in loose clusters surrounded by pink, fibrillar matrix material. Cytoplasm was basophilic, with many variably-sized vacuoles and variable numbers of small purple granules. The vacuoles within the cells were strongly positive with Oil-Red-O stain. The cytologic features were most suggestive of a neoplasm of epithelial cell origin or inadvertent aspiration of a fatty liver. At laparotomy, the mass was found to involve the left ovary. Histologically, the tumor consisted of dense sheets and nests of irregular polyhedral, pleomorphic cells with abundant, finely vesiculated cytoplasm. The tumor cells were separated into lobules by strands of connective tissue. Based on histologic evaluation, a diagnosis of ovarian luteoma was made. In this report, we document the cytologic and histologic features of an uncommon feline tumor, a luteoma, and address its possible misdiagnosis as hepatic lipidosis when using cytology alone to make a diagnosis.


The choice of representation for circuits and Boolean formulae in a formal verification tool is important for two reasons. First of all, representation compactness is necessary in order to keep the memory consumption low. This is witnessed by the importance of maximum processable design size for equivalence checkers. Second, many formal verification algorithms are sensitive to redundancies in the design that is processed. To address these concerns, three different auto-compressing representations for Boolean circuit networks and formulas have been suggested in the literature. We attempt to find a blend of features from these alternatives that allows us to remove as much redundancy as possible while not sacrificing runtime. By studying how the network representation size varies when we change parameters, we show that the use of only one operator node is suboptimal, and demonstrate that the most powerful of the proposed reduction rules, two-level minimization, actually can be harmful. We correct the bad behavior of two-level optimization by devising a simple linear simplification algorithm that can remove tens of thousands of nodes on examples where all obvious redundancies already have been removed. The combination of our compactor with the simplest representation outperforms all of the alternatives we have studied, with a theoretical runtime bound that is at least as good as the three studied representations.


A comparative analysis is performed of the electron emission characteristics as the electrons move in laser fields with ultra-relativistic intensity and different configurations corresponding to a plane or tightly focused wave. For a plane travelling wave, analytical expressions are derived for the emission characteristics, and it is shown that the angular distribution of the radiation intensity changes qualitatively even when the wave intensity is much less than that in the case of the radiation-dominated regime. An important conclusion is drawn that the electrons in a travelling wave tend to synchronised motion under the radiation reaction force. The characteristic features of the motion of electrons are found in a converging dipole wave, associated with the curvature of the phase front and nonuniformity of the field distribution. The values of the maximum achievable longitudinal momenta of electrons accelerated to the centre, as well as their distribution function are determined. The existence of quasi-periodic trajectories near the focal region of the dipole wave is shown, and the characteristics of the emission of both accelerated and oscillating electrons are analysed.


The modern era of information and technology leverages connectivity and information sharing for enhancing applications and reducing human intervention. The proliferation of Internet of Things (IoT) in almost all aspects of modern life raises major challenges of security and privacy in health care services and the pharmaceutical industry. Blockchain has emerged as a secure technology in a trustless network without central governance. The inherent attributes it provides can solve the security and privacy challenges related to IoT and extend its capabilities. However, traditional instances of Blockchain are not suited for the IoT environment for reasons such as computationally expensive consensus process. Proof of authentication is a lightweight consensus algorithm that can be implemented in the IoT environment. This paper presents an IoT‐friendly Blockchain scheme implemented to evaluate the feasibility of medical supply and drug transportation to aid security and mitigate privacy issues which are fault‐tolerant, transparent, and traceable. The proof of concept implementation on portable single board computer demonstrates proof of authentication consensus algorithm executed with block validation and block addition in 30 and 40 ms while consuming 45 and 60mJ, respectively. Additionally, the network performance of the proposed architecture was presented and evaluated in the application context.


Autism spectrum disorder (ASD) is characterized by deficits in social functioning and difficulties in forming social bonds. According to the social motivation theory of ASD, people with ASD fail to attend social stimuli because they do not experience them as rewarding, resulting in deficits in social cognition. In neurotypical (NT) individuals, more rewarding faces have been shown to elicit greater spontaneous facial mimicry. This association between reward and mimicry is reduced in people with high autistic traits, suggesting that altered reward processing might explain the deficits in spontaneous facial mimicry observed in individuals with ASD. In a previous study, we observed that learned reward value of a face modulates mimicry-related neural response to it and that this modulation is reduced in people with high autistic traits. Using an identical evaluative conditioning paradigm where neutral faces were conditioned with high and low rewards, we tested the modulating effect of reward value on mimicry-related brain activity in a group of adults with and without ASD. We focused on the activity in a cluster within the inferior frontal gyrus (IFG) identified through an independent meta-analysis of 139 neuroimaging studies of mimicry, in response to passively viewing videos of the conditioned faces. The blood oxygen level dependent (BOLD) response contrast of high- vs. low-reward faces was reduced in participants with ASD compared to NT controls. The extent of reward-driven modulation was negatively correlated with autistic traits across the whole sample. Our results indicate that the mimicry-related brain response is less modulated by learned reward value in individuals with ASD when compared to NT controls. In previous studies, we found in a similar sample that being mimicked by faces was associated with less reward-related brain response in individuals ASD compared to an NT sample, suggesting that the link between reward and mimicry is affected in both directions in ASD. Together, this reduced bidirectional link between reward and mimicry can point to a potential mechanism underlying some of the social cognitive features of ASD.


1. The response properties of 182 units were studied in the primary visual cortices (155 in area 18 and 27 in area 17) in eight cats reared from birth in a stroboscopically illuminated environment (frequency, 2/s; duration, 200 microseconds). Multihistogram quantitative testing was carried out in 82 units (64 in area 18 and 18 in area 17). Two hundred three neurons recorded and quantitatively tested in areas 17 and 18 of the normal adult cat were used for comparison. 2. Spatial characteristics of receptive fields investigated using hand-held stimuli were found to be abnormal. The correlation between receptive-field width and eccentricity was lost in area 18 and consequently, receptive fields were significantly wider in area 18 subserving central vision. Cells could be classified according to the spatial characteristics of their receptive fields. There was a much smaller proportion of end-stopped cells in strobe-reared animals. Orientation tuning in the deprived animals was normal except for a small number of cells that showed no selectivity for stimulus orientation. 3. Compilation of velocity-response curves made it possible to classify areas 17 and 18 neurons into four categories: velocity low-pass, velocity broad-band, velocity tuned, and velocity high-pass cells. The proportion of velocity high-pass cells was reduced in area 18 subserving peripheral vision, as was the proportion of velocity-tuned cells in area 18 subserving central vision. 4. In the strobe-reared animal velocity sensitivity was somewhat different from that of the normal animal. Neurons in area 18 subserving the peripheral visual field failed to respond to fast velocities. Neurons in area 17 subserving the central visual field in strobe-reared animals responded to slightly higher velocities than in the normal animal. 5. In the deprived animals the number of neurons that were selective to the direction of motion was strongly reduced. The majority of neurons failed to show a selectivity for direction at all velocities. A number of neurons could be directional at some velocities but were unreliable, since they inverted their preferred direction with velocity changes. 6. Binocular convergence onto visual cortical cells was perturbed. In area 18 the majority of neurons were driven by the contralateral eye. In area 17 most neurons could be driven only by either the ipsilateral or contralateral eye. 7. Quantitative testing (of direction selectivity, sensitivity to high velocities, response latency, and strength) and qualitative testing (receptive-field width, end stopping, and ocular dominance) showed that the normal influence of eccentricity on functional properties was strongly reduced by strobe rearing.


In this work properties of potential brushite (CaHPO4•2H2O) and hydroxyapatite (Ca10(PO4)6(OH)2) compound cements are investigated. Calcium dihydrogenphosphate monohydrate (MCPM) and α-tricalcium phosphate (α-TCP) were the starting materials for investigated cements. Setting time is controlled by adding setting time retarder – citrate ions and initially unreactive filler - monetite (CaHPO4). Some compositions of obtained cements contain both brushite and hydroxyapatite. However a substantial amount of monetite was present even if it is not added as filler. There is a strong evidence of presence of octacalcium phosphate – a precursor phase for hydroxyapatite that lacks long range order.


This paper discusses the pros and cons of a Transatlantic Free Trade Area (TAFTA) in comparison with an informal trade-facilitating marketplace between Europe and the US. It finds considerably more cons, especially since TAFTA would be expected to produce larger, more detrimental discriminatory effects on dynamic non-member economies, mainly in Asia but also in food-exporting regions as well. Efficiency-enhancing effects are argued to be achievable under a marketplace concept which does not separate insiders from outsiders. It is also shown that in foreign direct investment (FDI) and FDI-related service trade, TAFTA seems redundant as in recent years bilateral capital and trade flows have proven to be buoyant without preferential treatment.


The False Claims Act prohibits fraud by government contractors, including a contractor's false certification of compliance with the contract, statutes or regulations. In the early 1990s, some courts began holding that the mere act of requesting payment from the government implicitly represents such compliance, exposing breaching contractors to the FCA's penalty regime. Circuits are today split on the implied certification doctrine. This Article provides a theory of the FCA in general, and implied certification in particular, that explains the value of extracompensatory remedies in this area of contract law. There good reasons for the implied certification rule. It is an information-forcing majoritarian default. It tracks the special ethical obligations of government contractors. And it addresses agency lassitude in drafting and monitoring. But implied certification also has its costs. Most importantly, it lowers the bar to frivolous qui tam actions and threatens to impose FCA liability for violations better addressed by more discretionary and nuanced regulatory tools. This Article recommends rule for implied certification that both addresses these considerations and rationalizes case outcomes. It also argues that, by paying attention to the FCA when drafting contracts, agencies can approximate first-best results by requiring express certification of compliance with those duties for which FCA liability makes sense, and contracting-out of implied certification for those duties that are better enforced in other ways. In addition to these practical suggestions, the Article draws some general lessons about contractual duties to cooperate, interpretive defaults in contract and tort, and the special ethical obligations of government contractors.


We have cloned the cDNA of rat hsc70 (clathrin-uncoating ATPase) into a T7 expression system and have expressed this enzyme in Escherichia coli. The recombinant clathrin-uncoating ATPase is in the cytosolic fraction of the bacterium and is soluble. It was purified to homogeneity by DEAE-cellulose and ATP-agarose column chromatography. From 1 litre of bacterial culture (0.3-0.4 g of proteins), 5-20 mg of pure recombinant clathrin-uncoating ATPase was routinely obtained. The cloned enzyme is capable of dissociating clathrin from bovine coated vesicle. Furthermore, it is not methylated on basic amino acid residues and is not blocked at the N-terminus, indicating that these modifications on hsc70 are not essential for uncoating of clathrin. Binding of [alpha-32P]ATP by purified recombinant hsc70 was analysed by Scatchard plot. The results indicate that there one high-affinity binding component with a Kd (dissociation constant) of 0.2-0.3 microM. The peptide-stimulated ATPase activities of recombinant hsc70 at 37 degrees C with respect to S-peptide peptides P3a and GT4 at a concentration of 1.2 mM are 142 +/- 6, 214 +/- 8 and 362 +/- 5 pmol/h per micrograms of hsc70 protein respectively. The EC50 values of hsc70 ATPase for S-peptide, peptides P3a and GT4 are 2, 0.67 and 0.17 mM respectively. On the other hand, the dissociation constants of S-peptide, peptides P3a and GT4 for recombinant hsc70 are 7.6, 13 and 100 microM respectively. Thus peptide GT4 is the only peptide examined for which the binding constant is comparable with the EC50 for stimulation ATPase activity, albeit it has the lowest affinity for hsc70.


Background:  Hyperinsulinaemia is emerging as an independent risk factor for metabolic disease, but diagnostic measures are limited. It is plausible that insulin resistance measures, such as homeostatic model assessment (HOMA) type 2 variants, may model hyperinsulinaemia, but repeatability data are limited. Kraft and Hayashi insulin response patterns may not only add value in diagnosing hyperinsulinaemia, but also lack suitable repeatability data. Aim:  The aim of this study was to investigate the repeatability of insulin response patterns, and fasting and dynamic measures of insulin resistance, and to determine whether these latter measures can predict the insulin response pattern. Setting:  This study was conducted at Auckland University of Technology Millennium Institute's sports performance laboratories. Methods:  Oral glucose (100 g) tolerance tests were conducted weekly on eight people. Six people completed four tests, while two completed at least two tests. Each test assessed insulin resistance and response patterns. Insulin resistance measures included fasting tests (HOMA2, McAuley Index) and a dynamic test (oral glucose insulin sensitivity [OGIS]). The insulin response patterns were assessed with both Kraft and Hayashi methodologies. Repeatability characteristics of ordinal variables were assessed by Bland and Altman methods, while Fleiss' κ was applied to categorical variables. Results:  Fasting measures of insulin resistance recorded poor repeatability (HOMA2) or poor sensitivity (McAuley Index) compared to the dynamic measure (OGIS). Kraft insulin response patterns were more repeatable compared to Hayashi patterns, based on a combination of Fleiss' κ (0.290 vs. 0.186,)  p -value (0.15 vs. 0.798) and 95% confidence intervals. Conclusions:  Both hyperinsulinaemia and insulin resistance should be dynamically assessed with a multi-sampled oral glucose tolerance test. Further investigations are required to confirm a preferred methodology.


Adult neurogenesis persists in the subventricular zone (SVZ), a crucial brain area that can respond to insults by producing neuronal progenitor cells able to migrate to sites affected by injury and neurodegeneration. Understanding the property of these cells is essential to fully elucidate their potential in neuroregenerative strategies. In the past few years several factors regulating neuronal migration have been identified, however still very little is known about the exact molecular mechanisms controlling neural progenitor motility. In this study we investigate the function of two proteins, fascin and drebrin, which are highly expressed in the postnatal brain by SVZ-derived migrating neuroblasts. Fascin is an actin-bundling protein that contributes to the architecture and function of cell protrusions in cell adhesion, interaction and motility. Drebrin is expressed by migrating neuroblasts; interestingly, cessation of migration in these cells coincides with the disappearance of the protein. We show here that RNAi-mediated depletion of fascin significantly impairs neuroblast migration in vitro. Phosphorylation of fascin on Ser39 is important for its actin-bundling activity and is regulated by protein kinase C (PKC). We demonstrate that Ser39 phosphorylation plays a fundamental role in neuroblast migration. Indeed, the migration of neuroblasts is strongly impaired when these cells are nucleofected either with a phosphomimetic (S39D) or a non-phosphorylatable (S39A) fascin variant, pointing to a crucial role for PKC in the regulation of neuroblast motility. Importantly, these cells still retain the ability to extend a protrusion in the direction of migration. Similarly, drebrin knockdown also substantially impairs neural progenitor migration in vitro and leads to a highly branched, unpolarised neuroblast morphology. We are currently validating our findings in vivo by performing postnatal electroporation of shRNA-expressing plasmids and time-lapse imaging of cultured brain slices from CD1 lactating P3 mouse pups. Our preliminary observations strongly suggest that drebrin depletion may severely affect neuroblast morphology also in vivo. In summary, both fascin and drebrin appear to play a fundamental function by controlling neural progenitor motility and morphology. Our future studies will aim at elucidating the signalling pathways involving both proteins during neural progenitor migration.


Medium energy ion scattering (MEIS) has been used to measure at the monolayer scale the strain profile of self-organized GaN quantum dots grown on (11–20) or a-plane AlN by molecular-beam epitaxy. By confronting the MEIS results with a structural analysis carried out by atomic force microscopy, it is established that the strain profile is anisotropic, i.e., fully elastic along [1–100] and a combination of plastic and elastic along [0001]. High resolution transmission electron microscopy measurements reveal the presence of misfit dislocations with 1/2 [0001] Burgers vector, consistent with MEIS data.


FAN (factor associated with neutral sphingomyelinase activity) is an adaptor protein that specifically binds to the p55 receptor for TNF (TNF-RI). Previous investigations demonstrated that FAN plays a role in TNF-induced actin reorganisation by connecting the plasma membrane with actin cytoskeleton and FAN deficiency leads to an impaired migratory induction in MEF (mouse embryonic fibroblasts) cells and Langerhans cells after TNF stimulation suggesting that FAN may impact on cellular motility in response to TNF and in the context of immune inflammatory conditions. In this work the translucent zebrafish larvae was used for in vivo analysis of leukocyte migration after morpholino knockdown of FAN. FAN-deficient zebrafish leukocytes were impaired in their migration toward tail fin wounds leading to a reduced number of cells reaching the wound. Furthermore, FAN-deficient leukocytes show an impaired response to bacterial infections suggesting that FAN is generally required for the directed chemotactic response of immune cells independent of the nature of the stimulus. Cell-tracking analysis up to 3h after injury revealed that the reduced number of leukocytes is not due to a reduction in random motility or speed of movement. Leukocytes from FAN-deficient embryos protrude pseudopodia in all directions instead of having one clear leading edge. These results suggest that FAN-deficient leukocytes exhibit an impaired navigational capacity leading to a disrupted chemotactic response. Due to the involvement of FAN in the migratory behaviour in different cell types it is likely that FAN has a general role in the migration of cells. Another process, dependent on cell migration, is the metastasis of cancer cells. Cell migration of B16 mouse melanoma cells after TNF stimulation was reduced after FAN down-regulation. In addition, these cells displayed a reduced tumour growth and never developed metastasis after injection in the tail vein of wild-type mice.


We consider privacy-preserving algorithms for deep reinforcement learning. State-of-the-art methods that guarantee differential privacy are not extendable to very large state spaces because the noise level necessary to ensure privacy would scale to infinity. We address the problem of providing differential privacy in Q-learning where a function approximation through a neural network is used for parametrization. We develop a rigorous and efficient algorithm by inspecting the reproducing kernel Hilbert space in which the neural network is embedded. Our approach uses functional noise to guarantee privacy, while the noise level scales linearly with the complexity of the neural network architecture. There are no known theoretical guarantees on the performance of deep reinforcement learning, but we gain some insight by providing a utility analysis under the discrete space setting.


A technique is described for the optimal synthesis of n-variable combinational logic circuits with Multiplexer universal logic modules, which may readily be implemented without excessive computer storage requirements. The method requires knowledge of the Rademacher-Walsh spectrum, which is an alternative representation of the truthtable vector of the function being considered. It makes use of a property of chosen subsets of these spectra coefficients, which when operated upon can give good indications of the merits of particular decompositions. It is found that an optimal choice of control input variables, and hence aminimal number of multiplexer modules in the realisation, can be made by relatively few tests on the spectral coefficient values.


The chilling effect—historically associated with protecting First Amendment rights—has more recently become a tool used to argue against social media platform (e.g., Facebook, Twitter) policies of restricting content. The 70-year-old principle invalidates regulations if censoring the unwanted speech will also deter or "chill" related but valuable speech. Despite its longstanding use and recent significance, little to no empirical work has been done on whether this phenomenon exists. This Article finally fills this gap. It employs an empirical study using social media speech restrictions analyzed with text analysis to conclude that the chilling effect has little to no impact on the content of the message; at most, it subtly alters the specific style or tone used. This study therefore confirms the existence of the phenomenon but simultaneously raises serious concerns about its usefulness as a guiding constitutional legal principle when assessing speech regulations.


Cobalt–nickel alloy crystals with different morphologies, such as flower-like, column-like, mushroom-like and dendrite-like, were prepared by a facile hydrothermal or solvothermal reduction approach without the addition of any surfactant, using hydrazine hydrate as a reducing agent, ethanediamine as a capping agent and a mixture of nickel(II) chloride hexahydrate (NiCl2·6H2O) and cobalt(II) chloride hexahydrate (CoCl2·6H2O) as a precursor. The effect of hydrothermal temperature (120, 150 or 180 °C) and solvent (water or ethanol) on the shape of the CoNi crystals was investigated in this work. The corresponding Ru/CoNi catalysts (Ru-on-CoNi nanocrystals) were obtained via a galvanic replacement reaction. The sizes, element chemical states, morphologies and structures of the CoNi and Ru/CoNi samples were characterized by X-ray diffraction (XRD), scanning electronic microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), and high-sensitivity low-energy ion scattering (HS-LEIS) techniques. The catalytic performance of the as-synthesized catalysts was evaluated by using the benzene hydrogenation reaction. The Ru/CoNi catalyst with a dendrite-like morphology exhibited the highest catalytic hydrogenation activity among the Ru/CoNi catalysts with different shapes. This was mainly due to its high Ru dispersion, many defect sites and positive synergistic effect compared with ruthenium, nickel and cobalt related species. Importantly, the cost of recycling the Ru/CoNi catalysts was relatively low because they could be recycled by magnetic separation.


African American adolescents' career development has gained increased attention in light of various barriers affecting their educational and career development goals. The author examined relationships among career decision self-efficacy, ethnic identity, and academic self-concept of 104 African American high school students enrolled in Upward Bound programs. Participants responded to measures of career decision self-efficacy, ethnic identity, and academic self-concept. Results indicated that career decision self-efficacy was significantly and positively correlated with ethnic identity and academic self-concept. In addition, academic self-concept was found to be a stronger predictor of career decision self-efficacy than was ethnic identity. The results of this study may assist counselors, teachers, administrators, and parents to understand career decision self-efficacy as it relates to ethnic identity, academic self-concept, and demographic variables. This research supports the need for continued career-related interventions within the schools designed to focus on factors related to ethnic minorities to help foster their career development.


Curving bones On larger length scales, bone is known to have a hierarchical structure in which small crystals of calcium phosphates arrange themselves around helices of collagen. These make up larger structures, such as the osteons found in compact bone. However, at smaller lengths, does the hierarchical structure persist? By combining three-dimensional electron tomography with two-dimensional electron microscopy, Reznikov et al. observed structural ordering from the nanoscale upward. At the smallest scale, needle-shaped mineral units form platelets that organize into stacks bridging multiple collagen units. Science, this issue p. eaao2189 The hierarchical structure of bone is probed down to the nanoscale by using a combination of electron tomography and microscopy. INTRODUCTION The components of bone assemble hierarchically to provide stiffness and toughness. Deciphering the specific organization and relationship between bone's principal components—mineral and collagen—requires answers to three main questions: whether the association of the mineral phase with collagen follows an intrafibrillar or extrafibrillar pattern, whether the morphology of the mineral building blocks is needle- or platelet-shaped, and how the mineral phase maintains continuity across an extensive network of cross-linked collagen fibrils. To address these questions, a nanoscale level of three-dimensional (3D) structural characterization is essential and has now been performed. RATIONALE Because bone has multiple levels of 3D structural hierarchy, 2D imaging methods that do not detail the structural context of a sample are prone to interpretation bias. Site-specific focused ion beam preparation of lamellar bone with known orientation of the analyzed sample regions allowed us to obtain imaging data by 2D high-resolution transmission electron microscopy (HRTEM) and to identify individual crystal orientations. We studied higher-level bone mineral organization within the extracellular matrix by means of scanning TEM (STEM) tomography imaging and 3D reconstruction, as well as electron diffraction to determine crystal morphology and orientation patterns. Tomographic data allowed 3D visualization of the mineral phase as individual crystallites and/or aggregates that were correlated with atomic-resolution TEM images and corresponding diffraction patterns. Integration of STEM tomography with HRTEM and crystallographic data resulted in a model of 3D mineral morphology and its association with the organic matrix. RESULTS To visualize and characterize the crystallites within the extracellular matrix, we recorded imaging data of the bone mineral in two orthogonal projections with respect to the arrays of mineralized collagen fibrils. Three motifs of mineral organization were observed: "filamentous" (longitudinal or in-plane) and "lacy" (out-of-plane) motifs, which have been reported previously, and a third "rosette" motif comprising hexagonal crystals. Tomographic reconstructions showed that these three motifs were projections of the same 3D assembly. Our data revealed that needle-shaped, curved nanocrystals merge laterally to form platelets, which further organize into stacks of roughly parallel platelets separated by gaps of approximately 2 nanometers. These stacks of platelets, single platelets, and single acicular crystals coalesce into larger polycrystalline aggregates exceeding the lateral dimensions of the collagen fibrils, and the aggregates span adjacent fibrils as continuous, cross-fibrillar mineralization. CONCLUSION Our findings can be described by a model of mineral and collagen assembly in which the mineral organization is hierarchical at the nanoscale. First, the data reveal that mineral particles are neither exclusively needle- nor platelet-shaped, but indeed are a combination of both, because curved acicular elements merge laterally to form slightly twisted plates. This can only be detected when the organic extracellular matrix is preserved in the sample. Second, the mineral particles are neither exclusively intrafibrillar nor extrafibrillar, but rather form a continuous cross-fibrillar phase where curved and merging crystals splay beyond the typical dimensions of a single collagen fibril. Third, in the organization of the mineral phase of bone, a helical pattern can be identified. This 3D observation, integrated with previous studies of bone hierarchy and structure, illustrates that bone (as a material, as a tissue, and as an organ) follows a fractal-like organization that is self-affine. The assembly of bone components into nested, helix-like patterns helps to explain the paradoxical combination of enhanced stiffness and toughness of bone and results in an expansion of the previously known hierarchical structure of bone to at least 12 levels. Proposed model of crystal organization in bone. Patterns specified by our model (top) are compared with projections of the STEM tomogram reconstructed from a STEM tilt series, showing the mineral organization in different directions (bottom). The components of bone assemble hierarchically to provide stiffness and toughness. However, the organization and relationship between bone's principal components—mineral and collagen—has not been clearly elucidated. Using three-dimensional electron tomography imaging and high-resolution two-dimensional electron microscopy, we demonstrate that bone mineral is hierarchically assembled beginning at the nanoscale: Needle-shaped mineral units merge laterally to form platelets, and these are further organized into stacks of roughly parallel platelets. These stacks coalesce into aggregates that exceed the lateral dimensions of the collagen fibrils and span adjacent fibrils as continuous, cross-fibrillar mineralization. On the basis of these observations, we present a structural model of hierarchy and continuity for the mineral phase, which contributes to the structural integrity of bone.