The combined application of the novel, clinically relevant microtubule stabilizing agent
(MTSA) patupilone and ionizing radiation (IR) is a very promising treatment modality in
cancer therapy as previously investigated at a preclinical level in our laboratory. Patupilone
(epothilone B) is a compound of bacterial origin, which binds to the same site on beta-tubulin
as taxanes, but has number of advantages over the later, e.g. potent cytotoxicity in multi-drug
resistant tumors and – due to its relatively simple chemical structure – the availability of
derivatives with improved pharmacological properties. Patupilone has a strong supra-additive
inhibitory effect on the growth of tumor xenografts in mice when applied together with IR.
Interestingly, the additive cytotoxic effect was much less pronounced in vitro indicating that
an additional effect on the level of tumor microenvironment must exist. While the initial
hypothesis was that patupilone targets neovascular endothelial cells directly, further investigations
revealed that the additive effect in vivo could only be observed in tumors xenografts
derived from patupilone sensitive cancer cells. Thus the effect on the tumor microenvironment
might be induced in an indirect way, mediated by tumor cells, for example via the
secretion of biologically active molecules.
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases with a broad
variety of substrates including components of the extracellular matrix and growth factors (e.g.
the transforming growth factor β (TGF- β). MMPs play an important role in the regulation
of cell survival, apoptosis, angiogenesis, matrix remodelling and metastasis. The function
of MMPs is strictly regulated by a complex activation processes (MMPs are expressed as
zymogens) and natural inhibitors of their enzymatic activity. The tissue inhibitors of MMPs
(TIMPs) represent a group of the most important players in the MMP regulation cascade currently
known. TIMPs are a family of small proteins (size of 20-30 kDa), that contains 4
members: TIMP-1-4. All 4 TIMPs are potent inhibitors of the MMP enzymatic activity; TIMP-2
was also shown to be a co-activator of MMP-2 zymogen. Additionally, TIMPs have MMP
independent biological functions, for example mitogenic, pro- and anti-apoptotic. MMPs and
TIMPs are secreted both by tumor-associated stromal cells and by cancer cells and are important
components of the tumor microenvironment. Overexpression of MMPs and TIMPs was
reported for almost all tumor types and associated with a bad survival prognosis.
In the present study we focused our investigations on the effect of the microtubule stabilizing
agent patupilone on the MMP function in tumor cells after treatment with ionizing
radiation. The results presented herein further confirmed the radiosensitizing capacity of patupilone
to enhance IR-induced cytotoxicity in a wide range of human cancer cells (HCT116
colon carcinoma cells, HT1080 fibrosarcoma cells, U251 glioma cell and medulloblastoma
ii
cell lines DAOY, D425, D341). It is also interesting to note that patupilone sensitized
to ionizing radiation already in a very low dose range. At these doses patupilone was not
cytotoxic itself and did not alter microtubule cytoskeletal structures (0.2 nM patupilone in
HT1080 cells). The combined treatment modality with patupilone and IR is more potent in
vivo than in cellular model systems. Most probably, this is due to the additional treatment
effects on the level of the tumor microenvironment, which may be mediated by tumor cells.
Herein, we investigated an effect of the indicated treatment regimens on one of the important
components of the tumor microenvironment, namely MMPs. We identified that the activity of
secreted MMP was upregulated after treatment with IR and that pre-treatment with patupilone
could diminish this increase. MMP activity is required for tumor cell invasion as well as for
other cellular processes. In this study tumor cell invasiveness was indeed increased after IR
and, in line with the events on the level of MMP activity, patupilone could counteract this
effect of IR.
In an attempt to uncover mechanisms that contribute to the counteracting effect of
patupilone on IR-induced MMP activity, we dissected the MMP regulation cascade on vaious
levels. Patupilone did not influence IR-induced events on the level of cell cycle distribution
and gene transcription. Namely, patupilone did not interfere with the accumulation of cells in
G2/M phase after IR and did not alter IR-induced transcription of MMPs and TIMPs. Both
MMP and TIMP protein levels were elevated in the cell lysate and conditioned cell
culture media (CM) after treatment with 10 Gy of IR. Patupilone did not influence intracellular
and extracellular protein levels of MMPs. However, the amount of extracellular TIMP-1 and
TIMP-2 proteins after combined treatment with patupilone and IR was significantly reduced
when compared to treatment with IR alone. Furthermore, the counteracting effect of patupilone
on IR-induced MMP activity was not observed in TIMP-1 and TIMP-2 depleted cells.
After TIMP depletion the IR-increased MMP activity did not exceed the MMP activity level
after combined treatment in non-depleted cells, indicating that the proMMP activation
processes after IR requires TIMPs. These findings strongly suggest that patupilone counteracted
IR-induced MMP activity due to the interference with the MMP activation processes
by the depletion the secreted TIMP-1 and TIMP-2 proteins.
To our knowledge, we demonstrate for the first time that patupilone can counteract IRinduced
MMP-related processes. It is particularly interesting is that the counteracting effect
of patupilone was observed in human glioma cells. Glioblastoma (or grade IV glioma) is
one of the most treatment resistant tumors in adults. The primary reasons associated with the
poor prognosis are: extensive infiltration of surrounding brain tissue by tumor cells and the
blood-brain barrier as an obstacle for the adequate delivery of chemotherapeutics. The ability
of patupilone to cross the blood-brain barrier makes patupilone a very potent and promising
chemotherapeutical agent for the treatment of brain malignancies. The capacity of patupilone
to inhibit IR-induced glioma cell invasion, as shown in the present study, increases the value
iii
of the compound as a candidate for a combination with radiation therapy for glioblastoma
treatment.
MMPs play an important role in cancer progression by remodelling the extracellular
matrix and regulating multiple biologically active molecules. Overexpression of MMPs and
TIMPs in multiple tumor types positively correlates with the aggressiveness of the disease.
There is a strong indication that radiation therapy can promote MMP expression and tumor
invasiveness. Thus, therapeutic agents that cleverly target members of MMP and TIMP
families in selective and disease/function-specific way can represent an interesting class of
agents for a combination with ionizing radiation.
This study demonstrates that the MTSA patupilone is a compound of great interest. It is
a potent inhibitor of tumor cell proliferation under hypoxic and normoxic conditions, a very
promising anti-metastatic and anti-angiogenic agent, a potent radiosensitizer in vivo and in
vitro (as described elsewhere). In addition, the present study demonstrated that patupilone
inhibits IR-induced activity of secreted MMPs and IR-induced cell invasion. Since IR-induced
MMP activity may be relevant to cancer progression, the combined treatment modality
of IR and patupilone might, indeed, be of great clinical benefit for cancer therapy.


This paper presents a scheme that allows one to relax the all-or-none nature of two-level constraints in two-level morphology in a controlled manner, so that word forms with violations of some of the two-level constraints can be analyzed and ranked. The problem has been motivated by a recent phenomenon in Turkish with imported words that violate a fundamental assumption of Turkish that pronunciation and orthography have almost a one-to-one correspondence, and by a problem in Basque words with differing amounts of competence errors. We present the formulation of our proposal, and provide details of implementations for both problems using the XRCE Finite State Toolkit.


Over the past few decades, a consensus has emerged that breakthrough innovations emerge from exploration of novel terrain while more routine innovations are the product of exploitation. In this paper, we revisit this explore versus exploit dichotomy with an analysis of over two and half thousand firm-level innovation histories spanning three decades. Our data and a novel measure of search (Technological Focal Proximity) enable us to characterize at a detailed level the search strategies of firms and to examine breakthroughs and non-breakthroughs are associated with different search strategies. Using our novel firm-level data and method, we find (contrary to the existing literature) that breakthrough innovations evolve through a process involving both exploration (initially) and exploitation (subsequently). The breakthrough innovation process appears to evolve through phases. In the early phases, firms explore unfamiliar terrain. However, as the process unfolds, firms shift their search strategies to focus on exploiting cumulative knowledge. Our findings call into question the strong dichotomy between exploration versus exploitation that has played such a prominent role in thinking about the origins of breakthrough innovation, and have potential implications for strategy, organizational design, management practice, and corporate culture.


Prepare yourself for the IELTS exam using Collins Practice Tests for IELTS Book 2 By using Practice Tests for IELTS 2, you will: * Feel completely confident about how the IELTS exam works * Know what to expect on the day of the exam * Improve your score through realistic practice All you need for your ideal IELTS score: - Four complete Academic IELTS tests - PLUS Two complete General Reading and Writing papers - A clear guide to how the IELTS exam works - Useful information on common mistakes and how to avoid them - CD + audioscript for the Speaking and Listening papers - Answer key + model answers for the Speaking and Writing papers You can trust Collins COBUILD Practice Tests for IELTS 2 contains a mini-dictionary with definitions based on COBUILD content. The 4.5-billion-word Collins Corpus is the world's largest database of the English language. It is updated every month and has been at the heart of Collins COBUILD for over 20 years.


Background. Patient-centredness has been identified by most medical schools worldwide as a desired core graduate competence. Patient-centredness positions the patient at the centre of the consultation and, therefore, focuses on the patient instead of on the disease. The concept of patient-centredness is, however, multifaceted. The choice and development of approaches and interventions that can enhance or sustain the various dimensions of patient-centredness are challenges for undergraduate medical curriculum developers. Objectives. To determine what the extent and nature of published scientific literature on implemented interventions are and how these could assist in fostering the various constructs of patient-centredness in undergraduate medical curricula. Furthermore, to determine which of these interventions could potentially be applied and incorporated in the context of the undergraduate medical curriculum at the Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Methods. The study followed the 6-step scoping review methodology framework. Four electronic databases were searched. Two independent reviewers screened citations for inclusion and performed the data abstraction. Results. Articles ( N =581) were eligible for inclusion in this study. Information captured in the Excel spreadsheets resulted in 9 categories of teaching interventions, which could lead to the various constructs of patient-centredness. These included didactic sessions and workshops, simulated patients, reflection, small-group discussions, e-learning, peer role-play/drama/surrogate, narratives/storytelling/art, clinical experiences and mindfulness training. Conclusions. It is important to acknowledge that the development of patient-centredness in medical students is more than just a set of communication skills. Curricula need to provide learning opportunities for students to enhance knowledge, skills and attitudes related to patient-centredness to develop it as a strong competence. Furthermore, students need to be placed in clinical learning environments that foster a patient-centred approach, providing various opportunities where they can reflect on their learning, be more mindful of the needs of their patients and build caring relationships with them.


The bar for justifying the use of vertebrate animals for study is being increasingly raised, thus requiring increased rigor for species selection and study design. Although we have power analyses to provide quantitative backing for the numbers of organisms used, quantitative backing for selection of study species is not frequently employed. This can be especially important when measuring the impacts of ecosystem alteration, when study species must be chosen that are both sensitive to the alteration and of sufficient abundance for study. Just as important is providing justification for designation of surrogate species for study, especially when the species of interest is rare or of conservation concern and selection of an appropriate surrogate can have legal implications. In this study, we use a combination of GIS, a fish traits database and multivariate statistical analyses to quantitatively prioritize species for study and to determine potential study surrogate species. We provide two case studies to illustrate our quantitative, traits-based approach for designating study species and surrogate species. In the first case study, we select broadly representative fish species to understand the effects of turbine passage on adult fishes based on traits that suggest sensitivity to turbine passage. In our second case study, we present a framework for selecting a surrogate species for an endangered species. We suggest that our traits-based framework can provide quantitative backing and added justification to selection of study species while expanding the inference space of study results.


The transition from academy to the professional level is one of the pivotal key stages in the development of elite professional soccer players and our understanding of this process is incomplete (Mills et al. 2012). A comprehensive detailed assessment of elite youth players match performance is limited and a clear gap in the literature exists which has consequences for the development programs of academy players (Harley et al. 2010). Global positioning systems (GPS) have been developed for use within a sports context to measure distance and velocity, however the methods employed for determining accurate capture conditions has not been examined and rely solely on historical criteria established before its use in dynamic sports such as soccer. The studies contained in this thesis are designed to further examine how an increase understanding of the match demands of youth soccer through the use of GPS technology to allow the development of highly tailored training programs to maximise the development of youth players.
The aim of the first study (Chapter 4) was to compare data collected using 5Hz GPS (MinimaxX, Catapult) and the ProZone™ (PZ) match analysis system and to establish satellite and Horizontal Dilution of Precision (HDOP) threshold limits to allow direct comparison between the two data sets. Ten elite outfield youth team players were monitored with PZ and GPS during a match and the data grouped into 10 minute capture periods and categorised into players who averaged a mean satellite lock of more than 5.5, 5, 4.5, and 4 over the ten minute period and a mean an HDOP of less than 1.8, 2, 3 and 4. The distance covered in each of the predetermined PZ speed categories were compared. The data showed significant differences (p 0.05) with small to large effect sizes. These data therefore suggested that for the accurate assessment of high velocity running (>4m/s) using GPS a HDOP threshold of 1.8 be used.
Using the valid GPS capture conditions obtained in study 1, the aim of the second study (Chapter 5) was to quantify match play according to outfield playing position in elite youth soccer at a scholarship (U18) level and compare to First team players. Eleven Under 18 games were analysed using GPS. Total distance covered and the maximal sprinting speeds were comparable with first team players in addition to the type of sprint performed (leading or explosive). The very high intensity running distance was less than that of first team players (range 532 to 804m vs 632 to 1196m) with the youth performing less sprints (range 9 to 12 vs 23 to 44) and with each sprint over a longer distance (50% over 10m vs under 10m) . The data highlights that the acceleration profiles of youth players need to receive the greatest attention at Under 18 level for there to be successful progression to the elite level.
By highlighting the discrepancy in the number of sprints and the distance covered by elite youth players the purpose of study three (Chapter 6) was to adapt the Draper and Lancaster test (ADL) to soccer specific distances and determine its reliability and ability to discriminate between different levels of players. The reliability of the total time of the ADL proved to be highly reproducible (TE = 0.17, ICC = 0.99, CV =0.7) along with the three sub-component tests (LE7m TE = 0.38, ICC = 0.93, CV = 1.6, 505 TE = 0.28, ICC = 0.96, CV = 1.3, and EX7m TE = 0.21, ICC = 0.98, CV =1.2). In assessing the validity of the ADL test the national players showed that they were significantly quicker in the ADL (mean diff = 0.41, t = 5.32, p < 0.005, CI = 0.25, 0.57, d = 1.4) the EX7m (mean diff = 0.19, t = 6.72, p < 0.005 , CI = 0.14, 0.25, d = 1.76) and 505 (mean diff = 0.14, t = 3.27, p < 0.005, CI = 0.05, 0.22, d = 0.86) sub component tests compared to the club level players but not in the 7mLE (mean diff = 0.05, t = 1.79, p = 0.08, CI = 0.01, 0.11, d = 0.47). The data demonstrate that the ADL test was reliable in test retest situations and a valid predictor of level of sport participation because it discriminated between players of lesser ability (club) and higher ability (national) and can be used in a football setting to assess the main fitness components (explosive speed, leading speed and agility) which have been highlighted as important in the elite game.
Extending on this work, the aim of study 4 (Chapter 6) was to investigate the application of the A505 field test for the assessment of functional asymmetries of the lower limb. Measurement of the fastest time for each side was recorded along with the peak torque of the hamstrings and quadriceps measured on an isokinetic dynamometer. The data showed that there were significant differences recorded in three of the four categories of the dominant side movements, concentric extension (Mean difference = 44.18, t = 5.70, p <0.001, CI = 28.4, 60.1, ES = 1.57), concentric flexion (Mean difference = 4.17, t = 3.29, p = 0.003, CI = 1.58, 6.8, ES = 1.12) and eccentric extension (Mean difference = 35.71, t = 3.50, p = 0.001, CI = 14.9, 56.5, ES = 1.18) with the eccentric flexion group showing non-significant differences (Mean difference = 2.68, t = 1.73, p = 0.094, CI = -0.5, 5.8, ES = 0.66). The non-dominant side showed significant differences in all four, concentric extension (Mean difference = 37.07, t = 6.41, p <0.001, CI = 25.1, 49.0, ES = 1.51) concentric flexion (Mean difference = 4.14, t = 2.70, p = 0.011, CI = 1.0, 7.3, ES = 0.95), eccentric extension (Mean difference = 34.90, t = 3.49, p = 0.002, CI = 14.5, 55.3, ES = 1.18), and eccentric flexion (Mean difference = 2.20, t = 2.27, p = 0.031, CI = 0.2, 4.2, ES = 0.85). The results suggest that the use of the A505 field test can determine asymmetries during functional dynamic movements in elite youth soccer players when compared to isokinetic assessment and as imbalances may have functional consequences which can lead to injury, therefore there is a need to examine how best to correct these.
Using the subjects from the previous chapter the aim of study 5 (Chapter 7) was to examine the effect of isolateral plyometrics (PT) and strength training (ST) to correct bilateral imbalances in youth academy players. Players were separated into a PT or WT group and performed training over six weeks. The non-dominant leg improved in its performance in the A505 field test whilst there was no improvement in the dominant leg. There was no overall difference between the training groups in either the dominant (f = 0.026, p = 0.619, CI = -0.043, 0.026 s, p2 = 0.013) or the non-dominant leg (f = 1.946, p = 0.179, CI = -0.064, 0.013 s, p2 = 0.093). However this partial improvement decreased the bilateral A505 ratio and it can be postulated, as suggested in the previous chapter, that this would reduce the likelihood of injury in the players.
In summary, the work undertaken from the studies in this thesis provides novel information in relation to the measuring of match performance when using GPS and the application of this information to the programming of training programmes with elite youth soccer players. It has also examined and validated the use of a simple field test to highlight bilateral lower limb imbalances and possible training programs to improve the bilateral ratio and to maximise the development of youth players.


We present Bifocal RNN-T, a new variant of the Recurrent Neural Network Transducer (RNN-T) architecture designed for improved inference time latency on speech recognition tasks. The architecture enables a dynamic pivot for its runtime compute pathway, namely taking advantage of keyword spotting to select which component of the network to execute for a given audio frame. To accomplish this, we leverage a recurrent cell we call the Bifocal LSTM (BF-LSTM), which we detail in the paper. The architecture is compatible with other optimization strategies such as quantization, sparsification, and applying time-reduction layers, making it especially applicable for deployed, real-time speech recognition settings. We present the architecture and report comparative experimental results on voice-assistant speech recognition tasks. Specifically, we show our proposed Bifocal RNN-T can improve inference cost by 29.1% with matching word error rates and only a minor increase in memory size.


Importance Despite lack of evidence of their utility, biomarkers of ovarian reserve are being promoted as potential markers of reproductive potential. Objective To determine the associations between biomarkers of ovarian reserve and reproductive potential among women of late reproductive age. Design, Setting, and Participants Prospective time-to-pregnancy cohort study (2008 to date of last follow-up in March 2016) of women (N = 981) aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, recruited from the community in the Raleigh-Durham, North Carolina, area. Exposures Early-follicular-phase serum level of antimüllerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B and urinary level of FSH. Main Outcomes and Measures The primary outcomes were the cumulative probability of conception by 6 and 12 cycles of attempt and relative fecundability (probability of conception in a given menstrual cycle). Conception was defined as a positive pregnancy test result. Results A total of 750 women (mean age, 33.3 [SD, 3.2] years; 77% white; 36% overweight or obese) provided a blood and urine sample and were included in the analysis. After adjusting for age, body mass index, race, current smoking status, and recent hormonal contraceptive use, women with low AMH values (<0.7 ng/mL [n = 84]) did not have a significantly different predicted probability of conceiving by 6 cycles of attempt (65%; 95% CI, 50%-75%) compared with women (n = 579) with normal values (62%; 95% CI, 57%-66%) or by 12 cycles of attempt (84% [95% CI, 70%-91%] vs 75% [95% CI, 70%-79%], respectively). Women with high serum FSH values (>10 mIU/mL [n = 83]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (63%; 95% CI, 50%-73%) compared with women (n = 654) with normal values (62%; 95% CI, 57%-66%) or after 12 cycles of attempt (82% [95% CI, 70%-89%] vs 75% [95% CI, 70%-78%], respectively). Women with high urinary FSH values (>11.5 mIU/mg creatinine [n = 69]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (61%; 95% CI, 46%-74%) compared with women (n = 660) with normal values (62%; 95% CI, 58%-66%) or after 12 cycles of attempt (70% [95% CI, 54%-80%] vs 76% [95% CI, 72%-80%], respectively). Inhibin B levels (n = 737) were not associated with the probability of conceiving in a given cycle (hazard ratio per 1-pg/mL increase, 0.999; 95% CI, 0.997-1.001). Conclusions and Relevance Among women aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, biomarkers indicating diminished ovarian reserve compared with normal ovarian reserve were not associated with reduced fertility. These findings do not support the use of urinary or blood follicle-stimulating hormone tests or antimüllerian hormone levels to assess natural fertility for women with these characteristics.


Film-viewing is a unique aesthetic experience, and it seems to possess a unique sort of tension. On the one hand, a film's story seems to just be there before us: we're directly presented with sights and sounds and can perceive the objects, people, and places depicted in the same sort of way we perceive things in the world. On the other hand, there's an important sort of constructedness in film. Film-viewers have to cognize what's represented by a film's perceptual prompts; we have to bring our awareness of convention to understand shottransitions and montage; and we have to extrapolate from what's shown in order to pick up on what's implied by the shots we see. These two aspects—perceptual immediacy and constructedness—seem opposed. And theorists typically treat them as opposed, with cinematic realists focusing on film's perceptual content, semioticians focusing on how movies communicate, and narrative theorists focusing on how we cognize a film's fiction, and each of them engaging in those analyses independent of the others. In this dissertation, I argue for nuanced ways in which what we see and hear, what we know, and what we imagine interact throughout film-viewing. I argue that film's perceptual content and representational content entwine insofar as we perceive a film's fictional world. I argue that because movies show (in ways that other art forms, like novels, cannot), they have an epistemic directness—they present their fictional truths immediately. I argue that movies communicate, in a roughly Gricean way, and that they do so partly through showing—with their perceptual content helping imply certain fictional truths. My analyses pave the way for a full theory of film meaning that does not treat as separate different, intertwining layers of meaning. I use and apply concepts from philosophy of perception, philosophy of language, and epistemology in order to clarify what precisely goes on when we watch movies and to motivate ties between philosophy of film and other areas of philosophy. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Philosophy First Advisor Michael Weisberg


There is great interest in the Pacific Century and what its implications for the future will be. The rapid economic growth of East Asia was already setting the region apart from the rest of the world by the 1970s. By the 1980s the trend was seen to have spread southward to Thailand, Malaysia and Indonesia, while China's provinces had also become integral to the regional economic boom. In this exciting new study many of the ideas and expectations associated with the Pacific Century are placed under critical scrutiny. The book includes studies of particular countries such as China, Japan, South Korea, Vietnam, Indonesia and Malaysia. There is analysis of economic and political trends in the region, the reasons behind its rise and its importance on a global scale. The rise of East Asia represents an historic turning point with immense significance world-wide. This book will be of interest to anyone concerned about the new approaches to and the debate about the rise of east Asia and the coming of the Pacific Century.


Dr Dario Llinares interviews Dr Sarah Atkinson about the core themes addressed in her recent monograph Beyond the Screen: Emerging Cinema and Engaging Audiences (Bloomsbury, 2014). The conversation explores the context for new conceptualisations of cinema, which encompass and reflect the myriad ways film can be experienced beyond the auditorium in a digitally networked society. They also explore the historical antecedents for embodied cinema, discuss examples of expanded, extended and mobile film spectatorship, and postulate as to the effect of these transformations for film production, criticism and scholarship. KEYWORDS Expanded Cinema; Film Criticism; Film Theory; Digital Technology; Mobile Cinema; Spectatorship


List homomorphisms are functions that can be computed in parallel using the divide-and-conquer paradigm. We study the problem of nding a homomorphic representation of a given function, based on the Bird-Meertens theory of lists. A previous work proved that to each pair of leftward and rightward sequential representations of a function, based on cons-and snoc-lists, respectively, there is also a representation as a homomorphism. Our contribution is a mecha-nizable method to extract the homomorphism representation from a pair of sequential representations. The method is decomposed to a generalization problem and an inductive claim, both solvable by term rewriting techniques. To solve the former we present a sound generalization procedure which yields the required representation, and terminates under reasonable assumptions. We illustrate the method and the procedure by the parallelization of the scan-function (parallel preex). The inductive claim is provable automatically.


Do local populations bene t from resource booms? How strong are market linkages between the mining sector and the regional economy? This paper exploits exogenous variation in mine-level pro duction volumes generated by the recent copper boom in Zambia to shed light on these questions.Using a novel dataset, I nd robust evidence that an increase in local copper production improves living standards in the surroundings of the mines even for households not directly employed in the mining sector: a 10% increase in constituency-level copper output is associated with a 2% increase in real household expenditure; positive e ects on housing conditions, consumer durable ownership and child health are of similar magnitude. The positive spill-overs extend to the rural hinterland of mining cities, neighboring constituencies, and constituencies on the copper transportation route. Additionally,I identify boom-induced changes in the demand for services and agricultural products as key channels through which the urban and rural populations bene t from the mine expansions. Since the boom failed to generate scal revenues, these e ects can be interpreted as the result of the mines' backward linkages. Taken together, these ndings highlight the welfare potential of local procurement policies in resource rich developing countries.


This paper presents a polylithic framework of review and theory development (RTD) papers. Based upon a reflective analysis of review papers that I have written, read, and/or reviewed, I build a framework suggesting four types of RTD papers: organizing reviews, assessing reviews, specific-theorizing reviews, and broad-theorizing reviews. The four types vary according to the research focus and research objectives, with research focus ranging from primarily description to the identification of gaps, and research objective ranging from primarily synthesizing to primarily theorizing. The framework and accompanying discussion are intended to provide scholars a perspective of the different ways that theory development and review papers intersect. The paper proposes criteria to help evaluate the quality of RTD papers and provides suggestions to authors on how to craft RTD papers.


Universal hepatitis B vaccination was recommended for U.S. newborns in 1991; however, safety findings are mixed. The association between hepatitis B vaccination of male neonates and parental report of autism diagnosis was determined. This cross-sectional study used weighted probability samples obtained from National Health Interview Survey 1997–2002 data sets. Vaccination status was determined from the vaccination record. Logistic regression was used to estimate the odds for autism diagnosis associated with neonatal hepatitis B vaccination among boys age 3–17 years, born before 1999, adjusted for race, maternal education, and two-parent household. Boys vaccinated as neonates had threefold greater odds for autism diagnosis compared to boys never vaccinated or vaccinated after the first month of life. Non-Hispanic white boys were 64% less likely to have autism diagnosis relative to nonwhite boys. Findings suggest that U.S. male neonates vaccinated with the hepatitis B vaccine prior to 1999 (from vaccination record) had a threefold higher risk for parental report of autism diagnosis compared to boys not vaccinated as neonates during that same time period. Nonwhite boys bore a greater risk.


A practical and current overview of the entire field of allergy. Allergic disease, which frequently affects children, adolescents, and young adults, has seen an alarming increase in recent years. At the same time, an explosion of clinical and scientific advances in immunology and allergology have made it imperative that practitioners keep up with the newest knowledge. Unique in its scope, size, and format, here is a practical and current overview of the entire field of allergy. This succinct book incorporates colorful and educational illustrations throughout, with succinct information on: complex cell-mediated immune response; methods of in-vivo and in-vitro allergy diagnosis; antihistamine and corticosteroid treatments; prophylaxis and allergen avoidance; psychosomatic disease; and much more! The book is part of Thieme's acclaimed Flexibook series of clinical and basic science pocket guidebooks, which are sold worldwide and have been translated into more than 20 languages. Unique features of this pocket atlas: * Nearly 100 full-color illustrations that convey complex information simply and effectively * A wealth of concise and focused information in less than 250 pages - textbook knowledge in a pocketbook format! * Thorough diagnostic guidelines that incorporate the multidisciplinary expertise of a wide variety of specialists * An extensive Appendix that covers current topics such as emergency management, patch testing, allergy medications, and more! From basic allergy principles to diagnosis, treatment, organ-specific allergies, prevention, and more, this compact book comprehensively covers the field. It is essential for any specialist who needs a thorough understanding of allergy medicine - otorhinolaryngologists, dermatologists, internists, pediatricians, pulmonologists, as well as medical students. Use this beautifully illustrated pocket guide to keep up-to-date on an important clinical topic.


A combination of the plane-wave expansion method with the effective-index approximation is presented, which allows vectorial properties of electromagnetic field in three-dimensional structures to be considered. I formulate mathematical equations that are the basis of this combined approach, and then I show the simulation of the optical properties of oxide-confined vertical-cavity surface-emitting lasers (VCSELs). The results are compared with the ones obtained with the classical effective-index method and with the fully vectorial plane-wave admittance method. Next the semivectorial properties of the new model are utilized to analyze a birefringent VCSEL structure.


Trachinotus coppingeri is an important species for recreational and commercial ocean beach fishers in southeast Queensland and northern New South Wales. Tagging was carried out to examine the species movement pattern. 4,556 fish were tagged in thirteen locations from Mourilyan southwards to Pottsville. There were 243 recaptures (5.3%), the majority by recreational fishers (91.2%), and the remainder by commercial fishers (6.7%) and researchers (2.1%). It was concluded that the movements of T. coppingeri were more consistent with ranging than either station keeping or migration. The majority (49.3%) of T. copingeri were recaptured <4km from their release site, but movements of up to 275km were recorded. The distance between release and recapture site was positively correlated with fish size. Considering the comparative number of recaptures between recreational and commercial fishers it was concluded that the recreational catch of T. coppingeri was likely to far exceed the commercial catch.


We propose algorithms for approximate filtering and smoothing in high-dimensional factorial hidden Markov models. The approximation involves discarding, in a principled way, likelihood factors according a notion of locality in a factor graph associated with the emission distribution. This allows the exponential-in-dimension cost of exact filtering and smoothing to be avoided. We prove that the approximation accuracy, measured in a local total variation norm, is `dimension-free' in the sense that as the overall dimension of the model increases the error bounds we derive do not necessarily degrade. A key step in the analysis is to quantify the error introduced by localizing the likelihood function in a Bayes' rule update. The factorial structure of the likelihood function which we exploit arises naturally when data have known spatial or network structure. We demonstrate the new algorithms on synthetic examples and a London Underground passenger flow problem, where the factor graph is effectively given by the train network.


With the Treaty of Rome, European states designed a set of policy domains related to trade and the regulation of markets, a complex of governmental organisations, and a binding set of substantive and procedural rules to help them achieve the construction of a European Economic Community (Fligstein and McNichol, 1998). Although the Treaty traced the broad outlines of this new Community, it was the purposeful activities of representatives of national governments (Moravcsik 1999), of officials operating in the EC's organisations, like the Commission (Pollack 1998) and the Court (Burley and Mattli 1993; Stone Sweet and Caporaso 1998a; Weiler 1991, 1994), and of leaders of transnational interest groups (Mazey and Richardson, eds., 1993) that subsequently produced the extraordinarily dense web of political and social networks that now functions to generate and sustain supranational governance (Wallace and Young 1998; HA©ritier 1999; Sandholtz and Stone Sweet, eds., 1998).


We introduce an opportunistic downlink interference alignment (ODIA) for interference-limited cellular downlink, which intelligently combines user scheduling and downlink IA techniques. The proposed ODIA not only efficiently reduces the effect of inter-cell interference from other-cell base stations (BSs) but also eliminates intra-cell interference among spatial streams in the same cell. We show that compared to the existing downlink IA schemes, the minimum number of users required to achieve a target degrees-of-freedom (DoF) can be fundamentally reduced, i.e., the fundamental user scaling law can be improved, by using the ODIA. In addition, we introduce a limited feedback strategy in our ODIA framework, and then analyze the minimum number of feedback bits required to obtain the same performance as that of the ODIA assuming perfect feedback.


Abstract This work develops an analytical model of shear senses within an inclined ductile simple shear zone with parallel rigid boundaries and incompressible Newtonian viscous rheology. Taking account of gravity that tends to drive the material downdip and a possible pressure gradient that drives it upward along the shear zone, it is shown that (i) contradictory shear senses develop within two sub-zones even as a result of a single simple shear deformation; (ii) the highest velocity and least shear strain develop along the contact between the two sub-zones of reverse shear; (iii) for a uniform shear sense of the boundaries, a zone of reverse shear may develop within the top of the shear zone if the pressure gradient dominates the gravity component; otherwise it forms near the bottom boundary; (iv-a) a 'pivot' defined by the intersection between the velocity profile and the initial marker position distinguishes two sub-zones of opposite movement directions (not shear sense); (iv-b) a pivot inside any non-horizontal shear zone indicates a part of the zone that extrudes while the other subducts simultaneously; (v) the same shear sense develops: (v-a) when under a uniform shear of the boundaries, the shear zone remains horizontal and the pressure gradient vanishes; or alternatively (v-b) if the shear zone is inclined but the gravity component counterbalances the pressure gradient. Zones with shear sense reversal need to be reinterpreted since a pro-sheared sub-zone can retro-shear if the flow parameters change their magnitudes even though the same shear sense along the boundaries is maintained.


Background: No empirical evidence is available on whether or not information and communications technology (ICT) is adopted by South African township micro and small businesses (MSBs) in order to grow the business. ICT, as an enabler, can grow the business. It is evident from literature that ICT enables MSBs to be more productive and efficient. Objectives: This research determines to what extent ICT is adopted by MSBs in Soweto, and whether or not a positive correlation exists between the adoption rate of ICT and the financial and growth performance of the MSB itself. Method: A structured questionnaire was completed by 978 respondents to determine the extent of ICT adoption and for what ICT is used. This exploratory research provides new knowledge about the acceptance of ICT within township MSBs. Results: The results indicate that ICT is not used to the fullest by MSBs. Rather, it is used as a basic tool for doing business but it does not form an integral part of the business. This research provides insight into the usage and adoption of ICT and it opens the door for further cross-analysis research. Conclusion: Education and training are needed to ensure that MSBs use ICT to the fullest. MSBs embracing ICT can evolve from a survivalist SME to a more sustainable micro and small MSB.


Like any new parent, Joshua Gans felt joy mixed with anxiety upon the birth of his first child. Who was this blanket-swaddled small person and what did she want? Unlike most parents, however, Gans is an economist, and he began to apply the tools of his trade to raising his children. He saw his new life as one big economic management problem—and if economics helped him think about parenting, parenting illuminated certain economic principles. Parentonomics is the entertaining, enlightening, and often hilarious fruit of his "research." Incentives, Gans shows us, are as risky in parenting as in business. An older sister who is recruited to help toilet train her younger brother for a share in the reward given for each successful visit to the bathroom, for example, could give the trainee drinks of water to make the rewards more frequent. (Economics later offered another, better toilet training solution: outsourcing. For their third child, Gans and his wife put it in the hands of professionals—the day care providers.) Gans gives us the parentonomic view of delivery (if the mother shares her pain by yelling at the father, doesn't it really create more aggregate pain?), sleep (the screams of a baby are like an offer: "I'll stop screaming if you give me attention"), food (a question of marketing), travel ("the best thing you can say about traveling with children is that they are worse than baggage"), punishment (and threat credibility), birthday party time management, and more. Parents, if you're reading Parentonomics in the presence of other people, you'll be unable to keep yourself from reading the funny parts out loud. And if you're reading it late at night and wake a child with your laughter—well, you'll have some guidelines for negotiating a return to bed.


In this review, analytical results obtained for a wide class of stationary axisymmetric flows in the vicinity of compact astrophysical objects are analyzed, with an emphasis on quantitative predictions for specific sources. Recent years have witnessed a great increase in understanding the formation and properties of astrophysical jets. This is due not only to new observations but also to advances in analytical theory which has produced fairly simple relations, and to what can undoubtedly be called a breakthrough in numerical simulation which has enabled confirmation of theoretical predictions. Of course, we are still very far from fully understanding the physical processes occurring in compact sources. Nevertheless, the progress made raises hopes for near-future test observations that can give insight into the physical processes occurring in active astrophysical objects.


The purpose of this study was to understand the experiences of kindergarten
teachers as they worked to implement a developmentally appropriate approach to
teaching. Their stories included details related to the support they receive as well as
detailed descriptions of the many barriers faced during a time when accountability is very
high. As teachers with a high value for developmentally appropriate practice, they
experienced cognitive dissonance when circumstances arose to limit their ability to use
the best practices they favored. These practices included differentiation of instruction;
provision for active and meaningful learning experiences; small group instruction; the use
of centers that supported language development; problem solving; development of social
skills; literacy and numeracy skills; as well as learning through play—all practices
carefully planned to recognize and honor how children learn best.
Mandates requiring the teachers to use scripted curriculum programs were a
strong source of the dissonance. These programs were designed to reflect a more
academically structured approach to teaching. Instruction was required to be delivered in
a whole group setting, with little effort to differentiate instruction. Learning was more passive in nature with children being required to sit for long blocks of time working at
tables or desks completing worksheets. The teachers found creative ways to tweak the
mandated curriculum to make them more age and grade appropriate.
Other barriers reported by teachers included the lack of professional development
aligned specifically to their needs, the lack of collegial collaboration, and the
inappropriate expectations of parents and first grade teachers. Teachers indicated that
they wanted their administrators to be knowledgeable about early childhood education
and child development. They wanted to receive meaningful feedback to help them
improve their instructional practice. The teachers reported feeling that kindergarten did
not appear to be a highly valued component of the educational program. It did appear to
them that more attention and more resources were regularly aimed at tested grade levels.
The teachers were also concerned about not having a voice in decisions that directly
affected them.
The major source of support for the teachers came from a group organized by the
North Carolina Department of Public Instruction known as The Power of Kindergarten.
The teachers in the study were among the members of this group. Strong collegiality, gaining a sense of professional empowerment, and focused professional development
were reported by the teachers as being important outcomes of their experiences with
Power of K.


Background and Objectives Renal cell carcinoma is the most common and lethal form of all renal cancers, and accounts for 4.1% of all cancer cases in Qatar. Mutations to Von-Hippel Lindeau (VHL) gene in renal cells activates hypoxia inducible factor-1 alpha (HIF-1α) response pathway, and contributes to increased proliferation and progression to renal cell carcinoma. Hence, chemotherapeutic modalities available to treat renal cell carcinoma are targeted toward modulation of the VHL-HIF response pathway. Annonacin, a potent cytotoxic mono-tetrahydrofuran acetogenin found in Annonaceae plants, has been demonstrated to exert anticancer activity against breast cancer; however, its therapeutic potential against renal cell carcinoma is yet to be determined. Hence the objective of this study is to investigate anti-neoplastic potential of annonacin in renal carcinoma cells. Methods We investigated the effect of annonacin - at concentrations ranging from 0.5 to 2 μM – on cell viability (using MTT assay and Alamar blue assay), and the protein expression of markers of HIF signaling pathway (HIF-1α), mTOR pathway (Thr-389 phosphorylation of p70S6 kinase), cell cycle progression (p21 levels), and apoptosis (caspase-3 expression) in CaKi-2 cells, a human renal carcinoma cell line. The cells were treated with annonacin for 24 or 48 hours and assessed for the aforementioned parameters. Results hour annonacin treatment caused a significant and dose-dependent decrease in the viability of CaKi-2 cells, i.e., 42% in 0.5 μM, 36% in 1 μM and 29% in 2 μM annonacin treatment groups as compared to control set at 100%. This was further confirmed by Alamar blue assay, which revealed a significant decrease in the viability of CaKi-2 cells upon treatment with annonacin for 48 h. The expression of HIF-1α was reduced by 68% at 24 h in CaKi-2 cells treated with 2 μM annonacin. In addition, the expression of p21 (a key molecule that inhibits transition of cells from G1 to S phase in cell cycle) was induced by 1.34-fold in 0.5 μM annonacin-treated cells indicating an arrest in G1 phase of cell cycle. This was further confirmed through cell cycle analysis using Tali cytometer, in which annonacin treated groups (0.5 μM and 1 μM) showed cell cycle arrest at G1 phase, i.e., 57% of cells in G1 phase with 0.5 μM annonacin treated vs. 7% of cells in G1 phase in control group. In addition, a dose-dependent decrease in the phosphorylation of p70S6 kinase (a downstream target of mTOR) was observed with annonacin treatment at both 24 and 48 h end-points. This suggests that treatment of annonacin has possibly led to the inhibition of mTOR, in addition to suppression of HIF-1α activation, and underscores the cross-talk between HIF pathway and mTOR signaling pathway in renal cell carcinoma. Conclusions Our findings demonstrate that annonacin treatment (at concentrations ranging from 0.5 to 2 μM) inhibits HIF-1α and mTOR activation and causes cell cycle arrest at G1 phase and induces apoptosis in renal cell carcinoma. These findings indicate that annonacin exerts anti-cancer effects via modulation of HIF and mTOR signaling pathways, resulting in alterations in the cell cycle and activation of apoptosis in renal cell carcinoma. In conclusion, our study for the first time unveils the therapeutic potential of annonacin to inhibit the progression of renal cell carcinoma. Further studies in vivo are required to establish its efficacy to treat patients with renal cell carcinoma. Funding Source This study is supported by an intramural grant (#QUUG-CPH-CPH-14/15/7) funded by the Office of Academic Research, Qatar University, Doha, Qatar.


The attitude of the critical researcher, as opposed to the traditional researcher into 'objective' knowledge, lies in the conviction that the theorist-researcher is no mere observer or discoverer of knowledge, but is herself embedded in the social, historical, political context in which knowledge is formed (Horkheimer 1968). The critical researcher therefore aims to be self-reflective, and attentive to the conventional dimensions of scholarship. Some methodological questions for the critical researcher might be -what are the norms of 'good' scholarship, where do these derive from in cultural or political terms, on what basis can they be defended, and how should they be challenged or re-formed? Another question of some significance is -how do ethical and political beliefs influence the substance and methodology of research? This is the issue which I want to focus upon in this brief article, focusing particularly upon methodology. This journal article is available in Law Text Culture: http://ro.uow.edu.au/ltc/vol6/iss1/2 Ethics and Methodology in Legal Theory a (Personal) Research Anti-Manifesto


The definitive guide on how to prepare for any crisis--from global financial collapse to a pandemic It would only take one unthinkable event to disrupt our way of life. If there is a terrorist attack, a global pandemic, or sharp currency devaluation--you may be forced to fend for yourself in ways you've never imagined. Where would you get water? How would you communicate with relatives who live in other states? What would you use for fuel? Survivalist expert James Wesley, Rawles, author of Patriots and editor of SurvivalBlog.com, shares the essential tools and skills you will need for you family to survive, including: Water: Filtration, transport, storage, and treatment options. Food Storage: How much to store, pack-it-yourself methods, storage space and rotation, countering vermin. Fuel and Home Power: Home heating fuels, fuel storage safety, backup generators. Garden, Orchard Trees, and Small Livestock: Gardening basics, non-hybrid seeds, greenhouses; choosing the right livestock. Medical Supplies and Training: Building a first aid kit, minor surgery, chronic health issues. Communications: Following international news, staying in touch with loved ones. Home Security: Your panic room, self-defense training and tools. When to Get Outta Dodge: Vehicle selection, kit packing lists, routes and planning. Investing and Barter: Tangibles investing, building your barter stockpile. And much more. How to Survive the End of the World as We Know It is a must-have for every well-prepared family.


The overall address of the present thesis is the relationship between being 'on fire' and burning out. More specifically, the thesis focused largely on two representations of involvement in work (work engagement and Type A behavior) and their respective relationships to burnout. Another pervasive theme was construct validity in assessing burnout and work engagement. These themes were addressed in four empirical studies, conducted in a sample of health-care workers (Study I) and a sample of information communication technology consultants (Studies II, III, and IV). Study I aimed to extend the previously preliminary support for the construct validity of the Swedish version of the Maslach Burnout Inventory (MBI). The objective of Study II was the discriminant validity of the Utrecht Work engagement Scale (UWES) against the theoretically adjacent constructs job involvement and organizational commitment. Another objective was the translation and evaluation of a Swedish version of the UWES. In Study III, the aim was to investigate (cross-sectional) association between Type A behavior, work engagement and burnout. Study III had two foci: 1) whether Type A behavior interacts with job factors to affect burnout and work engagement, and 2) the associations between the main components of Type A behavior (achievement-striving and irritability/impatience) and burnout as well as work engagement. Study IV concerned the longitudinal relationships between Type A behavior and burnout, and between work engagement and burnout. The results presented in this dissertation supported the construct validity of Swedish versions of the MBI and the UWES. It was further indicated that emotional exhaustion and depersonalization (or cynicism) constitute the core aspects of burnout, and that work engagement was more prominently associated with lack of health complaints than job involvement and organizational commitment. Type A behavior was found to be associated with burnout and work engagement in cross-sectional data, however different aspects of Type A behavior appeared to have somewhat different association with burnout and work engagement respectively. The achievement-striving aspect of Type A behavior was related primarily to work engagement, whereas irritability was associated with less engagement and more burnout complaints. No indications of an interaction between Type A behavior and job stress were found. The most important finding of Study IV was that change in Type A behavior was unrelated to change in burnout across time (one-year interval). Furthermore, Study IV supported the notion that work engagement and burnout are bipolar opposites and constitute a work well-being continuum. To conclude, the present thesis suggests that burnout should be viewed as an erosion of intrinsic, affective engagement in work occurring when intrinsic motivation is frustrated by job stress. To avoid conceptual confusion, burnout should be distinguished form exhaustion syndrome however it should be acknowledged that burnout may have negative impact on health. The present study indicated that Type A behavior is unrelated to the specific burnout reaction, a finding that needs to be replicated before generalizability can be assumed. However, it was assumed that Type A behavior represents an instrumental approach to work, further corroborating that burnout is a specific construct referring to the draining of a specific energetic and affective state. This does not imply that Type A behavior is unrelated to health deterioration – most plausibly, Type A behavior generates exhaustion and fatigue from over-exertion of energy. Both research and practice would benefit from exploring how work engagement may best be enhanced using job redesign.


This article aims to explain the ideal construct of Indonesia democracy after the 2019 presidential election which is colored by the conflict of two blocks known as cebong vs kampret. This shows that democracy cannot be separated from conflict. However, despite the ongoing conflict, is it possible for Indonesia to build an ideal construction of Indonesian-style democracy? Democracy in 2019 Presidential election is an indicator of political development in Indonesia, whereas all state institutions must ensure basic rights of Indonesia peoples. A valuable lesson of Indonesia democracy is diversity as a blessing of Indonesian human life with Pancasila as democracy system. In this system, deliberation (musyawarah mufakat) and majority voice ensure direct presidential election based on people's will. The dynamic of 2019 presidential election is the emergence of the tightness and uniqueness of supporters of candidate pairs. At the end, this dynamic was coloured by flowing tears of the motherland mourning.


In The Syrian Rebellion, Fouad Ajami offers a detailed historical perspective on the current rebellion in Syria. Focusing on the similarities and the differences in skills between former dictator Hafez al-Assad and his successor son, Bashar, Ajami explains how an irresistible force clashed with an immovable object: the regime versus people who conquered fear to challenge a despot of unspeakable cruelty. Although the people at first hoped that Bashar would open up the prison that Syria had become under his father, it was not to be - and rebellion soon followed. Offering a detailed historical perspective, Ajami shows how, for four long decades, the Assad dynasty, the intelligence barons, and the brigade commanders had grown accustomed to a culture of quiescence and silence. But Syrians did not want to be ruled by Bashar's children the way they had been ruled by Bashar and their parents had been by Bashar's father. When the political hurricane known as the Arab Spring hit the region, Bashar al-Assad proclaimed his country's immunity to the troubles. He was wrong. This book tells how a proud people finally came to demand something more than a drab regime of dictatorship and plunder. Fouad Ajami is a senior fellow at the Hoover Institution and the co-chair of the Herbert and Jane Dwight Working Group on Islamism and the International Order.


The Global Entrepreneurship Monitor (GEM) is a project carried out by a research consortium dedicated to understanding the relationship between entrepreneurship and national economic development. Since 1999 GEM reports have been a key source of comparable data across a large variety of countries on attitudes toward entrepreneurship, start-up and established business activities, and aspirations of entrepreneurs for their businesses. The growing databases increasingly allow for in-depth academic research and this is mirrored by the rapidly increasing amount of GEM-based scientific publications in a wider range of academic journals. At this point it is appropriate to provide an overview on these publications, to summarize their main contributions, and to provide some directions for obtaining promising GEM-based academic contributions in the future. This publication provides a review of 89 GEM-based academic publications in SSCI-listed journals since 2004, with the objectives to highlight the particular advantages of GEM data, their quality and usability, as well as their limitations. It also recommends a number of ways in which the GEM project might evolve further and make more impact on entrepreneurship research, on entrepreneurship policy and practice, and ultimately on getting more grip on the complex relation between entrepreneurship and economic development.


Pleomorphic xanthoastrocytoma (PXA) has rarely been reported in combination with infiltrating glioma, historically interpreted as a "collision tumor." Isocitrate dehydrogenase 1 (IDH1) and BRAF V600E mutations are usually not concurrent. The former is typical of adult infiltrating gliomas, and the latter is identified in a variety of primary central nervous system neoplasms, including PXA, ganglioglioma, pilocytic astrocytoma, and rarely infiltrating gliomas. We report the case of a 56-year-old man presenting with seizures and headaches. Magnetic resonance imaging revealed a large right temporal lobe mass with low T1 and high T2/FLAIR signal and a discrete contrast-enhancing focus. Histologically, the tumor showed 2 distinct components: an infiltrating astrocytoma harboring 5 mitoses/10 high-power fields and a relatively circumscribed focus, resembling PXA with, at most, 2 mitoses/10 high-power fields. No microvascular proliferation or necrosis was present in either component. The infiltrating astrocytoma component contained numerous axons, whereas the PXA-like component had sparse axons, as demonstrated by the neurofilament immunostain. Both components were positive for the mutant IDH1 R132H and showed loss of ATRX expression, whereas BRAF V600E was restricted to the PXA-like component. On sequencing of the 2 components separately after microdissection, both showed identical IDH1 R132H and TP53 R273C point mutations, whereas the BRAF V600E mutation was limited to the PXA-like component. These findings are consistent with clonal expansion of a morphologically distinct focus, harboring a private BRAF V600E mutation within an IDH1-mutant glioma. Intratumoral heterogeneity and clonal evolution, as seems to have occurred here, suggest reevaluation of "collision tumors" as a concept.


In this study we explore the role of explicit metalinguistic knowledge (MLK) of first language (L1) in the learning of a third language (L3). We compare the oral production of 40 participants with varying degrees of explicit MLK of the L1, who are exposed to a completely new L3. In accordance with the second language (L2) status factor, which is further motivated by the distinction between implicit competence and explicit knowledge (Bardel & Falk, 2012; Paradis, 2009), we hypothesize that the participants with low explicit MLK in their L1 will transfer from their L2, and that the participants with high explicit MLK in the L1 will transfer from their L1. The structure of interest is adjective placement, which is the same in the L1 and the L3 (but not in the participants' L2s). The results show that the degree of explicit MLK in the L1 plays a decisive role at the initial state of L3 learning.


Parasitic, infectious and vector-borne diseases of humans and animals thrive in the typically hot and humid environment of the tropics. Many countries in these regions of the world remain underdeveloped with limited resources at their disposal to effectively combat the tremendous disease burdens borne by their human populations. Research, surveillance and control of veterinary diseases have been given priority only when those diseases have an impact on poverty alleviation or if they pose a significant zoonotic threat to the community. In some societies however, in Asia in particular, economic growth and increasing affluence has resulted in changing attitudes towards companion animal ownership and with this has come increasingly higher expectations and demands on veterinary surgeons for improved knowledge in canine and feline medicine and surgery. Yet despite expanding access to information technology, regionally pertinent information for veterinarians concerning the epidemiology, diagnosis and management of tropical diseases of these companion animals is scarce. The paper aims to redress this imbalance by providing, for the first time, a comprehensive review of the parasitic diseases of cats and dogs in the tropics. The first section discusses diseases and parasites of zoonotic importance; echinococcosis, toxocariasis, ancylostomiasis, the liver and intestinal flukes, gnathostomiasis, toxoplasmosis, leishmaniasis and American trypanosomiasis. In the second section the parasitic diseases of clinical importance for the animals themselves are considered, including babesiosis, dirofilariasis, hepatozoonosis, ectoparasitic diseases, angiostrongylosis and spirocercosis, with information provided on the diagnosis and treatment of these diseases.


BACKGROUND OF THE STUDY: Urinary tract infection is the major public health problem in terms of morbidity and financial cost and in cures the highest total health care cost among urological disease. The urinary tract infection is an infection in any part of the urinary system. One of the most common bacterial infections amongst in adolescents and prevalence of infection depends largely on age and gender. Female are most at the risk of urinary tract infection. OBJECTIVE: To assess knowledge and self-reported practices regarding prevention of urinary tract infection. METHOD AND MATERIAL: A quantitative research approach with nonexperimental descriptive study was adopted in this study. The Stratified random sampling technique was used to select the subject for the study. Data collected from 100 subjects were analyzed by descriptive and inferential statistics using SPSS version 22. RESULT: Among the selected subjects 44% of subjects have good knowledge regarding prevention of UTI and 58% of the subjects had a favourable practice regarding prevention of urinary tract infection. CONCLUSION: This study indicates that majority subjects have a good knowledge and less number of subjects have a poor knowledge regarding prevention of urinary tract infection and also majority of the subjects have a favourable practice and no one has unfavourable practice regarding prevention of UTI.


Over the past 30 years, a great deal of research has investigated the potential usefulness of early warning models as offsite supervisory tools. Accurate offsite models allow bank supervisors to identify high-risk banks at a reasonable length of time prior to marked deterioration in their financial condition, without the use of expensive, time-consuming on-site examinations. This allows scarce examination resources to be used more efficiently and permits supervisory constraints to be imposed or rehabilitative strategies put in place expeditiously and so minimize the risk of costly failures. This paper develops a Cox proportional hazard model that is designed to predict the probability that a low-risk community bank will be downgraded to high-risk status over an eight-quarter time horizon. The risk dichotomy is made on the basis of CAMELS composite supervisory ratings with a score of 2 separating the low-and high-risk groups. Models are estimated using independent variables measured at year-end 1997, 1998, and 1999. The out-of-sample forecasting accuracy of the estimated models is examined using data for year-end 2001. In general, the hazard models are found to produce relatively accurate risk classifications out-of-sample. The accuracy of the 1997 specification suggests that these hazard models are relatively stable over time, implying that frequent, costly re-specification is not required. The hazard models are also found to be considerably more accurate than two simpler supervisory screens. Taken together the out-of-sample tests of classification accuracy suggest that this sort of statistical model is a promising, relatively low cost early warning tool. * The opinions expressed here are those of the author and do not necessarily represent those of the OCC or the Treasury. The author would like to thank Mike Carhill, David Nebhut, and Jeffrey Brown for their comments and Amy Millen for editorial assistance.


Introduction: Menopause is one of the stages of life for women that cause a wide variety of symptoms, effects, and sometimes limitations. Therefore this study aims to describe the psychological symptoms of postmenopausal women. Method: This is a qualitative study using phenomenological method on postmenopausal women in the city of Isfahan. The sampling was at first carried out using simple sampling and later using snowball sampling method. The data gathering tool as interviews carried out in the office of obstetricians and gynecologists. Data were classified using colaizzi's seven stage data analysis method. Results: Various psychological symptoms were reported in the interviews which can be summarized as irritability, aggression, fatigue, feelings of helplessness, and uselessness. Conclusion: During the interviews, postmenopausal women mentioned a variety of psychological symptoms that can cause limitations and hardships and require suitable support and follow-up.


This study aimed to elucidate the risk factors of Sleep Disturbances in Depression (SDD) and to determine improvements related to anti-depressant treatment. One-hundred-and-forty-six patients with depression were included. The Simplified Coping Style Questionnaire (SCSQ) was used to determine patients' coping styles, while the Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA) were used to assess depression and anxiety. The Pittsburgh Sleep Quality Index Scale (PSQI) was used to assess sleep quality, and the Beck Scale for Suicide Ideation (BSS) and Suicide Attitude Questionnaire (QSA) were used to observe patients' suicidal tendencies. Except for the SCSQ, all other scales were assessed before and 3 months after anxiolytic therapy, for comparison. Sleep-associated factors were also analysed. In addition to relief from depression and anxiety, the patients' sleep conditions improved and their suicidal tendency declined after antidepressant treatment. Correlation analysis revealed that the risk factors of sleep disturbances included sex, anxiety and depression status, negative coping style, and suicidal tendency. After antidepressant treatment, some of the abovementioned risk factors were corrected and only anxiety and depression status, coping style, and suicidal tendency remained as risk factors. In conclusion, antidepressant treatment can bring about many benefits to patients with depression.


Simple content analysis methods, such as the Bechdel test and measuring percentage of female talk time or characters, have seen a surge of attention from mainstream media and in social media the last couple of years. Underlying assumptions are generally shared with the gender role socialization model and consequently, an importance is stated, due to a high degree to which impressions from media shape in particular young children's identification processes. For young girls, the Disney Princesses franchise (with Frozen included) stands out as the number one player commercially as well as in customer awareness. The vertical lineup of Disney princesses spans from the passive and domestic working Snow White in 1937 to independent and super-power wielding princess Elsa in 2013, which makes the line of films an optimal test subject in evaluating above-mentioned simple content analysis methods. As a control, a meta-study has been conducted on previous academic studies on the same range of films. The sampled research, within fields spanning from qualitative content analysis and semiotics to coded content analysis, all come to the same conclusions regarding the general changes over time in representations of female characters. The objective of this thesis is to answer whether or not there is a correlation between these changes and those indicated by the simple content analysis methods, i.e. whether or not the simple popular methods are in general coherence with the more intricate academic methods.


This paper will explore some of the implications of attending to the performative aspects of language for the sociological understanding of issues of risk and trust among lay communities. Ulrich Beck and Anthony Giddens have alerted us to the way that in late or reflexive modernity trust in authority cannot be taken for granted, but increasingly has to be actively earned and actively invested. For his part, Brian Wynne has pointed out that lay judgements are relational and hermeneutic, including as they do judgements about the behaviour of relevant expert institutions, and about the risk to one's self-identity incurred by being caught up in relationships of dependency. Wynne has also argued that public avowals of trust can often mask deep private distrust, and thus be expressions more of fatalistic acceptance than of genuine trust. However, all of these analyses work from a basic model of 'trust' as being the result of a cognitive process  as a judgement as to the trustworthiness of others. Yet trust is frequently 'active' in an even stronger sense than this. To take a posture of trust towards another can often be best understood not just as a cognitive judgement but as an attempt to bind the 'trusted' into a relationship and attitude of responsibility  and thus perhaps to alter their behaviour  through the taking up of a position in a social ritual. Speech act theory can help us be sensitive to this sort of use of the language of 'trust', by reminding us that language can perform a number of different functions  not just that of describing the world, or of acting out ascribed roles and identities, but also that of trying to change the world. The analysis of public discourse about risk, trust and mistrust must thus be sensitive to the range of things that people might be attempting to do when they are saying things if it is to avoid drawing misleading conclusions about public attitudes to risk.


Sanctions are used ubiquitously to enforce obedience to social norms. However, recent field studies and laboratory experiments have demonstrated that cooperation is sometimes reduced when incentives meant to promote prosocial decisions are added to the environment. Although various explanations for this effect have been suggested, the neural foundations of the effect have not been fully explored. Using a modified trust game, we found that trustees reciprocate relatively less when facing sanction threats, and that the presence of sanctions significantly reduces trustee's brain activities involved in social reward valuation [in the ventromedial prefrontal cortex (VMPFC), lateral orbitofrontal cortex, and amygdala] while it simultaneously increases brain activities in the parietal cortex, which has been implicated in rational decision making. Moreover, we found that neural activity in a trustee's VMPFC area predicts her future level of cooperation under both sanction and no-sanction conditions, and that this predictive activity can be dynamically modulated by the presence of a sanction threat.


Seagrass meadows, such as found in the Little Swanport estuary, Tasmania, Australia, provide a high ecosystem service that typically responds to natural destructive events and nitrogen loading at decadal to inter-decadal scales. Consequently, determining and understanding the effects of anthropogenic impacts, such as the estuary's shellfish aquaculture, requires an ecological time series of sufficient length to develop a long-term predictive theory behind changes to pattern and process and distinguish anthropogenic from natural effects. The aims of this study were to produce the appropriate long-term ecological time series for the Little Swanport estuary by combining sediment core and long term datasets (83 years to 139 years) in a palaeo-reconstruction that includes natural and anthropogenic variability, and to develop a general predictive theory behind pattern and process. The reconstructed time series was designed to include the elements of top down and bottom up control on the reconstructed seagrass–micro-algal assemblage: planktivorous fish predation, copepod feeding, calcareous sessile epifauna, seagrass-mediated nitrogen fixation, and external nutrient supply as the concentration of potential inorganic nitrogen (CPN).
Ecosystem variance in the upper region of the estuary differed from the lower estuary. Within the upper estuary, weight of evidence suggested variability was consistent with decadal periods of seagrass meadow destruction and recovery as two seagrass transient regime states, followed by stable natural and impacted seagrass regime states. The transient regimes appeared to be limited by nitrogen, the natural stable regimes appeared to be limited by light and the impacted regime had a near complete reliance on light mediated nitrogen fixation. The switch between nitrogen and light limiting resources was consistent with a change from a strong to weak top down control by a planktivorous fish–copepod–sestonic–calcareous epifaunal trophic cascade. Comparisons with both temporal and spatial natural patterns and processes indicated the dependence of nitrogen fixation was the result of the lower estuary shellfish aquaculture 'soaking up' the supply of inorganic nitrogen from coastal waters during an extended period of drought.
Within the lower estuary there was no evidence of direct effects of floods, tsunamis or shellfish aquaculture on the long-term pattern and process. Nevertheless, there was an uninterrupted repeatable natural ecosystem periodicity (i.e. a neutral model) of 57.9 years for the seagrass and micro-algal assemblage and a planktivorous fish–copepod–sestonic–calcareous epifaunal trophic cascade with a CPN at twice the biome frequency. The seagrass and micro-algal assemblage was inversely correlated but the trophic cascade was 13 years out of phase, driven by a CPN periodicity at twice the biome frequency in phase with the peaks and troughs of the seagrass and micro-algal assemblage. As a consequence, there was a change from a positive to a negative correlation of the CPN with seagrass abundance that was consistent with a change from seagrass nitrogen to light limitation. This switch was coincident during times of a CPN minimum together with strong and weak top down control respectively. By linking changes in top down control with the evolution of a seagrass meadow's configuration a general theory of seagrass meadow dynamics was developed, constructed, in part, from data and generic postulates taken from other seagrass ecosystems systems.
The theory unified two desperate approaches to seagrass meadow variance, namely light and nutrient limitation, within the framework of landscape ecology and consequently highlighted a number concerns for managers of seagrass ecosystems: (1) the loss of a seagrass meadow by flood damage may produce a seagrass transient regime and not a micro-algal regime, in which recovery of the transient is assisted by a moderate increase and not a reduction in nutrient supply; (3) changes to the extent of the landscape patch configuration can determine the light and nutrient limitation status of the seagrass meadow, consequently, rehabilitation of the seagrass meadow after loss or damage, by replanting or through the control of nutrient supply, may need to take into account the landscape patch configuration of the plantation or the damaged landscape in relation to the dynamics of nutrient supply; (4) the effects on the seagrass meadow from over-harvesting of planktivorous fish fishing or the introduction of piscivorous fish will depend on the light or nutrient limitation status of the seagrass meadows.


Gunter, Barrie (2002). Media Sex: What Are the Issues? Mahwah, NJ: Lawrence Erlbaum. pp. 350. Reichert, Tom and Jacqueline Lambiase, eds. (2003). Sex in Advertising: Perspectives on the Erotic Appeal. Mahwah, NJ: Lawrence Erlbaum. pp. 294. Media scholars have been writing extensively about sex in the media for decades. Many of the studies have focused on the kinds of sexual portrayals (Kunkel, Cope-Farrar, Biely, Farinola & Donnerstein, 2001). In addition, much of the concern surrounding these media images has been pointed toward advertising (Soley & Kruzbard, 1986; Ferguson, Kreshel, & Tinkham, 1990, for example). Given the plethora of research done already, it's logical to ask whether we really need two more books on sex in the media. After reviewing Gunter's Media Sex: What Are the Issues? and Reichert and Lambiase's Sex in Advertising: Perspectives on the Erotic Appeal, I'm ready to offer a resounding yes-and maybe. Throughout the majority of Media Sex: What Are the Issues?, Gunter explores a lot of important topics such as risky portrayals in the media, stereotypes, policy issues, etc. Although this is not new information, Gunter has categorized all of the major (and some minor) research on media sex and written about the studies in such a way that a graduate student could pick up this volume with very little initial understanding and walk away after reading it cover to cover finding himself not only well versed in media sex studies, but also having a handle on media theory and methodology. If I were teaching a graduate seminar in this area, I would choose this book. It offers a wealth of information. (For starters, the thirty-five pages of references would be a boon to anyone doing a literary search for a research paper.) It may be too dense for just one semester, but it ought to prove itself worthy over time for anyone conducting research on sexuality in the media. The book is not without its flaws. First, it doesn't have any pictures. This strikes me as odd, and not just because a book about sexual images seems like it ought to offer a least a few tantalizing pictures. Gunter's book is obviously an academic approach to the field-and rightly so. However, its sterile approach (starting with the lack of pictures, but also with the unemotional, somewhat remote writing) seems incongruous given some of the topics. For example, in Chapter 5, Degrading to women? Gunter reports on not one, but three, content analysis studies of slasher movies. It's fair to question whether "slasher movies" are mainstream enough for the detail reported in a book of this caliber. Gunter also reports on some studies that have examined x-rated and xxx-rated videos and other pornographic material. When Gunter writes about these topics, he does so with the same tone as when he writes about health risks and personal hygiene. The ultimate effect of this nonjudgmental approach is that all of the information presented in the book seems equally important. While this may have been the author's intent, it might have been helpful to have a wrap-up chapter that puts some of the topics into perspective. If Gunter's book is a hands-off, analytic, sterile report of media sex studies, than Reichert and Lambiase's book, Sex in Advertising: Perspectives on the Erotic Appeal is a roller coaster, rollicking ride of advertising sex studies. For one thing, it has pictures! The historical pictures are particularly helpful as they put into perspective the "it's in the eye of the beholder" approach to sex in advertising. However, one reason Reichert and Lambiase's book has highs and lows is because of the dizzying number of different approaches to advertising studies presented in the book. …


In a 1975 study conducted by the Centers for Disease Control, Department of Health, Education, and Welfare, 38.9 percent of the nurses surveyed were smokers--a substantially higher percentage than among women in the general U.S. population and higher than among other groups of health professionals. In a 1981 study of a 3-percent random sample of Connecticut nurses, only 25.5 percent of the nurses reported that they smoked. There are limitations to comparisons of the two studies. The 1975 sample was a national population, and the Connecticut study was limited to nurses in one State and may not reflect the habits and attitudes of this occupational group throughout the country. In the more recent study, however, there appear to be several differences in nurses' smoking habits. A trend toward a decrease in smoking seems to be emerging among nurses. The percentage of smokers among the Connecticut nurses resembles the prevalence in two other recent surveys: 25.8 percent in the American Cancer Society, Rhode Island Division study, and 23.6 percent in the University of Michigan Hospital survey. In the U.S. female population, 29.4 percent of the women are smokers. The percentage of former smokers in both the U.S. and this Connecticut population seems to be rising, and there appears to be a trend toward increasingly larger percentages of former smokers in each successive age group. Smoking more (25 or more cigarettes per day) was reported by 28 percent of the Connecticut nurses compared with 16 percent in the earlier study. Compared with the 1975 sample, significantly fewer Connecticut nurses who smoked agreed that a nurse should set a good example by not smoking and that most cigarette smokers can stop if they want to.


Like the law we teach our students, legal education itself isn't neutral. It is the product of both structural forces and individual decisions. Hierarchy and structural inequality permeate our society, so of course they permeate the institutions within our society, including law schools. But law schools are not only passive recipients of these permeating atoms of injustice. They have some agency in determining which inequities to nurture (or not) in the learning environment. As it stands, though, the environment that students learn the law in can be an incubator of inequality.

Students can feel these inequities affecting their legal education, even when they can't yet see them. These inequities had gradually become visible to us, during our time in legal academia. And we wanted our first-year students to be able to see them as well—to know what to call them, where they are reinforced, and how they affect the way law students learn to be lawyers. We hoped to foster understanding about the experiences and challenges different students have while attending the same institution and to practice talking explicitly about how different the law school environment can be for different people within it. Our students wanted to understand why individual professors, including us, couldn't fix the problems they called attention to. Ultimately, we wanted students to learn at least some invisible rules of "how law school works" in their first year so that they could better navigate the system and more effectively advocate for themselves and for change while they were still in school.

This essay describes the asynchronous unit we created in spring 2021 called "How Law School Works" and reflects on the experience.


The Lille metropolitan area awarded Veolia Water the contract to reconstruct the Marquette-lez-Lille wastewater treatment plant (WWTP) in 2010, the biggest such facility in the north of France. The capacity of the new WWTP is 700,000 m³/day, serving a population of 620,000. It will be built on the site of the previous one, which is now obsolete.

The renovation work comprises four treatment lines, including wastewater, stormwater sludge treatment lines, and a deodorization line. By applying state-of-the-art design and proven technologies, especially Hybas™ and Exelys™-DLD, a sustainable development solution was provided to local communities.

The effluent from the new plant will meet the requirements of the European Water Framework Directive (Directive 2000/60/EC) on 'good ecological status' of water, and the treated storm water will be used to irrigate 7 hectares wetland. Compared with conventional digestion, the Exelys™-DLD configuration will further reduce sludge quantities by 30% and increase biogas production by 20%. Thereby, 94% of the power requirements will be supplied from the plant itself.

The water line started operating in February 2013, and commissioning of the sludge line, which started in July 2014, was expected to finish in February 2015. In this paper, the design concept of the sustainable development solution is presented, as well as the application of showcase technologies for wastewater and sludge treatment.


A household icon of the environmental movement, Aldo Leopold (1887-1948) may be the most quoted conservationist in history. "A Sand County Almanac" has sold millions of copies and Leopold's writings are venerated for their perceptions about land and how people might live in concert with the whole community of life. But who is the man behind the words? How did he arrive at his profound and poetic insights, inspiring generations of environmentalists? Building on past scholarship and a fresh study of Leopold's unpublished archival materials, Julianne Lutz Newton retraces the intellectual journey generated by such passion and intelligence. "Aldo Leopold's Odyssey" illuminates his lifelong quest for answers to a fundamental issue: how can people live prosperously on the land and keep it healthy, too? Leopold's journey took him from Iowa to Yale to the Southwest to Wisconsin, with fascinating stops along the way to probe the causes of early land settlement failures, contribute to the emerging science of ecology, and craft a new vision for land use. More than a biography, this articulate volume is a guide to one man's intellectual growth and an inspirational resource for anyone pondering the relationships between people and the land.


Acute multiple sclerosis lesions are characterized by accumulation of T cells and macrophages, destruction of myelin and oligodendrocytes, and axonal damage. There is, however, limited information on neuroimmune interactions distal to sites of axonal damage in the Tcell-infiltrated central nervous system. We investigated T-cell infiltration, myelin clearance, microglial activation, and phagocytic activity distal to sites of axonal transection through analysis of the perforant pathway deafferented dentate gyrus in SJL mice that had received T cells specific for myelin basic protein (TMBP) or ovalbumin (TOVA). The axonal lesion of TMBP-recipient mice resulted in lesion-specific recruitment of large numbers of T cells in contrast to very limited T-cell infiltration in TOVA-recipient and -naïve perforant pathway-deafferented mice. By double immunofluorescence and confocal microscopy, infiltration with TMBP but not TOVA enhanced the microglial response to axonal transection and microglial phagocytosis of myelin debris associated with the degenerating axons. Because myelin antigen-specific immune responses may provoke protective immunity, increased phagocytosis of myelin debris might enhance regeneration after a neural antigen-specific T cell-mediated immune response in multiple sclerosis.


'Commercial oil deposits in basement rocks are not geological "accidents" but are oil accumulations which obey all the rules of oil sourcing, migration and entrapment; therefore in areas of not too deep basement, oil deposits within basement rocks should be explored with the same professional skill and zeal as ccumulations in the overlying sediments', Landes et al. (1960), AAPG Bulletin. Given that most OPEC countries are currently at or within 5% Production capacity, there is a growing need to look for 'new oil' and other hydrocarbons in non-traditional sources. While oil and gas fields in crystalline basement are still discovered mostly by accident, as shown in this book, such reservoirs can be very prolific, especially if the basement rock is highly faulted or fractured. The chapters in this volume cover a diverse range of topics related broadly to the theme of hydrocarbons in crystalline rocks, and challenge explorationists' definition of basement rock, which needs to be less narrow and more responsive to new geological ideas.


Comprehensive identification and cataloging of copy number variations (CNVs) is required to provide a complete view of human genetic variation. The resolution of CNV detection in previous experimental designs has been limited to tens or hundreds of kilobases. Here we present PennCNV, a hidden Markov model (HMM) based approach, for kilobase-resolution detection of CNVs from Illumina high-density SNP genotyping data. This algorithm incorporates multiple sources of information, including total signal intensity and allelic intensity ratio at each SNP marker, the distance between neighboring SNPs, the allele frequency of SNPs, and the pedigree information where available. We applied PennCNV to genotyping data generated for 112 HapMap individuals; on average, we detected approximately 27 CNVs for each individual with a median size of approximately 12 kb. Excluding common rearrangements in lymphoblastoid cell lines, the fraction of CNVs in offspring not detected in parents (CNV-NDPs) was 3.3%. Our results demonstrate the feasibility of whole-genome fine-mapping of CNVs via high-density SNP genotyping.


The human specific pathogen Neisseria meningitidis is a major cause of bacterial sepsis and meningitis. Effective vaccines have been developed against group A and C strains, but as yet there is no suitable vaccine available for group B N. meningitidis. The activation of Dendritic Cells (DCs) is fundamental to the initiation of an immune response. Microorganisms and microbial products induce DC maturation, including expression of co-stimulatory molecules, HLA molecules, chemokine receptors and cytokines. Maturation and migration of DCs to secondary lymphoid organs is required for the optimal induction of T-lymphocyte responses. This study investigated the importance of lipopolysaccharide (LPS) in the human pathogen N. meningitidis for DC maturation, migration and activation of T cells. DCs activated with wild type N. meningitidis increased expression of co-stimulatory molecules and HLA-DR, and produced high levels of cytokines (TNFalpha and IL-12). Expression of the chemokine receptor CCR7 was increased and DCs migrated in response to the chemokine MIPS? and showed enhanced migration through an endothelial monolayer. In co-culture experiments, T cell proliferation was enhanced by DCs that had been activated with wild type bacteria. In addition, T cell IFNgamma production was increased and IL-4/IL-13 decreased compared to controls, this is consistent with Thl differentiation. In contrast, although DCs activated by the LPS deficient isogenic mutant IpxA- increased expression of co-stimulatory molecules and HLA-DR, they produced less cytokines (TNFalpha and IL-1) than DCs stimulated with wild type bacteria and little or no IL-12. In addition, they did not increase expression of CCR7 or migrate in the presence of MIP3. DCs stimulated with IpxA- were able to activate T cells to proliferate but did not induce Thl differentiation. TLR4 has been shown to be important for responses to LPS but the Asp299Gly polymorphism described in humans was found not to affect monocyte responses to wild type N. meningitidis. These findings have important implications for vaccine design to group B N. meningitidis and suggest that in vitro responses to DCs may be used as a surrogate for in vivo immunisation experiments to test vaccine efficacy.


Dopamine (DA) is an important neurotransmitter for multiple brain functions, and dysfunctions of the dopaminergic system are implicated in neurological and neuropsychiatric disorders. Although the dopaminergic system has been studied at multiple levels, an integrated and efficient computational model that bridges from molecular to neuronal circuit level is still lacking. In this study, the authors aim to develop a realistic yet efficient computational model of a dopaminergic pre-synaptic terminal. They first systematically perturb the variables/substrates of an established computational model of DA synthesis, release and uptake, and based on their relative dynamical timescales and steady-state changes, approximate and reduce the model into two versions: one for simulating hourly timescale, and another for millisecond timescale. They show that the original and reduced models exhibit rather similar steady and perturbed states, whereas the reduced models are more computationally efficient and illuminate the underlying key mechanisms. They then incorporate the reduced fast model into a spiking neuronal model that can realistically simulate the spiking behaviour of dopaminergic neurons. In addition, they successfully include autoreceptor-mediated inhibitory current explicitly in the neuronal model. This integrated computational model provides the first step toward an efficient computational platform for realistic multiscale simulation of dopaminergic systems in in silico neuropharmacology.