High consumption of fruit-, vegetable-, and plant-based beverages has been associated with a reduced incidence and mortality of various chronic diseases including cancer. A wide variety of phytochemicals contribute to these chemopreventive effects. The largest group of phytochemicals belongs to the family of flavonoids, which all share the common polyphenol structure. Considerable effort has been made to quantitate the dietary intake and main food sources of flavonoids. In the U.S., based on the USDA flavonoid database and NHANES 1999-2002 24-h dietary recall data, the average daily intake of flavonoids is 189.7 mg/d. The main daily mean food sources of flavonoids were tea (157 mg), citrus fruit juices (8 mg), wine (4 mg), and citrus fruit (3 mg) (1). In Spain, the mean flavonoid intake was 313 mg/d with the main sources being apples (23%), red wine (21%), unspecified fruit (12.8%), and oranges (9.3%) (2). Tea polyphenols are consumed in such high quantity due to the popularity of tea worldwide and the high concentration of polyphenols per cup of tea (150 mg). Tea leaves from the plant Camellia sinensis are manufactured in nonfermented form as green tea or fermented form as black tea. Green tea contains the gallated polyphenols (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin-3-gallate (ECG) as well as non-gallated (-)-epigallocatechin (EGC) and (-)-epicatechin (EC). During fermentation to black tea these green tea polyphenols (GTP) undergo polymerization to theaflavin and thearubigin. Other examples of large polymeric polyphenols are ellagitannins from pomegranate and procyanidins from grape seed extract and cocoa. Daily pomegranate juice consumption has been shown to decrease the rate of rise of PSA in men treated for prostate cancer increasing the PSA doubling time from 15 to 54 weeks. We have conducted extensive studies of the bioavailability, metabolism by colonic microflora, and conjugation after absorption of polyphenols. For example, pomegranate ellagitannins are converted to gallagic acid (GA), ellagic acid (EA), urolithin A (UA) and B (UB), and tea polyphenols to phenolic acids, such as 3,4-dihydroxyphenyl acetic acid (3,4DHPAA) (3). These products can be found in the blood and urine and have biological activity. During the absorption process and in the tissues polyphenols and their metabolites are glucuronidated, sulfated and methylated. Interestingly, there are strong interindividual differences observed in the plasma and urine content of metabolites most likely due to differences in microbial composition, polymorphisms in metabolizing enzymes and transport proteins. Epidemiological studies show conflicting evidence of the chemopreventive effect of green tea. However, for prostate cancer, one randomized controlled trial (RCT) from Italy suggested that the consumption of GTP supplement inhibited the progression of premalignant lesions to prostate cancer and furthermore, that green tea catechins might positively influence quality-of-life issues in patients with high-grade prostate intraepithelial neoplasia. Another intervention study in the U.S. demonstrated a decrease in serum prostate-specific antigen, hepatocyte growth factor, and vascular endothelial growth factor after the consumption of 800 mg of EGCG for an average of 6 weeks. In an ongoing randomized pre-prostatectomy trial at UCLA we determined the concentration of GTPs and metabolites in prostate and urine of participants consuming 6 cups of green tea for 3-6 weeks. In the prostate only gallated tea polyphenols such as EGCG, 4″-O-MeEGCG and ECG were found with more than 50% in the nonconjugated free form. In urine the nongallated forms such as EGC, 4′-O-MeEGC and EC were found (3). The ratio of methylated EGCG to nonmethylated EGCG varies considerably among participants. Catechol-O-methyl transferase (COMT), the enzyme responsible for methylation of EGCG and other catechols, has three polymorphic sites. On codon 158 (exon 4) the G->A transition leading to Val->Met amino acid change is associated with a four time lower enzyme activity compare to wild type. An epidemiological cohort study by Wu et al. demonstrated that breast cancer risk reduction was only associated with green tea intake in women with at least one low-activity allele in COMT (4). However, in addition to the influence of the single nucleotide polymorphism on COMT activity, EGCG itself inhibits COMT activity. We demonstrated in PC3 prostate cancer cells that EGCG inhibited COMT enzyme activity significantly. The same effect was observed in vivo in severe combined immunodeficiency mice (SCID) implanted subcutaneously with LAPC4 prostate cancer cells. The administration of brewed green tea, instead of drinking water, lead to a decrease in tumor growth and COMT m-RNA expression. Methylation and conjugation may also alter the biologic activities of the parent compound. For example, our cell culture experiments demonstrated differences in the antiproliferative activity, anti-inflammatory activity (NFkB stimulation), and stimulation of apoptosis of methylated EGCG compared to the parent compound in androgen dependent (LNCaP) and androgen independent (PC-3) prostate cancer cells. In the case of EGCG, methylation leads to a significant decrease of biological activity. However, in case of quercetin, there was no significant difference in the antiproliferative activity between methylated quercetin and the parent compound. Since quercetin is known as a strong natural methylation inhibitor we tested the effect of co-treatment of EGCG and quercetin on EGCG methylation and bioavailability. In cell culture experiments combining EGCG with quercetin decreased EGCG methylation and increased intracellular EGCG 10-fold. These results demonstrate that combination of polyphenols with differential effects on metabolism may be useful to enhance bioavailability and bioactivity. In summary, in vitro mechanistic investigations with translational potential, will need to be performed with the appropriate metabolites and concentrations found in vivo. References: 1. Chun OK, Chung SJ, Song WO. Estimated dietary flavonoid intake and major food sources of U.S. adults. J Nutr. 2007, 137(5):1244-52. 2. Zamora-Ros R, Andres-Lacueva C, Lamuela-Raventos RM, Berenguer T, Jakszyn P, Barricarte A, Ardanaz E, Amiano P, Dorronsoro M, Larranaga N, Martinez C, Sanchez MJ, Navarro C, Chirlaque MD, Tormo MJ, Quiros JR, Gonzalez CA. Estimation of dietary sources and flavonoid intake in a Spanish adult population (EPIC-Spain). J Am Diet Assoc. 2010, 110(3):390-8. 3. Wang P,Aronson WJ, Huang M, Heber D, Henning SM. Methyl-Metabolites of Green Tea Polyphenols and Their Bioactivity in Prostate — Results of a Phase II Clinical Trial in Men with Prostate Cancer. Cancer Prev. Res. 2010, 3(8):985-93. 4. Wu AH, Tseng CC, Van Den Berg D, Yu MC. Tea intake, COMT genotype, and breast cancer in Asian-American women. Cancer Res. 2003, 63(21):7526-9. Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN06-03.


The European Union (EU) Horizon 2020 Coordination and Support Action ESMERALDA aimed at developing guidance and a flexible methodology for Mapping and Assessment of Ecosystems and their Services (MAES) to support the EU member states in the implementation of the EU Biodiversity Strategy's Target 2 Action 5. ESMERALDA's key tasks included network creation, stakeholder engagement, enhancing ecosystem services mapping and assessment methods across various spatial scales and value domains, work in case studies and support of EU member states in MAES implementation. Thus ESMERALDA aimed at integrating various project outcomes around four major strands: i) Networking, ii) Policy, iii) Research and iv) Application. The objective was to provide guidance for integrated ecosystem service mapping and assessment that can be used for sustainable decision-making in policy, business, society, practice and science at EU, national and regional levels. This article presents the overall ESMERALDA approach of integrating the above-mentioned project components and outcomes and provides an overview of how the enhanced methods were applied and how they can be used to support MAES implementation in the EU member states. Experiences with implementing such a large pan-European Coordination and Support Action in the context of EU policy are discussed and recommendations for future actions are given.


This paper proposes a framework that enables P2P users to trade for mutual benefit. The transaction system is based on the concept of so-called institutional facts to socially present accounts of finances as well as to govern the transaction. Set of protocols are developed as implementation of the transaction concept which utilizes distributed cryptography to achieve mutual authentication. Finally, an architecture of trading network is proposed. It is built as overlay network which utilizes existing P2P network for searching and delivery infrastructure.


This research aims to identify secondary metabolite compounds in Talas kemumu leaf stalk (Colocasia gigantea Hook.f) and to determine the effect of extract on the number of male Mus musculus leukocytes that have been induced aspirin. Aspirin is used to increase the number of M.musculus leucocytes.The method used in this research is the method of extraction by maceration to attract secondary metabolites of active compounds C.gigantea leaf stalk and the measurement of blood leukocyte counts are calculated using a hemocytometer (improved neubauer). Test of the effect of the leaf stalk of C.giganteaextract on the number leukocytes of M.musculus was performed by dividing into 5 groups with 5 replications according to the Federer formula, namely K (-) were given distilled water, K (+) were given aspirin, P1, P2 and P3 are each given a dose of extract of C.gigantea leaf stalk of 0,028 g/KgBB, 0,056 g/KgBB and 0,084 g/KgBB. The results showed that the identification of phytochemical profile in C.gigantea leaf stalk contains secondary metabolite compounds such as alkaloids, flavonoids, terpenoids, tannins and saponins. The results shows that giving of C.gigantea leaf stalk extract can reduce the number of leukocytes M.musculus which have induced aspirin. The giving of C.gigantea leaf stalk extract can decrease the number of aspirin-induced M.musculus leukocytes. This is evident from the results of One Way Anova analysis and the Smallest Real Difference Test (BNT) because in each treatment group has a significant influence. The effective dose that has the greatest activity in decreasing the number of M.musculus leukocytes found in the P1 treatment of 0,028 g /KgBB can decrease the blood leukocyte count by 6,830 / mm 3 .


BACKGROUND AND PURPOSE
The arctic and sub-arctic waters of Alaska provide a very hazardous work setting, with special hazards posed by great distances, seasonal darkness, cold waters, high winds, brief fishing seasons, and icing. Our intent is to reduce the remarkably high occupational fatality rate (200/100,000/year in 1991-1992) among Alaska's commercial fishing workers. Over 90% of these deaths have been due to drowning or drowning plus hypothermia, primarily associated with vessel capsizings and sinkings.

METHODS
Comprehensive surveillance for commercial fishing occupational fatalities was established during 1991 in Alaska. During 1990 through 1994, the U.S. Commercial Fishing Industry Vessel Safety Act of 1988 required the implementation of comprehensive prevention measures for all fishing vessels in offshore cold waters, including immersion suits and other personal flotation devices, survival craft (life rafts), emergency position-indicating radio beacons, and crew training in emergency response and first aid. Parallel to this, voluntary training efforts by nonprofit organizations have greatly increased.

RESULTS
During 1990-1994, drowning was the leading cause of occupational death in Alaska. During this period, 117 fishers died, 101 of them from drowning or drowning/hypothermia. During 1991-1994, there was a substantial decrease in Alaskan commercial fishing-related deaths, from 34 in 1991 to 35 in 1992, 22 in 1993, and 10 in 1994. While man-overboard drownings and some other categories of deaths (falls, fires) have continued to occur, the most marked progress has been in vessel-related events.

CONCLUSION
Specific measures tailored to prevent drowning in vessel capsizings and sinkings in Alaska's commercial fishing industry have been very successful so far. Additional efforts must be made to reduce the frequency of vessel events and to prevent man-overboard events and drownings associated with them.


This paper features an application of the Hafner and Herwartz (2006) approach to the analysis of multivariate GARCH models using volatility impulse response analysis. The data set used features ten years of daily return series for the New York Stock Exchange Index and the FTSE 100 index from the London stock Exchange, taken from 3rd January 2005 to January 31st 2015. This period captures both the Global Financial Crisis (GFC) and the subsequent European Sovereign Debt Crisis (ESDC). The attraction of the Hafner and Kerwartz (2006) approach is that it involves a novel application of the concept of impulse response functions, tracing the effects of independent shocks on volatility through time, whilst avoiding typical orthogonalization and ordering problems. Volatility impulse response functions (VIRF) provide information about the impact of independent shocks on volatility. Hafner and Herwartz's (2006) VIRF extends a framework, provided by Koop et al. (1996), for the analysis of impulse responses. This approach is novel because it explores the effects of shocks to the conditional variance, as opposed to the conditional mean. Hafner and Herwartz (2006) utilise the fact that GARCH models can be viewed as being linear in squares, and that multivariate GARCH models are known to have a VARMA representation with non-Gaussian errors. They use this particular structure to calculate conditional expectations of volatility analytically in their VIRF analysis. Hafner and Herwartz (2006) use a Jordan decomposition of St in order to obtain independent and identically defined (hence i.i.d.) innovations. One general issue in the approach is the choice of baseline volatilities. Hafner and Herwartz (2006) define VIRF as the expectation of volatility conditional on an initial shock and on history, minus the baseline expectation that only conditions on history. This makes the process endogenous, but the choice of the baseline shock within the data set still obviously makes a difference. We explore the impact of three different shocks, the first marks the onset of the GFC, which we date as 9th August 2007, (GFC1). This began with the seizure in the banking system precipitated by BNP Paribas announcing that it was ceasing activity in three hedge funds that specialised in US mortgage debt. It took a year for the financial crisis to come to a head, but it did so on 15th September 2008, when the US government allowed the investment bank Lehman Brothers to go bankrupt (GFC2). Our third shock point is May 9th 2010, which marked the point at which the focus of concern switched from the private sector to the public sector. A further contribution of this paper is the inclusion of leverage, or asymmetric effects, after Engle and Ng (1993). Our modelling is undertaken in the context of a multivariate GARCH model featuring pre-whitened return series, which are then analysed via a BEKK model using a t-distribution. A key result is that the impact of negative shocks is larger, in terms of the effects on variances and covariances, but shorter in duration, in this case a difference between three and six months, in the context of our particular return series. An effect previously reported by Tauchen et al., (1996), who use a different theoretical set up.


We investigated the effect of duloxetine, a norepinephrine (NE) and serotonin (5-HT) reuptake inhibitor, on the neurally evoked urethral continence reflex induced by sneezing in rats. To clarify the role of noradrenergic and serotonergic mechanisms in preventing stress urinary incontinence (SUI) during sneezing, we examined the effect of duloxetine followed by intrathecal (it) methiothepin maleate (5-HT receptor and alpha1-adrenoceptor antagonist) or terazosin or idazoxan (selective alpha1- and alpha2-adrenoceptor antagonists, respectively). Amplitude of urethral pressure responses during sneezing (A-URS), urethral baseline pressure (UBP) at the midurethra, and sneeze-induced leak point pressure (S-LPP) were measured in normal adult female rats and rats with SUI induced by vaginal distension (VD). In normal and VD rats, intravenous application of duloxetine (1 mg/kg) increased A-URS by 35% and 34% and UBP by 21% and 34%, respectively. Sneezing-induced fluid leakage from the urethral orifice was observed in VD rats but not in normal rats. S-LPP was increased from 39.1 to 92.2 cmH2O by intravenous duloxetine in incontinent VD rats. Duloxetine-mediated enhancement of A-URS was inhibited by terazosin but not methiothepin maleate (it). In addition, simultaneous intrathecal application of methiothepin and terazosin induced a reduction in A-URS during sneezing, which was not increased by intravenous duloxetine. However, the reduced A-URS after intrathecal application of methiothepin and terazosin returned to the control level when duloxetine (iv) was applied after intrathecal idazoxan administration. These results indicate that duloxetine can prevent SUI by facilitating noradrenergic and serotonergic systems in the spinal cord to enhance the sneeze-induced active urethral closure mechanism.


OBJECTIVE
To evaluate the effect and safety of Chinese medicine Compound Shenhua Tablet (SHT) on IgA nephropathy patients of TCM Qi-yin deficiency syndrome type, by using angiotensin-converting enzyme inhibitors (ACEI) fosinopril as the positive control.

METHODS
Adopting prospective, multicentered, double-blinded, double-dummy, randomized, controlled trial design, 131 patients with IgA nephropathy of Qi-yin deficiency syndrome type were assigned to two groups, the 65 patients in the treated group (SHG) and the 66 in the control group treated with SHT and fosinopril respectively for 12 weeks. The indexes of efficacy, including TCM syndrome scores, urinary protein, serum creatinine, urea nitrogen and endogenous creatinine clearance rate, as well as the indexes of safety, including liver function and occurrence of adverse events were observed.

RESULTS
There was no significant statistical difference between the two groups in aspects of baseline demographic characteristics and clinical figures, including gross hematuria, hypertension, incidence of renal insufficiency, total course of disease, urinary protein, TCM syndrome score, renal pathological Katafuchi score, glomerular score, tubular-interstitial score, vascular score and Lee grading. Afte 12 weeks of treatment, the content of 24-h urinary protein significantly decreased by 0.26 +/- 0.95 g/24 h and 0.26 + 0.92 g/24 h respectively in the two groups, showing significant difference in comparing with baseline, but insignificant difference between the two groups (P > 0.05); the scores of TCM dominant syndromes in them decreased by 2.52 +/- 2.34 scores and 1.74 +/- 2.12 scores respectively with significant difference as compared with baseline (P < 0.01), and in comparison between groups (P < 0.05). No significant change in levels of serum creatinine, urea nitrogen, endogenous creatinine clearance rate in both groups was found (P > 0.05). Scores of TCM accompanied syndromes in the two groups was significantly decreased (P < 0.01), but the difference between them was insignificant (P > 0.05). No severe adverse event occurred during treatment, and the occurrence in the two groups was similar.

CONCLUSION
SHT, just like the positive control medicine fosinopril, can effectively decrease the proteinuria and improve clinical syndrome of IgA nephropathy patients of Qi-yin deficiency syndrome type, and shows no serious adverse reaction.


Legal frameworks, and how they interact, are often invisible in the day to day. Yet they are powerful forces that influence government actions and that help to shape who benefits and who loses from foreign investment. Understanding these legal frameworks, and how they interact, is critical for anyone concerned with how foreign investment can be better harnessed to support, rather than weaken, sustainable development and human rights.

This primer provides a brief overview of host government obligations under international investment law, international human rights law, domestic law, and relevant investor-state contracts. It also highlights some of the ways in which those legal obligations may affect or conflict with each other.


: Echocardiography is a valuable and widespread clinical and research tool. The normal parameters and formulae for adults are widely dispersed throughout the medical literature. The purpose of this paper is to present, in a single source, the already acquired normal values and formulae used in the field.


Lightweight tent structures are allowed under European codes to be designed for reduced snow load if the interior of a tent is appropriately heated. The dependence of the resultant snow load on snowfall rate is considered in this paper for such cases. A simple thermodynamic model of the heat flux is derived. Numerical simulation reveals the occurrence of a precipitation rate threshold value above which safety measure provided by heating becomes ineffective.


COVID-19 is affecting many people throughout the world. With its rapid spread, SARS-CoV-2 is highly transmissible1. It has been suggested that an effective way of preventing transmission of the disease, is using masks. In the search of history behind the use of masks and one of the most ancient evidences of using this mouth and nose veil, we are led to more than 2500 years ago and its use by Zoroastrian clergymen living in Achaemenid era (700 to 330 BC; one of the most significant Ancient Persian empires)2. The territory of this Persian empire was very vast from Greece to India and from Libya to contemporary Afghanistan3. Zoroastrianism is one of the world's most ancient religions and used to be the prominent religion in ancient Persia. Persepolis is a royal palace complex remaining from Achaemenid era in Iran, Shiraz. There are different engravings and carvings on the stones which illustrate gift-bearers of different nations dedicating presents to the king. Among some of these reliefs, there are figures of some religious clergymen partly covering their face. One of the oldest carvings of Zoroastrian clergyman (Magi/Mobeds) that shows they covered their nose and mouth, dates back to 520-330 BC (Achaemenid era), and is kept in Istanbul Archaeological Museum now (carved on a relief in Daskyleion, a town in Turkey). It is a carving that illustrates the use of mouth and nose veil by two Zoroastrian clergymen while sacrificing a sheep and a bull in a religious ceremony (figure 1A). This usage of mouth and nose cover is still alive these days, and Zoroastrian clergymen always wear a piece of white cloth over their mouth and nose when they tend the fire or perform some specific ceremonies (figure 1B). This is done in order to prevent their breath or saliva droplets reaching and polluting the holy fire and other ritual implements4. Looking at Zoroastrians' sacred book, Avesta, we see that the word Panām (Paiti-dāna in Avestan language) is mentioned as the name of this mouth and nose cloth veil. Avestan language dates back to about 600 BC5. To put in a nutshell, the ritual of wearing Panām has existed among Zoroastrian clergymen since at least 2600 years ago and is still applied today. This may be an example of one of the most ancient applications of medical mask. So, the first use of masks was probably not medical purposes.


Abstract Introduction: Pseudomyxoma peritonei (PMP) is a rare condition caused by mucinous adenocarcinoma cancerous cells that produce abundance of mucin or gelatinous ascites. This cancer can cause tissue fibrosis and can impair normal organ function. Diagnosis can involve multiple imaging modalities including CT scan. There have been few cases of endoscopic ultrasound (EUS) being used as a means for diagnosis of this condition. Here we report a second case of PMP with a previous history of appendectomy diagnosed with EUS guided fine needle aspiration (FNA) biopsy. Case study: A 66-year-old male with a history of an appendectomy presented with intermittent abdominal pain for two years and weight loss of 40 pounds over two months. EGD and colonoscopy performed at an outside hospital was unremarkable. CT abdomen revealed perigastric ascities and lesions of the liver. ESR was elevated at 75. At our facility, EUS was performed revealing a peri-gastric and omental mass measuring 36.6 mm × 25.5 mm. FNA performed of both mass and ascetic fluid revealed low grade mucinous adenocarcinoma with mucinous deposits in the peritoneum consistent with PMP. Conclusions: Endoscopic ultrasound guided FNA, although very rarely used, can be a reliable and safe technique in diagnosis of PMP.


OBJECTIVE
To conduct preclinical studies and phase I trial of the recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF).

METHODS
Pharmacodynamics, pharmacokinetic and toxicology of the rhGM-CSF were studied in animal models, and the safety was also evaluated in humans.

RESULTS
The human bone marrow cells could be stimulated by purified rhGM-CSF to form multilineage colonies (CFU-GM and BFU-E). The rhGM-CSF administered for 7 days to Beagle dogs and monkeys subjected to 60Co r-ray irradiation was shown to induce both rapid and sustained increase in circulating leukocyte counts. Toxicology testing showed that the LD50 (i.v) was over 5000 micrograms/kg, and LD50 (i.p) over 10000 micrograms/kg in mice. Administration of the rhGM-CSF in excess of four times as much as clinical dosages was not associated with severe chronic toxicities. Most injected rhGM-CSF was excreted from urine, and did not accumulate in the body. In the phase I clinical trial, injecting 2.5-7.5 micrograms/day of rhGM-CSF was safe.

CONCLUSION
It is effective and safe to use rhGM-CSF in the treatment of leukocytopenia.


The high biomechanical loads in molar region wounds challenge the indication for short implants to be used as a single-unit implant. This study reports on the outcomes of single-unit short implants (≤ 8.0 mm) in the maxillary and mandibular molar regions. Forty-nine short implants were placed in 48 patients to replace a missing molar tooth. Two-piece restorations with screw retention were fabricated. During the follow-up, implant survival and marginal bone loss (MBL) were assessed. The known implant length was used as a reference to calibrate the linear measurements on digital periapical radiographs, and descriptive statistical analysis was performed. The implants were followed over a period of 47 ± 12 months. No implant failure was recorded, and no prosthesis failure was observed. The average MBL was 0.15 ± 0.5 mm. The mean crown height space was 13 ± 3 mm. The overall crown-to-implant ratio was 1.7 ± 0.4. Two technical complications occurred due to the loosening of the unit abutment. After screw re-tightening, no more screw loosening was observed. This study supports the use of short implants as a single-unit implant in the maxillary and mandibular molar regions.


Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA

GLG-302 (S3I-201, NSC 74859) from the National Cancer nstitute chemical libraries was identified as a STAT3 antagonist using structure-based virtual screening with a computer model of the Stat3 SH2 domain bound to its Stat3 phosphotyrosine peptide derived from the x-ray crystal structure of the Stat3 homodimer. In addition to preclinical therapeutic efficacy in breast, glioma, and pancreatic cancer, it ameliorated the resistance to cetuximab and doxorubicin in models of liver cancer. It was well tolerated in mice, rats and dogs in pilot safety studies. Since our laboratories have shown that activated STAT3 is present in normal mammary tissue of young mice and mammary cancers, we evaluated the efficacy of GLG-302, given orally, for its preventive activity in female MMTV-Neu mice that develop spontaneous estrogen receptor negative (ER−) mammary cancers. Previous studies had shown that acute dosing with GLG-302 would suppress the growth of established mammary cancers in mouse models at tolerable doses. We conducted a dose selection study lasting 3 months indicating that doses of GLG-302 as high as 500 mg/kg BW/day (administered by gavage 5X/week) would not alter body weights or induce other signs of toxicity. Proliferation rates (Ki67) in the mammary glands of the mice, determined after 2 weeks and after 3 months of GLG-302 administration, revealed that this dose of the agent caused reductions of 66% and 55%, respectively. A cancer prevention efficacy study was then initiated that included the following groups (15 mice/group); Group 1, GLG-302 (500 mg/kg BW/day); Group 2, GLG-302 (250 mg/kg BW/day); Group 3, GLG-302 (125 mg/kg BW/day); Group 4, Lapatinib (100 mg/kg BW/day) as a positive control; and Group 5, no treatment. Treatment (5X/week) was initiated when the mice were 65 days of age, and will continue for 10 months. Mammary tumors are detected by palpation of the mice 2X/week. The study is currently 5 months after the initial GLG-302 treatment. Average palpable mammary tumor number in each group is: Group 1, 0.07; Group 2, 0.33, Group 3, 0.50, Group 4, 0.08, and Group 5, 1.20. The 94% reduction in the average number of mammary tumors observed in mice receiving the high dose of GLG-302 compared to that in the no treatment group; and is comparable to the reduction observed following treatment with lapatinib. No body weight loss or other toxicity has been observed. In conclusion, IHC data demonstrated that GLG-302 can target the normal mammary epithelial cells of the mouse mammary gland during well-tolerated chronic dosing of the agent. Furthermore, current data in the prevention study has demonstrated a dose-dependent decrease in spontaneous mammary tumors in female MMTV/Neu mice. Additional studies using GLG-302 are ongoing in the dimethylbenzanthracene-induced mammary cancer (ER+) rat model, and will be presented. Studies supported by NCI contract HHSN261201200021I.

Citation Format: Robert H. Shoemaker, Michael W. Lovell, John J. Whalen, Fariba Moeinpour, Clinton J. Grubbs. Targeting STAT3 for mammary cancer prevention in MMTV/Neu mice employing the antagonist GLG-302. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4657. doi:10.1158/1538-7445.AM2015-4657


This article presents the strategy for developing a platform containing Language Processing Chains for European Union languages, consisting of Tokenization to Parsing, also including Named Entity recognition and with addition of Sentiment Analysis. These chains are part of the first step of an event-centric knowledge processing pipeline whose aim is to process multilingual media information about major events that can cause an impact in Europe and the rest of the world. Due to the differences in terms of availability of language resources for each language, we have built this strategy in three steps, starting with processing chains for the well-resourced languages and finishing with the development of new modules for the under-resourced ones. In order to classify all European Union official languages in terms of resources, we have analysed the size of annotated corpora as well as the existence of pre-trained models in mainstream Language Processing tools, and we have combined this information with the proposed classification published at META-NET whitepaper series.


The use of BIM in the electrical subcontractor community has been increasing over the past few years. The practice of using BIM for this sector varies in many ways as compared to the design profession or the use of BIM by general contractors. This study focuses on the current state of BIM implementation among the electrical subcontractors. A literature review of the topic lead to the adoption of a qualitative methodology to study the issue. The results of the qualitative study involved semistructured interviews with practitioners in the field. The results of the interviews found that the perception among electrical subcontractors regarding the successful use of BIM varies from the general contractor. The study lead to the identification of several key themes that govern the successful use of BIM for electrical construction. The study makes recommendations to electrical subcontractors for the successful use of BIM on projects.


LL-37, the only cathelicidin family member of cationic host defence peptides in humans, has been shown to mediate multiple immunomodulatory effects and as such is thought to be an important component of innate immune responses. A growing body of evidence suggests that LL-37 affects lung mucosal responses to pathogens through altered regulation of cell migration, proliferation, wound healing, and cell apoptosis. The aforementioned functions are consistent with LL-37 playing a role in regulating lung epithelial inflammatory responses, a role that is, however, not yet clearly defined. The effect of LL-37 on cytokine and chemokine production and signalling regulation in airway epithelial cells were investigated here. In this report I demonstrated that LL-37 induced protein release and transcriptional up-regulation of IL-6 and GRO-a in airway epithelial cells. LL-37 stimulation activated N F K B signalling, which was further demonstrated herein to robustly regulate production of IL-6 and GRO-a in airway epithelial cells.. With respect to receptor regulation, LL-37-stimulated IL-6 release was demonstrated to be regulated by EGFR and a G-protein coupled receptor, possibly FPRL-1. Furthermore, EGFR was shown to regulate LL-37-stimulated GRO-a. M A P kinase pathways mediated partial signalling regulation of both IL-6 and GRO-a release, while PI3K did not regulate this response. The evidence presented in this report shows that LL-37 is indeed a potent regulator of lung immune responses mediated through activation of multiple signalling pathways.


Recent data have shown that ferritin, a ubiquitous protein, has a role as a regulator of cellular differentiation. In the present study we have investigated the expression of ferritin mRNAs in cultured C6 cells, a rat glioma cell line, in response to insulin, which has an important role in cellular growth and differentiation. Insulin stimulated steady state levels of both ferritin heavy chain and ferritin light chain mRNAs. An increase in the level of ferritin heavy or light chain mRNA was detected after 2 h of incubation with insulin, and a plateau was reached after 48 h for heavy chain mRNA and after 72 h for light chain mRNA. The responses were dose-dependent and were maximal at 100 nM for both mRNAs. Treatment of cells with actinomycin-D showed that insulin had no effect on the posttranscriptional stability of these mRNAs. Actinomycin-D inhibited insulin-induced accumulation of both mRNAs, suggesting transcriptional stimulation of ferritin genes by insulin. A nuclear run-on assay showed that the insulin-induced increase in ferritin heavy chain mRNA was due to an increase in the rate of gene transcription. We also demonstrated that insulin-like growth factor-I (IGF-I) increased ferritin heavy and light chain mRNA levels in a dose-dependent fashion, and that the maximum effect was obtained at a concentration of 10 nM on both mRNA levels. IGF-I was not only 10-fold more potent, but the absolute level of maximum stimulation was also about 2-fold greater than that for insulin. The combination of insulin (100 nM) and IGF-I (10 nM) showed no additive effect. The results suggested that the ferritin heavy and light chain genes are transcriptionally regulated by insulin and influenced by IGF-I.


This paper uses a Foucauldian governmentality framework to analyse and interrogate the discourses and strategies adopted by the state and sections of the business community in their attempts to shape and influence emerging agendas of governance in post-devolution Scotland. Much of the work on governmentality has examined the ways in which governments have developed particular techniques, rationales and mechanisms to enable the functioning of governance programmes. This paper expands upon such analyses by also looking at the ways in which particular interests may use similar procedures, discourses and practices to promote their own agendas and develop new forms of resistance, contestation and challenge to emerging policy frameworks. Using the example of business interest mobilization in post-devolution Scotland, it is argued that governments may seek to mobilize defined forms of expertise and knowledge, linking them to wider political debates. This, however, creates new opportunities for interests to shape and contest the discourses and practices of government. The governmentalization of politics can, therefore, be seen as more of a dialectical process of definition and contestation than is often apparent in existing Foucault-inspired writing.


West syndrome is an age-dependent epileptic encephalopathy. Despite potential side effects, hormonal therapy remains the main treatment for West syndrome. Here, we report on 10 patients receiving steroid treatment who presented with unusual, mostly hyperkinetic, movements. Facial grimacing, repetitive mouth opening, adduction and abduction of upper and lower extremities, and periodical strabismus in different combinations were observed in all patients, independent of formulation, dose, duration, and efficacy of treatment. Symptoms disappeared in sleep and reappeared immediately on arousal. Dyskinesias stopped gradually after a month of discontinuation of treatment. Repeated EEGs did not show corresponding epileptiform activity. We conclude that these abnormal movements can be attributed to side effects of hormonal treatment.


Abstracts: Frontiers in Cancer Prevention Research 2008

ED08-02

Microelectrophoretic methods can make direct measurements of the activity of normal and oncogenic kinases in tumor cells. Issues of heterogeneity within cell populations, both in terms of cell type and biochemical behavior, often mandate single-cell studies for accurate determination of kinase activity in tumor cells. Chemical cytometry, the application of high-sensitivity chemical separations to characterize the contents of single or small numbers of cells, is emerging as an important approach for such studies. Electrophoretic separations within a glass capillary tube or a microfluidic channel combined with laser-induced fluorescence detection (LIF) are the most sensitive among these methods. Numerous groups have used these separation methods for a variety of biochemical studies in single cells. The Allbritton group has been a leader in using chemical cytometry to develop single-cell assays relevant to the field of signal transduction, particularly kinase assays. The method utilizes an integrated platform comprised of an inverted microscope, pulsed laser, and capillary electrophoresis (CE) system. For the assay, cells are loaded with fluorescently-labeled kinase substrates which function as reporters of the activity of the targeted kinase. For kinases, the substrate is typically a fluorescently labeled peptide, protein, or lipid. At the desired time after reporter loading, a cell is lysed within 10 microseconds by a focused 5 nansecond laser pulse. Dilution of cytoplasmic molecules by diffusion and turbulent mixing terminates cellular reactions with sufficient rapidity to prevent measurement artifacts from cell lysis. Following lysis, the cellular contents are immediately loaded into an overlying capillary or adjacent microfluidic channel and separated by electrophoresis. Due to their different chemical properties, the substrate and product forms of the reporter are readily separated, detected using LIF, and identified by their characteristic migration times. The ratio of the peak areas of the substrate and product are then used as a measure of the targeted enzyme's activation. Routine detection limits for fluorescein-labeled peptide substrates obtained from single mammalian cells are 10 zeptomoles, corresponding to an intracellular substrate concentration of ~10 nM in mammalian cells (~1 pl). The ability to detect the enzyme substrate present in nanomolar to low micromolar concentrations in the cell is an important feature of this assay as the exogenous substrate concentrations are at or below that of endogenous substrates so that competition between endogenous and exogenous substrate (reporter) is minimal. Fluorescent peptides, proteins, and lipids have been used successfully as substrates for kinases. An additional advantage to this approach is the ability to measure the activation of multiple enzymes simultaneously in a single cell by loading the cell with reporters for a variety of enzymes. At present, three kinases have been assayed at the same time in single cells, although the very high separation efficiency of microelectrophoretic methods makes it likely that a much larger number is possible. A second advantage of this microelectrophoresis-based method is that it is fully compatible with light microscopy so that the cells can be monitored using a variety of optical tools prior to electrophoretic analysis.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED08-02.


In 1946, after a period of internment that began in 1942, approximately four thousand Japanese Canadians were exiled to Japan and stripped of their citizenship. More than half were Canadian-born, and the majority of those who had been born in Japan were Canadian citizens. The exiles were given a choice of impossible options: to relocate outside of British Columbia or be sent to Japan. Drawing upon extensive archival research, this study examines the spatial patterns of migration between Japan and Canada with a particular focus on the exile of Japanese Canadians to Japan in 1946. Our findings indicate that the majority of the exiles were from Wakayama, Shiga, and Hiroshima prefectures, where rates of return prior to the 1940s were already high. Although more definitive explanations require further research, our exploratory analysis suggests that regional patterns of exile were likely influenced by the prefectural origin of the original migrants, obligations to re-establish the traditional Japanese agrarian household, and religious practices.


The stereospecific synthesis of the functionalized carbapenam core 16 from the serine-derived trisubstituted pyrrolidine 9 is reported. The synthetic strategy relies on synthesizing an appropriately functionalized pyrrolidine, followed by an intramolecular azetidone formation utilizing a modified Mukiyama reagent. The efficient one-pot conversion of the benzenesulfonamide-protected pyrrolidine 9 to the Cbz-protected pyrrolidine 10 is also reported.


Abstract  Background: A postoperative pseudoaneurysm may develop and gradually expand in the mediastinal space even late following Bentall operation for aortic root replacement, particularly in patients with dissection of the aorta. Methods: A very large (148 mm) pseudoaneurysm originating of the right coronary ostium suture line was observed in a patient admitted with unstable angina 6 years after Bentall procedure for type A aortic dissection. Angiograms showed reduced flow in the right coronary and thrombotic subocclusion of the left anterior descending (LAD) coronary artery due to extrinsic compression from the expanding mediastinal mass. Results: Reoperation was performed during femoro‐femoral cardiopulmonary bypass and brief period of circulatory arrest to clamp the tubular graft. After closure of the detected right coronary ostium in the tubular graft double bypass, grafting to the right coronary and LAD arteries was required. Postoperative course was uneventful. Conclusions: Close long‐term follow‐up after a Bentall procedure is required to minimize the risk of developing a large pseudoaneurysmal mass, in particular, after dissection of the aorta.


Reliable signal transmission represents a fundamental challenge for cortical systems, which display a wide range of weights of feedforward and feedback connections among heterogeneous areas. We re-examine the question of signal transmission across the cortex in network models based on recently available mesoscopic, directed‐ and weighted-inter-areal connectivity data of the macaque cortex. Our findings reveal that, in contrast to feed-forward propagation models, the presence of long-range excitatory feedback projections could compromise stable signal propagation. Using population rate models as well as a spiking network model, we find that effective signal propagation can be accomplished by balanced amplification across cortical areas while ensuring dynamical stability. Moreover, the activation of prefrontal cortex in our model requires the input strength to exceed a threshold, in support of the ignition model of conscious processing, demonstrating our model as an anatomically-realistic platform for investigations of the global primate cortex dynamics.


The main aim of this paper will be the analysis of specificational copular clauses in Serbian and their syntactic behavior in comparison to predicational copular clauses and predicate topicalized structures. Specificational copular clauses consist of the copula be and a non-referential expression in the clause initial and a referential DP in the clause final position (Winner is Peter). The main question is whether we can apply predicate inversion to Serbian specificational copular clauses. One of the most important arguments will be the subject-verb agreement as well as the case distribution in Serbian. Tests that Mikkelsen (2004) used for the distinction of Danish specificational clauses and predicate topicalized structures were used in Serbian. It will be argued that in Serbian DPref, in predicational clauses moves to the subject position in the TP layer, satisfying case and agreement features, while DPpred in specificational clauses moves to the subject position in the SpecTP, satisfying [top], thus leaving DPref in situ. It is assumed that these two types of copular clauses have similar syntactic structures in comparison to predicate topicalized structures.


Adequate urodynamic assessment of bladder behavior is essential in spinal cord injury (SCI) patients. Ambulatory urodynamics are more sensitive to detect detrusor overactivity (DO) than conventional urodynamics. The primary objective of this study was to determine the value of ambulatory urodynamics for the diagnosis of DO in SCI patients compared to conventional urodynamics.


Until the Holocaust in Lithuania annihilated 90% of its community between 1941 and 1944, Yiddish was a fully lived language with its own rich history and literature. David Fram escaped the genocide, having left his shtetl, the market town of Ponevezh in 1927. Once in South Africa, committed to the preservation of his mameloshn, his mother tongue, he created a rich body of Yiddish poetry. Though little known, his poems offer insights into the understanding of a particular Jewish survivor testimony as well as into the Lithuanian Holocaust more generally. Through detailed analysis of specific poems, this paper argues for their continued relevance, providing a valuable space for an account of aspects of memory and postmemory. In making them available to a wider audience through my own translations and transliterations in this small act of retrieval, my hope is to preserve a literary heritage and to memorialize a lost world.


In the rst part of the essay it will be argued that Welker's di erentiated understanding of the Word allows him to make sense of the relation between the Spirit and the Word. In the light of the unbreakable interrelation between the Word and the Spirit, it is possible to understand why Welker nds the biblical traditions to be the primary witness to the Spirit of God. It will also become clear why he understands the biblical traditions to be convincing in pluralistic societies. e second part of the essay focuses on the deep polemical foundations of Welker's theology of the Spirit. Welker, it is argued, who wants to write a 'realistic theology', develops his thoughts on the Spirit against the background of what he conceives to be the captivity of a theology of the Spirit in metaphysical and abstract theories, dialogical two-way thinking, and social moralism. ese forms of thought serve as the negative background against which Welker then further develops his thoughts on theology.


Annexins are a family of homologous proteins that associate with anionic phospholipid (aPL) in the presence of Ca(2+). Evidence that the function of one annexin type may be regulated by another was recently reported in studies investigating cytomegalovirus-aPL interactions, where the fusogenic function of annexin 2 (A2) was attenuated by annexin 5 (A5). This observation suggested that A2 may bind directly to A5. In the present study, we demonstrated this interaction. The A2-A5 complex was first detected utilizing (covalently linked) fluorescein-labelled A5 (F-A5) as a reporter group. The interaction required concentrations of Ca(2+) in the millimolar range, had an apparent dissociation constant [ K (d)(app)] of 1 nM at 2 mM Ca(2+) and was independent of aPL. A2 bound comparably with F-A5 pre-equilibrated with an amount of aPL that could bind just the F-A5 or to an excess amount of aPL providing sufficient binding sites for all of F-A5 and A2. A2-A5 complex formation was corroborated in an experiment, where [(125)I]A2 associated in a Ca(2+)-dependent manner with A5 coated on to polystyrene. Surface plasmon resonance was used as a third independent method to demonstrate the binding of A2 and A5 and, furthermore, supported the conclusion that the monomeric and tetrameric forms of A2 bind equivalently to A5. Together these results demonstrate an A2-A5 interaction and provide an explanation as to how A5 inhibits the previously reported A2-dependent enhancement of virus-aPL fusion.


The aim of the BEST-project is to support laymen in judging their legal position through intelligent disclosure of case-law in the area of Dutch tort law. A problem we have to face in this context is the discrepancy between the terminology laymen use to describe their case and the terminology found in legal documents. We address this problem by supporting users to describe their case in common sense terms taken from an ontology. We use logical reasoning to automatically determine law articles that are relevant for determining liability of parties in a case based on this description, thus bridging the gap between the laymen's description and the terminology relevant for certain articles that can be found in legal documents. We introduce the BEST-project and describe the ontology built for supporting case descriptions focussing on its use for automatically determining relevant articles of law.


This chapter examines issues relating to contract formation. It discusses the elements of an intention to create legal relations and the presumptions relating to commercial or business agreements and domestic agreements. It considers the law relating to capacity to contract, looking at the enforceability of different types of contracts made with minors. It considers the validity of contracts made with corporations and persons who may lack capacity through mental illness or intoxication. It also explains the importance of consideration in a contract, what constitutes consideration, whether consideration provided is sufficient, and who must provide the consideration. It discusses the law relating to part-payment of debts and promissory estoppel. Finally, the chapter considers the doctrine of privity of contract, and the exceptions to the doctrine, including the Contract (Rights of Third Parties) Act 1999


The effect of the anionic surfactant sodium dioleylsulfosuccinate on the extraction rate of copper with E-2-hydroxy-5-nonylbenzophenoneoxime in n-heptane was studied.The extraction rate of copper was remarkably enhanced by the addition of the anionic surfactant under appropriate conditions and it was found that the electrostatic interaction between copper and the anionic surfactant and the binding between the extractant and surfactant in the interfacial zone played an important role in the extraction kinetics of copper with the extractant.An extraction mechanism of copper with E-2-hydroxy-5-nonylbenzophenoneoxime in the presence of the surfactant was proposed.


Vast world reserves of methane gas are underutilized as a feedstock for production of liquid fuels and chemicals due to the lack of economical and sustainable strategies for selective oxidation to methanol. Current processes to activate the strong C‐H bond (104 kcal/mol) in methane require high temperatures, are costly and inefficient, and produce waste. In nature, methanotrophic bacteria perform this reaction under ambient conditions using metalloenzymes called methane monooxygenases (MMOs). There are two types of MMOs. Soluble MMO (sMMO), which is expressed by several strains of methanotrophs under copper limited conditions, oxidizes methane with a well characterized catalytic diiron center. Particulate methane monooxygenase (pMMO), an integral membrane metalloenzyme produced by all methanotrophs, is composed of three subunits, pmoA, pmoB, and pmoC, arranged in a trimeric α3β3γ3 complex. Despite 20 years of research and the availability of several crystal structures, the metal composition and location of the pMMO metal active site remain controversial. Here we show that pMMO activity is dependent on copper, not iron, and that the copper active site is located in the soluble domains of the pmoB subunit rather than within the membrane. Recombinant soluble fragments of pmoB (spmoB) bind copper and exhibit propylene and methane oxidation activities. Disruption of each copper center in spmoB by mutagenesis indicates that the active site is probably a dicopper center. Spectroscopic studies of both pMMO and spmoB provide evidence for dioxygen binding at the dicopper center.


In 5G wireless communication networks, the non-orthogonal multiple access (NOMA) and the simultaneous wireless information and power transfer (SWIPT) methods can be exploited to improve the spectral efficiency and link reliability, respectively. This paper focuses on a cooperative SWIPT NOMA protocol in MISO downlink case, where a user with strong channel conditions, i.e. user 2 (U2), acts as an energy harvesting (EH) relay to assist a user with poor channel conditions, i.e. user 1 (U1). Furthermore, U2 exploits sun energy harvesting, along with the RF signal energy harvesting through SWIPT, to improve the system performance. A jointly optimizing design is performed on the power splitting (PS) ratio of the relay and beamforming vector of the transmitt er to maximize the data rate of U2 subject to satisfying the QoS requirement of U1. We have formulated the optimization problem and evaluated the system performance for different values of harvested sun powers. Our results show that exploiting the solar ene rgy harvesting provides a considerable improvement for the cooperative SWIPT NOMA method in terms of system sum rate and feasible probability of the optimization, especially at low SNR regimes.


The corticosteroid concentration required to inhibit phytohemagglutinin stimulated human lymphocyte transformation by 50% was determined for three corticosteroids. The relative potency of hydrocortisone, prednisolone and dexamethasone determined in 16 patients was 1.00, 2.43, and 24.7 respectively. This assay is proposed as an objective tool for comparison of relative corticosteroid potency in man.


While much research has been done on the use of finite-difference time-domain to analyze structures containing dispersive material and curved dielectric structures, there is still a need for an efficient method to treat the general case of curved boundaries between dispersive anisotropic materials. In this paper, the state-of-the-art is extended by combining the auxiliary differential equation method for dispersive material with the use of dielectric smoothing for curved boundaries to allow efficient and accurate solutions for structures containing these sorts of boundary. The effectiveness of the method is demonstrated by means of the example of scattering from a spherical water droplet having Debye properties and the behavior of a spherical cloaking structure consisting of a material having anisotropic, space-dependent Drude properties. In each case improvement over standard techniques is shown.


Designing novel systems for efficient cancer treatment and improving the quality of life for patients is a prime requirement in the healthcare sector. In this regard, theranostics have recently emerged as a unique platform, which combines the benefits of both diagnosis and therapeutics delivery. Theranostics have the desired contrast agent and the drugs combined in a single carrier, thus providing the opportunity for real-time imaging to monitor the therapy results. This helps in reducing the hazards related to treatment overdose or underdose and gives the possibility of personalized therapy. Polysaccharides, as natural biomolecules, have been widely explored to develop theranostics, as they act as a matrix for simultaneously loading both contrast agents and drugs for their utility in drug delivery and imaging. Additionally, their remarkable physicochemical attributes (biodegradability, satisfactory safety profile, abundance, and diversity in functionality and charge) can be tuned via postmodification, which offers numerous possibilities to develop theranostics with desired characteristics. Hence, we provide an overview of recent advances in polysaccharide matrix-based theranostics for drug delivery combined with magnetic resonance imaging, computed tomography, positron emission tomography, single photon emission computed tomography, and ultrasound imaging. Herein, we also summarize the toxicity assessment of polysaccharides, associated contrast agents, and nanotoxicity along with the challenges and future research directions.


Slavery in the Late Antique World, 150 – 700 CE investigates the ideological, moral, cultural, and symbolic aspects of slavery, as well the living conditions of slaves in the Mediterranean basin and Europe during a period of profound transformation. It focuses on socially marginal areas and individuals on an unprecedented scale. Written by an international team of scholars, the volume establishes that late ancient slavery is a complex and polymorphous phenomenon, one that was conditioned by culture and geography. Rejecting preconceived ideas about slavery as static and without regional variation, it offers focused case studies spanning the late ancient period. They provide in-depth analyses of authors and works, and consider a range of factors relevant to the practice of slavery in specific geographical locations. Using comparative and methodologically innovative approaches, this book revisits and questions established assumptions about late ancient slavery. It also enables fresh insights into one of humanity's most tragic institutions.


Additive manufacturing (or 3D printing) is being increasingly used in a wide range of areas including civil, aerospace and biomedical engineering where it offers significant advantages over conventional methods for model prototyping. However, the reduced fracture resistance typically observed in 3D printed materials limits its application to functional components. The fracture of 3D printed polymer materials with various layer orientations is studied using the extended finite element method (XFEM) with the aid of finite element software ABAQUS. Single edge notch bend (SENB) specimens made of acrylonitrile-butadiene-styrene (ABS) materials through fused deposition modeling (FDM) with various crack tip/layer orientations subjected to 3point bending are considered. The XFEM with cohesive segment approach is employed to model the inter-laminar fracture (fracture between layers), cross-laminar fracture (fracture through layers), as well as mixed cross-/inter-laminar fracture of 3D printed ABS specimens. Both elastic and elastic-plastic fracture models are developed for the inter-laminar and cross-laminar fracture, respectively. For mixed cross-/inter laminar fracture, an anisotropic damage model is developed to predict the kinked crack propagation patterns as well as the dependence of fracture toughness on crack tip/layer orientations observed experimentally. Two damage initiation criteria were defined considering both the weak interfaces between layers and the maximum principle stress in the determination of the alternate crack growth paths. The anisotropic damage model developed in ABAQUS/XFEM through user-defined damage initiation subroutine is able to capture the fracture behavior of 3D printed polymer materials considering various layer orientations.


The capacity of gene delivery vehicles is considered to be a critical factor determining the success of gene therapy. To date, various types of gene delivery vehicle have been developed. Among them, recombinant adeno-virus (Ad) vectors have potential that has favored their worldwide use in vitro and in vivo. Conventional Ad vectors are composed of subgroup C Ad serotype 5 (Ad5), although it has been clarified that the drawbacks of Ad5 vectors are a high seroprevalence of Ad5 in adults and low transduction efficiencies in cells lacking the primary receptor for Ad5, coxsackievirus and adenovirus receptor. To overcome these problems, we developed a novel Ad vector fully composed of Ad serotype 35 (Ad35). Ad35 vectors show a wide tropism for human cells because Ad35 binds to human CD46, which is ubiquitously expressed on almost all human cells, as a primary receptor. In addition, anti-Ad5 antibodies do not inhibit Ad35 vector-mediated transduction and the seroprevalence of Ad35 in adults is lower than that of Ad5. This paper reviews our studies on the development and evaluation of Ad35 vectors. Ad vectors derived from other Ad serotypes different from Ad5, including Ad35, are expected to be gene delivery vehicles alternative to conventional Ad5 vectors.


Ag) T cell APCs pulsed at 15 (cid:56) C were both unable to induce T cell response. Remarkably, Pj CHO Ag presentation is independent of the expression of classical major histocompatibility complex (MHC) molecules or CD1. CD8 (cid:49) T cells stimulated by Pj CHO Ag-pulsed APCs undergo a sustained [Ca 2 (cid:49) ] i increase and downregulate their T cell antigen receptors (TCRs) in an antigen dose– and time-dependent fashion, similar to T cells stimulated by conventional ligands. Analysis of TCR V (cid:98) transcripts shows that six independent Pj CHO Ag-specific T cell clones carry the V (cid:98) 8 segment with a conserved motif in the CDR3 region, indicating a structural requirement for recognition of this antigen. Finally, after activation, the CD8 (cid:49) clones from the atopic patient express CD40L and produce high levels of interleukins 4 and 5, suggesting that the clones may have undergone a Th2-like polarization in vivo. These results reveal a new class of antigens which triggers T cells in an MHC-independent way, and these antigens appear to be carbohydrates. We suggest that this type of antigen may play a role in the immune response in vivo. centrifuged at 1,500 rpm for 1 min at 4 (cid:56) C allow conjugate formation, heated for 1 min at 37 (cid:56) C, and analyzed on a Coulter Elite Flow Cytometer to detect Ca 2 (cid:49) fluxes in conjugated T cells (25). Only live (based on forward and side scatter criteria) and Indo-1–loaded cells were included in the analysis. As positive control we recorded Ca (cid:49) fluxes in T cells after cross-linking of CD3 with a specific mAb (clone TR66).


Chimeric genes containing the beta-glucuronidase reporter gene under the control of the rolA, B, and C promoters of Agrobacterium rhizogenes are expressed in a regulated manner in transgenic plants. The intergenic region separating the rolB and C genes represents a bidirectional promoter. This bidirectional promoter regulates transcription for both genes in a similar fashion in aerial organs of the plants, but in a distinct way in roots. Moreover, both rolB and C promoter activities differ from those characteristic of the rolA promoter. Thus, promoters of bacterial origin show differential expression in transgenic plants, and regulation of roI gene expression plays a role in the biological effects caused by the rolA, B, and C genes.


The hypothesis that the Cordilleran geosyncline originated as an Atlantic-type continental margin by the rifting of an older Precambrian continental mass and the opening of a new ocean basin leads to the question of where the counterpart of the North American Precambrian craton may be. The Siberian platform—a large, discrete, older Precambrian craton, lodged in northeast Asia and surrounded by younger fold belts—is a likely candidate for the missing Precambrian continental fragment. The outline of its northeast margin fits the southwest margin of the North American Precambrian craton to produce a congruence of tectonic grain and age provinces. Both margins are overlapped by sediments of the same general type that began to accumulate about 1,500 m.y. ago, after the initiation of the separation.


Poly(ethylene oxide)-block-poly(methacryl-d-glucopyranoside) (PEO-GP) and poly(methacryl-d-glucopyranoside) (H-GP) glycopolymers were synthesized by deacetylation of acetylated polymers which were synthesized via atom transfer radical polymerization. The synthesized glycopolymers were characterized using 1H NMR, 13C NMR and Fourier transform infrared (FTIR) spectroscopies, gel permeation chromatography (GPC), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The deacetylated polymers exhibited onset decomposition temperatures about 60 °C lower compared to the polymers having acetyl pendants. The glass transition temperature (Tg) of the acetylated homopolymer was 133 °C and that of the PEO-based block copolymer was 124 °C. The deacetylated polymers H-GP and PEO-GP exhibited Tg values of about −30 °C. Biocompatibility of the H-GP and PEO-GP glycopolymers was obtained by studying osteoblast cell adhesion, viability and proliferation in vitro. The cell viability showed an increase with increasing concentration of H-GP from 0.1 to 1 µmol L−1 and then decreased with further increase in its concentration (10–1000 µmol L−1). PEO-GP did not show a significant variation in cell viability on variation of its concentration from 0.1 to 1000 µmol L−1. The significant improvement in biocompatibility with osteoblast cells in the presence of PEO-GP was considered as due to the covalently bonded PEO segment of the methacrylate glycopolymer block. © 2014 Society of Chemical Industry


Recent research has demonstrated that a central feature of many women's operatic creations from late eighteenth-century and early nineteenth-century France was a marked autobiographical element. Although this autobiographical style resulted in numerous box-office successes, it also limited the lifespan of these successes because it linked the works too closely with their authors. This article will discuss a work that appears to be an exception to this rule: Julie Candeille's Catherine, ou la belle fermière, a musical comedy that became the longest-running operatic work by a woman in history, playing virtually uninterruptedly between 1792 and 1839. In fact, the work and the title role remained intimately connected to the person of Candeille, who could never rid herself of the curiosity engendered by the public image she had earlier created for herself. (JL and RA)


Rose (Rosa ×hybrida) breeders historically have bred plants based on what they personally have deemed attractive and traits required by growers to produce the crop successfully. End-user preferences were not formally considered in breeding decisions. The purpose of this study was to investigate growers' and consumers' opinions of roses available on the market and preferences for future roses coming into the market. A web-based survey tool was developed to measure the attributes consumers were considering in purchasing and growing rose plants, their knowledge of diseases and pests, and their hopes for new plants coming to market. A link was sent to horticultural group mailing lists as well as distributed through personal e-mail lists, Facebook, and a news release from Texas A&M University. The survey was posted for 4 months. It included ≈66 questions and took 30 minutes or more to complete. More than 2000 responses were received from rose growers and nursery consumers worldwide. The respondents preferred roses that were disease resistant, with fragrant, abundant, red, and everblooming flowers. The ideal height of the preferred rose shrubs was waist to shoulder-height. Differences were found in preferences between experienced rose growers and those who were not affiliated with rose associations on variables such as the need to use chemicals to manage diseases, the importance of foliage glossiness and large vs. small blooms, the value of roses in the garden setting, the level of difficulty roses pose in growing situations, and the willingness to pay more for a rose shrub in comparison with other garden plants. Differences also were found among age groups and preferences for flower color, fragrance, foliage color, and foliage glossiness. This information could be helpful in targeting marketing of roses.


Some bankrupt municipalities have proposed plans of reorganization that offer substantially greater recoveries to their active workers and retirees than those offered to other creditors. Because these greater recoveries are not mandated by a priority enjoyed by the active workers and retirees, a judge can only approve such a plan if it does not "discriminate unfairly" against a class of disfavored creditors that votes against the plan. This paper describes the law defining the unfair discrimination standard, identifies the categories of circumstances in which discrimination between co-equal classes is permitted, and argues that the claims of retirees and active workers do not fall into any of these categories. We conclude that current law does not allow a judge to approve a reorganization plan that provides retirees and active workers with a greater recovery.


This study was conducted to investigate the adsorption characteristics of various surfactants including biosurfactant, SWA 1503, Triton X-100 and sodium dodecyl sulfate(SDS) on soil. The Freundlich adsorption isotherm equation was found to be the best to describe experimental results. The amount of adsorbed surfactant on soil increased as the content of clay increased. The results showed that surfactant was adsorbed mainly on the surface and the pores of soil since the surface area of clay was larger than that of sand. The amount of adsorbed surfactants on soil was as follows: Biosurfactant > SWA 1503 > Triton X-100 > SDS.


In this paper we present two practical methods of formalizing the metatheory of constructive type theory and demonstrate how they would be used to improve the reasoning capabilities of formal problem solving systems such as Nuprl. One method depends upon the design of a family of languages, and we sketch that construction. The second approach depends on a particular metatheorem that justifies partial reflection, and we outline this proof. We also illustrate the construction of simple metatheoretic functions, tactics, in Nuprl.


Image data security is the essential portion in communication and multi media world. During storing and sharing, avoid third party access of data is the challenge one. Providing security of data is the clever work and art also. Many protection algorithms are used in recent years. Protection may be given of a data is converting the original in to some unknown form, signals, sketch etc., which is not understand by any one. Cryptography is the best technique of image data security. In Greek, crypto refers "hidden" and graphy refers "script". Cryptography has two processes namely encryption and decryption. Encryption achieves the conversion by possessing a key of original data into unreadable form called encoding. Restoring of encrypted data in to original is decoding or decryption. Key, code or password is the vital role in cryptography. This paper presents the performance of encryption and decryption of an image using a single key algorithm and tested on some images and shows fine results.


Background Biologic DMARDs fall within the FDA category B or C. However many case series and registry data are available about women exposed during pregnancy. Objectives to extend information on this topic by the contribution of a tertiary single centre case series Methods Data were collected from a single-centre cohort of outpatients followed between 2006 and 2016. Women with rheumatic diseases (RD) exposed to biological (BE) agent during pregnancy or in the 3 months before conception were included. Outcomes in the BE group were compared with an age-matched group of pregnant women with RD non-exposed to biological agent (NE). Demographic and clinical data,obstetric outcome and neonatal complications were recorded. Results 34 pregnancies in 28 patients were included: 14 Rheumatoid Arthritis (RA), 6 ankylosing spondylitis (AS), 2 Psoriatic arthritis (PsA), 4 Undifferentiated spondyloarthritis (uSpA), 1 Dermatomyositis (DM), 1 Adult Onset Still's disease (AOSD); all were exposed to a biologic agent: 16 Etanercept (ETA), 7 Adalimumab (ADA), 4 Infliximab (IFX), 1 Certolizumab (CTZ), 5 Rituximab (RTX), 1 Anakinra (ANK). Median age was 34 yrs (range 24–50). All patients treated with TNFi and ANK withdrew therapy in early pregnancy (<10 weeks gestational age). 2 RA patients had 2 pregnancies each, during ETA treatment. A RA woman became pregnant 4 times during RTX therapy. 10 patients were also on csDMARDs therapy at the time of conceptions: 7 Hydroxycloroquine (HCQ),1 HCQ + Sulphasalazine (SSZ), 1 Cyclosporine A (CYA), which was continued, and 1 with Methotrexate which was immediately withdrawn. 1 RA patient started SSZ from the 24th week. 15 patients (7 RA, 2 PsA, 2 AS, 2 uSpA, 1 DM) started or increased oral and/or intra-articular steroids because of disease flare. A control group of 45 pregnancies observed in 42 patients not exposed to biologics was selected="selected" (19 RA, 12 uSpA, 3 Juvenile Idiopatic Arthritis (JIA), 5 PsA, 1 AS, 1 DM, 1 AOSD), median age 35 (range 22–42). 18 patients were treated with csDMARDs during pregnancy (8 HCQ; 4 SSZ; 2 CYA+HCQ; 4 SSZ+HCQ). No other drugs were taken at the time of conception, apart from low dose of steroids in 24 cases; in 1 case intra-articular steroids were given because of disease flare. Pregnancy outcomes are summarized in tab.1: therapeutic abortions were performed for an extrauterine pregnancy occurred twice in the patient with RA who became pregnant 4 times during RTX treatment, after the 5th and the 6th retreatment. After the 4th retreatment she had an early spontaneous abortion. Previously, she delivered 2 healthy children after exposure to ETA and 3 treatment cycles of RTX. No serious perinatal complication occurred, excluding very preterm baby delivery at 28th weeks, who needed neonatal intensive care. No congenital malformations were observed. Klinefelter syndrome was diagnosed in 1 case. Conclusions In our case series no significant differences did occur in pregnancy outcome between BE and NE group, according to the most recent data published in literature. Additional data from larger numbers of pregnacy exposed to biological agents are required. Disclosure of Interest None declared


The escalation of complexity and multidimensional (internal and external) factors bring companies to a position where risk management should be of main concern. Enterprise Risk Management (ERM) adoption and the extent of ERM implementation is seen as a guaranteeing element to increase the value of the companies over the long term due to adequate risk awareness and risk management strategies in all relevant business functions. This study examines the extent of ERM implementation on the initial performance of companies in the Malaysian IPO market. Testing a sample of 105 Malaysian IPOs issued from January 2012 to December 2020 using a linear regression model, ERM sophistication is positively and significantly related to the initial performance of Malaysian IPOs, offering support to the proposition in this study. Equally important is the reciprocal of offer price, subscription ratio, and market condition, which are also significant factors in companies' post-IPO performance. This study benefits the market regulators and investors on the importance of ERM sophistication to companies' initial performance.


A micro-computer based Pl and fuzzy logic automatic voltage regulator is applied to a micro-alternator system. This paper describes the design and implementation of PI and fuzzy logic automatic voltage regulator of a micro-alternator. A comparative study of Pl and fuzzy logic AVR Is analyzed and results show that the fuzzy logic improves the system damping subject to disturbances. Borland Delphi is used to develop the software algorithm for the controller.


This paper introduces a model in which the firm's returns depend on trading volume when the firm defers disclosure, because market makers use volume to draw inferences about better‐informed investors' private information on firm value. In addition, we show that a firm's commitment to a policy of timely disclosure of a broader range of outcomes dampens the slope coefficient on volume in a Taylor expansion of the log of the absolute value of returns on volume. The reason for this is that when a firm commits to a policy of timely disclosure of a broader range of outcomes, the deferral of a report indicates that the outcome is extreme. This heightens adverse selection. In turn, this makes informed trade more costly and hence less likely, thereby rendering returns less dependent on trading volume as a source of information about firm value. This result predicts that firms committing to more disclosure should experience a smaller slope coefficient on trading volume. Thus, the slope coefficient offers a potentia...


BACKGROUND
Concerns about duty hour and resident safety have fostered discussion about postshift fatigue and driving impairment.

OBJECTIVE
We assessed how converting to a night float schedule for overnight coverage affected driving safety for trainees.

METHODS
Brake reaction times were measured for internal medicine and orthopaedic surgery resident volunteers after a traditional 28-hour call shift and after a night float shift. We conducted matched paired t tests of preshift and postshift reaction time means. Participants also completed the Epworth Sleepiness Scale pre- and postshift.

RESULTS
From June to July 2013, we enrolled 58 interns and residents (28 orthopaedic surgery, 30 internal medicine). We included 24 (41%) trainees on night float rotations and 34 (59%) trainees on traditional 28-hour call shifts. For all residents on night float rotations, there was no significant difference pre- and postshift. An increase in reaction times was noted among trainees on 28-hour call rotations. This included no effect on reaction times for internal medicine trainees pre- and postshift, and an increase in reaction times for orthopaedic trainees. For both night float and traditional call groups, there were significant increases in the Epworth Sleepiness Scale.

CONCLUSIONS
Trainees on traditional 28-hour call rotations had significantly worse postshift brake reaction times, whereas trainees on night float rotations had no difference. Orthopaedic trainees had significant differences in brake reaction times after a traditional call shift.


Introduction All clinically effective antipsychotics are known to act on the dopaminergic system, and previous studies have demonstrated that repeated treatment with antipsychotics produced region-specific changes in dopamine receptor levels. Cariprazine is a dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors. We examined the effects of chronic cariprazine administration on dopamine receptor levels. Methods Rats were administered either vehicle or cariprazine (0.06, 0.2, or 0.6 mg/kg) for 28 days. Dopamine receptor levels were quantitated using autoradiographic assays on brain tissue sections from the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), caudate putamen (CPu), hippocampus (HIPP), olfactory tubercle (OT), and islands of Calleja (ICj). Results Chronic treatment with cariprazine did not alter D1 receptor levels in any brain region tested. Cariprazine increased D2 receptor levels in mPFC (27%–43%), NAc (40%–45%), medial (41%–53%) and lateral (52%–63%) CPu, and HIPP (38%). Cariprazine dose-dependently upregulated D3 receptor levels in ICj (32%–57%), OT (27%–67%), and NAc shell (31%–48%). Repeated cariprazine treatment increased D4 receptor in NAc (53%–82%), medial (54%–98%) and lateral (58%–74%) CPu, and HIPP (38%–98%). Conclusion Similar to other antipsychotics, cariprazine upregulated D2 and D4 receptor levels in various brain regions. Cariprazine was unique among antipsychotics in increasing D3 receptor levels, which may support its unique psychopharmacologic properties.


Purpose: To document primary care physicians' utilization and perceptions of genetics services.Methods: A randomized survey of physicians in the Pacific Northwest.Results: The greatest factor prompting a genetics referral was the patient's interest in the evaluation, and the most common reason not to obtain a consultation was the perception that it was of no benefit to the patient. Genetics consultation was rarely sought for a family history of cancer or for deafness, polycystic kidney disease, or congenital heart disease. Even when uncertain about relative risk, physicians usually counseled a patient themselves rather than referring to a specialist.Conclusion: Primary care physicians need more education about the genetic component of many diseases to provide directly and to refer appropriately for genetics services.


Creative and innovative therapy of media can increase children's interest in learning the language acquisition. The purpose of this paper is to reveal an increase in language skills in children with hi-tech therapy. This paper uses the method of instructional media development and action research (action research). Meda were developed with media programming by displaying various forms of impressions in the hi-tech tools both visually and audiovisually. This stimulus of media is applied to sensorimotor as a neurological processes by maninpulating, facilitating and adopting the environment in order to achieve improvement, repair, and maintenance competence language in children. The result of this research showed that the increasing the proficiency index is registered with hi-tech media therapy and able boost both value and creative character in children, especially the age of 5 years. It was seen in the change of any action by the author on the content and speech acts as well as the measurement index of child language skill, especially in terms of syntactic and pragmatic development. In addition, the development of media for language acquisition will ofster motivation, creativity, and positive character traits in children. Thus, development of media treatment of language acquisition can be used as a model for the improvement of language skills in normal children.


The invasion of the inferior vena cava (IVCI) due to hepatocellular carcinoma (HCC) is an unusual but aggressive entity. When it hap pens, the disease is considered to be in a very advanced stage, and the proposed treatment is palliative chemotherapy. However, there are recent studies that support radical surgical treatment as a therapeutic option, so their results show longer survivals than chemotherapy without major surgical complications. We present the clinical case of a patient with HCC and IVCI treated by hepatic resection and inferior vena cava (IVC) replacement with disease-free survival of 8 months after surgery.


A structural Auger spectroscopy study of MgB2 thin (~140 nm) oxygen-containing polycrystalline films produced by magnetron sputtering and 99% dense MgB2 bulks synthesized at 2 GPa allows us to conclude that jc of MgB2 depends to a high extent on the amount and distribution of oxygen in the material matrix. jc reached 7.8-2.7 MA/cm below 1T at 20 K in the films and 0.3-0.9 MA/cm (depending on the boron used) in the bulks. The higher jc in MgB2 thin films can be associated with finer oxygen-enriched Mg-B-O inclusions and their higher density in the film structure compared to the bulk. Calculations of the total electron density of states (DOS) in MgB2, MgB1.75O0.25, MgB1.5O0.5 and MgBO showed that all the compounds are conductors with metal-like behaviour. The DOS is even higher in MgB1.5O0.5 than in MgB2 and the binding energy is similar. So, the experimentally found presence of some dissolved oxygen in MgB2 does not contradict its high SC performance. The introduction of a high amount of oxygen into the MgB2 structure does not dramatically reduce the material's Tc and allows obtaining high jc as observed in our MgB2 films and bulks.


Background In recent years, with the acceleration of life rhythm and increased pressure, the problem of sleep disorders has become more and more serious. It affects people's quality of life and reduces work efficiency, so the monitoring and evaluation of sleep quality is of great significance. Sleep staging has an important reference value in sleep quality assessment. This article starts with the study of sleep staging to detect and analyze sleep quality. For the purpose of sleep quality detection, this article proposes a sleep quality detection method based on electroencephalography (EEG) signals. Materials and Methods This method first preprocesses the EEG signals and then uses the discrete wavelet transform (DWT) for feature extraction. Finally, the transfer support vector machine (TSVM) algorithm is used to classify the feature data. Results The proposed algorithm was tested using 60 pieces of data from the National Sleep Research Resource Library of the United States, and sleep quality was evaluated using three indicators: sensitivity, specificity, and accuracy. Experimental results show that the classification performance of the TSVM classifier is significantly higher than those of other comparison algorithms. This further validated the effectiveness of the proposed sleep quality detection method.


Karooprosbole magnifica gen. et sp. nov., oldest African cicadomorphan Prosbolidae, is described from middle Permian deposits (Abrahamskraal Formation, Karoo Supergoup) at the Onder Karoo locality in South Africa. It is compared to the genera currently included in Prosbolidae but also those in the Tettigarctidae: Cicadoprosbolinae. The limits and definitions of the two groups are discussed, because the new taxon has diagnostic characters of venation common to both groups. Also, some characters currently used to define these groups are clearly subject to homoplasy. This suggests that a phylogenetic analysis of the whole extant and fossil Cicadomorpha is needed to better define these families and verify their monophyly.


Classification trees and linear regression analysis were used to build models to predict probabilities of infestation and amount of tree mortality in terms of basal area resulting from roundheaded pine beetle, Dendroctonus adjunctus Blandford, activity in ponderosa pine, Pinus ponderosa Laws., in the Sacramento Mountains, New Mexico. Classification trees were built for combined habitat types sampled and for each habitat type series or type sampled. Cross-validation estimates of classification accuracy ranged from 0.64 to 0.79. The data suggest that stands attacked by the roundheaded pine beetle exhibit poor growth during the last 5 years prior to attack, abundant host type, and smaller diameter than uninfested stands. Trees prone to attack by the roundheaded pine beetle within infested points also exhibited reduced growth rates and smaller diameters than uninfested trees. Linear regression analysis indicates that initial amount of ponderosa pine basal area is a good predictor variable for the amount of basal area affected.


Pancreatic cancer is a challenging disease due to the low resection rate at the time of initial diagnosis. A relatively new classification of marginally resectable pancreatic cancer has emerged and there is some evidence that this subgroup of patients may benefit from neoadjuvant radiochemotherapy. The first major definition of marginally resectable pancreatic cancer was made at M. D. Anderson Cancer Center and published in 2006. This definition was purely anatomical and CT-based and only handles the relationship of the pancreatic, tumor to its surrounding major vessels. Later on, two other subtypes have been added to this definition: suspicion or known metastasis in regional lymph nodes (N1 disease), or severe pre-existing medical comorbidities requiring prolonged evaluation or recovery and precluding immediate surgery. Other definitions (anatomical and CT-based) for marginally resectable pancreatic cancer have also been established. For systematic research on neoadjuvant therapy in marginally resectable pancreatic cancer, however, the lack of uniform definitions and randomized trials have been troublesome. Nevertheless, several small cohort studies have demonstrated that 40-80% of the marginally resectable patients could proceed to resection after neoadjuvant treatment and also reporting some promising effects on microscopic resection margins, lymph node status and survival.


This article conducts a normative evaluation of Operation Iraqi Freedom undertaken in 2003 by employing principles of prudence to enquire whether the use of force could be described as an action by a responsible great power. Along with relating the principles of prudence to the concept of great power responsibility, it highlights two pillars of prudent decision-making: circumspection and awareness of one's limits. This normative framework is then utilised to evaluate the invasion of Iraq from the perspective of these specific aspects of prudence. The conclusion shows that on the basis of this normative yardstick, it is not possible to classify Operation Iraqi Freedom as a prudent action by a responsible great power.


GGA3-mediated BACE1 accumulation in dystrophic neurites is an early pathogenic event and is independent of Aβ extracellular deposition. Unraveling axonal traffic jam The protease BACE1 participates in Aβ production and has been shown to accumulate in dystrophic neurons and contribute to axonal pathology in patients with Alzheimer's disease (AD) and in animal models. The mechanisms mediating BACE1 accumulation are unclear. Here, Lomoio et al. showed that the Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) plays a main role in BACE1 localization. Deletion of Gga3 resulted in BACE1 accumulation and axonal swelling that was prevented by BACE inhibition. The authors identified a loss-of-function mutation in GGA3 in patients with AD, and Gga3 deletion worsened AD pathology in a mouse model. The results contribute to elucidate the mechanisms mediating axonal damage in AD. Axonal dystrophy, indicative of perturbed axonal transport, occurs early during Alzheimer's disease (AD) pathogenesis. Little is known about the mechanisms underlying this initial sign of the pathology. This study proves that Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) loss of function, due to Gga3 genetic deletion or a GGA3 rare variant that cosegregates with late-onset AD, disrupts the axonal trafficking of the β-site APP-cleaving enzyme 1 (BACE1) resulting in its accumulation in axonal swellings in cultured neurons and in vivo. We show that BACE pharmacological inhibition ameliorates BACE1 axonal trafficking and diminishes axonal dystrophies in Gga3 null neurons in vitro and in vivo. These data indicate that axonal accumulation of BACE1 engendered by GGA3 loss of function results in local toxicity leading to axonopathy. Gga3 deletion exacerbates axonal dystrophies in a mouse model of AD before β-amyloid (Aβ) deposition. Our study strongly supports a role for GGA3 in AD pathogenesis, where GGA3 loss of function triggers BACE1 axonal accumulation independently of extracellular Aβ, and initiates a cascade of events leading to the axonal damage distinctive of the early stage of AD.


Yanagita Kunio (1875–1962). Pioneer of Japanese folklore studies

The Meiji era (1868–1912) pushed Japan towards a modern, industrialized and, most of all, positivist state. This era plays an important role in shaping the ethnographic (anthropological, folklore) thought in the country. However, this is only one side of the coin, a medal which, apart from a gigantic leap in civilization, had a reverse – traditional, familiar, "Japanese" side. Japan went through two important periods of modernization in the years of 1868-1962. From a feudal country ruled by samurai transformed into a country capable of competing with the previously industrially developed colonial powers, and after World War II, giving up imperial ambitions, transformed into a modern state. During the century, numerous changes have occurred in the streets of the Japanese capital. From the carriages, trough automobiles, and finally, after 1945, to the jets flying overhead. It was in such times that the pioneer of Japanese ethnography, folklore or socio-cultural anthropology, Yanagita Kunio, came to live and work. This text aims to present the profile and main theses of this Japanese researcher.


Chaotic complex systems are utilized to characterize thermal convection of liquid flows and emulate the physics of lasers. This paper deals with the time-delay of a complex fractional-order Liu system. We have examined its chaos, computed the numerical solution and established the existence and uniqueness of those solutions. Ultimately, we have presented some examples. PACS (2008): 02.30.Fn,02.30.Ks,05.45.Df


Bites are currently the only physically abusive injury where we can potentially identify the perpetrator. This may be from the dental characteristics or additionally from salivary DNA.1 Bites may also be a source of cross infection, for example of hepatitis. It is essential therefore that paediatricians recognise a potential bite, and refer appropriately to a forensic odontologist (of which there about 20 in the UK; details on the BAFO website2). We conducted an all language systematic review of the literature spanning more than …


Approaches for automatically analyzing subcellular location on a proteome-wide basis have been developed. This permits proteins to be grouped into subcellular location families that share a statistically-indistinguishable pattern. This in turn creates a need for methods to connect these automatically determined locations to existing information in literature and databases, and to communicate the nature of the pattern for each family. The building of generative models is proposed to meet this need and their utility for simulations of cell behavior is discussed.


Cutaneous melanoma is a highly aggressive disease resistant to conventional treatment and characterized by poor prognosis. Targeted therapies against MAPK pathway and immune checkpoint inhibitors have dramatically improved survival of metastatic melanoma patients but the extent and duration of response are variable. Classification based on gene expression profiling have so far allowed identification of melanoma subtypes with distinctive biological features and with potential clinical impact. However, clinical translation of molecular subtypes is hampered by inconsistencies among the different classifications.

Here, through a harmonized bioinformatic analysis of public transcriptomic datasets, we compared and combined nine published classification systems to derive the consensus transcriptional subtypes of melanoma. Beyond confirming previously reported subtypes, our approach enabled the identification of a novel highly mitotic, chromosomally unstable group of melanomas that recapitulated a transitory state from a proliferative, melanocytic, differentiated phenotype to a more mesenchimal invasive program. We provided evidence that this classification has a prognostic role in metastatic melanoma patients, independently from the levels of tumour immune infiltration. We translated consensus subtypes to in vitro melanoma cell lines and combining them with pharmacological data we highlighted subtype-specific sensitivity to MAPK inhibitors and other drugs. Analysis of baseline gene expression data of metastatic melanoma patients treated with MAPK or immune checkpoint inhibitors showed that the predictive role of consensus subtypes in clinical setting remains to be elucidated. Finally, through the analysis of multi-omics data from the same set of patients, we comprehensively characterized the consensus subtypes at the genomic, transcriptional, and epigenomic levels.

Our results showed that melanoma gene expression classifications converged on five biological entities determined by transcriptional and epigenetic events, and with potential implications for prognostication.


Three 8-week-old kittens were presented with a history of acute, generalized weakness and severe fever. One cat was dead upon presentation, and necropsy findings were supportive of a group G Streptococcus spp. septicemia. During their clinical courses, two of the three kittens developed a progressive, marked swelling of one or more limbs. One moribund and severely hypothermic cat was euthanized a few hours after presentation, and necropsy was also supportive of a group G Streptococcus spp. septicemia. One kitten recovered. Group G streptococcal toxic shock-like syndrome was suspected because of the fulminant progression of the septicemia.