Toxoplasma gondii is an obligate intracellular protozoan that parasitizes several hosts worldwide, of which cats are definitive hosts. The objective of this study is to evaluate the risk factors associated with the epidemiology of T. gondii in cattle and buffaloes in the state of Pará, Brazil. A total of 2,070 bovine samples (1,749 cattle and 321 buffaloes) were evaluated in 100 rural properties distributed in 51 municipalities from all mesoregions of the state. The evaluated risk factors were animal gender, type of farm, and number of cats in the properties. The serological prevalence of T. gondii was evaluated using the indirect enzyme immunoadsorption assay (iELISA). The samples with a sample/positive (S/P) ratio ? 0.5 were considered positive and analyzed using the indirect immunofluorescence assay (IFA). The samples diluted at 1:64 were considered positive. The chi-square test with a level of significance of 5% and the odds ratio (OR) with a confidence interval of 95% was applied.The data were analyzed using BioEstat software version 5.0.The prevalence of T. gondii in bovines was 35.79% and 45.12% in ELISA and IFAT, respectively. The prevalence was 34.48% and 44.14% in cattle and 42.99% and 50.47% in buffaloes using ELISA and IFA, respectively. The mesoregion with the highest prevalence of infection was Marajó Island, corresponding to 42.86% (129) and 50.5% (152) in ELISA and IFA, respectively. In buffaloes, the prevalence of T. gondiiusing ELISA was higher in males (p < 0.05) in the two age groups. In contrast, the prevalence of T. gondii using IFA was higher in males in the age group 13 to 24 months (p < 0.05). The type of farm did not affect the prevalence of T. gondii in cattle (p > 0.05). However, the presence of cats strongly affected the occurrence of infection in cattle. These results demonstrate the high levels of anti-T. gondii antibodies in cattle and buffaloes in Pará and this may be a public health problem. Furthermore, the presence of cats is a risk factor for infection with T. gondii in these species in Pará.


Background: Measuring the effectiveness of continuing medical education (CME) activities has increasingly necessitated relating it to improvements in health care delivery and ultimately to patient outcomes. Recent increased emphasis on patient outcomes involves moving from a traditional evaluation model to an outcomes-based evaluation model. Making this shift to an outcomes-based model requires that CME providers develop a process for "evaluating their evaluations." Methods: We designed and completed a qualitative study of our evaluation instruments. Content analysis was used as the textual-analysis method for identifying coherent and important themes in the data, with the evaluation item being our unit of analysis. Once this analysis was completed, we identified the evaluation level and the updated Accreditation Council for Continuing Medical Education (ACCME) criteria that related to each evaluation item. We then developed strategies to increase the percentage of our outcomes-based evaluation items. Results: The majority (83%) of our evaluation items pertained to learners' participation and satisfaction, and the remaining items (17%) pertained to learners' enhanced knowledge and skills. All of our evaluation items were categorized as traditional evaluation items. The development of strategies to increase the percentage of outcomes-based evaluation items facilitated the shift from a traditional to an outcomes-based evaluation model. Conclusions: Completing this process of evaluating our evaluations provided us with the percentages of our evaluation items that were associated with the traditional evaluation model. The results of this analysis enabled us to develop and incorporate new strategies designed to shift us toward an outcomes-based evaluation model as a means of linking our CME activities to significant improvements in patient care.


Case 1. —A case of recurrent retrobulbar optic neuritis of one eye following successive childbirths, and ending in atrophy of optic nerve, with whitening of part of the eyelashes and eyebrow of same side. History. —The patient was a strong healthy woman, about 25 years of age, at the time of her third pregnancy when she first came under my observation. I learned from her at this time that her first pregnancy occurred about four years before the third, and the second more than two years before the third. Her eyes have always been good, she has never had an inflammation of the same, and the vision of both was excellent up to the time of her first pregnancy. Shortly after her first confinement she had an attack of transitory blindness in the right eye, from which she recovered completely. She had another temporary loss of vision in the right


Closing out a set of six articles, this text presents a descriptive analysis of Leontiev's career between 19367 in the context of the profound changes caused by the Decree against Pedology and subsequent public campaign against the Vygotskian legacy. This paper seeks to outline the meaning of this campaign within the sinister context of the Soviet Great Purge and place Leontiev's main critical text of Vygotsky in the context of the enforcement of a "pure and genuine" Marxism-Leninism on the sciences. We claim that Leontiev confused the ontological and epistemological problem of the relationship of consciousness to matter, reflecting the Stalinist divisions between them. When Leontiev moved away from Vygotsky's legacy, he pursued a dualist, objectivist, and mechanistic inflection of Vygotsky's psychological materialism.


In this review a detailed overview is given of the (electronic) structure and reactivity of open-shell (paramagnetic) alkene rhodium and iridium complexes Mx(alkene) (M = Rh, Ir; x = 0, +II). In most cases these species are highly reactive, but some notable exceptions of stable species for which not much reactivity has been described are also included (section 2). Understanding the electronic structure of the reactive nitrogen-ligand-based [MII(por)(alkene)] and [MII(alkene)(N-ligand)]2+ species (section 3) is complicated by a substantial spin distribution over the metal and the alkene ligand. This dual-mode metallo-radical and ligand radical behavior is reflected by their high and diverse reactivity. Metallo-radical character is demonstrated by a variety of metal-to-radical coupling reactions with a series of other radicals, as well as metal-based allylic hydrogen atom abstractions from MII(α-alkene) species. On the other hand, (donor induced) ligand radical character is crucial in a variety of M–C and C–C radical coupling reactions, C–O bond formation by oxygenation of MII(alkene) species and alkene "insertions" into (por)M–H bonds. The review concludes with some speculations about possible roles of paramagnetic M(olefin) (M = Rh, Ir) species in catalytic olefin oxygenation and carbene transfer reactions.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)


Dear Editor,

Regarding the article of Leonardi and La Rosa: "Are hepatitis B virus and celiac disease linked?", published in the 2010 issue of Hepatitis Monthly [1], we believe that there is no relationship between the hepatitis B virus (HBV) and celiac disease (CD). None of the study's patients tested positive for immunoglobulin A anti-endomysium or immunoglobulin A anti-tissue transglutaminase antibodies, nor did they exhibit symptoms of CD. Therefore, there is no reason to confirm a diagnosis of CD. We understand that the interest of the authors to study the possible relationship between CD and HBV is based on their own experience and the evidence of others that untreated patients with CD have a lower percentage of response to HBV vaccine than healthy subjects. However, in celiac children, treatment with a gluten-free diet may improve the immune response to HBV vaccine; the mechanism for this is unclear [2][3]. Several studies have linked both HBV infection and HBV vaccine to a variety of autoimmune manifestations, including autoimmune hepatitis, systemic lupus erythematous, rheumatoid arthritis, polyarteritis nodosa, type 1 diabetes, multiple sclerosis, thyroid disease and uveitis [4]. Although the role of HBV infection in the development of autoimmune diseases has been extensively discussed in the literature, it remains a controversial subject, and variety possible mechanisms have been suggested. Molecular mimicry, based on amino acid similarities shared by viral and self antigens, has long been proposed as a pathogenic mechanism. Iglesias et al. presented two patients who developed CD after resolution of an acute HBV infection. A diagnosis of CD was confirmed by positive serological tests and the presence of the typical histopathologic pattern. These authors suggested that the development of immune response for HBV clearance triggers the intestinal tissue damage observed in CD in genetically predisposed individuals [5]. In addition, a previous study reported activation of CD in susceptible individuals during interferon-alpha therapy for chronic hepatitis C infection. Interferon-alpha has the potential to exacerbate autoimmune disease either by direct effects on tissue or by interacting with the immune system; thus, altering the link between lymphocyte populations and the cytokine production profile [6]. In conclusion, no clinical evidence is available for an association between CD and hepatitis infection, and the occurrence of these two diseases in one patient may simply be a chance finding. The possibility of a cause-and-effect relationship might be better investigated.


Scandinavian crime fiction is recurrently concerned with the conditions and violent interruptions of democracy and the welfare state. Henning Mankell's Wallander-series seems predominantly preoccupied by the disturbance of this idyllic scenery by violent acts. Something seems to be afoot and the Scandinavian welfare society seems to be suffering. The upper current in Henning Mankell's stories show an idyllic manifestation disrupted by an undercurrent of "Swedish uneasiness". Although democracy and social maintenance seem to be running well, underneath a violent anxiety dislocates the basic preconditions of a democratic welfare system. Different models present various ways of analyzing these currencies of idyllic scenery and violent cruelty, which is very present in Before the Frost, both novel and film – the revolving points in this paper. The undercurrent of unease might be a cultural unconscious of suppressed guilt and anxiety, or it can be dealt with as a general way of delivering social critique through fiction. Nevertheless, the order of society and the democratic scenery is, in the narrative, muddled by religious problems with Christian roots. Correspondingly, this paper reflects upon the violent disruption of democracy and the ambivalent characteristics of both violence, the police officer Wallander and democracy.


Abstract For liberalism, values such as respect, reciprocity, and tolerance should frame cultural encounters in multicultural societies. However, it is easy to disregard that power differences and political domination also influence the cultural sphere and the relations between cultural groups. In this essay, I focus on some challenges for cultural pluralism. In relation to Indian political theorist Rajeev Bhargava, I discuss the meaning of cultural domination and epistemic injustice and their historical and moral implications. Bhargava argued that as a consequence of colonialism, "indigenous cultures" were inferiorized, marginalized, and anonymized. Although cultures are often changing due to external influences, I argue that epistemic injustice implies that a culture is forced to subjection, disrespected, and considered as inferior and that it threatens the dominated people's epistemic framework, collective identity, and existential security. Finally, I refer to John Rawls's theory of political liberalism as a constructive approach to avoid parochialism and Western cultural domination.


THERE is no question that total removal is the treatment of choice in acoustic tumor surgery. However, at the time of surgery there are a number of considerations which occasionally make total removal inadvisable. In 1925, Dandy1recommended total removal of acoustic tumors at the initial operation in all cases. He noted, as have other surgeons, that the second operation for acoustic tumor had a high mortality rate. This was believed to be due primarily to adhesions that developed in the posterior fossa which obscured the surgical planes and increased the bleeding, thus making injury to such structures as the cerebellum and brain stem much more likely. Dandy's concept, therefore, was that it would be better to remove the tumor totally at the first operation and thereby increase the initial operative mortality to some degree rather than face the vastly increased mortality of a second operation. In this way he


Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tickborne infectious disease caused by SFTS virus (SFTSV). We report 7 cases of spontaneous fatal SFTS in felines. Necropsies revealed characteristic lesions, including necrotizing lymphadenitis in 5 cases and necrotizing splenitis and SFTSV-positive blastic lymphocytes in all cases. We detected hemorrhagic lesions in the gastrointestinal tract in 6 cases and lungs in 3 cases, suggesting a more severe clinical course of SFTS in felids than in humans. We noted necrotic or ulcerative foci in the gastrointestinal tract in 3 cases, the lung in 2 cases, and the liver in 4 cases. We clarified that blastic lymphocytes are predominant targets of SFTSV and involved in induction of necrotic foci. We also found that thymic epithelial cells were additional targets of SFTSV. These results provide insights for diagnosing feline SFTS during pathological examination and demonstrate the similarity of feline and human SFTS cases.


The aim of the present study was to analyze the response of systolic (SBP) and di- astolic (DBP) blood following three experimental sessions: resistance exercise (RE), combined exercise (COMB-aerobic and RE) and control session (CON). Thirty women with metabolic syndrome (MS) were randomly assigned to one of three experimental groups: RE (n=10; 36.1 ± 9.0 years) (3 sets of 8-12 repetitions at 80% of 10RM in six exercises for whole body); COMB (n=10; 33.1 ± 5.0 years) (30 min of aerobic exercise at 65-70% of reserve heart rate which was followed by the same RE session) and CON (n=10; 30.4 ± 6.6 years). The SBP and DBP were measured before and every 15 min during 60 min following the experimental sessions. The COMB group presented greater delta SBP (ΔSBP) decrease at 15, 30 and 45 min post-exercise as compared with CON group (p <0.05); the RE group presented greater ΔSBP reduction at 30 and 45 min post-exercise also compared with CON group (p <0.05). In addition, the area under the curve of ΔSBP for COMB group (~30 mmHg of hypotension during 60 min, p ≤ 0.0005) and RE group (~19 mmHg of hypotension during 60 min, p = 0.024) were greater than the CON group. Therefore, RE and COMB elicited post-exercise hypotension in women with MS; COMB provided a greater decrease which may be of value in the prevention and treatment of cardiovascular disorders.


Many technical approaches for detecting and preventing cybercrime utilise big data and machine learning, drawing upon knowledge about the behaviour of legitimate customers and indicators of cybercrime. These include fraud detection systems, behavioural analysis, spam detection, intrusion detection systems, anti-virus software, and denial of service attack protection. However, criminals have adapted their methods in response to big data systems. We present case studies for a number of different cybercrime types to highlight the methods used for cheating such systems. We argue that big data solutions are not a silver bullet approach to disrupting cybercrime, but rather represent a Red Queen's race, requiring constant running to stay in one spot.


Literature review and original data concerning the most common cause of inherited thrombophilia - activated protein C resistance have been presented. One hundred and three patients with confirmed venous thromboembolism have been investigated for activated protein C resistance with 2 ( nd ) generation "Diagnostica Stago" test. Activated protein C resistance has been found in 22.3 % cases. In the group of 70 healthy unselected men and women, matched by sex and age, this mutation has been found in 7.1% cases. Out of 101 patients with pulmonary thromboembolism confirmed by pulmoangiography or perfusion lung scan, 78 have been investigated by Doppler echocardioscopy in order to detect pulmonary hypertension after 1.5 months. Statistically significant correlation between age and pulmonary artery pressure has been found. No correlation between pulmonary artery pressure and activated protein C resistance has been detected.


The contribution that the technique of ferromagnetic resonance (FMR) has made to the understanding of the magnetic behaviour of ultrathin single films is reviewed. Experimental methods to measure FMR in situ in ultrahigh vacuum are presented. The temperature dependence of the magnetization, of the magnetic relaxation rate in the vicinity of the Curie temperature, and of the second- and fourth-order magnetic anisotropy energy (MAE) constants can be measured by FMR in situ for magnetic monolayers. Using the cases of Ni/Cu(001) and Gd/W(110) as examples, the role of the MAE for the quantitative description of temperature- and thickness-dependent reorientation transitions of the magnetization is discussed. Initial results for the anisotropy of the g-factor which is related to the anisotropy of the orbital moment (and the MAE) are presented.


P16 was originally discovered by its ability to interact with CDK4 and to specifically inhibit the catalytic activity of the CDK4/D1 kinase. Increased attention has focused on the p16 gene because of its location on chromosome 9p21, a region involved in chromosomal rearrangements in a large number of tumor types. The p16 gene is also mutated in a large number of tumor cell lines and primary tumor cells. Furthermore, linkage analysis studies suggest that the p16 gene is involved in familial melanoma susceptibility. Due to the oncogenic potential of mutations in this tumor suppressor, it is important to identify and characterize those mutations which alter p16 activity. We have performed a systematic analysis of melanoma associated p16 mutants and of mutants generated in charge to Ala mutagenesis. Using microtiter plate assays to measure both p16-cdk4 binding and cdk4/D1 kinase activity, we show here that the melanoma associated mutants are defective, as are some of the Ala mutants. These results support the idea that p16 mutation, via its deregulation of the cdk4/D1 pathway, is of biological significance in the development of melanoma. Furthermore, we have defined a region within the p16 molecule in which changes are likely to result in a defective protein.


Background— Carvedilol but not metoprolol exhibits persistent binding to β-adrenergic receptors (β-ARs) even after washout in cell culture experiments. Here, we determined the significance of this phenomenon on human β-ARs in vitro and in vivo. Methods and Results— Experiments were conducted on human atrial trabeculae (n=8 to 10 per group). In the presence of metoprolol, isoproterenol potency was reduced compared with controls (P <0.001). In the presence of carvedilol, isoproterenol identified 2 distinct binding sites of high (36±6%; −8.8±0.4 log mol/L) and low affinity (−6.5±0.2 log mol/L). After β-blocker washout, isoproterenol potency returned to control values in metoprolol-treated muscles, whereas in carvedilol-treated preparations, isoproterenol potency remained decreased (P <0.001 versus control). In vivo studies were performed in 9 individuals receiving metoprolol succinate (190 mg/d) or carvedilol (50 mg/d) for 11 days in a randomized crossover design. Dobutamine stress echocardiography (5 to 40 μg · kg−1 · min−1) was performed before, during, and 44 hours after application of study medication. β-Blocker medication reduced heart rate, heart rate–corrected velocity of circumferential fiber shortening, and cardiac output compared with baseline (P <0.02 to 0.0001). After withdrawal of metoprolol, all parameters returned to baseline values, whereas after carvedilol, all parameters remained reduced (P <0.05 to 0.001) despite complete plasma elimination of carvedilol. Conclusions— Carvedilol but not metoprolol inhibits the catecholamine response of the human heart beyond its plasma elimination. The persistent β-blockade by carvedilol may be explained by binding of carvedilol to an allosteric site of β-ARs.


INTRODUCTION
Biochemical bone markers, such as the bone isoenzyme form of alkaline phosphatase, have been used to assess the bone formation phase of bone turnover in health and disease. Skeletal metastases often occur in patients with malignancies. Recent developments suggest that bone markers could be valuable clinical tools for the management of patients with metastatic bone disease.

PATIENTS AND METHODS
Serum levels of BAP, along with serum levels of beta-CrossLap, were measured in a large group (n = 200) of patients with newly-diagnosed or progressive cancer of the prostate, breast, colon, liver and pancreas. Tumour markers such as PSA, CEA, CA 19-9, AFP, CA 15-3 and bone marker levels were correlated with the presence or absence of bone scan-documented metastases.

RESULTS
Both of the bone markers examined were elevated in a high proportion of patients with confirmed metastases to bone. All patients with prostate, breast and colon carcinoma showed elevated beta-CrossLap values. The determined values of beta-CrossLap and BAP were significantly correlated with the number of skeletal metastases.

CONCLUSION
Markers of biochemical bone remodeling can be used in assessing and managing patients with malignancies that metastasize to bone. These markers are abnormally raised in the blood of patients with metastatic bone disease.


Standardized, hunter-based sampling of harvested beluga whales was initiated in the three main harvesting areas of the Mackenzie River delta (Shallow Bay, Kendall Island, Kugmallit Bay) in 1980 and near Paulatuk, Northwest Territories, in 1989. Standard length and sex of landed whales have been recorded for 90 to 110 belugas per year since 1980, and ages have been determined since 1988. Hunters select larger and older belugas; males outnumbered females 2.0 to 1 between 1980 and 1989, 3.0 to 1 between 1990 and 1999, and 3.6 to 1 between 2000 and 2009. Age classes younger than 10 growth layer groups (GLGs) were essentially absent from harvests both in the Delta and near Paulatuk. Asymptotic lengths, calculated using GLG counts from teeth of 839 males and 225 females sampled over 16 seasons (1989, 1993 – 2008), were 435.3 cm (SE 2.0) for males and 380.1 cm (SE 1.8) for females. Males were 14.5% longer than females. Belugas landed in the Delta and Paulatuk were mainly mature adults (by hunter selection). Mature belugas landed by Paulatuk hunters were younger and shorter than those taken in the Delta because of age and sex segregation in the hunting areas. There was no difference in the size-at-age relationships for belugas landed at Paulatuk vs the Delta. The linear trend in size-at-age indicated a decline of 0.08% (SE 0.038%) per year, or 1.75% over the 19 year time series. The 314 male belugas landed in the Delta between 2000 and 2007 showed statistically significant differences in blubber thickness among years, but only a slight downward trend over this short period. Mean blubber was thickest in 2002 and 2003 and thinnest in 2005. The thinness of belugas in 2005, and subtle changes in growth of the belugas over the time series, may reflect ecosystem changes that have reduced the availability or quality and quantity of their prey in recent years. Further research, including isotope and fatty acid profiling, would be helpful in substantiating the declining trend in growth and elucidating the causative factors.


AbstractWe present a case of multiplanar distraction osteogenesis for the simultaneous treatment of sagittal and unicoronal craniosynostosis in a nonsyndromic 2-month-old boy. Unilateral fronto-orbital advancement and sagittal suturectomy were performed. Distracters were fixed orthogonally in the sagittal and coronal positions to distract the affected coronal and sagittal sutures. The devices achieved 20 and 22 mm of advancement in the coronal and sagittal locations. A total intracranial volume increase of 62% was noted at 6 months' follow-up. This preliminary report demonstrates the procedure's short-term safety; future investigation is needed over the long term to determine its efficacy.


The study investigated the utilization of healthcare facilities among farming households in Yewa South Local Government Area of Ogun State. Multi-stage sampling technique was used to select 120 farming households and primary data were collected through the use of questionnaire. The data were analyzed using descriptive statistics and multivariate probit regression model. The results indicated that the mean age of the respondents was 41 years with an average household size of five people. About 31%of the respondents had no formal education and farming is the main occupation of respondents. Most (45.8%) of the respondents travelled a distance of 5 km or less before accessing health care facilities. Primary health care was the major health care service utilized by respondents in the study area. Results further revealed that age, education, household size, income, distance to healthcare facilities, severity of ailments and belief were the major socioeconomic factors determining demand for healthcare facilities in the study area. The findings call for government at all tiers to establish more healthcare facilities closer to the residence of the rural areas to increase the farming households' accessibility to these facilities. Keywords: healthcare, households, multivariate probit, trado-medicals


Despite recent molecular advances, the treatment of localized and metastatic prostate cancer has changed little in recent decades and it remains a major cause of cancer deaths in men. Localized prostate cancer may be either indolent or invasive, without reliable distinguishing markers, and the absence of tumor tissue from patients with metastatic bone disease has hampered understanding of acquired resistance to primary hormonal therapy. Given the predominant hematogenous spread of prostate cancer, circulating tumor cells (CTCs) may provide an indicator of vascular invasiveness, as well as a source of tumor specimens for molecular analysis, but available technologies have been limited by relatively low sensitivity. Huge strides in engineering at smaller scales have lead to the tremendous progress in microfabricated devices to facilitate both applied and basic research. Applying a multi-disciplinary approach, we have developed a microfluidic technology "CTC-Chip" for diagnosis and monitoring of non-hematological cancers. Using the CTC-Chip, we were able to isolate CTCs in patients with both localized and metastatic prostate cancer. In patients with advanced cancer, CTCs were present at a frequency of 34 CTCs/mL (range 14-653), with a profound decline in numbers during response to hormone withdrawal therapy. Molecular markers, including the characteristic TMPRSS2-ERG translocation, are readily identified in CTCs. In patients with early stage, resectable prostate cancer, we have monitored CTC load in circulation following surgical resection of the primary tumor. CTCs were examined the day following surgical resection, at postoperative day 9, and at greater than 3 months, coincident with scheduled postoperative clinical visits. Longitudinal monitoring of CTCs revealed all CTC-positive cases showed disappearance of CTCs following prostate resection, with some having an immediate decline and others having a delayed (>24 hours) response. No evident differences in tumor pathology or operative procedure distinguished patients with a rapid versus delayed postoperative CTC decline. Dual staining of captured CTCs for PSA and Ki67 indicated a broad range in proliferative index of CTCs among patients with different clinical courses. Thus, the quantitative isolation and analysis of CTCs in both localized and metastatic prostate cancer provides novel insights into early hematogenous dissemination and enables molecular analyses of treatment-responsive and -resistant disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1136.


[1] MgGeO3 post-perovskite (pPv) is a lower pressure analogue of MgSiO3-pPv, which is believed to be the main constituent of the Earth's D″ layer. Understanding the physical properties of this phase is critical to explain seismological observations as seismic anisotropy is likely linked to lattice preferred orientation in post-perovskite, which is governed by the motion of defects such as dislocations. Here, we apply in-situ three-dimensional X-ray diffraction to a polycrystalline sample of MgGeO3-pPv at 90 GPa. We demonstrate how the method can be used to follow individual grains within the material, including their individual orientations, positions, and strain tensors. We then use X-ray line profile analysis to characterize dislocations in the grains. The most probable slip systems are 12〈110〉 gliding on {1¯10} or (001) and [110](001), with a smaller contribution of [100](001) and [001] dislocations. These slip systems are shown to be consistent with observations of seismic anisotropy in D″.


Taking previous research work into account, I intend to formulate the anthropological issue in the context of contemporary philosophy, as it has been challenged in the last decades by accomplishments of biomedicine, especially molecular genetics and bioengineering, in their medical applications and different uses with other aims. Particular attention is given to epistemic, ontological and ethical aspects, by emphasizing the capacity of different technologies, in the wake of the different equations of knowledge and power, to make and create things, authorizing philosophical speculations about the new demiurge and the geneticist "playing God". From another perspective, with the powers of technology, especially of biotechnologies, the contemporary philosophical debate is marked by intense discussions about the dangers and the menaces caused by more radical and ambitious technologies, like CRISPR and transgenics. These debates give rise to proposals such as moratoria and stricter rules for bioproducts and biohackers, leading Chinese authorities to banish two geneticists who edited the HIV-immune twins. This is the more polemical and dramatic face of contemporary moral philosophy, whose foundations will be discussed in this paper and developed in further studies. Keywords: Philosophy, genetics and bioengineering; philosophy and anthropological issue; epistemics, ontological and ethical aspects; biotechnologies, CRISPR and transgenics; demiurge and playing God; moral implications.


Phosphorylated metabolites are omnipresent in cells, but their analytical characterization faces several technical hurdles. Here, we detail an improved NMR workflow aimed at assigning the high-resolution subspectrum of the phospho-metabolites in a complex mixture. Combining a pure absorption J-resolved spectrum (Pell, A. J.; J. Magn. Reson. 2007, 189 (2), 293-299) with alternate on- and off-switching of the 31P coupling interaction during the t1 evolution with a pure in-phase (PIP) HSQMBC experiment (Castañar, L.; Angew. Chem., Int. Ed. 2014, 53 (32), 8379-8382) without or with total correlation spectroscopy (TOCSY) transfer during the insensitive nuclei enhancement by polarization transfer (INEPT) gives access to selective identification of the individual subspectra of the phosphorylated metabolites. Returning to the initial J-res spectra, we can extract with optimal resolution the full trace for the individual phospho-metabolites, which can then be transposed on the high-resolution quantitative one dimensional spectrum.


Recent studies have highlighted the importance of the tumor metabolic environment for controlling immune activation. T-cells activated through the TCR/CD28 receptor switch to a highly glycolytic metabolism and increase their requirement for glucose and glutamine. Consequently, limited availability of glucose or glutamine can block T-cell activation and proliferation. Likewise, immune checkpoints proteins, PD-1 and CTLA-4, suppress T cell metabolism by inhibiting glycolysis, glutamine uptake and glutaminolysis (Patsoukis et al Nat Comm. 2015). Chang et al (Cell. 2015) recently demonstrated that glucose consumption by tumors restricts glucose availability and blocks activation of T cells, and that treatment with CTLA-4, PD-1, or PD-L1 antibodies can re-activate T cell glycolysis. CB-839 is a glutaminase inhibitor currently in Phase 1 trials in patients with solid and hematological malignancies. CB-839 blocks glutamine consumption in tumors and causes a significant elevation of tumor glutamine levels. Therefore, we hypothesized that CB-839 might enhance the activity of immune checkpoint inhibitors via metabolic modulation of the tumor microenvironment. We first confirmed that T- cell proliferation is dependent on glutamine but is only minimally inhibited by CB-839. In the absence of glutamine, splenic mouse T cells stimulated with anti-CD3/CD28 had reduced glucose consumption and did not proliferate. In contrast, CB-839 treatment did not mimic the effects of glutamine withdrawal on T-cells. CB-839 had no effect on glucose consumption by activated T-cells and only a minimal effect on proliferation. We also confirmed in the OVA vaccinia model that CB-839 had minimal effects on CD4 and CD8 T-cell proliferation in vivo, while the non-specific glutamine inhibitor DON caused a dramatic reduction in the number of CD4 and CD8 T-cells. To determine if CB-839 could enhance the anti-tumor efficacy of immune checkpoint inhibitors, we treated mice bearing syngeneic CT26 colon carcinoma tumors with anti PD-1 or anti PD-L1 alone or in combination with CB-839. The addition of CB-839 to either anti PD-1 or anti PD-L1 treatment enhanced anti-tumor activity, augmenting tumor regression and promoting survival. Depletion of CD8+ T-cells from CT26 tumors reversed the anti-tumor effects of PD-L1 and CB-839, demonstrating that the combination targets CD8+ T-cells in the immune microenvironment. These data are the first demonstration that modulation of glutamine metabolism in tumors can enhance the activity of checkpoint inhibitors and provide a rationale for combining CB-839 with immune checkpoint inhibitors in the clinic. Overall, these data highlight a new therapeutic approach to treating cancer by targeting tumor metabolism as a means of enhancing the efficacy of immunotherapy. Citation Format: Matt Gross, Jason Chen, Judd Englert, Julie Janes, Robert Leone, Andy MacKinnon, Francesco Parlati, Mirna Rodriquez, Peter Shwonek, Jonathan Powell. Glutaminase inhibition with CB-839 enhances anti-tumor activity of PD-1 and PD-L1 antibodies by overcoming a metabolic checkpoint blocking T cell activation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2329.


The admission procedure to higher education institutions in Turkey is based on the student's high school grades and Central University Entrance Examination (CUEE) score, with a much greater weight on the latter. However, whether the CUEE is an appropriate measure in the admission process to universities is still a much-debated question. This study assesses the validity of the CUEE as a selection tool for design-based departments by examining the relationship between CUEE scores and success in university education in two design-based departments, architecture and city planning. The analysis is then extended to test the relationship in three engineering departments, computer engineering, civil engineering, and mechanical engineering. Based on the bivariate correlation and one sample t-test result, we report that CUEE scores and graduation grades have no relationship at all. We conclude that the current admission procedure to design-based schools based on solely a central examination score is not preferable.


Students and teachers frequently speculate as to which foreign language is the most difficult for Englishspeaking students to learn and what makes some languages harder to learn then others. No qualitative or quantitative analysis of language learning difficulty has been applied thus far to answer these questions satisfactorily. In this article, we attempt to put forth a set of criteria by which foreign languages can be classified according to the degree of learning difficulty which they present to English-speaking students. These criteria are not intended to be a definitive basis for classifying learning difficulty. We believe, however, they can provide a useful framework for guiding operational decisions and testing policies at NSA. Language teachers realize that many difficulties in learning a second language are a function of the extent to which the second language differs from the first. Differences in pronunciation, grammar, and levels of politeness and honorifics can cause learning difficulties. If we describe the fundamental characteristics of the two languages and identify the set of characteristics which is unique to the second language, we can arrive at an approximate aggregate measure of relative learning difficulty. It is impossible to describe a specific number of characteristics that will do full justice to all the peculiarities of a given language. Language has so


Object recognition from a single view fails when the available features are not sufficient to determine the identity of a single object, either because of similarity with another object or because of feature corruption due to clutter and occlusion. Active object recognition systems have addressed this problem successfully, but they require complicated systems with adjustable viewpoints that are not always available. In this paper we investigate the performance gain available by combining the results of a single view object recognition system applied to imagery obtained from multiple fixed cameras. In particular, we address performance in cluttered scenes with varying degrees of information about relative camera pose. We argue that a property common to many computer vision recognition systems, which we term a weak target error, is responsible for two interesting limitations of multi-view performance enhancement: the lack of significant improvement in systems whose single-view performance is weak, and the plateauing of performance improvement as additional multi-view constraints are added.


Background: Despite the benefits of Computer Aided Detection (CAD), false detection of breast tumour is still a challenging issue with oncologist. A mammography is a non-invasive screening tool that uses low energy X-rays to show the pathology structure of breast tissue. Interpreting mammogram visually is a time consuming process and requires a great deal of skill and experience. Earlier Computer Aided Techniques emphasis detection of tumour in breast tissues rather than categorization of breast into Breast Imaging Report and Data System (BI-RADS) which is the medically understandable method of reporting. Aim: The work centred on developing a CAD system which is capable of not only detecting but also categorizing breast tissue in line with BI-RADS scale. Methodology: medical procedural approach was designed to categorize the tissue in breast images into low dense (fatty) and high dense. Tumours in the low dense breasts were segmented, and then classified as normal, benign and malignant. The developed system was evaluated using sensitivity, specificity, false positive reduction, false negative reduction and overall performance. Results: The developed CAD achieved 90.65% sensitivity, 73.59% specificity, 0.02 positive reduction, 0.04 false negative reduction and 85.71% overall performance. Conclusion: The false positive reduction result obtained shows that false detection has been minimized as a result of categorization procedure of the breast tissue in mammograms.


This thesis presents a novel policy assessment tool that serves as a decision support framework for analysis of energy policy problems involving multilevel, multidimensional and multi-stakeholder complexity. This new approach, The Energy Policy Assessment Technique (E-PAT), integrates System Dynamics Simulation and Multi-Criteria Evaluation models into a unified assessment framework. The E-PAT doubles as a systems-thinking model and a multi-criteria evaluation archetype. The E-PAT is designed for assessing policy issues, particularly those relating to energy planning in a national context. It is a suitable tool for evaluation and selection of optimal policies from competing and conflicting alternatives. To test its robustness and practical application, a case study on energy policy evaluation in Nigeria is carried out with this tool. A model of the Nigerian energy economy was constructed, and three proposed government policies for Sustainable Energy Development were evaluated relative to a Business-As-Usual case. The evaluation process identified 'best' policy options according to stakeholder viewpoints. The original contribution of this research is the creation of an integrated, transparent and comprehensive assessment tool, and the development of measurable Energy Sustainability Indicators (ESI), to aid policymakers in diverse policy analysis. The new tool is intended to support assessment of energy policies in relation to impacts on the economy, society and environment.


Abstract 1. The effect of the bacterium, Rhodopseudomonas palustris, on the growth performance and meat quality of broiler chickens was investigated. 2. A total of 900-d-old Arbor Acres broilers were allocated to three experimental treatments for 6 weeks. Chicks were administered with R. palustris in drinking water as follows: (i) control group without R. palustris; (ii) treatment 1 (R1) with R. palustris of 8 × 109 cells per chick per day in drinking water; (iii) treatment 2 (R2) with R. palustris of 1.6 × 1010 cells per chick per day in drinking water. 3. The results showed that, compared with that of control, both groups of R. palustris treatment increased daily weight gain and improved feed conversion ratio of broiler chickens significantly during the whole growing period of 6 weeks. 4. Both total and glutamic acid contents of chicken breast fillet in R. palustris treatment R2 were higher, while the fat content was lower, than those of the control group. Furthermore, R. palustris treatments also improved sensory attributes of chicken breast fillet. 5. As a probiotic providing rich nutrients and biological active substances, R. palustris administration in drinking water displayed a growth promoting effect and improved meat quality of broiler chickens.


The article is devoted to the oaths related to the inauguration of the authorities in medieval Cracow. The paper is mainly based on Cracow's two municipal codes: the Grabowski Codex (from the 14th and the 15th century) and the Balthasar Behem Codex (from the beginning of the 16th century).The oath played an enormous part in the legal and social relations in the Old Polish period. Cracow's burghers took an oath of homage (Latin homagium) to every single Polish monarch. Moreover, the clerks, municipal workers and craftsmen yearly pledged their allegiance to the city and took a vow to diligently perform their professional duties. The Grabowski Codex contains oaths (Latin iuramenta) which were written down chaotically for about two centuries. Consequently, it allows one to follow even minor changes in the content of the vows which highlights the significance of the contents of theoath themselves. On the other hand, the Balthasar Behem Code, which was a dignified book and a municipal insignia (Latin insignium), gathered the contemporary oaths in an orderly fashion. As a consequence, it outlines the hierarchy of the municipal clerks and institutions. This further emphasizes the huge importance of a municipal scribe whose oath is inscribed right after the pledge of the town council which was the main municipal institution in town. This paper also undertakes the topic of the elections of new people to perform various functions, pinpoints the dates of these nominations and it outlines the issue of the ceremonies which accompany them. At the same time, it emphasizes the splendour connected with the election of new members of the city council.


This thesis reports a study of the effects of ultrasound on crystal nuclcation from solution and particle breakage. Firstly, the effect of ultrasound on reactive crystallization when nuclcation is consistent with a predominantly homogeneous model is studied by measuring the induction time. Barium sulphate is used as the working substance precipitated by mixing aqueous BaCl2 and Na:S04 solutions. The relationship between amplitude of ultrasonic processor and power input was determined. The experiments were carried with various ultrasonic power inputs. It is observed that increasing ultrasound has a significant effect on reducing the induction time. At a given supersaturation level, the induction time decreases with increasing ultrasonic energy. The relationship between power input (E) and the activation energy of nucleation (E ) is discussed. And the equation between total power input (E) and the nucleation coefficient (A. ) is obtained. A cluster coagulation model, which brings together the current nucleation models and the theories describing the behavior of colloidal suspensions, was applied to estimate the induction time under various power inputs. A comparison between the predictions of the model and the results of experiments shows that the number of monomers in dominating clusters ( ) in the solution remains constant with increasing power input. The mechanism of the ultrasonic effect on homogeneous nucleation is analyzed. It is found that when temperature is kept constant, the main effect of ultrasound is to increase the diffusion coefficient (D,m)- Other parameters change only slightly or remain constant within the ultrasonic field. This suggests that diffusion acceleration is the main reason for the reduction of the induction time. The relationship of DAn and power input is also discussed. A mathematical model of power input and diffusion coefficient is presented, from which it is predicted that diffusivity enhancement (DAB- DAbo) has an exponential relationship with power input. The above relationship is consistent with the results of the experiments. Induction times have also been measured with and without ultrasound to investigate its effect on induction time of spectinomycin hydrochloride, roxithromycin and sucrose during anti-solvent crystallization. The relationship between ultrasonic power input and diffusion coefficient is also investigated. It is found that at the same power input, the ultrasonic effect on DAH decreases with increased solution viscosity. The effect of ultrasound on BaSO.* nucleation is also studied by measuring the induction time when nucleation is consistent with a predominantly heterogeneous model. In these experiments, barium sulphate is used as the working substance precipitated by mixing aqueous BaCb and Na2SC>4 solutions with relatively low concentrations compared to the experiments of homogeneous nucleation. It is observed that at a given supersaturation level, the induction time significantly decreases with increasing ultrasonic energy during heterogeneous nucleation. The mechanism of the ultrasonic effect on heterogeneous nucleation is analyzed. The effect of ultrasound is to increase the diffusion coefficient (DAb) while reducing the contact angle {lcub}0) and geometric factor if). This gives rise to an increase in the heterogeneous nucleation rate and shorter induction time. The ultrasonic effect on critical supersaturation ratio (Sfnf) is also investigated to determine the mechanism of ultrasonic effect on / and 0. It is proposed that both the force from the cavitational bubble implosion and the nucleation process occurring at bubble/solution/foreign solid interface are the predominant reasons why contact angle ( 0) decreases with the increase of power input. In addition, the effects of ultrasound on nucleation order (n) and the nucleation coefficient (ku) are also investigated, and compared with the corresponding effects during homogeneous nucleation. A cluster coagulation model is used to calculate the induction time at different levels of supersaturation when nucleation is consistent with a predominantly heterogeneous model. It is found that the dominant cluster size increases with increasing supersaturation and increasing ultrasonic energy. The effect of ultrasound on nucleation of BaS04 is studied by a Kodak Ektapro Hs motion analyzer. Firstly, the dispersion processes of ink with ultrasound and stirring are used to compare difference of the mixing processes and hydraulic flows. The vessel is divided into several sections to investigate the local mixing process by recording the movement of small silicon carbide crystals. Velocity variance is used to indicate the difference of turbulence when ultrasound is applied and when stirring is applied respectively. The cavitation distribution in different sections is also obtained. BaSC>4 is precipitated by mixing aqueous solutions of BaCb and Na2S04. The nucleation processes are observed by Kodak motion analyzer in different sections. The mechanism of nucleation by ultrasound is analyzed. Then, the induction times at different temperatures are measured with different power inputs at a given supersaturation level. The relationship between the cavitation distribution and temperature is established. (Abstract shortened by UMI.).


Using the Western Australian (WA) agricultural region as an example of a large-scale social-ecological system (SES), this paper applies a framework based on resilience theory to examine the region's resilience and capacity for change and renewal. Despite numerous policies directed at controlling natural resource degradation in this SES, sustainable natural resource management (NRM) has not been achieved. Disparities between the scale and complexity of the problem, the design of management policies, and region's history have all contributed to policy resistance. Historically, when considered as an integrated system, changes may be described by two iterations of the adaptive cycle. These cycles are also synchronous with the third and fourth Kondratiev long-wave economic cycles. The WA agricultural region has experienced sequential periods of growth and accumulation followed by reorganization and renewal, and currently is in the backloop (reorganization to exploitation phases) of the adaptive cycle. A region's adaptive capacity is achieved by substituting direct reliance on regional factors with institutional intervention and sophisticated technology, often generated at the global scale. This substitution alters the thresholds of the commodity system and gives the perception of an adaptive system. In contrast, however, if resource depletion, environmental pollution, and population decline, also effects of the commodity system, are included within the model then the region may be considered to be in a Lock-in pathological trap. We propose that the dynamics of land-use change between 1900-2003 were driven by macroeconomics at the global scale, mediated by institutions at the national and state scale. Also, the SES, which is composed of relatively fast-moving variables, is largely decoupled from the slow-moving ecological variables.


We report the enhancement of the blue upconversion emission in a Tm3+-Yb3+ codoped fluoroindate glass covered with silica microspheres. Each microsphere produces a photonic nanojet that concentrates the illuminating beam in a tiny region of the glass, increasing the intensity per unit area and so the upconversion emission by a factor of 3. Moreover, the mean size of the emission area has been reduced by a factor of 3 due to the three-photon process involved in the blue emission band. The experimental values of the full width at half-maximum of the emission spots have been found to be in agreement with the theoretical values obtained from finite-difference time-domain simulations.


We present results for entropy and kinetic energy spectra computed from direct numerical simulations for low-Prandtl-number (Pr < 1) turbulent flow in Rayleigh-Bénard convection with uniform rotation about a vertical axis. The simulations are performed in a three-dimensional periodic box for a range of the Taylor number (0 ≤ Ta ≤ 10(8)) and reduced Rayleigh number r = Ra/Ra(∘)(Ta,Pr) (1.0 × 10(2) ≤ r ≤ 5.0 × 10(3)). The Rossby number Ro varies in the range 1.34 ≤ Ro ≤ 73. The entropy spectrum E(θ)(k) shows bisplitting into two branches for lower values of wave number k. The entropy in the lower branch scales with k as k(-1.4 ± 0.1) for r>10(3) for the rotation rates considered here. The entropy in the upper branch also shows scaling behavior with k, but the scaling exponent decreases with increasing Ta for all r. The energy spectrum E(v)(k) is also found to scale with the wave number k as k(-1.4 ± 0.1) for r>10(3). The scaling exponent for the energy spectrum and the lower branch of the entropy spectrum vary between -1.7 and -2.4 for lower values of r (<10(3)). We also provide some simple arguments based on the variation of the Kolmogorov picture to support the results of simulations.


We investigate whether, in spite of the existence of cross‐market network externalities, platform competition can lead to segmentation of the two sides of the market served by the platforms. We address this question in the context of competition between two equity crowdfunding platforms that connect startups looking for capital with prospective investors. Given the heterogeneity in the populations of startups and investors in terms of the riskiness of the former population and the degree of risk aversion of the latter population, we investigate whether there exists an equilibrium where the two populations are segmented to ensure an improved match between them. We find that the segmenting equilibrium can arise only when compatibility in terms of their risk profiles is of high importance to both populations, and compatibility is significantly more important than the size of the network externality considered by startups. Segmentation is likely to improve the welfare of both populations when the basic benefit from any kind of match is relatively high.


The silvopastoral system is a viable technological alternative to extensive cattle grazing, however , for it to be successful, forage grass genotypes adapted to reduced light need to be identified. The objective of this study was to select progenies of Panicum maximum tolerant to low light conditions for use in breeding programs and to study the genetic control and performance of some traits associated with shade tolerance. Six full-sib progenies were evaluated in full sun, 50% and 70% of light reduction in pots and subjected to cuttings. Progeny genotypic values (GV) increased with light reduction in relation to plant height (H) and specific leaf area (SLA). The traits total dry mass accumulation (DM) and leaf dry mass accumulation (LDM) had GV higher in 50% shade and intermediate in 70% shade. The GV of tiller number (TIL) and root dry mass accumulation (RDM) decreased with light reduction. The highest positive correlations were obtained for the traits H and RDM with SLA and DM; the highest negative correlations were between TIL and SLA and RDM, and H and LDM. The progenies showed higher tolerance to 50% light reduction and, among them, two stood out and will be used in breeding programs. It was also found that it is not necessary to evaluate some traits under all light conditions. All traits had high broad sense heritability and high genotypic correlation between progenies in all light intensities. There is genetic difference among the progenies regarding the response to different light intensities, which will allow selection for shade tolerance.


Ecological vulnerability zoning research is an important basis for taking targeted regional ecological environment restoration and governance measures. This study analyzes the ecological vulnerability pattern and trend in the National Energy and Chemical Base (NECB) in the typical region of the Loess Plateau using GIS (Geographic Information System) data and the fuzzy analytic hierarchy process (FAHP) approach. Based on the human activity–natural environment factor index system, 13 factors representing human activities, socioeconomics, meteorology, soil and topography are selected to build an ecological vulnerability index (EVI) system in the NECB region, which aims at identifying the regional features of eco-environment and major environmental problems in the Loess Plateau. By calculating ecological vulnerability zoning, a model of ecological vulnerability trend change is constructed to quantitatively study the overall temporal and spatial variation of ecological vulnerability. The results indicate that the medium and heavy levels of ecological vulnerability index were mostly distributed in the areas with developed energy and chemical industries, and the slight and light levels were distributed in the southern area and developed agricultural regions. A comprehensive ecological vulnerability index had a score of 2.3207 in 2015 and 2.441 in 2000, indicating that the ecological security gradually improved. Nevertheless, highly intense human activities accelerated the degradation of regional eco-environment in recent years.


Cultural studies of the forest root pathogen Heterobasidion annosum (Fr.) Bref. have shown that the mycelium of the fungus possesses a high degree of developmental versatility, being able to grow in a variety of distinctive functional modes. Consequently the fungus can alternate between conidiogenous and meiotic reproductive pathways, rapid, sparsely branched and slow, densely branched mycelial extension, nutritive and non-nutritive modes, and'juvenile'and 'senescent'phases. This ability is probably of considerable importance in natural infection cycles and provides an interesting model for examining interrelationships between developmental regulation and host-pathogen interactions generally. It also raises important questions about the interface between environmental and endogenous controls of developmental pathways. CONTENTS Summary 245 I. Introduction 245 II. Spore germination and mycelial extension 246 III. Production of non-nutritive mycelium 249 IV. Sporophore production, senescence, somatic incompatibility and extracellular enzyme production 251 V. Discussion 254 Acknowledgements 255 References 255.


Abstract Previous studies of the Emar texts dealing with the Hittite administration in Emar have clarified that although there was a strong Hittite presence in Emar, the Hittites ruled it as a vassal kingdom, using the principle of indirect control. While admitting this point, this paper discusses an aspect of the rule which has been almost ignored, i. e., the aspect of direct control. In this regard, it is significant to note that there were Emariote citizens who performed the Hittite obligations (e.g., giš.tukul-duty) for the Hittite king (of Carchemish) in exchange for landed property. This indicates that the Hittites employed some of the Emariotes as local staff; in other words, they partly adopted the policy of direct control in the administration of Emar. The incident of the 'oppression' of Zū-Ba'la, an Emariote diviner of high rank, in which a certain Hittite official named Alziyamuwa tried to take away his landed property and to impose the šaḫḫan- and luzzi-duties on him (SMEA 45-T 1; BLMJE 32), should be understood in this context.


Abstract Through polarization observations masers are unique probes of the magnetic field in a variety of different astronomical objects, with the different maser species tracing different physical conditions. In recent years maser polarization observations have provided insights in the magnetic field strength and morphology in, among others, the envelopes around evolved stars, Planetary Nebulae (PNe), massive star forming regions and supernova remnants. More recently, maser observations have even been used to determine the magnetic field in megamaser galaxies. This review will present an overview of maser polarization observations and magnetic field determinations of the last several years and discuss the implications of the magnetic field measurements for several important fields of study, such as aspherical PNe creation and massive star formation.


The Large-Scale Social Limitation Policy (Pembatasan Sosial Berskala Besar/PSBB) was chosen by the Indonesian government in responding to the pandemic covid-19. The PSBB policy is preferred by the government to be implemented instead of lockdown. Much controversy in public over the PSBB policy has built the sentiment. Consideration of the economic aspects has been the main reason in making these policies. With consideration of the state of the Indonesian economy, the government believes that this policy is an effective and efficient pathway with a note that the public will be able to conduct pandemic covid-19 health protocol discipline and form herd immunity. This study aims to evaluate the effect of the implementation of the PSBB which has an impact on public sentiment fluctuations, using secondary stock return data on blue-chip stocks and the rupiah exchange rate in the range of time before and after the implementation of the PSBB begun, April 10, 2020. Wilcoxon test is used as data analysis tool of nonparametric statistics. The test results stated that the exchange rate of the rupiah against the US dollar was significantly affected by public sentiment towards the implementation of the PSBB, while the stock return was not significantly affected. Several factors beyond the implementation of PSBB need to be considered in influencing stock returns as well as the rupiah exchange rate.


The article considers a brief review of the last years of Russian and foreign research on the possibilities of improving mechanical properties of the Cantor quinary highentropy alloy (HEA) with different phase composition in wide temperature range. The alloy, one of the frst created equimolar HEAs with FCC structure, needs mechanical properties improvement in accordance with possible felds of application in spite of its high impact toughness and increased creep resistance. It has been noted that bimodal distribution of the grains by sizes under severe plastic torsional strain at high pressure of 7.8 GPa of cast alloy and subsequent shorttime annealing at 873 and 973 K can change strength and plastic properties. Nanodimensional scale of the grains surrounded by amorphous envelope has been obtained for HEA produced by the method of magnetron sputtering and subsequent annealing at 573 K. In such a twophase alloy nanohardness amounted to 9.44 GPa and elasticity modulus – to 183 GPa. Using plasticity effect induced by phase transformation in (CrMnFeCoNi)50Fe50 alloy obtained by the method of laser additive technology the ultimate strength of 415 – 470 MPa has been reached at high level of plasticity up to 77 %. It has been ensured by FCC → BCC diffusionless transformation. It is shown that difference in mechanisms of plastic strain of cast alloy at 77 K and 293 K (dislocation glide and twinning) determines a combination of increased "strengthplasticity" properties. Samples for generation of twins prestrained at 77 K exhibit increased strength and plasticity under subsequent loading at 293 K in comparison with the unstrained ones. For HEA obtained by laser additive technology this way of increasing properties is also true. The way of improving mechanical properties at the expense of electron beam processing is noted. The attention is paid to the necessity of taking into account the role of entropy, crystal lattice distortions, shortrange order, weak diffusion and "cocktail" effect in the analysis of mechanical properties.


The use of natural actives for cosmeceutical benefits has recently
gained high popularity due to their low side effects, natural origin and safety. The
fruits of Rosehip, a wild shrub native to Europe, Northwest Africa, and Western Asia
have been used in traditional medicines since ancient times. Seeds of Rosehip are known
to contain more than 50% of polyunsaturated fatty acids. Inherently, this class of phytoconstituents
has been reported to exhibit anti-aging potential.

The objective of the present study was to explore and establish the
photoprotective potential of Rosehip Seed Oil (RSO) obtained from Rosa rubigenosa and
develop a QbD-based topical nanoformulation.

The photo-protective potential of Rosehip Seed Oil was evaluated through
various in-vitro tests and biochemical assays. The o/w nanoemulsion (NE) of the oil was
prepared by the ultrasonication method following Central Composite Design (CCD) to
find the best possible formulation conditions. Nanoemulsion was further formulated into
a topical gel and evaluated for its semisolid attributes.

The antioxidant property of Rosehip Seed Oil assessed by estimating DPPH free
radical scavenging activity revealed that 45μg/ml of oil was equivalent to 8μg/ml of α-
tocopherol (standard). The total phenolic content of the oil was estimated to be
5.81μg/ml. IC50 values for anti-collagenase, anti-elastase and anti-hyaluronidase activities
were determined and found to be 7.34mg/ml, 42.3mg/ml and 36.34mg/ml, respectively.
The particle size, PDI, zeta potential, viscosity and pH of the optimized batch (R2)
were found to be 82.73nm, 0.214, -23.0 mV, 6.65cp and 6.94, respectively. The cumulative
release of the drug from the nanoemulsion gel was estimated for 7 hrs and found to
be 72.34%.

Results of all the in vitro studies performed led to the conclusion that Rosehip
oil possesses very good antioxidant, anti-inflammatory and photo-protective properties
and a nanoformulation of this plant seed oil has the potential to help in assuaging the
detrimental effects of UV rays like photoaging.


Abstract The usage of mobile phones is nowadays reaching full penetration rate in most countries. Smartphones are a valuable source for urban planners to understand and investigate passengers' behavior and recognize travel patterns more precisely. Different investigations tried to automatically extract transit mode from sensors embedded in the phones such as GPS, accelerometer, and gyroscope. This allows to reduce the resources used in travel diary surveys, which are time-consuming and costly. However, figuring out which mode of transportation individuals use is still challenging. The main limitations include GPS, and mobile sensor data collection, and data labeling errors. First, this paper aims at solving a transport mode classification problem including (still, walking, car, bus, and metro) and then as a first investigation, presents a new algorithm to compute waiting time and access time to public transport stops based on a random forest model. Several public transport trips with different users were saved in Rome to test our access trip phase recognition algorithm. We also used Convolutional Neural Network as a deep learning algorithm to automatically extract features from one sensor (linear accelerometer), obtaining a model that performs well in predicting five modes of transport with the highest accuracy of 0.81%.


The Truth about Patriotism is a bracing repudiation of the claim that patriotism is essential—or even beneficial—to democracy. Contending that even at its best patriotism subverts the democracy it purports to value, Steven Johnston turns to patriotism's defenders to show how they must jettison much of democracy to champion patriotism. Closely examined, patriotism itself effectively demonstrates the impossibility of love of country. Patriotism, Johnston argues, tends toward narcissistic self-regard, blind to its violent ways of being in the world and its dependence on death. Thus we would be better off without it.

Drawing largely from aspects of American political and popular culture, this wide-ranging book presents a wealth of examples to disclose patriotism's self-defeating character. They include Richard Rorty's and John Schaar's enmity-driven love of country, Socrates's angry judicial suicide, the violent obsessions of High Noon and Saving Private Ryan , the triumphalist self-display of the World War II Memorial, Oliver Stone's and Don DeLillo's spectacular representations of the assassination of President Kennedy, George W. Bush's symbolic sacrifice of more Americans in commemoration of September 2001, and yet other memorials to and apologies for patriotism. Ultimately, Johnston calls for a vision of democracy that uses the tragic possibilities inherent in politics as a spur to a life-affirming civic ethos of reciprocal generosity.


This chapter serves as an introductory chapter to the present volume on bank corporate governance. As such, it seeks to capture some of the specific corporate governance problems banks face, and to provide a useful background for the discussion of more detailed aspects of the topic in the forthcoming chapters. Of course, the views expressed herein are the author's own and other contributors to the volume may not agree with them. The analysis mainly focuses on UK banks that are listed on the London Stock Exchange, in other words, on large systemic banks. The corporate governance of banks is an area under continuous development which has changed dramatically in recent years both nationally and internationally. As all listed companies, UK banks are expected to comply with the UK Corporate Governance Code. In addition, the 2009 Walker Review introduced a series of governance recommendations specific to banks and other financial institutions. Many of these have since then been implemented by the PRA and now form part of the PRA Handbook. More recently, the report of the Parliamentary Commission on Banking Standards urged for broader changes to bank corporate governance including the approved persons' regime and directors' duties. In parallel, the fourth Capital Requirements Directive (CRD IV), impacts on bank corporate governance with regard to executive remuneration. Many of these issues will be explored in depth in the following chapters of this volume. The principal aim of this chapter is to illustrate that the private ordering model of bank corporate governance.


CRISPR-based high-throughput screens are a powerful method to unbiasedly assign function to a large set of genes, but current genome-wide libraries yield a substantial number of false positives and negatives. We use a retrieval-tree based approach to accurately characterize the off-target space of these libraries and show that they contain a notable fraction of highly promiscuous gRNAs. Promiscuous gRNAs are depleted from screens in a gene-independent manner, create noise in the data generated by these libraries, and ultimately lead to low accuracy in hit identification. This extensive off-targeting also contributes to low overlap between data generated by independent libraries. To minimize these problems we developed the CRISPR Specificity Correction (CSC), a computational approach that segregates on- and off-targeting effects on gRNA depletion. We demonstrate that CSC is able to reduce the occurrence of false positives, improve hit reproducibility between different libraries, and uncover both known and novel genetic dependencies in melanoma cells.


Abstract 2610 Background: Acute leukemia, characterized by the presence clonal hematopoietic cells in peripheral blood and bone marrow, comprises approximately 40% of newly diagnosed leukemias. First line treatment for acute leukemias with multi-agent cytotoxic chemotherapy is usually associated with significant toxicity. Advances in therapy have been slow, and nearly all effective therapies lead to prolonged marrow suppression and toxicities associated with subsequent cytopenias. Herein, we describe the biological and pharmacokinetic properties of TGR-1202, a novel small molecule PI3Kδ inhibitor with scope to be developed as a safe and effective therapy for acute myeloid (AML) and lymphoblastic (ALL) leukemia. Material & Methods: Activity of TGR-1202 against individual isoforms of the PI3K enzyme was determined via enzyme, cellular, and whole blood based assays. Potency of the compound was confirmed via leukemic cell viability and Annexin V/PI staining besides testing for inhibition of pAkt, a downstream kinase regulating cell survival and growth. These assays were conducted with cell lines (CCRF-CEM, HL-60, and MOLT-4) and patient derived cells. Anti-tumor efficacy of the compound was studied in vivo with the subcutaneous MOLT-4 xenograft model. Lastly, ADME and pharmacokinetic properties of the molecule were determined. Results: TGR-1202 demonstrated significant potency against PI3Kδ (22.2 nM) with several fold selectivity over the α (>10000), β (>50), and γ (>48) isoforms. Additionally, the compound inhibited B-cell proliferation (24.3 nM) and FceR1 induced CD63 expression in human whole blood basophils (68.2 nM) indicating specificity towards the delta isoform. Viability testing demonstrated that the compound caused a dose-dependent inhibition in growth of immortalized as well as patient-derived AML and ALL cells. Reduction in viability was accompanied by a reduction in pAKT (>50% @ 0.3–1 μM) along with a significant induction in apoptosis in both cell lines (CCRF-CEM, HL-60, and MOLT-4) and patient samples. In tumor xenografts, oral administration of 150 mg/kg RP5264 salt over a 25-day period resulted in significant inhibition (>50%) of MOLT-4 tumor growth in mice. Pharmacokinetic studies across species indicated good oral absorption (>40% bioavailability for mice, rat, and dog) with favorable plasma concentrations (3–10 μM @ 20 mg/kg for mice, rat, and dog) relevant for efficacy. In addition, early toxicological evaluation of the molecule indicated a MTD > 500 mg/kg over a 14-day treatment period in Balb/c mice. Conclusions: TGR-1202, primarily, through its activity at the δ isoform of PI3K, has activity in both myeloid and lymphoid acute leukemia cell lines and primary patient tumors. Further evaluation of this molecule in the treatment of AML and ALL is justified, and current testing of TGR-1202 in various leukemia cell lines and within a variety of primary leukemias is ongoing. Disclosures: Vakkalanka:Rhizen Pharmaceuticals S A: Employment, Equity Ownership. Viswanadha:Incozen Therapeutics: Employment. Niecestro:TG Therapeutics, Inc.: Consultancy, Equity Ownership. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership.


Autophagy is an evolutionary conserved, lysosome-involved cellular process that facilitates the recycling of damaged macromolecules, cellular structures, and organelles, thereby generating precursors for macromolecular biosynthesis through the salvage pathway. It plays an important role in mediating biological responses toward various stress, including those caused by ionizing radiation at the cellular, tissue, and systemic levels thereby implying an instrumental role in shaping the tumor responses to radiotherapy. While a successful execution of autophagy appears to facilitate cell survival, abortive or interruptions in the completion of autophagy drive cell death in a context-dependent manner. Pre-clinical studies establishing its ubiquitous role in cells and tissues, and the systemic response to focal irradiation of tumors have prompted the initiation of clinical trials using pharmacologic modifiers of autophagy for enhancing the efficacy of radiotherapy. However, the outcome from the Phase I/II trials in many human malignancies has so far been equivocal. Such observations have not only precluded the advancement of these autophagy modifiers in the Phase III trial but have also raised concerns regarding their introduction as an adjuvant to radiotherapy. This warrants a thorough understanding of the biology of the cancer cells, including its spatio-temporal context, as well as its microenvironment all of which might be the crucial factors that determine the success of an autophagy modifier as an anticancer agent. This review captures the current understanding of the interplay between radiation induced autophagy and the biological responses to radiation damage as well as provides insight into the potentials and limitations of targeting autophagy for improving the radiotherapy of tumors.


One of the main issues in distribution sector is to achieve simultaneously high system reliability and low capital costs. Distribution automation systems (DASs) involve automatic and remote-controlled switches. The switches play a significant role in system reliability improvement. This paper proposes the modified shuffled frog leaping algorithm (SFLA) to derive the optimal placement of manual and automatic switches in DASs. A fuzzy approach is used to handle the multi objective considerations, and a fuzzy membership function is defined for each term in the objective function. The first objective is reliability improvement by minimising the customer interruption cost (CIC), and the second objective is to minimise switches purchasing and maintenance cost (SPMC). In this paper, a new method is developed to evaluate CIC and SPMC indices in a distribution network. In the proposed method, customer types, customers load patterns, monthly, daily and hourly customers loading rates are considered. In addition, network branches' failure rate, restoration time and repair time are taken into account. The performance of the proposed approach is assessed and illustrated by studying on the IEEE 123-node feeder standard test system. The simulation results verify the capability of the proposed method.


A nonvolatile organic transistor memory device was developed using layer-by-layer assembly of 3-aminopropyltriethoxysilane (APTES) and solution-processed, reduced graphene oxide (rGO) as the charge trapping layer on flexible substrates. Reduction of graphene oxide and successful adsorption of the rGO on APTES-covered substrates were confirmed. The organic memory devices based on rGO exhibited reliable programmable memory operations, confirmed by program/erase operations, data retention, and endurance properties. These methods can potentially play a significant role in the fabrication of next-generation flexible nonvolatile memory devices based on graphene materials.


Enhancing the dispersion and dissolution of substrate particles in substrate/water suspen- sion is a feasible way to improve steroid bioconversion. The aim of the present study is to investi- gate the effects of applying surfactant to microbial conversion system on the dispersion, solubiliza- tion and in turn bioconversion of steroid substrate. The model system is hydroxylation of substrate 16α-, 17α-epoxy-4-pregnene- 3 ,20-dine by microbial enzymes from Rhizopus nigricanl. The results show that the presence of substrate leads to an increase in critical micelle concentration ( CMC) of surfactant PSE compared with the normal CMC of PSE in aqueous solution. The grinding time dur- ing substrate suspension preparation affects the substrate aqueous solubility differently with the va- ried surfactant concentrations while barely making any difference in substrate solubility in the ab- sence of surfactant. The properly prolonged grinding time can make up for the loss in substrate so- lubility arising from the reduction in surfactant concentration. The surfactant complexes composed of surfactants PSE and MGE at appropriate ratios are screened out with orthodoxy experiment meth- od, the interaction between PSE and MGE exerts the most prominent effects on substrate biocon- version. and the surfactant complexes show more beneficial effects on steroid bioconversion than the surfactant PSE used alone.


Patient follow-up based on PET scans is a promising approach for early assessment of tumor response and for detection of tumor recurrence. In this work, we introduce a parametric imaging method to detect and analyze the tumor changes between 2 consecutive PET scans. Fifteen pairs of consecutives PET/CT images obtained during the course of lung cancer patient monitoring were considered. For each pair, after CT- based registration of the PET images, the two PET datasets were subtracted. A biparametric graph of subtracted voxel values versus voxel values in the first scan was obtained. A model- based analysis of this graph was used to identify the tumor voxels in which significant changes occurred between the 2 scans, and yielded indices characterizing the changes. In our patients, the proposed approach correctly identified all tumor changes as confirmed using a conventional analysis. In addition, the parametric imaging approach can reveal heterogeneities in tumor response and does not require the preliminary identification of the tumors.


Markedly or mildly elevated circulating homocysteine concentrations are associated with increased risk of vascular occlusion. Here we review possible mechanisms that mediate these effects. Inborn errors of homocysteine metabolism result in markedly elevated plasma homocysteine (200-300 μmol/L) and thromboembolic (mainly venous) disease which is easily normalized with oral folate and ongoing trials are assessing the effect of folate treatment on outcomes. Some people have a common genetic variant (called methylenetetrahydrofolate reductase, abbreviated MTHFR) that also impairs their ability to process folate. Indeed, there are evidences suggesting an acute antioxidant effect of folic acid on homocysteine concentrations. This antioxidant mechanism may oppose an oxidant effect of homocysteine and be relevant to treatment of patients with vascular disease, especially those with chronic renal insufficiency. Such patients have moderately elevated plasma homocysteine and greatly increased cardiovascular risk that is largely unexplained.


Abstract We present the crystal structure, composition, and occurrence of stöfflerite, the naturally occurring Ca-aluminosilicate with hollandite-type structure. Stöfflerite is a high-pressure polymorph of anorthite and an approved mineral. The type material was found in the shergottitic martian meteorite Northwest Africa 856. Type stöflerite (Sto60Lin40) assumes space group I4/m with unit-cell dimensions a = 9.255(1) Å, c = 2.742(3) Å, V = 235.1(2) Å3, and Z = 2.


(Lymph)angiogenesis into the cornea prior to and after corneal transplantation is a critical risk factor for allograft rejection. Lymphatic vessels even more than blood vessels seem important in mediating immune responses, as they facilitate allograft sensitization in the draining lymph nodes. Thus, the concept of modulating lymphatic trafficking to promote corneal graft survival seems promising. A variety of approaches has been developed to inhibit progressive lymphangiogenesis in experimental settings. Recently, additionally to pharmacological approaches, clinically available techniques such as UVA-based corneal collagen crosslinking and fine needle diathermy were reported to be effective in regressing lymphatic vessels and to experimentally promote graft survival. Clinical pilot studies also suggest the efficacy of blocking antigen presenting cell trafficking to regional lymph nodes by regressing corneal lymphatic vessels to enhance allograft survival in high-risk eyes. In this article, we will give an overview of current strategies to modulate lymphatic trafficking with a special focus on recently reported strategies, which may be easy to translate into clinical practice. This novel concept of temporary, pretransplant regression of lymphatic vessels at the site of transplantation to promote subsequent corneal transplant survival ("lymphangioregressive preconditioning") may also be applicable to other transplantation sites later.


Whilst tight-binding bandstructure calculations are very successful in describing the Fermi-surface configuration in many quasi-two-dimensional organic molecular metals, the detailed topology of the predicted Fermi surface often differs from that measured in experiments. This is very significant when, for example, the formation of a density-wave state depends critically on details of the nesting of Fermi-surface sheets. These differences between theory and experiment probably result from the limited accuracy to which the -orbitals of the component molecules (which give rise to the transfer integrals of the tight-binding bandstructure) are known. In order to surmount this problem, we have derived a method whereby the transfer integrals within a tight-binding bandstructure model are adjusted until the detailed Fermi-surface topology is in good agreement with a wide variety of experimental data. The method is applied to the charge-transfer salt -(BEDT-TTF)2KHg(SCN)4, the Fermi surface of which has been the source of much speculation in recent years. The Fermi surface obtained differs in detail from previous bandstructure calculation findings. In particular, the quasi-one-dimensional component of the Fermi surface is more strongly warped. This implies that upon nesting of these sheets, significant parts of the quasi-one-dimensional sheets remain, leading to a complicated Fermi-surface topology within the low-temperature, low-magnetic-field phase. In contrast to previous models of this phase, the model for the reconstructed Fermi surface in this work can explain virtually all of the current experimental observations in a consistent manner.


The persistence of difficulties caused by misconceptions under - underlying the concept force identified in the learner, is not caused only from his misconceptions, but also, sometimes and especially strengthened by the mathematical approach based on a reduction of the mechanical questions to vector geometry problems, during the transposition of learned knowledge to teach and taught knowledge. In this context, the worst here is that the didactic act instead of conveying knowledge built, generates erroneous conceptions. We show in this paper , with examples to support that language tools (the definition of force , symbolization, selected physical situations , and application's exercises ) involved in the theory of content knowledge to teach are reduced in order to adapt to this mathematical model. Therefore , errors of transmission of force deplored in learner by didacticians are being taught in textbooks of physics. As a result , the persistence of errors in learner is than evident


It is estimated that there are 750,000 people each year who are intimately affected by suicide. Prominent among these are the family survivors and their family physician. This paper offers a time frame which divides the period following the suicide into three phases: Immediate (the first ten days after the suicide); Intermediate (after the first ten days through the first year); and Extended (from the first year until restitution occurs). It identifies the chief emotional reactions which occur in each phase, explores their psychodynamic origins, and proposes suggestions for appropriate management during each of the three periods. The goal of this plan of management is to enable the family physician to function in a supportive emphatic, and restorative manner for the post-suicide family.


Involuntary irresponsible parenthood is compounding the welfare and illegitimacy problems of the U.S. population. There is medical apathy toward fertility control because doctors are conservative by nature. However there is a trend for medical men to become more active in all kinds of social economic community and even political matters. In December 1961 there were 7250000 persons in the U.S. ON some kind of relief or welfare aid. In 1960 830 million tax dollars went to support unwanted or inadequately cared for children in the U.S.. The author states that women who have had many children usually are delighted to hear that they can be "fixed" so that they may never have any more children. The doctor should take a few minutes in explaining the details of a postpartum tubal section and to stress that no organ is being removed and that the women will go on menstruating etc.


We investigated the common difficulties that students have with concepts related to rotational and rolling motion covered in the introductory physics courses. We compared the performance of calculus- and algebra-based introductory physics students with physics juniors who had learned rotational and rolling motion concepts in an intermediate level mechanics course. Interviews were conducted with six physics juniors and ten introductory students using demonstration-based tasks. We also administered free-response and multiple-choice questions to a large number of students enrolled in introductory physics courses, and interviewed six additional introductory students on the test questions (during the test design phase). All students showed similar difficulties regardless of their background, and higher mathematical sophistication did not seem to help acquire a deeper understanding. We found that some difficulties were due to related difficulties with linear motion, while others were tied specifically to the more intricate nature of rotational and rolling motion.


The purpose of this paper is to consider the accessibility of Apple's iPad. The discussion focusses on the accessibility of this technology to children and young people with cerebral palsy (CP), reviewing a range of literature. Terms including "inclusion" are debated alongside the practicalities associated with implementing assistive technologies in educational settings. The benefits of technology for those with CP are explored, with examples including augmentative and alternative communication systems. The current suitability of the iPad for children and young people with CP is discussed, alongside ways in which eye-gaze technology may be employed to increase inclusivity.,The paper provides a consideration of multiple methods for evaluating the inclusivity of mainstream technologies. It is contended that the universal design for learning (UDL) principles are likely to be the most appropriate, due to their applicability to educational settings. Furthermore, the UDL principles acknowledge the heterogeneity of those with CP, and this is suggested to be useful due to its ability to be integrated alongside some of the principles of assistive technology.,The discussion contends that Apple's iPad may be redesigned in order to meet the needs of users with CP. Eye-gaze technology is suggested as one way to include this group of users, due to the altered interface interaction. Despite some challenges with the eye-gaze technology, the paper suggests that this alteration to the iPad may result in increased accessibility not only for those with CP, but also others with fine motor difficulties. It is concluded that the integration of eye-gaze technology with Apple's iPad may be a potential avenue for future investigation.,By altering the interface interaction on Apple's iPad, the device may be more accessible to users with fine motor difficulties, such as those with CP. It is suggested that the paper may inspire future research concerning the practicalities of integrating eye-gaze technology on a small, portable device.,Those who are of lower socioeconomic status are less likely to have access to assistive technologies; the cost of Apple's devices is relatively higher than those produced by other technology companies, confining their availability to wealthier consumers. This may also lead to a divide in inclusive technical capital (Hayhoe, 2015), whereby wealthier users may have an increased potential to access inclusive assistive technologies and thus increase their capital.,The paper integrates a discussion of the UDL principles with their application to both assistive technologies and educational settings. It is speculated that this paper may be valuable to those researching in the field of assistive technologies, who may build upon the present discussion with a research study. It is also anticipated that the consideration of the use of the iPad for children and young people with CP may be of use to those working in education who wish to integrate technology into the education of those with a range of special educational needs.


Targeting of histone modifications is clinically feasible due to the development of histone deacetylase inhibitors (HDACi), several of which are FDA-approved. In order to identify strategies to augment activity of HDACi, we tested inhibition of lysine specific demethylase-1 (KDM1A/LSD1) in combination with HDACi in malignancies where single agent activity was limited in clinical trials: acute leukemia and glioblastoma, In brain tumor cell lines, patient derived glioblastoma stem cells, and a series of acute leukemia lines, we find high expression of LSD1 protein. Using either knockdown of LSD1, or chemical inhibition via the FDA approved drug, tranylcypromine, we report significant enhancement of HDACi induced cell death. Multiple HDACi were used including vorinostat, panobinostat and entinostat, and cytoxicity was consistently heightened when combined with LSD1 inhibition. Indicative of selectivity of this therapeutic approach, augmentation of HDACi cytotoxicity occurred exclusively in tumor cells, and not in normal counterparts. Caspase activation is a feature of cell death induction by HDAC and LSD1 inhibition and pan-caspase inhibition blocks cell death. Using chemical inhibitors of caspase-8, -9 and -3 and caspase-8 deficient cells, we demonstrate a reliance upon extrinsic pathways of caspase activation by the combination therapy. However, data obtained with caspase-8 deficient cells showed a lack of protection in cells treated with LSD1 inhibitor combined with pan-HDACi (vorinostat and panobinostat), whereas there was significant protection in cells treated with entinostat (a Class I HDACi) and LSD1 inhibitor. This suggests that pan-HDACi may trigger alternate caspases, such as caspase-10, which are blocked by peptide inhibitors but are still active in caspase-8 deficient cells. To gain additional insight into the contribution of LSD1 to cytotoxicity, an apoptosis focused array and RNA-Seq were conducted. The majority of gene expression changes were seen in cells exposed to HDACi alone. However, some of these gene expression changes were further enhanced when LSD1 was also inhibited. Expression of the tumor suppressor genes, p53 and p73, was significantly reduced by HDACi alone, and by the combination of HDACi and LSD1 inhibition. Hrk, a pro-apoptotic Bcl-2 family member, known to be silenced in glioblastoma, was re-expressed by the combination therapy. Time course analyses indicated the loss of p53, p73 and increased Hrk, was an early event, occurring within 6 hours of exposure to HDACi and LSD1 inhibitors, and preceded caspase activation. Upregulation of Hrk transcript was robust and rapid. We observed a ten-fold increase within 3 h of exposure to these agents. Further studies will evaluate the contribution of these early changes to caspase activation, thereby delineating the pathway by which HDACs and LSD1 can be optimally targeted in leukemia and brain tumor model systems. Citation Format: Melissa Singh, Hayley Donnella, Lorimar Ramirez, Joya Chandra. Mechanism of cell death induction by dual targeting of HDACs and lysine specific demethylase, LSD1, in leukemias and brain tumors. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B49.


We provide evidence that dividends signal sustainable earnings generated by assets-in-place for firms with weak investment opportunities. In the cross-section, both dividend levels and changes contain more earnings information among firms with weaker investment opportunities. Intertemporally, when aggregate investment opportunities in the economy are worse, dividend changes convey more earnings information. In contrast, dividends have a more negative association with investment spending for firms with strong growth options, as funding investment is a higher priority for those firms. Collectively, our findings suggest that dividends serve as a counter-signal, whereby additional information about investment opportunities give rise to signaling that is non-monotonic in firm quality.


This engaging and objective biography gives us a comprehensive account of Ervin's life and career, tracing his development from a shy romantic youth into the complex and mature man. The author tells of the boyhood years in North Carolina, the influences of family, friends, and history, the college years, World War I, and Harvard, as well as Ervin's frequently colorful apprenticeship as country lawyer, judge, state legislator, congressman, and senator. Clancy brings to his task a thorough knowledge of Ervin developed while covering his activities prior to and during Watergate. He has had many exclusive private interviews with the Senator, his wife, family, friends, and staff during which Ervin in particular shared many reminiscences, anecdotes, and stories which have not appeared before.


The taxonomy of pedunculate cirripedes belonging to the genus Pollicipes has essentially remained unchanged since Charles Darwin described them in his exhaustive work on the Cirripedia. This genus includes three species of stalked barnacles: Pollicipes pollicipes in the north-eastern Atlantic, P. polymerus in the north-eastern Pacific and P. elegans in the central-eastern Pacific. However, a population genetics analysis of P. pollicipes suggested the presence of a putative cryptic species collected from the Cape Verde Islands in the central-eastern Atlantic. This study examines the morphology of these genetically divergent specimens and compares them with that of representative Atlantic samples of the biogeographically closely related P. pollicipes and with the poorly described P. elegans. Molecular data, including mitochondrial COX1 and nuclear ribosomal interspaces sequences, were obtained for all species of the genus Pollicipes. Morphological distinctiveness, diagnostic characters, congruent divergence level and monophyletic clustering, at both nuclear and mitochondrial loci support the taxonomic status of this new species, Pollicipes darwini.