Miracle-dz/UniFAR-FTUs huggingface dataset:
Treatment of lymphocyte-predominant Hodgkin lymphoma.

Lymphocyte-predominant Hodgkin lymphoma (LPHL) was first described as Hodgkin’s paragranuloma by Jackson and Parker in 1944 [1]. Subsequently, a number of different terms such as lymphocytic-predominant Hodgkin’s disease or lymphocytic and histiocytic-predominant Hodgkin’s disease were used [2]. LPHL is rare, accounting for 5% of all Hodgkin lymphoma (HL) cases in western countries [3]. LPHL and classical HL (cHL) differ substantially in their histopathology and clinical cause. Histologically, LPHL can present with two distinct morphological patterns: nodular and diffuse. The nodular subtype is characterized by the presence of atypical lymphocytic and histiocytic (L&H) or popcorn cells that are embedded in a nodular background of small B lymphocytes and other reactive cells. In the diffuse subtype, the L&H cells are set against a diffuse background consisting mainly of reactive T cells. However, it remains controversial whether the diffuse subtype can be discriminated reliably. According to the current WHO definition, at least a partial nodular pattern is required for the diagnosis of NLPHL [4]. Compared with cHL, LPHL has been associated with less aggressive tumor growth and lymphadenopathy often preceding the diagnosis for many years [5]. Since the treatment of patients with LPHL results in complete remission (CR) in >95% of patients, the need for different treatment approaches particularly for early-stage patients has been questioned recently.
Pseudomonas aeruginosa ExoT Induces Mitochondrial Apoptosis in Target Host Cells in a Manner That Depends on Its GTPase-activating Protein (GAP) Domain Activity*

Background: The GAP domain of ExoT induces apoptosis in epithelial cells, but the mechanism underlying GAP-induced apoptosis remains unknown. Results: GAP domain activates JNK1/2, causes cytochrome c release, and activates caspase-9 and caspase-3. Conclusion: GAP domain of ExoT induces intrinsic apoptosis in epithelial cells. Significance: The GAP and the ADPRT domains make ExoT into a potent cytotoxin, capable of inducing different forms of apoptosis. Pseudomonas aeruginosa is the most common cause of hospital-acquired pneumonia and a killer of immunocompromised patients. We and others have demonstrated that the type III secretion system (T3SS) effector protein ExoT plays a pivotal role in facilitating P. aeruginosa pathogenesis. ExoT possesses an N-terminal GTPase-activating protein (GAP) domain and a C-terminal ADP-ribosyltransferase (ADPRT) domain. Because it targets multiple non-overlapping cellular targets, ExoT performs several distinct virulence functions for P. aeruginosa, including induction of apoptosis in a variety of target host cells. Both the ADPRT and the GAP domain activities contribute to ExoT-induced apoptosis. The ADPRT domain of ExoT induces atypical anoikis by transforming an innocuous cellular protein, Crk, into a cytotoxin, which interferes with integrin survival signaling. However, the mechanism underlying the GAP-induced apoptosis remains unknown. In this study, we demonstrate that the GAP domain activity is both necessary and sufficient to induce mitochondrial (intrinsic) apoptosis. We show that intoxication with GAP domain results in: (i) JNK1/2 activation; (ii) substantial increases in the mitochondrial levels of activated pro-apoptotic proteins Bax and Bid, and to a lesser extent Bim; (iii) loss of mitochondrial membrane potential and cytochrome c release; and (iv) activation of initiator caspase-9 and executioner caspase-3. Further, GAP-induced apoptosis is partially mediated by JNK1/2, but it is completely dependent on caspase-9 activity. Together, the ADPRT and the GAP domains make ExoT into a highly versatile and potent cytotoxin, capable of inducing multiple forms of apoptosis in target host cells.
Selective Tumor Hypoxia Targeting by Hypoxia-Activated Prodrug TH-302 Inhibits Tumor Growth in Preclinical Models of Cancer

Purpose: Tumor hypoxia underlies treatment failure and yields a more aggressive, invasive, and metastatic cancer phenotype. TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard (Br-IPM). The purpose of this study is to characterize the antitumor activity of TH-302 and investigate its selective targeting of the hypoxic cells in human tumor xenograft models. Experimental Design: Antitumor efficacy was assessed by tumor growth kinetics or by clonogenic survival of isolated cells after tumor excision. Hypoxic fractions (HF) were determined by immunohistochemistry and morphometrics of pimonidazole staining. Tumor hypoxia levels were manipulated by exposing animals to different oxygen concentration breathing conditions. The localization and kinetics of TH-302 induced DNA damage was determined by γH2AX immunohistochemistry. Results: TH-302 antitumor activity was dose-dependent and correlated with total drug exposure. Correlation was found between antitumor activity and tumor HF across 11 xenograft models. Tumor-bearing animals breathing 95% O2 exhibited attenuated TH-302 efficacy, with whereas those breathing 10% O2 exhibited enhanced TH-302 efficacy, both compared with air (21% O2) breathing. TH-302 treatment resulted in a reduction in the volume of the HF 48 hours after dosing and a corresponding increase in the necrotic fraction. TH-302 induced DNA damage as measured by γH2AX was initially only present in the hypoxic regions and then radiated to the entire tumor in a time-dependent manner, consistent with TH-302 having a “bystander effect. ” Conclusions: The results show that TH-302 has broad antitumor activity and selectively targets hypoxic tumor tissues. Clin Cancer Res; 18(3); 758–70. ©2011 AACR.
Comprehensive Review in Current Developments of Imidazole‐Based Medicinal Chemistry

Imidazole ring is an important five‐membered aromatic heterocycle widely present in natural products and synthetic molecules. The unique structural feature of imidazole ring with desirable electron‐rich characteristic is beneficial for imidazole derivatives to readily bind with a variety of enzymes and receptors in biological systems through diverse weak interactions, thereby exhibiting broad bioactivities. The related research and developments of imidazole‐based medicinal chemistry have become a rapidly developing and increasingly active topic. Particularly, numerous imidazole‐based compounds as clinical drugs have been extensively used in the clinic to treat various types of diseases with high therapeutic potency, which have shown the enormous development value. This work systematically gives a comprehensive review in current developments of imidazole‐based compounds in the whole range of medicinal chemistry as anticancer, antifungal, antibacterial, antitubercular, anti‐inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral, and other medicinal agents, together with their potential applications in diagnostics and pathology. It is hoped that this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic imidazole‐based medicinal drugs, as well as more effective diagnostic agents and pathologic probes.
Meta-analysis of the Effects of Insect Vector Saliva on Host Immune Responses and Infection of Vector-Transmitted Pathogens: A Focus on Leishmaniasis

A meta-analysis of the effects of vector saliva on the immune response and progression of vector-transmitted disease, specifically with regard to pathology, infection level, and host cytokine levels was conducted. Infection in the absence or presence of saliva in naïve mice was compared. In addition, infection in mice pre-exposed to uninfected vector saliva was compared to infection in unexposed mice. To control for differences in vector and pathogen species, mouse strain, and experimental design, a random effects model was used to compare the ratio of the natural log of the experimental to the control means of the studies. Saliva was demonstrated to enhance pathology, infection level, and the production of Th2 cytokines (IL-4 and IL-10) in naïve mice. This effect was observed across vector/pathogen pairings, whether natural or unnatural, and with single salivary proteins used as a proxy for whole saliva. Saliva pre-exposure was determined to result in less severe leishmaniasis pathology when compared with unexposed mice infected either in the presence or absence of sand fly saliva. The results of further analyses were not significant, but demonstrated trends toward protection and IFN-γ elevation for pre-exposed mice.
TAMOT: MASCULINITIES IN TRANSITION IN PAPUA NEW GUINEA

This thesis is an exploration of gender relations in contemporary Papua New Guinea. It is dedicated to unveiling the standpoints of senior men in a range of powerful senior positions towards issues of gender, and asks the question ‘How do contemporary big men conceptualise their own and others’ masculinity? ’ Firstly, it begins with a discussion of the legacy of the colonial era in terms of gendered power and looks at some of the ways in which Western Anthropologists typified masculinities and, to a lesser extent, femininities. Secondly, it surveys a range of literature written within the West which deals with theories of gender and attempts to apply these to the Papua New Guinean context. Following this is the chapter which gives an overview of the methodological considerations and research methods employed in the thesis. Using a feminist perspective, it goes on to investigate the perspectives of a number of men who hold senior positions within the education system, the public service, non-government organisations and the government itself in order to ascertain what, if any, contribution they offer the project of developing gender equity. In doing so, it considers the typologies of masculinity problematised by the participants and a model of their interrelation and intersections is offered.
Social Development and Happiness in Nations

The term "social development" is used rhetorically in pleas for less focus on "economic development". In that context it is commonly assumed that social development will add to human happiness and more so than economic development does. These claims are checked in an analysis of 141 contemporary nations. Social development is measured using five ISD "Indices of Social Development": a) civic activism, b) participation voluntary associations, c) harmony among groups, d) harmony among individuals and d) gender-equality. Average happiness in nations is measured using responses to survey questions on life satisfaction, available in the World Database of Happiness. Comparisons across nations in 2010 and analysis of change between 1990-2010 show mixed effects. Civic activism and gender equality seems to add a bit to happiness, possibly more so that economic growth. Yet more involvement in associations and less conflict among individuals rather goes together with less happiness. Intergroup conflict appears to be unrelated to average happiness. So not all things called "social development" add to happiness, some work out positively, some negatively and some do not affects happiness at all. Future research should look for contingencies.
CO and CO‐releasing molecules (CO‐RMs) in acute gastrointestinal inflammation

Carbon monoxide (CO) is enzymatically generated in mammalian cells alongside the liberation of iron and the production of biliverdin and bilirubin. This occurs during the degradation of haem by haem oxygenase (HO) enzymes, a class of ubiquitous proteins consisting of constitutive and inducible isoforms. The constitutive HO2 is present in the gastrointestinal tract in neurons and interstitial cells of Cajal and CO released from these cells might contribute to intestinal inhibitory neurotransmission and/or to the control of intestinal smooth muscle cell membrane potential. On the other hand, increased expression of the inducible HO1 is now recognized as a beneficial response to oxidative stress and inflammation. Among the products of haem metabolism, CO appears to contribute primarily to the antioxidant and anti‐inflammatory effects of the HO1 pathway explaining the studies conducted to exploit CO as a possible therapeutic agent. This article reviews the effects and, as far as known today, the mechanism(s) of action of CO administered either as CO gas or via CO‐releasing molecules in acute gastrointestinal inflammation. We provide here a comprehensive overview on the effect of CO in experimental in vivo models of post‐operative ileus, intestinal injury during sepsis and necrotizing enterocolitis. In addition, we will analyse the in vitro data obtained so far on the effect of CO on intestinal epithelial cell lines exposed to cytokines, considering the important role of the intestinal mucosa in the pathology of gastrointestinal inflammation.
Non-neutral processes drive the nucleotide composition of non-coding sequences in Drosophila

The nature of the forces affecting base composition is a key question in genome evolution. There is uncertainty as to whether differences in the GC contents of non-coding sequences reflect differences in mutational bias, or in the intensity of selection or biased gene conversion. We have used a polymorphism dataset for non-coding sequences on the X chromosome of Drosophila simulans to examine this question. The proportion of GC→AT versus AT→GC polymorphic mutations in a locus is correlated with its GC content. This implies the action of forces that favour GC over AT base pairs, which are apparently strongest in GC-rich sequences.
Sympathetic mechanisms in cerebral blood flow alterations induced by spinal cord stimulation.

OBJECT Cervical spinal cord stimulation (SCS) has been found to augment cerebral blood flow (CBF) in a number of animal models, although the mechanisms underlying the cerebrovascular effects of SCS are poorly described. In this study, the authors examined the role of sympathetic tone in CBF alterations induced by SCS in rats. METHODS Spinal cord stimulation was performed at three intervals while CBF was monitored with laser Doppler flowmetry (LDF). Either hexamethonium (5, 10, or 20 mg/kg), prazosin (0.25, 0.5, or 1 mg/kg), idazoxan (0.5, 1, or 2 mg/kg), propranolol (1, 2, or 4 mg/kg), or vehicle was administered intravenously before the second stimulation. Changes in LDF values due to SCS were recorded as the percentage of change from baseline values and were analyzed. In vehicle-treated animals, SCS increased LDF values by 60.5 +/- 1.8% over baseline, whereas both high-dose hexamethonium and prazosin completely abolished the SCS-induced increases in LDF values. On the other hand, LDF values increased by 50.9 +/- 4% and 61.4 +/- 4% after SCS in the presence of idazoxan or propranolol, respectively. Administration of sympathetic nervous system blockers resulted in a variable degree of systemic hypotension as well. Nevertheless, induced hypotension without sympathetic blockade had only a minimal effect on SCS-induced augmentation of LDF values (48 +/- 1.4% over baseline). CONCLUSIONS Sympathetic tone plays a major role in SCS-induced increases in CBF. This effect seems to be mediated primarily by alpha1-adrenergic receptors. Systemic hypotension alone cannot explain the effects of sympathetic blockade on the SCS response. Clinical use of SCS in the treatment of cerebral ischemia should take alpha1-adrenergic receptor sympathetic tone into account.
Photophysical Properties of Ricin

The molar absorption coefficient of ricin in phosphate‐buffered saline (PBS) at 279 nm was measured as (93 900 ± 3300) L mol−1 cm−1. The concentration of ricin was determined using amino acid analysis. The absorption spectrum of ricin was interpreted in terms of 69% contribution from absorption by tryptophan residues and 31% contribution from absorption by tyrosine residues. The total dipole strength of the ricin band at 280 nm was determined to be (147 ± 8) D2 and was consistent with the combined dipole strengths of 10 tryptophan ([11.7 ± 1.0] D2) and 23 tyrosine ([1.4 ± 0.2] D2) residues. The structure of ricin was used to determine the coupling of the tryptophan residues in ricin. The maximum interaction energy was found to be 424 cm−1/ɛ while the average interaction between any two pairs of tryptophan residues was approximately 18 cm−1/ɛ. In this study, ɛ is the dielectric constant inside the protein. The fluorescence from ricin, excited at 280 nm, was dominated by fluorescence from tryptophan residues suggesting the presence of energy transfer from tyrosine to tryptophan residues. The absorbance and fluorescence of ricin increased slightly when ricin was denatured in a high concentration of guanidine. Irreversible thermal unfolding of ricin occurred between 65°C and 70°C.
Chat-Line interaction and negative feedback

In recent years researchers have investigated the use of Internet applications for language and cultural learning. While this new technology seems to have provided an educational breakthrough, relatively little linguistic research has been conducted particularly in relation to second language acquisition. Therefore the efficacy of the Internet applications not just for cultural studies or the expansion of knowledge, but also for second/foreign language acquisition remains uncertain. This study explores communicative interactions between native speakers (NSs) and non-native speakers (NNSs) of Japanese. Internet Relay Chat (IRC) was chosen as the setting for this study, because of the resemblance of chat line interactions to verbal exchanges. The linguistic focus in this study was specifically on one form of corrective feedback, namely implicit negative feedback (NF), which provides information to language learners about what is unacceptable in target language (e.g. Long, 1996). It has been claimed that NF plays an important facilitative role in language development. Therefore, the aim of this study is to investigate whether NSs provide NF to their NNS interlocutors in interactions during chat line conversations, and whether the NNS’s used this feedback in their subsequent production. The participants were NNSs and NSs of Japanese, formed into 12 gender-matched dyads. Each pair had free on-line “conversation” in three separate sessions. The results show that the proportion of NSs’ NF to the number of NNSs’ non-target-like turns was . lower than that found in the previous studies based on face to face verbal interactions. Even so NF was provided, and it was used – however it remains unclear as to whether or not on-line interactions elicit sufficient NF for acquisition to occur.
Antibodies to the Plasmodium falciparum Antigens Circumsporozoite Protein, Thrombospondin-Related Adhesive Protein, and Liver-Stage Antigen 1 Vary by Ages of Subjects and by Season in a Highland Area of Kenya

ABSTRACT Immunoglobulin G (IgG) antibodies to three vaccine candidate preerythrocytic Plasmodium falciparum antigens were evaluated in children and adults in an epidemic-prone highland area of Kenya during rainy (high-transmission) and dry (low-transmission) seasons. The frequencies and median levels of IgG antibodies to circumsporozoite protein (CSP) and thrombospondin-related adhesive protein (TRAP) were compared to the frequencies and median levels of IgG antibodies to liver-stage antigen 1 (LSA-1) reported previously. The frequencies and median levels of IgG antibodies to CSP and TRAP were similar in children and adults in the rainy season, but they were lower in children than in adults in the dry season. The frequencies and median levels of antibodies to LSA-1 were lower in children than in adults in both the rainy and dry seasons. Antibodies to CSP and LSA-1 were primarily members of the IgG1 and IgG3 subclasses, while antibodies to TRAP were primarily members of the IgG3 and IgG4 subclasses. In a treatment-reinfection study following dry season testing, antibodies to TRAP were associated with a trend toward protection from infection in children (P = 0.051) but not in adults. Antibodies to LSA-1 and CSP did not correlate with protection in children or adults. In this highland area of Kenya with unstable transmission, IgG antibodies to preerythrocytic P. falciparum antigens vary in subjects by age and season, and the protective effects of these antibodies against infection may be different in adults and children.
Sentimentos, emoções e projetos vitais da juventude: um estudo exploratório na perspectiva da teoria dos modelos organizadores do pensamento

A pesquisa tem como objetivo analisar a funcao psiquica dos sentimentos e das emocoes na construcao de projetos vitais de jovens. Partindo da indissociabilidade entre cognicao e afetividade, e de perspectivas recentes do campo da moralidade humana, a investigacao fundamenta-se na Teoria dos Modelos Organizadores do Pensamento, segundo a qual o ser humano constroi modelos da realidade com base em processos cognitivos e afetivos. Parte-se igualmente do conceito de projeto vital (purpose), entendido como objetivos e metas significativos para o sujeito e que trazem, ao mesmo tempo, implicacoes para o mundo mais amplo, atribuindo um sentido etico a vida e as acoes do individuo. Para o desenvolvimento da pesquisa, foram realizadas entrevistas semiestruturadas com um total de 30 jovens, entre 15 e 17 anos, estudantes de escola publica de Ensino Medio do interior do estado do Parana. A analise dos dados pautou-se nos pressupostos dos referenciais teoricos utilizados. A partir dos modelos organizadores identificados, foi possivel identificar uma influencia dos sentimentos e das emocoes no engajamento dos jovens em projetos vitais a partir dos seguintes aspectos: configuracao dos sentimentos e das emocoes no raciocinio; posicionamento dos jovens diante dos conflitos, dos obstaculos e das dificuldades; relacoes entre o self e o outro. Destacou-se, ainda, no processo de construcao dos projetos vitais, a importância das relacoes interpessoais, do bem-estar e da satisfacao do self, alem dos valores morais que sustentam os projetos vitais. Diante de tais resultados, sao tecidas consideracoes acerca das implicacoes para o campo da psicologia moral e da educacao. %%%%The research aimed at analyzing the psychological function of feelings and emotions to the construction of youth purpose. The research is grounded in indissociability of cognition and affectivity, and in recent perspectives of human morality, as well as in the theory of Organizing Models of Thinking which proposes that human being constructs models of reality based on cognitive and affective processes. It is also based on the concept of youth purpose, understood as goals and objectives that are meaningful to the self and of consequences beyond the self, giving an ethical sense to life and actions. It was applied semi-structured interviews with 30 youth aged from 15 to 17, from public high school in the state of Parana. Data analysis was based on theoretical bases used. Organizing models showed an influence of feelings and emotions in youth purpose linked by the following aspects: configuration of feelings and emotions in reasoning; youth positioning before the conflicts, obstacles and difficulties; relations between self and others. It was also emphasized the importance of interpersonal relationships, welfare and self satisfaction, and the moral values that support purpose. Given these results, considerations are made about the implications for moral psychology and education.