Recent evidence suggests OPG deficiency may promote breast cancer development

Recent evidence suggests OPG deficiency may promote breast cancer development. Serum OPG analysis in >6000 healthy subjects (Vik et al., 2015) showed an inverse relation in younger women (<60years) between serum OPG and risk of incident cancer at all sites, but primarily in the breast and reproductive tract (Vik et al., 2015). High OPG levels protected against breast cancer and mortality (Vik et al., 2015). An independent analysis of ~4500 primary breast cancers showed no prognostic value for RANK/RANKL expression, but a substantially better prognosis in oestrogen receptor-positive breast cancer cases showing high OPG expression (Sanger et al., 2014). A “suppressed” RANK pathway was likewise associated with better prognosis in another large breast cancer set (Santini et al., 2011). Denosumab, an antibody against RANKL that mimics the physiological role of OPG, is currently in clinical use for osteoporosis and for the treatment of skeletal related events in patients with bone metastasis resulting from solid tumours. In patients with breast cancer, denosumab has recently been shown to reduce the risk of clinical fractures in postmenopausal women with breast cancer receiving aromatase inhibitors and is currently being studied for any effect on prolonging bone metastasis free survival in women with early-stage breast cancer who are at high risk for disease recurrence (Gnant et al., 2015). While our previous data highlighted the potential for antiprogestogens for breast cancer prevention, the current data additionally support a clinical breast cancer prevention trial using denosumab to compensate for the low OPG levels throughout the menstrual GSK503 in BRCA-mutation carriers.

Contributors

Declaration of Interests
The following are the supplementary data related to this article.

Acknowledgements
This work was funded by Amgen Inc. and the Eve Appeal (http://www.eveappeal.org.uk/) and undertaken at UCLH/UCL, which received a proportion of its funding from the Department of Health NIHR Biomedical Research Centres (BRC) funding scheme. The UKFOCSS was core funded by Cancer Research UK (grants C315/A2621 and C1005/A6383), the UK Department of Health and the Eve Appeal with additional support from grants MRC8804/A/A7058, CA152990 & CA086381 from the NCI Early Detection Research Network. This work was aided by grant number R01 CA133117 from the US National Institutes of Health, by Organon Pharmaceuticals, and the Martin and Sharleen Cohen Foundation for Biomedical Research. Editing and formatting support was provided by Albert Y. Rhee (Amgen Inc).

Introduction
The immune system recognizes and eliminates tumor cells (Dunn et al., 2002), which defend themselves by different mechanisms (Villalba et al., 2013). The lymphocyte lineage natural killer (NK) cell belongs to the innate immune system (Lanier, 2008; Vivier et al., 2008) and show strong anti-leukemia activity when engrafted in allogeneic settings in hematological cancer patients (Velardi, 2008; Ruggeri et al., 2007; Anel et al., 2012). However, the presence of an anti-leukemia NK cell population in patients with hematological malignancies has not been proven.
NK cells are not a homogenous population and different subsets have different physiological activities. Moreover, different stimuli (e.g., cytokines vs targets cells) give rise to different immunophenotypes (Fujisaki et al., 2009; Sanchez-Martinez et al., 2014). In peripheral blood, human NK cells are mostly CD3−CD56dim cells with high cytotoxic activity, while CD3−CD56brigth cells excel in cytokine production (Bryceson et al., 2011). In vitro evidence indicates that CD56bright NK cells are precursors of CD56dim NK cells and this might also be the case in vivo (Domaica et al., 2012). In addition, combined analysis of CD56 and CD16 expression during NK cell development indicates that their profiles change as follows: CD56brigthCD16−→CD56brigthCD16dim→CD56dimCD16dim→CD56dimCD16+. Additional markers can be used to identify specific subsets within these NK cell populations (Moretta, 2010; Freud et al., 2014).

br Author contributions br Acknowledgements br

Author contributions

Acknowledgements

Introduction
Diabetes type 2 is an epidemic public health problem. Poorly controlled diabetes results in accelerated microvascular disease and chronic debilitating morbidities and mortality (Beckman et al., 2002). Diabetic microvascular angiopathy is the leading cause of blindness, end stage renal disease and amputations worldwide, as well as myocardial infarction, stroke and peripheral arterial disease.
Preventing or delaying microvascular disease could improve the lives of millions, prevent catastrophic illness, and save billions of dollars. The pathogenesis of microangiopathy in diabetes is unknown. Clinical efforts are based on glycemic control. The research focus of some prevention efforts is the endothelium and its role in protecting blood vessels (Fioretto et al., 2010; Wong et al., 2010). Vascular smooth muscle abnormalities, platelet dysfunction, abnormal coagulation and impaired vascular repair are other pathologies proposed to lead to diabetic vasculopathy (Beckman et al., 2002; Cubbon et al., 2013). Oxidants generated by hyperglycemia within endothelial MK-1775 (Nishikawa et al., 2000) or other vascular cells may initiate endothelial cell damage (Yu et al., 2006; Wang et al., 2012).
Endothelial cell damage secondary to hyperglycemia can be one initiator of diabetic microangiopathy by impairing oxygen delivery, resulting in microvascular hypoxia. Another plausible pathway is that oxidants generated by hyperglycemia, from endothelial cells or others, impair oxygen delivery by affecting the delivery system itself: red blood cells (RBCs). In fact, substantial evidence indicates that diabetes induces changes in RBC structure and function through a progressive decline in RBC deformability (Peterson et al., 1977; McMillan et al., 1978; Kamada et al., 1992; Virtue et al., 2004; Diamantopoulos et al., 2004; Brown et al., 2005; Shin et al., 2007; Kung et al., 2009; Keymel et al., 2011; Buys et al., 2013). RBC deformability is vital to RBC function, and plays a major role in microvascular flow. Impaired deformability adversely affects capillary perfusion (Simchon et al., 1987; Parthasarathi and Lipowsky, 1999). Consistent with decreased deformability, diabetes is associated with increased RBC fragility and decreased RBC survival (Peterson et al., 1977; Parthasarathi and Lipowsky, 1999; Virtue et al., 2004; Kung et al., 2009). Because stiffer RBCs may compromise the microcirculation and oxygen delivery, strategies to improve RBC deformability could modify microvascular hypoxia, with direct clinical implications.
In this regard, there are underappreciated links between RBCs, vitamin C, and diabetes. Multiple reports describe lower vitamin C concentrations in diabetic subjects, especially those with microvascular complications such as retinopathy and nephropathy (Som et al., 1981; Ali and Chakraborty, 1989; Sinclair et al., 1991; Will and Byers, 1996; Lindsay et al., 1998; Cunningham, 1998; Chen et al., 2006). However, many datasets utilized unreliable vitamin C assays, making it difficult to interpret findings (Will and Byers, 1996; Padayatty et al., 2003). Diabetic vascular disease and vitamin C deficiency were tied together in an early hypothesis (Mann and Newton, 1975), but it lacked mechanism and supportive evidence. Consistent with a hypothesized role for a RBC deformability defect in diabetes, anemia and hemolysis are manifestations of vitamin C deficiency in humans, and in mice (Gulo) unable to synthesize the vitamin (Chazan and Mistilis, 1963; Hart et al., 1964; Cox, 1968; Maeda et al., 2000). Unfortunately, deformability measures were not described in vitamin C deficient patients, and their clinical data are confounded by co-existent vitamin deficiencies.
Here we couple original links between diabetes and vitamin C with RBCs as a key cell type; oxidized vitamin C (dehydroascorbic acid, DHA) as a key transported substrate; and the chemical structure similarity between DHA and glucose (Vera et al., 1993; Rumsey et al., 1997; Corpe et al., 2013). For nearly all tissues, ascorbate transport is mediated by sodium-dependent vitamin C transporter SVCT2 (Sotiriou et al., 2002). However, SVCT2 is absent from RBCs (May et al., 2007). Because RBCs contain ascorbate (Li et al., 2012), another transport mechanism exists. It is likely that the product of ascorbate oxidation, dehydroascorbic acid, is transported on facilitated glucose transporters (GLUTs) and immediately reduced to ascorbate within RBCs (Hughes and Maton, 1968; Bianchi and Rose, 1986; Mendiratta et al., 1998). Based on expressed transporter data, hyperglycemia from diabetes could inhibit dehydroascorbic acid entry into RBCs (Vera et al., 1993; Rumsey et al., 1997). Some data do not support this rationale, but experiments were performed using DHA concentrations 2–3 orders of magnitude above physiological concentrations, and indirect assays that did not account for substrate degradation (Montel-Hagen et al., 2008a; Sage and Carruthers, 2014). Lower DHA concentrations could not be investigated due to assay limitations, also precluding accurate RBC ascorbate measurements (May et al., 2001; Montel-Hagen et al., 2008a; Li et al., 2012).

The Sirt requirement for SRT

The Sirt1 requirement for SRT1720 action (Feige et al., 2008; Minor et al., 2011b; Mitchell et al., 2014) does not necessarily mean that SRT1720 mediates these actions by activating Sirt1; it is possible that basal activity of Sirt1 may be required and is sufficient for these effects. In fact, unlike SRT1720 treatment (Feige et al., 2008), Sirt1 gain of function does not mimic CR nor increase mitochondrial function in skeletal muscle (Boutant et al., 2016). If SRT1720 acts solely by activating Sirt1, then the salient effects of SRT1720 such as the stimulation of expression of mitochondrial genes (e.g. PGC-1α) should not occur in Sirt1-deficient cells. However, partial and muted response (6–12h) to SRT1720 is present in Sirt1-deficient mefs (Fig. 4A), suggesting that another pathway is also required for the full effect of SRT1720. Indeed, SRT1720 activates AMPK in a Sirt1-independent manner, and AMPK is absolutely required for the metabolic effects of SRT1720 both in mefs and in obese mice (Figs. 4 and 5). Our results contradict previous studies that reported SRT1720 does not acutely activate AMPK in C2C12 myotubes (Feige et al., 2008; Svensson et al., 2015). However, this discrepancy is most likely due to using different SRT1720 concentrations as well as visualizing AMPK activity at different time points (Figs. 1B and C).
It should be noted that the concentration of SRT1720 used for i.p. injection (Fig. 1D, F) is considerably lower than that added to the food (Fig. 5): 10–30mg/kg vs. 300mg/kg/day. The reason for this is that the dose given i.p. is delivered nearly instantaneously whereas the dose in the food is consumed over a 24h period.
SRT1720 leads to weight loss in obese mice (Feige et al., 2008), but the effect of weight loss on glucose homeostasis has not been investigated. Our finding that SRT1720 decreases body weight equally in both WT and AMPKα2 KO mice, but does not increase glucose tolerance or mitochondrial content in AMPKα2 KO mice indicates that the effect of SRT1720 on glucose homeostasis is not simply due to weight loss (Fig. 5). The reason weight loss occurred in AMPKα2 KO mice is most likely due to the fact that AMPKα1, not AMPKα2, is the Phenyl sulfate AMPK in adipose tissue (Daval et al., 2005; Lihn et al., 2004). Consistent with this, resveratrol reduced body weight in AMPKα2 KO mice but not in AMPKα1 KO mice (Um et al., 2010). Viollet et al. reported that untreated AMPKα2 KO mice were less glucose tolerant than untreated WT mice, which conflicts with our findings (Fig. 5) (Viollet et al., 2003). The most likely reason for this difference is that Viollet et al. measured glucose tolerance with mice on regular chow, whereas we measured glucose tolerance with mice which were made obese by feeding HFD; the HFD and obesity it induced could have masked any difference in glucose tolerance without treatment.
Our results indicate that SRT1720, like resveratrol (Park et al., 2012), increases AMPK activity and cAMP signaling by inhibiting cAMP PDEs. Pacholec et al. also found that PDEs were inhibited by resveratrol and the SRT compounds, including SRT1720 (Pacholec et al., 2010). It appears that activation of Sirt1 by SRT1720 is downstream of Epac/AMPK (Fig. 3L). Therefore, our findings, together with previous studies (Feige et al., 2008; Minor et al., 2011a; Mitchell et al., 2014), indicate that the metabolic effects of SRT1720 are mediated by both AMPK and Sirt1, which are activated by independent pathways (Fig. 6). The effects of cAMP on AMPK and Sirt1 activities are complicated: it has been reported that Sirt1 can be activated by cAMP directly (Wang et al., 2015) as well as by a kinase(s) downstream of cAMP (Gerhart-Hines et al., 2011; Nin et al., 2012) and PKA can activate LKB1, an upstream kinase for AMPK (Shelly et al., 2007). Which of these pathways is dominant most likely depends on the cell types and the physiological context. Although the physiological effects of cAMP are diverse, there are evidences of beneficial effects of cAMP signaling in amelioration of the aging-related phenotype. For example, exogenous cAMP increases lifespan in fruit flies (Tong et al., 2007) and activates AMPK and Sirt1 and mimics the anti-aging effects of calorie-restriction in mice (Wang et al., 2015). Increasing the cAMP level with the PDE4 inhibitor rolipram (Park et al., 2012) or roflumilast (Tikoo et al., 2014; Wouters et al., 2012) also activates AMPK and Sirt1 and protects against obesity and type 2 diabetes in mice and humans. In addition, Sirt1 expression level decreases with aging, but this is rescued by cAMP (Wang et al., 2015).

Despite viral etiologies driving most cases of acute

Despite viral etiologies driving most cases of acute respiratory infection, definitive diagnostic tools for these syndromes are lacking. Even highly sensitive pathogen-specific tests such as PCR are dependent upon proper sampling technique and inclusion of virus-type-specific reagents and processing methods. Moreover, detection of a specific microbe in a clinical sample does not necessarily indicate the cause of the acute clinical syndrome. For example, it has been reported that HRV has been detected in up to 44% of asymptomatic individuals (Byington et al., 2015; Johnston et al., 1993). Therefore, better tools that help providers define the etiology of a suspected infectious syndrome in a safe, rapid, accurate, and cost-effective manner are of paramount importance for both individual and public health as recently noted by the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria (House, 2014), and others (O\’Neill, 2015; Organization, 2015). A complementary diagnostic strategy to pathogen detection could focus on utilizing the varied (but pathogen-class specific) host-response to infection (Ramilo and Mejias, 2009; Zaas et al., 2014). This approach discriminates between infection and colonization. It is pathogen-agnostic and therefore circumvents another limitation of pathogen detection assays, which due to technical limitations are only capable of detecting a limited subset of microorganisms. Furthermore, categorizing infection based on host response provides additional insights into the mechanisms of infection and disease response, and may offer new targets, pathways, or strategies for therapeutic intervention.
We recently identified gene buy BIBF1120 patterns in peripheral whole blood capable of differentiating (Zaas et al., 2009; Woods et al., 2013; McClain et al., 2016; Tsalik et al., 2016; Huang et al., 2011) individuals with symptomatic infection due to influenza H3N2, HRV, or RSV from uninfected individuals with >90% accuracy. Moreover, this ARV signature was validated in an independent population of patients with influenza A infection, demonstrating an ability to distinguish from bacterial respiratory infections (93% accuracy) and healthy controls (100% accuracy) (Zaas et al., 2009). Thus, host derived biomarkers are capable of making these types of distinction. However, considering the technical challenges inherent in developing buy BIBF1120 peripheral blood host gene expression classifiers as a diagnostic tool – including semi-invasive venipuncture, RNA instability, processing complexity, relatively high cost of RNA profiling, and time to result – we sought to extend this host response paradigm for ARV diagnosis to an alternative and potentially more suitable sample matrix and analyte class.
Upon contact with the respiratory epithelium, respiratory viruses incite activation of type I interferons (IFNs) and pro-inflammatory cytokines, orchestrate proliferation of inflammatory cells and the innate immune response, and regulate induction of adaptive immunity (Yoneyama and Fujita, 2010; Koyama et al., 2008; Bhoj et al., 2008). Based on the prominent role of the nasopharyngeal epithelium in mediating ARV infections, we hypothesized that nasopharyngeal lavage (NPL) would reflect the in situ host response and serve as a potential target for diagnostic development. Furthermore, the NPL protein fraction represents an accessible sample matrix, providing a highly tractable diagnostic analyte class. Multiple reaction monitoring (MRM), a quantitative mass spectrometry (MS) platform for facile development of multiplexed, quantitative assays for measuring specific protein levels in biologic fluids and is routinely used for biomarker verification in clinical cohorts (Kiyonami et al., 2011; Gerszten et al., 2010; Boja and Rodriguez, 2011). In addition to being customizable for nearly any target protein, MRM assays provide a more specific quantitation of individual proteins and protein isoforms by targeting multiple unique peptides per protein target. Combined with internal stable-isotope labeled (SIL) peptide standards, these assays match or exceed the quantitative precision of ELISA assays with low femtomole limits of quantitation and analytical precision coefficient of variation<10% across clinically sized cohorts (Addona et al., 2009; Aebersold et al., 2013).

br Communication The first area of

Communication
The first area of precise communication is internal to the field. Authors, reviewers, editors, and journals should provide and demand much more precise reporting in papers, and a suite of associated practices which will facilitate cumulative progress. One step in particular we now feel strongly about is the need to report main effects, by group, at the whole-brain level. It is particularly common to focus on interactions (e.g., task versus control for adolescents versus adults), but that hampers our ability to combine information across studies (e.g., in meta-analyses). For example, in the Silverman et al. (2015) meta-analysis, 62 studies were identified in a literature search addressing adolescent reward sensitivity, but according to the methods only 26 could be included in the meta-analysis, and 21 were excluded specifically because the manuscript did not provide sufficient detail or relied solely upon ROI analysis.
We also feel that more precision in the labeling of regions is critical. For example, there are meaningful differences between components of the basal 3-Deazaneplanocin A – caudate, nucleus accumbens, putamen – and the way in which we often confuse and/or equate these certainly undermines our precision. Other regions that are less well-defined structurally, such as the temporal–parietal junction (TPJ), are sometimes labeled as such with too large a degree of latitude, especially given that different subregions exhibit different anatomical and functional connectivity (for example with respect to the TPJ, see Carter et al., 2012). Still other often-used regional labels – chief among them “prefrontal cortex” – are so imprecise as to be largely uninformative. Even simple lateral and medial distinctions in PFC provide only a fraction more precision. In dual-systems and related models, we propose that a great deal more precision must be achieved especially with respect to subregions of the PFC. An advance in the dual-systems review by Shulman and colleagues (2016) is its assignment of medial PFC and orbitofrontal cortex with the striatum to the “socioemotional system,” distinct from lateral PFC, anterior cingulate cortex, and lateral parietal cortex in the “control system.” However, this quickly becomes complicated since ventromedial PFC has consistently been implicated in regulation networks (Etkin et al., 2011), and dorsomedial PFC is strongly associated with social cognition circuitry (Eickhoff et al., 2014; Bzdok et al., 2013). We believe a key challenge for the development of these models is not only to differentiate social 3-Deazaneplanocin A cognitive processes but also to meaningfully integrate them as a key feature of adolescent development, especially in terms of their specific neurobiological substrates. This is an issue that Shulman and colleagues do not address explicitly, although social cognitive processes and networks are clearly a central concern in the social reorientation model by Nelson and colleagues.
Interrogating ROIs as the sole reported analytical approach can be problematic even if defined with a high degree of precision. A targeted ROI analysis may be seen to some extent as a more risky test of one\’s theory, presuming that one has specified directional effects. However, this neglects the exponentially increasing emphasis in the field on networks and circuits (Pfeifer and Allen, 2012; Casey, 2015). Additionally, reporting only ROI analyses limits the contribution that rich whole-brain datasets may provide, particularly when combined with many other studies.
Some conservative data thresholding procedures bias us towards detecting more circumscribed regions with high magnitudes. This is an important practice that supports making more precise regional inferences, unlike the use of lower magnitude thresholds that produce low spatial sensitivity (Woo et al., 2014), but there may be reliable peaks at lower thresholds that will only be identified using whole-brain big data approaches. Furthermore, inclusion of whole-brain data allows for direct comparison of effects observed in predicted and non-predicted regions, once again improving the testing of the specificity of the predicted effects.

At the age of years all three groups

At the age of 5 years, all three groups exhibited more negative responses to the deviant stimuli in the 335–535ms interval, and there was no group difference in the LDN mean amplitude. This suggests that the lexical tone perception abilities of late-talking children continue to develop with age, growing closer to the ability level of the TLD group. Nevertheless, we observed less mature MMRs in LTs in the change of topography. The results showed a site-by-group interaction in the 185–335ms and 335–535ms intervals. The differences between the frontal and central MMRs (i.e., Fz–Cz, F4–C4) were negative in the two time intervals for the TLD group. In the two late-talking groups, the MMRs were more positive than those of the TLD group at the frontal sites in the mid and right channels in the 185–335ms and 335–535ms intervals.
Studies using the MMN paradigm to investigate the categorical perception of Mandarin lexical tone in native Chinese adults reported that across-category deviants elicited higher MMN than within-category deviants in the left frontal site (Xi et al., 2010), but children with dyslexia did not show this pattern (Zhang et al., 2012). Furthermore, when infants’ neural responses to Finnish consonant-vowel syllables were tested, the Dihydromyricetin responses to/ga/at approximately 600ms in at-risk newborns had a slower polarity shift from the major positive peak toward the later negative deflection; this pattern was the clearest at the right hemisphere (Guttorm et al., 2001). A subsequent longitudinal study showed that children who exhibit at-risk processing patterns at birth achieve lower receptive language skill scores between the ages of 2.5 and 5 years and have lower word/nonword reading accuracy and fluency measures in the first grade than children who exhibit normative responses do (Guttorm et al., 2005). Corresponding to the previous study, the rightward site differences in our study indicated that LTs still possess a less sophisticated speech perception ability at 5 years of age.
Grossheinrich et al., (2010) compared MMN responses to frequency change in pure tones (1000Hz vs. 1200Hz) under two interstimulus (ISI) conditions to investigate whether a reduced duration of auditory sensory memory is found in late talking children. Their results showed that MMN mean amplitude was reduced only for the ISI of 2000ms in former late talking children both with and without persistent language deficits. Comparing the results of Grossheinrich et al. (2010) and our study, while their LT participants exhibit a MMN comparable to those of controls for shorter ISI conditions (500ms), our results demonstrated the group differences in MMR amplitude at 3 years old and topographic distribution at 5 years old. One of the reasons for the discrepancy might be resulted by the participants’ age (4 years and 7 months); the other possibility would be that LTs only have deficits in discriminating speech stimuli and have preserved ability to discriminate nonspeech (pure tone) frequency changes. Future studies directly compare MMRs to speech and nonspeech stimuli would clarify this issue.
Several studies have suggested that the MMR elicited in infants is predictive of later language outcomes (Leppänen et al., 2002; van Leeuwen et al., 2006; van Zuijen et al., 2013). Our correlation analysis extended the predictive role of MMRs to later language outcome measures in the preschool period. The mean MMR amplitude at 3 years of age in the frontocentral channels were significantly correlated with vocabulary, syntax, and overall language performance on standardized tests at 6 years.
Comparing with previous behavioral studies, MacRoy-Higgins et al. (2013) examined the causal relationship between phonology and lexical acquisition in 24-month-old children who either were LTs or had TLD. The toddlers were taught 12 novel words differing in phonotactic probability (high vs. low) by using focused stimulation procedures over the course of 10 training sessions. After the training sessions, a preferential-looking paradigm was used to test word retention through comprehension, production, and toddlers’ ability to detect mispronunciations of the newly learned words. The results showed that LTs did not differentiate between words containing high and those containing low phonotactic probability. The authors concluded that the underlying impairment in late-talking toddlers could be an early inability to detect regularities in the phonological system of the language that they are exposed to, which in turn inhibits their ability to store the phonological forms required to acquire lexical items. The correlation results in our study confirmed that the sophisticated speech discrimination ability at the early age might not only be a supporting mechanism for establishing stable phonological representation but also be essential for language development in children with late expressive language.

br Conclusion Most specifications to test hyperinflation

Conclusion
Most specifications to test hyperinflation bubbles, following the footsteps of Flood and Garber (1980), have used an inappropriate theoretical framework to build their tests. The inflation tax curve used in this NCT-501 paper provides a very simple and sound way to test hyperinflation bubbles.

Acknowledgements

Introduction
We identified almost 1000 documents, including books, articles, theses, dissertations and selected working papers which were directly or indirectly related to BNDES. Our aim was to understand what were the major themes and questions raised in this literature, what types of methodologies were employed and how these changed over time as the bank grew and its mission changed. Issues of authorship, collaboration and institutional affiliation were also investigated. In order to achieve this objective, we employed bibliometric tools to explore this database and constructed new indicators. We also performed network analysis by mapping the economic literature produced on the BNDES since its creation, in the 1950s, up until the time of this writing (2013).
This article aims to address these questions and, in doing so, to provide an overview of the existing academic literature regarding the BNDES over the last 60 years. Three specific contributions stand out: the first is a survey of publications analysing the BNDES, including bibliographic information and the references cited by them. This information was systemized into a database which consists of 919 documents and 923 authors whose research is related to the bank. The second contribution is the use of bibliometric analysis, which allows us to create a profile of the whole economic literature on the BNDES by incorporating the original use of networks to evaluate citation, co-citation and co-authorship links amongst these documents. The article\’s third and final contribution lies in the use of an internal database which was constructed to consider the entirety of the relevant documents on the BNDES, thereby increasing the reliability of the bibliometric analysis.
The article is divided into five sections, including this introduction. Section 2 provides a description of bibliometric analysis while Section 3 gives an explanation of the methodology used to compile the database and discusses the indicators which were chosen for analysis. In Section 4, the results are presented and discussed and finally, Section 5 concludes the paper.

Bibliometric indicators
The term bibliometrics has been defined as the application of mathematical and statistical methods to measure the quantity and performance of publications such as books, articles and other types of media (Pritchard, 1969). Literature on these methodologies has essentially identified three types of bibliometric indicator: (1) quantitative/production; (2) performance/impact; (3) structural/relational (Moed et al., 1995; Rousseau, 1998; Gauthier, 1998; Van Leeuwen et al., 2003; Lundberg, 2006; Durieux and Gevenois, 2010). Although a variety of terminology has been used within the literature, these terms are essentially related to the same concepts.
Quantitative indicators are used to measure production by counting the number of publications per author, document type, research institution or country. When these indicators are available for a long enough period of time, we can make conjectures about trends in publication (Durieux and Gevenois, 2010).
Unlike the quantitative indicators, performance indicators aim to measure the quality and impact of a publication, author or institution (Durieux and Gevenois, 2010). For example, bibliometric analysis widely uses the number of citations received by an author, article or institution as an indicator of its performance or impact. Garfield (1955) considered citation indexes to be an important source of information for researchers and argues that, in the case of a relevant article, the citation index provides a measure of how influential this article has been to fellow researchers.

Calcium Ionophore I Es interesante notar que el consumo en

Es interesante notar que el consumo en este caso es una forma de elusión. En vez de los Calcium Ionophore I contactos que Guillermo desearía tener, ve porno. Antepone el control Calcium Ionophore I su deseo. Cuando puede irse a dormir tarde, porque no trabaja al otro día, entonces madruga viendo porno. Trabajo – porno – masturbación. Sería un circuito de autocontrol de baja intensidad, dado que entrega placer, pero de modo vicario: lo veo, luego me masturbo. Es autoproducción solitaria del placer, en la que la masturbación solo es un ejercicio físico desestresante.
Se producen acoplamientos técnicos entre los discursos sexuales y los laborales. Liliana es diseñadora gráfica y dice que antes de tener una relación sexual “hace un boceto” en su cabeza: diseña sus coitos. Se define a sí misma como imaginativa y le gusta ver por anticipado lo que hará. Dice que maquina en su cabeza sus deseos, así como Guillermo regulaba sus impulsos mediantes frenos y válvulas.
El lenguaje del sexo y sus prácticas se entrecruza con el lenguaje de la rapidez del consumo y de los servicios. Algunos informantes hablan desexo exprés, como los servicios de mensajería que ofrecen celeridad en sus entregas o las tiendas de comida rápida. Augusto habla de evitar los trámites, nuevamente en términos organizacionales o burocráticos. Prefiere ir a los cuartos oscuros o ligar por el chat, porque así se evitan los rodeos, todos los rituales del cortejo. Entre un deseo y su cumplimiento se acorta el tiempo y se simplifican los procedimientos. Entre el deseo y su satisfacción se extiende una línea recta que evita las complicaciones y los desvíos. Paradójicamente, esa rapidez y expedición en el contacto representan un proceso de desubjetivación. Augusto dice que el sexo se despersonaliza en el anonimato y señala que finalmente solo se es un cuerpo. La historia personal que el informante menciona se significa como una ropa que uno se saca y se pone según lo desee. En la rapidez del contacto de algún modo desaparece el sujeto, hay un lapsus subjetivo; la subjetividad en la topología de Augusto sería justamente el rodeo, el trámite, el nombre y la historia. La subjetividad es una línea curva. Esta desaparece y queda el cuerpo, anónimo y expuesto.
El cuerpo, que aparece, en alguna medida, como el último reducto para que el sujeto despliegue sus fantasías, ausentándose y despojándose de sí mismo, surge como una superficie que permite momentos diferenciados de satisfacción. Un uso del saber científico permite describir el cuerpo como objeto y distinguir sus funciones. La sexualidad se incluye dentro de ellas. Nino se pregunta: “¿qué es mi cuerpo?”, y despliega su teoría personal sobre el tema. Responde mediante una descripción cuasi científica de sí mismo: vincula necesidades fisiológicas, crea una degradé de interacciones posibles. Cada cosa tiene un lugar dentro de esta corporalidad tecnificada. El sexo ocupa uno, de mayor intensidad, pero contiguo a parasites otras necesidades y demandas corporales: comer, bañarse, ir al baño.
La penetración de los lenguajes organizacionales y del desarrollo personal permite leer la propia identidad sexual como un factor de éxito o fracaso. David, quien ocupa un alto cargo en una empresa multinacional, dice que ser gay es un hándicap ante los otros. Lo considera un defecto o una discapacidad que lo pone a él, de algún modo, fuera del convenio social. El informante tiene claro que ese convenio es heteronormativo, pero no lo cuestiona, sino que lee su diferencia como un defecto personal que debe considerar para relacionarse con los demás y actuar en el mundo. En los mercados laborales competitivos y flexibles, David tiene un factor en contra que debe compensar. Abandonando el lenguaje y los imaginarios de la enfermedad, las diferencias se transforman en cualidades o defectos personales.
El consumo, los discursos y prácticas sociales que articula forman parte, en nuestra opinión, de un régimen de significación posmoderno, en términos de Lash (2007). El posmodernismo, escribe Featherstone, “comprende cambios en las prácticas y experiencias cotidianas de distintos grupos que […] comienzan a emplear regímenes de significación de distintas formas y a crear nuevos medios de orientación y nuevas estructuras de identidad” (Featherstone 2000: 113). Lash describe el régimen de significación posmoderno como figural: privilegia lo visual, desvaloriza los formalismos y yuxtapone significantes que provienen de distintos contextos, enfatiza el hacer, y opera “a través de la inmersión del espectador (consumidor), de la investidura relativamente inmediata de su deseo en el objeto cultural (de consumo)” (Lash 2007: 220). La desregulación aparente de la vida social, la cual hemos leído como un rasgo de las sociedades de control, y la diversificación de las relaciones sociales obligan a cada sujeto a construir una narrativa para su deseo y su sexualidad. El mercado y el consumo operan como narrativas modulares: entregan las piezas para que cada sujeto las arme como quiera. Ante la pesada y obligatoria gramática de la religión, por ejemplo, estas narrativas son flexibles, diversas y acomodables en distintos contextos. Cada cual debe hacer su propio boceto, como nos dijo Liliana, o regular sus máquinas psíquicas y corporales, como lo hace Guillermo. En el campo de la sexualidad no parece haber otra regulación que la que cada quien se pone a sí mismo.

Esto explica que en M

Esto explica que en México sea escasa la publicación de libros y artículos en torno Cy3-dUTP la disputa por la “prostitución”. Existen, sin duda, espléndidas investigaciones históricas sobre la “prostitución” y muy serias investigaciones sobre distintos aspectos del comercio sexual, además de los trabajos clásicos sobre el tema: las tesis universitarias de distintas disciplinas que abordan aspectos específicos del comercio sexual. Sin embargo, en nuestro país casi no hay reflexiones políticas y teóricas que den cuenta de la disputa entre abolicionistas y defensoras de los derechos de las trabajadoras sexuales.
La visibilidad abolicionista en la disputa la tiene Lydia Cacho, la feminista más importante de México en la lucha contra la trata, con una trayectoria personal de gran compromiso y riesgo personal. Preocupada por la violencia hacia las mujeres, fundó el Centro Integral de Atención a las Mujeres en Cancún, y su trabajo la llevó a registrar y denunciar el abuso sexual a niñas y adolescentes, lo cual le ocasionó una brutal persecución —que puso, y hasta la fecha sigue poniendo, en peligro su vida— tanto por parte de los delincuentes como de los políticos que los protegen. Lydia Cacho es un caso excepcional en la defensa de los más vulnerables, y en su libro Esclavas del poder. Un viaje al corazón de la trata sexual de mujeres y niñas en el mundo (Cacho, 2010) lleva a cabo un alegato en contra de la trata abusiva y criminal en varias partes del mundo, México incluido. Pese a su valentía e integridad personal, su trabajo periodístico mezcla conceptualmente prostitución y trata, además de que carece de ciertos soportes de rigor académico, como el de citar sus fuentes o poner bibliografía. Esta mezcla hace que su trabajo resulte sesgado y, en ocasiones, panfletario. No obstante, su arrojo le ha ganado admiración como heroína en la lucha contra la trata.
Una figura emblemática en la lucha contra la violencia hacia las mujeres en México es Marcela Lagarde. Ya desde su tesis doctoral de antropología (Lagarde, 1990), en la que construye el concepto de “cautiverio” como “la expresión político-cultural de la condición subalterna de la mujer”, Lagarde habla de la prostitución de dos maneras distintas. Una, en la que coincido con ella, cuando usa el concepto de “puta” como una categoría de la cultura política patriarcal que sataniza el erotismo de las mujeres, y plantea: “Puta es un concepto genérico que designa a hormones las mujeres definidas por el erotismo, en una cultura que lo ha construido como tabú para ellas” (Lagarde, 1990, p. 543). Pero en la otra, de la cual discrepo, la vincula con la violencia y asume una perspectiva abolicionista: “La prostitución presenta afinidad con otro tipo de relación entre el hombre y la mujer. Se trata de la violación” (Lagarde, 1990, p. 555). Por eso Lagarde considera que:
El trabajo fundamental de Lagarde se ha centrado en los feminicidios, sin ampliar su activismo al campo del comercio sexual. Sin embargo, en ocasiones ha hecho comentarios respecto de la trata, con una postura cercana al abolicionismo.
En nuestro país la disputa feminista en relación con el comercio sexual cobró visibilidad en 2014, luego de que una jueza federal ordenó a la Secretaría de Trabajo y Fomento al Empleo del Gobierno del Distrito Federal (GDF) otorgar a las personas que trabajan en el comercio sexual callejero la licencia de “trabajadores no asalariados”. Esta resolución judicial fue la culminación de una larga lucha de un grupo de trabajadoras/es sexuales que tuvo que recurrir a un juicio de amparo, pues con anterioridad el GDF se había negado a otorgarles dicho reconocimiento laboral. La primera entrega de las licencias se realizó el 10 de marzo de 2014 en las instalaciones de la Secretaría, y cuando la prensa la dio a conocer, la sección latinoamericana de la Coalition Against Trafficking in Women (CATWLAC) desató en twitter una campaña en contra de la entonces secretaria, Patricia Mercado (véase Lamas, 2014). Esa reacción de la CATWLAC y otras feministas abolicionistas, que atacan e intentan denigrar cualquier iniciativa que tienda hacia la regulación (como es el otorgamiento de las licencias), me impulsaron a entrar en la disputa pública.

Introduction Global warming is undoubtedly

Introduction
Global warming is undoubtedly real and the very likely increase in the frequency of heat waves (GIEC, 2007) is one of the chief concerns facing mid-latitude cities. The principal effects of summer temperature increases are to heighten the urban heat island phenomenon and to reduce interior thermal comfort in buildings. Assuming a significant rise in summer temperatures, the populations of mid-latitude cities would be more greatly affected as they are not acclimatized to extreme heat (Braga et al., 2001),
Architects and urban designers represent pivotal actors in climate change adaptation. At the urban scale, their decisions can create comfortable microclimates or, on the contrary, can contribute to urban heat island (UHI) formation. Moreover, architectural elements can determine whether a building offers passively comfortable internal spaces. However, these professionals continue to perceive gingerol as an element to be taken into account “later”, in the future (Wheeler, 2008). We argue that these professionals have the following “four catalysts for action” at their disposal to strengthen the capacity of adapting the built environment of mid-latitude cities to higher summer temperatures: urban form, natural cover, architecture, and coating materials.
International students and Canadian architecture and urban design professionals working in the Québec City metropolitan context (province of Québec, Canada) participated in two workshops where it was found that they actually have only partial knowledge of the UHI phenomenon and of the passive cooling principles (Dubois et al., 2012). This appears paradoxical considering the substantial and rapidly developing body of scientific literature available today. The issue lies with its transfer to professionals and not with the production of scientific literature per se. First, the profusion of specialized knowledge can be overwhelming for these lay professionals. Second, the methods, tools and terminology used by researchers are alien to them. Third, the problem-solving procedure is fundamentally different from the traditional scientific approach. As architects and urban designers, they must be prepared to deal with “wicked” problems (Rittel and Webber, 1973). These problems require a prospective approach: in order to develop a further understanding of the problem and search for potential solutions, decisions must be taken, experiments must be conducted, pilot studies must be carried-out, and prototypes must be tested (Conklin, 2005). Thus, “wicked” problems foster new knowledge and creativity.
We hypothesize that a design support tool (DST) focused on the issue of adaptation of mid-latitude cities to rising summer temperatures could help improve knowledge and skills of professionals in the field. DSTs can facilitate designers׳ understanding by transferring appropriate multidisciplinary knowledge that is derived from the popularization of technical or scientific insight. Such tools apply mainly during the upstream phases of any project, when decisions on the various urban, architectural and technical options are taken and when the information available to the designer is limited (Adolphe, 1995). They can also suggest orientations, indicate trends or compare solutions according to their performance (Fernandez, 2010).

Methodology

Results and discussion
Results are presented in a way that combines tools with similar features (category, project status) or dealing with similar issues (UHI mitigation or passive architectural strategies. First, results are discussed on the use of the manual “Sun Wind and Light” (Brown and DeKay, 2000) as a hybrid DST in relation to the simplified computation tools “PET” (Potvin et al., 2004) and “LUMcalcul” (Demers and Potvin, 2004). These three tools are tailored to the initial design phases and address one or more passive architectural strategies. Second, the results of the integration of indicators in the workshop project are discussed separately as they concern essentially the urban scale, which is not the case with previous tools. Third, the appraisal of the use of the numerical simulation software Ecotect Autodesk Analysis© is examined by comparing it to the analogical simulation tools “mirror box” and the heliodon. These three tools based on “performance” are more suitable for the more advanced stages of the design process, and deal with some or all passive architectural strategies.