Charged lepton flavour violation from low scale seesaw neutrinos

In the work presented here, we have studied the impact of right handed neutrinos, which are introduced to account for the evidence of neutrino masses, on charged lepton flavour violating observables. In particular, we have focused on the loop induced decays of the Z boson into two leptons of different flavour. We have performed a numerical study of the rates predicted for these processes within the Inverse Seesaw model, specifically considering scenarios where $\mu -e$ transitions are suppressed. Our conclusion, after comparison with the most relevant experimental constraints, is that branching ratios as large as $10^{-7}$ can be predicted in the $\tau -\mu$ or $\tau -e$ channels, together with heavy neutrinos having masses of the TeV order. Such rates could be accessible at next generation colliders.Comment: 13 pages, 5 figures, 3 tables. Proceedings of the Corfu Summer Institute 2016 "School and Workshops on Elementary Particle Physics and Gravity", 31 August - 23 September 2016, Corfu, Greec

Identificación de nuevos biomarcadores y dianas terapéuticas en la interacción patológica entre la desregulación del sistema endocrino-metabólico y el cáncer de próstata

Obesity (OB) is a metabolic chronic disease with a growing incidence and elevated morbidities and mortality [1, 2]. OB is also associated with elevated economic costs for the health systems representing a worldwide public health problem [3, 4]. Specifically, in 2016, 650 million adults were obese [5]; among them, 10% to 30% presented with metabolic disorders [6] including type 2 diabetes (T2DM), hypertension (HT), heart disease, high total cholesterol and triglycerides, stroke, obstructive sleep apnea, nonalcoholic fatty liver disease, and certain types of cancer [7-9]. In this sense, bariatric surgery (BS) is a well-recognized treatment for OB that has superior outcomes for patients who have been unable to keep weight loss by nonsurgical methods [10]. Worldwide, the most commonly performed bariatric procedures are laparoscopic Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), wherein both procedures encompass nearly 80% of all bariatric operations worldwide [11]. BS induces and maintains substantial weight loss through a variety of mechanisms, including caloric restriction (due to anatomical surgical-induced changes of the gastrointestinal tract), increased meal-induced thermogenesis, modulation of hypothalamic neuronal circuits (that regulate energy balance and/or appetite regulation), modifications in gut-brain signaling pathways and changes in taste, food preferences, and eating behavior patterns [12-15]. All these changes are accompanied by reduction in metabolic complications, especially T2DM [16], and a rapid alteration of the inflammatory status, due in part to the modulation of cytokine production after BS, which may be also accompanied by improvement in other metabolic complications [17]. In this context, inflammation is a protective immune response, wherein innate immune function depends upon recognition of pathogen-associated molecular patterns, which are derived from invading pathogens, and danger-associated molecular patterns, being induced endogenously by germline-encoded pattern recognition receptors (PRRs). The activation of PRRs induces production of interferon-α, interferon-β, and proinflammatory cytokines [18]. These responses are mediated by the inflammasome machinery, an intracellular multiprotein complex that plays a central role in innate immunity and is responsible for the activation of inflammatory responses. This complex is composed of some families of PRRs, including the nucleotide-binding domain, leucine-rich repeat containing proteins [nucleotide binding oligomerization (NOD) domain-like receptors (NLRs)], and by the absent in melanoma 2-like (AIM2- like) receptors [19]. NLRs and AIM-like receptors can oligomerize and act as caspase-1– activating scaffolds—for example, activating the proinflammatory interleukin (IL)-1 family through the production of IL-18 and IL-1β [20]. Remarkably, the activity of these inflammasome components is regulated by different regulatory proteins, metabolic pathways, and a regulatory mitochondrial hub [21]. Consequently, the activation of these inflammasome components leads to the secretion of diverse inflammatory cytokines and the activation of key receptors in immune cells, thus inducing the activation of inflammatory cascades, which can lead in some cases in cellcycle alterations and DNA damage [20, 21]. Different components of the inflammasome machinery have been linked to a variety of autoinflammatory, autoimmune, and metabolic disorders including atherosclerosis, T2DM, and OB [22]. Some studies have found that inflammasome components are dysregulated in several tissues/cells including peripheral blood mononuclear cells (PBMCs), and that these changes may be associated with the development of atherosclerosis, autoimmune (e.g., multiple sclerosis), and neurodegenerative (e.g., Alzheimer´s or Parkinson´s) diseases [20]. In the same line, alterations in some specific inflammasome components have been described in OB, but their specific roles are still not well understood [23]. However, to the best of our knowledge, changes in inflammasome components induced by acute weight loss related to BS have not been fully described yet. Interestingly, it has been reported that inflammasome-induced cytokines promote OB-related inflammatory diseases following stimulation by high-fat diet metabolites and adipose tissue changes that occur during weight gain [24], which suggests that inflammasome modulation due to weight loss may be associated to an improvement in OB-related comorbidities. As mentioned above, OB is the most common cause of insulin resistance; however, overt diabetes does not develop in most obese individuals, as they can preserve normoglycemia through an enhanced insulin secretion, resulting in compensatory hyperinsulinemia [25]. Conversely, in susceptible individuals, compensatory hyperinsulinemia cannot be maintained, consequently developing prediabetes and T2DM [6]. In this sense, it is critical to understand the molecular mechanisms involved in the onset of OB and its associated comorbidities. In fact, it has been demonstrated that the development and progression of OB and other associated comorbidities, including insulin resistance [26], is closely linked to the dysregulation of key metabolic factors, especially those implicated in the cellular control of the energy balance (e.g. insulin, leptin, glucose transporters, etc.), which are, in turn, controlled by specific cellular regulatory mechanisms, such as microRNAs. MicroRNAs (or miRNAs) are short non-coding RNAs (20-22 nucleotides) that act at post-transcriptional level to regulate gene expression [27]. Evidence is accumulating that circulating miRNAs can act as endocrine factors in that they are released to the circulation by many tissues [28]. Indeed, miRNAs seem to serve as endocrine and paracrine messengers that facilitate communication between donor and target cells, thereby potentially exerting important roles in metabolic organs crosstalk [28]. For these reasons, it has been postulated that circulating miRNAs could exert crucial roles in the development and progression of OB and its related comorbidities. Previous, scattered studies have reported that some miRNAs are dysregulated in plasma samples of obese subjects, including miR-142-3p, miR-221 or miR-222 [29-34]. However, these results are inconsistent among studies and cannot be compared due to several factors, including different cohort characteristics (obese, morbid obese, diabetic), study designs (cross-sectional, transversal) or detection methods (TaqMan, SYBR Green, micro or macro arrays, small RNA or miRNA sequencing). Hence, the whole pattern of dysregulations of miRNAs in obese condition is still to be reliably defined. Indeed, it has been shown by previous studies that high-throughput technologies may represent one of the most precise and reliable tools for the quantification of miRNAs [35]. Unfortunately, although several of the previously mentioned studies have reported the dysregulation of different miRNAs in OB condition, to the best of our knowledge there are not studies to date describing the whole miRNome using microRNAs specific arrays. Finally, as previously mentioned, OB promotes the appearance of multiple pathological problems/defects, which cause serious alterations of the homeostasis of the organism (e.g. dysregulation of hormones, growth and inflammatory factors, etc.) that frequently promote or influence the development of the severe pathologies including different endocrine-related tumors/cancers [36]. In this context, it is important to mention that Prostate Cancer (PCa) has emerged as the most frequent tumor type among men and represents a severe health problem worldwide [49]. A key limitation in PCa management is that the gold-standard screen test is based on the plasma levels of prostate-specific antigen (PSA), a biomarker that exhibits profound drawbacks, especially in the so-called “grey zone” (defined as a PSA range of 3-10 ng/mL) [37]. In fact, PSA test displays low specificity in that multiple factors can increase PSA levels without necessarily indicating the presence of a tumor, such as benign prostatic hyperplasia or inflammatory conditions. In addition, PSA test is not able to accurately distinguish clinically relevant tumors from indolent cases [38]. For these reasons, the anatomo-pathological analysis of prostate biopsies, which represent a highly invasive technique, is still necessary to appropriately diagnose PCa nowadays. Therefore, there is an important unmet clinical need for the identification and validation of new, reliable and specific non-invasive PCa diagnostic biomarkers, ideally from a personalized point of view and showing prognostic and/or therapeutic potential. In this sense, miRNAs are attractive biomarker candidates as they can be reproducibly extracted from a wide range of biologic samples and are generally stable and resistant to various storage conditions [28, 39]. Indeed, recent studies have suggested a relationship between circulating miRNAs and PCa presence and outcome [40-42]. Specifically, recent studies have identified some miRNAs differentially present in plasma samples from PCa patients; however, only some of them seem to be specifically derived from PCa tissues [43-45]. Unfortunately, although various studies have identified some putative PCa-specific miRNAs (e.g. miR-141 [46], miR-375 [47], and miR-21 [48]), there is not a consensus in the utility of plasma miRNAs as circulating non-invasive biomarkers for PCa. In fact, there are no studies describing the dysregulation of the whole miRNome in PCa vs. healthy patients. For these reasons, this field requires further investigation in order to ascertain whether a specific miRNA or a plasma/serum miRNA signature could be associated with PCa risk and provide diagnostic and prognostic value through a fast, easy, and non-invasive test. Based on all the information mentioned above, in this Doctoral Thesis we deploy a set of innovative clinical and experimental approaches commonly used in our team, including numerous clinical samples and cellular models, to pursue a triple OBJECTIVE with the ultimate goal of identifying new and more personalized diagnostic, prognostic, and therapeutic tools for the management of OB and PCa. To that end, we explored: 1) Changes in components of the inflammasome machinery (i.e., inflammasome components and inflammatoryassociated factors) in obese patients after BS and their relation with clinical/biochemical parameters at baseline and after bariatric surgery; 2) The differential expression pattern of miRNAs in OB and their putative role in OB -related comorbidities such as insulin resistance; and, 3) The dysregulation of the human miRNome in PCa patients, considering the OB condition of the patients (normoweight, overweight, or OB), and the potential pathophysiological role and the molecular mechanisms underlying the role of miR-107 in PCa…La obesidad (OB) es una enfermedad crónica metabólica con una incidencia creciente y una elevada morbilidad y mortalidad [1, 2]. La obesidad también se asocia a elevados costes económicos para los sistemas de salud y representa un problema de salud pública a nivel mundial [3, 4]. En concreto, en 2016, 650 millones de adultos eran obesos [5]; entre ellos, entre el 10% y el 30% presentaban trastornos metabólicos [6], entre los que se encuentran la diabetes tipo 2 (T2DM), la hipertensión (HT), las cardiopatías, el colesterol total y los triglicéridos elevados, los accidentes cerebrovasculares, la apnea obstructiva del sueño, la enfermedad del hígado graso no alcohólico y ciertos tipos de cáncer [7-9]. En este sentido, la cirugía bariátrica (BS) es un tratamiento bien reconocido para la OB que tiene resultados superiores para los pacientes que no han podido mantener la pérdida de peso por métodos no quirúrgicos [10]. En todo el mundo, los procedimientos bariátricos más realizados son el bypass gástrico en Y de Roux (RYGB) y la gastrectomía en manga (SG) por vía laparoscópica, donde ambos procedimientos abarcan casi el 80% de todas las operaciones bariátricas del mundo [11]. La BS induce y mantiene una pérdida de peso sustancial a través de diversos mecanismos, como la restricción calórica (debido a los cambios anatómicos inducidos por la cirugía en el tracto gastrointestinal), el aumento de la termogénesis inducida por las comidas, la modulación de los circuitos neuronales hipotalámicos (que regulan el equilibrio energético y/o la regulación del apetito), las modificaciones en las vías de señalización intestino-cerebro y los cambios en el gusto, las preferencias alimentarias y los patrones de conducta alimentaria [12-15]. Todos estos cambios se acompañan de una reducción de las complicaciones metabólicas, especialmente de la T2DM [16], y de una rápida alteración del estado inflamatorio, debida en parte a la modulación de la producción de citoquinas tras la BS, que puede ir acompañada también de una mejora de otras complicaciones metabólicas [17]. En este contexto, la inflamación es una respuesta inmunitaria protectora, en la que la función inmunitaria innata depende del reconocimiento de patrones moleculares asociados a patógenos, que proceden de patógenos invasores, y de patrones moleculares asociados al peligro, siendo inducidos de forma endógena por receptores de reconocimiento de patrones (PRRs) codificados en la línea germinal. La activación de los PRRs induce la producción de interferón-α, interferón-β y citoquinas proinflamatorias [18]. Estas respuestas están mediadas por la maquinaria del inflamasoma, un complejo multiproteico intracelular que desempeña un papel central en la inmunidad innata y es responsable de la activación de las respuestas inflamatorias. Este complejo está compuesto por algunas familias de PRRs, incluyendo el dominio de unión a nucleótidos, proteínas que contienen repeticiones ricas en leucina [receptores similares al dominio de unión a nucleótidos (NOD)], y por los receptores ausentes en el melanoma 2-like (AIM2- like) [19]. Los receptores tipo NOD (NLRs) y los receptores similares a AIM pueden oligomerizarse y actuar como andamios activadores de la caspasa-1, por ejemplo, activando la familia proinflamatoria de la interleucina (IL)-1 mediante la producción de IL-18 e IL-1β [20]. Sorprendentemente, la actividad de estos componentes del inflamasoma está regulada por diferentes proteínas reguladoras, vías metabólicas y un eje regulador mitocondrial [21]. En consecuencia, la activación de estos componentes del inflamasoma conduce a la secreción de diversas citoquinas inflamatorias y a la activación de receptores clave en las células inmunitarias, induciendo así la activación de cascadas inflamatorias, que pueden conducir en algunos casos a alteraciones del ciclo celular y a daños en el DNA [20, 21]. Diferentes componentes de la maquinaria del inflamasoma se han relacionado con diversos trastornos autoinflamatorios, autoinmunes y metabólicos, como la aterosclerosis, la T2DM y la OB [22]. Algunos estudios han descubierto que los componentes del inflamasoma están desregulados en varios tejidos/células, incluidas las células mononucleares de sangre periférica (PBMC), y que estos cambios pueden estar asociados al desarrollo de la aterosclerosis, las enfermedades autoinmunes (por ejemplo, la esclerosis múltiple) y las neurodegenerativas (por ejemplo, el Alzheimer o el Parkinson) [20]. En la misma línea, se han descrito alteraciones en algunos componentes específicos del inflamasoma en la OB, pero sus funciones específicas aún no se conocen bien [23]. Sin embargo, hasta donde sabemos, aún no se han descrito completamente los cambios en los componentes del inflamasoma inducidos por la pérdida de peso aguda relacionada con el BS. Curiosamente, se ha informado de que las citocinas inducidas por el inflamasoma promueven las enfermedades inflamatorias relacionadas con la OB tras la estimulación de los metabolitos de la dieta alta en grasas y los cambios en el tejido adiposo que se producen durante el aumento de peso [24], lo que sugiere que la modulación del inflamasoma debido a la pérdida de peso puede estar asociada a una mejora de las comorbilidades relacionadas con la OB. Como se ha mencionado anteriormente, la OB es la causa más común de resistencia a la insulina; sin embargo, la diabetes manifiesta no se desarrolla en la mayoría de los individuos obesos, ya que pueden preservar la normoglucemia mediante una mayor secreción de insulina, lo que da lugar a una hiperinsulinemia compensatoria [25]. Por el contrario, en los individuos susceptibles, la hiperinsulinemia compensatoria no se puede mantener, por lo que se desarrolla prediabetes y T2DM [6]. En este sentido, es fundamental comprender los mecanismos moleculares implicados en la aparición de la OB y sus comorbilidades asociadas. De hecho, se ha demostrado que el desarrollo y la progresión de la OB y otras comorbilidades asociadas, incluida la resistencia a la insulina [26], están estrechamente relacionados con la desregulación de factores metabólicos clave, especialmente los implicados en el control celular del balance energético (por ejemplo, la insulina, la leptina, los transportadores de glucosa, etc.), que a su vez están controlados por mecanismos reguladores celulares específicos, como los microARN. Los microRNAs (o miRNAs) son RNA cortos no codificantes (20-22 nucleótidos) que actúan a nivel post-transcripcional para regular la expresión génica [27]. Se están acumulando pruebas de que los miRNAs circulantes pueden actuar como factores endocrinos, ya que son liberados a la circulación por muchos tejidos [28]. De hecho, los miRNAs parecen servir como mensajeros endocrinos y paracrinos que facilitan la comunicación entre las células donantes y las dianas, ejerciendo así potencialmente importantes funciones en la integración de los órganos metabólicos [28]. Por estas razones, se ha postulado que los miRNAs circulantes podrían ejercer papeles cruciales en el desarrollo y la progresión de la OB y sus comorbilidades relacionadas. Estudios anteriores y dispersos han informado de que algunos miRNAs están desregulados en muestras de plasma de sujetos obesos, incluyendo miR-142-3p, miR- 221 o miR-222 [29-34]. Sin embargo, estos resultados son inconsistentes entre los estudios y no pueden ser comparados debido a varios factores, incluyendo las diferentes características de la cohorte (obesos, obesos mórbidos, diabéticos), los diseños de los estudios (paralelo, transversal) o los métodos de detección (TaqMan, SYBR Green, micro o macro arrays, secuenciación de ARN pequeños o miRNA). Por lo tanto, el patrón completo de desregulación de los miRNAs en la condición de obesidad está aún por definir de forma fiable. De hecho, estudios anteriores han demostrado que las tecnologías de alto rendimiento pueden representar una de las herramientas más precisas y fiables para la cuantificación de miRNAs [35]. Lamentablemente, aunque varios de los estudios mencionados anteriormente han informado de la desregulación de diferentes miRNAs en la condición de OB, hasta donde sabemos no hay estudios hasta la fecha que describan todo el miRNome utilizando arrays específicos de microRNAs. Por último, como se ha mencionado anteriormente, la OB promueve la aparición de múltiples problemas/defectos patológicos, que provocan graves alteraciones de la homeostasis del organismo (por ejemplo, desregulación de las hormonas, factores de crecimiento e inflamatorios, etc.) que con frecuencia promueven o influyen en el desarrollo de las patologías graves, incluyendo diferentes tumores/cánceres relacionados con el sistema endocrino [36]. En este contexto, es importante mencionar que el Cáncer de Próstata (PCa) se ha convertido en el tipo de tumor más frecuente entre los hombres y representa un grave problema de salud en todo el mundo [36]. Una limitación clave en el manejo del PCa es que la prueba de cribado de referencia se basa en los niveles plasmáticos del antígeno prostático específico (PSA), un biomarcador que presenta profundos inconvenientes, especialmente en la llamada "zona gris" (definida como un rango de PSA de 3-10 ng/mL) [37]. De hecho, la prueba del PSA muestra una baja especificidad, ya que hay múltiples factores que pueden aumentar los niveles de PSA sin indicar necesariamente la presencia de un tumor, como la hiperplasia prostática benigna o las afecciones inflamatorias. Además, la prueba del PSA no es capaz de distinguir con precisión los tumores clínicamente relevantes de los casos indolentes [38]. Por estas razones, el análisis anatomopatológico de las biopsias de próstata, que representan una técnica altamente invasiva, sigue siendo necesario para diagnosticar adecuadamente el PCa en la actualidad. Por lo tanto, existe una importante necesidad clínica insatisfecha de identificar y validar nuevos biomarcadores diagnósticos de PCa no invasivos, fiables y específicos, idealmente desde un punto de vista personalizado y que muestren un potencial pronóstico y/o terapéutico. En este sentido, los miRNAs son atractivos candidatos a biomarcadores ya que pueden ser extraídos de forma reproducible de una amplia gama de muestras biológica y son generalmente estables y resistentes a diversas condiciones de almacenamiento [28, 39]. De hecho, estudios recientes han sugerido una relación entre los miRNAs circulantes y la presencia y el resultado del PCa [40-42]. En concreto, estudios recientes han identificado algunos miRNAs presentes de forma diferencial en muestras de plasma de pacientes con PCa; sin embargo, sólo algunos de ellos parecen derivar específicamente de los tejidos del PCa [43-45]. Lamentablemente, aunque varios estudios han identificado algunos miRNAs putativos específicos del PCa (por ejemplo, miR-141 [46], miR

Reply to “Comment on ‘Influence of Focal Mechanism in Probabilistic Seismic Hazard Analysis’ by Vincenzo Convertito and André Herrero,” by F. O. Strasser, V. Montaldo, J. Douglas, and J. J. Bommer

We thank F. O. Strasser, V. Montaldo, J. Douglas, and J. J. Bommer for the interest they have shown in our article (Convertito and Herrero, 2004). Strasser et al. (2006) present a critical comment of our work arguing that the solution proposed by Bommer et al. (2003) is a better solution. Note that the authors are nearly the same in both article and comment, except for V. Montaldo. Because this brief article is a reply, we will focus on the arguments directly concerning our article. The main objection supported by Strasser et al. (2006) is that the method we proposed is not appropriate to "styleof-faulting" correction. We completely agree with this assertion because it is simply not the scope of our article. We speak about "focal mechanism" intended as radiation pattern and nothing else. This point is clearly stated in the introduction of Convertito and Herrero (2004): "in this article we consider that the focal mechanism influence is only expressed by radiation pattern changes. In particular we do not consider any tectonic influence, stress drop variation or dynamic effects." The style-of-faulting parameter, even if its identity is blurred (e.g., Bommer et al., 2003), is an empirical definition of a complex set of physical conditions including the tectonic regime, the medium behavior, rock mechanics, rupture dynamics, and so on. In our opinion, the style of faulting is simply too complex to be used directly in our approach. Because the scope of our article is to show how it is possible to insert inside the main equation of probabilistic seismic-hazard analysis (PSHA; e.g., Cornell, 1968), simple physical parameters of the seismic source, that is, how it is possible to integrate deterministic parameters inside a probabilistic approach, we have chosen a small target, limiting ourselves only to the radiation pattern. We believe that the same approach can be used to insert many other parameters of the seismic source inside PSHA by using only a theoretical approach such as the fault strike (which has already been shown by Convertito, 2004), the directivity and stress drop. The second important argumentation is that a method based on regression (i.e., Bommer et al., 2003) is better than the method we propose. Once again we agree with Strasser et al. (2006) and this is clearly stated in the conclusion of our article: "when an attenuation law, including a faulting style parameter, is available for a given region, the use of this attenuation law gives a more reliable estimate of the hazard than the one obtained using the corrective coefficient we propose in this article.

Improved determination of the 1(0)-0(0) rotational frequency of NH3D+ from the high resolution spectrum of the v4 infrared band

The high resolution spectrum of the v4 band of NH3D+ has been measured by difference frequency IR laser spectroscopy in a multipass hollow cathode discharge cell. From the set of molecular constants obtained from the analysis of the spectrum, a value of 262817(6) MHz (3sigma) has been derived for the frequency of the 1(0)-0(0) rotational transition. This value supports the assignment to NH3D+ of lines at 262816.7 MHz recorded in radio astronomy observations in Orion-IRc2 and the cold prestellar core B1-bS.Comment: Accepted for publication in the Astrophysical Journal Letters 04 June 201

3He-Rich Solar Energetic Particles in Helical Jets on the Sun

Particle acceleration in stellar flares is ubiquitous in the Universe, however, our Sun is the only astrophysical object where energetic particles and their source flares can both be observed. The acceleration mechanism in solar flares, tremendously enhancing (up to a factor of ten thousand) rare elements like 3He and ultra-heavy nuclei, has been puzzling for almost 50 years. Here we present some of the most intense 3He- and Fe-rich solar energetic particle events ever reported. The events were accompanied by non-relativistic electron events and type III radio bursts. The corresponding high-resolution, extreme-ultraviolet imaging observations have revealed for the first time a helical structure in the source flare with a jet-like shape. The helical jets originated in relatively small, compact active regions, located at the coronal hole boundary. A mini-filament at the base of the jet appears to trigger these events. The events were observed with the two Solar Terrestrial Relations Observatories STEREO on the backside of the Sun, during the period of increased solar activity in 2014. The helical jets may be a distinct feature of these intense events that is related to the production of high 3He and Fe enrichments.Comment: accepted for publication in The Astrophysical Journa

Heat kernel methods for Lifshitz theories

We study the one-loop covariant effective action of Lifshitz theories using the heat kernel technique. The characteristic feature of Lifshitz theories is an anisotropic scaling between space and time. This is enforced by the existence of a preferred foliation of space-time, which breaks Lorentz invariance. In contrast to the relativistic case, covariant Lifshitz theories are only invariant under diffeomorphisms preserving the foliation structure. We develop a systematic method to reduce the calculation of the effective action for a generic Lifshitz operator to an algorithm acting on known results for relativistic operators. In addition, we present techniques that drastically simplify the calculation for operators with special properties. We demonstrate the efficiency of these methods by explicit applications.Comment: 36 pages, matches journal versio