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Hyperparasitism is defined as the interaction where one parasite is infected by another parasite. In bat flies (Streblidae and Nycteribiidae), both hyperparasites and microparasites (bacteria, viruses, fungi, and arthropods such as mites) have been documented. Fungi belonging to the order Laboulbeniales are microscopic parasites of a wide diversity of arthropod hosts. Three genera exclusively target bat flies: Arthrorhynchus, which parasitizes species within Nycteribiidae in the Eastern Hemisphere, while genus Gloeandromyces and Nycteromyces parasitize Streblidae in the Western Hemisphere. Among the hyperparasitic arthropods, mites of family Neothrombidiidae, particularly the monospecific genus Monunguis, are known to parasitize bat flies. Here we present the first records of the hyperparasites Monunguis streblida and Gloeandromyces pageanus f. polymorphus parasitizing Streblidae bat flies in Colombia and a summary of these hyperparasitic interactions in the Neotropics. We detected fungi and mites parasitizing bat flies that were collected in the Magdalena River Basin, Colombia, in field expeditions in 2018, 2022, and 2023. We identified 17 bat flies and two species of hyperparasites, specifically M. streblida and the fungi Gloeandromyces. Our search for reports of these interactions in the Neotropics revealed that seven species of Trichobius (Streblidae) are parasitized by M. streblida, whereas Paratrichobius longicrus (Streblidae) is parasitized by Gloeandromyces pageanus f. polymorphus. These interactions have been reported in 11 countries, but our records are the first of M. streblida and Laboulbeniales fungi parasitizing bat flies in Colombia. So far, a total of 14 species of fungi and one species of mite have been associated with 19 species of bat flies, which in turn, are linked to 15 species of Neotropical bats. [ABSTRACT FROM AUTHOR]

Purpose: The main purpose of this study was to perform an immunohistochemical, functional, and anatomical evaluation of patients with idiopathic epiretinal membrane (ERM). Methods: Twenty-four specimens of idiopathic ERM from 24 consecutive patients who underwent 23 G pars plana vitrectomy for ERM and internal limiting membrane (ILM) peeling at the San Juan University Hospital in Alicante (Spain) in 2019 were analyzed. All patients underwent a complete ophthalmological examination including measurement of best corrected visual acuity (BCVA) and macular analysis by spectral-domain optical coherence tomography (SD-OCT) at the time of diagnosis and 3 months after surgery. Specific glial fibrillar acid protein antibodies (GFAP) and S100 calcium-binding protein β (S100β) immunostaining markers were used to identify the macroglial component of the ERM, Müller cells, and astrocytes. Ionized calcium-binding adapter molecule 1 protein (Iba1) antibodies were used as specific markers for inflammatory cells, such as microglia and macrophages. Results: Mean preoperative BCVA measured with Snellen chart was 0.3 and 0.6 preoperatively and at 3 months after surgery, respectively. SD-OCT identified 15 patients (62.5%) with a disruption of the outer retinal hyperreflective bands. The immunohistochemical study showed the presence of Müller cells in almost all cases (91.6%), as well of abundant microglia and macrophages. Microglia and macrophages were more frequently present in earlier stages of ERM. Microglia were present in ERM independently of the outer retinal hyperreflective bands integrity as measured by SD-OCT. A greater presence of macrophages was found in those ERMs with no outer retinal hyperreflective band disruption. Conclusions: Müller cells seem to be the most frequent cell group in ERMs, with also presence of microglia cells and macrophages. Astrocytes were more frequently found in early stages of ERMs. Microglia and macrophages were most frequent in ERMs with early stage (1, 2, or 3) than in advanced stages (4). [ABSTRACT FROM AUTHOR]

The mammal retina does not have the capacity to regenerate throughout life, although some stem and progenitor cells persist in the adult retina and might retain multipotentiality, as previously described in many tissues. In this work we demonstrate the presence of a small lineage− Sca-1+ cell population in the adult mouse retina which expresses functional TLR2 receptors as in vitro challenge with the pure TLR2 agonist Pam3CSK4 increases cell number and upregulates TLR2. Therefore, this population could be of interest in neuroregeneration studies to elucidate its role in these processes. [ABSTRACT FROM AUTHOR]

Modern height systems are based on the combination of satellite positioning and gravity field models of high resolution. However, in many regions, especially developing or newly industrializing countries, there is no (reliable) regional gravity model at all, due to challenges such as limited data availability, unknown/low data quality, and missing metadata. This paper addresses this issue in a case study of Colombia, where eight decades of historical terrestrial and airborne gravity measurements are available but widely contain systematic errors, outliers, and biases. Correspondingly, processing strategies and structures are proposed and applied to validate and improve the quality of old gravity datasets. A novel method is developed based on spherical radial basis functions (SRBFs) for estimating biases, which are found in different airborne surveys with values exceeding 40 mGal. The validity of this bias estimation method is demonstrated both by a simulation test and by the evaluation of the airborne data in comparison to the SATOP (SAtellite-TOPography) model, which merges the satellite-only global gravity model GOCO06s with the Earth2014 topography model. The terrestrial and airborne data are then combined with a global gravity model (GGM), ultra-high-resolution topography models, as well as altimetry-derived gravity anomalies from DTU21GRA for the offshore areas. The results are presented in terms of height anomalies (QGeoidCOL2023), and they are thoroughly validated using GPS/leveling data both in the absolute and relative manner. The standard deviation in comparison to the GPS/leveling data after applying a correction surface to account for the datum inconsistencies amounts to 15.76 cm, which is 27% smaller compared to the mean standard deviation value given by five recent high-resolution GGMs, and 36% smaller than the one delivered by the latest South American quasi-geoid model QGEOID2021. The relative validation results show that QGeoidCOL2023 performs better, i.e., delivers lower RMS errors than the GGMs and QGEOID2021 in all the baseline length groups. These results indicate the validity and benefits of the developed methods and procedures, which can be used for other data-challenging areas to facilitate the realization of geopotential-based height systems. [ABSTRACT FROM AUTHOR]

There is a widely recognized need to reduce human activity's impact on the environment. Many industries of the leather and textile sector (LTI), being aware of producing a significant amount of residues (Keßler et al. 2021; Liu et al. 2021), are adopting measures to reduce the impact of their processes on the environment, starting with a more comprehensive characterization of the chemical risk associated with the substances commonly used in LTI. The present work contributes to these efforts by compiling and toxicologically annotating the substances used in LTI, supporting a continuous learning strategy for characterizing their chemical safety. This strategy combines data collection from public sources, experimental methods and in silico predictions for characterizing four different endpoints: CMR, ED, PBT, and vPvB. We present the results of a prospective validation exercise in which we confirm that in silico methods can produce reasonably good hazard estimations and fill knowledge gaps in the LTI chemical space. The proposed protocol can speed the process and optimize the use of resources including the lives of experimental animals, contributing to identifying potentially harmful substances and their possible replacement by safer alternatives, thus reducing the environmental footprint and impact on human health. [ABSTRACT FROM AUTHOR]

An electrocardiogram (b) showing normal sinus rhythm Graph: Figure 2 Maximum Intensity Projection (MIP) image of 2-[18F]FDG PET/CT (a), showing a highly hypermetabolic cardiac mass, splenomegaly and bone marrow reaction. A chest radiograph and electrocardiogram (Figure 1), obtained in the emergency room, showed clear lung and pleural spaces and normal sinus rhythm. [Extracted from the article]

The multiplication of sugarcane (Saccharum spp.) variety LAICA 04-809 by direct organogenesis was evaluated using four cultivation systems: (1) the traditional system which uses a semisolid medium and (2) three temporary immersion systems with liquid medium (RITA®, BIT®, and SETIS™). In addition, three planting densities (10, 30, and 50 mL of medium per explant) were studied for each system as initial inoculum. Sucrose consumption was observed in all temporary immersion systems after 4 weeks of culture. Photomixotrophic metabolism was identified in all three temporary immersion systems evaluated (RITA®, BIT®, and SETIS™). In addition, at density of 30 mL medium/explant, the BIT® bioreactor generated the highest number of quality shoots (425.33 ± 24.58). No hyperhydricity was observed in the explants. In TISs, the 50 mL volume of medium per explant obtained the highest multiplication coefficient (RITA® 25.53 ± 11.42, BIT® 20.08 ± 4.1 and SETIS™ 11.47 ± 1.27). The results of this study suggest that the combination of the BIT® system with the 50 mL volume of medium/explant represents the best conditions for mass propagation of sugarcane shoots after four weeks of cultivation. Key message: The response of in vitro multiplication of sugarcane depends on the type TISs and the planting density (mL of media per explant). Higher quality of shoots was obtained with BIT®. [ABSTRACT FROM AUTHOR]

Three studies on the biology of Ornithodoros puertoricensis are available in the literature, using different hosts and incubation temperatures. In a previous study, we identified O. puertoricensis in the Colombian Caribbean. The aim of the present work was to analyze life cycle data along one generation from these specimens under laboratory conditions. Eggs of O. puertoricensis were collected in between fragments of bahareque material in a rural dwelling in the municipality of Planeta Rica (Córdoba Department, Colombia), and transported to the laboratory. All post-egg stages (i.e., larvae, nymphs, and adults) were incubated at 27 °C and 85% RH and fed on laboratory mice (Mus musculus). Sixteen engorged larvae were obtained to start a laboratory colony. Average feeding period for larvae was 4.6 days (4–5). The first nymphal instar (N1) did not require feeding and the subsequent nymphal stages (N2, N3, and N4) and adults had feeding periods ranging from 55 to 75 min. Average pre-molting period in nymphs was 15 days (10–21). Most of the N3 molted to males and all N4 molted to females. Two gonotrophic cycles were recorded: the first had a preoviposition period of 12 days (7–18) and produced 190 eggs (171–223), the second lasted 6.6 days (6–7) and produced 146 eggs (104–201). The mean life cycle duration (from parental eggs to F1 eggs) was 70.7 days (58.7–82.7) without fasting periods. The collected data agree with previous studies even with differences in hosts and maintenance conditions. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is one of the leading causes of blindness in the world. While there is a major focus on the study of juvenile/adult DR, the effects of hyperglycemia during early retinal development are less well studied. Recent studies in embryonic zebrafish models of nutritional hyperglycemia (high-glucose exposure) have revealed that hyperglycemia leads to decreased cell numbers of mature retinal cell types, which has been related to a modest increase in apoptotic cell death and altered cell differentiation. However, how embryonic hyperglycemia impacts cell proliferation in developing retinas still remains unknown. Here, we exposed zebrafish embryos to 50 mM glucose from 10 h postfertilization (hpf) to 5 days postfertilization (dpf). First, we confirmed that hyperglycemia increases apoptotic death and decreases the rod and Müller glia population in the retina of 5-dpf zebrafish. Interestingly, the increase in cell death was mainly observed in the ciliary marginal zone (CMZ), where most of the proliferating cells are located. To analyze the impact of hyperglycemia in cell proliferation, mitotic activity was first quantified using pH3 immunolabeling, which revealed a significant decrease in mitotic cells in the retina (mainly in the CMZ) at 5 dpf. A significant decrease in cell proliferation in the outer nuclear and ganglion cell layers of the central retina in hyperglycemic animals was also detected using the proliferation marker PCNA. Overall, our results show that nutritional hyperglycemia decreases cellular proliferation in the developing retina, which could significantly contribute to the decline in the number of mature retinal cells. [ABSTRACT FROM AUTHOR]

The optimal combination of different types of gravity observations is the key to obtaining a high-resolution and high-precision regional gravity model. Current studies based on spherical radial basis functions (SRBFs) majorly consider a single-level approach for data combination. Despite the promising results reported in numerous publications, it has been suspected that the single-level model might be biased towards high-resolution measurements. Instead, a multi-resolution representation (MRR) can be applied to further take into consideration the varying spectral sensitivities of different observation techniques. In this study, we develop a new MRR scheme based on the pyramid algorithm and sequential parameter estimation. We propose strategies to solve the challenges in the practical application of the pyramid algorithm, and this study represents its first successful realization in regional gravity field modeling. The modeling results based on both simulated and real gravity data show that either the single-level approach or the MRR without pyramid algorithm is able to capture gravity information from lower resolution measurements as sufficient as our newly developed MRR algorithm. In the simulated case, the RMS error w.r.t. the validation data obtained by the MRR based on the pyramid algorithm decreases by 50% and 35%, in comparison to that of the single-level model and the MRR without pyramid algorithm, respectively. In the real case, the improvement achieved by the MRR based on the pyramid algorithm is 35% and 23% in the onshore area, and it reaches 63% and 57% in the offshore area, compared to the single-level approach and the MRR without pyramid algorithm, respectively. [ABSTRACT FROM AUTHOR]

One of the major sources of uncertainty affecting vertical land motion (VLM) estimations are discontinuities and trend changes. Trend changes are most commonly caused by seismic deformation, but can also stem from long-term (decadal to multidecadal) surface loading changes or from local origins. Although these issues have been extensively addressed for Global Navigation Satellite System (GNSS) data, there is limited knowledge of how such events can be directly detected and mitigated in VLM, derived from altimetry and tide-gauge differences (SATTG). In this study, we present a novel Bayesian approach to automatically and simultaneously detect such events, together with the statistics commonly estimated to characterize motion signatures. Next to GNSS time series, for the first time, we directly estimate discontinuities and trend changes in VLM data inferred from SATTG. We show that, compared to estimating a single linear trend, accounting for such variable velocities significantly increases the agreement of SATTG with GNSS values (on average by 0.36 mm/year) at 339 globally distributed station pairs. The Bayesian change point detection is applied to 606 SATTG and 381 GNSS time series. Observed VLM, which is identified as linear (i.e. where no significant trend changes are detected), has a substantially higher consistency with large-scale VLM effects of glacial isostatic adjustment (GIA) and contemporary mass redistribution (CMR). The standard deviation of SATTG (and GNSS) trend differences with respect to GIA+CMR trends is by 38% (and 48%) lower for time series with constant velocity compared to variable velocities. Given that in more than a third of the SATTG time series variable velocities are detected, the results underpin the importance to account for such features, in particular to avoid extrapolation biases of coastal VLM and its influence on relative sea-level-change determination. The Bayesian approach uncovers the potential for a better characterization of SATTG VLM changes on much longer periods and is widely applicable to other geophysical time series. [ABSTRACT FROM AUTHOR]

Massive molecular testing for COVID-19 has been pointed out as fundamental to moderate the spread of the pandemic. Pooling methods can enhance testing efficiency, but they are viable only at low incidences of the disease. We propose Smart Pooling, a machine learning method that uses clinical and sociodemographic data from patients to increase the efficiency of informed Dorfman testing for COVID-19 by arranging samples into all-negative pools. To do this, we ran an automated method to train numerous machine learning models on a retrospective dataset from more than 8000 patients tested for SARS-CoV-2 from April to July 2020 in Bogotá, Colombia. We estimated the efficiency gains of using the predictor to support Dorfman testing by simulating the outcome of tests. We also computed the attainable efficiency gains of non-adaptive pooling schemes mathematically. Moreover, we measured the false-negative error rates in detecting the ORF1ab and N genes of the virus in RT-qPCR dilutions. Finally, we presented the efficiency gains of using our proposed pooling scheme on proof-of-concept pooled tests. We believe Smart Pooling will be efficient for optimizing massive testing of SARS-CoV-2. [ABSTRACT FROM AUTHOR]

In the quest for more effective radiation treatment options that can improve both cell killing and healthy tissue recovery, combined radiation therapies are lately in the spotlight. The molecular response to a combined radiation regime where exposure to an initial low dose (priming dose) of ionizing radiation is administered prior to a subsequent higher radiation dose (challenging dose) after a given latency period have not been thoroughly explored. In this study we report on the differential response to either a combined radiation regime or a single challenging dose both in mouse in vivo and in human ex vivo thymocytes. A differential cell cycle response including an increase in the subG1 fraction on cells exposed to the combined regime was found. Together with this, a differential protein expression profiling in several pathways including cell cycle control (ATM, TP53, p21CDKN1A), damage response (γH2AX) and cell death pathways such as apoptosis (Cleaved Caspase-3, PARP1, PKCδ and H3T45ph) and ferroptosis (xCT/GPX4) was demonstrated. This study also shows the epigenetic regulation following a combined regime that alters the expression of chromatin modifiers such as DNMTs (DNMT1, DNMT2, DNMT3A, DNMT3B, DNMT3L) and glycosylases (MBD4 and TDG). Furthermore, a study of the underlying cellular status six hours after the priming dose alone showed evidence of retained modifications on the molecular and epigenetic pathways suggesting that the priming dose infers a "radiation awareness phenotype" to the thymocytes, a sensitization key to the differential response seen after the second hit with the challenging dose. These data suggest that combined-dose radiation regimes could be more efficient at making cells respond to radiation and it would be interesting to further investigate how can these schemes be of use to potential new radiation therapies. [ABSTRACT FROM AUTHOR]

The primary objective of the 1-cm geoid experiment in Colorado (USA) is to compare the numerous geoid computation methods used by different groups around the world. This is intended to lay the foundations for tuning computation methods to achieve the sought after 1-cm accuracy, and also evaluate how this accuracy may be robustly assessed. In this experiment, (quasi)geoid models were computed using the same input data provided by the US National Geodetic Survey (NGS), but using different methodologies. The rugged mountainous study area (730 km × 560 km) in Colorado was chosen so as to accentuate any differences between the methodologies, and to take advantage of newly collected GPS/leveling data of the Geoid Slope Validation Survey 2017 (GSVS17) which are now available to be used as an accurate and independent test dataset. Fourteen groups from fourteen countries submitted a gravimetric geoid and a quasigeoid model in a 1′ × 1′ grid for the study area, as well as geoid heights, height anomalies, and geopotential values at the 223 GSVS17 marks. This paper concentrates on the quasigeoid model comparison and evaluation, while the geopotential value investigations are presented as a separate paper (Sánchez et al. in J Geodesy 95(3):1. , 2021). Three comparisons are performed: the area comparison to show the model precision, the comparison with the GSVS17 data to estimate the relative accuracy of the models, and the differential quasigeoid (slope) comparison with GSVS17 to assess the relative accuracy of the height anomalies at different baseline lengths. The results show that the precision of the 1′ × 1′ models over the complete area is about 2 cm, while the accuracy estimates along the GSVS17 profile range from 1.2 cm to 3.4 cm. Considering that the GSVS17 does not pass the roughest terrain, we estimate that the quasigeoid can be computed with an accuracy of ~ 2 cm in Colorado. The slope comparisons show that RMS values of the differences vary from 2 to 8 cm in all baseline lengths. Although the 2-cm precision and 2-cm relative accuracy have been estimated in such a rugged region, the experiment has not reached the 1-cm accuracy goal. At this point, the different accuracy estimates are not a proof of the superiority of one methodology over another because the model precision and accuracy of the GSVS17-derived height anomalies are at a similar level. It appears that the differences are not primarily caused by differences in theory, but that they originate mostly from numerical computations and/or data processing techniques. Consequently, recommendations to improve the model precision toward the 1-cm accuracy are also given in this paper. [ABSTRACT FROM AUTHOR]

Background: Previous studies have investigated weight loss caused by exercise following bariatric surgery. However, in most cases, the training program is poorly reported; the exercise type, volume, and intensity are briefly mentioned; and the sample size, selection criteria, and follow-up time vary greatly across studies. Purpose: The EFIBAR study aims to investigate over 1 year the effects of a 16-week supervised exercise program, initiated immediately after bariatric surgery, on weight loss (primary outcome), body composition, cardiometabolic risk, physical fitness, and quality of life in patients with severe/extreme obesity. Material and Methods: The EFIBAR study is a parallel-group, superiority, randomized controlled trial (RCT), comprising 80 surgery patients. Half of the participants, randomly selected, perform a 16-week supervised exercise program, including both strength and aerobic training, starting immediately after the surgery (7–14 days). For each participant, all primary and secondary outcomes are measured at three different time points: (i) before the surgery, (ii) after the intervention (≈4 months), and (iii) 1 year after the surgery. Conclusion: The EFIBAR study will provide new insights into the multidimensional benefits of exercise in adults with severe/extreme obesity following bariatric surgery. Trial Registration: EFIBAR randomized controlled trial was prospectively registered at Clinicaltrials.gov (NCT03497546) on April 13, 2018. [ABSTRACT FROM AUTHOR]

Background: Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory pathology that has been reported to affect principally the retroperitoneum, hepatobiliary system, salivary glands, orbital structures or lymph nodes. However, IgG4-RD with laryngeal involvement is a very rare entity. Our aims were to describe a case of subglottic stenosis as first and only manifestation of IgG4-RD and review the literature. A patient with IgG4-RD affecting the larynx that presented as subglottic stenosis is described. A MEDLINE database search of IgG4-RD cases with laryngopharyngeal manifestations was also conducted. A 30-year-old Caucasian woman was referred to a tertiary care hospital for dyspnea on exertion, which had been increasing for the last 4 months. Medical and surgical procedures revealed a subglottic stenosis, with a histological finding of IgG4 positive plasma cell infiltration. There was no evidence of other organ involvement. She was successfully treated with oral glucocorticoids and rituximab infusions. Glucocorticoids were rapidly tapered and the rituximab regimen was optimized, with no evidence of relapses. In the literature review, we found a total of 12 reported cases with laryngopharyngeal involvement, two of them with subglottic stenosis. IgG4-RD of the larynx is rare but should be considered after excluding more common disorders. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) is known for being very aggressive, heterogeneous and highly metastatic. The standard of care treatment is still chemotherapy, with adjacent toxicity and low efficacy, highlighting the need for alternative and more effective therapeutic strategies. Edelfosine, an alkyl-lysophospholipid, has proved to be a promising therapy for several cancer types, upon delivery in lipid nanoparticles. Therefore, the objective of this work was to explore the potential of edelfosine for the treatment of TNBC. Edelfosine nanoemulsions (ET-NEs) composed by edelfosine, Miglyol 812 and phosphatidylcholine as excipients, due to their good safety profile, presented an average size of about 120 nm and a neutral zeta potential, and were stable in biorelevant media. The ability of ET-NEs to interrupt tumor growth in TNBC was demonstrated both in vitro, using a highly aggressive and invasive TNBC cell line, and in vivo, using zebrafish embryos. Importantly, ET-NEs were able to penetrate through the skin barrier of MDA-MB 231 xenografted zebrafish embryos, into the yolk sac, leading to an effective decrease of highly aggressive and invasive tumoral cells' proliferation. Altogether the results demonstrate the potential of ET-NEs for the development of new therapeutic approaches for TNBC. [ABSTRACT FROM AUTHOR]

Fish chemosensory olfactory receptors allow them to detect a wide range of water-soluble chemicals, that mediate fundamental behaviours. Zebrafish possess a well-developed sense of smell which governs reproduction, appetite, and fear responses. The spatial organization of functional properties within the olfactory epithelium and bulb are comparable to those of mammals, making this species suitable for studies of olfactory differentiation and regeneration and neuronal representation of olfactory information. The advent of genomic techniques has been decisive for the discovery of specific olfactory cell types and the identification of cell populations expressing vomeronasal receptors. These advances have marched ahead of morphological and neurochemical studies. This study aims to fill the existing gap in specific histological, lectin-histochemical and immunohistochemical studies on the olfactory rosette and the olfactory bulb of the zebrafish. Tissue dissection and microdissection techniques were employed, followed by histological staining techniques, lectin-histochemical labelling (UEA, LEA, BSI-B4) and immunohistochemistry using antibodies against G proteins subunits αo and αi2, growth-associated protein-43, calbindin, calretinin, glial-fibrillary-acidic-protein and luteinizing-hormone-releasing-hormone. The results obtained enrich the available information on the neurochemical patterns of the zebrafish olfactory system, pointing to a greater complexity than the one currently considered, especially when taking into account the peculiarities of the nonsensory epithelium. [ABSTRACT FROM AUTHOR]

In 2015, the International Association of Geodesy defined the International Height Reference System (IHRS) as the conventional gravity field-related global height system. The IHRS is a geopotential reference system co-rotating with the Earth. Coordinates of points or objects close to or on the Earth's surface are given by geopotential numbers C(P) referring to an equipotential surface defined by the conventional value W0 = 62,636,853.4 m2 s−2, and geocentric Cartesian coordinates X referring to the International Terrestrial Reference System (ITRS). Current efforts concentrate on an accurate, consistent, and well-defined realisation of the IHRS to provide an international standard for the precise determination of physical coordinates worldwide. Accordingly, this study focuses on the strategy for the realisation of the IHRS; i.e. the establishment of the International Height Reference Frame (IHRF). Four main aspects are considered: (1) methods for the determination of IHRF physical coordinates; (2) standards and conventions needed to ensure consistency between the definition and the realisation of the reference system; (3) criteria for the IHRF reference network design and station selection; and (4) operational infrastructure to guarantee a reliable and long-term sustainability of the IHRF. A highlight of this work is the evaluation of different approaches for the determination and accuracy assessment of IHRF coordinates based on the existing resources, namely (1) global gravity models of high resolution, (2) precise regional gravity field modelling, and (3) vertical datum unification of the local height systems into the IHRF. After a detailed discussion of the advantages, current limitations, and possibilities of improvement in the coordinate determination using these options, we define a strategy for the establishment of the IHRF including data requirements, a set of minimum standards/conventions for the determination of potential coordinates, a first IHRF reference network configuration, and a proposal to create a component of the International Gravity Field Service (IGFS) dedicated to the maintenance and servicing of the IHRS/IHRF. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer death, has a 5-year survival rate of approximately 7–9%. The ineffectiveness of anti-PDAC therapies is believed to be due to the existence of a subpopulation of tumor cells known as cancer stem cells (CSCs), which are functionally plastic, and have exclusive tumorigenic, chemoresistant and metastatic capacities. Herein, we describe a 2D in vitro system for long-term enrichment of pancreatic CSCs that is amenable to biological and CSC-specific studies. By changing the carbon source from glucose to galactose in vitro, we force PDAC cells to utilize OXPHOS, resulting in enrichment of CSCs defined by increased CSC biomarker and pluripotency gene expression, greater tumorigenic potential, induced but reversible quiescence, increased OXPHOS activity, enhanced invasiveness, and upregulated immune evasion properties. This CSC enrichment method can facilitate the discovery of new CSC-specific hallmarks for future development into targets for PDAC-based therapies. Long-term cultures of pancreatic cancer stem cells (PaCSCs) are difficult to obtain. Here, the authors present a 2D culture method, based on the use of galactose, to establish cell cultures from pancreatic ductal adenocarcinoma xenotransplants enriched in PaCSCs. [ABSTRACT FROM AUTHOR]

This study presents a solution of the ‘1 cm Geoid Experiment’ (Colorado Experiment) using spherical radial basis functions (SRBFs). As the only group using SRBFs among the fourteen participated institutions from all over the world, we highlight the methodology of SRBFs in this paper. Detailed explanations are given regarding the settings of the four most important factors that influence the performance of SRBFs in gravity field modeling, namely (1) the choosing bandwidth, (2) the locations of the SRBFs, (3) the type of the SRBFs as well as (4) the extensions of the data zone for reducing the edge effect. Two types of basis functions covering the same spectral range are used for the terrestrial and the airborne measurements, respectively. The non-smoothing Shannon function is applied to the terrestrial data to avoid the loss of spectral information. The cubic polynomial (CuP) function which has smoothing features is applied to the airborne data as a low-pass filter for filtering the high-frequency noise. Although the idea of combining different SRBFs for different observations was proven in theory to be possible, it is applied to real data for the first time, in this study. The RMS error of our height anomaly result along the GSVS17 benchmarks w.r.t the validation data (which is the mean results of the other contributions in the ‘Colorado Experiment’) drops by 5% when combining the Shannon function for the terrestrial data and the CuP function for the airborne data, compared to those obtained by using the Shannon function for both the two data sets. This improvement indicates the validity and benefits of using different SRBFs for different observation types. Global gravity model (GGM), topographic model, the terrestrial gravity data, as well as the airborne gravity data are combined, and the contribution of each data set to the final solution is discussed. By adding the terrestrial data to the GGM and the topographic model, the RMS error of the height anomaly result w.r.t the validation data drops from 4 to 1.8 cm, and it is further reduced to 1 cm by including the airborne data. Comparisons with the mean results of all the contributions show that our height anomaly and geoid height solutions at the GSVS17 benchmarks have an RMS error of 1.0 cm and 1.3 cm, respectively; and our height anomaly results give an RMS value of 1.6 cm in the whole study area, which are all the smallest among the participants. [ABSTRACT FROM AUTHOR]

We report the case of a Caucasian Spanish boy, who showed profound neonatal hypotonia, feeding difficulties, apnea, severe developmental delay, epilepsy, bilateral convergent strabismus, poor verbal language development and a large brainstem. Whole-exome sequence uncovered a novel de novo mutation in the purine-rich element binding protein A gene (PURA; NM_005859.4:c.72del:p.(Gly25AlafsTer53)) that encodes the transcriptional activator protein Pur-alpha (PURA). Mutations in this gene have been identified in patients with PURA syndrome, a rare disorder characterized by an early hypotonia, developmental delay, severe intellectual disability with or without epilepsy, and disability in expressive language development. Although, up to 75 cases have been identified worldwide, to the best of our knowledge, this is the first patient described with a brainstem larger than normal. In conclusion, our data expand both genetic and phenotypic spectrum associated with PURA gene mutations. [ABSTRACT FROM AUTHOR]

Purpose: The aim was to assess perceived health status and health-related quality of life (HRQL) according to persistence of and variation in weight status among children from the age of 4 to 6 years.Methods: Longitudinal study of 1883 participants in the ELOIN cohort (Madrid Region, Spain), with physical examination at ages 4 and 6 years. Perceived health status and HRQL were assessed using parent-reported Kidscreen-10 scores, with excess weight being defined on the basis of body mass index (BMI) using the WHO reference tables (z-BMI > 1 standard deviation), and abdominal obesity being defined on the basis of waist circumference (percentile ≥ 90) using the tables proposed by Fernández et al. Variation in these two parameters at age 6 years was associated with incident cases of suboptimal health by logistic regression, and with HRQL by linear regression.Results: Compared to children without excess weight or abdominal obesity in both periods, incident cases of excess weight or abdominal obesity had odds ratios (ORs) of suboptimal health of 2.41 (95% CI 1.21 to 4.80) and 2.99 (95% CI 1.31 to 6.84) respectively. In terms of HRQL, children with remission of excess weight had a higher Kidscreen-10 score: β coefficient = 2.02 (95% CI 0.36 to 3.68), whereas new cases of abdominal obesity had a lower Kidscreen-10 score: β = - 2.22 (95% CI - 4.40 to - 0.03).Conclusions: Incident cases of excess weight and abdominal obesity had a higher risk of suboptimal health. Incident cases of abdominal obesity were also associated with worse HRQL. [ABSTRACT FROM AUTHOR]

Spa mineral waters are used for the treatment of chronic diseases' symptoms. Anti-inflammatory, analgesic, anti-ageing and tissue repair effects have been attributed to them. This work seeks to improve knowledge about the effect of spa mineral waters on human cells. For this, human lung fibroblasts were treated with mineral waters from Ledesma, Paracuellos and Archena spas, three Spanish health resorts with different water chemical composition. A significant increase of cell proliferation together with an enhanced antioxidant capacity (reactive oxygen and nitrogen species, glutathione levels and superoxide dismutase activity) in mineral water-treated fibroblasts compared to control fibroblasts was observed. Moreover, cytokine profiling revealed an increase in the release of MIF, IL-6, CL-1, CCL-5 and ICAM-1, which are described as mediators in proliferation, wound healing and cell migration processes. In conclusion, our results could be in line with the effects attributed to spa mineral waters in wound healing strategies and oxidative damage protection. [ABSTRACT FROM AUTHOR]

Adenoviruses are important pathogens known to infect vertebrate hosts, including a wide range of primates. Despite its importance, data on the diversity of these viruses in non-human primates living in their natural habitat remain scarce. In this study, we conducted a surveillance of adenoviral infection in wild black howler monkeys from two protected natural areas in Mexico. This was achieved by analyzing 67 fecal samples using a nested PCR that targets the adenovirus DNA polymerase gene. Adenoviral DNA was detected in 12 samples from both study sites, with an overall prevalence of 17.9%. The amplified DNA sequences shared 100% nucleotide identity and phylogenetic analyses revealed that the haplotype detected was novel, and clustered with Platyrrhini mastadenovirus A, which was previously described in captive New World monkeys. Our data, along with the previous evidence, confirm that monkeys native to the Americas are the original hosts of these adenoviruses. [ABSTRACT FROM AUTHOR]

A transesophageal echocardiogram shows vegetation on MitraClip, which was confirmed by focal uptake of 2-[ SP 18 sp F]FDG on a PET/CT which also revealed two septic emboli in the soft tissue of the right foot. The MitraClip is a percutaneously implantable device, for patients with significant symptomatic mitral regurgitation (MR) who have been determined to be at prohibitive risk for mitral valve surgery. [Extracted from the article]

Studying, understanding and modelling global change require geodetic reference frames with an order of accuracy higher than the magnitude of the effects to be actually studied and with high consistency and reliability worldwide. The International Association of Geodesy, taking care of providing a precise geodetic infrastructure for monitoring the Earth system, promotes the implementation of an integrated global geodetic reference frame that provides a reliable frame for consistent analysis and modelling of global phenomena and processes affecting the Earth's gravity field, the Earth's surface geometry and the Earth's rotation. The definition, realization, maintenance and wide utilization of the International Terrestrial Reference System guarantee a globally unified geometric reference frame with an accuracy at the millimetre level. An equivalent high-precision global physical reference frame that supports the reliable description of changes in the Earth's gravity field (such as sea level variations, mass displacements, processes associated with geophysical fluids) is missing. This paper addresses the theoretical foundations supporting the implementation of such a physical reference surface in terms of an International Height Reference System and provides guidance for the coming activities required for the practical and sustainable realization of this system. Based on conceptual approaches of physical geodesy, the requirements for a unified global height reference system are derived. In accordance with the practice, its realization as the International Height Reference Frame is designed. Further steps for the implementation are also proposed. [ABSTRACT FROM AUTHOR]

Paradoxically, N-methyl-D-aspartate (NMDA) receptor antagonists are used to model certain aspects of schizophrenia as well as to treat refractory depression. However, the role of different subunits of the NMDA receptor in both conditions is poorly understood. Here we used biochemical and behavioral readouts to examine the in vivo prefrontal efflux of serotonin and glutamate as well as the stereotypical behavior and the antidepressant-like activity in the forced swim test elicited by antagonists selective for the GluN2A (NVP-AAM077) and GluN2B (Ro 25-6981) subunits. The effects of the non-subunit selective antagonist, MK-801; were also studied for comparison. The administration of MK-801 dose dependently increased the prefrontal efflux of serotonin and glutamate and markedly increased the stereotypy scores. NVP-AAM077 also increased the efflux of serotonin and glutamate, but without the induction of stereotypies. In contrast, Ro 25-6981 did not change any of the biochemical and behavioral parameters tested. Interestingly, the administration of NVP-AAM077 and Ro 25-6981 alone elicited antidepressant-like activity in the forced swim test, in contrast to the combination of both compounds that evoked marked stereotypies. Our interpretation of the results is that both GluN2A and GluN2B subunits are needed to induce stereotypies, which might be suggestive of potential psychotomimetic effects in humans, but the antagonism of only one of these subunits is sufficient to evoke an antidepressant response. We also propose that GluN2A receptor antagonists could have potential antidepressant activity in the absence of potential psychotomimetic effects. [ABSTRACT FROM AUTHOR]

Understanding the genetic basis of sex determination mechanisms is essential for improving the productivity of farmed aquaculture fish species like turbot ( Scophthalmus maximus). In culture conditions turbot males grow slower than females starting from eight months post-hatch, and this differential growth rate is maintained until sexual maturation is reached, being mature females almost twice as big as males of the same age. The goal of this study was to identify sex-specific DNA markers in turbot using comparative random amplified polymorphism DNA (RAPD) profiles in males and females to get new insights of the genetic architecture related to sex determination. In order to do this, we analyzed 540 commercial 10-mer RAPD primers in male and female pools of a gynogenetic family because of its higher inbreeding, which facilitates the detection of associations across the genome. Two sex-linked RAPD markers were identified in the female pool and one in the male pool. After the analysis of the three markers on individual samples of each pool and also in unrelated individuals, only one RAPD showed significant association with females. This marker was isolated, cloned and sequenced, containing two sequences, a microsatellite (SEX01) and a minisatellite (SEX02), which were mapped in the turbot reference map. From this map position, through a comparative mapping approach, we identified Foxl2, a relevant gene related to initial steps of sex differentiation, and Wnt4, a gene related with ovarian development, close to the microsatellite and minisatellite markers, respectively. The position of Foxl2 and Wnt4 was confirmed by linkage mapping in the reference turbot map. [ABSTRACT FROM AUTHOR]

We investigated NO and CH fluxes from soils of Quercus ilex, Quercus pyrenaica and Pinus sylvestris stands located in the surrounding area of Madrid (Spain). The fluxes were measured for 18 months from both mature stands and post fire stands using the static chamber technique. Simultaneously with gas fluxes, soil temperature, soil water content, soil C and soil N were measured in the stands. Nitrous oxide fluxes ranged from −11.43 to 8.34 μg NO-N m h in Q.ilex, −7.74 to 13.52 μg NO-N m h in Q. pyrenaica and −28.17 to 21.89 μg NO-N m h in P. sylvestris. Fluxes of CH ranged from −8.12 to 4.11 μg CH-C m h in Q.ilex, −7.74 to 3.0 μg CH-C m h in Q. pyrenaica and −24.46 to 6.07 μg CH-C m h in P. sylvestris. Seasonal differences were detected; NO fluxes being higher in wet months whereas NO fluxes declined in dry months. Net consumption of NO was related to low N availability, high soil C contents, high soil temperatures and low moisture content. Fire decreased NO fluxes in spring. NO emissions were closely correlated with previous day's rainfall and soil moisture. Our ecosystems generally were a sink for methane in the dry season and a source of CH during wet months. The available water in the soil influenced the observed seasonal trend. The burned sites showed higher CH oxidation rates in Q. ilex, and lower rates in P. sylvestris. Overall, the data suggest that fire alters both NO and CH fluxes. However, the magnitude of such variation depends on the site, soil characteristics and seasonal climatic conditions. [ABSTRACT FROM AUTHOR]

Genetically modified animals represent a resource of immense potential for cancer research. Classically, genetic modifications in mice were obtained through selected breeding experiments or treatments with powerful carcinogens capable of inducing random mutagenesis. A new era began in the early 1980s when genetic modifications by inserting foreign DNA genes into the cells of an animal allowed for the development of transgenic mice. Since that moment, genetic modifications have been able to be made in a predetermined way. Gene targeting emerged later as a method of in vivo mutagenesis whereby the sequence of a predetermined gene is selectively modified within an intact cell. In this review we focus on how genetically modified mice can be created to study tumour development, and how these models have contributed to an understanding of the genetic alterations involved in human cancer. We also discuss the strengths and weaknesses of the different mouse models for identifying cancer genes, and understanding the consequences of their alterations in order to obtain the maximum benefit for cancer patients. [ABSTRACT FROM AUTHOR]

One of the earliest signs of mucosal immune activation in celiac disease (CD) is an increase in the intraepithelial lymphocyte (IEL) count in the small intestinal epithelium. Though most of those IELs express T cell receptor (TcR)-alphabeta chains, CD is characterized by an increase in TcR-gammadelta+ IELs and by the loss of CD3- IELs. There is currently little evidence that these changes in IEL subset distribution are of relevance in the pathogenesis of CD. We aimed to determine the pattern of cytokine production by IEL subsets isolated from duodenal biopsy specimens from control subjects and CD patients at different stages of the disease. We quantified the capacity of IEL subsets to produce IFN-gamma, TNF-alpha, IL-2, IL-4, and IL-10 by intracellular staining by flow cytometry. All IEL subsets studied displayed a type I cytokine profile in both CD and control subjects, with TcR-alphabeta+ IELs being the main IFN-y producers. Untreated CD exhibited a trend toward a superior accumulation of IFN-gamma per cell but a reduced proportion of INF-gamma+ cells in vitro in association with a significantly increased apoptotic rate of IELs. IL-4 was almost undetectable in all cases and IL-10 showed a tendency to increase in treated and "silent" celiac patients. IEL subsets have a similar Th1 profile in controls and CD patients, and the superior in vitro apoptosis of IELs from CD patients may reflect their superior in vivo activation. The induction of IL-10-dependent regulatory Tr1 responses may be of potential clinical significance in this disease and merits further investigation. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Autoimmune enteropathy is a rare disorder of unknown pathogenesis, characterized by protracted diarrhea, villous atrophy, and enterocyte autoantibodies. Its association with extended inflammation of the whole gastrointestinal tract is termed as generalized autoimmune gut disorder (GAGD), generally a pediatric disease of difficult management due to its association with immunodeficiency. The aim of our work is to describe the mucosal immunological basis of an adult-onset case of GAGD.METHODS: We studied an adult female with a severe inflammatory involvement of the gastrointestinal tract (stomach, small and large bowel, and liver) and antienterocyte autoantibodies. She had antibody deficiency and a predisposition to systemic autoimmunity. We analyzed, by immunohistochemistry and flow cytometry, the phenotypic and functional characteristics of her intestinal intraepithelial and lamina propria (LP) lymphocytes.RESULTS: We observed the prominent and constant presence of an unusual CD4+αE/β7− Tc subset in the jejunal epithelium. Signs of the lymphocyte activation as well as the prominent lymphoid TNF-α production observed in the rectal mucosa support the involvement of a cell-mediated pro-inflammatory response in the pathogenesis of GAGD.CONCLUSIONS: We report the second case of an adult fulfilling all diagnostic criteria for GAGD. We propose that the activated LP CD4+ T lymphocytes, as well as those atypically located in the epithelium, may play a pathogenic role. TheαE/β7− IEL could constitute a diagnostic marker of intestinal autoimmunity in the cases when autoantibodies are not evidenced, and mucosal TNF-α might represent a novel therapeutic target in this severe disease. [ABSTRACT FROM AUTHOR]

In this paper we present the analysis of nucleolar organizer regions (NORs) in five species of the order Pleuronectiformes (Scophthalmus maximus, Scophthalmus rhombus, Platichthys flesus, Solea solea and Solea lascaris), a group of fish poorly studied cytogenetically. In spite of the small chromosome sizes, which characterize the karyotypes of this group, we implement both classical (Ag- and CMA3-staining) and molecular (in situ hybridization with a major rDNA probe) techniques for NOR location. NORs were localized in a single chromosome pair in all species studied and showed size variation within each species. Evidence of a NOR-site polymorphism was detected in Platichthys flesus and Scophthalmus maximus. NOR location was apparently the same within families (S. rhombus vs. S maximus, and S. solea vs. S. lascaris) but clearly differed among families, and supports the phylogenetic relationships proposed for the order Pleuronectiformes. [ABSTRACT FROM AUTHOR]

A population analysis of an unusual NOR-site polymorphism previously detected in brown trout (Salmo trutta L.) from North-western Spain was carried out in 225 individuals from 20 native populations from this area. The analysis performed has permitted us to reveal: (i) the ubiquity of this phenomenon in most river basins from NW Spain, 13 extra-NORs not observed in standard trout being detected; (ii) the rDNA constitution of all extra-NORs, as confirmed by CMA3-staining and rDNA-FISH, and their capability to constitute their own nucleolus; (iii) the constant location of extra-NORs within individuals and their stable transmission across generations; and (iv) the telomeric location of Ag-NORs, which were randomly distributed in the karyotype of S. trutta, mostly in the heterozygous condition. Repetitive sequences in the IGS or scattered along rDNA units, rather than chromosome rearrangements, could play an important role in the dispersion of NORs. The polymorphism described seems to have a single geographical origin, since a positive correlation was demonstrated between the degree of polymorphism and geographical distance to a central point of the river basin where the phenomenon showed a higher intensity. The distribution of NOR-site variation as compared with allozyme variation in the populations studied, showed significant statistical differences. Selection against high copy number, or mutation due to changes in NOR location, could be acting on this polymorphism to explain the observed distribution. The high dispersion of NOR-site variants within and among populations suggests the transposition phenomenon responsible for NOR jumping could be still active. [ABSTRACT FROM AUTHOR]

Nearly half of the human genome is made of transposable elements (TEs) whose activity continues to impact its structure and function. Among them, Long INterspersed Element class 1 (LINE-1 or L1) elements are the only autonomously active TEs in humans. L1s are expressed and mobilized in different cancers, generating mutagenic insertions that could affect tumor malignancy. Tumor suppressor microRNAs are ∼22nt RNAs that post-transcriptionally regulate oncogene expression and are frequently downregulated in cancer. Here we explore whether they also influence L1 mobilization. We show that downregulation of let-7 correlates with accumulation of L1 insertions in human lung cancer. Furthermore, we demonstrate that let-7 binds to the L1 mRNA and impairs the translation of the second L1-encoded protein, ORF2p, reducing its mobilization. Overall, our data reveals that let-7, one of the most relevant microRNAs, maintains somatic genome integrity by restricting L1 retrotransposition. Human Long INterspersed Element class 1 (LINE-1) elements are expressed and mobilized in many types of cancer, contributing to malignancy. Here the authors show that the tumor suppressor microRNA let-7 targets the LINE-1 mRNA and reduces LINE-1 mobilization. [ABSTRACT FROM AUTHOR]