Mine water as a source of energy: an application in a coalfield in Laciana Valley (León, NW Spain).

Mine water can be a renewable and economical source of geothermal and hydraulic energy. Nine discharges from closed and flooded coal mines in the Laciana Valley (León, NW Spain) have been studied. Various technologies for the energy use of mine water, as well as the influence of factors such as temperature, the need for water treatment, investment, potential customers and expansion capacity, have been evaluated by means of a decision-making tool. It is concluded that the most advantageous option is an open-loop geothermal system using the waters of a mountain mine, the temperature of which exceeds 14 °C and whose distance to customers is less than 2 km. A technical-economic viability study for a district heating network designed to supply heating and hot water to six public buildings in the nearby town of Villablino is presented. The proposed use of mine water might help areas that have been greatly affected socioeconomically by the closure of the mines and has other advantages compared to conventional energy systems, such as the reduction of CO2 emissions. Graphical Abstract: It showing the advantages of using mine water as an energy source for district heating and a simplified layout. Supplementary Information: The online version contains supplementary material available at 10.1007/s10098-023-02526-y.

Generation of a novel three-dimensional scaffold-based model of the bovine endometrium.

Bovine in vitro endometrial models that resemble tissue function in vivo are needed to study infertility, long-term uterine alterations induced by pathogens and impact of endocrine disruptor chemicals on reproductive function and other reproductive system complications that cause high economic losses in livestock species. The present study aimed to generate an innovative, reproducible, and functional 3D scaffold-based model of the bovine endometrium structurally robust for long term-culture. We developed a multicellular model containing both endometrial epithelial and stromal cells. Epithelial cells organized to form a luminal-like epithelial layer on the surface of the scaffold. Stromal cells produced their own extracellular matrix forming a stable subepithelial compartment that physiologically resembles the normal endometrium. Both cell types released prostaglandin E2 and prostaglandin F2α following a treatment with oxytocin and arachidonic acid. Additionally signal pathways mediating oxytocin and arachidonic acid stimulation of prostaglandin synthesis were analyzed by real time PCR (RT-PCR). Oxytocin receptor (OXTR), prostaglandin E2 receptor 2 (EP2), prostaglandin E2 receptor 4 (EP4), prostaglandin F receptor (PTGFR), prostaglandin E synthase (PTGES), PGF-synthase (PGFS) and prostaglandin-endoperoxide synthase 2 (COX-2) expression was detected in both control and treatment groups, however, only significant changes in abundance of OXTR mRNA transcripts were found. The results obtained by this study are a step forward in bovine in vitro culture technology. This 3D scaffold-based model provides a platform to study regulatory mechanisms involved in endometrial physiology and can set the basis for a broader tool for designing and testing novel therapeutic strategies for recurrent uterine pathologies.

A finely tuned interplay between calcium binding, ionic strength and pH modulates conformational and oligomerization equilibria in the Respiratory Syncytial Virus Matrix (M) protein.

As in most enveloped RNA viruses, the Respiratory Syncytial Virus Matrix (RSV-M) protein plays key roles in viral assembly and uncoating. It also plays non-structural roles related to transcription modulation through nucleo-cytoplasmic shuttling and nucleic acid binding ability. We dissected the structural and conformational changes underlying the switch between multiple functionalities, identifying Ca2+ binding as a key factor. To this end, we tackled the analysis of M's conformational stability and equilibria. While in silico calculations predict two potential calcium binding sites per protomer, purified RSV-M dimer contains only one strongly bound calcium ion per protomer. Incubation of RSV-M in the presence of excess Ca2+ leads to an increase in the thermal stability, confirming additional Ca2+ binding sites. Moreover, mild denaturant concentrations trigger the formation of higher order oligomers which are otherwise prevented under Ca2+ saturation conditions, in line with the stabilizing effect of the additional low affinity binding site. On the other hand, Ca2+ removal by chelation at pH 7.0 causes a substantial decrease in the thermal stability leading to the formation of amorphous, spherical-like aggregates, as assessed by TEM. Even though the Ca2+ content modulates RSV-M oligomerization propensity, it does affect its weak RNA binding ability. RSV-M undergoes a substantial conformational change at pHs 4.0 to 5.0 that results in the exposure of hydrophobic surfaces, an increase beta sheet content but burial of tryptophan residues. While low ionic strength promotes dimer dissociation at pH 4.0, physiological concentrations of NaCl lead to the formation of soluble oligomers smaller than 400 kDa at pH 4.0 or insoluble aggregates with tubular morphology at pH 5.0, supporting a fine tuning by pH. Furthermore, the dissociation constants estimated for the low- and high affinity calcium binding sites are 13 µM and 58 nM, respectively, suggesting an intracellular calcium sensing mechanism of RSV-M upon infection. We uncover a finely tuned interplay between calcium binding, ionic strength, and pH changes compatible with the different cellular compartments where M plays key roles, revealing diverse conformational equilibria, oligomerization, and high order structures, required to stabilize the virion particle by a layer of molecules positioned between the membrane and the nucleocapsid.

Estimating personal solar ultraviolet radiation exposure through time spent outdoors, ambient levels and modelling approaches.

BACKGROUND: Evidence on validation of surrogates applied to evaluate the personal exposure levels of solar ultraviolet radiation (UVR) in epidemiological studies is scarce. OBJECTIVES: To determine and compare the validity of three approaches, including (i) ambient UVR levels, (ii) time spent outdoors and (iii) a modelling approach integrating the aforementioned parameters, to estimate personal UVR exposure over a period of 6 months among indoor and outdoor workers and in different seasons (summer/winter). METHODS: This validation study was part of the European Commission-funded ICEPURE project and was performed between July 2010 and January 2011 in a convenience sample of indoor and outdoor workers in Catalunya, Spain. We developed linear regression models to quantify the variation in the objectively measured personal UVR exposure that could be explained, separately, by the ambient UVR, time spent outdoors and modelled UVR levels. RESULTS: Our 39 participants - mostly male and with a median age of 35 years - presented a median daily objectively measured UVR of 0·37 standard erythemal doses. The UVR dose was statistically significantly higher in summer and for outdoor workers. The modelled personal UVR exposure and self-reported time spent outdoors could reasonably predict the variation in the objectively measured personal UVR levels (R2 range 0·75-0·79), whereas ambient UVR was a poor predictor (R2 = 0·21). No notable differences were found between seasons or occupation. CONCLUSIONS: Time outdoors and our modelling approach were reliable predictors and of value to be applied in epidemiological studies of the health effects of current exposure to UVR.

Efficacy of a topical gel containing chitosan, chlorhexidine, allantoin and dexpanthenol for pain and inflammation control after third molar surgery: A randomized and placebo-controlled clinical trial.

BACKGROUND: The aim of this study was to evaluate and compare the postoperative effect of a topic gel containing chlorhexidine, chitosan, allantoine and dexpanthenol versus a placebo for pain and inflammation control after third molar surgery. MATERIAL AND METHODS: A gel combining 0.2% chlorhexdine, 0.5% chitosan, 5% dexpanthenol, 0.15% allantoin and 0.01% sodium saccharin was selected for this split mouth randomized controlled and double-blind trial including 36 patients with bilaterally and symmetrically impacted lower third molars. The teeth (n=72) were randomly divided into two groups before surgical removal: control group (CG; in which a placebo was given) and experimental group (EG). Swelling, trismus, postoperative pain, wound healing and complications were measured and recorded in order to evaluate differences between the placebo and experimental product. RESULTS: Five patients suffered from an alveolitis in the CG (13.9%), and none in the study group (0%), but no statistically significant difference was found (p=0.063). From day 0 to day 7, trismus and swelling were significantly less pronounced in the EG, and wound healing was considered 'good' in 22.2% for the CG and 97.2% for the EG (p<0.001). Mean VAS scores during the seven postoperative days were statistically lower in the study (2.56±1,19) compared to the placebo group (3.25±1.6) (p=0.002). The mean consumption of analgesic pills during the first 92 hours was also statistically lower in the EG (0.26±0.51) in comparison to the CG (0.56±0.67) (p=0.003). CONCLUSIONS: The use of an experimental gel containing chlorhexidine, chitosan, allantoine and dexpanthenol seems to significantly reduce postoperative pain, trismus and signs of inflammation. Future studies should further evaluate, if the gel is effective in dry socket preventing after third molar removal.

Fusobacterium nucleatum persistence and risk of recurrence after preoperative treatment in locally advanced rectal cancer.

BACKGROUND: Accumulating evidence has identified Fusobacterium as an important pathogenic gut bacterium associated with colorectal cancer. Nevertheless, only limited data exist about the role of this bacterium in locally advanced rectal cancer (LARC). In this study, we quantified Fusobacterium nucleatum in untreated and post-neoadjuvant chemoradiotherapy (nCRT) samples from LARC patients and investigated its association with therapy response and survival. PATIENTS AND METHODS: A total of 254 samples from 143 patients with rectal adenocarcinomas were analyzed for the presence and abundance of F. nucleatum using RNA in situ hybridization and digital image analysis. Assay accuracy was determined using infected cell lines and tumor samples with available quantitative PCR data. We studied the impact of F. nucleatum load on pathologic complete response and relapse-free survival. Treatment-induced changes were evaluated in paired pre- and post-nCRT samples (n = 71). Finally, tumor microenvironment changes during nCRT were assessed in paired samples (n = 45) by immune contexture analysis. RESULTS: F. nucleatum tissue levels by RNA in situ hybridization strongly correlated with quantitative PCR (r = 0.804, P < 0.001). F. nucleatum abundance was higher in untreated [median, 7.4; 95% confidence interval (3.7-16.2)] compared with treated [median, 1.6; 95% confidence interval (1.3-2.4)] tumors (P <0.001) with 58% (73/126) and 26% (22/85) positive tumors, respectively (P < 0.001). Baseline F. nucleatum levels were not associated with pathologic complete response. F. nucleatum positivity after nCRT, but not baseline status, significantly increased risk of relapse [hazard ratio = 7.5, 95% confidence interval (3.0-19.0); P < 0.001]. Tumors that turned F. nucleatum-negative after nCRT had a strong increase in CD8+ T cells post-nCRT (P < 0.001), while those that persisted F. nucleatum-positive after nCRT lacked CD8+ T cells induction in post-nCRT samples compared with baseline (P = 0.69). CONCLUSION: F. nucleatum persistence post-nCRT is associated with high relapse rates in LARC, potentially linked to suppression of immune cytotoxicity.

The IL-2RG R328X nonsense mutation allows partial STAT-5 phosphorylation and defines a critical region involved in the leaky-SCID phenotype.

In addition to their detection in typical X-linked severe combined immunodeficiency, hypomorphic mutations in the interleukin (IL)-2 receptor common gamma chain gene (IL2RG) have been described in patients with atypical clinical and immunological phenotypes. In this leaky clinical phenotype the diagnosis is often delayed, limiting prompt therapy in these patients. Here, we report the biochemical and functional characterization of a nonsense mutation in exon 8 (p.R328X) of IL2RG in two siblings: a 4-year-old boy with lethal Epstein-Barr virus-related lymphoma and his asymptomatic 8-month-old brother with a Tlow B+ natural killer (NK)+ immunophenotype, dysgammaglobulinemia, abnormal lymphocyte proliferation and reduced levels of T cell receptor excision circles. After confirming normal IL-2RG expression (CD132) on T lymphocytes, signal transducer and activator of transcription-1 (STAT-5) phosphorylation was examined to evaluate the functionality of the common gamma chain (γc ), which showed partially preserved function. Co-immunoprecipitation experiments were performed to assess the interaction capacity of the R328X mutant with Janus kinase (JAK)3, concluding that R328X impairs JAK3 binding to γc . Here, we describe how the R328X mutation in IL-2RG may allow partial phosphorylation of STAT-5 through a JAK3-independent pathway. We identified a region of three amino acids in the γc intracellular domain that may be critical for receptor stabilization and allow this alternative signaling. Identification of the functional consequences of pathogenic IL2RG variants at the cellular level is important to enable clearer understanding of partial defects leading to leaky phenotypes.

Geometrical and spectral study of ß-skeleton graphs.

We perform an extensive numerical analysis of ß-skeleton graphs, a particular type of proximity graphs. In a ß-skeleton graph (BSG) two vertices are connected if a proximity rule, that depends of the parameter ß∈(0,∞), is satisfied. Moreover, for ß>1 there exist two different proximity rules, leading to lune-based and circle-based BSGs. First, by computing the average degree of large ensembles of BSGs we detect differences, which increase with the increase of ß, between lune-based and circle-based BSGs. Then, within a random matrix theory (RMT) approach, we explore spectral and eigenvector properties of random BSGs by the use of the nearest-neighbor energy-level spacing distribution and the entropic eigenvector localization length, respectively. The RMT analysis allows us to conclude that a localization transition occurs at ß=1.

Analysis of the order-implantation relationship for musculoskeletal tissue transplantation. / Análisis de la relación solicitud-implante de injerto para trasplante osteomuscular.

OBJECTIVE: To analyze orders requested from a musculoskeletal tissue bank and to evaluate the percentage of tissue implantation. MATERIAL AND METHODS: Two hundred and sixty-five orders for musculoskeletal tissue were analyzed over the course of a year. EXCLUSIONS: 5 duplications and 5 orders for which there was no availability to cover the need. We analyzed the number of surgeries in which the graft was finally used. RESULTS: Of a total of 255 orders, the graft was used in 178 (70%), and the graft was not used in 77 (30%). Of the 178 used, there was a partial refund in 23 (10%). Of the 77 orders not used, surgery was performed in 32 (13%) without the use of bank tissue, while surgery was discontinued in the remaining 45 (17%). DISCUSSION: A non-utilization rate of 30% was identified, of which 17% was from surgery that was not performed and 13% from surgery that was performed, but the tissue was returned to the tissue bank, because it was not required. In a further 10% there was partial return of the tissue. Based on this analysis, we consider that it is important to have direct confirmation of the surgery to avoid sending tissue for discontinued surgeries, since in addition to the economic impact, the bank must ensure adequate temperature maintenance during transportation and storage in the transplantation centre, to avoid discarding said tissue if it is returned.

Identifying network structure similarity using spectral graph theory.

Most real networks are too large or they are not available for real time analysis. Therefore, in practice, decisions are made based on partial information about the ground truth network. It is of great interest to have metrics to determine if an inferred network (the partial information network) is similar to the ground truth. In this paper we develop a test for similarity between the inferred and the true network. Our research utilizes a network visualization tool, which systematically discovers a network, producing a sequence of snapshots of the network. We introduce and test our metric on the consecutive snapshots of a network, and against the ground truth. To test the scalability of our metric we use a random matrix theory approach while discovering Erdös-Rényi graphs. This scaling analysis allows us to make predictions about the performance of the discovery process.

Prenatal Therapy with Magnesium Sulfate and Its Correlation with Neonatal Serum Magnesium Concentration.

INTRODUCTION: Antenatal magnesium sulfate (MgSO4) administration has shown to be effective in minimizing cerebral palsy and severe motor dysfunction at the age of 2 years. The aim of this study is to determine the relationship between the magnesium dose delivered to the mother and the magnesium concentration in the neonates. MATERIALS AND METHODS: A prospective cohort study was conducted on neonates of less than 32 weeks' gestation admitted to the neonatal intensive care unit of University Hospital Complex of Vigo from December 2012 to July 2015. Comparative analysis of magnesium levels between the groups of neonates exposed to MgSO4 and the control group. RESULTS: A total of 118 neonates were included in the study. The mothers of 62 of them had received MgSO4 as a neuroprotective agent. There was a significant correlation between the full dose of MgSO4 received by the mother and the levels of magnesium in the neonate in the first 24 hours of life (r2 = 0.397; p < 0.001). CONCLUSION: The MgSO4 dose received by the mother has a linear relationship with the magnesium levels obtained in neonates.

Bioactive compounds and antioxidant activity in scalded Jalapeño pepper industrial byproduct (Capsicum annuum).

Bioactive compounds and antioxidant activity were evaluated from industrial Jalapeño pepper byproducts and simulated non processed byproducts from two Mexican states (Chihuahua and Sinaloa) to determine their value added potential as commercial food ingredients. Aqueous 80% ethanol produced about 13% of dry extract of polar compounds. Total phenolic content increased and capsaicin and dihydrocapsaicin decreased on scalding samples (80 °C, 2 min) without affecting ascorbic acid. The major phenolic compounds, rutin, epicatechin and catechin comprised 90% of the total compounds detected by HPLC of each Jalapeño pepper byproducts. ORAC analysis showed that the origin and scalding process affected the antioxidant activity which correlated strongly with capsaicin content. Although scalding decreased capsaicinoids (up to 42%), phenolic content by (up to 16%), and the antioxidant activity (variable). Jalapeño pepper byproduct is a good source of compounds with antioxidant activity, and still an attractive ingredient to develop useful innovative products with potential food/non-food applications simultaneously reducing food loss and waste.

Pembrolizumab for advanced melanoma: experience from the Spanish Expanded Access Program.

BACKGROUND: The programmed death (PD-1) inhibitor pembrolizumab has been recently approved for the treatment of advanced melanoma. We evaluated the clinical activity of pembrolizumab in melanoma patients treated under the Spanish Expanded Access Program. METHODS: Advanced melanoma patients who failed to previous treatment lines were treated with pembrolizumab 2 mg/kg every three weeks. Patients with brain metastases were not excluded if they were asymptomatic. Data were retrospectively collected from 21 centers in the Spanish Melanoma Group. RESULTS: Sixty-seven advanced melanoma patients were analyzed. Most patients were stage M1c (73.1%), had high LDH levels (55.2%) and had ECOG PS 1 or higher (59.7%). For cutaneous melanoma patients, median overall survival was 14.0 months; the 18-month overall survival rate was 47.1%. Overall response rate was 27%, including three patients with complete responses (6.5%). Median response duration was not reached, with 83.3% of responses ongoing (3.5 m+ to 20.4 m+). From ten patients included with brain metastases, four (40%) had an objective response, two (20%) of them achieved a complete response. Significant prognostic factors for overall survival were LDH level, ECOG PS and objective response. There were no serious adverse events. CONCLUSION: Although this was a heavily pretreated cohort, pembrolizumab activity at the approved dose and schedule was confirmed in the clinical setting with long-term responders, also including patients with brain metastases.

[Current aspects of prostate cancer screening]. / Aspectos actuales sobre el cribado en el cáncer de próstata.

Screening programs for prostate cancer based on the determination of serum prostate specific antigen has led to overdiagnosis, and consequently overtreatment. A percentage of men diagnosed with prostate cancer have a tumour that will not progress, or do so slowly (overdiagnosis or pseudo-disease). This overdiagnosis rate ranges from 17-50%. Mass screening is defined as the systematic examination of asymptomatic men. Early detection or opportunistic screening involves the pursuit of individual cases being initiated by the doctor or the patient. In the case of a patient who requests a prostate specific antigen from their general practitioner, a number of issues on overdiagnosis, over-treatment and possible damage from the biopsy, should be explained to him. With data from randomised studies on prostate specific antigen and prostate cancer screening, population screening is not recommended by any urological society.

Impact of perinatal exposure to high-fat diet and stress on responses to nutritional challenges, food-motivated behaviour and mesolimbic dopamine function.

BACKGROUND/OBJECTIVES: Energy-dense food exposure and stress during development have been suggested to contribute to obesity and metabolic disorders later in life. Although these factors are frequently associated, the effects of their combination have not yet been investigated. In this study, using an animal model, we examined the long-term impact of maternal high-fat diet (HFD) and early-life stress (ELS) on energy homoeostasis control and food motivation. METHODS: Body weight growth under HFD, adipose tissue, body weight control in response to fasting and refeeding, food-motivated behaviour and mesolimbic dopamine function were examined in adult male offspring exposed to maternal HFD (during gestation and lactation) and/or ELS (maternal separation 3 h per day from postnatal day 2 to 14). RESULTS: Maternal HFD or ELS alone had no significant effect on offspring body weight; however, the combination of these factors exacerbated body weight gain when animals were exposed to HFD after weaning. There are no other significant combinatory effects of these perinatal events. In contrast, independently of the maternal diet, ELS disrupted body weight control during a fasting-refeeding procedure, increased adipose tissue mass and altered lipid metabolism. Finally, maternal HFD and ELS both resulted in exacerbated food-motivated behaviour and blunted dopamine release in the nucleus accumbens during palatable food consumption. CONCLUSIONS: We report a synergistic effect of perinatal HFD exposure and stress on the susceptibility to gain weight under HFD. However, ELS has a stronger impact than maternal HFD exposure on energy homoeostasis and food motivation in adult offspring. Altogether, our results suggest a programming effect of stress and nutrition supporting the hypothesis of the developmental origin of health and disease.

On the origin of the highest ozone episodes in Spain.

The 2000-2015 occurrences of the highest ozone (O3) pollution episodes in Spain were evaluated to investigate their origin. To this end, data series available for urban and regional background (UB and RB), traffic (TR) and industrial (IN) sites were analysed separately and intercompared. Results evidenced that during these 16years mean O3 levels in the RB sites did not change significantly, and remained constantly high. However, there is a clear increase at the TR and UB sites. Although sensitivity analysis is needed to interpret the cause of this increasing trend, this might be caused probably by the lower O3 titration intensity due to the preferential abatement of NO vs NO2, as supported from the neutral trend of OX (NO2+O3) at these sites. We found that the exceedances of the hourly information threshold for O3 (>180µg/m3) are recorded mostly at UB and IN sites located in seven areas of Spain (specific hotspots or at the tail end of large urban plumes), and that these increased during summer heatwaves (i.e. 2003 and 2015). Although the external contribution of regional-to-subcontinental transported O3 might be relevant during the highest O3 episodes in the Western Mediterranean, our results evidenced that in the above specific areas, regional-local O3 production decisively contributes to the exceedances of the information threshold. Also that the human protection threshold and the AOT40 are more frequently exceeded in the Central, Southern and Mediterranean sides of the Iberian Peninsula. The design of effective episode abatement measures is quite complex in those conditions, due to both the nonlinearity of the chemical processes of O3 formation and destruction, and to the interplay with the complex meteorological setting, causing frequent recirculation and in situ aging of air masses. However, the combination of meteorological forecasting of the main recirculation processes and sensitivity analysis of NOX/VOC emission abatement measures might be powerful tools to evaluate the effectiveness of potential O3 mitigation strategies. Finally we would like to highlight that the current UB, RB, IN and TR classification (somewhat subjective) is not adequate to interpret the origin of O3 exceedances in complex areas of Southern Europe. Thus, a UB station recording exceedances, and located in a small city in the tail end of an urban plume of a large city, receives not only the contribution from its own UB, but mainly from the specific high O3 RB caused by the urban plume transport.

Safety of vemurafenib in patients with BRAF V600 mutated metastatic melanoma: the Spanish experience.

OBJECTIVES: Vemurafenib tolerability was assessed in a large, open-label, multicentre study in patients with BRAF V600 mutated advanced melanoma. We investigated safety, tolerability and efficacy of vemurafenib in Spanish patients participating in that study. METHODS: Patients with previously treated or treatment-naive, unresectable stage IIIC or stage IV, BRAF V600 mutation-positive melanoma received vemurafenib 960 mg twice daily until disease progression, unacceptable toxicity, withdrawal of consent or death. The primary endpoint was safety; secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: 301 Spanish patients were included, 70 % with M1c disease, 22 % with brain metastases and 51 % with prior systemic therapy for metastatic disease. Most frequent adverse events included fatigue (48 %), arthralgia (45 %), rash (41 %), photosensitivity (34 %) and skin neoplasms (21 %). Grade 3/4 adverse events occurred in 156 patients (52 %), including cutaneous squamous cell carcinoma (including keratoacanthoma; 16 %), fatigue (6 %) and arthralgia (5 %). The ORR was 28 % (95 % CI 23-34 %). Responses occurred in patients with brain metastases (18 %), elevated baseline lactate dehydrogenase (19 %) and poor performance status (15 %), and elderly patients (22 %). Median PFS was 5.8 (95 % CI 5.0-6.4) months; median OS was 10.5 (95 % CI 9.5-13.5) months. CONCLUSION: Our results for Spanish patients in the vemurafenib safety study indicate similar efficacy and a comparable safety profile in Spanish patients with no new safety signals compared with the overall population. Clinical benefit was demonstrated in poor-prognosis patients and in those with favourable baseline characteristics, suggesting that poor-prognosis patients may also benefit from vemurafenib treatment.