Search

Water distribution systems (WDSs) are designed to convey water from sources to consumers. Their operation is a main concern for engineers, researchers, and practitioners and is subject to demand, pressure, and quality constraints. Pumping stations require power to pump water and keep system pressure at a desired level. On the other hand, power is generally supplied through power grids (PGs), which require optimal operation while satisfying operational constraints, such as generation limits, power consumption, and voltage constraints. Since the two infrastructure systems are interconnected, decision-makers could benefit from a holistic approach that would allow solving the two operational optimization problems together as one conjunctive problem. This paper presents the full mathematical formulation of the conjunctive optimization problem, including a novel modelling approach for the operation of a variable speed pump, which does not include integer variables for pump status, thus allowing to solve the model as a non-linear programming (NLP) problem. The formulation is applied to two illustrative case studies, and the results are compared to the optimal operation of the independent WDS. The inclusion of the PG in the optimization problem is observed clearly in the results and influences them quite significantly. WDS operation is shown adjust to the PG constraints, and the application of the conjunctive model results in a cost reduction rate of more than 10 % for both case studies.

Introduction: Responses to first-line programmed cell death protein 1 inhibition vary among patients with metastatic NSCLC and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) greater than or equal to 50%. We previously reported improved clinical outcomes to first-line programmed cell death protein 1 inhibition in patients with metastatic NSCLC with a PD-L1 TPS of greater than or equal to 90% versus 50% to 89% in a pilot study. Here, we report the three-year survival with first-line pembrolizumab and cemiplimab in two large independent cohorts of patients with PD-L1 TPS greater than or equal to 90% versus 50% to 89% and characterize genomic and immunophenotypic differences between these PD-L1 expression groups, which were largely unknown. Methods: We analyzed three-year outcomes of the following two independent cohorts: (1) a multicenter cohort of patients from four academic centers in the United States treated with pembrolizumab and (2) EMPOWER-Lung 1, randomized, phase III trial comparing first-line cemiplimab with chemotherapy. Tumor genomic profiling and multiplexed immunofluorescence were performed to evaluate genomic and immunophenotypic correlates of very high PD-L1 expression. Results: At three years of follow-up, progression-free survival (hazard ratio [HR], 0.69; p < 0.001) and overall survival (HR, 0.70; p < 0.01) to first-line commercial pembrolizumab were significantly improved in patients with a PD-L1 TPS greater than or equal to 90% versus 50% to 89%. In the EMPOWER-Lung 1, patients assigned to the cemiplimab arm with a PD-L1 TPS greater than or equal to 90% also had significant improvements in progression-free survival (HR, 0.53; p < 0.0001) and overall survival (HR, 0.63; p = 0.007) compared with those with a PD-L1 of 50% to 89%. Tumor genomic profiling of 553 NSCLC samples revealed that mutations in STK11 and SMARCA4 were significantly more frequent in tumors with a PD-L1 TPS of 50% to 89% compared with those with a PD-L1 TPS greater than or equal to 90% (Q < 0.15), whereas BRCA2 was enriched in NSCLC samples with a PD-L1 TPS greater than or equal to 90% (Q < 0.15). Multiplexed immunofluorescence on 93 NSCLC samples identified higher intratumoral CD8+PD1+ T cells (p = 0.02) in tumors with PD-L1 TPS greater than or equal to 90% versus 50% to 89%. Conclusion: Pembrolizumab and cemiplimab were found to have long-term survival benefit and favorable genomic and immunophenotypic profile in patients with advanced NSCLC with PD-L1 TPS greater than or equal to 90% compared with TPS 50% to 89%.

Abstract Biofuels are essential to ensure the energy transition and mitigating of climate change. However, understanding the impact of land use change (LUC) and management practices on soil organic carbon (SOC) stocks is fundamental to ensuring well‐founded policymaking and assessing the sector's carbon footprint. Here, we conducted a meta‐analysis (511 pairwise observations) to obtain Brazil's SOC stock change factors (SOCscf) for LUC and management practices in sugarcane fields. Our results showed that converting native vegetation to sugarcane reduced the SOC stock in all assessed periods. The conversion from annual crops to sugarcane showed a reduction in SOC stock in the first 10 years but with a recovery over time. The conversion of pasture to sugarcane reduced the SOC stock only in the 10–20‐year period and had a neutral effect in other periods evaluated. However, our dataset showed high variability in SOCscf, with many observations indicating an increase in SOC stock, which is related to degraded pastures. We observed that the SOC accumulation rate for each ton of sugarcane straw was affected by the interaction between soil texture and precipitation. Regarding straw management, a low removal rate ( 66%) removal resulted in losses of 5.0% (SOCscf 0.950) and 9.9% (SOCscf 0.901), respectively. Our results also showed that reduced tillage and vinasse application increased SOC stocks by 24.0% (SOCscf 1.24) and 10.0% (SOCscf 1.10) respectively, proving to be good strategies to support C sequestration in sugarcane fields. Finally, we highlight that our results can contribute to the improvement of public policies and also be used in future life cycle assessment (LCA) and modeling studies, as they provide robust data to establishing regional SOCscf induced by LUC and management practices, enhancing the reliability of the C footprint assessment of biofuel production.

Objective: Cochlear receptors are sensitive to vibratory stimuli. Based on this sensibility, bone-anchored hearing aids have been introduced to correct unilateral or bilateral conductive or mixed hearing loss and unilateral deafness. The vestibular system is also sensitive to the vibratory stimulus and this type of response is used in clinics to test its functionality. Being aware of this double separated sensibility, we wondered whether bone vibration, which activates the acoustic receptors of patients with bone conduction aids, can also influence the functionality of the vestibular system. Methods: To this end, we recruited 12 patients with a bone-anchored hearing aid and evaluated their vestibular function with and without an activated vibratory acoustic device. Results: Our results show that the vibratory stimulus delivered by the bone conduction aid also reaches and stimulates the vestibular receptors; this stimulation is evidenced by the appearance or modification of some nystagmus findings during bedside vestibular testing. Despite this, none of these patients complained of dizziness or vertigo during prosthesis use. Nystagmus that appeared or changed during acoustic vibratory stimulation through the prosthesis was almost all predominantly horizontal, unidirectional with respect to gaze or body position, inhibited by fixation, and most often consistent with vestibular function tests indicating peripheral vestibular damage. Conclusions: The findings of sound-evoked nystagmus seem to indicate peripheral rather than central vestibular activation. The occurrence of some predominantly horizontal and high-frequency induced nystagmus seems to attribute the response mainly to the utricle and lateral semicircular canal.

ABSTRACTInstantaneous determinations of photosynthetically active radiation (PAR) over the sea from the Ocean and Land Color Instrument (OLCI) on Sentinel-3 are compared with in-situ measurements at the island of Lampedusa in the central Mediterranean Sea. Radiative transfer calculations show that the PAR measured at the island site is representative for open ocean conditions. Satellite data show a good agreement (5.2% positive bias, R2 = 0.97) with in-situ data, in line with similar analyses for other satellite sensors. Larger satellite-in situ differences are found during summer, and the possible role of aerosols in degrading PAR estimate has been investigated by comparing AOD values measured at Lampedusa and derived by OLCI. The relative difference between OLCI and in-situ PAR appears to be negatively correlated with the relative differences between OLCI and in-situ AOD, suggesting that a more accurate determination of AOD, in particular, for cases with AOD > 0.2, mostly related to Saharan dust, may lead to improved satellite PAR estimates.

Summary: The KRAS mutation is the most common oncogenic driver in patients with non-small cell lung cancer (NSCLC). However, a detailed understanding of how self-reported race and/or ethnicity (SIRE), genetically inferred ancestry (GIA), and their interaction affect KRAS mutation is largely unknown. Here, we investigated the associations between SIRE, quantitative GIA, and KRAS mutation and its allele-specific subtypes in a multi-ethnic cohort of 3,918 patients from the Boston Lung Cancer Survival cohort and the Chinese OrigiMed cohort with an independent validation cohort of 1,450 patients with NSCLC. This comprehensive analysis included detailed covariates such as age at diagnosis, sex, clinical stage, cancer histology, and smoking status. We report that SIRE is significantly associated with KRAS mutations, modified by sex, with SIRE-Asian patients showing lower rates of KRAS mutation, transversion substitution, and the allele-specific subtype KRASG12C compared to SIRE-White patients after adjusting for potential confounders. Moreover, GIA was found to correlate with KRAS mutations, where patients with a higher proportion of European ancestry had an increased risk of KRAS mutations, especially more transition substitutions and KRASG12D. Notably, among SIRE-White patients, an increase in European ancestry was linked to a higher likelihood of KRAS mutations, whereas an increase in admixed American ancestry was associated with a reduced likelihood, suggesting that quantitative GIA offers additional information beyond SIRE. The association of SIRE, GIA, and their interplay with KRAS driver mutations in NSCLC highlights the importance of incorporating both into population-based cancer research, aiming to refine clinical decision-making processes and mitigate health disparities.

This study aimed to analyze the acute impact of exercise on serum irisin levels in 22 young (YA, 24.6 ± 3.5 yrs) and in 12 middle-aged male adults (MA, 54.6 ± 5.7 yrs) 15 min and 24 h after an incremental cycling exercise test to exhaustion. ELISA assay was used for serum irisin detection. Circulating irisin increased significantly from baseline (9.0 ± 2.0 ng/ml) to 15 min post-exercise (10.2 ± 2.0 ng/ml, P < 0.001), but the greatest increment was detected after 24 h (13.5 ± 2.5 ng/ml, P < 0.001) reaching more than 50% of the basal release. Levels were significantly higher in YA (9.7 ± 1.7 to 11.1 ± 1.8 to 14.5 ± 2.2 ng/ml) than MA (7.6 ± 1.6 to 8.7 ± 1.5 to 11.8± 2.2 ng/ml) for all measured time-points (P < 0.05). Nevertheless, MA showed a comparable increase in serum irisin levels when compared to YA. These findings highlight the importance of acute physical exercise as a countermeasure against age-related deterioration of skeletal muscle mass and function in both YA and MA.

Maize (Zea mays L.) is one of the most widely planted crops globally with Argentina leading world production and exportation. Santiago del Estero province, east of Tucumán and north of Córdoba encompasses eight agro-climatic zones in the Chaco Semi-arid region, agro-ecologically characterized by a wide temperature range and frequent drought periods that expose the crop to pathogens, particularly Aspergillus flavus. This pathogen is responsible for ear rot and grain contamination with mycotoxins such as aflatoxin B1 and cyclopiazonic acid. This study obtained fungal isolates from ears of maize and characterized them according to toxigenic capability and morphotype of sclerotia (S < 400 μm, associated with high levels of aflatoxins and L > 400 μm, related to variable levels of aflatoxins). In addition, those not producing aflatoxins were studied to determine phylogenetic relationships based on sequences of a segment of the CaM gene. Fifty-eight isolates were obtained in eight localities representing each agro-climatic zone, 30 of which were non-aflatoxigenic, 28 aflatoxigenic, and all producers of ciclopiazonic acid. Six isolates did not produce sclerotia, 51 were L and only one was S, the latter being a non-producer of aflatoxins. The number of sclerotia was positively correlated with the production of aflatoxin B1, while size was negatively correlated. The CaM gene sequences corroborated that the isolates belonged to the A. flavus clade and the high nucleotide similarity among them (99.4% to 100%) revealed almost zero genetic diversity in this geographic region. No significant differences were observed in the proportion of isolates between growing seasons or among agroclimatic districts. This research revealed characteristics of fungus populations in this agricultural region of north Argentina. Highlights: • Aspergillus flavus isolates from ears of maize were characterized according to toxigenic capability, morphotype of sclerotia and phylogenetic relationships. • Fifty-eight isolates were obtained, 30 non-aflatoxigenic, 28 aflatoxigenic, and all producers of ciclopiazonic acid. • Six isolates did not produce sclerotia, 51 were L and only one was S, the latter being a non-producer of aflatoxins. • All isolates belonged to the flavus clade. High nucleotide similarity among the isolates (99.4% to 100%) revealed almost zero genetic diversity in the region.

Abstract Winter cover crop performance metrics (i.e., vegetative biomass quantity and quality) affect ecosystem services provisions, but they vary widely due to differences in agronomic practices, soil properties, and climate. Cereal rye (Secale cereale) is the most common winter cover crop in the United States due to its winter hardiness, low seed cost, and high biomass production. We compiled data on cereal rye winter cover crop performance metrics, agronomic practices, and soil properties across the eastern half of the United States. The dataset includes a total of 5,695 cereal rye biomass observations across 208 site-years between 2001–2022 and encompasses a wide range of agronomic, soils, and climate conditions. Cereal rye biomass values had a mean of 3,428 kg ha−1, a median of 2,458 kg ha−1, and a standard deviation of 3,163 kg ha−1. The data can be used for empirical analyses, to calibrate, validate, and evaluate process-based models, and to develop decision support tools for management and policy decisions.

Abstract Background About 30% of Prostate cancer (PCa) patients progress to metastatic PCa that remains largely incurable. This evidence underlines the need for the development of innovative therapies. In this direction, the potential research focus might be on long non-coding RNAs (lncRNAs) like H19, which serve critical biological functions and show significant dysregulation in cancer. Previously, we showed a transcriptional down-regulation of H19 under combined pro-tumoral estrogen and hypoxia treatment in PCa cells that, in turn, induced both E-cadherin and β4 integrin expression. H19, indeed, acts as transcriptional repressor of cell adhesion molecules affecting the PCa metastatic properties. Here, we investigated the role of H19/cell adhesion molecules circuitry on in vivo PCa experimental tumor growth and metastatic dissemination models. Methods H19 was silenced in luciferase-positive PC-3 and 22Rv1 cells and in vitro effect was evaluated by gene expression, proliferation and invasion assays before and after treatment with the histone lysine demethylase inhibitor, GSK-J4. In vivo tumor growth and metastasis dissemination, in the presence or absence of GSK-J4, were analyzed in two models of human tumor in immunodeficient mice by in vivo bioluminescent imaging and immunohistochemistry (IHC) on explanted tissues. Organotypic Slice Cultures (OSCs) from fresh PCa-explant were used as ex vivo model to test GSK-J4 effects. Results H19 silencing in both PC-3 and 22Rv1 cells increased: i) E-cadherin and β4 integrin expression as well as proliferation and invasion, ii) in vivo tumor growth, and iii) metastasis formation at bone, lung, and liver. Of note, treatment with GSK-J4 reduced lesions. In parallel, GSK-J4 efficiently induced cell death in PCa-derived OSCs. Conclusions Our findings underscore the potential of the H19/cell adhesion molecules circuitry as a targeted approach in PCa treatment. Modulating this interaction has proven effective in inhibiting tumor growth and metastasis, presenting a logical foundation for targeted therapy.

Introduction: Metastatic prostate cancer (PCa) presents a significant challenge in oncology due to its high mortality rate and the absence of effective biomarkers for predicting patient outcomes. Building on previous research that highlighted the critical role of the long noncoding RNA (lncRNA) H19 and cell adhesion molecules in promoting tumor progression under hypoxia and estrogen stimulation, this study aimed to assess the potential of these components as prognostic biomarkers for PCa at the biopsy stage. Methods: This research utilized immunohistochemistry and droplet digital PCR to analyze formalin-fixed paraffin-embedded (FFPE) biopsies, focusing on specific markers within the H19/cell adhesion molecules pathway. Results: A novel multivariate analysis led to a “BioScore”, a composite biomarker score to predict disease progression. This score is based on evaluating five key markers: the expression levels of Hypoxia-Inducible Factor 2 Alpha (HIF-2α), endothelial Nitric Oxide Synthase (eNOS), β4 integrin, E-cadherin transcript (CDH1), and lncRNA H19. The criteria for the “BioScore” involve identifying three out of these five markers, combining elevated levels of HIF-2α, eNOS, β4 integrin, and CDH1 with reduced H19 expression. Conclusions: This finding suggests the possibility of identifying, at the time of biopsy, PCa patients at higher risk of metastasis based on dysregulation in the H19/cell adhesion molecules circuitry. This study provides a valuable opportunity for early intervention in managing PCa, potentially contributing to personalized treatment strategies.

En este artículo se aborda la cuestión de la producción, comercialización y consumo de vino en el Noroeste peninsular, en particular en la región portuguesa de Trás-os-Montes, inscrita en el sur del conventus Asturum (antigua provincia de la Gallaecia). A pesar de la total ausencia de ánforas en el yacimiento romano de Castro de Avelãs (Bragança) y en su entorno inmediato, es posible que este producto, tan importante en época romana, se haya consumido y quizás hasta producido y distribuido en la zona usando contenedores diferentes. En par ticular se propone que un tipo de tinajas se hayan usado para el almacenamiento, transpor te y quizás hasta para la producción de vino. Esta hipótesis se refuerza con los análisis realizados mediante cromatografia de gases/espectometría de masas sobre tres de estos recipientes cerámicos recuperados en el yacimiento, registrando marcadores compatibles con el vino. Ante estos datos, se ha abierto la discusión sobre el consumo y la producción de vino (y de otros productos) en este territorio del sureste de la Gallaecia.

Abstract Hematopoietic stem and progenitor cells (HSPCs) continuously generate platelets throughout one's life. Inherited Platelet Disorders affect ≈ 3 million individuals worldwide and are characterized by defects in platelet formation or function. A critical challenge in the identification of these diseases lies in the absence of models that facilitate the study of hematopoiesis ex vivo. Here, a silk fibroin‐based bioink is developed and designed for 3D bioprinting. This bioink replicates a soft and biomimetic environment, enabling the controlled differentiation of HSPCs into platelets. The formulation consisting of silk fibroin, gelatin, and alginate is fine‐tuned to obtain a viscoelastic, shear‐thinning, thixotropic bioink with the remarkable ability to rapidly recover after bioprinting and provide structural integrity and mechanical stability over long‐term culture. Optical transparency allowed for high‐resolution imaging of platelet generation, while the incorporation of enzymatic sensors allowed quantitative analysis of glycolytic metabolism during differentiation that is represented through measurable color changes. Bioprinting patient samples revealed a decrease in metabolic activity and platelet production in Inherited Platelet Disorders. These discoveries are instrumental in establishing reference ranges for classification and automating the assessment of treatment responses. This model has far‐reaching implications for application in the research of blood‐related diseases, prioritizing drug development strategies, and tailoring personalized therapies.

BackgroundMonitoring external load demands in soccer is crucial for optimizing performance and reducing injury risk. However, events like the FIFA World Cup Qatar 2022 and unexpected interruptions can disrupt load management strategies. Understanding the impact of such events on player performance is essential for effective training and recovery strategies.ObjectiveThis study retrospectively assessed the impact of the FIFA World Cup Qatar 2022 on the physical performance of LaLiga elite soccer players who were not part of the tournament. The aim was to analyze various external load parameters and determine the direction of their changes post-tournament.MethodsData from 239 LaLiga players who were not selected for the World Cup were analyzed. External load parameters from 8 matches before and after the tournament were compared. Statistical analyses, including repeated measures ANOVA, were conducted to evaluate changes in performance metrics.ResultsMinutes played and total distance covered showed no significant changes post-tournament. However, maximal speed decreased significantly (p 85% Vel Max. Acceleration metrics showed significant improvements in Accel_HighIntensityAccAbsCount (p = 0.024; η2p = 0.021), while Accel_Accelerations showed no significant changes. Deceleration metrics remained unchanged, but Accel_HighIntensityDecAbsCount and Accel_HighIntensityDecAbsDistance increased significantly post-tournament (p = 0.002; η2p = 0.040, p = 0.001; η2p = 0.044, respectively).ConclusionNon-participant LaLiga players demonstrated enhanced performance in most external load metrics after the FIFA World Cup Qatar 2022. These findings highlight the importance of effective load management during periods of competition interruption and suggest strategies to optimize performance and reduce injury risk. Further research should consider holistic performance metrics and internal load parameters to provide comprehensive insights into player response to mid-season tournaments.