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KEYWORDS: Ocean; Arctic; Sea ice; Ocean dynamics; Small scale processes; Atmosphere-ocean interaction Inaugural Workshop and Early Career School of the Consortium for the Advancement of Marine Arctic Science (CAMAS) What: [...]

The tumor microenvironment (TME) encompasses the complex and diverse surroundings in which tumors arise. Emerging insights highlight the TME's critical role in tumor development, progression, metastasis, and treatment response. Consequently, the TME has attracted significant research and clinical interest, leading to the identification of numerous novel therapeutic targets. Advances in molecular technologies now enable detailed genomic and transcriptional analysis of cancer cells and the TME and the integration of microenvironmental data to the tumor genomic landscape. This comprehensive review discusses current progress in targeting the TME for drug development, addressing associated challenges, strategies for modulating the pro-tumor microenvironment, and the discovery of new targets.

The second pillar of the European Union’s (EU) Common Agricultural Policy (CAP) aims at supporting rural areas by meeting the economic, environmental and social challenges. To deal with these challenges, countries are faced with the question of selecting the best tools among a large set of policy instruments. The problem of choosing the best policy instruments is aggravated by the very heterogeneous character of the societal demands that differ among member countries with very different economic and institutional structures. This study aims to introduce the agent-based modelling platforms that have been widely used in the impact analysis of recent rural development policies in the EU in a comparative manner. It also aims to explain how the above-mentioned sources of heterogeneity are handled in these models. To achieve the stated objectives, the study first examines the historical development of rural development policies within the EU. Subsequently, it proceeds to analyse several agent-based platforms that have been employed for the purpose of assessing the impact of agricultural policies with respect to certain features such as integration of land market, modelling unit, decision rule, rules of exit, labour market and price formation. To conclude, it is observed that as the rural development policies are formulated on farm-basis and as farms have a heterogeneous structure within themselves, in addition, the expansion of databases and the development of empirical analysis tools and technologies have led to a shift in empirical analyses towards agent-based models. However, these modelling platforms still embody various problems, especially in terms of database adjustments and parameterization and calibration of the model.

ObjectivesTo present an innovative integrated manualized psychotherapeutic intervention for fibromyalgia (FM) based on cognitive and behavioral therapy, acceptance and commitment therapy, and somatic experiential techniques (namely the INTEGRated Psychotherapeutic InterventiOn, INTEGRO) and illustrate its application on two case studies.MethodsINTEGRO is composed of 12 individual sessions. The main objectives of the intervention were psychoeducation of chronic pain mechanisms, understanding the role of cognitive and emotional variables in one’s pain perception, teaching patient-tailored skills to increase pain awareness and its management, and learning how to live with pain experience. A 57-year-old woman (patient A) and a 26-year-old woman (patient B) with FM have been selected to describe their care pathways connected to the INTEGRO protocol. Data related to assessment variables and clinical processes have been reported, focusing on the mechanisms that contribute to the maintenance (i.e., avoidance or overcompensation) of chronic pain in FM, on the role of patients’ naïf theories, and on the implications that all these aspects may have on the burden related to pain management.ResultsBoth patients showed a reduction in FM burden and an increase in self-efficacy in pain management: patient A reported an improvement in emotional regulation ability; patient B showed a decrease in pain interference in work activities and on emotional dimension.ConclusionExamining each phase of the clinical protocol through the lens of its clinical application, the paper provides insights into the relationship among crucial psychosocial mechanisms, pain perception, management in FM treatment, and how all these aspects have been dealt with during psychotherapeutic treatment.

ABSTRACT Purpose: Medical expulsive therapy (MET) is recommended for distal ureteral stones from 5 to 10 mm. The best drug for MET is still uncertain. In this review, we aim to compare the effectiveness of tadalafil and tamsulosin for distal ureteral stones from 5 to 10 mm in terms of stone expulsion rate (SER), stone expulsion time (SET) and the side effect profile. Materials and methods: A comprehensive literature search was conducted on MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Scopus and Web of Science, from inception until April 2023. Only randomized controlled trials were included in the analysis. Results: Eleven publications with 1,330 patients were included. We observed that tadalafil has a higher SER (OR 0.55, CI 95% 0.38;0.80, p=0.02, I2=52%) and the same efficacy in SET (MD 1.07, CI 95% -0.25; 2.39, p=0.11, I2=84%). No differences were found when comparing side effects as headache, backache, dizziness, and orthostatic hypotension. Conclusion: Tadalafil has a higher stone expulsion rate than tamsulosin as a medical expulsive therapy for patients with distal stones from 5 to 10 mm without differences in side effects.

This work documents version two of the Department of Energy's Energy Exascale Earth System Model (E3SM). E3SMv2 is a significant evolution from its predecessor E3SMv1, resulting in a model that is nearly twice as fast and with a simulated climate that is improved in many metrics. We describe the physical climate model in its lower horizontal resolution configuration consisting of 110 km atmosphere, 165 km land, 0.5° river routing model, and an ocean and sea ice with mesh spacing varying between 60 km in the mid-latitudes and 30 km at the equator and poles. The model performance is evaluated with Coupled Model Intercomparison Project Phase 6 Diagnosis, Evaluation, and Characterization of Klima simulations augmented with historical simulations as well as simulations to evaluate impacts of different forcing agents. The simulated climate has many realistic features of the climate system, with notable improvements in clouds and precipitation compared to E3SMv1. E3SMv1 suffered from an excessively high equilibrium climate sensitivity (ECS) of 5.3 K. In E3SMv2, ECS is reduced to 4.0 K which is now within the plausible range based on a recent World Climate Research Program assessment. However, a number of important biases remain including a weak Atlantic Meridional Overturning Circulation, deficiencies in the characteristics and spectral distribution of tropical atmospheric variability, and a significant underestimation of the observed warming in the second half of the historical period. An analysis of single-forcing simulations indicates that correcting the historical temperature bias would require a substantial reduction in the magnitude of the aerosol-related forcing.

Ocean stratification on Arctic shelves critically influences nutrient availability, essential for primary production. However, discerning the changes in stratification and their drivers is challenging. Through the use of a high-resolution ocean–sea-ice model, this study investigates the variability in stratification within the northeastern Chukchi Sea over the period from 1987 to 2016. Our analysis, validated against available observations, reveals that summers with weak stratification are marked by a warmer water column that features a saltier upper layer and a fresher lower layer, thereby diminishing the vertical density gradient. In contrast, summers with strong stratification are characterized by a cooler column with a fresher upper layer and a saltier lower layer, resulting in an increased density gradient. This variability is primarily driven by the timing of sea-ice retreat and the consequent variations in meltwater flux, with early retreat leading to less meltwater and saltier surface conditions. This factor significantly outweighs the influence of changes in circulation and associated lateral freshwater transport driven by the Bering Strait inflow. We also find that the synchronization of sea-ice retreat and Bering Strait inflow intensity is linked to the timing and strength of the Aleutian Low’s westward shift from the Gulf of Alaska to the Aleutian Basin in the early winter. These insights are crucial for understanding nutrient dynamics and primary production in the region. Furthermore, monitoring sea-ice retreat timing could serve as a useful proxy for predicting subsequent summer stratification changes.

Abstract We investigate the role of ocean heat transport (OHT) in driving the decadal variability of the Arctic climate by analyzing the pre‐industrial control simulation of a high‐resolution climate model. While the OHT variability at 65°N is greater in the Atlantic, we find that the decadal variability of Arctic‐wide surface temperature and sea ice area is much better correlated with Bering Strait OHT than Atlantic OHT. In particular, decadal Bering Strait OHT variability causes significant changes in local sea ice cover and air‐sea heat fluxes, which are amplified by shortwave feedbacks. These heat flux anomalies are regionally balanced by longwave radiation at the top of the atmosphere, without compensation by atmospheric heat transport (Bjerknes compensation). The sensitivity of the Arctic to changes in OHT may thus rely on an accurate representation of the heat transport through the Bering Strait, which is difficult to resolve in coarse‐resolution ocean models.

The productivity of virgin olive oil depends not only on agronomic factors but also on the technological factors of the extraction process. The ‘Arbequina’ variety has extractability problems, which is a challenge for master millers anywhere. This work aims to evaluate the behavior of different decanters and seeks to modulate the effect of some processing parameters and their interactions with oil extraction efficiency in the case of ‘Arbequina.’ Fruit characteristics, processing parameters, and extractability were collected over 10 years from 38 decanters that belong to five different brands. The results have shown that fruit moisture is the most relevant factor for oil extractability, especially over 52%. Furthermore, extractability is positively correlated with malaxing temperature, addition of water, and total fat content in the fruit. However, the results show that before applying a regulation, the type of decanter must be considered. The model used in this study has allowed us to optimize the regulations for each type of decanter to reduce oil losses within the pomace, achieving an extraction efficiency within the range of 78%–91.5%. In fact, the best extraction efficiency results (91.5%) were obtained by processing at temperatures >26°C and water injection of 5%.

Adverse early interactions with parents deeply affect the socio-emotional development of an individual, leading to feelings of inferiority and negatively influencing the development of self-conscious emotions, such as shame. Moreover, dysfunctional parenting was found in the histories of people suffering from substance and behavioral addictions. In this context, there is currently no agreement in the literature regarding the role of shame proneness on the severity of the addiction. The present study aimed to evaluate the mediating (risk or protective) role of the two shame dimensions (withdrawal action tendencies and negative self-evaluation) in the association between dysfunctional parenting and the severity of addiction, testing two structural equation models (SEMs; for substance and behavioral addiction respectively). An online survey recruiting 710 Italian young adults was administered using the Measure of Parental Styles, the Guilt and Shame Proneness Scale, and the brief Screener for Substance and Behavioral Addiction. The SEMs confirmed the predictive role of dysfunctional parenting on the severity of the addiction. Moreover, two dimensions of shame mediated the association in opposite ways. The withdrawal action tendencies positively mediated the association between dysfunctional parenting and the severity of substance and behavioral addiction, potentially acting as a risk factor. Negative self-evaluation negatively mediated the association between dysfunctional parenting and the severity of substance addiction, playing a potential protective role. In a therapeutic context, the findings emphasized the importance of evaluating the different dimensions of shame experiences among addicted individuals and assessing the strategies used to withdraw from these experiences., Author(s): Giorgio Veneziani [sup.1] , Chiara Ciacchella [sup.1] , Virginia Campedelli [sup.1] , Carlo Lai [sup.1] Author Affiliations: (1) https://ror.org/02be6w209, grid.7841.a, Department of Dynamic and Clinical Psychology, and Health Studies, [...]

Background/Objectives: Brazilian red propolis has attracted attention for its pharmacological properties. However, signs of toxicity were recently observed in long-term studies using the hydroalcoholic extract of red propolis (RPHE), likely due to polyprenylated benzophenones. This study aimed to develop a benzophenone-free red propolis extract (BFRP) and validate an HPLC-PDA method to quantify its main constituents: isoliquiritigenin, vestitol, neovestitol, medicarpine, and 7-O-methylvestitol. Methods: BFRP’s toxicity was assessed in zebrafish larvae through a vibrational startle response assay (VSRA) and morphological analysis. Genotoxicity was evaluated using the micronucleus test in rodents, and the extract’s effects on chemically induced preneoplastic lesions in rat colon were studied. An HPLC-PDA method was used to quantify BFRP’s main compounds. Results: BFRP primarily contained vestitol (128.24 ± 1.01 μg/mL) along with isoliquiritigenin, medicarpin, neovestitol, and 7-O-methylvestitol. Zebrafish larvae exposed to 40 µg/mL of BFRP exhibited toxicity, higher than the 10 µg/mL for RPHE, though no morphological differences were found. Fluorescent staining in the notochord, branchial arches, and mouth was observed in larvae treated with both BFRP and RPHE. No genotoxic or cytotoxic effects were observed up to 2000 mg/kg in rodents, with no impact on hepatotoxicity or nephrotoxicity markers. Chemoprevention studies showed a 41.6% reduction in preneoplastic lesions in rats treated with 6 mg/kg of BFRP. Conclusions: These findings indicate that BFRP is a safe, effective propolis-based extract with potential applications for human health, demonstrating reduced toxicity and chemopreventive properties.

The improvement of the extra virgin olive oil (EVOO) extraction process involves the proper management of endogenous enzymes of the olive fruit and all the technological conditions that can affect their activities. Coratina and Peranzana cultivars were processed to assess the influence of different technologies for fruit breaking (crushing and stoning) with and without controlled oxygen addition during this critical phase. The study of volatile compounds revealed that the enzymes that are responsible for their genesis during the technological process were significantly affected by oxygen addition in both the systems of fruit crushing. The results from the stoning technology proved that the quality improvement was a consequence of the prevention of the seed breaking and the oxidation catalyzed by the olive stone enzymes. In Peranzana EVOOs, it was possible to increase the aldehyde concentration up to 97% using stoning technology with a 0.2 L/min oxygen addition compared with traditional crushing. At the same time, non-significant reductions in phenolic compounds were detected when comparing crushing and stoning with and without the addition of oxygen, and similar trends were observed for the two studied cultivars. The sensory analyses confirmed the differences in phenolic and volatile composition detected in the EVOO samples.

Background/Objectives: Leishmaniasis, a neglected disease caused by Leishmania spp. including L. amazonensis, urgently requires new treatments. Polyalthic acid (PA), a natural diterpene from Copaifera spp., has previously demonstrated significant antiparasitic potential. This study evaluated the leishmanicidal effects of polyalthic acid (PA), alone and with amphotericin B (AmpB), on L. amazonensis promastigote and amastigote forms. Results: PA showed significant activity against promastigotes, with 50% effective concentration (EC50) values of 2.01 μM at 24 h and an EC50 of 3.22 μM against amastigotes after 48 h. The PA and AmpB combination exhibited a synergistic effect on both forms without inducing cytotoxicity or hemolysis. Morphological changes in promastigotes, including vacuole formation and cell rounding, were more pronounced with the combination. Conclusions: These findings suggest that PA and AmpB together could form a promising new treatment strategy against Leishmania infections, offering enhanced efficacy without added toxicity.

Solo sermone: Uberlieferung und Deutung politischer Ansprachen der Papste im Mittelalter. By Georg Strack (Wiesbaden: Harrassowitz Verlag, 2022. Pp. 328. $75.28. ISBN: 978-3-447-11388-5.) Georg Strack's Solo sermone is the latest [...]

BackgroundIn early infected or severe coronavirus disease 2019 (COVID-19) patients, circulating NK cells are consistently reduced, despite being highly activated or exhausted. The aim of this paper was to establish whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (SP) may directly trigger NK cells and through which receptor(s).MethodsSP-stimulated human NK cells have been evaluated for the expression of activation markers, cytokine release, and cytotoxic activity, as well as for gene expression profiles and NF-kB phosphorylation, and they have been silenced with specific small interfering RNAs.ResultsSPs from the Wuhan strain and other variants of concern (VOCs) directly bind and stimulate purified NK cells by increasing activation marker expression, cytokine release, and cytolytic activity, prevalently in the CD56brightNK cell subset. VOC-SPs differ in their ability to activate NK cells, G614, and Delta-Plus strains providing the strongest activity in the majority of donors. While VOC-SPs do not trigger ACE2, which is not expressed on NK cells, or other activating receptors, they directly and variably bind to both Toll-like receptor 2 (TLR2) and TLR4. Moreover, SP-driven NK cell functions are inhibited upon masking such receptors or silencing the relative genes. Lastly, VOC-SPs upregulate CD56dimNK cell functions in COVID-19 recovered, but not in non-infected, individuals.ConclusionsTLR2 and TLR4 are novel activating receptors for SP in NK cells, suggesting a new role of these cells in orchestrating the pathophysiology of SARS-CoV-2 infection. The pathogenic relevance of this finding is highlighted by the fact that free SP providing NK cell activation is frequently detected in a SARS-CoV-2 inflamed environment and in plasma of infected and long-COVID‐19 subjects.

Acrylamide (AA) is a contaminant resulting from the Maillard reaction and classified by the International Agency for Research on Cancer (IARC) as a probable carcinogen in Group 2A, with proven neurotoxic effects on humans. European Union (EU) Regulation No. 2017/2158 is currently in force, which establishes measures meant to reduce AA levels in food and sets reference values, but not legal limits, equal to 40 and 150 μg/kg AA in processed cereal-based foods intended for infants and young children and in biscuits and rusks, respectively. For this reason, sixty-two baby foods were analyzed using ultra-high performance liquid chromatography with diode array detector and quadrupole time-of-flight mass spectrometry (UHPLC-DAD-Q-TOF/MS) to check whether industries were complying with these values, even though AA control is not legally mandatory. In total, 14.5% of the samples exceeded the reference values; these were homogenized chicken products (211.84 ± 16.53, 154.32 ± 12.71, 194.88 ± 7.40 μg/kg), three biscuits (276.36 ± 0.03, 242.06 ± 0.78, 234.78 ± 4.53 μg/kg), a wheat semolina (46.07 ± 0.23 μg/kg), a homogenized product with plaice and potatoes (45.52 ± 0.28 μg/kg), and a children’s snack with milk and cocoa (40.95 ± 0.32 μg/kg). Subsequently, the daily intake of AA was estimated, considering the worst-case scenario, as provided by the consumption of homogenized chicken products and biscuits. The results are associated with margins of exposure (MOEs) that are not concerning for neurotoxic effects but are alarming for the probable carcinogenic effects of AA.

Helicobacter pylori is associated with gastrointestinal diseases, and its treatment is challenging due to antibiotic-resistant strains, necessitating alternative therapies. Brazilian red propolis (BRP), known for its diverse bioactive compounds with pharmaceutical properties, was investigated for its anti-H. pylori activity, focusing on biofilm formation inhibition and eradication. BRP was tested against H. pylori (ATCC 43526) using several assays: time–kill, nucleotide leakage, biofilm formation inhibition (determining the minimum inhibitory concentration of biofilm of 50%—MICB50, and cell viability), and biofilm eradication (determining the minimum eradication concentration of biofilm of 99.9%—MBEC). Standardization of H. pylori biofilm formation was also conducted. In the time–kill assay, BRP at 50 µg/mL eliminated all H. pylori cells after 24 h. The nucleotide leakage assay showed no significant differences between control groups and BRP-treated groups at 25 µg/mL and 50 µg/mL. H. pylori formed biofilms in vitro at 109 CFU/mL after 72 h. The MICB50 of BRP was 15.6 µg/mL, and at 500, 1000, and 2000 µg/mL, BRP eradicated all bacterial cells. The MBEC was 2000 µg/mL. These findings suggest that BRP has promising anti-H. pylori activity, effectively inhibiting and eradicating biofilms. Further studies are necessary to elucidate BRP’s mechanisms of action against H. pylori.

Reduced-order models (ROMs) have achieved a lot of success in reducing the computational cost of traditional numerical methods across many disciplines. In fluid dynamics, ROMs have been successful in providing efficient and relatively accurate solutions for the numerical simulation of laminar flows. For convection-dominated (e.g., turbulent) flows, however, standard ROMs generally yield inaccurate results, usually affected by spurious oscillations. Thus, ROMs are usually equipped with numerical stabilization or closure models in order to account for the effect of the discarded modes. The literature on ROM closures and stabilizations is large and growing fast. In this paper, instead of reviewing all the ROM closures and stabilizations, we took a more modest step and focused on one particular type of ROM closure and stabilization that is inspired by large eddy simulation (LES), a classical strategy in computational fluid dynamics (CFD). These ROMs, which we call LES-ROMs, are extremely easy to implement, very efficient, and accurate. Indeed, LES-ROMs are modular and generally require minimal modifications to standard (“legacy”) ROM formulations. Furthermore, the computational overhead of these modifications is minimal. Finally, carefully tuned LES-ROMs can accurately capture the average physical quantities of interest in challenging convection-dominated flows in science and engineering applications. LES-ROMs are constructed by leveraging spatial filtering, which is the same principle used to build classical LES models. This ensures a modeling consistency between LES-ROMs and the approaches that generated the data used to train them. It also “bridges” two distinct research fields (LES and ROMs) that have been disconnected until now. This paper is a review of LES-ROMs, with a particular focus on the LES concepts and models that enable the construction of LES-inspired ROMs and the bridging of LES and reduced-order modeling. This paper starts with a description of a versatile LES strategy called evolve–filter–relax (EFR) that has been successfully used as a full-order method for both incompressible and compressible convection-dominated flows. We present evidence of this success. We then show how the EFR strategy, and spatial filtering in general, can be leveraged to construct LES-ROMs (e.g., EFR-ROM). Several applications of LES-ROMs to the numerical simulation of incompressible and compressible convection-dominated flows are presented. Finally, we draw conclusions and outline several research directions and open questions in LES-ROM development. While we do not claim this review to be comprehensive, we certainly hope it serves as a brief and friendly introduction to this exciting research area, which we believe has a lot of potential in the practical numerical simulation of convection-dominated flows in science, engineering, and medicine.

Antarctic coastal polynyas produce dense shelf water, a primary source of Antarctic Bottom Water that contributes to the global overturning circulation. This paper investigates Antarctic dense water formation in the high-resolution version of the Energy Exascale Earth System Model (E3SM-HR). The model is able to reproduce the main Antarctic coastal polynyas, although the polynyas are smaller in area compared to observations. E3SM-HR also simulates several occurrences of open-ocean polynyas (OOPs) in the Weddell Sea at a higher rate than what the last 50 years of the satellite sea ice observational record suggests, but similarly to other high-resolution Earth system model simulations. Furthermore, the densest water masses in the model are formed within the OOPs rather than on the continental shelf as is typically observed. Biases related to the lack of dense water formation on the continental shelf are associated with overly strong atmospheric polar easterlies, which lead to a strong Antarctic Slope Front and too little exchange between on- and off-continental shelf water masses. Strong polar easterlies also produce excessive southward Ekman transport, causing a build-up of sea ice over the continental shelf and enhanced ice melting in the summer season. This, in turn, produces water masses on the continental shelf that are overly fresh and less dense relative to observations. Our results indicate that high resolution alone is insufficient for models to properly reproduce Antarctic dense water; the large-scale polar atmospheric circulation around Antarctica must also be accurately simulated.

Methemoglobinemia (MET) is a life-threatening condition resulting from the development of methemoglobin (MetHb), which binds oxygen irreversibly, causing refractory hypoxia and so-called “functional anemia”. MET can be caused by hereditary or acquired processes. Acquired forms are the most common. Symptoms correlate with the MetHb level and range from cyanosis and dyspnea to dysrhythmias, metabolic acidosis, coma, and cardiac arrest. MetHb levels above 70% are fatal. Methylene blue (MB) is the specific antidote. In all cases, supportive treatment, including intravenous hydration, glucose correction, and oxygen supplementation, must be started immediately. Exchange transfusion has been used successfully to treat MET and may be appropriate in patients for whom MB is ineffective. We report the case of a 54-year-old woman who presented to our emergency department for the acute and sudden development of chest pain, shortness of breath, and severe cyanosis after drinking a significant amount of boiled courgette water. Arterial blood gas analysis revealed a MetHb level of 26%. She was treated immediately with MB, oxygen supplementation, and hydration with normalization of her MetHb in 12 hours. Our recommendation is to always investigate MET in patients with unexplained cyanosis and refractory hypoxia.