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Integrated approaches for managing natural resources are said to meet increasing demand for water, energy, and food, while maintaining the integrity of ecosystems, and ensuring equitable access to resources. The Water-Energy-Food (WEF) Nexus has been proposed as a cross-sectoral approach to manage trade-offs and exploit synergies that arise among these sectors. Although not initially included as a component of the Nexus, the role of nature in sustaining the water, energy, and food sectors and in regulating their interrelationships is increasingly recognised by Nexus researchers and practitioners. To converge existing approaches that integrate nature into the WEF Nexus and suggest a common framework, we - an interdisciplinary group of natural resources management researchers and systems thinkers from the European research network NEXUSNET COST Action - followed a collaborative process of knowledge creation combining literature review, elicitation of expert opinion and collaborative writing. Our results reveal a multiplicity of concepts utilised in the literature to represent, partially or fully, "nature" in the Nexus, such as "environment", "ecosystems", "ecosystem services", "social-ecological systems", and "biodiversity". Disparity was also found in the role attributed to nature, represented by three key paradigms: (1) ecosystems as the fourth component of an expanded Nexus, i.e., the WEF-Ecosystems (WEFE) Nexus; (2) ecosystems as a foundational layer to the Nexus; and (3) the WEF Nexus as a central component of social-ecological systems (SES). By creating a hybrid approach that brings together the benefits of the respective paradigms, we present a forward-looking WEFE Nexus conceptualisation. This paradigm expands the mutual interlinkages among water, energy and food to the entirety of SES, thus acknowledging the social-ecological processes that are affected by and affect the WEF Nexus. The results of this collaborative research effort intend to provide researchers and stakeholders with means to better understand and ultimately manage Nexus issues towards a transformative change., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is the leading cause of progressive neurodegenerative dementia, affecting approximately 50 million individuals globally. Recent studies have highlighted the differential expression of circular RNAs (circRNAs) in AD, which may disrupt the circRNA-miRNA-mRNA regulatory networks in neuronal cells. This work aims to integrate network pharmacology with in silico drug design to identify novel druggable targets for AD and propose promising drug candidates. We analyzed two circRNA datasets from the Gene Expression Omnibus, employing enrichment analysis and constructing a circRNA-miRNA-mRNA network. The RNAenrich platform facilitated the identification of hub genes and potential druggable targets. The identified target was subjected to virtual screening against a chemical drug library comprising over 6000 compounds in clinical trials while ensuring compliance with Lipinski's Rule of Five. Our findings reveal that differentially expressed circRNAs are significantly involved in gland development, apoptosis regulation, hypoxic response, and neuronal death. Notably, CDK-6 emerged as the most promising druggable target, exhibiting strong binding affinity with five selected ligands: DB06963, DB06888, DB07020, DB08683, and DB06976. These ligands demonstrated distinct binding modes and stable interactions over 500 ns of molecular dynamics simulations conducted via Desmond. In conclusion, our study identifies CDK-6 as a viable target for therapeutic intervention in Alzheimer's disease. The top five ligands present a compelling case for further investigation as innovative CDK-6 inhibitors and potential drug candidates for AD treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Background: Cefazolin is used as a prophylactic antibiotic to reduce surgical site infections (SSIs). Obesity has been identified as a risk factor for SSIs. Cefazolin dosing recommendations and guidelines are currently inconsistent for obese patients. As plasma and target-site exposure might differ, pharmacokinetic data from the sites of SSIs are essential to evaluate treatment efficacy: these data can be obtained via tissue microdialysis. This analysis was designed to evaluate the need for dosing adaptations in obese patients for surgical prophylaxis., Methods: Data from 15 obese (BMI median  = 52.6 kg m -2 ) and 15 age- and sex-matched nonobese patients (BMI median  = 26.0 kg m -2 ) who received 2 g cefazolin i.v. infusion for infection prophylaxis were included in the analysis. Pharmacokinetic data from plasma and interstitial space fluid (ISF) of adipose tissue were obtained and analysed simultaneously using nonlinear mixed-effects modelling. Dosing regimens were evaluated by calculating the probability of target attainment (PTA) and the cumulative fraction of response (CFR) for plasma and ISF using unbound cefazolin concentration above minimum inhibitory concentration 100% of the time as target (fT >MIC  = 100%). Dosing regimens were considered adequate when PTA and CFR were ≥90%., Results: Evaluation of cefazolin doses of 1 and 2 g with redosing at either 3 or 4 h by PTA and CFR in plasma and ISF found 2 g cefazolin with redosing at 4 h to be the most suitable dosing regimen for both obese and nonobese patients (PTA >90% and CFR >90% for both)., Conclusions: This model-based analysis, using fT >MIC  = 100% as a target, showed that cefazolin dosing adaptations are not required for surgical prophylaxis in obese patients., Competing Interests: Declarations of interest DBi, DBu, RM, and LA have no conflict of interest. CK and WH report grants from an industry consortium (AbbVie Deutschland GmbH & Co. K.G., Astra Zeneca, Boehringer Ingelheim Pharma GmbH & Co. K.G., F. Hoffmann-La Roche Ltd., Merck KGaA, Novo Nordisk, and Sanofi) for the PharMetrX PhD programme (Berlin/Potsdam, Germany). CK reports an additional grant from the Innovative Medicines Initiative-Joint Undertaking (‘DDMoRe’) and grants from the Federal Ministry of Education and Research within the Joint Programming Initiative on Antimicrobial Resistance Initiative (JPIAMR) and from the European Commission within in the Horizon 2020 framework programme (‘FAIR’), all outside the submitted work. HW and PS received grants from Pfizer (Investigator Initiated Trial Program, Berlin, Germany) and InfectoPharm (Heppenheim, Germany), both for the clinical microdialysis trials. PS reports lecture fees from InfectoPharm (Heppenheim, Germany). HW received lecture fees from Arjo (Mainz-Kastel, Germany)., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Acute respiratory tract infections (ARIs) often occur in early childhood and are mostly self-limited. However, they impose a high socioeconomic burden and can be associated with chronic diseases later in life. To date, data on self-reported ARIs beyond infancy are limited. This study aimed to describe the incidence and characteristics of self-reported ARIs in the first 6 years of life., Methods: Data were obtained from the LoewenKIDS birth cohort study, including 782 children born between 2014 and 2018. Parents recorded daily ARI symptoms, which were classified into episodes for incidence and characteristics analysis. Regression analyses explored the influence of exposure factors on ARI incidence., Results: This longitudinal birth cohort study of a subsample of 258 children found a mean cumulative duration of 51.5 weeks (95% confidence interval: 47.5-55.6 weeks) of respiratory symptoms in the first 6 years of life, with large individual differences. Children with frequent infections in infancy had more infections in preschool age. Exposure factors explained only a small fraction of variation in incidence (5%)., Conclusions: There is a substantial variation in susceptibility to ARIs in childhood, which is not explained by exposure factors., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Although tissue engineering science has made great progress, wound healing has remained a significant clinical challenge, especially in cases of severe injuries requiring advanced treatment strategies. This study aimed to develop patient-friendly in situ gelling nanofibers composed of oxidized carboxymethyl cellulose (OCMC) and gelatin for wound healing applications. A two-axial electrospinning technique was employed to fabricate OCMC/PVA-Gelatin hybrid nanofibers. Because of the nanofibers' high surface area, the resulting scaffold can quickly absorb wound exudates, resulting in a cross-linked hydrogel via the Schiff-base reaction between OCMC and gelatin. The nanofibers were thoroughly characterized using SEM, FTIR, XRD, and TGA, confirming their successful fabrication and structural integrity. Notably, the nanofibers demonstrated full degradation within 21 days, aligning with the requirements for skin tissue regeneration. Antibacterial assays revealed 99.9 % efficacy against Pseudomonas aeruginosa and Methicillin-Resistant Staphylococcus aureus (MRSA). The electrospun OCMC/PVA and OCMC/PVA-Gel samples exhibited 91 ± 10 % and 92 ± 7 % cell viability after 7 days of L929 fibroblast cell culture, confirming their excellent biocompatibility. These findings highlight the potential of the developed nanofibers as antimicrobial and biocompatible wound dressings with an appropriate degradation profile, presenting a practical and effective alternative to conventional hydrogel systems for advanced wound healing applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier B.V.)

The interactions between landscape structure, land use intensity (LUI), climate change, and ecological processes significantly impact hydrological processes, affecting water quality. Monitoring these factors is crucial for understanding their influence on water quality. Remote sensing (RS) provides a continuous, standardized approach to capture landscape structures, LUI, and landscape changes over long-term time series. In this study, RS-based indicators from Landsat data (2018-2021) were used to assess landscape structure, LUI, and land use change for a study area in northern Germany, applying the ESIS/Imalys tool. These indicators were then used to model and predict water quality (Chl a ) in 119 standing waters. Various machine learning methods, including Generalised Linear Models, Support Vector Machines, Deep Learning, Decision Trees, Random Forest, and Gradient Boosted Trees, were tested. The Random Forest model performed best, with a correlation of 0.744 ± 0.11. Indicators related to landscape structure, such as diversity_mean (0.376) and relation_mean (0.292), had the highest global correlation weights, while LUI and land use change indicators like NirV2_mean (0.369) and NirV_regme (0.284) were also significant. All indicators and their effects on water quality (Chl a ) are discussed in detail. The study highlights the potential of the ESIS/Imalys tool for quantifying landscape structure, LUI, and land use change with RS to model and predict water quality and suggests directions for future model improvements by incorporating additional influencing factors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Gene expression manipulation is pivotal in therapeutic approaches for various diseases. Non-viral delivery systems present a safer alternative to viral vectors, with reduced immunogenicity and toxicity. However, their effectiveness in promoting endosomal escape, a crucial step in gene transfer, remains limited. To address this drawback, we developed a reducible conjugate combining the StIW111C mutant of Sticholysin I, a pore-forming protein, with a polylysine peptide. This conjugate aims to enhance plasmid DNA (pDNA) release from endosomes, thereby improving gene expression. A 16-polylysine peptide was attached to StIW111C via a disulfide bridge to block its membrane-binding site, enabling controlled modulation of pore-forming activity in response to a reductive environment. This modification also enhances the conjugate's positive charge, facilitating binding to nucleic acids. Formation of positively charged nanometric complexes was achieved by mixing pDNA with the bio-responsive StIW111C conjugate and polylysine peptide. In vitro assays showed the conjugate could permeabilize endosomes, but reporter gene expression was limited, likely due to the largest complexes or aggregates that reduced conjugate entry and blocked nucleic acid release. CryoTEM imaging revealed the presence of small aggregate fraction, highlighting the need for further redesign to prevent aggregation and optimize endosomal release of non-viral systems for enhanced gene expression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier B.V.)

As a result of anti-inflammatory activity-guided fractionation, 16 secondary metabolites from the underground parts of Valeriana phu L. were obtained, including five new ones belonging to iridoid (1, 2, and 5), phenylpropanoid (6) and neolignan (7) chemical classes. Their structures were elucidated by 1D and 2D NMR analyses as well as HRESIMS. The in vitro anti-inflammatory activities of the extract, fractions and isolates were evaluated through NO inhibition assay on LPS-induced RAW 264.7 cells. Compounds 1-3, 7-9, 11, 13, and 16 which significantly inhibited the nitrite release (IC 50 14.94-94.81 μM) were also assessed for their reducing capacity on TNF-α, IL-1β, IL-6, PGE2 and COX-2 production. Compounds 3, 8, and 16 inhibited LPS induced iNOS expression levels in Western blotting. Molecular docking studies for the active compounds targeting iNOS, TNF-α and COX-2 were also carried out. Moreover, compounds with remarkable anti-inflammatory activities were tested for their potential cytotoxicity against breast (MCF-7 and MDA-MB-231), glioblastoma (U87 and A172), pancreas (MIA PaCa-2 and PANC-1), hepatocellular (Mahlavu and Hep3B) cancer cell lines by WST-8. Compounds, 7, 8, and 16 showed significant cytotoxicity against A172 and PANC-1 cell lines (IC 50 18.3-21.8 μM) via causing cell cycle arrest, especially in the G2/M phase and triggering the apoptotic pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Objective: Research suggests that people with type 2 diabetes (PWT2D) exhibit different approaches to learning about disease-management. This study's aims to identify distinct learner groups among PWT2D and stratify them by educational status (ES)., Methods: Cross-sectional data from 227 PWT2D, collected through 46 Likert-scale questions on learning behaviors, preferences, and attitudes, were analyzed using latent class analysis, to identify learner groups. Participants were recruited via healthcare practices in central Germany and a countrywide online survey. Group membership was displayed according to low, medium, and high ES, defined by years of schooling., Results: Four learner groups were identified: casual, versatile, insecure, and theorist learners. Insecure learners accounted for almost half of all respondents in the low ES group (46 %), casual learners were most prevalent among PWT2D with a medium (27 %), versatile (34 %) and theorist (29 %) learners among those with a high ES., Conclusion: This study sheds light on learner groups among PWT2D, which differ by ES, suggesting social disparities in diabetes care. Further research is needed to validate these findings., Practice Implications: Understanding individual learning preferences and motivations is crucial for developing effective diabetes self-management trainings, which may involve providing additional background material for theorists and practical applications for insecure learners., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Here we report for the first time the entire 13 C-NMR spectral assignments of 119 (out of 127) triterpenoids from the oleo-gum resins of the medicinally important genus Boswellia, which includes the culturally highly valuable Frankincense species. The complete 13 C-NMR resonances of these triterpenoids isolated between 1998 and 2024 and their biological activities are presented. 13 C-NMR spectroscopy is a highly powerful tool for the characterization of these bioactive natural products. The compounds are arranged according to their skeletons, i.e., ursane, oleanane, lupane, dammarane, and tirucallane triterpenes. This review will be a future reference for the identification of these compounds, which have key medicinal properties in the areas of cytotoxicity and inflammation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Heatwave events increase in frequency and duration, yet there is a strong gap in assessing their nonlethal effects on tropical insects, including beneficial social species. The stingless bees are a highly diverse group of pantropical pollinators that provide key ecosystem services. Here, we simultaneously analyzed for the first time the effect of sublethal heat stress (HS) during immature (pupal) development on adult morphology (size, shape, symmetry) and immune response of the three castes/sexes in stingless bee colonies: workers, unmated queens (gynes) and males, as well as its impact on the onset of foraging and lifespan in workers. Individuals experimentally heat stressed during development had smaller body size and reduced symmetry as adults compared with control, non-heat stressed (NHS) individuals, though the strength of the effects of HS also varied between castes and sexes. Notably, males were more prone to the effects of HS compared with workers, and less so gynes; HS reduced the immune response of males, though not that of workers or queens. Workers had significantly earlier onset of foraging and a shorter lifespan when exposed as immatures to HS. Under a worst-case scenario, knock-on negative impacts on individual survival caused by HS could compromise colony fitness. In the long-term, heatwaves may also have repercussions for the persistence of stingless bee species, the sustainability of key ancestral activities like meliponiculture and ecosystem services. Measures to ameliorate the effect of climatic warming are urgently needed to protect these pollinators, which represent an iconic world heritage., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jose Javier G. Quezada-Euan reports financial support was provided by CONAhCYT Mexico. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Whether inherited in the context of multiple endocrine neoplasia 2B at germline level or acquired in a lifetime, all RET p.M918T (RET c.2753T>C) mutations should activate the RET tyrosine kinase receptor alike, with similar degrees of medullary thyroid cancer (MTC) progression when disparities in disease onset and multifocal growth are accounted for., Methods: This cross-sectional analysis of RET p.M918T-driven progression of hereditary MTC (33 patients) vs. sporadic MTC (36 patients) sought to explore this hypothesis., Results: Patients with hereditary disease were significantly younger at thyroidectomy (medians of 10 vs. 57 yrs.) and featured significantly more often multifocal growth (69 vs. 14 %) with more thyroid tumor foci (medians of 2 foci vs. 1 focus) than patients with sporadic disease. Although the former had 3.6-fold smaller primary thyroid tumor diameters (medians of 5 vs. 18 mm) and twice as many neck nodes dissected (medians of 66.5 vs. 32 nodes) than the latter, extrathyroid tumor extension (42 vs. 36 %), node metastasis (64 vs. 77 %), distant metastasis (33 vs. 17 %), and biochemical cure rates (45 vs. 35 %) were fairly comparable, as was the number of dissected node metastases (medians of 7 vs. 8 involved nodes). Sensitivity analyses, with breakdown of patients by tumor multifocality and nodal status, corroborated these findings., Conclusion: RET p.M918T-driven progression of MTC is similar in hereditary and sporadic disease, barring earlier development and more frequent multifocal growth of hereditary MTC. This makes a compelling case for referral of patients with RET p.M918T-driven MTCs to specialist surgical centers., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objectives: We conducted a cluster-randomized-controlled trial (cRCT) in 18 German nursing homes (NH) to evaluate the cost-effectiveness of reinstruction and remotivation of nursing staff by dental assistants (DAs) over 13 months., Methods: In the intervention arm, dentists examined NH residents, identified oral health conditions, and prescribed individualized oral care interventions. Nursing staff delivered these interventions, with regular follow-up support from DAs (reinstruction and remotivation). In the control group, similar interventions were prescribed via a standardized form, without reinstruction and remotivation (standard of care). The primary outcome was Oral-Health-related Quality-of-Life (OHrQoL) using the Geriatric/General Oral Health Assessment Index (ADD-GOHAI). Secondary outcomes included Health-related Quality-of-Life (HrQoL) using the EQ-5D summary index and caries experience (DMFT index). Costs, including those for staff, materials, and travel, were assessed in Euro 2022. Cost-effectiveness ratios and bootstrapping simulations assessed cost-effectiveness-acceptability at different willingness-to-pay thresholds., Results: Of 358 recruited participants, 68 and 63 in the intervention and control group completed the study. No significant differences existed between groups in demographics or baseline health measures. After 13 months, changes in ADD-GOHAI and DMFT scores were minimal and non-significant, while EQ-5D scores decreased in the intervention group (p < 0.001). Total costs were higher in the intervention arm (median 121.10 Euro) versus the control (median 0 Euro, p < 0.001), mainly due to travel expenses. The intervention increased dental service use but demonstrated lower cost-effectiveness acceptability., Conclusions: DA-led reinstruction did not improve OHrQoL, negatively impacted HrQoL, and increased costs. Notably, our study was suffering from significant attrition, impacting on statistical power., Clinical Significance: Reinstruction and remotivation by dental assistants did not improve OHrQoL, but generated significant costs, mainly due to an uptake of dental services., Trial Registration: ClinicalTrials.gov (Trial registration number NCT04140929)., Competing Interests: Declaration of competing interest The authors have no conflicting interests to declare., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Ampullary adenocarcinoma (AAC) typically presents at an early stage due to biliary obstruction and therefore might be specifically suitable for minimally invasive pancreatoduodenectomy (MIPD). However, studies assessing MIPD specifically for AAC, including the robotic and laparoscopic approach, are limited. The aim of this study is to compare short- and long-term oncological resection and perioperative outcomes of robotic (RPD), laparoscopic (LPD) and open pancreatoduodenectomy (OPD) performed specifically for AAC., Methods: In this multicenter international cohort study, encompassing 35 centers from 11 countries, MIPD versus OPD and subgroup analyses of LPD versus RPD were undertaken. The primary outcomes regarded the oncological resection (R1 resection rate, lymph node yield) and 5-years overall survival. Secondary outcomes were perioperative outcomes (including intra-operative variables, surgical complications and hospital stay)., Results: In total, patients with AAC who underwent OPD (1721) or MIPD (141) were included. After propensity-score matching, 134 patients per cohort were included. The MIPD group consisted of 53 RPDs and 71 LPDs (50 per group after PSM). There was no difference in overall survival between MIPD and OPD (61.6 % vs 56.2 %, P = 0.215). In the MIPD group, operative time was longer (439 vs 360 min, P < 0.001). Between RPD and LPD, overall survival was not significantly different (75.8 % vs 47.4 %, P = 0.098) and lymph node yield was higher in RPD (21 vs 18, P = 0.014)., Conclusion: In conclusion, patients with AAC seem to have comparable oncological resection and perioperative outcomes from MIPD compared to the traditional OPD. Both RPD as LPD appear to be safe alternatives for patients with AAC, which warrants confirmation by future randomized studies., Competing Interests: Conflict of interest Mario Serradilla-Martín received research funding from Baxter S.L.. Patrick Pessaux is co-founder of Virtualisurg; Marc G. Besselink has received grants from Intuitive for the LEARNBOT European robot Whipple training program, the DIPLOMA-2 trial, and the E-MIPS quality registry, from Medtronic for the investigator-initiated DIPLOMA trial and from Ethicon for the PANDORA trial and the E-MIPS quality registry; Mohammed Abu Hilal received funding from Associazione Italiana per la Ricerca sul Cancro (AIRC). All remaining authors (BAU, AM, UB, MM, BGK, RDV, SK, LB, AM, ML, BKPG, MASM, BB, GK, BI, JK, PG, VKM, GKF, RS, AZ, KJR, AA, BAS, MV, DK, ZS, MG, SB, CMV, SWB, JDC) claim no conflicts of interests and no disclosures., (Copyright © 2024. Published by Elsevier Ltd.)

Heat emitted by buildings and other infrastructure accumulates in the subsurface. This additional heat can cause a pronounced shift in thermal boundary conditions of the important groundwater ecosystem. Shallow groundwater systems in Central Europe are often inhabited by communities of fauna adapted to cold and stable conditions as well as microorganisms, whose activity is dependent on ambient temperatures. At a local groundwater temperature hotspot of up to 23 °C, caused by a water park, we assessed the environmental impact of this thermal alteration on the shallow groundwater system. The results show that the overall groundwater quality at the site is influenced by anthropogenic land use, compared to wells in a nearby water protection zone. However, neither hydrochemical nor ecological characteristics of groundwater from wells in the vicinity of the water park indicate any significant dependence on temperature. Hence, we conclude that in this eutrophic and anoxic aquifer moderate heat stress does not lead to significant alterations in terms of hydrochemistry as well as microbiological properties. Due to the overall low oxygen concentrations (<1 mg/l), stygofauna is present only occasionally and cannot be used as bioindicators. These results have to be verified for other aquifer types and would benefit from a more in-depth analysis of microbial community composition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Organic soil amendments (OSA) with long residence times, such as biochar, have a high potential for soil organic carbon (SOC) sequestration. The highly aromatic structure of biochar reduces microbial decomposition and explains the slow turnover of biochar, indicating long persistence in soils and thus potential SOC sequestration. However, there is a lack of data on biochar-induced SOC sequestration in the long-term and under field conditions. We sampled two long-term field experiments in Germany, where biochar was applied 12 and 14 years ago. Both locations differ in soil characteristics and in the types and amounts of biochar and other OSA. Amendments containing compost and 31.5 Mg ha -1 of biochar on a loamy soil led to a SOC stock increase of 38 Mg ha -1 after OSA addition. The additional increase is due to non-biochar co-amendments such as compost or biogas digestate. After eleven years, this SOC stock increase was still stable. High biochar amount additions of 40 Mg ha -1 combined with biogas digestate, compost or synthetic fertilizer on a sandy soil led to an increase of SOC stocks of 61 Mg ha -1 ; 38 Mg ha -1 dissipated in the following four years most likely due to lacking physical protection of the coarse soil material, and after nine years the biochar-amended soils showed only slightly higher SOC stocks (+7 Mg ha -1 ) than the control. Black carbon stocks on the same soil increased in the short- and mid-term and decreased almost to the original stock levels after nine years. Our results indicate that in most cases the long-term effect on SOC and black carbon stocks is controlled by biochar quality and amount, while non-biochar co-amendments can be neglected. This study proves that SOC sequestration through the use of biochar is possible, especially in loamy soils, while non-biochar OSA cannot sequester SOC in the long term., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Understanding the mechanisms that drive biodiversity-productivity relationships is critical for guiding forest restoration. Although complementarity among trees in the canopy space has been suggested as a key mechanism for greater productivity in mixed-species tree communities, empirical evidence remains limited. Here, we used data from a tropical tree diversity experiment to disentangle the effects of tree species richness and community functional characteristics (community-weighted mean and functional diversity of leaf traits) on canopy space filling, and how these effects are related to overyielding. We found that canopy space filling was largely explained by species identity effects rather than tree diversity effects. Communities with a high abundance of species with a conservative resource-use strategy were those with most densely packed canopies. Across monocultures and mixtures, a higher canopy space filling translated into an enhanced wood productivity. Importantly, most communities (83 %) produced more wood volume than the average of their constituent species in monoculture (i.e. most communities overyielded). Our results show that overyielding increased with leaf functional diversity and positive net biodiversity effects on canopy space filling, which mainly arose due to a high taxonomic diversity. These findings suggest that both taxonomic diversity-enhanced canopy space filling and canopy leaf diversity are important drivers for overyielding in mixed-species forests. Consequently, restoration initiatives should promote stands with functionally diverse canopies by selecting tree species with large interspecific differences in leaf nutrition, as well as leaf and branch morphology to optimize carbon capture in young forest stands., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

In the ever-evolving world of materials science, modifying natural polymers has garnered significant attention across diverse industries, driven by their inherent availability and cost-effectiveness. Among these, chitosan, a pseudo-natural cationic polymer, has emerged as a versatile player, finding applications in medical, pharmaceutical, filtration, and textile sectors, owing to its exceptional biodegradability, non-allergenicity, antimicrobial properties, and eco-friendly nature. However, the limitations of chitosan, such as low surface area, poor solubility at neutral to alkaline pH, and inadequate thermal-mechanical properties, have prompted researchers to explore innovative modification strategies, including graft copolymerization, quaternization, and cross-linking. This review delves into the remarkable potential of a specific chitosan derivative, N-[(2-hydroxy-3-trimethylammonium) propyl] chitosan salts (N-HTCS), a quaternized form of chitosan. This review uniquely examines the properties and multifaceted applications of N-HTCS, spanning biomedical, textile, food packaging, and environmental domains. The outstanding features of N-HTCS, including antioxidant, anticancer, and antimicrobial bioactivity, as well as biocompatibility, biodegradability, hemostatic, piezoelectric, superparamagnetic, water solubility, and permeation-enhancing effects, offer novel solutions to the limitations of unmodified chitosan. Notably, while previous reviews have addressed the significance of chitosan, this work presents a groundbreaking focus on the N-HTCS derivative, providing a fresh perspective and paving the way for the design and engineering of cutting-edge N-HTCS-based devices and applications. The comprehensive coverage of this review aims to inspire researchers and industry professionals to explore the untapped potential of this remarkable chitosan derivative, unlocking new frontiers in material science and technology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of advanced chronic liver disease (ACLD). Portal hypertension drives hepatic decompensation and is best diagnosed by hepatic venous pressure gradient (HVPG) measurement. Here, we investigate the prognostic value of HVPG in MASLD-related compensated ACLD (MASLD-cACLD)., Methods: This European multicentre study included patients with MASLD-cACLD characterised by HVPG at baseline. Hepatic decompensation (variceal bleeding/ascites/hepatic encephalopathy) and liver-related mortality were considered the primary events of interest., Results: A total of 340 patients with MASLD-cACLD (56.2% male; median age 62 [55-68] years, median MELD 8 [7-9], 71.2% with diabetes) were included. Clinically significant portal hypertension (CSPH: i.e., HVPG ≥10 mmHg) was found in 209 patients (61.5%). During a median follow-up of 41.5 (27.5-65.8) months, 65 patients developed hepatic decompensation with a cumulative incidence of 10.0% after 2 years (2Y) and 30.7% after 5 years (5Y) in those with MASLD-cACLD with CSPH, compared to 2.4% after 2Y and 9.4% after 5Y in patients without CSPH. Variceal bleeding did not occur without CSPH. CSPH (subdistribution hazard ratio [SHR] 5.13; p <0.001) was associated with an increased decompensation risk and a higher HVPG remained an independent risk factor in the multivariable model (adjusted SHR per mmHg: 1.12, p <0.001). Liver-related mortality occurred in 37 patients at a cumulative incidence of 3.3% after 2Y and 21.4% after 5Y in CSPH. Without CSPH, the incidence after 5Y was 0.8%. Accordingly, a higher HVPG was also independently associated with a higher risk of liver-related death (adjusted SHR per mmHg: 1.20, p <0.001)., Conclusion: HVPG measurement is of high prognostic value in MASLD-cACLD. In patients with MASLD-cACLD without CSPH, the short-term risk of decompensation is very low and liver-related mortality is rare, while the presence of CSPH substantially increases the risk of both., Impact and Implications: While the incidence of compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide, insights into the impact of clinically significant portal hypertension (CSPH) on the risk of liver-related events in MASLD-cACLD remain limited. Based on the findings of this European multicentre study including 340 MASLD-cACLD patients, we could show that increasing HVPG values and the presence of CSPH in particular were associated with a significantly higher risk of first hepatic decompensation and liver-related mortality. In contrast, the short-term incidence of decompensation in patients with MASLD-cACLD without CSPH was low and the risk of liver-mortality remained negligible. Thus, HVPG measurements can provide important prognostic information for individualised risk stratification in MASLD-cACLD and may help facilitate the study of novel and promising treatment possibilities for MASLD., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Several lactic acid bacteria are capable of producing water-soluble exopolysaccharides such as dextran from sucrose by using glucansucrases. Several recombinant glucansucrases were described, however, yields were often limited and most dextrans were branched at position O3. In this study, the dextransucrase from Ligilactobacillus animalis TMW 1.971 was recombinantly produced without its N-terminal variable region and used for dextran synthesis. The enzyme expressed well and showed very high total as well as transferase activities compared to other glucansucrases. It was able to transfer nearly all glucose from sucrose to oligo- and polymeric products under certain conditions (about 95 % of glucose transferred). The high efficiency of the enzyme made it possible to obtain absolute dextran yields of up to 214.9 g/L from a 1.5 M sucrose solution. Structural characterization of the products showed that the dextrans produced have a rather low molecular weight, a narrow size distribution, and are completely linear. Furthermore, we showed that various low molecular weight dextrans or 1,6-linked isomalto-oligosaccharides can be efficiently produced by acid hydrolysis. Overall, we demonstrated that Ligilactobacillus animalis TMW 1.971 dextransucrase can be used to efficiently synthesize dextrans with a quite unique structural composition. The dextrans produced have a high potential for further applications such as synthesis of copolymers or size standards with a very defined molecular structure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Multifocal growth is characteristic of hereditary medullary thyroid cancer (MTC), whereas origin and impact of multifocal growth is enigmatic for sporadic MTC. To address this, 460 RET-negative patients with sporadic MTC, stratified by 1 (93.3 %), 2 (5.7 %) and 3 (1.1 %) thyroid tumor foci, were compared with 219 RET-positive patients with hereditary MTC, stratified by 1 (38.4 %), 2 (45.7 %), 3 (6.4 %), 4 (6.8 %) and ≥5 (2.7 %) thyroid tumor foci. For sporadic MTC, significant associations were identified with bilateral thyroid lobe involvement, microscopic lymphatic invasion, extrathyroid extension, node and distant metastases, number of node metastases, preoperative basal calcitonin level, and decreasing biochemical cure. For hereditary MTC, significant associations were limited to bilateral thyroid lobe involvement, largest thyroid tumor diameter, and preoperative basal calcitonin level. In sporadic MTC, multifocal growth is due to lymphatic invasion with frequent node metastases, whereas in hereditary MTC, it reflects malignant progression from C-cell hyperplasia to cancer., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Host-directed antivirals (HDAs) represent an attractive treatment option and a strategy for pandemic preparedness, especially due to their potential broad-spectrum antiviral activity and high barrier to resistance development. Particularly, dual-targeting HDAs offer a promising approach for antiviral therapy by simultaneously disrupting multiple pathways essential for viral replication. Izumerogant (IMU-935) targets two host proteins, (i) the retinoic acid receptor-related orphan receptor γ isoform 1 (RORγ1), which modulates cellular cholesterol metabolism, and (ii) the enzyme dihydroorotate dehydrogenase (DHODH), which is involved in de novo pyrimidine synthesis. Here, we synthesized optimized derivatives of izumerogant and characterized their antiviral activity in comparison to a recently described structurally distinct RORγ/DHODH dual inhibitor. Cell culture-based infection models for enveloped and non-enveloped DNA and RNA viruses, as well as a retrovirus, demonstrated high potency and broad-spectrum activity against human viral pathogens for RORγ/DHODH dual inhibitors at nanomolar concentrations. Comparative analyses with equipotent single-target inhibitors in metabolite supplementation approaches revealed that the dual-targeting mode represents the mechanistic basis for the potent antiviral activity. For SARS-CoV-2, an optimized dual inhibitor completely blocked viral replication in human airway epithelial cells at 5 nM and displayed a synergistic drug interaction with the nucleoside analog molnupiravir. In a SARS-CoV-2 mouse model, treatment with a dual inhibitor alone, or in combination with molnupiravir, reduced the viral load by 7- and 58-fold, respectively. Considering the clinical safety, oral bioavailability, and tolerability of izumerogant in a recent Phase I study, izumerogant-like drugs represent potent dual-targeting antiviral HDAs with pronounced broad-spectrum activity for further clinical development., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C. G., D.V. and H.K. have patent application WO2023/232870 filed on this topic. All other authors declare no competing interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: We tested the feasibility of a randomized controlled trial for comparing primary nursing with standard care., Research Methodology: Elective cardiac surgical patients were eligible for inclusion. Patients with an intensive care unit stay of ≥ 3 days were followed up until intensive care unit discharge. Recruitment period was one year., Setting: Two intensive care units at a university hospital specialized in cardiovascular and diabetic diseases., Main Outcome Measures: Primary outcomes were recruitment and delivery rate. Primary clinical outcome was duration of delirium, as assessed by the Confusion Assessment Method for Intensive Care Units. Secondary outcomes included the incidence of delirium, anxiety (10-point Numeric Rating Scale), and the satisfaction of patient relatives (validated questionnaire)., Results: Of 369 patients screened, 269 could be allocated to primary nursing (n = 134) or standard care (n = 135), of whom 46 patients and 48 patients, respectively, underwent an intensive care unit stay ≥ 3 days. Thus, recruitment and delivery rates were 73 and 26 %, respectively. During primary nursing and standard care, 18 and 24 patients developed a delirium, with a median duration of 32 (IQR: 14-96) and 24 (IQR: 8-44) hours (P = 0.10). The risk difference of delirium for primary nursing versus standard care was 11 % and the relative risk was 0.65 (95 % CI: 0.28-1.46; P = 0.29). The extent of anxiety was similar between groups (P = 0.13). Satisfaction could be assessed in 73.5 % of relatives, without substantial differences between groups., Conclusion: Data demonstrate that a trial for comparing primary nursing with standard care is generally feasible. However, the incidence of delirium may be a better primary outcome parameter than delirium duration, both in terms of long-term patient outcome and robustness of data quality., Implications for Clinical Practice: A randomized clinical trial regarding nursing organization during intensive care unit stay requires detailed planning of patient recruitment, data evaluation, and power calculation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Concentrations of starch, mono- and disaccharides, fructans, hemicellulose and cellulose were analysed in feed and gastric digesta of horses in relation to acid insoluble ash as a marker indigestible in the stomach. Twenty-four horses were allocated to pasture 24 h/d (PST; n = 4), hay ad libitum (HAY; n = 8), hay ad lib. and oats at 1 g starch/kg body weight (BWT)/meal (OS1; n = 6) and hay ad lib. and oats at 2 g starch/kg BWT/meal (OS2; n = 5). One horse was excluded from the analysis. The horses were fed the ration a minimum of 34 days. Following euthanasia and dissection, digesta was sampled from Pars nonglandularis (PNG) and Pars glandularis (PG). Oat starch concentration in gastric digesta decreased from 309 to 174 g/kg dry matter (DM) in OS1 (44 %-reduction) and from 367 to 261 g/kg DM in OS2 (29 %-reduction) (P < 0.001). Glucose, fructose and sucrose disappeared from gastric digesta distinctly more in PST, HAY and OS1 than in OS2. In PST and HAY, sucrose concentration was completely cleared (P < 0.001). The concentration of fructans was reduced predominantly in PST (84 %-reduction) and HAY (54 %-reduction), mainly in the PNG (P < 0.05). Fructan degradation did not occur in the high-starch diet (OS2). Some evidence for fibre degradation was observed in PST (P < 0.01). Soluble carbohydrates disappear from the stomach dependent on the type of ration, which may lead to changes in the composition of the gastric microbial community and the endogenous response., Competing Interests: Declaration of competing interest None of the authors has any financial or personal relationships that could inappropriately influence or bias the content of the paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The single-stranded RNA genome of SARS-CoV-2 encodes several structural and non-structural proteins, among which the papain-like protease (PLpro) is crucial for viral replication and immune evasion and has emerged as a promising therapeutic target. The current study aims to discover new inhibitors of PLpro that can simultaneously disrupt its protease and deubiquitinase activities. Using multiple computational approaches, six compounds (CP1-CP6) were selected from our in-house compounds database, with higher docking scores (-7.97 kcal/mol to -8.14 kcal/mol) and fitted well in the active pocket of PLpro. Furthermore, utilizing microscale molecular dynamics simulations (MD), the dynamic behavior of selected compounds was studied. Those molecules strongly binds at the PLpro active site and forms stable complexes. The dynamic motions suggest that the binding of CP1-CP6 brought the protein to a closed conformational state, thereby altering its normal function. In an in vitro evaluation, CP2 showed the most significant inhibitory potential for PLpro (protease activity = 2.71 ± 0.33 μM and deubiquitinase activity = 3.11 ± 0.75 μM), followed by CP1, CP5, CP4 and CP6. Additionally, CP1-CP6 showed no cytotoxicity at a concentration of 30 μM in the human BJ cell line., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

There is growing concern about the rising levels of dissolved organic matter (DOM) in surface waters across the Northern hemisphere. However, only limited research has been conducted to unveil its precise origin. Compositional changes along terrestrial-aquatic pathways can help determine the terrestrial sources of DOM in streams. Stream water, soil water and soil horizons were sampled at four sites representing typical settings within a forested catchment in the Ore Mountains (Erzgebirge, Germany) from winter 2020 to spring 2022. The samples were analyzed using pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS). The resulting data were successfully subjected to semi-automatic processing of the molecular composition of DOM, reaching a percentage of identified peaks up to 98 %. Principal component analysis (PCA) and cluster analyses were carried out to identify distinct differences between DOM from the potential sources and in the streams. According to the PCA, organic soil horizons, soil water, and stream water samples could be clearly distinguished. Cluster analysis revealed that soil water DOM at all depths of Peats and deeper horizons of the Peaty Gleysols contributed the most to DOM in the stream section dominated by organic soils. In areas dominated by mineral soils, stream DOM resembled the DOM from the deeper mineral horizons of Cambisols and Podzols. Overall, our results suggested that most of the DOM exported from the catchment was derived from deeper mineral soil horizons, with little contribution of DOM derived from organic soils. Therefore, DOM fingerprint analysis of in-situ soil water proved to be a promising approach for tracing back the main sources of stream water DOM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: We present the 'COVID-19 evidence ecosystem' (CEOsys) as a German network to inform pandemic management and to support clinical and public health decision-making. We discuss challenges faced when organizing the ecosystem and derive lessons learned for similar networks acting during pandemics or health-related crises., Study Design and Setting: Bringing together 18 university hospitals and additional institutions, CEOsys key activities included research prioritization, conducting living systematic reviews (LSRs), supporting evidence-based (living) guidelines, knowledge translation (KT), detecting research gaps, and deriving recommendations, backed by technical infrastructure and capacity building., Results: CEOsys rapidly produced 31 high-quality evidence syntheses and supported three living guidelines on COVID-19-related topics, while also developing methodological procedures. Challenges included CEOsys' late initiation in relation to the pandemic outbreak, the delayed prioritization of research questions, the continuously evolving COVID-19-related evidence, and establishing a technical infrastructure. Methodological-clinical tandems, the cooperation with national guideline groups and international collaborations were key for efficiency., Conclusion: CEOsys provided a proof-of-concept for a functioning evidence ecosystem at the national level. Lessons learned include that similar networks should, among others, involve methodological and clinical key stakeholders early on, aim for (inter)national collaborations, and systematically evaluate their value. We particularly call for a sustainable network., Competing Interests: Declaration of competing interest F.B. reports a relationship with Pfizer that includes: speaking and lecture fees; reports a relationship with Hans-Bockler-Foundation that includes: funding grants; reports a relationship with German Research Foundation that includes: funding grants; reports a relationship with German Federal Ministry of Health that includes: funding grants; reports a relationship with Federal German Ministry of Education and Research that includes: funding grants; reports a relationship with Charité Foundation that includes: funding grants; reports a relationship with Joint Federal Committee that includes: funding grants; reports a relationship with General Electric that includes: speaking and lecture fees; reports a relationship with Medtronic that includes: board membership. I.K. reports the following grants or contracts from any entity in the past 36 months (type of grant: third party fund; recipient: institutional): German Cancer Aid Foundation, German Ministry of Health (BMG), German Federal Joint Committee independent Funding Programme for Clinical Practice Guidelines developed under the auspices of AWMF member societies (2020-2023), German Ministry for Education and Research (BMBF; 2020-2022); reports consulting fees (recipient: personal) were provided by: European Federation of Periodontology (honoraria, travel costs; 2020-2023), British Society for Periodontology (honoraria, travel costs; 2020-2023), European Society of Endotontology (ESE; honoraria; 2021 – 2023), European Society for Contact Dermatitis (ESCD; honoraria; 2021-2021); reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (recipient: personal) by EBM Frankfurt, Working Group at the Institute for Family Medicine, Goethe-University Frankfurt (honoraria, travel costs; 2020-2022), German Society for Pediatric Infectiology (honoraria; 2021-2022), European Business School (EBS) Wiesbaden (honoraria; 2021-2022), European Association of Dental Implantologists (BDIZ; honoraria, travel costs; 2022-2022); reports payment for expert testimony was provided by German Accreditation Body (DAkkS; honoraria, travel costs); reports participation on a Data Safety Monitoring Board or Advisory Board (Agency for Quality in Medicine (ÄZQ) (a nonprofit organization)—advisory board; type of grant: honoraria, 2020-2023); reports leadership or a fiduciary role in other board, society, committee, or advocacy group (unpaid, nonfinancial): AWMF-Representative in the Board of Trustees- IQTIG (German Institute for Quality and Transparency in Health Care) a nonprofit, governmental institution), Honorary Member—German Society for Breast Health, Member—German Network for Evidence based Medicine (DNEbM), German Society of Surgery (DGCH), Member—Steering Committee for the Guideline Program in Oncology of the German Cancer Society, German Cancer Aid and AWMF, Member—Advisory Board for the Program National Disease Management Guidelines under the auspices of AWMF, German Cancer Society and AWMF, Deputy Chair- Standing Commission on Guidelines of the German Medical Association, the National Association of Statutory Health Insurance Physicians, and the AWMF, Primary Contact on behalf of the AWMF in the Guidelines International Network, Trustee, Guidelines International Network, AWMF Curriculum for guideline developers and guideline advisors; Reviewer, GIN-Mcmaster INGUIDE Program. Other financial or nonfinancial interests: Research interests (Guidelines, Health Services Research, Digitalization); and explicitly declares that she has no ties to pharmaceutical or medical product industry. M.S. reports financial support and administrative support were provided by Charité Universitätsmedizin Berlin Infectious Diseases; reports a relationship with Charité University Hospital Berlin that includes: employment. F.v.D. reports a relationship with Charité University Hospital Berlin that includes: funding grants; reports a relationship with University Medicine Greifswald that includes: funding grants. There are no competing interests for any other author., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

While researchers and practitioners attribute an essential role to executive functions (EFs) for soccer performance, the usefulness of respective diagnostics and the predictive value remain unclear. One limitation restricting the translation and relevance of study results to improve actual game performance is the insufficient consideration of competitive conditions. Thus, this study aimed to conduct soccer-specific cognitive diagnostics under a soccer-specific psychophysiological stress condition, mimicing the demands of a competitive game. A total of 92 (M age  = 15.17, SD age  = 1.45) youth elite players performed tests for inhibition (flanker task) or cognitive flexibility (number-letter task) with a soccer-specific motor response (i.e., pass into goals). After a pre-test in a neutral condition, players were randomly assigned to a neutral (moderate soccer-specific exercise) or a stress condition (physical stress and competitive instructions and filming for psychological stress). Objective (i.e., cortisol, heart rate variability) and subjective stress-related measures (i.e., SAM, VAS) were assessed six times throughout experimental procedure. Analyses revealed significant interaction effects between time and condition for all objective and subjective variables indicating a successful experimental stress induction. For cognitive performance, results revealed significant main effects of time, but no significant interaction effects between time and condition. However, descriptive statistics suggested improved performance under stress, with decreased flanker effect and switch costs. Additionally, response time variability in the flanker task significantly decreased in the stress condition. These findings offer insights into individual stress perception and processing under game-related psychophysiological demands, expanding previous research on situational EF alterations that also hold relevance for applied practitioners., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Anti-BCMA-directed chimeric antigen receptor (CAR) T cells are effective treatment for patients with refractory/relapsed multiple myeloma (RRMM). However, little is known about the impact of previous allogeneic hematopoietic stem cell transplantation (allo-HSCT) on lymphocyte collection for production of CAR T cells and subsequent treatment with CAR T cells., Patients and Methods: We performed a retrospective analysis of cellular composition of lymphocyte collections, CAR T cell expansion and treatment outcomes of RRMM patients undergoing therapy with idecabtagene vicleucel (ide-cel) with and without history of allo-HSCT. 27 patients (11/27 female) with median age 63 (range 39-75) years were analyzed. Five patients (19%) had the history of allo-HSCT median of 5.5 years before ide-cel., Results: Prior to apheresis, the white blood cell, absolute lymphocyte counts, CD3+ cells and monocytes did not differ in patients with and without prior allo-HSCT. We also noticed no differences in the collected CD3+ yields or cellular compositions of lymphocyte collections. One year after ide-cel infusion, the progression-free survival and overall survival of patients with and without previous allo-HSCT did not differ with 60% and 45% respectively (P = .58) and 66.7% and 74% respectively (P = .84). The highest expansion of CAR T was detected between day 7 after infusion and showed no difference regarding previous allo-HSCT (P = .71). No graft-versus-host disease during the follow-up was detected., Conclusion: Our data confirm that the treatment with ide-cel is feasible for patients with prior allo-HSCT. Furthermore, allo-HSCT did not influence cellular composition of lymphocyte collections, clinical outcome or in vivo expansion of ide-cel., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

This manuscript describes the Advanced Breast Cancer (ABC) international consensus guidelines updated at the last two ABC international consensus conferences (ABC 6 in 2021, virtual, and ABC 7 in 2023, in Lisbon, Portugal), organized by the ABC Global Alliance. It provides the main recommendations on how to best manage patients with advanced breast cancer (inoperable locally advanced or metastatic), of all breast cancer subtypes, as well as palliative and supportive care. These guidelines are based on available evidence or on expert opinion when a higher level of evidence is lacking. Each guideline is accompanied by the level of evidence (LoE), grade of recommendation (GoR) and percentage of consensus reached at the consensus conferences. Updated diagnostic and treatment algorithms are also provided. The guidelines represent the best management options for patients living with ABC globally, assuming accessibility to all available therapies. Their adaptation (i.e. resource-stratified guidelines) is often needed in settings where access to care is limited., Competing Interests: Declaration of competing interest Matti S. Aapro: Consultant for Accord Pharmaceuticals, Amgen, BMS, Celgene, Clinigen Group, Daiichi Sankyo, Eisai Co.Ltd, Eli Lilly, Genomic Health (Exact Sciences), G1 Therapeutics, Inc., GlaxoSmithKline (GSK), Helsinn Healthcare SA, Hospira (Pfizer), Johnson & Johnson, Merck, Merck Serono (Merck KGaA), Mundipharma International Limited, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz, Tesaro (GSK), Teva Pharmaceuticals Industries Ltd., Vifor Pharma. Received honoraria for lectures at symposia of Accord Pharmaceuticals, Amgen, Astellas, Bayer HealthCare Pharmaceuticals (Schering), Biocon, Boeringer Ingelheim, Cephalon, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Dr Reddy's Laboratories, Genomic Health (Exact Sciences), Glenmark Pharmaceuticals Limited, GSK, Helsinn Healthcare SA, Hospira (Pfizer), Ipsen, Janssen Biotech, Kyowa Kirin Group, Merck, Merck Serono (Merck KGaA), Mundipharma International Limited, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz, Sanofi, Tesaro (GSK), Taiho Pharmaceutical, Teva Pharmaceutical Industries Ltd., Vifor Pharma. Grant/Research supports: Amgen, Eisai, Genomic Health (Exact Sciences), Helsinn, Hospira, Novartis, Merck, Mundipharma, Pfizer, Roche, Sandoz, Tesaro, Teva, Vifor. Jyoti Bajpai: Institutional financial interests for conducting research: Eli Lilly, MSD, Novartis, Roche, Paxman Coolers Ltd, Samsung Bioepis co. Ltd, Sun Pharma. Carlos H. Barrios: Receipt of grants/research supports: (to the institution) Nektar, Pfizer, Polyphor, Amgen, Daiichi Sankyo, Sanofi, Exelixis, Regeneron, Novartis, GSK, Janssen, OBI Pharma, Lilly, Seagen, Roche, BMS, MSD, Merck Serono, AstraZeneca, Novocure, Aveo Oncology, Takeda, TRIO, PharmaMar, Celgene, PPD, Syneos Health, Labcorp, ICON, IQVIA, Parexel, Nuvisan, PSI, Worldwide, Gilead Sciences, Bayer, Servier. Receipt of honoraria or consultation fees: Advisory Boards and Consulting: Boehringer-Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, Bayer, MSD, AstraZeneca, Zodiac, Lilly, Sanofi, Daiichi. Stock shareholder: Ownership or stocks: Tummi, MEDSir. Jonas Bergh: Receipt of grants/research supports: Research grants from Amgen, AstraZeneca, Bayer, Merck, Pfizer, Roche & Sanofi-Aventis to Karolinska Institutet and/or University Hospital. No personal payments. Other support: Payment for a chapter in UpToDate on breast cancer prediction to Asklepios Medicin HB. Laura Biganzoli: Personal financial interests (Honoraria, consultancy or advisory role): Amgen, AstraZeneca, Boehringer-Ingelheim, Daiichi-Sankyo, Eisai, Exact Sciences, Gilead, Lilly, Menarini, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, SeaGen. Institutional financial interests: Celgene, Genomic Health, Novartis. Travel grants: AstraZeneca, Daiichi-Sankyo. Fatima Cardoso: Receipt of honoraria or consultation fees: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, Gilead, GlaxoSmithKline, Iqvia, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva, Touchime. Maria-Joao Cardoso: Receipt of honoraria or consultation fees: AstraZeneca, Merck-Sharp, Novartis and Roche. Lisa A. Carey: Other support: Research funding (institution): NanoString Technologies, Seagen, Veracyte, AstraZeneca. Uncompensated relationships: Lilly, Seagen, Novartis, Genentech/Roche, GlaxoSmithKline. Mariana Chavez-MacGregor: Receipt of grants/research supports: BCRF, Susan G Komen. Receipt of honoraria or consultation fees: Astra Zeneca, Pfizer, Lilly, Roche, Merck. Javier Cortés: Receipt of grants/research supports: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Expres2ion Biotechnologies. Receipt of honoraria or consultation fees: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo, Astrazeneca. Stock shareholder: MedSIR, Nektar Pharmaceuticals, Leuko (relative). Other support: Research funding to the Institution: Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London. Travel, accommodation, expenses: Roche, Novartis, Eisai, pfizer, Daiichi Sankyo, Astrazeneca, Gilead. Patents: Pharmaceutical Combinations of a Pi3k Inhibitor and A Microtubule Destabilizing Agent. Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A. ISSUED. Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Aleix Prat, Antonio Llombart, Javier Cortés.US 2019/0338368 A1. LICENSED. Giuseppe Curigliano: Receipt of grants/research supports: Merck. Receipt of honoraria or consultation fees: Merck, Lilly, Pfizer, Daichi Sankyo, Seagen, Novartis, Roche, Astra Zeneca, Ellipsis. Participation in a sponsored speakers' bureau: Seagen, Novartis, Lilly, Pfizer, Daichii Sankyo. Rebecca A. Dent: Receipt of grants/research supports: AstraZeneca, Roche. Receipt of honoraria or consultation fees: AstraZeneca, DKSH, Eisai, Merck, Novartis, Pfizer, Roche. Nagi S. El Saghir: Receipt of honoraria or consultation fees: Roche, Novartis, Lilly. Alexandru Eniu: Receipt of honoraria or consultation fees: Astra Zeneca, Daiichi Sankyo, Gilead, Janssen, MSD, Novartis, SeaGen. Receipt of grants/research supports: AstraZeneca. Full or part-time employment: European School of Oncology (ESO). Lesley Fallowfield: Receipt of grants/research supports: Novartis, Bristol-Myers Squibb, Lilly. Receipt of honoraria or consultation fees: Voluntis, Genomic Health, NanoString Technologies, Novartis, Pfizer, MSD, Novartis, Abbvie, Clovis Oncology, Puma Biotechnology, AstraZeneca, Takeda, Genomic Health/Exact Sciences, Lilly, Seagen, Roche. Sandra X. Franco Millan: Receipt of honoraria or consultation fees: Novartis, Pfizer, Eli Lilly. Participation in a sponsored speakers' bureau: Novartis, Pfizer, Eli Lilly. Karen Gelmon: Receipt of grants/research supports: Pfizer, AstraZeneca. Receipt of honoraria or consultation fees: Pfizer, Lilly, Novartis, AstraZeneca, Merck, Gilead, Seagen. Jenny Gilchrist: Receipt of honoraria or consultation fees: Eli-Lilly, AstraZeneca, Novartis, Pfizer, MSD, Gilead, Juniper Biologics. Joseph Gligorov: Receipt of grants/research supports: Eisai, Exact Science, Guardant, Roche Genentech. Receipt of honoraria or consultation fees: Astra Zeneca, Daiichi, Eisai, Evapharma, Exact Science, Gilead, Guardant Lilly, Merck, Novartis, Onxeo, Pfizer, Roche Genentech, Seattle Genetics. Participation in a sponsored speakers' bureau: Eisai, Eva Pharm, Novartis, Roche Genentech, Seattle Genetics. Other support (please specify): Institutional: Institut Universitaire de Cancérologie AP-HP Sorbonne Université; French breast cancer guidelines St Paul. Nadia Harbeck: Receipt of grants/research supports: all to institution. Receipt of honoraria or consultation fees: AstraZeneca, Daiichi-Sankyo, Gilead, Lilly, MSD, Novartis, PierreFabre, Pfizer, Roche, Sandoz, Seagen, Viatris, Zuelligpharma. Participation on a sponsored speakers' bureau: EPG Communication, MEDSCAPE, Springer. Stock shareholder: WSG minority ownership. Spouse/Partner: Consulting for WSG. Ranjit Kaur: Receipt of grants/research supports: Novartis, Roche, Pfizer, Astrazeneca. Receipt of honoraria or consultation fees: Novartis, Roche, Pfizer, Astrazeneca. Participation in a sponsored speakers' bureau: Novartis, Roche, Pfizer, Astrazeneca. Belinda Kiely: Receipt of honoraria or consultation fees: Speakers fees: Novartis, Eisai. Advisory boards: Roche, Gilead, Novartis. Other support (please specify): meeting registrations fees: Novartis, Pfizer, MSD. Sung-Bae Kim: Receipt of grants/research supports: Novartis, Sanofi-Aventis, and DongKook Pharm Co. Receipt of honoraria or consultation fees: Novartis, AstraZeneca, Lilly, Dae Hwa Pharmaceutical Co. Ltd, ISU Abxis, OBI pharma, Beigene and Daiichi-Sankyo. Stock shareholder: Genopeaks. Smruti Koppikar: Receipt of honoraria or consultation fees: Eli Lilly, Novartis, Cipla, Roche. Participation in a sponsored speakers' bureau: Eli Lilly, Novartis, Cipla, Roche. Marion Kuper-Hommel: Receipt of honoraria or consulting fees: Astra Zeneca. Ginny Mason: Participation in a sponsored speakers' bureau: Novartis. Volkmar Mueller: Receipt of grants/research supports: Institutional research support from Novartis, Roche, Seagen, Genentech, Astra Zeneca. Receipt of honoraria or consultation fees: Speaker honoraria: Astra Zeneca, Daiichi-Sankyo, Eisai, GSK, Pfizer, MSD, Medac, Novartis, Roche, Seagen, Onkowissen, high5 Oncology, Medscape, Gilead, Pierre Fabre. Consultancy honoraria from Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, DaiichiSankyo, Eisai, Lilly, Sanofi, Seagen, Gilead, Stemline, ClinSol. Other support (please specify): Travel grants: Roche, Pfizer, Daiichi Sankyo, Gilead. Claire Myerson: Receipt of honoraria or consultation fees: Novartis Pharma. Silvia Neciosup: Receipt of grants/research supports: Roche, Pfizer. Participation in a sponsored speakers' bureau: Tecnofarma, AZ, Roche, Pfizer. Larry Norton: Receipt of honoraria or consultation fees: Blackrock QLS Advisors, Cold Spring Harbor Laboratory, UNC Breast Spore EAB Meeting, Codagenix Scientific Advisory Board Meeting, Martell Diagnostic Laboratories, Inc., Celgene, Agenus, Immix Biopharma, Inc. Shinji Ohno: Participation in a sponsored speakers' bureau: Chugai, Lilly, MSD, Nippon Kayaku. Shani Paluch-Shimon: Receipt of grants/research supports: Pfizer. Receipt of honoraria or consultation fees: Pfizer, Lily, Novartis, Astra Zeneca, Roche, MSD, Gilead, Rhenium/Exact Sciences, Stemline, Daichi Sankyo. Participation in a sponsored speakers' bureau: Pfizer, Lily, Novartis, Astra Zeneca, Roche, MSD, Gilead. Ann H. Partridge: Uptodate Royalties. Aleix Prat: Receipt of grants/research supports: Boehringer, Novartis, Roche, Nanostring, Sysmex Europa GmbH, Medica Scientia inno. Research, SL, Celgene, Astellas and Pzifer. Receipt of honoraria or consultation fees: Roche, Pfizer, Novartis, Amgen, BMS, Puma, Oncolytics Biotech, MSD, Guardan Health, Peptomyc and Lilly, Nanostring Technologies and Daiichi Sankyo. Other support: Clinical trials: Boehringer, Lilly, Roche, Novartis, Amgen and Daiichi Sankyo. Hope S. Rugo: Receipt of grants/research supports: Astellas Pharma Inc.; AstraZeneca; Daiichi Sankyo, Inc.; F. Hoffmann-La Roche AG/Genentech, Inc.; Gilead Sciences, Inc.; GlaxoSmithKline; Lilly; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; Pfizer; Pionyr Immunotherapeutics; Sermonix Pharmaceuticals Inc.; Taiho Oncology, Inc. and Veru Inc. Receipt of honoraria or consultation fees: Puma, NAPO, Blueprint, and Scorpion Therapeutics Daichi Sankyo. Elzbieta Senkus: Receipt of honoraria or consultation fees: AstraZeneca, Curio Science, Egis, Eli Lilly, Gilead, high5md, MSD, Novartis, Pfizer, Roche, Swixx. Other support: travel support: AstraZeneca, Egis, Gilead, Novartis, Roche. Contracted research: Amgen, AstraZeneca, Eli Lilly, Gilead, Novartis, OBI Pharma, Roche, Samsung, Seagen. Medical writing: AstraZeneca, Eli Lilly. Royalties: Springer. Sandra M. Swain: Receipt of grants/research supports: Kailos Genetics, Genentech/Roche. Receipt of honoraria or consultation fees: Athenex, AstraZeneca, Biotheranostics, Natera, Exact Sciences, Lilly, Merck, Genentech/Roche, Sanofi, Daiichi Sankyo, Molecular Templates, Napo Pharmaceuticals. Stock shareholder: SEAGEN. Other support: CO- PI of INAVO 122 Genentech/Roche with in-kind travel to investigator meetings, Travel related expenses in kind Sanofi and Daiichi Sankyo. Peter Vuylsteke: Receipt of grants/research supports: UICC grant. Receipt of honoraria or consultation fees: Roche, Novartis and MSD. Theresa Wiseman: Receipt of grants/research supports: Receiver of SPCC Pfizer grant. Binghe Xu: Receipt of grants/research supports: sponsored research to my institution from Roche, AstraZeneca and Pfizer. Receipt of honoraria or consultation fees: advisory or consultancy fees from Novartis and Roche. Participation in a sponsored speakers' bureau: speakers’ bureau fees from AstraZeneca, Pfizer, Roche, Eisai. Elizabeth Bergsten-Nordström, Alberto Costa, Runcie C. W. Chidebe, Prudence A. Francis, Xichun Hu, Renate Haidinger, Leonor Matos, Shirley A. Mertz, Birgitte V. Offersen, Olivia Pagani, Eva Schumacher-Wulf, Daniel A. Vorobiof, Frédéric E. Lecouvet, and Eric P. Winer reported no significant relationships. William J. Gradishar, George W. Sledge and Christoph Thomssen have not submitted a disclosure of interests’ form., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Polychlorinated biphenyls (PCBs), extensively used in various products, prompt ongoing concern despite reduced exposure since the 1970s. This systematic review explores prenatal PCB and hydroxylated metabolites (OH-PCBs) exposure's association with child neurodevelopment. Encompassing cognitive, motor development, behavior, attention, ADHD, and ASD risks, it also evaluates diverse methodological approaches in studies., Methods: PubMed, Embase, PsycINFO, and Web of Science databases were searched through August 23, 2023, by predefined search strings. Peer-reviewed studies published in English were included. The inclusion criteria were: (i) PCBs/OH-PCBs measured directly in maternal and cord blood, placenta or breast milk collected in the perinatal period; (ii) outcomes of cognitive development, motor development, attention, behavior, attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD) among children≤18 years old. Quality assessment followed the National Heart, Lung, and Blood Institute's tool., Results: Overall, 87 studies were included in this review. We found evidence for the association between perinatal PCB exposure and adverse cognitive development and attention issues in middle childhood. There appeared to be no or negligible link between perinatal PCB exposure and early childhood motor development or the risk of ADHD/ASD. There was an indication of a sex-specific association with worse cognition and attention scores among boys. Some individual studies suggested a possible association between prenatal exposure to OH-PCBs and neurodevelopmental outcomes. There was significant heterogeneity between the studies in exposure markers, exposure assessment timing, outcome assessment, and statistical analysis., Conclusions: Significant methodological, clinical and statistical heterogeneity existed in the included studies. Adverse effects on cognitive development and attention were observed in middle childhood. Little or no apparent link on both motor development and risk of ADHD/ASD was observed in early childhood. Inconclusive evidence prevailed regarding other neurodevelopmental aspects due to limited studies. Future research could further explore sex-specific associations and evaluate associations at lower exposure levels post-PCB ban in the US. It should also consider OH-PCB metabolites, co-pollutants, mixtures, and their potential interactions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Several fungi belonging to the genus Psilocybe, also called "magic mushrooms", contain the hallucinogenic drugs psilocybin and psilocin. They are chemically related to serotonin (5-HT). In addition to being abused as drugs, they are now also being discussed or used as a treatment option for depression. Here, we hypothesized that psilocybin and psilocin may act also on cardiac serotonin receptors and studied them in vitro in atrial preparations of our transgenic mouse model with cardiac myocytes-specific overexpression of the human 5-HT 4 receptor (5-HT 4 -TG) as well as in human atrial preparations. Both psilocybin and psilocin enhanced the force of contraction in isolated left atrial preparations from 5-HT 4 -TG, increased the beating rate in isolated spontaneously beating right atrial preparations from 5-HT 4 -TG and augmented the force of contraction in the human atrial preparations. The inotropic and chronotropic effects of psilocybin and psilocin at 10 µM were smaller than that of 1 µM 5-HT on the left and right atria from 5-HT 4 -TG, respectively. Psilocybin and psilocin were inactive in WT. In the human atrial preparations, inhibition of the phosphodiesterase III by cilostamide was necessary to unmask the positive inotropic effects of psilocybin or psilocin. The effects of 10 µM psilocybin and psilocin were abrogated by 10 µM tropisetron or by 1 µM GR125487, a more selective 5-HT 4 receptor antagonist. In summary, we demonstrated that psilocin and psilocybin act as agonists on cardiac 5-HT 4 receptors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: In winter of 2022/2023 SARS-CoV-2 had developed into one of many seasonal respiratory pathogens, causing an additional burden of acute respiratory infections (ARIs). Although testing was still widely used, many positive tests were not reported for the official statistics. Using data from a population-based cohort, we aimed to investigate the contribution of SARS-CoV-2 to the burden of ARI., Methods: Over 70,000 participants of the German population-based DigiHero study were invited to a questionnaire about the number and time point of ARI and SARS-CoV-2 test results in winter 2022/2023. We calculated the incidence of non-severe acute respiratory syndrome (SARS) ARI, the additional contribution of SARS-CoV-2, and extrapolated the age-specific estimates to obtain the total burden of SARS-CoV-2 in Germany., Results: For the winter of 2022/2023, 37,708 participants reported 54,813 ARIs, including 9358 SARS-CoV-2 infections. This translated into a cumulative incidence of 145 infections/100 persons for all ARIs, 120 infections/100 persons for non-SARS ARI, and 25 infections/100 persons for SARS ARI (+21%)., Conclusions: Our estimate for ARI related to SARS-CoV-2 is consistent with the difference in all ARI between pre-pandemic years and 2022/2023. This additional burden should be considered, particularly, with respect to the implications for the work force., Competing Interests: Declarations of competing interest The authors have no competing interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Mitochondrial DNA (mtDNA) deletions which clonally expand in skeletal muscle of patients with mtDNA maintenance disorders, impair mitochondrial oxidative phosphorylation dysfunction. Previously we have shown that these mtDNA deletions arise and accumulate in perinuclear mitochondria causing localised mitochondrial dysfunction before spreading through the muscle fibre. We believe that mito-nuclear signalling is a key contributor in the accumulation and spread of mtDNA deletions, and that knowledge of how muscle fibres respond to mitochondrial dysfunction is key to our understanding of disease mechanisms. To understand the contribution of mito-nuclear signalling to the spread of mitochondrial dysfunction, we use imaging mass cytometry. We characterise the levels of mitochondrial Oxidative Phosphorylation proteins alongside a mitochondrial mass marker, in a cohort of patients with mtDNA maintenance disorders. Our expanded panel included protein markers of key signalling pathways, allowing us to investigate cellular responses to different combinations of oxidative phosphorylation dysfunction and ragged red fibres. We find combined Complex I and IV deficiency to be most common. Interestingly, in fibres deficient for one or more complexes, the remaining complexes are often upregulated beyond the increase of mitochondrial mass typically observed in ragged red fibres. We further find that oxidative phosphorylation deficient fibres exhibit an increase in the abundance of proteins involved in proteostasis, e.g. HSP60 and LONP1, and regulation of mitochondrial metabolism (including oxidative phosphorylation and proteolysis, e.g. PHB1). Our analysis suggests that the cellular response to mitochondrial dysfunction changes depending on the combination of deficient oxidative phosphorylation complexes in each fibre., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Michael F. Marusich declares receipt of licensing revenues from Abcam and EMD/Millipore on sales of anti-mtDNA-encoded protein antibodies. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Oral squamous cell carcinoma (OSCC) is the most frequent type of cancer of the head and neck area accounting for approx. 377,000 new cancer cases every year. The epithelial-to-mesenchymal transition (EMT) program plays an important role in OSCC progression and metastasis therefore contributing to a poor prognosis in patients with advanced disease. Transforming growth factor beta (TGF-ß) is a powerful inducer of EMT thereby increasing cancer cell aggressiveness. Here, we aimed at identifying RNA-binding proteins (RBPs) that affect TGF-ß-induced EMT. To this end we treated oral cancer cells with TGF-ß and identified a total of 643 significantly deregulated protein-coding genes in response to TGF-ß. Of note, 19 genes encoded RBPs with NANOS1 being the most downregulated RBP. Subsequent cellular studies demonstrated a strong inhibitory effect of NANOS1 on migration and invasion of SAS oral cancer cells. Further mechanistic studies revealed an interaction of NANOS1 with the TGF-ß receptor 1 (TGFBR1) mRNA, leading to increased decay of this transcript and a reduced TGFBR1 protein expression, thereby preventing downstream TGF-ß/SMAD signaling. In summary, we identified NANOS1 as negative regulator of TGF-ß signaling in oral cancer cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

This investigation delves into the inhibitory capabilities of a specific set of triterpenoic acids on diverse isoforms of human carbonic anhydrase (hCA). Oleanolic acid (1), maslinic acid (2), betulinic acid (3), platanic acid (4), and asiatic acid (5) were chosen as representative triterpenoids for evaluation. The synthesis involved acetylation of parent triterpenoic acids 1-5, followed by sequential reactions with oxalyl chloride and benzylamine, de-acetylation of the amides, and subsequent treatment with sodium hydride and sulfamoyl chloride, leading to the formation of final compounds 21-25. Inhibition assays against hCAs I, II, VA, and IX demonstrated noteworthy outcomes. A derivative of betulinic acid, compound 23, exhibited a K i value of 88.1 nM for hCA VA, and a derivative of asiatic acid, compound 25, displayed an even lower K i value of 36.2 nM for the same isoform. Notably, the latter compound displayed enhanced inhibitory activity against hCA VA when compared to the benchmark compound acetazolamide (AAZ), which had a K i value of 63.0 nM. Thus, this compound surpasses the inhibitory potency and isoform selectivity of the standard compound acetazolamide (AAZ). In conclusion, the research offers insights into the inhibitory potential of selected triterpenoic acids across diverse hCA isoforms, emphasizing the pivotal role of structural attributes in determining isoform-specific inhibitory activity. The identification of compound 25 as a robust and selective hCA VA inhibitor prompts further exploration of its therapeutic applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Kombucha is prepared by fermenting sugared green or black tea with a symbiotic culture of bacteria and yeast (SCOBY). Some of the bacteria within the SCOBY are known to form exopolysaccharides (EPS) from sucrose. However, it is yet unknown whether water-soluble EPS are formed in kombucha, and if so, which specific EPS are present. Therefore, different kombucha samples were prepared by fermentation of green and black tea with SCOBYs from different manufacturers. Subsequently, the EPS were isolated and characterized by using various chromatographic methods, partial enzymatic hydrolyses and NMR spectroscopy. It was demonstrated that levans with a varying degree of branching at position O1 (4.3-7.9 %) are present, while only trace amounts of glucans were detected. Furthermore, levans isolated from kombucha had a comparably low molecular weight and the content of levan within the kombucha samples varied from 33 to 562 mg levan/L kombucha. Therefore, our study demonstrated that levans are the main EPS type in kombucha and that levan amounts and structures varied when different starter cultures and ingredients were used. Furthermore, we provide a comprehensive data set on the structural variability of levans from kombucha., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Impaired polarization of M1 to M2 macrophages has been reported in diabetic wounds. We aimed to improve this polarization by down-regulation of expression of the "Suppressor of Cytokine Signaling 3" (SOCS3) gene in macrophages. Two oligodeoxynucleotide (ASO) sequences were designed against SOC3 mRNA and were loaded to mannosylated-polyethyleneimine (Man-PEI). The optimum N/P ratio for Man-PEI-ASO was determined to be 8 based on loading efficiency, particle size, zeta potential, cellular uptake and cytotoxicity assay. pH stability of ASO in Man-PEI-ASO and its protection from DNase I was confirmed. After in vitro treatment of macrophages with Man-PEI-ASO, SOCS3 was downregulated, SOCS1 upregulated, and SOCS1/SOCS3 ratio increased. Also, expressions of macrophage markers of M2 (IL-10, Arg1, CD206) increased and those of M1 (IL-1β, NOS2, CD68) decreased, and secretion of pro-inflammatory cytokines (TNF-α and IL-1β) decreased while that of anti-inflammatory cytokine IL-4 increased. All suggested a polarization into M2 phenotype. Finally, the Man-PEI-ASO was loaded in hydrogel and applied to a diabetic wound model in mice. It improved the healing to the level observed in non-diabetic wounds. We show that using antisense sequences against SOC3 mRNA, macrophage polarization could be directed into the M2 phenotype and healing of diabetic wound could be highly improved., Competing Interests: Declaration of competing interest Samadikuchaksaraei and Amoupour are inventors and owners of a patent related to this project, which has been filed in the Iranian Intellectual Property Office, but has not been licensed yet. Samadikuchaksaraei is shareholder and CEO of Baztarmim Company, which is mainly focused on production of tissue engineering products. Other authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: The aim of this study was to systematically review and analyze differences in the levels of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) comparing metabolically healthy but obese (MHO) with metabolically healthy non-obese (MHNO), metabolically unhealthy non-obese (MUNO), and metabolically unhealthy obese (MUO) subjects., Data Synthesis: We searched PubMed, Embase, Web of Science, and Scopus for studies that matched the relevant search terms. Differences in inflammatory marker levels between MHO and the other three phenotypes were pooled as standardized mean differences (SMD) or differences of medians (DM) using a random-effects model. We included 91 studies reporting data on 435,007 individuals. The CRP levels were higher in MHO than in MHNO subjects (SMD = 0.63, 95% CI: 0.49, 0.76; DM = 0.83 mg/L, 95% CI: 0.56, 1.11). The CRP levels were higher in MHO than in MUNO subjects (SMD = 0.16, 95% CI: 0.05, 0.28; DM = 0.39 mg/L, 95% CI: 0.09, 0.69). The CRP levels were lower in MHO than in MUO individuals (SMD = -0.43, 95% CI: -0.54, -0.31; DM = -0.82 mg/L, 95% CI: -1.16, -0.48). The IL-6 levels in MHO were higher than in MHNO while lower than in MUO subjects. The TNF-α levels in MHO were higher than in MHNO individuals., Conclusions: This review provides evidence that CRP levels in MHO are higher than in MHNO and MUNO subjects but lower than in MUO individuals. Additionally, IL-6 levels in MHO are higher than in MHNO but lower than in MUO subjects, and TNF-α levels in MHO are higher than in MHNO individuals., Systematic Review Registration: PROSPERO number: CRD42021234948., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Pentameric FocA permeates either formate or formic acid bidirectionally across the cytoplasmic membrane of anaerobically growing Escherichia coli. Each protomer of FocA has its own hydrophobic pore, but it is unclear whether formate or neutral formic acid is translocated in vivo. Here, we measured total and dicyclohexylcarbodiimide (DCCD)-inhibited proton flux out of resting, fermentatively grown, stationary-phase E. coli cells in dependence on FocA. Using a wild-type strain synthesizing native FocA, it was shown that using glucose as a source of formate, DCCD-independent proton efflux was ∼2.5 mmol min -1 , while a mutant lacking FocA showed only DCCD-inhibited, F O F 1 -ATPase-dependent proton-efflux. A strain synthesizing a chromosomally-encoded FocA H209N variant that functions exclusively to translocate formic acid out of the cell, showed a further 20 % increase in FocA-dependent proton efflux relative to the parental strain. Cells synthesizing a FocA T91A variant, which is unable to translocate formic acid out of the cell, showed only DCCD-inhibited proton efflux. When exogenous formate was added, formic acid uptake was shown to be both FocA- and proton motive force-dependent. By measuring rates of H 2 production, potassium ion flux and ATPase activity, these data support a role for coupling between formate, proton and K + ion translocation in maintaining pH and ion gradient homeostasis during fermentation. FocA thus plays a key role in maintaining this homeostatic balance in fermenting cells by bidirectionally translocating formic acid., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interest None declared.

Rice accumulates arsenic (As) when cultivated under flooded conditions in paddy soils threatening rice yield or its safety for human consumption, depending on As speciation. During long-term paddy use, repeated redox cycles systematically alter soil biogeochemistry and microbiology. In the present study, incubation experiments from a 2000-year-old paddy soil chronosequence revealed that As mobilization and speciation also change with paddy soil age. Younger paddies (≤100 years) showed the highest total As mobilization, with speciation dominated by carcinogenic inorganic oxyarsenic species and highly mobile inorganic thioarsenates. Inorganic thioarsenates formed by a high availability of reduced sulfur (S) due to low concentrations of reducible iron (Fe) and soil organic carbon (SOC). Long-term paddy use (>100 years) resulted in higher microbial activity and SOC, increasing the share of phytotoxic methylated As. Methylated oxyarsenic species are precursors for cytotoxic methylated thioarsenates. Methylated thioarsenates formed in soils of all ages being limited either by the availability of methylated As in young soils or that of reduced-S in older ones. The present study shows that via a linkage of As to the biogeochemistry of Fe, S, and C, paddy soil age can influence the kind and the extent of threat that As poses for rice cultivation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jose M. Leon Ninin reports financial support was provided by the German Academic Scholarship Foundation. Britta Planer-Friedrich reports financial support was provided by the Federal Ministry of Education and Research., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Arsenic is a ubiquitous environmental toxi substance that affects human health. Compared to inorganic arsenicals, reduced organoarsenicals are more toxic, and some of them are recognized as antibiotics, such as methylarsenite [MAs(III)] and arsinothricin (2-amino-4-(hydroxymethylarsinoyl)butanoate, or AST). To date, organoarsenicals such as MAs(V) and roxarsone [Rox(V)] are still used in agriculture and animal husbandry. How bacteria deal with both inorganic and organoarsenic species is unclear. Recently, we identified an environmental isolate Mucilaginibacter rubeus P2 that has adapted to high arsenic and antinomy levels by triplicating an arsR-mrarsU Bact -arsN-arsC-(arsRhp)-hp-acr3-mrme1 Bact -mrme2 Bact gene cluster. Heterologous expression of mrarsM Bact , mrarsU Bact , mrme1 Bact and mrme2 Bact , encoding putative arsenic resistance determinants, in the arsenic hypersensitive strain Escherichia coli AW3110 conferred resistance to As(III), As(V), MAs(III) or Rox(III). Our data suggest that metalloid exposure promotes plasticity in arsenic resistance systems, enhancing host organism adaptation to metalloid stress., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In agriculture, overfertilization with liquid organic manures (LOM) is causing environmental issues including eutrophication of non-agricultural ecosystems and nitrate pollution of groundwater. To avoid such problems, a precise and demand-oriented fertilization with LOM is needed. This can only be achieved if the nutrient composition of the LOM is known. However, traditional chemical analysis is cost- and time-intensive and furthermore dependent on a representative sample. Optical spectrometry in the visible and near-infrared range could provide an efficient alternative, if a chemometric calibration assures sufficient accuracy. To improve chemometric calibration, this study investigated several spectral preprocessing and regression algorithms, and compared predictions based either on dry or wet weight concentration. In addition, the capability of low-cost spectrometers was evaluated by simulating low-resolution spectra with smaller wavelength ranges. The reflectance spectra of 391 pig manure, 155 cattle manure, and 89 biogas digestate samples were used to predict plant macronutrients (N, P, K, Mg, Ca, S), micronutrients (Mn, Fe, Cu, Zn, B), dry matter (DM) and pH. The experiments demonstrate the general aptness of optical spectrometry to accurately predict DM, pH and all nutrients except boron in pig, cattle, and digestate LOM, even with simulated low-cost spectrometers. Best results show r 2 between 0.80 and 0.97, ratios of performance to interquartile distance (RPIQ) between 2.1 and 7.8, and mean absolute errors normalized by the median (nMAE) between 5 and 36 %. The regression methods PLSR, LASSO, and least angle regression predominantly performed best. The innovative preprocessing methods named simple ratios (SR) and normalized differences (ND) proved to be very useful algorithms, especially for N and P predictions, outperforming the accuracy of classical techniques in several cases. Concentrations on dry weight basis improved predictions of K, Mn, and pH., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Many plant traits covary with environmental gradients, reflecting shifts in adaptive strategies and thus informing about potential consequences of future environmental change for vegetation and ecosystem functioning. Yet, the evidence of trait-environment relationships (TERs) remains too heterogeneous for reliable predictions, partially due to insufficient consideration of trait syndromes specific to certain growth forms and habitats. Moreover, it is still unclear whether non-native and native plants' traits align similarly along environmental gradients, limiting our ability to assess the impacts of future plant invasions. Using a Bayesian multilevel modelling framework, we assess TERs for native and non-native woody and herbaceous plants across six broad habitat types in Central Europe at a resolution of c. 130 km 2 and use them to project trait change under future environmental change scenarios until 2081-2100. We model TERs between three key plant traits (maximum height, H max ; specific leaf area, SLA; seed mass, SM) and individual environmental factors (7 climate variables and % urban land cover) and estimate trait change summed across all environmental effects. We also quantify the change in the average trait difference between native and non-native plants. Our models depict multiple TERs, with important differences attributed to biogeographical status and woodiness within and across habitat types. The overall magnitude of trait change is projected to be greater for non-native than native taxa and to increase under more extreme scenarios. Native woody plant assemblages may generally experience a future increase across all three traits, whereas woody non-natives may decline in H max and increase in SLA and SM. Herbaceous H max is estimated to increase and SLA to decrease in most habitats. The obtained trait projections highlight conditions of competitive advantage of non-native plants over natives and vice versa and can serve as starting points for projecting future changes in ecosystem functions and services., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In recent decades, nanopores have become a promising diagnostic tool. Protein and solid-state nanopores are increasingly used for both RNA/DNA sequencing and small molecule detection. The latter is of great importance, as their detection is difficult or expensive using available methods such as HPLC or LC-MS. DNA aptamers are an excellent detection element for sensitive and specific detection of small molecules. Herein, a method for quantifying small molecules using a ready-to-use sequencing platform is described. Taking ethanolamine as an example, a strand displacement assay is developed in which the target-binding aptamer is displaced from the surface of magnetic particles by ethanolamine. Non-displaced aptamer and thus the ethanolamine concentration are detected by the nanopore system and can be quantified in the micromolar range using our in-house developed analysis software. This method is thus the first to describe a label-free approach for the detection of small molecules in a protein nanopore system., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Inc.)