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Ecosystem functioning depends on biodiversity at multiple trophic levels, yet relationships between multitrophic diversity and ecosystem multifunctionality have been poorly explored, with studies often focusing on individual trophic levels and functions and on specific ecosystem types. Here, we show that plant diversity can affect ecosystem functioning both directly and by affecting other trophic levels. Using data on 13 trophic groups and 13 ecosystem functions from two large biodiversity experiments-one representing temperate grasslands and the other subtropical forests-we found that plant diversity increases multifunctionality through elevated multitrophic diversity. Across both experiments, the association between multitrophic diversity and multifunctionality was stronger than the relationship between the diversity of individual trophic groups and multifunctionality. Our results also suggest that the role of multitrophic diversity is greater in forests than in grasslands. These findings imply that, to promote sustained ecosystem multifunctionality, conservation planning must consider the diversity of both plants and higher trophic levels., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background & Aims: Survodutide is a glucagon/glucagon-like peptide-1 receptor dual agonist in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). We investigated the pharmacokinetic and safety profile of survodutide in people with cirrhosis., Methods: This multinational, non-randomized, open-label, phase I clinical trial initially evaluated a single subcutaneous dose of survodutide 0.3 mg in people with Child-Pugh class A, B or C cirrhosis and healthy individuals with or without overweight/obesity matched for age, sex, and weight; the primary endpoints were the area under the plasma concentration-time curve from 0 to infinity (AUC 0-∞ ) and maximal plasma concentration (C max ). Subsequently, people with overweight/obesity with or without cirrhosis (Child-Pugh class A or B) received once-weekly subcutaneous doses escalated from 0.3 mg to 6.0 mg over 24 weeks then maintained for 4 weeks; the primary endpoint was drug-related treatment-emergent adverse events, with MASH/cirrhosis-related endpoints explored., Results: In the single-dose cohorts (n = 41), mean AUC 0-∞ and C max were similar in those with cirrhosis compared with healthy individuals (90% CIs for adjusted geometric mean ratios spanned 1). Drug-related adverse events occurred in 25.0% of healthy individuals and ≤25.0% of those with cirrhosis after single doses, and 82.4% and 87.5%, respectively, of the multiple-dose cohorts (n = 41) over 28 weeks. Liver fat content, liver stiffness, liver volume, body weight, and other hepatic and metabolic disease markers were generally reduced after 28 weeks of survodutide treatment., Conclusions: Survodutide is generally tolerable in people with compensated or decompensated cirrhosis, does not require pharmacokinetic-related dose adjustment, and may improve liver-related non-invasive tests, supporting its investigation for MASH-related cirrhosis., Impact and Implications: Survodutide is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH), which causes cirrhosis in ∼20% of cases. This trial delineates the pharmacokinetic and safety profile of survodutide in people with compensated or decompensated cirrhosis, and revealed associated reductions in liver fat content, markers of liver fibrosis and body weight. These findings have potential relevance for people with MASH-including those with decompensated cirrhosis, who are usually excluded from clinical trials of investigational drugs. Based on this study, further investigation of survodutide for MASH-related cirrhosis is warranted., Gov Identifier: NCT05296733., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Multispecies planting is an important approach to deliver ecosystem functions in afforestation projects. However, the importance of species richness vs specific species composition in this context remains unresolved. To estimate species or functional group richness and compositional change between two communities, we calculated nestedness, where one community contains a subset of the species of another, and turnover, where two communities differ in species composition but not in species richness. We evaluated the effects of species/functional group nestedness and turnover on stand productivity using 315 mixed plots from a pool of 40 tree species in a large forest biodiversity experiment in subtropical China. We found that the greater the differences in species or functional group nestedness and turnover, the greater the differences in stand productivity between plots. Additionally, the strong effects of both nestedness and turnover on stand productivity developed over the 11-yr observation period. Our results indicate that selection of specific tree species is as important as planting a large number of species to support the productivity function of forests. Furthermore, the selection of specific tree species should be based on functionality, because beneficial effects of functional group composition were stronger than those of species composition., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

The density of wood is a key indicator of the carbon investment strategies of trees, impacting productivity and carbon storage. Despite its importance, the global variation in wood density and its environmental controls remain poorly understood, preventing accurate predictions of global forest carbon stocks. Here we analyse information from 1.1 million forest inventory plots alongside wood density data from 10,703 tree species to create a spatially explicit understanding of the global wood density distribution and its drivers. Our findings reveal a pronounced latitudinal gradient, with wood in tropical forests being up to 30% denser than that in boreal forests. In both angiosperms and gymnosperms, hydrothermal conditions represented by annual mean temperature and soil moisture emerged as the primary factors influencing the variation in wood density globally. This indicates similar environmental filters and evolutionary adaptations among distinct plant groups, underscoring the essential role of abiotic factors in determining wood density in forest ecosystems. Additionally, our study highlights the prominent role of disturbance, such as human modification and fire risk, in influencing wood density at more local scales. Factoring in the spatial variation of wood density notably changes the estimates of forest carbon stocks, leading to differences of up to 21% within biomes. Therefore, our research contributes to a deeper understanding of terrestrial biomass distribution and how environmental changes and disturbances impact forest ecosystems., (© 2024. The Author(s).)

Genetically diverse populations can increase plant resistance to natural enemies. Yet, beneficial genotype pairs remain elusive due to the occurrence of positive or negative effects of mixed planting on plant resistance, respectively called associational resistance or susceptibility. Here, we identify key genotype pairs responsible for associational resistance to herbivory using the genome-wide polymorphism data of the plant species Arabidopsis thaliana. To quantify neighbor interactions among 199 genotypes grown in a randomized block design, we employ a genome-wide association method named "Neighbor GWAS" and genomic prediction inspired by the Ising model of magnetics. These analyses predict that 823 of the 19,701 candidate pairs can reduce herbivory in mixed planting. We planted three pairs with the predicted effects in mixtures and monocultures, and detected 18-30% reductions in herbivore damage in the mixed planting treatment. Our study shows the power of genomic prediction to assemble genotype mixtures with positive biodiversity effects., (© 2024. The Author(s).)

Aims: Pharmacotherapeutic options for obesity treatment include glucagon-like peptide-1 receptor (GLP-1R) agonists, for example, liraglutide. However, an unmet need remains, particularly in patients with a high body mass index (BMI), as GLP-1R agonists are associated with gastrointestinal adverse events (AEs) and some patients do not respond to treatment. Neuropeptide Y (NPY) and peptide YY bind G-protein-coupled Y receptors and represent attractive targets for modulating bodyweight., Materials and Methods: This first-in-human, three-part, partially blinded phase I study (NCT04903509) investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of the peptidic NPY2R agonist BI 1820237, with/without low-dose liraglutide: part 1 (participants randomized to receive BI 1820237: 0.075-2.4 mg or placebo), part 2 (BI 1820237: 1.2 mg or placebo) and part 3 (BI 1820237: 0.025-1.2 mg + liraglutide 0.6 mg or placebo + liraglutide 0.6 mg). Primary endpoint is the proportion of participants with drug-related AEs. Secondary endpoints are tolerability, PK and PD., Results: In total, 95 otherwise healthy men with increased BMI (25.0-34.9 kg/m 2 ) were randomized. Drug-related AEs, mainly gastrointestinal events, were reported by 39.0% of participants (n = 23) in parts 1 + 2 and 30.6% of participants (n = 11) in part 3; one drug-related AE (11.1%, part 3) was reported in a participant receiving placebo with liraglutide. Post-dose paracetamol PK suggested that BI 1820237 and low-dose liraglutide exhibited additive effects on gastric emptying., Conclusions: BI 1820237 treatment was associated with transient nausea and vomiting at higher doses. No differences in tolerability were observed when combined with liraglutide; effects on gastric emptying appeared additive., (© 2024 John Wiley & Sons Ltd.)

Introduction: Repair of thoracoabdominal aortic aneurysms (TAAAs) represents a technical challenge regardless of which technique is used. Open surgical repair (OSR) is the time-tested option against which novel techniques must be compared and it is still considered the gold standard option for younger, fit patients with heritable aortic diseases. Endovascular repair offers a less-invasive alternative in patients with suitable anatomy. This article aims to present a tabular review of the contemporary published data on endovascular repair of TAAAs using fenestrated-branched techniques., Evidence Acquisition: The published literature for single-center and multicenter studies evaluating the outcomes of FB-EVAR for TAAAs was searched using MEDLINE and Embase databases. Studies published between January 1 st 2010 and July 11 th 2024, in the English language which provided data on FB-EVAR of TAAAs with more than fifty reported cases were included., Evidence Synthesis: The average patient age at time of repair was 71 years old with majority of males (65.5%). Most patients presented with a Crawford Extent II TAAAs (21.6%), followed by Extent III (21.2%). Early mortality was 4.9% for the entire cohort. The most prevalent adverse event was acute kidney injury (9.4%), followed by spinal cord injury (8.0%)., Conclusions: FB-EVAR of TAAAs continues to evolve. Pooled analysis of early mortality and morbidity is lower in this tabular review than historical outcomes of open TAAA repair.

Acute lymphoblastic leukemia (ALL) is the most common type of malignancy in children. ALL prognosis after initial diagnosis is generally good; however, patients suffering from relapse have a poor outcome. The tumor microenvironment is recognized as an important contributor to relapse, yet the cell-cell interactions involved are complex and difficult to study in traditional experimental models. In the present study, we established an innovative larval zebrafish xenotransplantation model, that allows the analysis of leukemic cells (LCs) within an orthotopic niche using time-lapse microscopic and flow cytometric approaches. LCs homed, engrafted and proliferated within the hematopoietic niche at the time of transplant, the caudal hematopoietic tissue (CHT). A specific dissemination pattern of LCs within the CHT was recorded, as they extravasated over time and formed clusters close to the dorsal aorta. Interactions of LCs with macrophages and endothelial cells could be quantitatively characterized. This zebrafish model will allow the quantitative analysis of LCs in a functional and complex microenvironment, to study mechanisms of niche mediated leukemogenesis, leukemia maintenance and relapse development., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Arner et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Decades of studies have demonstrated links between biodiversity and ecosystem functioning, yet the generality of the relationships and the underlying mechanisms remain unclear, especially for forest ecosystems. Using 11 tree-diversity experiments, we tested tree species richness-community productivity relationships and the role of arbuscular (AM) or ectomycorrhizal (ECM) fungal-associated tree species in these relationships. Tree species richness had a positive effect on community productivity across experiments, modified by the diversity of tree mycorrhizal associations. In communities with both AM and ECM trees, species richness showed positive effects on community productivity, which could have resulted from complementarity between AM and ECM trees. Moreover, both AM and ECM trees were more productive in mixed communities with both AM and ECM trees than in communities assembled by their own mycorrhizal type of trees. In communities containing only ECM trees, species richness had a significant positive effect on productivity, whereas species richness did not show any significant effects on productivity in communities containing only AM trees. Our study provides novel explanations for variations in diversity-productivity relationships by suggesting that tree-mycorrhiza interactions can shape productivity in mixed-species forest ecosystems., (© 2024 The Authors. New Phytologist © 2024 New Phytologist Foundation.)

The birth of a premature infant and its subsequent hospitalization in the neonatal intensive care unit are stressful experiences for mothers. Because of uncertainty concerning interactions with a premature baby, mothers often feel helpless and only hesitantly assume their maternal role. This may have a negative impact on the mother-child interaction and prevents mothers from taking an active part in E46www.jpnnjournal.com the care for their child. "Creating Opportunities for Parent Empowerment" (COPE) is a 4-phase educational intervention program aiming to systematically involve parents into caring for their premature infant. In this pretest-posttest quasi-experimental study in 2 Swiss university hospitals, we focused on maternal self-efficacy. We compared self-efficacy in mothers receiving the COPE program or standard care alone at baseline and 3 months after estimated delivery date. To measure maternal self-efficacy, we used the "Tool to measure Parenting Self-Efficacy" (TOPSE). While scores for "Emotion and Affection," "Empathy and Understanding," as well as "Learning and Knowledge" increased in both groups, only "Learning and Knowledge" scores were significantly higher in the intervention group. Given the intention of improving learning and knowledge, the COPE program might be a promising intervention contributing to enhanced maternal self-efficacy., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Young children learn selectively from reliable over unreliable sources. However, the cognitive underpinnings of their selectivity (attentional biases or trait ascriptions) and its early ontogeny are unclear. Thus, across three studies (N = 139, monolingual German speakers, 67 female), selective-trust tasks were adapted to test both preschoolers (5-year-olds) and toddlers (24-month-olds), using eye-tracking and interactive measures. These data show that preschoolers' selectivity is not based on attentional biases, but on person-specific trait ascriptions. In contrast, toddlers showed no selective trust, even in the eye-tracking tasks. They succeeded, however, in eye-tracking tasks with the same word-learning demands, if no ascriptions of reliability were required. Thus, these findings suggest that preschoolers, but not toddlers, use trait-like ascriptions of reliability to guide their selective learning., (© 2024 The Authors. Child Development published by Wiley Periodicals LLC on behalf of Society for Research in Child Development.)

The decline in global plant diversity has raised concerns about its implications for carbon fixation and global greenhouse gas emissions (GGE), including carbon dioxide (CO 2 ), nitrous oxide (N 2 O) and methane (CH 4 ). Therefore, we conducted a comprehensive meta-analysis of 2103 paired observations, examining GGE, soil organic carbon (SOC) and plant carbon in plant mixtures and monocultures. Our findings indicate that plant mixtures decrease soil N 2 O emissions by 21.4% compared to monocultures. No significant differences occurred between mixtures and monocultures for soil CO 2 emissions, CH 4 emissions or CH 4 uptake. Plant mixtures exhibit higher SOC and plant carbon storage than monocultures. After 10 years of vegetation development, a 40% reduction in species richness decreases SOC content and plant carbon storage by 12.3% and 58.7% respectively. These findings offer insights into the intricate connections between plant diversity, soil and plant carbon storage and GGE-a critical but previously unexamined aspect of biodiversity-ecosystem functioning., (© 2024 John Wiley & Sons Ltd.)

The global biodiversity crisis has stimulated decades of research on three themes: species coexistence, biodiversity-ecosystem functioning relationships (BEF), and biodiversity-ecosystem functional stability relationships (BEFS). However, studies on these themes are largely independent, creating barriers to an integrative understanding of the causes and consequences of biodiversity. Here we review recent progress towards mechanistic integration of coexistence, BEF, and BEFS. Mechanisms underlying the three themes can be linked in various ways, potentially creating either positive or negative relationships between them. That said, we generally expect positive associations between coexistence and BEF, and between BEF and BEFS. Our synthesis represents an initial step towards integrating causes and consequences of biodiversity; future developments should include more mechanistic approaches and broader ecological contexts., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Global patterns of leaf nitrogen (N) and phosphorus (P) stoichiometry have been interpreted as reflecting phenotypic plasticity in response to the environment, or as an overriding effect of the distribution of species growing in their biogeochemical niches. Here, we balance these contrasting views. We compile a global dataset of 36,413 paired observations of leaf N and P concentrations, taxonomy and 45 environmental covariates, covering 7,549 sites and 3,700 species, to investigate how species identity and environmental variables control variations in mass-based leaf N and P concentrations, and the N:P ratio. We find within-species variation contributes around half of the total variation, with 29%, 31%, and 22% of leaf N, P, and N:P variation, respectively, explained by environmental variables. Within-species plasticity along environmental gradients varies across species and is highest for leaf N:P and lowest for leaf N. We identified effects of environmental variables on within-species variation using random forest models, whereas effects were largely missed by widely used linear mixed-effect models. Our analysis demonstrates a substantial influence of the environment in driving plastic responses of leaf N, P, and N:P within species, which challenges reports of a fixed biogeochemical niche and the overriding importance of species distributions in shaping global patterns of leaf N and P., (© 2024. The Author(s).)

Background: The key pathological signature of ALS/ FTLD is the mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm. However, TDP-43 gain of function in the cytoplasm is still poorly understood since TDP-43 animal models recapitulating mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm are missing., Methods: CRISPR/Cas9 technology was used to generate a zebrafish line (called CytoTDP), that mis-locates endogenous TDP-43 from the nucleus to the cytoplasm. Phenotypic characterization of motor neurons and the neuromuscular junction was performed by immunostaining, microglia were immunohistochemically localized by whole-mount tissue clearing and muscle ultrastructure was analyzed by scanning electron microscopy. Behavior was investigated by video tracking and quantitative analysis of swimming parameters. RNA sequencing was used to identify mis-regulated pathways with validation by molecular analysis., Results: CytoTDP fish have early larval phenotypes resembling clinical features of ALS such as progressive motor defects, neurodegeneration and muscle atrophy. Taking advantage of zebrafish's embryonic development that solely relys on yolk usage until 5 days post fertilization, we demonstrated that microglia proliferation and activation in the hypothalamus is independent from food intake. By comparing CytoTDP to a previously generated TDP-43 knockout line, transcriptomic analyses revealed that mis-localization of endogenous TDP-43, rather than TDP-43 nuclear loss of function, leads to early onset metabolic dysfunction., Conclusions: The new TDP-43 model mimics the ALS/FTLD hallmark of progressive motor dysfunction. Our results suggest that functional deficits of the hypothalamus, the metabolic regulatory center, might be the primary cause of weight loss in ALS patients. Cytoplasmic gain of function of endogenous TDP-43 leads to metabolic dysfunction in vivo that are reminiscent of early ALS clinical non-motor metabolic alterations. Thus, the CytoTDP zebrafish model offers a unique opportunity to identify mis-regulated targets for therapeutic intervention early in disease progression., (© 2024. The Author(s).)

The β-secretase β-site APP cleaving enzyme (BACE1) is a central drug target for Alzheimer's disease. Clinically tested, BACE1-directed inhibitors also block the homologous protease BACE2. Yet little is known about physiological BACE2 substrates and functions in vivo. Here, we identify BACE2 as the protease shedding the lymphangiogenic vascular endothelial growth factor receptor 3 (VEGFR3). Inactivation of BACE2, but not BACE1, inhibited shedding of VEGFR3 from primary human lymphatic endothelial cells (LECs) and reduced release of the shed, soluble VEGFR3 (sVEGFR3) ectodomain into the blood of mice, nonhuman primates, and humans. Functionally, BACE2 inactivation increased full-length VEGFR3 and enhanced VEGFR3 signaling in LECs and also in vivo in zebrafish, where enhanced migration of LECs was observed. Thus, this study identifies BACE2 as a modulator of lymphangiogenic VEGFR3 signaling and demonstrates the utility of sVEGFR3 as a pharmacodynamic plasma marker for BACE2 activity in vivo, a prerequisite for developing BACE1-selective inhibitors for safer prevention of Alzheimer's disease.

An industrial-scale pharmaceutical powder blending process was studied via discrete element method (DEM) simulations. A DEM model of two active pharmaceutical ingredient (API) components and a combined excipient component was calibrated by matching the simulated response in a dynamic angle of repose tester to the experimentally observed response. A simulation of the 25-minute bin blending process predicted inhomogeneous API distributions along the rotation axis of the blending container. These concentration differences were confirmed experimentally in a production-scale mixing trial using high-performance liquid chromatography analysis of samples from various locations in the bin. Several strategies to improve the blend homogeneity were then studied using DEM simulations. Reversing the direction of rotation of the blender every minute was found to negligibly improve the blending performance. Introducing a baffle into the lid at a 45° angle to the rotation axis sped up the axial mixing and resulted in a better final blend uniformity. Alternatively, rotating the blending container 90° around the vertical axis five minutes prior to the process end was predicted to reduce axial segregation tendencies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Benedict Benque reports financial support was provided by Sandoz GmbH. 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.)

Neuroscientists studying the neural correlates of mouse behavior often lack access to the brain-wide activity patterns elicited during a specific task of interest. Fortunately, large-scale imaging is becoming increasingly accessible thanks to modalities such as Ca2+ imaging and functional ultrasound (fUS). However, these and other techniques often involve challenging cranial window procedures and are difficult to combine with other neuroscience tools. We address this need with an open-source 3D-printable cranial implant-the COMBO (ChrOnic Multimodal imaging and Behavioral Observation) window. The COMBO window enables chronic imaging of large portions of the brain in head-fixed mice while preserving orofacial movements. We validate the COMBO window stability using both brain-wide fUS and multisite two-photon imaging. Moreover, we demonstrate how the COMBO window facilitates the combination of optogenetics, fUS, and electrophysiology in the same animals to study the effects of circuit perturbations at both the brain-wide and single-neuron level. Overall, the COMBO window provides a versatile solution for performing multimodal brain recordings in head-fixed mice., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Edelman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Neurogenin 2 (NGN2), a neuronal transcription factor, can expedite differentiation of stem cells into mature glutamatergic neurons. We have utilized an allelic series of previously published and characterized isogenic Huntington's disease (IsoHD) human embryonic stem cell lines (Ooi et al., 2019), carrying different CAG repeat lengths in the first exon of the huntingtin gene. These IsoHDs were modified using CRISPR/Cas9 to insert NGN2 under the TET-ON doxycycline inducible promoter. The resulting IsoHD-NGN2 cell lines retained pluripotency in the absence of doxycycline (DOX), and via addition of DOX to the culturing media differentiation to neurons was achieved within 14 days., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Abinaya Chandrasekaran reports financial support was provided by Lundbeck Foundation. Sofie Amalie Flintholm Andersen reports financial support was provided by Lundbeck Foundation. Kristine Karla Freude reports a relationship with University of Copenhagen that includes: employment and funding grants. 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., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Late-onset Alzheimer's disease (AD) has become the paradigm of a non-mendelian complex neurodegenerative disease, for which a major genetic determinant is known, the APOE locus. A rare APOE variant named Christchurch (APOEch) yielding a missense mutation from Arginine to Serine at amino acid 136, has been suggested to exert a protective effect in an individual carrying the most penetrant form of Familial AD (Paisa mutation in PSEN1 gene, E280A). We describe here a new set of induced pluripotent stem cell (iPSC) lines, where the Christchurch mutation (Ch) has been introduced by gene editing into the APOE locus of three isogenic iPSC lines carrying the more common APOE variants (APOE 2/2, APOE 3/3, and an APOE 4/4) in homozygosity. Brain cells derived from these iPSC lines will enable a better understanding of APOE biology in general and facilitate the study of how the Christchurch variant affects the function of each APOE genotype. This set of iPSC lines are globally available via the European Bank of iPSCs, EBiSC.org., 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 Janssen Research & Development NV. Published by Elsevier B.V. All rights reserved.)

α-Amylase/trypsin inhibitor proteins (ATI) are discussed as possible triggers for non-celiac gluten sensitivity. The potential of high-performance thin-layer chromatography (HPTLC) was studied for the first time to analyse the inhibitory properties of ATIs from flour of wheat, spelt, and einkorn. Inhibition by each flour of the digestive enzymes trypsin or α-amylase was determined by the reduction of released metabolisation products in comparison to non-digested flour, and positive (acarbose) and negative (water) controls. Firstly, amylolysis was carried out in miniaturized form on the HPTLC surface (HPTLC-nanoGIT) after in-vial pre-incubation of the amylase with the inhibitors from flour. α-Amylase inhibition was evident via the reduction of released saccharides, as analysed by normal phase HPTLC. A strong influence of the flour matrix on the assay results (individual saccharides) was evident, caused by an increased amylolysis of further polysaccharides present, making HPTLC analysis more reliable than currently used spectrophotometric sum value assays. The detection and visualization of such matrix influence helps to understand the problems associated with spectrophotometric assays. Only maltotriose was identified as a reliable marker of the amylolysis. The highest α-amylase inhibition and thus the lowest saccharide response was detected for maltotriose in refined spelt, whereas the lowest α-amylase inhibition and thus the highest saccharide response was detected for maltotriose in refined wheat. A comparison of refined and whole grain flours showed no clear trend in the responses. Secondly, trypsin inhibition and proteolysis were performed in-vial, and any inhibition was evident via the reduction of released peptides, analysed by reversed-phase HPTLC. Based on the product pattern of the proteolysis, einkorn and whole wheat showed the highest trypsin inhibition, whereas refined wheat and refined spelt showed the lowest inhibition. Advantageously, HPTLC analysis provided important information on changes in individual saccharides or peptides, which was more reliable and sustainable than spectrophotometric in-vial assays (only sum value) or liquid column chromatography analysis (targeting only the ATI proteins).

Plot-scale experiments indicate that functional diversity (FD) plays a pivotal role in sustaining ecosystem functions such as net primary productivity (NPP). However, the relationships between functional diversity and NPP across larger scale under varying climatic conditions are sparsely studied, despite its significance for understanding forest-atmosphere interactions and informing policy development. Hence, we examine the relationships of community-weighted mean (CWM) and functional dispersion (FDis) of woody plant traits on NPP across China and if such relationships are modulated by climatic conditions at the national scale. Using comprehensive datasets of distribution, functional traits, and productivity for 9120 Chinese woody plant species, we evaluated the distribution pattern of community-weighted mean and functional dispersion (including three orthogonal trait indicators: plant size, leaf morphology, and flower duration) and its relationships with NPP. Finally, we tested the effects of climatic conditions on community-weighted mean/functional dispersion-NPP relationships. We first found overall functional diversity-NPP relationships, but also that the magnitude of these relationships was sensitive to climate, with plant size community-weighted mean promoting NPP in warm regions and plant size functional dispersion promoting NPP in wet regions. Second, warm and wet conditions indirectly increased NPP by its positive effects on community-weighted mean or functional dispersion, particularly through mean plant size and leaf morphology. Our study provides comprehensive evidence for the relationships between functional diversity and NPP under varying climates at a large scale. Importantly, our results indicate a broadening significance of multidimensional plant functional traits for woody vegetation NPP in response to rising temperatures and wetter climates. Restoration, reforestation actions and natural capital accounting need to carefully consider not only community-weighted mean and functional dispersion but also their interactions with climate, to predict how functional diversity may promote ecosystem functioning under future climatic conditions., Competing Interests: The authors declare no competing interest., (© 2024 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Purpose: To preserve fertility before gonadotoxic therapy, ovarian tissue can be removed, cryopreserved, and transplanted back again after treatment. An alternative is the artificial ovary, in which the ovarian follicles are extracted from the tissue, which reduces the risk of reimplantation of potentially remaining malignant cells. The PTEN inhibitor bpV(HOpic) has been shown to activate human, bovine and alpacas ovarian follicles, and it is therefore considered a promising substance for developing the artificial ovary. The purpose of this study was to examine the impact of different scaffolds and the vanadate derivative bpV(HOpic) on mice follicle survival and hormone secretion over 10 days., Methods: A comparative analysis was performed, studying the survival rates (SR) of isolated mice follicle in four different groups that differed either in the scaffold (polycaprolactone scaffold versus polyethylene terephthalate membrane) or in the medium-bpV(HOpic) versus control medium. The observation period of the follicles was 10 days. On days 2, 6, and 10, the viability and morphology of the follicles were checked using fluorescence or confocal microscopy. Furthermore, hormone levels of estrogen (pmol/L) and progesterone (nmol/L) were determined., Results: When comparing the SR of follicles among the four groups, it was observed that on day 6, the study groups utilizing the polycaprolactone scaffold with bpV(HOpic) in the medium (SR: 0.48 ± 0.18; p = 0.004) or functionalized in the scaffold (SR: 0.50 ± 0.20; p = 0.003) exhibited significantly higher survival rates compared to the group using only the polyethylene terephthalate membrane (SR: 0). On day 10, a significantly higher survival rate was only noted when comparing the polycaprolactone scaffold with bpV(HOpic) in the medium to the polyethylene terephthalate membrane group (SR: 0.38 ± 0.20 versus 0; p = 0.007). Higher levels of progesterone were only significantly associated with better survival rates in the group with the polycaprolactone scaffold functionalized with bpV(HOpic) (p = 0.017)., Conclusion: This study demonstrates that three-dimensional polycaprolactone scaffolds improve the survival rates of isolated mice follicles in comparison with a conventional polyethylene terephthalate membrane. The survival rates slightly improve with added bpV(HOpic). Furthermore, higher rates of progesterone were also partly associated with improved survival., (© 2024. The Author(s).)

In line with the peer reviewers comments, the authors have added highlights in stead of an abstract. It was felt that it was better able to capture the findings and is more in line with the paper's target audience., Competing Interests: 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., (© 2024 The Authors. Published by Elsevier Ltd.)

The human MDR1 gene encodes the efflux transporter P-glycoprotein, which plays an important part of the blood-brain barrier function of brain microvascular endothelial cells (BMECs). Here, we report the generation of an iPSC line, where a construct of the human MDR1 gene was inserted into the safe-site locus AAVS1. This iPSC line (BIONi010-C-48) shows functional expression of P-gp and can further be differentiated and cultured into electrically tight BMEC-like monolayers exhibiting polarized expression of P-gp in the apical membrane., 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.)

In this commentary, we advocate for the wider implementation of integrated care models for NCDs within humanitarian preparedness, response, and resilience efforts. Since experience and evidence on integrated NCD care in humanitarian settings is limited, we discuss potential benefits, key lessons learned from other settings, and lessons from the integration of other conditions that may be useful for stakeholders considering an integrated model of NCD care. We also introduce our ongoing project in North Lebanon as a case example currently undergoing parallel tracks of program implementation and process evaluation that aims to strengthen the evidence base on implementing an integrated NCD care model in a crisis setting., Competing Interests: 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., (© 2024 The Authors. Published by Elsevier Ltd.)

Background: The androgen/androgen receptor (AR)-signaling axis plays a central role in prostate cancer (PCa). Upon androgen-binding the AR dimerizes with another AR, and translocates into the nucleus where the AR-dimer activates/inactivates androgen-dependent genes. Consequently, treatments for PCa are commonly based on androgen deprivation therapy (ADT). The clinical benefits of ADT are only transitory and most tumors develop mechanisms allowing the AR to bypass its need for physiological levels of circulating androgens. Clinical failure of ADT is often characterized by the synthesis of a constitutively active AR splice variant, termed AR-V7. AR-V7 mRNA expression is considered as a resistance mechanism following ADT. AR-V7 no longer needs androgenic stimuli for nuclear entry and/or dimerization., Methods: Our goal was to mechanistically decipher the interaction between full-length AR (AR-FL) and AR-V7 in AR-null HEK-293 cells using the NanoLuc Binary Technology under androgen stimulation and deprivation conditions., Results: Our data point toward a hypothesis that AR-FL/AR-FL homodimers form in the cytoplasm, whereas AR-V7/AR-V7 homodimers localize in the nucleus. However, after androgen stimulation, all the AR-FL/AR-FL, AR-FL/AR-V7 and AR-V7/AR-V7 dimers were localized in the nucleus., Conclusions: We showed that AR-FL and AR-V7 form heterodimers that localize to the nucleus, whereas AR-V7/AR-V7 dimers were found to localize in the absence of androgens in the nucleus., (© 2024. The Author(s).)

Plant diversity effects on community productivity often increase over time. Whether the strengthening of diversity effects is caused by temporal shifts in species-level overyielding (i.e., higher species-level productivity in diverse communities compared with monocultures) remains unclear. Here, using data from 65 grassland and forest biodiversity experiments, we show that the temporal strength of diversity effects at the community scale is underpinned by temporal changes in the species that yield. These temporal trends of species-level overyielding are shaped by plant ecological strategies, which can be quantitatively delimited by functional traits. In grasslands, the temporal strengthening of biodiversity effects on community productivity was associated with increasing biomass overyielding of resource-conservative species increasing over time, and with overyielding of species characterized by fast resource acquisition either decreasing or increasing. In forests, temporal trends in species overyielding differ when considering above- versus belowground resource acquisition strategies. Overyielding in stem growth decreased for species with high light capture capacity but increased for those with high soil resource acquisition capacity. Our results imply that a diversity of species with different, and potentially complementary, ecological strategies is beneficial for maintaining community productivity over time in both grassland and forest ecosystems., (© 2024. The Author(s).)

It is well known that biodiversity positively affects ecosystem functioning, leading to enhanced ecosystem stability. However, this knowledge is mainly based on analyses using single ecosystem functions, while studies focusing on the stability of ecosystem multifunctionality (EMF) are rare. Taking advantage of a long-term grassland biodiversity experiment, we studied the effect of plant diversity (1-60 species) on EMF over 5 years, its temporal stability, as well as multifunctional resistance and resilience to a 2-year drought event. Using split-plot treatments, we further tested whether a shared history of plants and soil influences the studied relationships. We calculated EMF based on functions related to plants and higher-trophic levels. Plant diversity enhanced EMF in all studied years, and this effect strengthened over the study period. Moreover, plant diversity increased the temporal stability of EMF and fostered resistance to reoccurring drought events. Old plant communities with shared plant and soil history showed a stronger plant diversity-multifunctionality relationship and higher temporal stability of EMF than younger communities without shared histories. Our results highlight the importance of old and biodiverse plant communities for EMF and its stability to extreme climate events in a world increasingly threatened by global change., (© 2024 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Background: Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease in which patients are sensitized towards a plethora of allergens. The hosts fungal microbiota, the mycobiota, that is believed to be altered in patients suffering from AD acts as such an allergen. The correlation context of specific sensitization, changes in mycobiota and its impact on disease severity however remains poorly understood., Objectives: We aim to enhance the understanding of the specific sensitization towards the mycobiota in AD patients in relation to their fungal skin colonization., Methods: Sensitization pattern towards the Malassezia spp. and Candida albicans of 16 AD patients and 14 healthy controls (HC) were analyzed with the newly developed multiplex-assay ALEX 2® and the established singleplex-assay ImmunoCAP ® . We compared these findings with the fungal skin colonization analyzed by DNA sequencing of the internal transcribed spacer region 1 (ITS1)., Results: Sensitization in general and towards Malassezia spp. and C. albicans is increased in AD patients compared to HC with a quantitative difference in severe AD when compared to mild to moderate AD. Further we saw an association between sensitization towards and skin colonization with Candida spp. yet a negative correlation between sensitization towards and skin colonization with Malassezia spp., Conclusion: We conclude that AD in general and severe AD in particular is associated with increased sensitization towards the hosts own mycobiota. There is positive correlation in Candida spp. skin colonization and negative in Malassezia spp. skin colonization when compared to AD, AD severity as well as to specific sensitization patterns., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Storz, Schmid, Bosshard, Schmid-Grendelmeier, Brüggen and Lang.)

Objective: The objective is to identify risk factors that potentially prolong the hospital stay in patients after undergoing first single-level open lumbar microdiscectomy., Methods: A retrospective single-centre study was conducted. Demographic data, medical records, intraoperative course, and imaging studies were analysed. The outcome measure was defined by the number of days stayed after the operation. A prolonged length of stay (LOS) stay was defined as a minimum of one additional day beyond the median hospital stay in our patient collective. Bivariate analysis and multiple stepwise regression were used to identify independent factors related to the prolonged hospital stay., Results: Two hundred consecutive patients who underwent first lumbar microdiscectomy between 2018 and 2022 at our clinic were included in this study. Statistical analysis of factors potentially prolonging postoperative hospital stay was done for a total of 24 factors, seven of them were significantly related to prolonged LOS in bivariate analysis. Sex (p = 0.002, median 5 vs. 4 days for females vs. males) and age (r s  = 0.35, p ≤ 0.001, N = 200) were identified among the examined demographic factors. Regarding preoperative physical status, preoperative immobility reached statistical significance (p ≤ 0.001, median 5 vs. 4 days). Diabetes mellitus (p = 0.043, median 5 vs. 4 days), anticoagulation and/or antiplatelet agents (p = 0.045, median 5 vs. 4 days), and postoperative narcotic consumption (p ≤ 0.001, median 5 vs. 4 days) as comorbidities were associated with a prolonged hospital stay. Performance of nucleotomy (p = 0.023, median 5 vs. 4 days) was a significant intraoperative factor. After linear stepwise multivariable regression, only preoperative immobility (p ≤ 0.001) was identified as independent risk factors for prolonged length of postoperative hospital stay., Conclusion: Our study identified preoperative immobility as a significant predictor of prolonged hospital stay, highlighting its value in preoperative assessments and as a tool to pinpoint at-risk patients. Prospective clinical trials with detailed assessment of mobility, including grading, need to be done to verify our results., (© 2024. The Author(s).)

TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein that regulates gene expression, and its malfunction in neurons has been causally associated with multiple neurodegenerative disorders. Although progress has been made in understanding the functions of TDP-43 in neurons, little is known about its roles in endothelial cells (ECs), angiogenesis, and vascular function. Using inducible EC-specific TDP-43-KO mice, we showed that TDP-43 is required for sprouting angiogenesis, vascular barrier integrity, and blood vessel stability. Postnatal EC-specific deletion of TDP-43 led to retinal hypovascularization due to defects in vessel sprouting associated with reduced EC proliferation and migration. In mature blood vessels, loss of TDP-43 disrupted the blood-brain barrier and triggered vascular degeneration. These vascular defects were associated with an inflammatory response in the CNS with activation of microglia and astrocytes. Mechanistically, deletion of TDP-43 disrupted the fibronectin matrix around sprouting vessels and reduced β-catenin signaling in ECs. Together, our results indicate that TDP-43 is essential for the formation of a stable and mature vasculature.

The associations of arbuscular mycorrhizal (AM) or ectomycorrhiza (EcM) fungi with plants have sequentially evolved and significantly contributed to enhancing plant nutrition. Nonetheless, how evolutionary and ecological forces drive nutrient acquisition strategies of AM and EcM woody plants remains poorly understood. Our global analysis of woody species revealed that, over divergence time, AM woody plants evolved faster nitrogen mineralization rates without changes in nitrogen resorption. However, EcM woody plants exhibited an increase in nitrogen mineralization but a decrease in nitrogen resorption, indicating a shift towards a more inorganic nutrient economy. Despite this alteration, when evaluating present-day woody species, AM woody plants still display faster nitrogen mineralization and lower nitrogen resorption than EcM woody plants. This inorganic nutrient economy allows AM woody plants to thrive in warm environments with a faster litter decomposition rate. Our findings indicate that the global pattern of nutrient acquisition strategies in mycorrhizal plants is shaped by the interplay between phylogeny and climate., (© 2023 John Wiley & Sons Ltd.)

Forests are a substantial terrestrial carbon sink, but anthropogenic changes in land use and climate have considerably reduced the scale of this system 1 . Remote-sensing estimates to quantify carbon losses from global forests 2-5 are characterized by considerable uncertainty and we lack a comprehensive ground-sourced evaluation to benchmark these estimates. Here we combine several ground-sourced 6 and satellite-derived approaches 2,7,8 to evaluate the scale of the global forest carbon potential outside agricultural and urban lands. Despite regional variation, the predictions demonstrated remarkable consistency at a global scale, with only a 12% difference between the ground-sourced and satellite-derived estimates. At present, global forest carbon storage is markedly under the natural potential, with a total deficit of 226 Gt (model range = 151-363 Gt) in areas with low human footprint. Most (61%, 139 Gt C) of this potential is in areas with existing forests, in which ecosystem protection can allow forests to recover to maturity. The remaining 39% (87 Gt C) of potential lies in regions in which forests have been removed or fragmented. Although forests cannot be a substitute for emissions reductions, our results support the idea 2,3,9 that the conservation, restoration and sustainable management of diverse forests offer valuable contributions to meeting global climate and biodiversity targets., (© 2023. The Author(s).)

The rapid diversification and high species richness of flowering plants is regarded as 'Darwin's second abominable mystery'. Today the global spatiotemporal pattern of plant diversification remains elusive. Using a newly generated genus-level phylogeny and global distribution data for 14,244 flowering plant genera, we describe the diversification dynamics of angiosperms through space and time. Our analyses show that diversification rates increased throughout the early Cretaceous and then slightly decreased or remained mostly stable until the end of the Cretaceous-Paleogene mass extinction event 66 million years ago. After that, diversification rates increased again towards the present. Younger genera with high diversification rates dominate temperate and dryland regions, whereas old genera with low diversification dominate the tropics. This leads to a negative correlation between spatial patterns of diversification and genus diversity. Our findings suggest that global changes since the Cenozoic shaped the patterns of flowering plant diversity and support an emerging consensus that diversification rates are higher outside the tropics., (© 2023. The Author(s).)

Functional and structural alterations of peritubular capillaries (PTCs) are a major determinant of chronic kidney disease (CKD). Using a software-based algorithm for semiautomatic segmentation and morphometric quantification, this study analyzes alterations of PTC shape associated with chronic tubulointerstitial injury in three mouse models and in human biopsies. In normal kidney tissue PTC shape was predominantly elongated, whereas the majority of PTCs associated with chronic tubulointerstitial injury had a rounder shape. This was reflected by significantly reduced PTC luminal area, perimeter and diameters as well as by significantly increased circularity and roundness. These morphological alterations were consistent in all mouse models and human kidney biopsies. The mean circularity of PTCs correlated significantly with categorized glomerular filtration rates and the degree of interstitial fibrosis and tubular atrophy (IFTA) and classified the presence of CKD or IFTA. 3D reconstruction of renal capillaries revealed not only a significant reduction, but more importantly a substantial simplification and reconfiguration of the renal microvasculature in mice with chronic tubulointerstitial injury. Computational modelling predicted that round PTCs can deliver oxygen more homogeneously to the surrounding tissue. Our findings indicate that alterations of PTC shape represent a common and uniform reaction to chronic tubulointerstitial injury independent of the underlying kidney disease., (© 2023. The Author(s).)

Allergen-specific immunotherapy (AIT) is the only treatment for type I allergy, which achieves long-lasting effects. Repeated subcutaneous applications of allergen extracts cause a protective antibody response and an immune deviation of T cells. In AIT with allergoids, chemically modified allergen extracts are injected. During a so-called special pre-seasonal application scheme, after the initial phase of applying increased doses of allergoids is followed by natural allergen exposure as a maintenance phase. The effectiveness of allergoid vaccines has been described regarding the improvement of clinical symptoms and the development of protective humoral responses. In this longitudinal observational study, we sought to investigate changes at the T cell level in pre-seasonal AIT with allergoid. Different subsets within CD4 + and CD8 + T cells were monitored by flow cytometry in PBMC of patients known to possess protective antibody responses. Compared to before treatment, a small early boost among allergenic Th cells was observed after 4 months of AIT. In line, a slight Th2 bias was observed after 4 months within circulating T follicular T cells, Tfh and Tfc, representing pre-existing memory Th2 cells. Furthermore, it was demonstrated that responsiveness of CD8 + T cells to allergen stimulation decreased during the course of treatment. Apart from that, we found an influence of the meteorological season on the activation profile of Tfh and Tfc over the course of the treatment. Together, this is the first study investigating changes of different T cell subsets over the course of an allergoid AIT against airborne allergens. Our findings match previous reports on conventional AIT, especially the initial increase of Th2 responses. However, the observed changes were less pronounced which may be either due to the modification of allergens or to the reduced maintenance dose provided by natural allergen exposure compared to a perennial protocol., Competing Interests: All authors declare to have no commercial or financial conflict of interest., (© 2023 The Authors.)

Understanding what controls global leaf type variation in trees is crucial for comprehending their role in terrestrial ecosystems, including carbon, water and nutrient dynamics. Yet our understanding of the factors influencing forest leaf types remains incomplete, leaving us uncertain about the global proportions of needle-leaved, broadleaved, evergreen and deciduous trees. To address these gaps, we conducted a global, ground-sourced assessment of forest leaf-type variation by integrating forest inventory data with comprehensive leaf form (broadleaf vs needle-leaf) and habit (evergreen vs deciduous) records. We found that global variation in leaf habit is primarily driven by isothermality and soil characteristics, while leaf form is predominantly driven by temperature. Given these relationships, we estimate that 38% of global tree individuals are needle-leaved evergreen, 29% are broadleaved evergreen, 27% are broadleaved deciduous and 5% are needle-leaved deciduous. The aboveground biomass distribution among these tree types is approximately 21% (126.4 Gt), 54% (335.7 Gt), 22% (136.2 Gt) and 3% (18.7 Gt), respectively. We further project that, depending on future emissions pathways, 17-34% of forested areas will experience climate conditions by the end of the century that currently support a different forest type, highlighting the intensification of climatic stress on existing forests. By quantifying the distribution of tree leaf types and their corresponding biomass, and identifying regions where climate change will exert greatest pressure on current leaf types, our results can help improve predictions of future terrestrial ecosystem functioning and carbon cycling., (© 2023. The Author(s).)

Frontotemporal dementia (FTD) is a common cause of early-onset dementia, with no current treatment options. FTD linked to chromosome 3 (FTD3) is a rare sub-form of the disease, caused by a point mutation in the Charged Multivesicular Body Protein 2B (CHMP2B). This mutation causes neuronal phenotypes, such as mitochondrial deficiencies, accompanied by metabolic changes and interrupted endosomal-lysosomal fusion. However, the contribution of glial cells to FTD3 pathogenesis has, until recently, been largely unexplored. Glial cells play an important role in most neurodegenerative disorders as drivers and facilitators of neuroinflammation. Microglia are at the center of current investigations as potential pro-inflammatory drivers. While gliosis has been observed in FTD3 patient brains, it has not yet been systematically analyzed. In the light of this, we investigated the role of microglia in FTD3 by implementing human induced pluripotent stem cells (hiPSC) with either a heterozygous or homozygous CHMP2B mutation, introduced into a healthy control hiPSC line via CRISPR-Cas9 precision gene editing. These hiPSC were differentiated into microglia to evaluate the pro-inflammatory profile and metabolic state. Moreover, hiPSC-derived neurons were cultured with conditioned microglia media to investigate disease specific interactions between the two cell populations. Interestingly, we identified two divergent inflammatory microglial phenotypes resulting from the underlying mutations: a severe pro-inflammatory profile in CHMP2B homozygous FTD3 microglia, and an "unresponsive" CHMP2B heterozygous FTD3 microglial state. These findings correlate with our observations of increased phagocytic activity in CHMP2B homozygous, and impaired protein degradation in CHMP2B heterozygous FTD3 microglia. Metabolic mapping confirmed these differences, revealing a metabolic reprogramming of the CHMP2B FTD3 microglia, displayed as a compensatory up-regulation of glutamine metabolism in the CHMP2B homozygous FTD3 microglia. Intriguingly, conditioned CHMP2B homozygous FTD3 microglia media caused neurotoxic effects, which was not evident for the heterozygous microglia. Strikingly, IFN-γ treatment initiated an immune boost of the CHMP2B heterozygous FTD3 microglia, and conditioned microglia media exposure promoted neural outgrowth. Our findings indicate that the microglial profile, activity, and behavior is highly dependent on the status of the CHMP2B mutation. Our results suggest that the heterozygous state of the mutation in FTD3 patients could potentially be exploited in form of immune-boosting intervention strategies to counteract neurodegeneration., 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 Author(s). Published by Elsevier Inc. All rights reserved.)

Experiments under controlled conditions have established that ecosystem functioning is generally positively related to levels of biodiversity, but it is unclear how widespread these effects are in real-world settings and whether they can be harnessed for ecosystem restoration. We used remote-sensing data from the first decade of a long-term, field-scale tropical restoration experiment initiated in 2002 to test how the diversity of planted trees affected recovery of a 500-ha area of selectively logged forest measured using multiple sources of satellite data. Replanting using species-rich mixtures of tree seedlings with higher phylogenetic and functional diversity accelerated restoration of remotely sensed estimates of aboveground biomass, canopy cover, and leaf area index. Our results are consistent with a positive relationship between biodiversity and ecosystem functioning in the lowland dipterocarp rainforests of SE Asia and demonstrate that using diverse mixtures of species can enhance their initial recovery after logging.

Insects are of increasing conservation concern as a severe decline of both biomass and biodiversity have been reported. At the same time, data on where and when they occur in the airspace is still sparse, and we currently do not know whether their density is linked to the type of landscape above which they occur. Here, we combined data of high-flying insect abundance from six locations across Switzerland representing rural, urban and mountainous landscapes, which was recorded using vertical-looking radar devices. We analysed the abundance of high-flying insects in relation to meteorological factors, daytime, and type of landscape. Air pressure was positively related to insect abundance, wind speed showed an optimum, and temperature and wind direction did not show a clear relationship. Mountainous landscapes showed a higher insect abundance than the other two landscape types. Insect abundance increased in the morning, decreased in the afternoon, had a peak after sunset, and then declined again, though the extent of this general pattern slightly differed between landscape types. We conclude that the abundance of high-flying insects is not only related to abiotic parameters, but also to the type of landscapes and its characteristics, which, on a long-term, should be taken into account for when designing conservation measures for insects., (© 2023. Springer Nature Limited.)

Determining the drivers of non-native plant invasions is critical for managing native ecosystems and limiting the spread of invasive species 1,2 . Tree invasions in particular have been relatively overlooked, even though they have the potential to transform ecosystems and economies 3,4 . Here, leveraging global tree databases 5-7 , we explore how the phylogenetic and functional diversity of native tree communities, human pressure and the environment influence the establishment of non-native tree species and the subsequent invasion severity. We find that anthropogenic factors are key to predicting whether a location is invaded, but that invasion severity is underpinned by native diversity, with higher diversity predicting lower invasion severity. Temperature and precipitation emerge as strong predictors of invasion strategy, with non-native species invading successfully when they are similar to the native community in cold or dry extremes. Yet, despite the influence of these ecological forces in determining invasion strategy, we find evidence that these patterns can be obscured by human activity, with lower ecological signal in areas with higher proximity to shipping ports. Our global perspective of non-native tree invasion highlights that human drivers influence non-native tree presence, and that native phylogenetic and functional diversity have a critical role in the establishment and spread of subsequent invasions., (© 2023. The Author(s).)

Carbon-focused climate mitigation strategies are becoming increasingly important in forests. However, with ongoing biodiversity declines we require better knowledge of how much such strategies account for biodiversity. We particularly lack information across multiple trophic levels and on established forests, where the interplay between carbon stocks, stand age, and tree diversity might influence carbon-biodiversity relationships. Using a large dataset (>4600 heterotrophic species of 23 taxonomic groups) from secondary, subtropical forests, we tested how multitrophic diversity and diversity within trophic groups relate to aboveground, belowground, and total carbon stocks at different levels of tree species richness and stand age. Our study revealed that aboveground carbon, the key component of climate-based management, was largely unrelated to multitrophic diversity. By contrast, total carbon stocks-that is, including belowground carbon-emerged as a significant predictor of multitrophic diversity. Relationships were nonlinear and strongest for lower trophic levels, but nonsignificant for higher trophic level diversity. Tree species richness and stand age moderated these relationships, suggesting long-term regeneration of forests may be particularly effective in reconciling carbon and biodiversity targets. Our findings highlight that biodiversity benefits of climate-oriented management need to be evaluated carefully, and only maximizing aboveground carbon may fail to account for biodiversity conservation requirements., (© 2023 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Acute graft-versus-host disease (GvHD) remains the biggest clinical challenge and prognosis-determining complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Donor T cells are acceptedly key mediators of alloreactivity against host tissues and here especially the gut. In support of previous studies, we found that the intestinal intra-epithelial lymphocyte (IEL) compartment was dynamically regulated in the course of MHC class I full mismatch allo-HSCT. However, while intestinal epithelial cell (IEC) damage endangers the integrity of the intestinal barrier and is a core signature of intestinal GvHD, the question whether and to what degree IELs are contributing to IEC dysregulation is poorly understood. To study lymphoepithelial interaction, we employed a novel ex vivo T cell/organoid co-culture model system. Here, allogeneic intra-epithelial T cells were superior in inducing IEC death compared to syngeneic IEL and allogeneic non-IEL T cells. The ability to induce IEC death was predominately confined to TCRβ+ T cells and was executed in a largely IFNγ-dependent manner. Alloreactivity required a diverse T cell receptor (TCR) repertoire since IELs genetically modified to express a TCR restricted to a single, non-endogenous antigen failed to mediate IEC pathology. Interestingly, minor histocompatibility antigen (miHA) mismatch was sufficient to elicit IEL-driven IEC damage. Finally, advanced live cell imaging analyses uncovered that alloreactive IELs patrolled smaller areas within intestinal organoids compared to syngeneic controls, indicating their unique migratory properties within allogeneic IECs. Together, we provide here experimental evidence for the utility of a co-culture system to model the cellular and molecular characteristics of the crosstalk between IELs and IEC in an allogeneic setting ex vivo . In the light of the emerging concept of dysregulated immune-epithelial homeostasis as a core aspect of intestinal GvHD, this approach represents a novel experimental system to e.g. screen therapeutic strategies for their potential to normalize T cell/IEC- interaction. Hence, analyses in pre-clinical in vivo allo-HSCT model systems may be restricted to hereby positively selected, promising approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Matthe, Dinkel, Schmid, Vogler, Neurath, Poeck, Neufert, Büttner-Herold and Hildner.)

Objective: Cancer cells convert more glucose into lactate than healthy cells, what contributes to their growth advantage. Pyruvate kinase (PK) is a key rate limiting enzyme in this process, what makes it a promising potential therapeutic target. However, currently it is still unclear what consequences the inhibition of PK has on cellular processes. Here, we systematically investigate the consequences of PK depletion for gene expression, histone modifications and metabolism., Methods: Epigenetic, transcriptional and metabolic targets were analysed in different cellular and animal models with stable knockdown or knockout of PK., Results: Depleting PK activity reduces the glycolytic flux and causes accumulation of glucose-6-phosphate (G6P). Such metabolic perturbation results in stimulation of the activity of a heterodimeric pair of transcription factors MondoA and MLX but not in a major reprogramming of the global H3K9ac and H3K4me3 histone modification landscape. The MondoA:MLX heterodimer upregulates expression of thioredoxin-interacting protein (TXNIP) - a tumour suppressor with multifaceted anticancer activity. This effect of TXNIP upregulation extends beyond immortalised cancer cell lines and is applicable to multiple cellular and animal models., Conclusions: Our work shows that actions of often pro-tumorigenic PK and anti-tumorigenic TXNIP are tightly linked via a glycolytic intermediate. We suggest that PK depletion stimulates the activity of MondoA:MLX transcription factor heterodimers and subsequently, increases cellular TXNIP levels. TXNIP-mediated inhibition of thioredoxin (TXN) can reduce the ability of cells to scavenge reactive oxygen species (ROS) leading to the oxidative damage of cellular structures including DNA. These findings highlight an important regulatory axis affecting tumour suppression mechanisms and provide an attractive opportunity for combination cancer therapies targeting glycolytic activity and ROS-generating pathways., 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 Author(s). Published by Elsevier GmbH.. All rights reserved.)

A key problem in development is to understand how genes turn on or off at the right place and right time during embryogenesis. Such decisions are made by non-coding sequences called 'enhancers.' Much of our models of how enhancers work rely on the assumption that genes are activated de novo as stable domains across embryonic tissues. Such a view has been strengthened by the intensive landmark studies of the early patterning of the anterior-posterior (AP) axis of the Drosophila embryo, where indeed gene expression domains seem to arise more or less stably. However, careful analysis of gene expression patterns in other model systems (including the AP patterning in vertebrates and short-germ insects like the beetle Tribolium castaneum ) painted a different, very dynamic view of gene regulation, where genes are oftentimes expressed in a wavelike fashion. How such gene expression waves are mediated at the enhancer level is so far unclear. Here, we establish the AP patterning of the short-germ beetle Tribolium as a model system to study dynamic and temporal pattern formation at the enhancer level. To that end, we established an enhancer prediction system in Tribolium based on time- and tissue-specific ATAC-seq and an enhancer live reporter system based on MS2 tagging. Using this experimental framework, we discovered several Tribolium enhancers, and assessed the spatiotemporal activities of some of them in live embryos. We found our data consistent with a model in which the timing of gene expression during embryonic pattern formation is mediated by a balancing act between enhancers that induce rapid changes in gene expression patterns (that we call 'dynamic enhancers') and enhancers that stabilize gene expression patterns (that we call 'static enhancers'). However, more data is needed for a strong support for this or any other alternative models., Competing Interests: CM, HR, FS, BS, TR, RP, ES, LT, EE No competing interests declared, (© 2023, Mau et al.)