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Abstract Background Arbuscular mycorrhizas (AM) are the most widespread terrestrial symbiosis and are both a key determinant of plant health and a major contributor to ecosystem processes through their role in biogeochemical cycling. Until recently, it was assumed that the fungi which form AM comprise the subphylum Glomeromycotina (G-AMF), and our understanding of the diversity and ecosystem roles of AM is based almost exclusively on this group. However recent evidence shows that fungi which form the distinctive 'fine root endophyte’ (FRE) AM morphotype are members of the subphylum Mucoromycotina (M-AMF), so that AM symbioses are actually formed by two distinct groups of fungi. Results We investigated the influence of nitrogen (N) addition and wheat variety on the assembly of AM communities under field conditions. Visual assessment of roots showed co-occurrence of G-AMF and M-AMF, providing an opportunity to compare the responses of these two groups. Existing ‘AM’ 18S rRNA primers which co-amplify G-AMF and M-AMF were modified to reduce bias against Mucoromycotina, and compared against a new ‘FRE’ primer set which selectively amplifies Mucoromycotina. Using the AM-primers, no significant effect of either N-addition or wheat variety on G-AMF or M-AMF diversity or community composition was detected. In contrast, using the FRE-primers, N-addition was shown to reduce M-AMF diversity and altered community composition. The ASV which responded to N-addition were closely related, demonstrating a clear phylogenetic signal which was identified only by the new FRE-primers. The most abundant Mucoromycotina sequences we detected belonged to the same Endogonales clades as dominant sequences associated with FRE morphology in Australia, indicating that closely related M-AMF may be globally distributed. Conclusions The results demonstrate the need to consider both G-AMF and M-AMF when investigating AM communities, and highlight the importance of primer choice when investigating AMF community dynamics.

Abstract Cancer cells must develop strategies to adapt to the dynamically changing stresses caused by intrinsic or extrinsic processes, or therapeutic agents. Metabolic adaptability is crucial to mitigate such challenges. Considering metabolism as a central node of adaptability, it is focused on an energy sensor, the AMP‐activated protein kinase (AMPK). In a subtype of pancreatic ductal adenocarcinoma (PDAC) elevated AMPK expression and phosphorylation is identified. Using drug repurposing that combined screening experiments and chemoproteomic affinity profiling, it is identified and characterized PF‐3758309, initially developed as an inhibitor of PAK4, as an AMPK inhibitor. PF‐3758309 shows activity in pre‐clinical PDAC models, including primary patient‐derived organoids. Genetic loss‐of‐function experiments showed that AMPK limits the induction of ferroptosis, and consequently, PF‐3758309 treatment restores the sensitivity toward ferroptosis inducers. The work established a chemical scaffold for the development of specific AMPK‐targeting compounds and deciphered the framework for the development of AMPK inhibitor‐based combination therapies tailored for PDAC.

Abstract The objective of this study is to define CT imaging derived phenotypes for patients with hepatic steatosis, a common metabolic liver condition, and determine its association with patient data from a medical biobank. There is a need to further characterize hepatic steatosis in lean patients, as its epidemiology may differ from that in overweight patients. A deep learning method determined the spleen-hepatic attenuation difference (SHAD) in Hounsfield Units (HU) on abdominal CT scans as a quantitative measure of hepatic steatosis. The patient cohort was stratified by BMI with a threshold of 25 kg/m2 and hepatic steatosis with threshold SHAD ≥ − 1 HU or liver mean attenuation ≤ 40 HU. Patient characteristics, diagnoses, and laboratory results representing metabolism and liver function were investigated. A phenome-wide association study (PheWAS) was performed for the statistical interaction between SHAD and the binary characteristic LEAN. The cohort contained 8914 patients—lean patients with (N = 278, 3.1%) and without (N = 1867, 20.9%) steatosis, and overweight patients with (N = 1863, 20.9%) and without (N = 4906, 55.0%) steatosis. Among all lean patients, those with steatosis had increased rates of cardiovascular disease (41.7 vs 27.8%), hypertension (86.7 vs 49.8%), and type 2 diabetes mellitus (29.1 vs 15.7%) (all p

Arbuscular mycorrhizal fungi (AMF) play a crucial role in enhancing plant growth, but their use in agriculture is limited due to several constraints. Elevated soil phosphate levels resulting from fertilization practices strongly inhibit fungal development and reduce mycorrhizal growth response. Here, we investigated the possibility of adapting Rhizoglomus irregulare to high phosphate (Pi) levels to improve its tolerance. A fungal inoculum was produced through multiple generations in the presence of elevated Pi and used to inoculate melon plants grown under low and high phosphate conditions. Our results revealed distinct phenotypic and transcriptomic profiles between the adapted and non-adapted Rhizoglomus irregulare. The Pi adapted phenotype led to enhanced root colonization under high Pi conditions, increased vesicle abundance, and higher plant biomass at both phosphate levels. Additionally, the adaptation status influenced the expression of several genes involved in Pi uptake, Pi signaling, and mitochondrial respiration in both symbiotic partners. While the underlying mechanisms of the adaptation process require further investigation, our study raises intriguing questions. Do naturally occurring phosphate-tolerant AMF already exist? How might the production and use of artificially produced inocula bias our understanding? Our findings shed light on the adaptive capacities of Glomeromycota and challenge previous models suggesting that plants control mycorrhizal fungal growth. Moreover, our work pave the way for the development of innovative biotechnological tools to enhance the efficacy of mycorrhizal inoculum products under practical conditions with high phosphate fertilization.

Therapies targeting pancreatic ductal adenocarcinoma (PDAC), driven in most cases by the KRAS oncogene, continue to present a clinical challenge. This emphasizes the need to explore alternative treatment paradigms in translational research. In this issue of EMBO Mol. Med., Santofimia-Castano et al, highlight that stress-inducible nuclear protein 1 (NUPR1), an intrinsically disordered protein, serves as a regulator of KRAS-associated stress granules (SGs) (Santofimia-Castaño et al, 2024). Targeting NUPR1 by a small molecule inhibitor prevents SG formation as well as the development and progression of pancreatic intraepithelial neoplasia (PanINs). Moreover, the NUPR1 inhibitor ZW-115 triggers apoptosis of PDAC cells dependent on KRAS expression. In essence, these findings are supportive of targeting SGs as a therapeutic approach for PDAC (Santofimia-Castaño et al, 2024).

Abstract Alkannin/shikonin and their derivatives are specialised metabolites of high pharmaceutical and ecological importance exclusively produced in the periderm of members of the plant family Boraginaceae. Previous studies have shown that their biosynthesis is induced in response to methyl jasmonate but not salicylic acid, two phytohormones that play important roles in plant defence. However, mechanistic understanding of induction and non-induction remains largely unknown. In the present study, we generated the first comprehensive transcriptomic dataset and metabolite profiles of Lithospermum officinale plants treated with methyl jasmonate and salicylic acid to shed light on the underlying mechanisms. Our results highlight the diverse biological processes activated by both phytohormones and reveal the important regulatory role of the mevalonate pathway in alkannin/shikonin biosynthesis in L. officinale. Furthermore, by modelling a coexpression network, we uncovered structural and novel regulatory candidate genes connected to alkannin/shikonin biosynthesis. Besides providing new mechanistic insights into alkannin/shikonin biosynthesis, the generated methyl jasmonate and salicylic acid elicited expression profiles together with the coexpression networks serve as important functional genomic resources for the scientific community aiming at deepening the understanding of alkannin/shikonin biosynthesis.

Background. To evaluate clinical characteristics and factors associated with survival among liver transplantation (LT) recipients with Budd-Chiari syndrome (BCS), with or without transjugular intrahepatic portosystemic shunt (TIPS), in the post–Model for End-stage Liver Disease era. Methods. We extracted data from the United Network for Organ Sharing database on all adult (≥18 y old) waitlisted candidates and recipients of LT with BCS in the United States between 2002 and 2019. Multivariable Cox regression was used to determine predictors of mortality and hazard ratios (HRs). Results. A total of 647 BCS patients were waitlisted between 2002 and 2019. BCS was an indication for LT in 378 (0.2%) of all adult LT recipients during the study period. Of BCS patients who received LT, approximately three-fourths (72.3%) were alive for up to 10 y. We found no significant difference in LT outcomes in BCS patients with or without TIPS. Longer length of hospital stay following LT (HR, 1.32; 95% confidence interval [CI], 1.19-1.47), Black/African American race (HR, 2.24; 95% CI, 1.38-3.64), diabetes (HR, 3.17; 95% CI, 1.62-6.21), donor risk index (HR, 1.44; 95% CI, 1.05-1.99), and lower albumin levels at the time of transplantation (HR, 0.66; 95% CI, 0.50-0.88) were negatively associated with survival after LT. Interestingly, neither the Model for End-stage Liver Disease nor prior TIPS showed a significant association with survival after LT. Conclusions. These findings demonstrate good comparable survival among TIPS versus no TIPS in LT recipients with BCS. The decision for TIPS versus LT should be individualized on a case-by-case basis.

Plants are colonized by a wide range of bacteria, several of which are known to confer benefits to their hosts such as enhancing plant growth and the biosynthesis of secondary metabolites (SMs). Recently, it has been shown that Chitinophaga sp. strain R-73072 enhances the production of alkannin/shikonin, SMs of pharmaceutical and ecological importance. However, the mechanisms by which this bacterial strain increases these SMs in plants are not yet understood. To gain insight into these mechanisms, we analyzed the molecular responses of Lithospermum officinale, an alkannin/shikonin producing member of Boraginaceae, to inoculation with R-73072 in a gnotobiotic system using comparative transcriptomics and targeted metabolite profiling of root samples. We found that R-73072 modulated the expression of 1,328 genes, of which the majority appeared to be involved in plant defense and SMs biosynthesis including alkannin/shikonin derivatives. Importantly, bacterial inoculation induced the expression of genes that predominately participate in jasmonate and ethylene biosynthesis and signaling, suggesting an important role of these phytohormones in R-73072-mediated alkannin/shikonin biosynthesis. A detached leaf bioassay further showed that R-73072 confers systemic protection against Botrytis cinerea. Finally, R-73072-mediated coregulation of genes involved in plant defense and the enhanced production of alkannin/shikonin esters further suggest that these SMs could be important components of the plant defense machinery in alkannin/shikonin producing species.

Bacteria influence plant growth and development and therefore are attractive resources for applications in agriculture. However, little is known about the impact of these microorganisms on secondary metabolite (SM) production by medicinal plants. Here we assessed, for the first time, the effects of bacteria on the modulation of SM production in the medicinal plant Lithospermum officinale (Boraginaceae family) with a focus on the naphthoquinones alkannin/shikonin and their derivatives (A/Sd). The study was conducted in an in vitro cultivation system developed for that purpose, as well as in a greenhouse. Targeted and non-targeted metabolomics were performed, and expression of the gene PGT encoding for a key enzyme in the A/S biosynthesis pathway was evaluated with qPCR. Three strains, Chitinophaga sp. R-73072, Xanthomonas sp. R-73098 and Pseudomonas sp. R-71838 induced a significant increase of A/Sd in L. officinale in both systems, demonstrating the strength of our approach for screening A/Sd-inducing bacteria. The bacterial treatments altered other plant metabolites derived from the shikimate pathway as well. Our results demonstrate that bacteria influence the biosynthesis of A/Sd and interact with different metabolic pathways. This work highlights the potential of bacteria to increase the production of SM in medicinal plants and reveals new patterns in the metabolome regulation of L. officinale.

Summary: Microbial inoculants containing arbuscular mycorrhizal (AM) fungi are potential tools in increasing the sustainability of our food production systems. Given the demand for sustainable agriculture, the production of such inoculants has potential economic value and has resulted in a variety of commercial inoculants currently being advertised. However, their use is limited by inconsistent product efficacy and lack of consumer confidence. Here, we propose a framework that can be used to assess the quality and reliability of AM inoculants. First, we set out a range of basic quality criteria which are required to achieve reliable inoculants. This is followed by a standardized bioassay which can be used to test inoculum viability and efficacy under controlled conditions. Implementation of these measurements would contribute to the adoption of AM inoculants by producers with the potential to increase sustainability in food production systems.

Systemic therapies for pancreatic ductal adenocarcinoma (PDAC) remain unsatisfactory. Clinical prognosis is particularly poor for tumor subtypes with activating aberrations in the MYC pathway, creating an urgent need for novel therapeutic targets. To unbiasedly find MYC-associated epigenetic dependencies, we conducted a drug screen in pancreatic cancer cell lines. Here, we found that protein arginine N-methyltransferase 5 (PRMT5) inhibitors triggered an MYC-associated dependency. In human and murine PDACs, a robust connection of MYC and PRMT5 was detected. By the use of gain- and loss-of-function models, we confirmed the increased efficacy of PRMT5 inhibitors in MYC-deregulated PDACs. Although inhibition of PRMT5 was inducing DNA damage and arresting PDAC cells in the G2/M phase of the cell cycle, apoptotic cell death was executed predominantly in cells with high MYC expression. Experiments in primary patient-derived PDAC models demonstrated the existence of a highly PRMT5 inhibitor–sensitive subtype. Our work suggests developing PRMT5 inhibitor–based therapies for PDAC.

Since the mutualistic nature of arbuscular mycorrhiza (AM) had been discovered, an enormous amount of experiments elucidated the huge potential of mycorrhizal technology. Nevertheless, the predict-ability of mycorrhizal effectiveness (i.e. the quantitative measure of a pronounced effect) in agro-ecosystems and plant production systems remained low. On this background, Directed Inoculum Production (DIP) had been developed based on quantitative genetics. During the inoculum production process the ecological niche of an arbuscular mycorrhizal fungus (AMF) is considered, the effective ecological niche widened and population engineering included in large-scale inoculum production. This is done in order to place effective mycor-rhiza products on the market. This article reviews briefly the histori-cal development and the idea of DIP and its performance in the last 25 years. Recent and current scientific explanations for the variabili-ty of mycorrhizal effectiveness and future demands of research are outlined.

The Language Zone at the University of Leeds, UK, is well established as a hub for language learners across the campus, both those on language courses and those studying languages independently for a variety of reasons. It has been operating entirely online since March 2020 and will do so until the campus fully re-opens. This written account gives a brief overview of the changes made to the Language Zone’s services and provision of learning materials in response to the Covid-19 pandemic, including how the team members’ roles were adapted to ensure staff skills were taken into account. In addition to showing how services were maintained when the campus was closed at short notice and teaching was moved online until further notice, the study outlines how the Language Zone developed a platform to support the 2020 summer pre-sessional programmes to be delivered completely online. Finally, reflecting on the recent achievements and considering how to support students in the future, it aims to inspire other self-access centres to think about what they can do to develop their services in response to the crisis and beyond.

This empirical case study explores the (co-)construction and negotiation of identities through code-switching (CS) as found on the video-sharing platform YouTube, disentangling the complexities of social practice anchored in a discursive online environment. Drawing on a YouTube comment corpus and paying special attention to the socio-technical affordances of the platform, the study examines users’ positioning practices and metapragmatic replies in response to a culturally themed video priming discussion about LatinX family stereotypes. More specifically, it analyses how users discursively position themselves vis-à-vis the video and which linguistic strategies they exploit to (co-)construct and negotiate their cultural identity. Focusing on interrelated positioning devices such as code-choice, identity labels and quoting, this contribution proposes a multi-level model of analysis to account for the dynamic interplay between CS practices and identity construction in a heterogeneous online space. Following a social-constructivist approach to identity, CS is shown to reinforce in-group solidarity rooted in the shared experience and discussion of LatinX culture and provides evidence of a sense of togetherness in an emerging community of practice.

ObjectivePrevious research has shown reduced interoceptive accuracy (IAcc) in depression. Attention deficit represents a key symptom of depression. Moreover, IAcc is positively correlated with attention. There is no study that investigates the effect of depression on IAcc and attention. The aim of this study is to examine the mediating effect of IAcc on depression and attention.MethodsThirty-six depressed patients from the Psychosomatic Clinic in Windach were matched with 36 healthy controls according to age and sex and were assessed at Ulm University. All participants completed the Beck Depression Inventory-II, the heartbeat perception task to examine IAcc, and the d2 test assessing selective attention.ResultsDepressed patients showed attention deficits—both for general visual attention and IAcc—compared to healthy controls. The mediation analyses revealed that the relationship between depression and attention is not mediated via IAcc. Furthermore, depression predicts IAcc and attention, but these effects are direct and largely unaffected by the respective other variable.DiscussionThe results of the present study highlight both interoceptive as well as attention deficits in depressed patients. No clear mediation between these variables could be shown in this study. More elaborative research is needed to clarify whether different approaches to improve IAcc are effective for these deficits in depressed patients and could therefore be of importance as an additional aspect of therapy in depression.

Alkannin and shikonin (A/S) are enantiomeric naphthoquinones produced in the roots of certain plants from the Boraginaceae family such as Lithospermum spp. and Alkanna spp. They possess antimicrobial, anti-tumoral and wound healing properties. The production of secondary metabolites by Alkanna tinctoria might be influenced by its endomicrobiome. To study the interaction between this medicinal plant and its bacterial endophytes, we isolated bacteria from the roots of wild growing Alkanna tinctoria collected near to Athens and Thessaloniki in Greece. Representative strains selected by MALDI-TOF mass spectrometry were identified by partial 16S rRNA gene sequence analysis. In total, 197 distinct phylotypes of endophytic bacteria were detected. The most abundant genera recovered were Pseudomonas, Xanthomonas, Variovorax, Bacillus, Inquilinus, Pantoea, and Stenotrophomonas. Several bacteria were then tested in vitro for their plant growth promoting activity and the production of cell-wall degrading enzymes. Strains of Pseudomonas, Pantoea, Bacillus and Inquilinus showed positive plant growth properties whereas those of Bacteroidetes and Rhizobiaceae showed pectinase and cellulase activity in vitro. In addition, bacterial responses to alkannin and shikonin were investigated through resistance assays. Gram negative bacteria were found to be resistant to the antimicrobial properties of A/S, whereas the Gram positives were sensitive. A selection of bacteria was then tested for the ability to induce A/S production in hairy roots culture of A. tinctoria. Four strains belonging to Chitinophaga sp., Allorhizobium sp., Duganella sp., and Micromonospora sp., resulted in significantly more A/S in the hairy roots than the uninoculated control. As these bacteria can produce cell-wall degrading enzymes, we hypothesize that the A/S induction may be related with the plant-bacteria interaction during colonization.

Since the first experiments of Gottlieb Haberlandt (1854-1945) in the early 1900 on the in vitro cultivation of plant tissue, the fields of application have expanded from research of plant physiology to applications in breeding, molecular and microbiology and it became also an important tool for commercial plant production (Laimer and Rücker, 2003). Different fields of application and their perspectives will be discussed. Numbers of commercial micropropagation in Germany will be presented from 2004 to 2017 and possible reasons for changes investigated.

Arbuscular mycorrhizal (AM) fungi establish probably one of the oldest mutualistic relationships with the roots of most plants on earth. The wide distribution of these fungi in almost all soil ecotypes and the broad range of host plant species demonstrate their strong plasticity to cope with various environmental conditions. AM fungi elaborate fine-tuned molecular interactions with plants that determine their spread within root cortical tissues. Interactions with endomycorrhizal fungi can bring various benefits to plants, such as improved nutritional status, higher photosynthesis, protection against biotic and abiotic stresses based on regulation of many physiological processes which participate in promoting plant performances. In turn, host plants provide a specific habitat as physical support and a favorable metabolic frame, allowing uptake and assimilation of compounds required for the life cycle completion of these obligate biotrophic fungi. The search for formal and direct evidences of fungal energetic needs raised strong motivated projects since decades, but the impossibility to produce AM fungi under axenic conditions remains a deep enigma and still feeds numerous debates. Here, we review and discuss the initial favorable and non-favorable metabolic plant context that may fate the mycorrhizal behavior, with a focus on hormone interplays and their links with mitochondrial respiration, carbon partitioning and plant defense system, structured according to the action of phosphorus as a main limiting factor for mycorrhizal symbiosis. Then, we provide with models and discuss their significances to propose metabolic targets that could allow to develop innovations for the production and application of AM fungal inocula.

This article gives a brief overview of a recent library refurbishment project I have managed, hopefully encouraging others to think about how they can improve their own self-access spaces. My experience will illustrate that a major refurbishment project does not need to be daunting, and can have a big impact on student and staff experience, whether it is a new or established self-access centre. The Language Zone provides learning materials and resources to language learners at the University of Leeds. It supports students enrolled on modules in the Language Centre and the School of Languages, Cultures and Societies, as well as independent learners, who might be learning a new language for work, study or leisure.

The Language Centre at the University of Leeds concentrates on the full range of language training and preparation courses, both for pre-sessional and for current university students. These courses relate both to the learning of English and of foreign languages. The Self-Access Area constitutes the Language Centre’s resource library for language learning materials and supports learners on Language Centre and other modern language courses, as well as independent language learners from across the university. Catering for approximately 11,000 users, the Self-Access Area opens, on average, for 46 hours per week, with evening and Saturday opening times during term time and exam weeks. Among the services that the Self-Access Area provides are a wide range of language learning resources in print and various audiovisual formats, induction tours, an up-to-date online library catalogue and a social media presence. As part of the Language Centre, the Self- Access Area team is connected with staff and students across the university. The service also offers a range of opportunities which encourage human interaction both amongst language learners and between learners and specialists. It also acts as a flexible social and study space. The main initiatives or valuable ‘accessories’ for language learning to be discussed in this brief overview are: Language learning advising; Language exchange; and Conversation sessions

Arbuscular mycorrhizal fungi (AMF) are root-inhabiting fungi that form mutualistic symbioses with their host plants. AMF symbiosis improves nutrient uptake and buffers the plant against a diversity of stresses. Rhizophagus irregularis is one of the most widespread AMF species in the world, and its application in agricultural systems for yield improvement has increased over the last years. Still, from the inoculum production perspective, a lack of consistency of inoculum quality is referred to, which partially may be due to a high genetic variability of the fungus. The alternative oxidase (AOX) is an enzyme of the alternative respiratory chain already described in different taxa, including various fungi, which decreases the damage caused by oxidative stress. Nevertheless, virtually nothing is known on the involvement of AMF AOX on symbiosis establishment, as well on the existence of AOX variability that could affect AMF effectiveness and consequently plant performance. Here, we report the isolation and characterisation of the AOX gene of R. irregularis (RiAOX), and show that it is highly expressed during early phases of the symbiosis with plant roots. Phylogenetic analysis clustered RiAOX sequence with ancient fungi, and multiple sequence alignment revealed the lack of several regulatory motifs which are present in plant AOX. The analysis of RiAOX polymorphisms in single spores of three different isolates showed a reduced variability in one spore relatively to a group of spores. A high number of polymorphisms occurred in introns; nevertheless, some putative amino acid changes resulting from non-synonymous variants were found, offering a basis for selective pressure to occur within the populations. Given the AOX relatedness with stress responses, differences in gene variants amongst R. irregularis isolates are likely to be related with its origin and environmental constraints and might have a potential impact on inoculum production.