Miracle-dz/UniFAR-FTUs huggingface dataset:
More than just an eagle killer: The freshwater cyanobacterium Aetokthonos hydrillicola produces highly toxic dolastatin derivatives

Cyanobacteria are infamous producers of toxins. While the toxic potential of planktic cyanobacterial blooms is well documented, the ecosystem level effects of toxigenic benthic and epiphytic cyanobacteria are an understudied threat. The freshwater epiphytic cyanobacterium Aetokthonos hydrillicola has recently been shown to produce the “eagle killer” neurotoxin aetokthonotoxin causing the fatal neurological disease Vacuolar Myelinopathy. The disease affects a wide array of wildlife in the southeastern United States, most notably waterfowl and birds of prey, including the bald eagle. In an assay for cytotoxicity, we found the crude extract of the cyanobacterium to be much more potent than pure aetokthonotoxin, prompting further investigation. Here, we describe the isolation and structure elucidation of the aetokthonostatins, linear peptides belonging to the dolastatin compound family, featuring a unique modification of the C-terminal phenylalanine derived moiety. Using immunofluorescence microscopy and molecular modeling, we confirmed that aetokthonostatin acts as a potent tubulin binder. We also show that aetokthonostatin inhibits reproduction of the nematode C. elegans, resulting in increased population lethality of the combined action of the two toxins produced by A. hydrillicola. Bioinformatic analysis revealed the aetokthonostatin biosynthetic gene cluster encoding a non-ribosomal peptide synthe-tase/polyketide synthase accompanied by a unique tailoring machinery. The biosynthetic activity of a specific N-terminal methyltransferase was confirmed by in vitro biochemical studies, establishing a mechanistic link between the gene cluster and its product. Significance Statement Cyanotoxins have adverse effects on ecosystems. Our understanding of their potential risk has recently been expanded by the discovery of aetokthonotoxin, produced by the cyanobacterium Aetokthonos hydrillicola growing on invasive plants. Via trophic transfer, it acts as a neurotoxin causing mortality in animals including top predators like Bald Eagles. Closer examination of A. hydrillicola revealed that it also produces highly toxic dolastatin derivatives. A. hydrillicola is the first cultured cyanobacterium producing dolastatin derivatives, allowing us to uncover biosynthetic gene clusters of this compound family. In contrast to all other known dolastatin-producers, which are marine cyanobacteria, A. hydrillicola thrives in freshwater reservoirs, making it a potential threat also for human health. Monitoring of the cyanobacterium and its toxins is strongly recommended.
A GH81-type β-glucan-binding protein facilitates colonization by mutualistic fungi in barley

Cell walls are important interfaces of plant-fungal interactions. Host cell walls act as robust physical and chemical barriers against fungal invaders, making them an essential line of defense. Upon fungal colonization, plants deposit phenolics and callose at the sites of fungal penetration to reinforce their walls and prevent further fungal progression. Alterations in the composition of plant cell walls significantly impact host susceptibility. Furthermore, plants and fungi secrete glycan hydrolases acting on each other’s cell walls. These enzymes release a wide range of sugar oligomers into the apoplast, some of which trigger the activation of host immunity via host surface receptors. Recent characterization of cell walls from plant-colonizing fungi have emphasized the abundance of β-glucans in different cell wall layers, which makes them suitable targets for recognition. To characterize host components involved in immunity against fungi, we performed a protein pull-down with the biotinylated β-glucan laminarin. Thereby, we identified a glycoside hydrolase family 81-type glucan-binding protein (GBP) as the major β-glucan interactor. Mutation of GBP1 and its only paralogue GBP2 in barley led to decreased colonization by the beneficial root endophytes Serendipita indica and S. vermifera, as well as the arbuscular mycorrhizal fungus Rhizophagus irregularis. The reduction of symbiotic colonization was accompanied by enhanced responses at the host cell wall. Moreover, GBP mutation in barley also increased resistance to fungal infections in roots and leaves by the hemibiotrophic pathogen Bipolaris sorokiniana and the obligate biotrophic pathogen Blumeria graminis f. sp. hordei, respectively. These results indicate that GBP1 is involved in the establishment of symbiotic associations with beneficial fungi, a role that has potentially been appropriated by barley-adapted pathogens. In Brief GBP1, a family 81 glycoside hydrolase, is an important β-glucan interactor in barley. Mutation of GBP1 and its sole paralogue GBP2 leads to reduced colonization by beneficial root endophytes, AM fungi and pathogens, accompanied by enhanced responses at the plant cell wall. This indicates that GBP1 and β-glucans are compatibility factors involved in the establishment of symbiotic associations with beneficial fungi, a role possibly hijacked by pathogens.
Context-Aware Amino Acid Embedding Advances Analysis of TCR-Epitope Interactions

Accurate prediction of binding interaction between T cell receptors (TCRs) and host cells is fundamental to understanding the regulation of the adaptive immune system as well as to developing data-driven approaches for personalized immunotherapy. While several machine learning models have been developed for this prediction task, the question of how to specifically embed TCR sequences into numeric representations remains largely unexplored compared to protein sequences in general. Here, we investigate whether the embedding models designed for protein sequences, and the most widely used BLOSUM-based embedding techniques are suitable for TCR analysis. Additionally, we present our context-aware amino acid embedding models (catELMo) designed explicitly for TCR analysis and trained on 4M unlabeled TCR sequences with no supervision. We validate the effectiveness of catELMo in both supervised and unsupervised scenarios by stacking the simplest models on top of our learned embeddings. For the supervised task, we choose the binding affinity prediction problem of TCR and epitope sequences and demonstrate notably significant performance gains (up by at least 14% AUC) compared to existing embedding models as well as the state-of-the-art methods. Additionally, we also show that our learned embeddings reduce more than 93% annotation cost while achieving comparable results to the state-of-the-art methods. In TCR clustering task (unsupervised), catELMo identifies TCR clusters that are more homogeneous and complete about their binding epitopes. Altogether, our catELMo trained without any explicit supervision interprets TCR sequences better and negates the need for complex deep neural network architectures in downstream tasks.
The Impact of Stability Considerations on Genetic Fine-Mapping

Fine-mapping methods, which aim to identify genetic variants responsible for complex traits following genetic association studies, typically assume that sufficient adjustments for confounding within the association study cohort have been made, e.g., through regressing out the top principal components (i.e., residualization). Despite its widespread use, however, residualization may not completely remove all sources of confounding. Here, we propose a complementary stability-guided approach that does not rely on residualization, which identifies consistently fine-mapped variants across different genetic backgrounds or environments. We demonstrate the utility of this approach by applying it to fine-map eQTLs in the GEUVADIS data. Using 378 different functional annotations of the human genome, including recent deep learning-based annotations (e.g., Enformer), we compare enrichments of these annotations among variants for which the stability and traditional residualization-based fine-mapping approaches agree against those for which they disagree, and find that the stability approach enhances the power of traditional fine-mapping methods in identifying variants with functional impact. Finally, in cases where the two approaches report distinct variants, our approach identifies variants comparably enriched for functional annotations. Our findings suggest that the stability principle, as a conceptually simple device, complements existing approaches to fine-mapping, reinforcing recent advocacy of evaluating cross-population and cross-environment portability of biological findings. To support visualization and interpretation of our results, we provide a Shiny app, available at: https://alan-aw.shinyapps. io/stability_v0/.
Intracranial electrophysiological recordings on a swine model of mesial temporal lobe epilepsy

Objective To test the feasibility and reliability of intracranial electrophysiological recordings in an acute status epilepticus model on laboratory swine. Method Intrahippocampal injection of kainic acid (KA) was performed on 17 male Bama pigs (Sus scrofa domestica) weighing between 25 and 35 kg. Two stereoelectroencephalography (SEEG) electrodes with a total of 16 channels were implanted bilaterally along the sensorimotor cortex to the hippocampus. Brain electrical activity was recorded 2 h daily for 9–28 days. Three KA dosages were tested to evaluate the quantities capable of evoking status epilepticus. Local field potentials (LFPs) were recorded and compared before and after the KA injection. We quantified the epileptic patterns, including the interictal spikes, seizures, and high-frequency oscillations (HFOs), up to 4 weeks after the KA injection. Test–retest reliability using intraclass correlation coefficients (ICCs) were performed on interictal HFO rates to evaluate the recording stability of this model. Results The KA dosage test suggested that a 10 μl (1.0 μg/μl) intrahippocampal injection could successfully evoke status epilepticus lasting from 4 to 12 h. At this dosage, eight pigs (50% of total) had prolonged epileptic events (tonic-chronic seizures + interictal spikes n = 5, interictal spikes alone n = 3) in the later 4 weeks of the video-SEEG recording period. Four pigs (25% of total) had no epileptic activities, and another four (25%) had lost the cap or did not complete the experiments. Animals that showed epileptiform events were grouped as E + (n = 8) and the four animals showing no signs of epileptic events were grouped as E– (n = 4). A total of 46 electrophysiological seizures were captured in the 4-week post-KA period from 4 E + animals, with the earliest onset on day 9. The seizure durations ranged from 12 to 45 s. A significant increase of hippocampal HFOs rate (num/min) was observed in the E+ group during the post-KA period (weeks 1, 2,4, p < 0.05) compared to the baseline. But the E-showed no change or a decrease (in week 2, p = 0.43) compared to their baseline rate. The between-group comparison showed much higher HFO rates in E + vs. E – (F = 35, p < 0.01). The high ICC value [ICC (1, k) = 0.81, p < 0.05] quantified from the HFO rate suggested that this model had a stable measurement of HFOs during the four-week post-KA periods. Significance This study measured intracranial electrophysiological activity in a swine model of KA-induced mesial temporal lobe epilepsy (mTLE). Using the clinical SEEG electrode, we distinguished abnormal EEG patterns in the swine brain. The high test–retest reliability of HFO rates in the post-KA period suggests the utility of this model for studying mechanisms of epileptogenesis. The use of swine may provide satisfactory translational value for clinical epilepsy research.
An explorative study on respiratory health among operators working in polymer additive manufacturing

Additive manufacturing (AM), or 3D printing, is a growing industry involving a wide range of different techniques and materials. The potential toxicological effects of emissions produced in the process, involving both ultrafine particles and volatile organic compounds (VOCs), are unclear, and there are concerns regarding possible health implications among AM operators. The objective of this study was to screen the presence of respiratory health effects among people working with liquid, powdered, or filament plastic materials in AM. Methods In total, 18 subjects working with different additive manufacturing techniques and production of filament with polymer feedstock and 20 controls participated in the study. Study subjects filled out a questionnaire and underwent blood and urine sampling, spirometry, impulse oscillometry (IOS), exhaled NO test (FeNO), and collection of particles in exhaled air (PEx), and the exposure was assessed. Analysis of exhaled particles included lung surfactant components such as surfactant protein A (SP-A) and phosphatidylcholines. SP-A and albumin were determined using ELISA. Using reversed-phase liquid chromatography and targeted mass spectrometry, the relative abundance of 15 species of phosphatidylcholine (PC) was determined in exhaled particles. The results were evaluated by univariate and multivariate statistical analyses (principal component analysis). Results Exposure and emission measurements in AM settings revealed a large variation in particle and VOC concentrations as well as the composition of VOCs, depending on the AM technique and feedstock. Levels of FeNO, IOS, and spirometry parameters were within clinical reference values for all AM operators. There was a difference in the relative abundance of saturated, notably dipalmitoylphosphatidylcholine (PC16:0_16:0), and unsaturated lung surfactant lipids in exhaled particles between controls and AM operators. Conclusion There were no statistically significant differences between AM operators and controls for the different health examinations, which may be due to the low number of participants. However, the observed difference in the PC lipid profile in exhaled particles indicates a possible impact of the exposure and could be used as possible early biomarkers of adverse effects in the airways.
Molecular and pathological investigation of avian reovirus (ARV) in Egypt with the assessment of the genetic variability of field strains compared to vaccine strains

Avian orthoreovirus (ARV) is among the important viruses that cause drastic economic losses in the Egyptian poultry industry. Despite regular vaccination of breeder birds, a high prevalence of ARV infection in broilers has been noted in recent years. However, no reports have revealed the genetic and antigenic characteristics of Egyptian field ARV and vaccines used against it. Thus, this study was conducted to detect the molecular nature of emerging ARV strains in broiler chickens suffering from arthritis and tenosynovitis in comparison to vaccine strains. Synovial fluid samples (n = 400) were collected from 40 commercial broiler flocks in the Gharbia governorate, Egypt, and then pooled to obtain 40 samples, which were then used to screen ARV using reverse transcriptase polymerase chain reaction (RT-PCR) with the partial amplification of ARV sigma C gene. The obtained RT-PCR products were then sequenced, and their nucleotide and deduced amino acid sequences were analyzed together with other ARV field and vaccine strains from GenBank. RT-PCR successfully amplified the predicted 940 bp PCR products from all tested samples. The phylogenetic tree revealed that the analyzed ARV strains were clustered into six genotypic clusters and six protein clusters, with high antigenic diversity between the genotypic clusters. Surprisingly, our isolates were genetically different from vaccine strains, which aligned in genotypic cluster I/protein cluster I, while our strains were aligned in genotypic cluster V/protein cluster V. More importantly, our strains were highly divergent from vaccine strains used in Egypt, with 55.09–56.23% diversity. Sequence analysis using BioEdit software revealed high genetic and protein diversity between our isolates and vaccine strains (397/797 nucleotide substitutions and 148-149/265 amino acid substitutions). This high genetic diversity explains the vaccination failure and recurrent circulation of ARV in Egypt. The present data highlight the need to formulate a new effective vaccine from locally isolated ARV strains after a thorough screening of the molecular nature of circulating ARV in Egypt.
Real-world clinical outcomes of nivolumab and taxane as a second- or later-line therapy for recurrent or unresectable advanced esophageal squamous cell carcinoma

Background Nivolumab is approved in Japan as a second-line treatment for patients with advanced esophageal squamous cell carcinoma (ESCC) resistant to fluoropyrimidine and platinum-based drugs. It is also used in adjuvant and primary postoperative therapies. This study aimed to report real-world data on nivolumab use for esophageal cancer treatment. Methods In total, 171 patients with recurrent or unresectable advanced ESCC who received nivolumab (n = 61) or taxane (n = 110) were included. We collected real-world data of patients treated with nivolumab as a second- or later-line therapy and evaluated treatment outcomes and safety. Results Median overall survival was longer and progression-free survival (PFS) was significantly longer (p = 0.0172) in patients who received nivolumab than in patients who received taxane as a second- or later-line therapy. Furthermore, subgroup analysis for second-line treatment only showed the superiority of nivolumab in increasing the PFS rate (p = 0.0056). No serious adverse events were observed. Conclusions In real-world practice, nivolumab was safer and more effective than taxane in patients with ESCC with diverse clinical profiles who did not meet trial eligibility criteria, including those with poor Eastern Cooperative Oncology Group performance status, comorbidities, and receiving multiple treatments.
Transitioning to sustainable dietary patterns: learnings from animal-based and plant-based dietary patterns in French Canadian adults

Introduction Many dietary guidelines promote the substitution of animal proteins with plant-based proteins for health benefits but also to help transitioning toward more sustainable dietary patterns. The aim of this study was to examine the food and nutrient characteristics as well as the overall quality and costs of dietary patterns consistent with lower intakes of animal-based protein foods and with higher intakes of plant-based protein foods among French Canadian adults. Methods Dietary intake data, evaluated with 24 h recalls, from 1,147 French-speaking adults of the PRÉDicteurs Individuels, Sociaux et Environnementaux (PREDISE) study conducted between 2015 and 2017 in Québec were used. Usual dietary intakes and diet costs were estimated with the National Cancer Institute’s multivariate method. Consumption of animal- and plant-based protein foods was classified into quarters (Q) and differences in food and nutrient intakes, Healthy Eating Food Index (HEFI)-2019 scores and diet costs across quarters were assessed using linear regression models adjusted for age and sex. Results Participants with lower intakes of animal-based protein foods (Q1 vs. Q4) had a higher HEFI-2019 total score (+4.0 pts, 95% CI, 0.9 to 7.1) and lower daily diet costs (-1.9 $CAD, 95% CI, –2.6 to -1.2). Participants with higher intakes of plant-based protein foods (Q4 vs. Q1) had a higher HEFI-2019 total score (+14.6 pts, 95% CI, 12.4 to 16.9) but no difference in daily diet costs (0.0$CAD, 95% CI, -0.7 to 0.7). Discussion In a perspective of diet sustainability, results from this study among French-speaking Canadian adults suggest that a shift toward a dietary pattern focused primarily on lower amounts of animal-based protein foods may be associated with a better diet quality at lower costs. On the other hand, transitioning to a dietary pattern focused primarily on higher amounts of plant-based protein foods may further improve the diet quality at no additional cost.
A combined cuff electrode array for organ-specific selective stimulation of vagus nerve enabled by Electrical Impedance Tomography

Previously developed spatially-selective Vagus Nerve Stimulation (sVNS) allows the targeting of specific nerve fascicles through current steering in a multi-electrode nerve cuff but relies on a trial-and-error strategy to identify the relative orientation between electrodes and fascicles. Fast Neural Electrical Impedance Tomography (FN-EIT) has been recently used for imaging neural traffic in the vagus nerves of pigs in a cross-correlation study with sVNS and MicroCT fascicle tracking. FN-EIT has the potential for allowing targeted sVNS; however, up to now, stimulation and imaging have been performed with separate electrode arrays. In this study, different options were evaluated in-silico to integrate EIT and stimulation into a single electrode array without affecting spatial selectivity. The original pig vagus EIT electrode array geometry was compared with a geometry integrating sVNS and EIT electrodes, and with direct use of sVNS electrodes for EIT imaging. Modelling results indicated that both new designs could achieve image quality similar to the original electrode geometry in all tested markers (e.g., co-localisation error <100 µm). The sVNS array was considered to be the simplest due to the lower number of electrodes. Experimental results from testing evoked EIT imaging of recurrent laryngeal activity using electrodes from the sVNS cuff returned a signal-to-noise ratio similar to our previous study (3.9 ± 2.4 vs. 4.1 ± 1.5, N = 4 nerves from 3 pigs) and a lower co-localisation error (≈14% nerve diameter vs. ≈25%, N = 2 nerves from 2 pigs). Performing FN-EIT and sVNS on the same nerve cuff will facilitate translation to humans, simplify surgery and enable targeted neuromodulation strategies.
Identification of NETs-related biomarkers and molecular clusters in systemic lupus erythematosus

Neutrophil extracellular traps (NETs) is an important process involved in the pathogenesis of systemic lupus erythematosus (SLE), but the potential mechanisms of NETs contributing to SLE at the genetic level have not been clearly investigated. This investigation aimed to explore the molecular characteristics of NETs-related genes (NRGs) in SLE based on bioinformatics analysis, and identify associated reliable biomarkers and molecular clusters. Dataset GSE45291 was acquired from the Gene Expression Omnibus repository and used as a training set for subsequent analysis. A total of 1006 differentially expressed genes (DEGs) were obtained, most of which were associated with multiple viral infections. The interaction of DEGs with NRGs revealed 8 differentially expressed NRGs (DE-NRGs). The correlation and protein-protein interaction analyses of these DE-NRGs were performed. Among them, HMGB1, ITGB2, and CREB5 were selected as hub genes by random forest, support vector machine, and least absolute shrinkage and selection operator algorithms. The significant diagnostic value for SLE was confirmed in the training set and three validation sets (GSE81622, GSE61635, and GSE122459). Additionally, three NETs-related sub-clusters were identified based on the hub genes’ expression profiles analyzed by unsupervised consensus cluster assessment. Functional enrichment was performed among the three NETs subgroups, and the data revealed that cluster 1 highly expressed DEGs were prevalent in innate immune response pathways while that of cluster 3 were enriched in adaptive immune response pathways. Moreover, immune infiltration analysis also revealed that innate immune cells were markedly infiltrated in cluster 1 while the adaptive immune cells were upregulated in cluster 3. As per our knowledge, this investigation is the first to explore the molecular characteristics of NRGs in SLE, identify three potential biomarkers (HMGB1, ITGB2, and CREB5), and three distinct clusters based on these hub biomarkers.