bluuebunny/crossref_metadata_2025 huggingface dataset:
Molybdate delays sulphide formation in the sediment and transfer to the bulk liquid in a model shrimp pond
Authors: Torun Funda , Hostins Barbara , De Schryver Peter , Boon Nico , De Vrieze Jo
Published: November 2023

Shrimp are commonly cultured in earthen aquaculture ponds where organic-rich uneaten feed and faeces accumulate on and in the sediment to form anaerobic zones. Since the pond water is rich in sulphate, these anaerobic conditions eventually lead to the production of sulphide. Sulphides are toxic and even lethal to the shrimp that live on the pond sediment, but physicochemical and microbial reactions that occur during the accumulation of organic waste and the subsequent formation of sulphide in shrimp pond sediments remain unclear. Molybdate treatment is a promising strategy to inhibit sulphate reduction, thus, preventing sulphide accumulation. We used an experimental shrimp pond model to simulate the organic waste accumulation and sulphide formation during the final 61 days of a full shrimp growth cycle. Sodium molybdate (5 and 25 mg/L Na2MoO4.2H2O) was applied as a preventive strategy to control sulphide production before oxygen depletion. Molybdate addition partially mitigated H2S production in the sediment, and delayed its transfer to the bulk liquid by pushing the higher sulphide concentration zone towards deeper sediment layers. Molybdate treatment at 25 mg/L significantly impacted the overall microbial community composition and treated samples (5 and 25 mg/L molybdate) had about 50% higher relative abundance of sulphate reducing bacteria than the control (no molybdate) treatment. In conclusion, molybdate has the potential to work as mitigation strategy against sulphide accumulation in the sediment during shrimp growth by directly steering the microbial community in a shrimp pond system.
Scalable De Novo Classification of Antibiotic Resistance of Mycobacterium Tuberculosis
Authors: Serajian Mohammadali , Marini Simone , Alanko Jarno N. , Noyes Noelle R. , Prosperi Mattia , Boucher Christina
Published: November 2023

We develop a robust machine learning classifier using both linear and nonlinear models (i.e., LASSO logistic regression (LR) and random forests (RF)) to predict the phenotypic resistance ofMycobacterium tuberculosis(MTB) for a broad range of antibiotic drugs. We use data from the CRyPTIC consortium to train our classifier, which consists of whole genome sequencing and antibiotic susceptibility testing (AST) phenotypic data for 13 different antibiotics. To train our model, we assemble the sequence data into genomic contigs, identify all unique 31-mers in the set of contigs, and build a feature matrixM, whereM[i, j] is equal to the number of times thei-th 31-mer occurs in thej-th genome. Due to the size of this feature matrix (over 350 million unique 31-mers), we build and use a sparse matrix representation. Our method, which we refer to as MTB++, leverages compact data structures and iterative methods to allow for the screening of all the 31-mers in the development of both LASSO LR and RF. MTB++ is able to achieve high discrimination (F-1 greater than 80%) for the first-line antibiotics. Moreover, MTB++ had the highest F-1 score in all but three classes and was the most comprehensive since it had a F-1 score greater than 75% in all but four (rare) antibiotic drugs. We use our feature selection to contextualize the 31-mers that are used for the prediction of phenotypic resistance, leading to some insights about sequence similarity to genes in MEGARes. Lastly, we give an estimate of the amount of data that is needed in order to provide accurate predictions.
The Role of Electron Spin, Chirality, and Charge Dynamics in Promoting the Persistence of Nascent Nucleic Acid-Peptide Complexes
Authors: Vyas Pratik , Santra Kakali , Preeyanka Naupada , Gupta Anu , Weil-Ktorza Orit , Zhu Qirong , Metanis Norman , Fransson Jonas , Longo Liam M. , Naaman Ron
Published: November 2023

Primitive nucleic acids and peptides likely collaborated during the earliest stages of biochemistry. What forces drove their interactions, and how did these forces shape the properties of primitive complexes? We investigated the association of two model primordial polypeptides with DNA. Coupling the peptides to a ferromagnetic substrate results in a dependence of the association rate and the extent of DNA binding on the orientation of magnetic moment of the substrate. The DNA binding could be nearly abolished by inverting the orientation of the magnetic field, despite the two polymers having complementary net charges. Inverting the chirality of either the entire peptide or just the connecting cysteine residue inverted the effect of the magnetic moment orientation. These results are attributed to the chiral-induced spin selectivity (CISS) effect, in which molecular chirality and electron spin interact to alter the electric polarizability of the protein. The observation of CISS effects governing simple protein-DNA complexes, suggests that this phenomenon was plausibly operative and potentially significant for primitive biomolecules. A key consequence of the CISS effect is to increase the kinetic stability of primitive protein-nucleic acid complexes. Taken together, our results show how emergent phenomena due to chirality and spin enhance bio-association.
Viral infection disrupts intestinal homeostasis via Sting-dependent NF-kB signaling
Authors: Nigg Jared C. , Blanc Hervé , Frangeul Lionel , Mongelli Vanesa , Godron Xavier , Bardin Allison J. , Saleh Maria-Carla
Published: November 2023

Host-microbe interactions influence intestinal stem cell (ISC) activity to modulate epithelial turnover and composition. Here we investigated the functional impacts of viral infection on intestinal homeostasis and the mechanisms by which viral infection alters ISC activity. We report that Drosophila A virus (DAV) infection disrupts intestinal homeostasis inDrosophilaby inducing sustained ISC proliferation, resulting in intestinal dysplasia, loss of gut barrier function, and reduced lifespan. We found that additional viruses common in laboratory-rearedDrosophilaalso promote ISC proliferation. The mechanism of DAV-induced ISC proliferation involves progenitor-autonomous EGFR signaling, JNK activity in enterocytes, and requires Sting-dependent NF-kB (Relish) activity. We further demonstrate that activating Sting-Relish signaling is sufficient to induce ISC proliferation, promote intestinal dysplasia, and reduce lifespan in the absence of infection. Our results reveal that viral infection can significantly disrupt intestinal physiology, highlight a novel role for Sting-Relish signaling, and support a role for viral infection in aging.

Graphical Abstract
A comparison of EEG encoding models using audiovisual stimuli and their unimodal counterparts
Authors: Desai Maansi , Field Alyssa M. , Hamilton Liberty S.
Published: November 2023

Communication in the real world is inherently multimodal. When having a conversation, typically sighted and hearing people use both auditory and visual cues to understand one another. For example, objects may make sounds as they move in space, or we may use the movement of a person’s mouth to better understand what they are saying in a noisy environment. Still, many neuroscience experiments rely on unimodal stimuli (visual only or auditory only) to understand encoding of sensory features in the brain. The extent to which visual information may influence encoding of auditory information and vice versa in natural environments is thus unclear. Here, we addressed this question by recording scalp electroencephalography (EEG) in 11 subjects as they listened to and watched movie trailers in audiovisual (AV), visual (V) only, and audio (A) only conditions. We then fit linear encoding models that described the relationship between the brain responses and the acoustic, phonetic, and visual information in the stimuli. We also compared whether auditory and visual feature tuning was the same when stimuli were presented in the original AV format versus when visual or auditory information was removed. We found that auditory feature tuning was similar in the AV and A-only conditions, and similarly, tuning for visual information was similar when stimuli were presented with the audio present (AV) and when the audio was removed (V only). In a cross prediction analysis, we investigated whether models trained on AV data predicted responses to A or V only test data as well as using the unimodal conditions for training. Overall, prediction performance using AV training and V test sets was similar to using V training and V test sets, suggesting that the auditory information has a relatively smaller effect on EEG. In contrast, prediction performance using AV training and A only test set was slightly worse than using matching A only training and test sets. This suggests the visual information has a stronger influence on EEG, though this makes no qualitative difference in the derived feature tuning. In effect, our results show that researchers may benefit from the richness of multimodal datasets, which can then be used to answer more than one research question.
Water inside the selectivity filter of a K+ion channel: structural heterogeneity, picosecond dynamics, and hydrogen-bonding
Authors: Ryan Matthew J. , Gao Lujia , Valiyaveetil Francis I. , Kananenka Alexei A. , Zanni Martin T.
Published: November 2023

Water inside biological ion channels regulates the key properties of these proteins such as selectivity, ion conductance, and gating. In this Article we measure the picosecond spectral diffusion of amide I vibrations of an isotope labeled KcsA potassium channel using two-dimensional infrared (2D IR) spectroscopy. By combining waiting time (100 - 2000 fs) 2D IR measurements of the KcsA channel including13C18O isotope labeled Val76 and Gly77 residues with molecular dynamics simulations, we elucidated the site-specific dynamics of water and K+ions inside the selectivity filter of KcsA. We observe inhomogeneous 2D lineshapes with extremely slow spectral diffusion. Our simulations quantitatively reproduce the experiments and show that water is the only component with any appreciable dynamics, whereas K+ions and the protein are essentially static on a picosecond timescale. By analyzing simulated and experimental vibrational frequencies, we find that water in the selectivity filter can be oriented to form hydrogen bonds with adjacent, or non-adjacent carbonyl groups with the reorientation timescales being three times slower and comparable to that of water molecules in liquid, respectively. Water molecules can reside in the cavity sufficiently far from carbonyls and behave essentially like “free” gas-phase-like water with fast reorientation times. Remarkably, no interconversion between these configurations were observed on a picosecond timescale. These dynamics are in stark contrast with liquid water that remains highly dynamic even in the presence of ions at high concentrations.
Intermittent water stress favors microbial generalists that better help wheat under drought
Authors: Schmidt Ruth Lydia , Azarbad Hamed , Bainard Luke , Tremblay Julien , Yergeau Etienne
Published: November 2023

Microorganisms can improve plant resistance to drought through various mechanisms such as the production of plant hormones, osmolytes, antioxidants, and exopolysaccharides. It is, however, unclear how previous exposure to water stress affects the functional capacity of the soil microbial community to help plants resist drought. We compared two soils that had either a continuous or intermittent water stress history for almost forty years. We grew wheat in these soils and subjected it to a water stress, after which we collected the rhizosphere soil and shotgun sequenced its metagenome. Wheat growing in the soil with an intermittent water stress history maintained a higher fresh biomass when subjected to water stress. Genes related to resistance to drought were more abundant in the metagenome and more prevalent, diversified, and redundant in the metagenome assembled genomes of the soil with an intermittent water stress history as compared to the soil with a continuous water stress history. We suggest that an intermittent water stress history selects for generalists that are adapted to both low and replete water contents, and that these generalists harbor a larger repertoire of genes beneficial for life under water stress.
The sleep quality- and myopia-linked PDE11A-Y727C variant impacts neural physiology by reducing catalytic activity and altering subcellular compartmentalization of the enzyme
Authors: Sbornova Irina , van der Sande Emilie , Milosavljevic Snezana , Amurrio Elvis , Burbano Steven D. , Das Prosun , Do Helen , Fisher Janet L. , Kargbo Porschderek , Patel Janvi , Porcher Latarsha , De Zeeuw Chris I. , Meester-Smoor Magda A , Winkelman Beerend H.J. , Klaver Caroline C.W. , Pocivavsek Ana , Kelly Michy P.
Published: November 2023

Recently, a Y727C variant in the dual-specific 3’,5’-cyclic nucleotide phosphodiesterase 11A (PDE11A-Y727C) was linked to increased sleep quality and reduced myopia risk in humans. Given the well-established role that the PDE11 substrates cAMP and cGMP play in eye physiology and sleep, we determined if 1) PDE11A protein is expressed in the retina or other eye segments in mouse, 2) PDE11A-Y7272C affects catalytic activity and/or subcellular compartmentalization more so than the nearby suicide-associated PDE11A-M878V variant, and 3)Pde11adeletion alters eye growth or sleep quality in male and female mice. Western blots show distinct protein expression of PDE11A4, but not PDE11A1-3, in eyes ofPde11aWT—but not KO mice—that vary by eye segment and age. In HT22 and COS-1 cells, PDE11A4-Y727C reduces PDE11A4 catalytic activity far more than PDE11A4-M878V, with both variants reducing PDE11A4-cAMP more so than PDE11A4-cGMP activity. Despite this,Pde11adeletion does not alter age-related changes in retinal or lens thickness, axial length, nor vitreous or anterior chamber depth. Further,Pde11adeletion only minimally changes refractive error and sleep quality. That said, both variants also dramatically alter the subcellular compartmentalization of human and mouse PDE11A4, an effect occurring independently of dephosphorylating PDE11A4-S117/S124 or phosphorylating PDE11A4-S162. Rather, re-compartmentalization of PDE11A4-Y727C is due to the loss of the tyrosine changing how PDE11A4 is packaged/repackaged via the trans-Golgi network. Therefore, the protective impact of the Y727C variant may reflect a gain-of-function (e.g., PDE11A4 displacing another PDE) that warrants further investigation in the context of reversing/preventing sleep disturbances or myopia.
Genome of the North American wild apple speciesMalus angustifolia
Authors: Mansfeld Ben N. , Ou Shujun , Burchard Erik , Yocca Alan , Harkess Alex , Gutierrez Ben , van Nocker Steve , Tang Lisa , Gottschalk Christopher
Published: November 2023

Apple (Malus×domesticaBorkh.) production faces many challenges stemming from abiotic and biotic stresses. Abiotic stressors, such as extreme temperatures, droughts, and spring frosts, can lead to diminished yields and tree loss, while biotic stresses like fire blight and pest infestations further reduce tree health and fruit quality. To lessen the threat of these challenges, plant breeders aim to introduce resistance and resilience genes into cultivated varieties. However, high-relatedness among cultivated varieties and breeding lines, coupled with the long juvenility and generation times in apples, hinder the breeding process. The introduction of resistance traits from wild relatives is also constrained by these factors, as well as the lack of genomic resources that could assist in accelerating the introgression process. Herein, we report the assembly and annotation ofMalus angustifolia, the Southern Crabapple, one of Eastern North America’s native species. Using a combination of Pacific Biosciences High Fidelity reads, Next-generation short read sequencing, as well as chromatin conformation capture sequencing, we achieve an extremely contiguous haplotype-resolved assembly. We perform comparative haplotypic analyses to identify SNPs and large structural variants, shedding light on the genomic landscape ofM. angustifolia. Finally, we explore the phylogenetic and syntenic relationships between EurasianMalusprogenitors and the recently sequenced North American species, contributing valuable insights to the broader understanding of apple evolution and potential breeding strategies.
Neutrophil motility is regulated by both cell intrinsic and endothelial cell ARPC1B
Authors: Peterson Ashley , Bennin David , Lasarev Michael , Chini Julia , Beebe David J. , Huttenlocher Anna
Published: November 2023

Neutrophil directed motility is necessary for host defense, but its dysregulation can also cause collateral tissue damage. Actinopathies are monogenic disorders that affect the actin cytoskeleton and lead to immune dysregulation. Deficiency in ARPC1B, a component of the ARP2/3 complex, results in vascular neutrophilic inflammation; however, the mechanism remains unclear. Here we generated ARPC1B-deficient human iPSC-derived iNeutrophils that show impaired migration and a switch from pseudopodia to the formation of elongated filopodia. We show, using a blood vessel on a chip model, that primary human neutrophils have impaired movement across an endothelium deficient in APRC1B. We also show that the combined deficiency of ARPC1B in iNeutrophils and endothelium results in further reduction in neutrophil migration. Taken together, these results suggest that ARPC1B in endothelium is sufficient to drive neutrophil behavior.

Summary statement

The actin regulator ARPC1B in both neutrophils and endothelium drives neutrophil motility.
Acetyl-CoA Carboxylase Obstructs CD8+T-Cell Lipid Utilization and Energy Synthesis in the Tumor Microenvironment
Authors: Hunt Elizabeth G. , Hurst Katie E. , Kennedy Andrew S. , Riesenberg Brian P. , Gandy Evelyn J. , Andrews Alex M. , Gao Peng , Coleman Michael F. , Wallace Emily D. , Thaxton Jessica E.
Published: November 2023

The solid tumor microenvironment (TME) imprints a compromised metabolic state in tumor infiltrating T cells (TILs) hallmarked by the inability to maintain effective energy synthesis for antitumor function and survival. T cells in the TME must catabolize lipids via mitochondrial fatty acid oxidation (FAO) to supply energy in nutrient stress, and it is established that T cells enriched in FAO are adept at cancer control. However, endogenous TILs and unmodified cellular therapy products fail to sustain bioenergetics in tumors. Using patient samples and mouse models, we reveal that the solid TME imposes perpetual acetyl-CoA carboxylase (ACC) activity, enforcing lipid biogenesis and storage in TILs that directly opposes FAO. Using metabolic, lipidomic, and confocal imaging strategies, we find that restricting ACC wholly rewires T cell metabolism, enabling energy maintenance in TME stress. Moreover, limiting ACC activity potentiates a gene and phenotypic program indicative of T cell memory, engendering TILs with increased survival and polyfunctionality, with the ability to control solid cancer.
Redefining phenotypic intratumor heterogeneity of pancreatic ductal adenocarcinoma: a bottom-up approach
Authors: Hilmi Marc , Delecourt Flore , Raffenne Jérôme , Bourega Taib , Dusetti Nelson , Iovanna Juan , Blum Yuna , Richard Magali , Neuzillet Cindy , Couvelard Anne , de Mestier Louis , Rebours Vinciane , Nicolle Rémy , Cros Jérôme
Published: November 2023

Background

Pancreatic ductal adenocarcinoma (PDAC) tumor inter-patient heterogeneity has been well described with two major prognostic subtypes (classical and basal-like). An important intra-patient heterogeneity has been reported but has not yet been extensively studied due to the lack of standardized, reproducible and easily accessible high throughput methods.

Material and Methods

We built an immunohistochemical (IHC) tool capable of differentiating RNA-defined classical and basal-like tumors by selecting relevant antibodies using a multi-step process. The successive stages of i) anin-silicoselection from a review literature and a bulk transcriptome analysis of 309 PDACs, ii) a tumor-specific selection from 30 patient-derived xenografts followed by iii) the validation on tissue microarrays in 50 PDAC were conducted. We used our final IHC panel on two independent cohorts of resected PDAC (n=95, whole-slide, n=148, tissue microarrays) for external validation. After digitization and registration of pathology slides, we performed a tile-based-analysis in tumor and pre-neoplastic epithelial areas and a k-means clustering to identify relevant marker combinations.

Results

Sequential marker selection led to the following panel: GATA6, CLDN18, TFF1, MUC16, S100A2, KRT17, PanBasal. Four different phenotypes were identified: 1 classical, 1 intermediate (KRT17+) and 2 basal-like (MUC16+ vs S100A2+) with specific biological properties. The presence of a minor basal contingent drastically reduced overall survival, even in classical predominant PDACs (HR=2.36, p=0.01). Analysis of preneoplastic lesions suggested that pancreatic carcinogenesis may follow a progressive evolution from classical toward a basal through an early intermediate phenotype.

Conclusion

Our IHC panel redefined and easily assessed the high degree of intra- and inter-tumoral heterogeneity of PDAC.
Protein-Ligand Binding Site Prediction andDe NovoLigand Generation from Cryo-EM Maps
Authors: Lu Chunyang , Mitra Kaustav , Mitra Kiran , Meng Hanze , Rich-New Shane Thomas , Wang Fengbin , Si Dong
Published: November 2023

Identification of protein-ligand binding sites is one of the most challenging tasks in drug discovery and design. Recent advances in machine learning community, particularly deep learning, inspired considerable research into deep learning-based methods for protein ligand binding site prediction (PLBP) and have achieved promising results. However one limitation of these methods and models is that they are developed and evaluated using conventional databases consisting of relatively small protein structures determined from X-ray crystallography and NMR with high resolution. When current PLBP methods are directly applied to large protein complexes, they either fail or produce very poor results. Given the increasing popularity of protein structures determined from Cryo-EM maps, which usually capture large protein complexes at relatively low resolution, there is a strong need to apply PLBP methods to Cryo-EM maps. For this purpose, we created a novel database (EMD-Ligand Dataset) consisting of Cryo-EM maps and information about their ligand-binding partners. Our study of several state-of-the-art PLBP methods show that even though they perform reasonably well on conventional databases, they do poorly on the novel EMD-Ligand Dataset, which calls for more research and work to be done by the community. As current methods for determining protein structures experimentally from Cryo-EM maps are time-consuming and expensive, we integrated PLBP methods with DeepTracer, an automatic and fast, de novo Cryo-EM protein structure modeling method, and established an end-to-end system capable of predicting ligand binding sites directly from Cryo-EM maps. Additionally, we leveraged an existing ligand generator to generate drug-like ligands from our predicted ligand-binding pockets and demonstrated its effectiveness.
Quantifying potential abiotic drivers of the ‘nurse-plant effect’ in two dominant shrub species of the northern Chihuahuan Desert
Authors: Ferrenberg Scott , Faist Akasha M. , Osborne Brooke , Lee Steven R.
Published: November 2023

Aggregations of plants surrounded by areas without vegetation cover in dryland ecosystems are thought to arise when larger plants facilitate the recruitment and/or performance of smaller “protégé” plants—a phenomenon referred to as the “nurse-plant” effect. While numerous drivers can generate a nurse-plant effect, efforts to quantify multiple drivers simultaneously are rare. After verifying a higher density of protégés beneath the foundational shrubsLarrea tridentataandProsopis glandulosa, multiple potential mechanisms underlying the nurse-plant effect were quantified in the Chihuahuan Desert of southern New Mexico. Comparisons of properties under shrub canopies relative to unvegetated interspaces revealed significantly greater concentrations of soil nutrients and lower photosynthetically active radiation and soil temperatures beneath shrubs but a consistently higher soil moisture in interspaces despite a greater water holding capacity in soils beneath shrubs. Nutrient concentrations were greater, on average, in soils beneathP. glandulosathanL. tridentatabut protégé plant numbers did not significantly differ among the species. Further, inL. tridentataandP. glandulosa,canopy size was positively related to levels of understory shading, and canopy size ofP. glandulosawas also positively related to soil nitrogen and microbial biomass. Results of this study suggest that a majority of the variance in the abiotic nurse-plant effect of this low-latitude system is explained by radiation interception and the concomitant reduction in temperatures experienced by protégé plants as opposed to direct effects of shrubs on soil water availability. As global change pressures intensify in drylands, a loss of perennial plant cover through mortality or dieback in canopies could have substantial, negative effects on soil biogeochemical pools and plant diversity. Additional quantification of the spatial and temporal variance in different mechanisms driving the nurse-plant effect across environmental and climatic gradients is needed to improve our understanding of plant community dynamics in dryland ecosystems.
CRISPR-Cas13d screens identifyKILR, a breast cancer risk-associated lncRNA that regulates DNA replication and repair
Authors: Wang Lu , Bitar Mainá , Lu Xue , Jacquelin Sebastien , Nair Sneha , Sivakumaran Haran , Hillman Kristine M. , Kaufmann Susanne , Ziegman Rebekah , Casciello Francesco , Gowda Harsha , Rosenbluh Joseph , Edwards Stacey L. , French Juliet D.
Published: November 2023

Long noncoding RNAs (lncRNAs) have surpassed the number of protein-coding genes, yet the majority have no known function. We previously discovered >800 lncRNAs at regions identified by breast cancer genome-wide association studies (GWAS). Here, we performed a pooled CRISPR-Cas13d RNA knockdown screen to identify which of these lncRNAs altered cell proliferation. We found thatKILR,a lncRNA that functions as a tumor suppressor, safeguards breast cells against uncontrolled proliferation. The half-life ofKILRis significantly reduced by the risk haplotype, revealing an alternative mechanism by which variants alter cancer risk. We showed thatKILRsequesters RPA1, a subunit of the RPA complex, required for DNA replication and repair. ReducedKILRexpression promotes cell proliferation by increasing the available pool of RPA1 and the speed of DNA replication. Our findings confirm lncRNAs as mediators of breast cancer risk, emphasize the need to annotate noncoding transcripts in relevant cell types when investigating GWAS variants and provide a scalable platform for mapping phenotypes associated with lncRNAs.
Fungi of the order Mucorales express a “sealing-only” tRNA ligase
Authors: Ahammed Khondakar Sayef , van Hoof Ambro
Published: November 2023

Some eukaryotic pre-tRNAs contain an intron that is removed by a dedicated set of enzymes. Intron-containing pre-tRNAs are cleaved by tRNA splicing endonuclease (TSEN), followed by ligation of the two exons and release of the intron. Fungi use a “heal and seal” pathway that requires three distinct catalytic domains of the tRNA ligase enzyme, Trl1. In contrast, humans use a “direct ligation” pathway carried out by RTCB, an enzyme completely unrelated to Trl1. Because of these mechanistic differences, Trl1 has been proposed as a promising drug target for fungal infections. To validate Trl1 as a broad-spectrum drug target, we show that fungi from three different phyla contain Trl1 orthologs with all three domains. This includes the major invasive human fungal pathogens, and these proteins each can functionally replace yeast Trl1. In contrast, species from the order Mucorales, including the pathogensRhizopus arrhizusandMucor circinelloides, contain an atypical Trl1 that contains the sealing domain, but lack both healing domains. Although these species contain fewer tRNA introns than other pathogenic fungi, they still require splicing to decode three of the 61 sense codons. These sealing-only Trl1 orthologs can functionally complement defects in the corresponding domain of yeast Trl1 and use a conserved catalytic lysine residue. We conclude that Mucorales use a sealing-only enzyme together with unidentified non-orthologous healing enzymes for their heal and seal pathway. This implies that drugs that target the sealing activity are more likely to be broader-spectrum antifungals than drugs that target the healing domains.
The Neotropical endemic liverwort subfamily Micropterygioideae had circum-Antarctic links to the rest of the Lepidoziaceae during the early Cretaceous
Authors: Rayos Antonio L. , Renner Matthew A. M. , Ho Simon Y. W.
Published: November 2023

Lepidoziaceae are the third-largest family of liverworts, with about 860 species distributed on all continents. The evolutionary history of this family has not been satisfactorily resolved, with taxa such as Micropterygioideae yet to be included in phylogenetic analyses. We inferred a dated phylogeny of Lepidoziaceae using a data set consisting of 13 genetic markers, sampled from 147 species. Based on our phylogenetic estimate, we used statistical dispersal-vicariance analysis to reconstruct the biogeographic history of the family. We inferred a crown age of 197 Ma (95% credible interval 157–240 Ma) for the family in the Australian region, with most major lineages also originating in the same region. Micropterygioideae are placed as the sister lineage to Lembidioideae, with these two groups diverging from each other about 132 Ma in the South American–Australian region. Our results suggest a circum-Antarctic link between Micropterygioideae and the rest of the family, along with extinction of the lineage in the region. Crown Micropterygioideae were inferred to have arisen 45 million years ago in South America, before the continent separated from Antarctica. Our study reveals the influence of past geological events on the evolution and distribution of a widespread and diverse family of liverworts.
Using digital spatial profiling to analyse onco-immune-related gene expression within oropharyngeal tumours in relation to HPV and p16 status
Authors: Brooks Jill M. , Zheng Yuanning , Hunter Kelly , Willcox Benjamin E. , Gevaert Olivier , Mehanna Hisham
Published: November 2023

Human Papilloma virus (HPV)-mediated oropharyngeal cancer (OPC) has significantly better prognosis compared with HPV-negative, stimulating interest in treatment de-intensification approaches to reduce long-term sequelae. Routine clinical testing frequently utilises immunohistochemistry to detect upregulation of p16 protein as a surrogate marker of HPV-mediation. However, this does not detect discordant HPV+/p16-cases and incorrectly assigns HPV-/p16+ cases, which, given their inferior prognosis compared to HPV+/p16+, may have important clinical implications. The biology underlying poorer prognosis of HPV/p16 discordant OPC requires exploration. Here, we utilised digital spatial profiling to compare the expression patterns of selected immuno-oncology-related genes within the tumour and stromal compartments of HPV+/p16+, HPV-/p16+ and HPV-/p16-OPC tumour tissues (n=12). KRT andHIF1Awere upregulated in HPV-/p16+ and HPV-/p16-tumours relative to HPV+/p16+. Conversely, multiple genes associated with antitumour immune responses (such asCXCL9, CXCL10, CD74) were upregulated in HPV+/p16+ tumours. Of note, HPV-/p16+ and HPV-/p16-tumours displayed highly similar gene expression profiles, with only CXCL9 showing differential expression in stromal regions. These results are consistent with described prognostic patterns (HPV+p16+ > HPV-/p16+ > HPV-/p16-) and underline the need for dual HPV and p16 testing to guide clinical decision making.
Stroke Risk Prediction from Medical Survey Data: AI-Driven Risk Analysis with Insightful Feature Importance using Explainable AI (XAI)
Authors: Akter Simon Bin , Akter Sumya , Pias Tanmoy Sarkar
Published: November 2023

Prioritizing dataset dependability, model performance, and interoperability is a compelling demand for improving stroke risk prediction from medical surveys using AI in healthcare. These collective efforts are required to enhance the field of stroke risk assessment and demonstrate the transformational potential of AI in healthcare. This novel study leverages the CDC’s recently published 2022 BRFSS dataset to explore AI-based stroke risk prediction. Numerous substantial and notable contributions have been established from this study. To start with, the dataset’s dependability is improved through a unique RF-based imputation technique that overcomes the challenges of missing data. In order to identify the most promising models, six different AI models are meticulously evaluated including DT, RF, GNB, RusBoost, AdaBoost, and CNN. The study combines top-performing models such as GNB, RF, and RusBoost using fusion approaches such as soft voting, hard voting, and stacking to demonstrate the combined prediction performance. The stacking model demonstrated superior performance, achieving an F1 score of 88%. The work also employs Explainable AI (XAI) approaches to highlight the subtle contributions of important dataset features, improving model interpretability. The comprehensive approach to stroke risk prediction employed in this study enhanced dataset reliability, model performance, and interpretability, demonstrating AI’s fundamental impact in healthcare.
Knowledge of self-care and complications of diabetes mellitus among diabetes mellitus patients in Addis Ababa, Ethiopia
Authors: Getachew Roman , Tewahido Dagmawit
Published: November 2023

Background

Diabetes mellitus is a progressive disease that compromises the quality of life of the victims. Patients’ knowledge about diabetes mellitus self-care is vital in achieving targeted glycemic control and minimizing complications of the disease. However, there are limited studies in Ethiopia on the subject to guide interventions. Hence, this paper aimed to assess knowledge about diabetic self-care and complications among diabetes mellitus patients in Addis Ababa, Ethiopia.

Methods

An institutional-based cross-sectional study design was employed. A structured questionnaire was used to assess knowledge; participants who responded correctly to at least 6 of the eight questions were classified as having good knowledge about the complications and those who answered <6 questions correctly were classified as having poor knowledge. Participants who correctly responded to ≥30 of the 37 self-care questions were classified as having good knowledge about diabetes self-care; those who correctly responded to <30 questions were classified as having poor knowledge. Multivariate logistic regression analyses were used to identify associated factors.

Result

Overall, 202 (51.7%) of the study participants had good knowledge about the complications, and 279 (71.4%) of the participants had a good knowledge of self-care. Receiving diabetic education was a significant modifiable factor for having poor knowledge about both the complication (AOR= 3.078(1.323,7.160)) and the self-care (AOR=7.645(3.153,18.538)).

Conclusion

About half (51.7%) of the participants had good knowledge about the complications, and about three in four (71.4%) had good knowledge about self-care. Receiving diabetic education was significantly associated with both complication and self-care knowledge status. Focusing on the quality and quantity of the information that is delivered to diabetes mellitus patients can improve the quality of care and the outcome.
Analysing biodiversity observation data collected in continuous time: Should we use discrete- or continuous-time occupancy models?
Authors: Pautrel Léa , Moulherat Sylvain , Gimenez Olivier , Etienne Marie-Pierre
Published: November 2023

Biodiversity monitoring is undergoing a revolution, with fauna observations data being increasingly gathered continuously over extended periods, through sensors like camera traps and acoustic recorders, or via opportunistic observations. These data are often analysed with discrete-time ecological models, requiring the transformation of continuously collected data into arbitrarily chosen non-independent discrete time intervals. To overcome this issue, ecologists are increasingly turning to the existing continuous-time models in the literature. Closer to the real detection process, they are lesser known than discrete-time models, not always easily accessible, and can be more complex. Focusing on occupancy models, a type of species distribution models, we asked ourselves: Should we dedicate time and effort to learning and using these continuous-time models, or can we go on using discrete-time models?

We conducted a comparative simulation study using data generated within a continuous-time framework. We assessed the performance of five static occupancy models with varying detection processes: discrete detection/non-detection process, discrete count process, continuous-time Poisson process, and two types of modulated Poisson processes. Our goal was to assess their abilities to estimate occupancy probability with continuously collected data. We applied all models to empirical lynx data as an illustrative example.

In scenarios with easily detectable animals, we found that all models accurately estimated occupancy. All models reached their limits with highly elusive animals. Variation in discretisation intervals had minimal impact on the discrete models’ capacity to estimate occupancy accurately.

Our study underscores that opting for continuous-time models with an increased number of parameters, aiming to get closer to the sensor detection process, may not offer substantial advantages over simpler models when the sole aim is to accurately estimate occupancy. Model choice can thus be driven by practical considerations such as data availability or implementation time. However, occupancy models can encompass goals beyond estimating occupancy probability. Continuous-time models, particularly those considering temporal variations in detection, can offer valuable insights into specific species behaviour and broader ecological inquiries. We hope that our findings offer valuable guidance for researchers and practitioners working with continuously collected data in wildlife monitoring and modelling.
Phenology and ecological role of Aerobic Anoxygenic Phototrophs in fresh waters
Authors: Villena-Alemany Cristian , Mujakić Izabela , Fecskeová Livia K. , Woodhouse Jason , Auladell Adrià , Dean Jason , Hanusova Martina , Socha Magdalena , Gazulla Carlota R. , Ruscheweyh Hans-Joachim , Sunagawa Shinichi , Kavagutti Vinicius , Andrei Adrian-Ştefan , Grossart Hans-Peter , Ghai Rohit , Koblížek Michal , Piwosz Kasia
Published: November 2023

Aerobic anoxygenic phototrophic (AAP) bacteria are heterotrophic bacteria that supply their metabolism with light energy harvested by bacteriochlorophyll-a-containing reaction centres. Despite their substantial contribution to bacterial biomass, microbial food webs and carbon cycle, their phenology in freshwater lakes remains unknown. Hence, we investigated seasonal variations of AAP abundance and community composition biweekly across three years in a temperate, meso-oligotrophic freshwater lake. AAP bacteria displayed a clear seasonal trend with a spring maximum following the bloom of phytoplankton and a secondary maximum in autumn. As the AAP bacteria represent a highly diverse assemblage of species, we followed their seasonal succession using the amplicon sequencing of thepufM marker gene. To enhance the accuracy of the taxonomic assignment, we developed newpufM primers that generate longer amplicons and compiled the currently largest database ofpufM gene, comprising 3633 reference sequences spanning all phyla known to contain AAP species. With this novel resource we demonstrated recurrent and dynamic seasonal succession of the AAP community. The majority of the species appeared during specific phases of the seasonal cycle, with less than 2% of AAP species detected during the whole year. Our results document the indigenous freshwater nature of the AAP community, characterized by high resilience and heterogenic adaptations to varying conditions of the freshwater environment. By integrating this information with the indicator of primary production (Chlorophyll-a) and existing ecological models, we show that AAP bacteria play a pivotal role in the recycling of dissolved organic matter released during spring phytoplankton bloom, contributing significantly to the ecological dynamics of lakes.
Enhancing Ligand-Based Virtual Screening with 3D Shape Similarity via a Distance-Aware Transformer Model
Authors: Sellner Manuel S. , Mahmoud Amr H. , Lill Markus A.
Published: November 2023

Following the assumption that chemically similar molecules exhibit similar biologcial properties, ligand-based virtual screening can be a valuable starting point in drug discovery projects. While 2D-based similarity metrics generally focus on similar scaffolds or substructures, 3D-based methods can capture the shape of a molecule, allowing for the identification of compounds with different scaffolds. We recently published a proof-of-concept study which demonstrated how a Transformer model can be adapted to preserve 2D similarities in latent space in the form of Euclidean distances. In this work, we extend this research and prove that the approach can be adapted to 3D similarities. We use pharmacophore-based shape similarity as 3D similarity measure. We show that the model is able to enrich the predicted most similar hits with compounds with different scaffolds that are indeed similar in 3D space. Whereas classical pharmacophore- or shape-based 3D similarity methods rely on expensive alignment processes, in our approach, we identify similar compounds directly by the Euclidean distances in latent space. This enables for the first time the 3D screening of ultra-large databases with high efficiency.
Chromosomal Integrons are Genetically and Functionally Isolated Units of Genomes
Authors: Blanco Paula , da Roza Filipa Trig , Toribio-Celestino Laura , García-Pastor Lucía , Caselli Niccolò , Ojeda Francisco , Darracq Baptiste , Vergara Ester , Millán Álvaro San , Skovgaard Ole , Mazel Didier , Loot Céline , Escudero José Antonio
Published: November 2023

Integrons are genetic elements that increase the evolvability of bacteria by capturing new genes and stockpiling them in arrays. Sedentary chromosomal integrons (SCIs), can be massive and highly stabilized structures encoding hundreds of genes, whose function remains generally unknown. SCIs have co-evolved with the host for aeons and are highly intertwined with their physiology from a mechanistic point of view. But, paradoxically, other aspects, like their variable content and location within the genome, suggest a high genetic and functional independence. In this work, we have explored the connection of SCIs to their host genome using as a model the Superintegron (SI), a 179-cassette long SCI in the genome ofVibrio choleraeN16961. We have relocated and deleted the SI using SeqDelTA, a novel method that allows to counteract the strong stabilization conferred by toxin-antitoxin systems within the array. We have characterized in depth the impact inV. cholerae’sphysiology, measuring fitness, chromosome replication dynamics, persistence, transcriptomics, phenomics and virulence. The deletion of the SI did not produce detectable effects in any condition, proving that -despite millions of years of co-evolution-, SCIs are genetically and functionally isolated units of genomes.
Neutrophil subsets play dual roles in tuberculosis by producing inflammasome dependent-IL-1β or suppressing T-cells via PD-L1
Authors: Doz-Deblauwe Emilie , Bounab Badreddine , Carreras Florence , Silveira-Fahel Julia , Oliveira Sergio C. , Lamkanfi Mohamed , Vern Yves Le , Germon Pierre , Pichon Julien , Kempf Florent , Paget Christophe , Remot Aude , Winter Nathalie
Published: November 2023

Neutrophils can be beneficial or deleterious during tuberculosis (TB). Based on the expression of MHC-II and programmed death ligand 1 (PD-L1), we distinguished two functionally and transcriptionally distinct neutrophil subsets in the lungs of mice infected with mycobacteria. Inflammatory [MHC-II-, PD-L1lo] neutrophils produced inflammasome-dependent IL-1β in the lungs in response to virulent mycobacteria and “accelerated” deleterious inflammation, which was highly exacerbated in IFN-γR-/-mice. Regulatory [MHC-II+, PD-L1hi] neutrophils “brake” inflammation by suppressing T-cell proliferation and IFN-γ production. Such beneficial regulation, which depends on PD-L1, is controlled by IFN-γR signaling in neutrophils. The hypervirulent HN878 strain from the Beijing genotype curbed PD-L1 expression by regulatory neutrophils, abolishing the braking function and driving deleterious hyper-inflammation in the lungs. These findings add a layer of complexity to the roles played by neutrophils in TB and may explain the reactivation of this disease observed in cancer patients treated with anti-PD-L1.

One Sentence Summary

Regulatory and inflammatory neutrophil subsets play inverse roles in tuberculosis.
Evidence that the Isc Iron-Sulfur Cluster Biogenesis Machinery Delivers Iron for [NiFe]-Cofactor Biosynthesis inEscherichia coli
Authors: Haase Alexander , Arlt Christian , Sinz Andrea , Sawers R. Gary
Published: November 2023

[NiFe]-hydrogenases have a bimetallic NiFe(CN)2CO cofactor in their large, catalytic subunit. The 136 Da Fe(CN)2CO group of this cofactor is assembled on a distinct HypC-HypD scaffold complex prior to delivery to the apo-catalytic subunit, but the intracellular source of the iron ion is unresolved. Native mass spectrometric (native MS) analysis of HypCD complexes defined the [4Fe-4S] cluster associated with HypD and identified +26 - 28 Da and +136 Da modifications specifically associated with HypC. A HypCC2Avariant dissociated from its complex with native HypD lacked all modifications. HypC dissociated from HypCD complexes isolated fromEscherichia colistrains deleted for theiscSoriscUgenes, encoding core components of the Isc iron-sulfur cluster biogenesis machinery, specifically lacked the +136 Da modification; however, it was retained on HypC isolated fromsufmutants. The presence or absence of the +136 Da modification on the HypCD complex correlated with the hydrogenase enzyme activity profiles of the respective mutant strains. Notably, the [4Fe-4S] cluster on HypD was identified in all HypCD complexes analyzed. These results suggest that the iron of the Fe(CN)2CO group on HypCD derives from the Isc machinery, while either the Isc or the Suf machinery can deliver the [4Fe-4S] cluster to HypD.