bluuebunny/crossref_metadata_2025_split huggingface dataset:
Benchmarking software tools for trimming adapters and merging next-generation sequencing data for ancient DNA
Authors: Lien Annette , Legori Leonardo Pestana , Kraft Louis , Sackett Peter Wad , Renaud Gabriel 
Published: July 2023

AbstractAncient DNA is highly degraded, resulting in very short sequences. Reads generated with modern high-throughput sequencing machines are generally longer than ancient DNA molecules, therefore the reads often contain some portion of the sequencing adaptors. It is crucial to remove those adaptors, as they can interfere with downstream analysis. Furthermore, overlapping portions when DNA has been read forward and backward (paired-end) can be merged to correct sequencing errors and improve read quality. Several tools have been developed for adapter trimming and read merging, however, no one has attempted to evaluate their accuracy and evaluate their potential impact on downstream analyses. Through the simulation of sequencing data, seven commonly used tools were analyzed in their ability to reconstruct ancient DNA sequences through read merging. The analyzed tools exhibit notable differences in their abilities to correct sequence errors and identify the correct read overlap, but the most substantial difference is observed in their ability to calculate quality scores for merged bases. Selecting the most appropriate tool for a given project depends on several factors, although some tools such as fastp have some shortcomings, whereas others like leeHom outperform the other tools in most aspects. While the choice of tool did not result in a measurable difference when analyzing population genetics using principal component analysis, it is important to note that downstream analyses that rely on quality scores can be significantly impacted by the choice of tool.
Gamma responses to colored natural stimuli can be predicted from local low-level stimulus features
Authors: Kanth Sidrat Tasawoor , Ray Supratim 
Published: July 2023

AbstractThe role of gamma rhythm (30-80 Hz) in visual processing is debated; stimuli like gratings and hue patches generate strong gamma, but many natural images do not. Could image gamma responses be predicted by approximating images as gratings or hue patches? Surprisingly, this question remains unanswered, since the joint dependance of gamma on multiple features is poorly understood. We recorded local field potentials and electrocorticogram from two monkeys while presenting natural images and parametric stimuli varying along several feature dimensions. Gamma responses to different grating/hue features were separable, allowing for a multiplicative model based on individual features. By fitting a hue patch to the image around the receptive field, this simple model could predict gamma responses to chromatic images across scales with reasonably high accuracy. Our results provide a simple “baseline” model to predict gamma from local image properties, against which more complex models of natural vision can be tested.
Frequent allopolyploidy with distant progenitors in the moss generaPhyscomitriumandEntosthodon(Funariaceae) identified via subgenome phasing of targeted nuclear genes
Authors: Patel Nikisha , Medina Rafael , Williams Lindsay D. , Lemieux Olivia , Goffinet Bernard , Johnson Matthew G. 
Published: July 2023

AbstractAllopolyploids represent a new frontier in species discovery among embryophytes. Within mosses, allopolyploid discovery is challenged by low morphological complexity. The rapid expansion of sub-genome sequencing approaches in addition to computational developments to identifying genome merger and whole-genome duplication using variation among nuclear loci representing homeologs has allowed for increased allopolyploid discovery among mosses. We confirm the intergeneric hybrid nature ofEntosthodon hungaricus, and the allopolyploid origin ofP. eurystomumand of one population ofP. collenchymatum. We also reveal that hybridization gave rise toP. immersum, as well as to yet unrecognized lineages sharing the phenotype ofP. pyriforme, andP. sphaericum.Our findings demonstrate the utility of a novel approach to phasing homeologs within loci and phasing loci across subgenomes, or subgenome assignment, called homologizer, when working with polyploid genomes, and its value in identifying progenitor species using target capture data.
The most remarkable migrants – systematic analysis of the Western European insect flyway at a Pyrenean mountain pass
Authors: Hawkes Will L , Doyle Toby , Massy Richard , Weston Scarlett , Davies Kelsey , Cornelius Elliott , Collier Connor , Chapman Jason W. , Reynolds Don R. , Wotton Karl 
Published: July 2023

AbstractIn 1950 David and Elizabeth Lack chanced upon a huge migration of insects and birds flying through the Pyrenean Pass of Bujaruelo, later describing the spectacle as combining both grandeur with novelty. The intervening years have seen many changes to land use and climate, posing the question as to the current status of this migratory phenomenon, while a lack of quantitative data has prevented insights into the ecological impact of this mass insect migration and into the factors affecting it. To address this, we revisited the site in autumn over a 4-year period and systematically monitored diurnal insect species and numbers. We document an annual mean of 17.1 million day-flying insects from 5 orders moving south, with ‘mass migration’ events associated with warmer temperatures, the presence of a headwind, sunlight, low windspeed, and low rainfall. Diptera dominated the migratory assemblage and annual numbers varied by more than fourfold with larger annual migration flows associated with higher autumn temperatures in Northwest Europe. Finally, using observed environmental thresholds for migration, we estimate an annual ‘bioflow’ of at least 14.6 billion day-flying insects migrating south over the whole Pyrenean Mountain range, highlighting the importance of this route for seasonal insect migrants.
Schizophrenia Risk Mapping and Functional Engineering of the 3D Genome in Three Neuronal Subtypes
Authors: Powell Samuel K. , Liao Will , O’Shea Callan , Kammourh Sarah , Ghorbani Sadaf , Rigat Raymond , Elahi Rahat , Deans PJ Michael , Le Derek J. , Agarwal Poonam , Seow Wei Qiang , Wang Kevin C. , Akbarian Schahram , Brennand Kristen J. 
Published: July 2023

ABSTRACTCommon variants associated with schizophrenia are concentrated in non-coding regulatory sequences, but their precise target genes are context-dependent and impacted by cell-type-specific three-dimensional spatial chromatin organization. Here, we map long-range chromosomal conformations in isogenic human dopaminergic, GABAergic, and glutamatergic neurons to track developmentally programmed shifts in the regulatory activity of schizophrenia risk loci. Massive repressive compartmentalization, concomitant with the emergence of hundreds of neuron-specific multi-valent chromatin architectural stripes, occurs during neuronal differentiation, with genes interconnected to genetic risk loci through these long-range chromatin structures differing in their biological roles from genes more proximal to sequences conferring heritable risk. Chemically induced CRISPR-guided chromosomal loop-engineering for the proximal risk geneSNAP91and distal risk geneBHLHE22profoundly alters synaptic development and functional activity. Our findings highlight the large-scale cell-type-specific reorganization of chromosomal conformations at schizophrenia risk loci during neurodevelopment and establish a causal link between risk-associated gene-regulatory loop structures and neuronal function.
Beyond the MEP Pathway: a novel kinase required for prenol utilization by malaria parasites
Authors: Crispim Marcell , Verdaguer Ignasi Bofill , Hernández Agustín , Kronenberger Thales , Fenollar Àngel , Alberione María Pía , Ramirez Miriam , Katzin Alejandro Miguel , Izquierdo Luis 
Published: July 2023

AbstractA promising treatment for malaria is a combination of fosmidomycin and clindamycin. Both compounds inhibit the methylerythritol 4-phosphate (MEP) pathway, the parasitic source of farnesyl and geranylgeranyl pyrophosphate (FPP and GGPP, respectively). Both FPP and GGPP are crucial for the biosynthesis of several essential metabolites such as ubiquinone and dolichol, as well as for protein prenylation. Dietary prenols, such as farnesol (FOH) and geranylgeraniol (GGOH), can rescue parasites from MEP inhibitors, suggesting the existence of a missing pathway for prenol salvage via phosphorylation, by competition. In this study, we identified a gene in the genome ofP. falciparum, encoding a transmembrane prenol kinase (PolK) involved in the salvage of FOH and GGOH. The enzyme was expressed inSaccharomyces cerevisiae, and its FOH/GGOH kinase activities were experimentally validated. Furthermore, conditional gene knockouts were created to investigate the biological importance of the FOH/GGOH salvage pathway. The knockout parasites were viable but more susceptible to fosmidomycin, and their sensitivity to MEP inhibitors could not be rescued by the addition of prenols. Moreover, the knockout parasites lost their ability to use prenols for protein prenylation. These results demonstrate that FOH/GGOH salvage is an additional source of isoprenoids by malaria parasites whende novobiosynthesis is inhibited. This study also identifies a novel kind of enzyme whose inhibition may potentiate the antimalarial efficacy of drugs that affect isoprenoid metabolism.
Development of potent dual BET/HDAC inhibitorsviapharmacophore merging and structure-guided optimization
Authors: Bauer Nicolas , Balourdas Dimitrios-Ilias , Schneider Joel R. , Zhang Xin , Berger Lena M. , Berger Benedict-Tilman , Klopp Nick A. , Siveke Jens T. , Knapp Stefan , Joerger Andreas C. 
Published: July 2023

ABSTRACTBromodomain and extra-terminal motif (BET) proteins and histone deacetylases (HDACs) are prime targets in cancer therapy. Recent research has particularly focused on the development of dual BET/HDAC inhibitors for hard-to-treat tumors such as pancreatic cancer. Here, we have developed a new series of potent dual BET/HDAC inhibitors by choosing starting scaffolds that enabled us to optimally merge the two functionalities into a single compound. Systematic structure-guided modification of both warheads then led to optimized binders that were superior in potency to both parent compounds, with the best molecules of this series binding to both BRD4 bromodomains as well as HDAC1/2 with EC50values in the 100-nanomolar range in cellular NanoBRET target engagement assays. Importantly, this on-target activity also translated into promising efficacy in pancreatic cancer and NUT midline carcinoma cells. Our lead molecules effectively blocked histone H3 deacetylation in pancreatic cancer cells and upregulated the tumor suppressorHEXIM1and proapoptoticp57, both markers of BET inhibition. In addition, they have the potential to downregulate oncogenic drivers of NUT midline carcinoma, as demonstrated forMYCandTP63mRNA levels. Overall, this study expands the portfolio of available dual BET/class I HDAC inhibitors for future translational studies in different cancer models.
Spatial Dynamic Subspaces Encode Sex-Specific Schizophrenia Disruptions in Transient Network Overlap and its Links to Genetic Risk
Authors: Iraji A. , Chen J. , Lewis N. , Faghiri A. , Fu Z. , Agcaoglu O. , Kochunov P. , Adhikari B. M. , Mathalon D.H. , Pearlson G.D. , Macciardi F. , Preda A. , van Erp T.G.M. , Bustillo J. R. , Díaz-Caneja C. M. , Andrés-Camazón P. , Dhamala M. , Adali T. , Calhoun V.D. 
Published: July 2023

AbstractBackgroundRecent advances in resting-state fMRI allow us to study spatial dynamics, the phenomenon of brain networks spatially evolving over time. However, most dynamic studies still use subject-specific, spatially-static nodes. As recent studies have demonstrated, incorporating time-resolved spatial properties is crucial for precise functional connectivity estimation and gaining unique insights into brain function. Nevertheless, estimating time-resolved networks poses challenges due to the low signal-to-noise ratio, limited information in short time segments, and uncertain identification of corresponding networks within and between subjects.MethodsWe adapt a reference-informed network estimation technique to capture time-resolved spatial networks and their dynamic spatial integration and segregation. We focus on time-resolved spatial functional network connectivity (spFNC), an estimate of network spatial coupling, to study sex-specific alterations in schizophrenia and their links to multi-factorial genomic data.ResultsOur findings are consistent with the dysconnectivity and neurodevelopment hypotheses and align with the cerebello-thalamo-cortical, triple-network, and frontoparietal dysconnectivity models, helping to unify them. The potential unification offers a new understanding of the underlying mechanisms. Notably, the posterior default mode/salience spFNC exhibits sex-specific schizophrenia alteration during the state with the highest global network integration and correlates with genetic risk for schizophrenia. This dysfunction is also reflected in high-dimensional (voxel-level) space in regions with weak functional connectivity to corresponding networks.ConclusionsOur method can effectively capture spatially dynamic networks, detect nuanced SZ effects, and reveal the intricate relationship of dynamic information to genomic data. The results also underscore the potential of dynamic spatial dependence and weak connectivity in the clinical landscape.
FAIMS-enabled N-terminomics analysis reveals novel legumain substrates in murine spleen
Authors: Ziegler Alexander R. , Dufour Antoine , Scott Nichollas E. , Edgington-Mitchell Laura E. 
Published: July 2023

AbstractAberrant levels of the asparaginyl endopeptidase legumain have been linked to inflammation, neurodegeneration and cancer, yet our understanding of this protease is incomplete. Systematic attempts to identify legumain substrates have previously been confined toin vitrostudies, which fail to mirror physiological conditions and obscure biologically relevant cleavage events. Using high-field asymmetric waveform ion mobility spectrometry (FAIMS), we developed a sensitive and streamlined approach for proteome and N-terminome analyses in a single analytical method without the need for N-termini enrichment. Compared to unfractionated proteomic analysis, we demonstrate FAIMS fractionation improves neo-N- termini identification by >2.5 fold, resulting in identification of >2,882 unique neo-N-termini from limited sample amounts. Within murine spleens, this approach identifies 6,366 proteins and 2,528 unique neo-N-termini, with 235 cleavage events enriched in wild-type compared to legumain-deficient spleens. Among these, 119 neo-N-termini arose from asparaginyl endopeptidase activities, representing novel putative physiological legumain substrates. The direct cleavage of selected substrates by legumain was confirmed usingin vitroassays, providing support for the existence of physiologically relevant extra-lysosomal legumain activity. Combined, these data shed critical light on the functions of legumain and demonstrates the utility of FAIMS as an accessible method to improve depth and quality of N- terminomics studies.
Strategy of selection and optimization of single domain antibodies targeting the PHF6 linear peptide within the Tau intrinsically disordered protein
Authors: Mortelecque Justine , Zejneli Orgeta , Bégard Séverine , Marine Nguyen , Cantrelle François-Xavier , Hanoulle Xavier , Rain Jean-Christophe , Colin Morvane , Buée Luc , Landrieu Isabelle , Danis Clément , Dupré Elian 
Published: July 2023

AbstractThe use of VHHs (Variable domain of the Heavy-chain of the Heavy-chain-only antibodies) as disease-modifying biomolecules in neurodegenerative disorders holds promises including to target aggregation-sensitive proteins. Exploitation of their clinical values dependents however on the capacity to deliver VHHs with optimal physico-chemical properties for their specific context of use. We described previously a VHH with high therapeutic potential in a family of neurodegenerative diseases called tauopathies. The activity of this promising parent VHH named Z70 relies on its binding within the central region of the Tau protein. Accordingly, we carried out random mutagenesis followed by yeast two-hybrid screening to obtain optimized variants. The VHHs selected from this initial screen targeted the same epitope as VHH Z70 as shown using nuclear magnetic resonance spectroscopy and had indeed improved binding affinities according to dissociation constant values obtained by surface plasmon resonance spectroscopy. The improved affinities can be partially rationalized based on three-dimensional structures of three complexes consisting of an optimized VHH and a peptide containing the Tau epitope. Interestingly, the ability of the VHH variants to inhibit Tau aggregation and seeding could not be predicted from their affinity alone. We indeed showed that thein vitroandin celluloVHH stabilities are other limiting key factors to their efficacy. Our results demonstrate that only a complete pipeline of experiments, here described, permits a rational selection of optimized VHH variants, resulting in our capacity to propose two VHH variants derived from the parent Z70 for their next development steps.
Taxonomy ofPseudomonasspp determines interactions withBacillus subtilis
Authors: Lyng Mark , Þórisdóttir Birta , Sveinsdóttir Sigrún H. , Hansen Morten L. , Maróti Gergely , Jelsbak Lars , Kovács Ákos T. 
Published: July 2023

AbstractBacilli and pseudomonads are among the most well-studied microorganisms commonly found in soil, and frequently co-isolated. Despite this, no systematic approach has been employed to assess the pairwise compatibility of members from these genera. Here, we screened 720 fluorescent soil isolates for their effects onBacillus subtilispellicle formation in two types of media and found a predictor for interaction outcome inPseudomonastaxonomy. Interactions were context-dependent and both medium composition and culture conditions strongly influenced interactions. Negative interactions were associated withPseudomonas capeferrum, Pseudomonas entomophilaandPseudomonas protegens, and 2,4-diacetylphloroglucinol was confirmed as a strong (but not exclusive) inhibitor ofB. subtilis. Non-inhibiting strains were closely related toPseudomonas trivialisandPseudomonas lini, but in this case, cocultures with increasedB. subtilispellicle formation were spatially segregated. Our study is the first to propose an overall negative outcome from pairwise interactions betweenB. subtilisand fluorescent pseudomonads, hence cocultures comprising members from these groups are likely to require additional microorganisms for coexistence.
Increased susceptibility to ischemia causes exacerbated response to microinjuries in the cirrhotic liver
Authors: Leaker Ben D. , Sojoodi Mozhdeh , Tanabe Kenneth K. , Popov Yury V. , Tam Joshua , Anderson R. Rox 
Published: July 2023

AbstractBackgroundFractional laser ablation is a technique developed in dermatology to induce remodeling of skin scars by creating a dense pattern of microinjuries. Despite remarkable clinical results, this technique has yet to be tested for scars in other tissues. As a first step towards determining the suitability of this technique, we aimed to (1) characterize the response to microinjuries in the healthy and cirrhotic liver, and (2) determine the underlying cause for any differences in response.MethodsHealthy and cirrhotic rats were treated with a fractional laser then euthanized from 0hr up to 14d after treatment. Differential expression was assessed using RNAseq with a difference-in-differences model. Spatial maps of tissue oxygenation were acquired with hyperspectral imaging and disruptions in blood supply were assessed with tomato lectin perfusion.ResultsHealthy rats showed little damage beyond the initial microinjury and healed completely by 7d without scarring. In cirrhotic rats, hepatocytes surrounding microinjury sites died 4-6hr after ablation, resulting in enlarged and heterogeneous zones of cell death. Hepatocytes near blood vessels were spared, particularly near the highly vascularized septa. Gene sets related to ischemia and angiogenesis were enriched at 4hr. Laser-treated regions had reduced oxygen saturation and broadly disrupted perfusion of nodule microvasculature, which matched the zones of cell death.ConclusionsThe cirrhotic liver has an exacerbated response to microinjuries and increased susceptibility to ischemia from microvascular damage, likely related to the vascular derangements that occur during cirrhosis development. Modifications to the fractional laser tool, such as using a femtosecond laser or reducing the spot size, may be able to prevent large disruptions of perfusion and enable further development of a laser-induced microinjury treatment for cirrhosis.
Gene Set-Based Analysis of the Endosomal Sorting Processes Cargo Selection and Membrane Tubulation with Human Reward System Reactivity
Authors: Treutlein Jens , Krämer Bernd , Rex-Haffner Monika , Awasthi Swapnil , Ripke Stephan , Binder Elisabeth B. , Gruber Oliver 
Published: July 2023

ABSTRACTDysfunction of the dopaminergic reward system has been implicated in the pathophysiology of several neuropsychiatric disorders. The endosomal network encompasses important processes related to neurotransmission in dopamine neurons, e.g, endocytosis, sorting, recycling and degradation of receptors. In the present study, we investigated whether genetic variation influencing the endosomal sorting machinery, in particular cargo selection and membrane tubulation, may impact on the activation strength in key regions of the mesolimbic reward system, i.e. the ventral tegmental area (VTA) and the nucleus accumbens (NAc).To test our hypothesis, the VTA and NAc responses to conditioned reward stimuli were investigated using the ‘desire-reason dilemma’ (DRD) paradigm during functional magnetic resonance imaging (fMRI). Association of these neural responses with a set of genetic variants related to endosomal sorting processes were tested in two independent samples (N = 182; N = 214).In the first sample, the gene set was associated with both VTA and NAc responses to conditioned reward stimuli [empirical P -values: R-VTA 0.0036; R-NAc 0.0016; L-NAc 0.0094], while the effect in the R-VTA could be replicated in the second sample [empirical P -value: R-VTA 0.0443] at the level of the gene set. For the NAc, an additional exploratory analysis of a patient-only subsample of the first sample (N = 64) suggested that the gene set may express its effect in this brain region predominantly in patients.These findings provide first evidence that the endosomal sorting processes cargo selection and membrane tubulation influence neural responses of the reward system to conditioned stimuli. Further studies are required to clarify the role of endosomal sorting processes in the pathophysiology of neuropsychiatric disorders.