bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intrinsic Neural Timescales in Autism Spectrum Disorder and Schizophrenia. A Replication and Direct Comparison Study
Authors: Uscătescu Lavinia Carmen , Kronbichler Martin , Said-Yürekli Sarah , Kronbichler Lisa , Calhoun Vince , Corbera Silvia , Bell Morris , Pelphrey Kevin , Pearlson Godfrey , Assaf Michal 
Published: June 2022

AbstractIntrinsic neural timescales (INT) reflect the duration for which brain areas store information. A posterior – anterior hierarchy of increasingly longer INT has been revealed in both typically developed individuals (TD), as well as patients diagnosed with autism spectrum disorder (ASD) and schizophrenia (SZ), though INT are, overall, shorter in both patient groups. In the present study, we attempted to replicate previously reported group differences by comparing INT of TD to ASD and SZ. We replicated the previously reported result showing reduced INT in the left lateral occipital gyrus and the right post-central gyrus in SZ compared to TD. For the first time, we also directly compared the INT of the two patient groups and found that these same two areas show significantly reduced INT in SZ compared to ASD. In ASD, significant correlations were found between INT and their clinical and phenotypic characteristics. Our results point to the left lateral occipital gyrus and the right post-central gyrus as holding potential for further diagnostic refinement of SZ.
Mechanism of the ANT-mediated transport of fatty acid anions across the inner mitochondrial membrane
Authors: Kreiter Jürgen , Brkljača Zlatko , Škulj Sanja , Bardakji Sarah , Vazdar Mario , Pohl Elena E. 
Published: June 2022

ABSTRACTThe additional protonophoric function of the mitochondrial adenine nucleotide translocase (ANT1) is now recognized. However, the molecular mechanism remains controversial. Fatty acid (FA) cycling hypothesis postulates that FAs transport protons across the inner mitochondrial membrane to the matrix by a flip-flop, whereas ANT1 facilitates the translocation of FA anions (FA-) back to the intermembrane space. By a combined approach involving measurements of current through the planar lipid bilayers reconstituted with recombinant ANT1, site-directed mutagenesis and molecular dynamics simulations, we show that FA- is initially caught by R59 on the matrix side of ANT1, then moves along the positively charged protein-lipid interface, and binds to R79, where it is protonated in the hydrated cavity in the presence of D134. R79 is crucial for the competitive binding of ANT1 substrates (ATP and ADP) and inhibitors (carboxyatractyloside, bongkrekic acid). The binding sites are well-conserved in mitochondrial SLC25 members, implying a general transporting mechanism for FA anions.
Epo-IGF1R crosstalk expands stress-specific progenitors in regenerative erythropoiesis and myeloproliferative neoplasm
Authors: Hsieh Hsi-Hsien , Yao Huiyu , Ma Yue , Zhang Yuannyu , Xiao Xue , Stephens Helen , Chung Stephen S. , Xu Lin , Xu Jian , Rampal Raajit K. , Huang Lily Jun-shen 
Published: June 2022

ABSTRACTWe find that in regenerative erythropoiesis, the erythroid progenitor landscape is reshaped, and a previously undescribed progenitor population with CFU-E activity (stress CFU-E/sCFU-E) is markedly expanded to restore the erythron. sCFU-E are targets of erythropoietin (Epo) and sCFU-E expansion requires signaling from the Epo receptor (EpoR) cytoplasmic tyrosines. Molecularly, Epo promotes sCFU-E expansion via JAK2/STAT5-dependent expression of IRS2, thus engaging the pro-growth signaling from the IGF1 receptor (IGF1R). Inhibition of IGF1R/IRS2 signaling impairs sCFU-E cell growth, whereas exogenous IRS2 expression rescues cell growth in sCFU-E expressing truncated EpoR lacking cytoplasmic tyrosines. This sCFU-E pathway is the major pathway involved in erythrocytosis driven by the oncogenic JAK2 mutant, JAK2(V617F), in myeloproliferative neoplasm. Inability to expand sCFU-E cells by truncated EpoR protects against JAK2(V617F)-driven erythrocytosis. In myeloproliferative neoplasm patient samples, the number of sCFU-E like cells increases, and inhibition of IGR1R/IRS2 signaling blocks Epo-hypersensitive erythroid cell colony formation. In summary, we identify a new stress-specific erythroid progenitor cell population that links regenerative erythropoiesis to pathogenic erythrocytosis.Key PointsEpo-induced IRS2 allows engagement of IGF1R signaling to expand a previously unrecognized progenitor population in erythropoietic stress.Truncated EpoR does not support stress CFU-E expansion and protects against JAK2(V617F)-driven erythrocytosis in MPN.
fimpera: drastic improvement of Approximate Membership Query data-structures with counts
Authors: Robidou Lucas , Peterlongo Pierre 
Published: June 2022

AbstractMotivationHigh throughput sequencing technologies generate massive amounts of biological sequence datasets as costs fall. One of the current algorithmic challenges for exploiting these data on a global scale consists in providing efficient query engines on these petabyte-scale datasets. Most methods indexing those datasets rely on indexing words of fixed lengthk, calledk-mers. Many applications, such as metagenomics, require the abundance of indexedk-mers as well as their simple presence or absence, but no method scales up to petabyte-scaled datasets. This deficiency is primarily because storing abundance requires explicit storage of thek-mers in order to associate them with their counts. Using counting Approximate Membership Queries (cAMQ) data structures, such as counting Bloom filters, provides a way to index large amounts ofk-mers with their abundance, but at the expense of a sensible false positive rate.ResultsWe propose a novel algorithm, calledfimpera, that enables the improvement of any cAMQ performance. Applied to counting Bloom filters, our proposed algorithm reduces the false positive rate by two orders of magnitude and it improves the precision of the reported abundances. Alternatively, fimpera allows for the reduction of the size of a counting Bloom filter by two orders of magnitude while maintaining the same precision.fimperadoes not introduce any memory overhead and may even reduces the query time.Availabilityhttps://github.com/lrobidou/fimperaSupplementary informationSupplementary data are available atBioinformaticsonline.
Modeling and inference of spatial intercellular communications and multilayer signaling regulations using stMLnet
Authors: Cheng Jinyu , Yan Lulu , Nie Qing , Sun Xiaoqiang 
Published: June 2022

AbstractMulticellular organisms require intercellular and intracellular signaling to coordinately regulate different cell functions. Although many methods of cell-cell communication (CCC) inference have been developed, they seldom account for both the intracellular signaling responses and global spatial information. The recent advancement of spatial transcriptomics (ST) provides unprecedented opportunities to better decipher CCC signaling and functioning. In this paper, we propose anST-basedmultilayernetwork method, stMLnet, for inferring spatial intercellular communication and multilayer signaling regulations by quantifying distance-weighted ligand–receptor signaling activity based on diffusion and mass action models and mapping it to intracellular targets. We benchmark stMLnet with existing methods using simulation data and 8 real datasets of cell type-specific perturbations. Furthermore, we demonstrate the applicability of stMLnet on six ST datasets acquired with four different technologies (e.g., seqFISH+, Slide-seq v2, MERFIS and Visium), showing its effectiveness and reliability on ST data with varying spatial resolutions and gene coverages. Finally, stMLnet identifies positive feedback circuits between alveolar epithelial cells, macrophages, and monocytes via multilayer signaling pathways within a COVID-19 microenvironment. Our proposed method provides an effective tool for predicting multilayer signaling regulations between interacting cells, which can advance the mechanistic and functional understanding of spatial CCCs.
Biofilms with a dash of color: A hands-on activity for school students to build a biofilm model, and use it to understand antibiotic tolerance in biofilms
Authors: Kadam Snehal , Methwani Kashish , Kaushik Karishma S 
Published: June 2022

AbstractIt is increasingly recognized that microbes, such as bacteria, exist in communities or biofilms, both in the environment and human body. However, school biology curriculum continues to focus on the free-floating form of bacterial life, with minimal descriptions of biofilms. Consequently, there is a need to introduce biofilms to school students, to not only to develop a fundamental understanding of microbial life, but to also highlight the challenges posed by biofilm infections to antibiotic treatment. We have developed a hands-on activity in which students build a biofilm model, and use it to understand the role of the extracellular matrix in the antibiotic tolerance of biofilms. The activity uses simple, easy to obtain supplies, and can be conducted in an in-person or virtual format, with students participating from school or home. We conducted the activity in virtual mode for a group of 59 school students across India, and present feedback and learnings that could be used to execute and adapt this accessible and engaging science experience.
Deep Learning Explains the Biology of Branched Glycans from Single-Cell Sequencing Data
Authors: Qin Rui , Mahal Lara K. , Bojar Daniel 
Published: June 2022

SummaryGlycosylation is ubiquitous and often dysregulated in disease. However, the regulation and functional significance of various types of glycosylation at cellular levels is hard to unravel experimentally. Multi-omics, single-cell measurements such as SUGAR-seq, which quantifies transcriptomes and cell surface glycans, facilitate addressing this issue. Using SUGAR-seq data, we pioneered a deep learning model to predict the glycan phenotypes of cells (mouse T lymphocytes) from transcripts, with the example of predicting β1,6GlcNAc-branching across T cell subtypes (test set F1 score: 0.9351). Model interpretation via SHAP (SHapley Additive exPlanations) identified highly predictive genes, in part known to impact (i) branched glycan levels and (ii) the biology of branched glycans. These genes included physiologically relevant low-abundance genes that were not captured by conventional differential expression analysis. Our work shows that interpretable deep learning models are promising for uncovering novel functions and regulatory mechanisms of glycans from integrated transcriptomic and glycomic datasets.
Morphological integrity of insulin amyloid-like aggregates depends on preparation methods and post-production treatments
Authors: Thorlaksen Camilla , Stanciu Adriana-Maria , Neergaard Martin Busch , Hatzakis Nikos , Foderà Vito , Groenning Minna 
Published: June 2022

AbstractProtein aggregates are often varying extensively in their morphological characteristics, which may lead to various biological outcomes related to e.g., immunogenicity risk. However, isolation of aggregates with a specific morphology within an ensemble is often challenging. To gain vital knowledge on the effects of aggregate characteristics, samples containing a single morphology must be produced by direct control of the aggregation process. Moreover, the formed aggregates need to be in a solvent suitable for biological assays, while keeping their morphology intact. Here we evaluated the dependence of morphology and integrity of amyloid-like fibrils and spherulites on preparation conditions and post-treatment methods. Samples containing either amyloid-like fibrils or spherulites produced from human insulin in acetic acid solutions are dependent on the presence of salt (NaCl). Moreover, mechanical shaking (600 rpm) inhibits spherulite formation, while only affecting the length of the formed fibrils compared to quiescent conditions. Besides shaking, the initial protein concentration in the formulation was found to control fibril length. Surprisingly, exchanging the solvent used for aggregate formation to a physiologically relevant buffer, had a striking effect on the morphological integrity of the fibril and spherulite samples. Especially the secondary structure of one of our spherulite samples presented dramatic changes of the aggregated β-sheet content after solvent exchange, emphasizing the importance of the aggregate stability. These results and considerations have profound implications on the data interpretation and should be implemented in the workflow for both fundamental characterization of aggregates as well as assays for evaluation of their corresponding biological effects.
Massive accumulation of strontium and barium in diplonemid protists
Authors: Pilátová Jana , Tashyreva Daria , Týč Jiří , Vancová Marie , Hussain Bokhari Syed Nadeem , Skoupý Radim , Klementová Mariana , Küpper Hendrik , Mojzeš Peter , Lukeš Julius 
Published: June 2022

SUMMARYBarium (Ba) and strontium (Sr) are often used as proxies for the reconstruction of past marine productivity and global climate. The ability to accumulate Ba2+ and Sr2+ in the form of crystals is rare among eukaryotes. Here we report that unicellular heterotrophs called diplonemids (Euglenozoa), one of the most abundant groups of marine planktonic protists, accumulate conspicuous amounts of these trace elements in the form of intracellular barite (BaSO4) and celestite (SrSO4) crystals, in concentrations greater than in other known Ba/Sr-accumulating organisms. Moreover, these flagellates can uptake Sr2+ exclusively or together with Ba2+ and form (Ba,Sr)SO4. One species, Namystinia karyoxenos, is naturally capable of intracellular accumulation of Ba2+ and Sr2+ 42,000 and 10,000 times relative to the surrounding medium. Altering the amounts of both elements in the medium resulted in corresponding changes in the quantity and composition of crystals. Planktonic copepods fed with diplonemids produce celestite-rich fecal pellets, which facilitate deposition of these minerals on the seafloor. We propose that diplonemids, which emerged during the Neoproterozoic era, qualify as impactful players of Ba2+/Sr2+ cycling in the ocean that possibly contributed to sedimentary rock formation over long geological periods.
Assessing the pathogenic potential of less common Salmonella enterica serotypes circulating in the Thai pork production chain
Authors: Eiamsam-ang Thanaporn , Tadee Pakpoom , Pascoe Ben , Patchanee Prapas 
Published: June 2022

AbstractSalmonella is a frequent zoonotic foodborne pathogen, with swine and pork meats the most common source of human infection. In Chiang Mai and Lamphun Province in northern Thailand, there has been a high prevalence of salmonellosis for over a decade. Infection is usually with several dominant S. enterica serotypes, including serotypes Rissen and Monophasic Typhimurium. However, several less common serotypes also contribute to disease. Whole genome sequencing of 43 of these less common S. enterica serotypes isolated from the pork production chain through 2011-2014 were used to evaluate their genetic diversity and virulence potential. Salmonella contamination at local retail markets represented cross-contamination from multiple sources, including decontaminated foodstuff. Previous studies have highlighted the importance of host cell adhesion, invasion and intracellular survival for the development of clinical salmonellosis. We screened our dataset for known virulence genes and antimicrobial resistance genes, identifying at least 10 antimicrobial resistance genes in all isolates. These results indicate that these less common S. enterica serotypes also pose a significant public health risk. Our findings support the need for appropriate surveillance of food products going to market to reduce public exposure to highly pathogenic, multi-drug resistant Salmonella. Surveillance throughout the pork production chain would motivate stakeholders to reinforce sanitation standards and help reduce the risk of salmonellosis in humans.
Emerging Evidence for Poxvirus-Mediated Unfolded Protein Response: Lumpy Skin Disease Virus Maintains Self-replication by Activating PERK and IRE1
Authors: Tan Jinlong , Liu Yinju , Yang Fan , Chen Guohua , Fang Yongxiang , He Xiaobing , Lou Zhongzi , Jia Huaijie , Jing Zhizhong , Li Weike 
Published: June 2022

ABSTRACTThe cytoplasmic replication of poxviruses requires extensive protein synthesis, challenging the capacity of the endoplasmic reticulum (ER). However, the role of the ER in the life cycle of poxviruses is unclear. In this study, we demonstrate that infection with the lumpy skin disease virus (LSDV), a poxvirus, causes ER stressin vivoandin vitro, further facilitating the activation of the unfolded protein response (UPR). Although UPR activation aids in the restoration of the cellular environment, its significance in the LSDV life cycle remains unclear. Furthermore, the role of ER imbalance for viral replication is also unknown. We show that LSDV replication is hampered by an unbalanced ER environment. In addition, we verify that the LSDV replication depends on the activation of PERK-eIF2α and IRE1-XBP1 signaling cascades rather than ATF6, implying that global translation and XBP1 cleavage are deleterious to LSDV replication. Our findings suggest that LSDV engages all UPR signaling sensors, and that activation of PERK and IRE1 sensors is indispensable to maintaining its own replication.IMPORTANCEAlthough numerous viruses cause ER stress and employ endogenous UPR components to control viral growth, there is no such evidence for poxviruses. Recent real-world epidemics of poxviruses such as monkeypox and LSDV indicated a lack of available coping strategies. Our findings show that LSDV encoding up to 156 open reading frames (ORFs) causes pressure to the stabilization of ER, triggers ER stress, and further promotes the activation of all three UPR signaling pathways. However, inhibiting PERK-eIF2α and IRE1-XBP1 was not conducive for LSDV replication. Since LSDV efficiently utilizes UPR components to assist its own replication, signal-blocking agents of PERK and IRE1 may be useful in the treatment of LSDV. More evidence for the efficacy of such therapy for LSDV, even monkeypox, could come from a clearer characterization of the ER stress-mediated viral replication process.
Avian Influenza A Virus polymerase can utilise human ANP32 proteins to support cRNA but not vRNA synthesis
Authors: Swann Olivia C. , Rasmussen Amalie B. , Peacock Thomas P. , Sheppard Carol M. , Barclay Wendy S. 
Published: June 2022

AbstractHost restriction limits the emergence of novel pandemic strains from the Influenza A Virus avian reservoir. For efficient replication in mammalian cells, the avian influenza RNA-dependent RNA polymerase must adapt to use human orthologues of the host factor ANP32, which lack a 33 amino acid insertion relative to avian ANP32A. Here we find that influenza polymerase requires ANP32 proteins to support both steps of replication: cRNA and vRNA synthesis. Nevertheless, avian strains are only restricted in vRNA synthesis in human cells. Therefore, avian polymerase can use human ANP32 orthologues to support cRNA synthesis, without acquiring mammalian adaptations. This implies a fundamental difference in the mechanism by which ANP32 proteins support cRNA vs vRNA synthesis.ImportanceIn order to infect humans and cause a pandemic, avian influenza must first learn how to use human versions of the proteins the virus hijacks for replication – instead of the avian versions found in bird cells. One such protein is ANP32. Understanding the details of how host proteins such as ANP32 support viral activity may allow the design of new antiviral treatments that disrupt these interactions. In this work, we use cells that lack ANP32 to unambiguously demonstrate ANP32 is needed for both steps of influenza genome replication. Surprisingly however, we find that avian influenza can use human ANP32 proteins for the first step of replication without any adaptation, but only avian ANP32 for the second step of replication. This suggests ANP32 may have an additional role in supporting the second step of replication, and it is this activity that is specifically blocked when avian influenza infects human cells.
Human gut metagenomes encode diverse GH156 sialidases
Authors: Mann Evan , Shekarriz Shahrokh , Surette Michael G. 
Published: June 2022

AbstractThe intestinal lining is protected by a mucous barrier composed predominantly of complex carbohydrates. Gut microbes employ an array of glycoside hydrolases (GHs) to liberate mucosal sugars as a nutrient source to facilitate host colonization. Intensive catabolism of mucosal glycans, however, may contribute to barrier erosion, pathogen encroachment and inflammation.Sialic acid is an acidic sugar featured at terminal positions of host glycans. Characterized sialidases from the microbiome belong to the GH33 family, according to CAZy (Carbohydrate Active enZyme) database classification. A 2018 functional metagenomics screen using thermal spring DNA uncovered the founding member of the GH156 sialidase family, which lacks homology to GH33 sialidases and could not be taxonomically assigned. Subsequent structural analysis revealed critical active site residues. We sought to determine if GH156 sialidases are present in the human gut microbiome where they might contribute to mucous erosion.A subset of GH156 sequences from the CAZy database containing key sialidase residues was used to build a Hidden Markov Model. HMMsearch against public databases revealed ∼10X more putative GH156 sialidases than currently recognized by CAZy. Represented phyla include Bacteroidota, Verrucomicrobiota and Firmicutes_A from human microbiomes, all of which play notable roles in carbohydrate fermentation. Genomic analyses suggested that taxa containing GH156-encoding genes may utilize host-glycans. Analyses of metagenomic datasets revealed that GH156s are frequently encoded in metagenomes, with a greater variety and abundance of GH156 genes observed in traditional hunter-gatherer or agriculturalist societies than in industrialized societies, particularly relative to individuals with IBD. A GH156 gene frequently detected in traditional populations was cloned from stool sample DNA and the recombinant protein exhibited sialidase activity with a fluorogenic substrate.ImportanceSialic acids occupy terminal positions of human glycans where they act as receptors for microbes, toxins and immune signaling molecules. Microbial enzymes that remove sialic acids, sialidases, are abundant in the human microbiome where they may contribute to shaping the microbiota community structure or contribute to pathology. Furthermore, sialidases have proven to hold therapeutic potential for cancer therapy. Here we examined the sequence space of a sialidase family of enzymes, GH156, previously unknown to the human gut environment. Our analyses suggest that human populations with disparate dietary practices harbour distinct varieties and abundances of GH156-encoding genes. Furthermore, we demonstrate the sialidase activity of a gut derived GH156. These results expand the diversity of sialidases that may contribute to host glycan degradation and these sequences may have biotechnological or clinical utility.