bluuebunny/crossref_metadata_2025_split huggingface dataset:
White matter connections of high-level visual areas predict cytoarchitecture better than category-selectivity in childhood, but not adulthood
Authors: Kubota Emily , Grotheer Mareike , Finzi Dawn , Natu Vaidehi S. , Gomez Jesse , Grill-Spector Kalanit 
Published: January 2022

AbstractVentral temporal cortex (VTC) consists of high-level visual regions that are arranged in consistent anatomical locations across individuals. This consistency has led to several hypotheses about the factors that constrain the functional organization of VTC. A prevailing theory is that white matter connections influence the organization of VTC, however, the nature of this constraint is unclear. Here, we test two hypotheses: (1) white matter tracts are specific for each category or (2) white matter tracts are specific to cytoarchitectonic areas of VTC. To test these hypotheses, we used diffusion magnetic resonance imaging (dMRI) to identify white matter tracts and functional magnetic resonance imaging (fMRI) to identify category-selective regions in VTC in children and adults. We find that in childhood, white matter connections are linked to cytoarchitecture rather than category-selectivity. In adulthood, however, white matter connections are linked to both cytoarchitecture and category-selectivity. These results suggest a rethinking of the view that category-selective regions in VTC have category-specific white matter connections early in development. Instead, these findings suggest that the neural hardware underlying the processing of categorical stimuli may be more domain-general than previously thought, particularly in childhood.
A draft genome assembly for the heterozygous wild tomato Solanum habrochaites highlights haplotypic structural variations of intracellular immune receptors
Authors: Seong Kyungyong , Shaw China Lunde , Seo Eunyoung , Li Meng , Krasileva Ksenia V , Staskawicz Brian 
Published: January 2022

AbstractSolanum habrochaites LA1353 is a self-incompatible, highly heterozygous wild tomato that is a useful germplasm resource for the study of metabolism, reproduction and disease resistance. We generated a draft genome assembly with PacBio HiFi reads and genome annotations, which underscored the expansion of gene families associated with metabolite-production, self-incompatibility, DNA regulation and immunity. After manually curating intracellular nucleotide-binding leucine-rich repeat immune receptors (NLRs), we found that S. habrochaites LA1353 has a larger NLR inventory than other wild tomato species. A great number of heterozygous local copy number variations (CNVs) driven by haplotypic structural variations further expands the inventory, both enhancing NLR diversity and providing more opportunities for sequence evolution. The NLRs associated with local CNVs predominantly appear in the helper NLR (NRC)-related phylogenetic clades and are concentrated in a few physical NLR gene clusters. Synteny analysis points out that these genomic regions correspond to the known NLR clusters from which experimentally validated, functional NLRs, such as Hero, Mi-1.2 and Rpi-amr1, have been identified. Producing and incorporating Resistance Gene Enrichment Sequencing (RenSeq) data across wild tomato species, we reveal that the regions with local CNVs might have been shaped nearly equally by recent NLR gains and losses, along with enhanced sequence diversification that diminishes one-to-one orthology between heterozygous alleles. Our analysis suggests that these genomic regions may have accelerated evolutionary dynamics for NLR diversity generation in S. habrochaites LA1353.
Pharmacological inhibition of HDAC6 downregulates TGF-β via Smad2/3 acetylation and improves dystrophin-deficient muscles
Authors: Osseni Alexis , Ravel-Chapuis Aymeric , Scionti Isabella , Gangloff Yann-Gaël , Moncollin Vincent , Mounier Remi , Leblanc Pascal , Jasmin Bernard J. , Schaeffer Laurent 
Published: January 2022

Abstract / SummaryThe absence of dystrophin in Duchenne muscular dystrophy (DMD) disrupts the dystrophin dystroglycan glycoprotein complex (DGC) resulting in fibers fragility and atrophy, associated with fibrosis and microtubules and neuromuscular junction (NMJ) disorganization. The specific non-conventional cytoplasmic histone deacetylase 6 (HDAC6) was previously shown to regulate acetylcholine receptor distribution and muscle atrophy. Here we show that administration of the HDAC6 specific inhibitor tubastatin A to the DMD mouse model mdx improves muscle strength, restores microtubules, NMJ and DGC organization, and reduces muscle atrophy and fibrosis. These effects involve the known action of HDAC6 on microtubules acetylation and muscle atrophy but also involve a yet undiscovered action of HDAC6 on transforming growth factor beta (TGF-β) signaling. Conversely, to inhibitors of nuclear HDACs that regulate TGF-β signaling via the activation of Follistatin expression, HDAC6 inhibition acts downstream of TGF-β ligands and receptors by increasing Smad2/3 acetylation in the cytoplasm which in turn inhibits its phosphorylation and transcriptional activity.
Deciphering polymorphism in 61,157 Escherichia coli genomes via epistatic sequence landscapes
Authors: Vigué Lucile , Croce Giancarlo , Petitjean Marie , Ruppé Etienne , Tenaillon Olivier , Weigt Martin 
Published: January 2022

AbstractCharacterizing the effect of mutations is key to understand the evolution of protein sequences and to separate neutral amino-acid changes from deleterious ones. Epistatic interactions between residues can lead to a context dependence of mutation effect. Context dependence constrains the amino-acid changes that can contribute to polymorphism in the short term, and the ones that can accumulate between species in the long term. We use computational approaches to accurately predict the polymorphisms segregating in a panel of 61,157 Escherichia coli genomes from the analysis of distant homologues. By comparing a context-aware Direct-Coupling Analysis modelling to a non-epistatic approach, we show that the genetic context strongly constrains the tolerable amino acids in 30% to 50% of amino-acid sites. The study of more distant species suggests the gradual build-up of genetic context over long evolutionary timescales by the accumulation of small epistatic contributions.
Can double PPO mutations exist in a same allele and are such mutants functional?
Authors: Porri Aimone , Noguera Matheus M. , Betz Michael , Sälinger Daniel , Brändle Frank , Bowe Steven J. , Lerchl Jens , Meyer Lucie , Knapp Michael , Roma-Burgos Nilda 
Published: January 2022

AbstractBackgroundResistance to PPO-inhibiting herbicides is primarily endowed by target site mutations at thePPO2gene that compromise binding of the herbicide to the catalytic domain. InAmaranthusssp.PPO2, the most prevalent target mutations are deletion of the G210 codon and the R128G and G339A substitutions. These mutations strongly affect the dynamic of the PPO2 binding pocket resulting in reduced affinity with the ligand. Here we investigated the likelihood of co-occurrence of the most widespread target site mutations in the sameppo2allele.ResultsPlants carrying R128G+/+ ΔG210+/-, where + indicates presence of the mutation, were crossed with each other. Theppo2of the offspring was subjected to pyrosequencing andE. coli-based Sanger sequencing to determine mutation frequencies and allele co-occurrence. The data show that R128G ΔG210 can occur only in one allele; the second allele carries only one mutation. Double mutation in both alleles is less likely because of significant loss of enzyme activity. The segregation of offspring populations derived from a cross between heterozygous plants carrying ΔG210 G399A also showed no co-occurrence in the same allele. The offspring exhibited the expected mutation distribution patterns with few exceptions.ConclusionsHomozygous double-mutants are not physiologically viable. Double-mutant plants can only exist in a heterozygous state. Alternatively, if two mutations are detected in one plant, each mutation would occur in a separate allele.NomenclaturePalmer amaranth,Amaranthus palmeriS. Wats.; protoporphyrinogen oxidase, PPO; tall waterhemp,Amaranthus tuberculatus(Moq.) J.D.Sauer
Deep learning can predict multi-omic biomarkers from routine pathology images: A systematic large-scale study
Authors: Arslan Salim , Mehrotra Debapriya , Schmidt Julian , Geraldes Andre , Singhal Shikha , Hense Julius , Li Xiusi , Bass Cher , Kather Jakob Nikolas , Pandya Pahini , Raharja-Liu Pandu 
Published: January 2022

AbstractWe assessed the pan-cancer predictability of multi-omic biomarkers from haematoxylin and eosin (H&E)-stained whole slide images (WSI) using deep learning (DL) throughout a systematic study. A total of 13,443 DL models predicting 4,481 multi-omic biomarkers across 32 cancer types were trained and validated. The investigated biomarkers included a broad range of genetic, transcriptomic, proteomic, and metabolic alterations, as well as established markers relevant for prognosis, molecular subtypes and clinical outcomes. Overall, we found that DL can predict multi-omic biomarkers directly from routine histology images across solid cancer types, with 50% of the models performing at an area under the curve (AUC) of more than 0.633 (with 25% of the models having an AUC larger than 0.711). A wide range of biomarkers were detectable from routine histology images across all investigated cancer types, with a mean AUC of at least 0.62 in almost all malignancies. Strikingly, we observed that biomarker predictability was mostly consistent and not dependent on sample size and class ratio, suggesting a degree of true predictability inherent in histomorphology. Together, the results of our study show the potential of DL to predict a multitude of biomarkers across the omics spectrum using only routine slides. This paves the way for accelerating diagnosis and developing more precise treatments for cancer patients.
Butterfly wings exhibit spatial variation in chromatin accessibility
Authors: Connahs Heidi , das Gupta Mainak , Monteiro Antónia 
Published: January 2022

AbstractButterfly wings exhibit a diversity of patterns which can vary between forewings and hindwings and spatially across the same wing. Regulation of morphological variation involves changes in how genes are expressed across different spatial scales which is driven by chromatin dynamics during development. How patterns of chromatin dynamics correspond to morphological variation remains unclear. Here we compared the chromatin landscape between forewings and hindwings and also across the proximal and distal regions of the hindwings in two butterfly species, Bicyclus anynana and Danaus plexippus. We found that the chromatin profile varied significantly between the different wing regions, however, there was no clear correspondence between the chromatin profile and the wing patterns. In some cases, wing regions with different phenotypes shared the same chromatin profile whereas those with a similar phenotype had a different profile. We also found that in the forewing, open chromatin regions (OCRs) were AT rich whereas those in the hindwing were GC rich. GC content of the OCRs also varied between the proximal and hindwing regions. These differences in GC content were also reflected in the transcription factor binding motifs that were differentially enriched between the wings and wing regions. Our results suggest that distinct wing patterns may result from the interaction of pioneer factors, including Hox genes, differentially opening chromatin in different wings and wing regions and cooperating with other transcriptions factors, that show preferences for specific GC content, to function either as activator or repressors of nearby genes.
Prostaglandin E1 as therapeutic molecule for Nephronophthisis and related ciliopathies
Authors: Garcia Hugo , Serafin Alice , Silbermann Flora , Poree Esther , Mahaut Clémentine , Viau Amandine , Billot Katy , Birgy Éléonore , Garfa-Traore Meriem , Roy Stéphanie , Cecarelli Salomé , Mehraz Manon , Rodriguez Pamela C. , Deleglise Bérangère , Furio Laetitia , Jabot-Hanin Fabienne , Cagnard Nicolas , Del Nery Elaine , Fila Marc , Sin-Monnot Soraya , Antignac Corinne , Lyonnet Stanislas , Krug Pauline , Salomon Rémi , Annereau Jean-Philippe , Benmerah Alexandre , Delous Marion , Briseño-Roa Luis , Saunier Sophie 
Published: January 2022

SummaryNephronophthisis (NPH) is an autosomal recessive tubulointerstitial nephropathy belonging to the ciliopathy disorders and known as the most common cause of hereditary end-stage renal disease in children. Yet, no curative treatment is available. The major gene, NPHP1, encodes a protein playing key functions at the primary cilium and cellular junctions. Using an in cellulo medium-throughput drug-screen, we identified 51 FDA-approved compounds and selected 11 for their physicochemical properties, including prostaglandin E1 (PGE1). PGE1 was further validated to rescue ciliogenesis in immortalized patient NPHP1-/- urine-derived renal tubular cells and corroborated by the effects of its analog PGE2. The two molecules reduced pronephric cyst occurrence in vivo in nphp4 zebrafish model, and PGE1 treatment in Nphp1-/- mice led to a significant reduction of renal tubular dilatations, partially restoring cilia length within tubules. Finally, comparative transcriptomics allowed identification of key molecules downstream PGE1. Altogether, our drug-screen strategy led to the identification of PGE1 as the first potential therapeutic molecule for NPH-associated ciliopathies.Significant statementJuvenile nephronophthisis (NPH) is a renal ciliopathy due to a dysfunction of primary cilia and a common genetic cause of end-stage renal disease in children and young adults. No curative treatment is available. This paper describes the identification of Prostaglandin E1 (PGE1) as the first potential therapeutic molecule for NPH-associated ciliopathies. We demonstrated that PGE1 rescues defective ciliogenesis and ciliary composition in NPHP1-/- patient urine-derived renal tubular cells. Furthermore, PGE1 improves ciliary and kidney phenotypes in our NPH zebrafish and Nphp1-/- mouse models. Finally, in vitro experiments as well as transcriptomic analyses pointed out several pathways downstream PGE1 as cAMP, cell-cell/cell-matrix adhesion or actin cytoskeleton. Altogether, our findings provide a new alternative for treatment of NPH.
Microglia integration into human midbrain organoids leads to increased neuronal maturation and functionality
Authors: Sabate-Soler Sonia , Nickels Sarah Louise , Saraiva Cláudia , Berger Emanuel , Dubonyte Ugne , Barmpa Kyriaki , Lan Yan Jun , Kouno Tsukasa , Jarazo Javier , Robertson Graham , Sharif Jafar , Koseki Haruhiko , Thome Christian , Shin Jay W. , Cowley Sally A. , Schwamborn Jens C. 
Published: January 2022

AbstractThe human brain is a complex, three-dimensional structure. To better recapitulate brain complexity, recent efforts have focused on the development of human specific midbrain organoids. Human iPSC-derived midbrain organoids consist of differentiated and functional neurons, which contain active synapses, as well as astrocytes and oligodendrocytes. However, the absence of microglia, with their ability to remodel neuronal networks and phagocytose apoptotic cells and debris, represents a major disadvantage for the current midbrain organoid systems. Additionally, neuro-inflammation related disease modeling is not possible in the absence of microglia. So far, no studies about the effects of human iPSC-derived microglia on midbrain organoid neural cells have been published. Here we describe an approach to derive microglia from human iPSCs and integrate them into iPSC-derived midbrain organoids. Using single nuclear RNA Sequencing, we provide a detailed characterization of microglia in midbrain organoids as well as the influence of their presence on the other cells of the organoids. Furthermore, we describe the effects that microglia have on cell death and oxidative stress- related gene expression. Finally, we show that microglia in midbrain organoids affect synaptic remodeling and increase neuronal excitability. Altogether, we show a more suitable system to further investigate brain development, as well as neurodegenerative diseases and neuro- inflammation.Main Points–Macrophage precursors can be efficiently co-cultured with midbrain organoids, they integrate into the tissue and differentiate into microglia in 3D.–Organoids containing microglia have a smaller size and show a down-regulation of oxidative stress-related genes.–Organoids co-cultured with microglia show differences in genes related to synaptic remodeling and action potential, as well as a more spontaneous action potential firing.
Histochemical Examination of Changes In Testis After Vasectomy In Rats And Qualitative Analysis Of Tissue Zinc Content
Authors: Ozcinar Emine , Ersoy Canillioglu Yasemin , Cetinel Sule 
Published: January 2022

ABSTRACTIt is claimed that around 100 million men worldwide have undergone vasectomy for birth control. Vasectomy is an operation to prevent the transfer of sperm by preventing the luminal continuity of the vas deferens. Degenerative changes after vasectomy usually start with loss of spermatogenic cells in the germinal epithelium, while Sertoli cells are affected later. There is no change in Leydig cells. Zinc, which is found at high rates in the male reproductive system, is an element in the structure of many enzymes necessary for cell membrane integrity, growth and sexual maturity.In this study, bilateral vasectomy was performed on 18 young adult male rats and control operation was performed on 18 rats. Afterwards, 6 animals from each group were sacrificed after 6 weeks, 12 weeks and 12 months. Germinal epithelium, tubule structure, basement membrane, interstitium and collagen fiber changes were examined at microscope and transmission electron microscope level. On the other hand, zinc content in testicular tissue was measured by Energy-dispersive X-ray spectroscopy (EDS). Six weeks after vasectomy, localized losses in the germinal epithelium and disorganization of spermatogenic cells were observed. In addition to the loss of spermatogenic cells at the 12th week, separations, thickening and an increase in the collagen fiber in the peritubular area were observed in the interstitium and perinuclear area. Tissue zinc content was also found to be the lowest in the 12 months group.In conclusion, our study showed that the degenerative changes in the rat testis that increased with time after vasectomy were parallel to the decrease in tissue zinc content.
A common venomous ancestor? Prevalent bee venom genes evolved before the aculeate stinger while few major toxins are bee-specific
Authors: Koludarov Ivan , Velasque Mariana , Timm Thomas , Greve Carola , Ben Hamadou Alexander , Gupta Deepak Kumar , Lochnit Günter , Heinzinger Michael , Vilcinskas Andreas , Gloag Rosalyn , Harpur Brock A. , Podsiadlowski Lars , Rost Burkhard , Jackson Timothy N. W. , Dutertre Sebastien , Stolle Eckart , von Reumont Björn M 
Published: January 2022

AbstractVenoms, which have evolved numerous times in animals, are ideal models of convergent trait evolution. However, detailed genomic studies of toxin-encoding genes exist for only a few animal groups. The hyper-diverse hymenopteran insects are the most speciose venomous clade, but investigation of the origin of their venom genes has been largely neglected. Utilising a combination of genomic and proteo-transcriptomic data, we investigated the origin of 11 toxin genes in 29 published and three new hymenopteran genomes and compiled an up-to-date list of prevalent bee venom proteins. Observed patterns indicate that bee venom genes predominantly originate through single gene co-option with gene duplication contributing to subsequent diversification. Most Hymenoptera venom genes are shared by all members of the clade and only melittin and the new venom protein family anthophilin1 appear unique to the bee lineage. Most venom proteins thus predate the mega-radiation of hymenopterans and the evolution of the aculeate stinger.
FOXO dictate initiation of B cell development and myeloid restriction in common lymphoid progenitors
Authors: Peña-Pérez Lucía , Kharazi Shabnam , Frengen Nicolai , Krstic Aleksandra , Bouderlique Thibault , Hauenstein Julia , He Minghui , Somuncular Ece , Li Wang Xiaoze , Dahlberg Carin , Gustafsson Charlotte , Johansson Ann-Sofie , Walfridsson Julian , Kadri Nadir , Woll Petter , Kierczak Marcin , Qian Hong , Westerberg Lisa , Luc Sidinh , Månsson Robert 
Published: January 2022

ABSTRACTThe development of B cells relies on an intricate network of transcription factors critical for developmental progression and lineage commitment. In the B cell developmental trajectory, a temporal switch from predominant Foxo3 to Foxo1 expression occurs at the CLP stage. Utilizing VAV-iCre mediated conditional deletion, we found that the loss of FOXO3 impaired B cell development from LMPP down to B cell precursors, while the loss of FOXO1 impaired B cell commitment and resulted in a complete developmental block at the CD25 negative proB cell stage. Strikingly, the combined loss of FOXO1 and FOXO3 resulted in the failure to restrict the myeloid potential of CLPs and the complete loss of the B cell lineage. This is underpinned by the failure to enforce the early B-lineage gene regulatory circuitry upon a predominantly pre-established open chromatin landscape. Altogether, this demonstrates that FOXO3 and FOXO1 cooperatively govern early lineage restriction and initiation of B-lineage commitment in CLPs.SUMMARYCommon lymphoid progenitors co-express the transcription factors FOXO1 and FOXO3. Removing FOXO1 and FOXO3 at this developmental stage results in regained myeloid potential, failed establishment of the early B cell gene regulatory program, and the complete loss of the B cell lineage.
Impact of neonatal activation of nuclear receptor CAR (Nr1i3) on Cyp2 gene expression in adult mouse liver
Authors: Shin Aram , Waxman David J. 
Published: January 2022

AbstractPerinatal exposure to environmental chemicals is proposed to reprogram development and alter disease susceptibility later in life. Supporting this, neonatal activation of the nuclear receptor CAR (Nr1i3) by TCPOBOP induces persistent expression of mouse hepatic Cyp2 genes into adulthood, attributed to long-term epigenetic memory of the early life exposure [Hepatology (2012) 56:1499-1509]. Here, we confirm that the same high-dose (15x ED50) neonatal TCPOBOP exposure used in that work induces prolonged (12 weeks) increases in hepatic Cyp2 expression; however, we show that the persistence of expression can be fully explained by the persistence of residual TCPOBOP in liver tissue. When the long-term presence of TCPOBOP in tissue was eliminated by decreasing the neonatal TCPOBOP dose 22-fold (0.67x ED50), strong neonatal increases in hepatic Cyp2 expression were still obtained but did not persist into adulthood. Furthermore, the neonatal ED50-range TCPOBOP exposure did not sensitize mice to a subsequent, low-dose TCPOBOP treatment. In contrast, neonatal treatment with phenobarbital, a short half-life (t1/2=8 h) agonist of CAR and of PXR (Nr1i2), induced high-level neonatal activation of Cyp2 genes and also altered their responsiveness to low-dose phenobarbital exposure at adulthood by either increasing (Cyp2b10) or decreasing (Cyp2c55) expression. Thus, neonatal xenobiotic exposure can reprogram hepatic Cyp2 genes and alter their responsiveness to exposures later in life. These findings highlight the need to carefully consider xenobiotic dose, half-life and persistence in tissue when evaluating the long-term effects of early life environmental chemical exposures.