bluuebunny/crossref_metadata_2025_split huggingface dataset:
MitoHiFi: a python pipeline for mitochondrial genome assembly from PacBio High Fidelity reads
Authors: Uliano-Silva Marcela , Gabriel R. N. Ferreira João , Krasheninnikova Ksenia ,   Darwin Tree of Life Consortium, Formenti Giulio , Abueg Linelle , Torrance James , Myers Eugene W. , Durbin Richard , Blaxter Mark , McCarthy Shane A. 
Published: December 2022

AbstractBackgroundPacBio high fidelity (HiFi) sequencing reads are both long (15-20 kb) and highly accurate (>Q20). Because of these properties, they have revolutionised genome assembly leading to more accurate and contiguous genomes. In eukaryotes the mitochondrial genome is sequenced alongside the nuclear genome often at very high coverage. A dedicated tool for mitochondrial genome assembly using HiFi reads is still missing.ResultsMitoHiFi was developed within the Darwin Tree of Life Project to assemble mitochondrial genomes from the HiFi reads generated for target species. The input for MitoHiFi is either the raw reads or the assembled contigs, and the tool outputs a mitochondrial genome sequence fasta file along with annotation of protein and RNA genes. Variants arising from heteroplasmy are assembled independently, and nuclear insertions of mitochondrial sequences are identified and not used in organellar genome assembly. MitoHiFi has been used to assemble 374 mitochondrial genomes (369 from 12 phyla and 39 orders of Metazoa and from 6 species of Fungi) for the Darwin Tree of Life Project, the Vertebrate Genomes Project and the Aquatic Symbiosis Genome Project. Inspection of 60 mitochondrial genomes assembled with MitoHiFi for species that already have reference sequences in public databases showed the widespread presence of previously unreported repeats.ConclusionsMitoHiFi is able to assemble mitochondrial genomes from a wide phylogenetic range of taxa from Pacbio HiFi data. MitoHiFi is written in python and is freely available on github (https://github.com/marcelauliano/MitoHiFi). MitoHiFi is available with its dependencies as a singularity image on github (ghcr.io/marcelauliano/mitohifi:master).
Native Adiponectin Plays a Role in the Adipocyte Mediated Conversion of Fibroblasts to Myofibroblasts
Authors: El-Hattab Mariam , Sinclair Noah , Liszewski Jesse , Schrodt Michael , Herrmann Jacob , Klingelhutz Aloysius J. , Sander Edward A. , Ankrum James A. 
Published: December 2022

AbstractAdipocytes regulate tissues through production of adipokines that can act both locally and systemically. Adipocytes also have been found to play a critical role in regulating the healing process. To better understand this role, we developed a 3D human adipocyte spheroid system that has an adipokine profile similar toin vivoadipose tissues. Previously, we found that conditioned medium from these spheroids induces human dermal fibroblast conversion into highly contractile, collagen producing myofibroblasts through a transforming growth factor beta-1 (TGF-β1) independent pathway. Here, we sought to identify how mature adipocytes signal to dermal fibroblasts through adipokines to induce myofibroblast conversion. By using molecular weight fractionation, heat inactivation, and lipid depletion, we determined mature adipocytes secrete a factor that is 30-100 kDa, heat labile, and lipid associated that induces myofibroblast conversion. We also show that depletion of the adipokine adiponectin, which fits those physiochemical parameters, eliminates the ability of adipocyte conditioned media to induce fibroblast to myofibroblast conversion. Interestingly, native adiponectin secreted by cultured adipocytes consistently elicited a stronger level ofα-SMA expression than exogenously added adiponectin. Thus, adiponectin secreted by mature adipocytes induces fibroblast to myofibroblast conversion and may lead to a phenotype of myofibroblasts distinct from TGF-β1 induced myofibroblasts.
Nucleotide binding halts diffusion of the eukaryotic replicative helicase during activation
Authors: Ramírez Montero Daniel , Sánchez Humberto , van Veen Edo , van Laar Theo , Solano Belén , Diffley John F. X. , Dekker Nynke H. 
Published: December 2022

SummaryThe eukaryotic replicative helicase CMG centrally orchestrates the replisome and leads the way at the front of replication forks1. Understanding the motion of CMG on the DNA is therefore key to our understanding of DNA replication.In vivo, CMG is assembled and activated through a cell-cycle-regulated mechanism involving 36 polypeptides that has been reconstituted from purified proteins in ensemble biochemical studies2,3. Conversely, single-molecule studies of CMG motion have thus far4–6relied on pre-formed CMG assembled through an unknown mechanism upon overexpression of individual constituents7,8. Here, we report the first activation at the single-molecule level of CMG fully reconstituted from purified yeast proteins and the quantification of its motion. We observe that CMG can move on DNA in two ways: by unidirectional translocation and by diffusion. We demonstrate that CMG preferentially exhibits unidirectional translocation in the presence of ATP, whereas it preferentially exhibits diffusive motion in the absence of ATP. We also demonstrate that nucleotide binding halts diffusive CMG. Taken together, our findings support a mechanism by which nucleotide binding allows newly assembled CMG to engage with the DNA within its central channel without melting it, halting its diffusion and facilitating the initial DNA melting required to initiate DNA replication.
Analysis of splicing abnormalities in the white matter of myotonic dystrophy type 1 brain using RNA-sequence
Authors: Yoshizumi Kazuki , Nishi Masamitsu , Igeta Masataka , Nakamori Masayuki , Matsumura Tsuyoshi , Fujimura Harutoshi , Jinnai Kenji , Kimura Takashi 
Published: December 2022

AbstractMyotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by the genomic expansions of CTG repeats, in which RNA-binding proteins, such as muscleblind-like protein, are sequestered in the nucleus, and abnormal splicing is observed in various genes. Although abnormal splicing reportedly occurs in the brains of patients with DM1, it is relation to the central nervous system symptoms is unknown. Several imaging studies have indicated substantial white matter (WM) defects in patients with DM1. Here, we performed RNA-sequencing and analysis of CTG repeat lengths in the frontal lobe of patients with DM1, separating the grey matter (GM) and WM, to investigate the splicing abnormalities in the DM1 brain, especially in the WM. The results demonstrated the number of repeats in the GM tended to be increase, with several genes showing similar levels of splicing abnormalities in the GM and WM, suggesting that the WM defects in DM1 are not only caused by aberrant splicing of GM RNA but also of WM RNA, which could be attributed to abnormal splicing of glial cell RNAs.
Longitudinal development of category representations in ventral temporal cortex predicts word and face recognition
Authors: Nordt Marisa , Gomez Jesse , Natu Vaidehi S. , Rezai Alex A. , Finzi Dawn , Kular Holly , Grill-Spector Kalanit 
Published: December 2022

AbstractRegions in ventral temporal cortex (VTC) that are involved in visual recognition of categories like words and faces, undergo differential development during childhood. However, categories are also represented in distributed responses across VTC. How do distributed category representations develop and relate to behavioral changes in recognition? Here, we used fMRI to longitudinally measure the development of distributed responses across VTC to 10 categories in school-age children over several years. Our results reveal both strengthening and weakening of category representations with age, which was mainly driven by changes across category-selective voxels. Representations became particularly more distinct for words in the left hemisphere and for faces bilaterally. Critically, distinctiveness for words and faces across category-selective voxels in left and right lateral VTC, respectively, predicted individual children’s word and face recognition performance. These results suggest that the development of distributed VTC representations has behavioral ramifications and advance our understanding of prolonged cortical development during childhood.
Antibody reliability influences observed mRNA-protein correlations in tumour samples
Authors: Upadhya Swathi Ramachandra , Ryan Colm J. 
Published: December 2022

AbstractReverse phase protein arrays (RPPA) have been used to quantify the abundances of hundreds of proteins across thousands of tumour samples in the Cancer Genome Atlas (TCGA). By number of samples, this is the largest tumour proteomic dataset available and it provides an opportunity to systematically assess the correlation between mRNA and protein abundances. However, the RPPA approach is highly dependent on antibody reliability and approximately one third of the antibodies used in the TCGA are deemed to be somewhat less reliable. Here, we assess the impact of antibody reliability on observed mRNA-protein correlations. We find that, in general, proteins measured with less reliable antibodies have lower observed mRNA-protein correlations. This is not true of the same proteins when measured using mass spectrometry. Furthermore, in cell lines, we find that when the same protein is quantified by both mass spectrometry and RPPA, the overall correlation between the two measurements is lower for proteins measured with less reliable antibodies. Overall our results reinforce the need for caution in using RPPA measurements from less reliable antibodies.
Quantitative pathogenicity and host adaptation in a fungal plant pathogen revealed by whole-genome sequencing
Authors: Amezrou Reda , Ducasse Aurélie , Compain Jérôme , Lapalu Nicolas , Pitarch Anais , Dupont Laetitia , Confais Johann , Goyeau Henriette , Kema Gert HJ , Croll Daniel , Amselem Joëlle , Sanchez-Vallet Andrea , Marcel Thierry C 
Published: December 2022

AbstractKnowledge of genetic determinism and evolutionary dynamics mediating host-pathogen interactions is essential to manage fungal plant diseases. Studies on the genetic architecture of fungal pathogenicity often focus on large-effect effector genes triggering strong, qualitative resistance. It is not clear how this translates to predominately quantitative interactions. Here, we use theZymoseptoria tritici-wheat model to elucidate the genetic architecture of quantitative pathogenicity and mechanisms mediating host adaptation. With a multi-host genome-wide association study, we identify 19 high-confidence candidate genes associated with quantitative pathogenicity. Analysis of genetic diversity reveals that sequence polymorphism is the main evolutionary process mediating differences in quantitative pathogenicity, a process that is likely facilitated by genetic recombination and transposable element dynamics. Finally, we use functional approaches to confirm the role of an effector-like gene and a methyltransferase in phenotypic variation. This study highlights the complex genetic architecture of quantitative pathogenicity, extensive diversifying selection and plausible mechanisms facilitating pathogen adaptation.
Resistance mechanism to Notch inhibition and combination therapy in human T cell acute lymphoblastic leukemia
Authors: Cao Linlin , Ruiz Buendía Gustavo A. , Fournier Nadine , Liu Yuanlong , Armand Florence , Hamelin Romain , Pavlou Maria , Radtke Freddy 
Published: December 2022

AbstractGain-of-function mutations inNOTCH1are among the most frequent genetic alterations in T cell acute lymphoblastic leukemia (T-ALL), making the Notch signaling pathway a promising therapeutic target for personalized medicine. Yet, a major limitation for long-term success of targeted therapy is relapse due to tumor heterogeneity or acquired resistance. Thus, we performed a genome-wide CRISPR-Cas9 screen to identify prospective resistance mechanisms to pharmacological NOTCH inhibitors and novel targeted combination therapies to efficiently combat T-ALL. Mutational loss ofPhosphoinositide-3-Kinase regulatory subunit 1 (PIK3R1)causes resistance to Notch inhibition.PIK3R1deficiency leads to increased PIK3/Akt signaling which regulates the cell cycle and spliceosome machinery, both at the transcriptional and post-translational level. Moreover, several therapeutic combinations have been identified, where simultaneous targeting of the cyclin-dependent kinases 4 and 6 (CDK4/6) and NOTCH proved to be the most efficacious in T-ALL xenotransplantation models.Key pointsMutational loss ofPIK3R1induces resistance to NOTCH1 inhibition in T-ALLPharmacological Notch inhibition synergizes with CDK4/6 inhibitors in T-ALL
Inter-domain distance prediction based on deep learning for domain assembly
Authors: Ge Fengqi , Peng Chunxiang , Cui Xinyue , Xia Yuhao , Zhang Guijun 
Published: December 2022

AbstractAlphaFold2 achieved a breakthrough in protein structure prediction through the end-to-end deep learning method, which can predict nearly all single-domain proteins at experimental resolution. However, the prediction accuracy of full-chain proteins is generally lower than that of single-domain proteins because of the incorrect interactions between domains. In this work, we develop an inter-domain distance prediction method, named DeepIDDP. In DeepIDDP, we design a neural network with attention mechanisms, where two new inter-domain features are used to enhance the ability to capture the interactions between domains. Furthermore, we propose a data enhancement strategy termed DPMSA, which is employed to deal with the absence of co-evolutionary information on targets. We integrate DeepIDDP into our previously developed domain assembly method SADA, termed SADA-DeepIDDP. Tested on a given multi-domain benchmark dataset, the accuracy of SADA-DeepIDDP inter-domain distance prediction is 11.3% and 21.6% higher than trRosettaX and trRosetta, respectively. The accuracy of the domain assembly model is 2.5% higher than that of SADA. Meanwhile, we reassemble 68 human multi-domain protein models with TM-score ≤0.80 from the AlphaFold protein structure database, where the average TM-score is improved by 11.8% after the reassembly by our method. The online server is athttp://zhanglab-bioinf.com/DeepIDDP/.
The plant stress hormone jasmonic acid evokes defensive responses in streptomycetes
Authors: van der Meij Anne , Elsayed Somayah S. M. A. , Du Chao , Willemse Joost , Wood Thomas M. , Martin Nathaniel I. , Raaijmakers Jos M. , van Wezel Gilles P. 
Published: December 2022

ABSTRACTActinobacteria are prevalent in the rhizosphere and phyllosphere of diverse plant species where they help to enhance tolerance of plants against biotic and abiotic stresses. Here, we show that the plant hormones jasmonic acid (JA) and methyljasmonate (MeJA) alter growth, development and specialized metabolism ofStreptomyces. Challenge ofStreptomyces coelicolorwith JA or MeJA led to strongly enhanced production of the polyketide antibiotic actinorhodin. JA is toxic toStreptomycetaceae, whereby members of the genusStreptacidiphilusare generally more sensitive than streptomycetes. As a defensive response, extensive amino acid conjugation of JA was observed; the most prevalent conjugation was with glutamine (Gln), while conjugates with Val, Tyr, Phe and Leu/Ile were identified after longer exposure to JA. Synthetic JA conjugates failed to activate antibiotic production and had strongly reduced toxicity, strongly suggesting that conjugation inactivates JA and serves to detoxify the hormone. Thus, for the first time we provide evidence that plant hormones modulate growth, development and secondary metabolism of streptomycetes, whereby amino acid conjugation serves as a defense strategy by the bacteria to circumvent plant hormone toxicity.IMPORTANCEMicroorganisms that live on or inside plants greatly influence plant health. Streptomycetes are considered to have an important role in defense against plant diseases, but the mechanisms through which they protect plants are currently not fully understood. It has been suggested that streptomycetes respond to changes in the plant’s physiology, among others by producing protective molecules; however, little is known of the signal transduction from plant to bacterium. We here demonstrate that the plant hormones jasmonic acid (JA) and methyljasmonate (MeJA) directly influence the life cycle of streptomycetes by modulating antibiotic synthesis and promoting faster development. Moreover, the plant hormones specifically stimulate the synthesis of the polyketide antibiotic actinorhodin inStreptomyces coelicolor. Jasmonic acid is then modified in the cell by amino acid conjugation, which reduces the bioactivity of the hormone and thus quenches the signal. To the best of our knowledge, this has not been reported previously. Collectively, these results suggest a relationship between plant physiological changes and the response of streptomycetes in multiple ways.
Magnetic bioprinting of stem cell-based tissues
Authors: Van de Walle Aurore , Perez Jose Efrain , Wilhelm Claire 
Published: December 2022

AbstractAn attractive approach in cell therapies and medically oriented nanotechnologies is to interface magnetic nanoparticles with cells. This will supply the cells with sufficient magnetization for theranostic applications and for external magnetic field manipulation.In tissue engineering, one challenge is to produce tissue analogues that are large, precisely organized, and responsive to stimuli, preferably without the need for an artificial supporting scaffold. One powerful tool for such biofabrication is certainly the bioprinting technology.In magnetic tissue engineering, it appears possible to use magnetic forces to manipulate cells, both individually and within aggregates, and thereby to produce three-dimensional artificial tissues with inherent capacities for further physical stimulation, a possibility that bioprinting does not offer yet.We here introduce the feasibility of using magnetic forces created by external (micro)magnets to form 3D tissue-like scaffold-free structures. Because stem cells are essential in tissue engineering, such magnetic technologies were developed with magnetized stem cells, and applied for instance to vascular or cartilage tissue engineering. One precondition to this approach, which lies in the magnetization of (stem) cells endowed through internalization of iron oxide magnetic nanoparticles, is to ensure the safety of magnetic nanoparticles with respect to cellular functions, which is initially discussed.Finally, we introduce a magnetic tissue stretcher which, in a single step, allows to create a tissue composed of any type of component cell, then to mature it, stimulate it by compression or stretching at any desired frequency, e.g. cyclically, opening new possibilities in the cardiac muscle tissue engineering field.
Tau depletion in human neurons mitigates Aβ-driven toxicity
Authors: Ng Bryan , Vowles Jane , Beccano-Kelly Dayne , Stefana M Irina , O’Brien Darragh P. , Bengoa-Vergniory Nora , Betherat Feodora , Abey Ajantha , Carling Philippa , Kilfeather Peter , Todd John A. , Caffrey Tara M. , Connor-Robson Natalie , Cowley Sally A. , Wade-Martins Richard 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is an age-related neurodegenerative condition and the most common type of dementia, characterised by pathological accumulation of extracellular plaques and intracellular neurofibrillary tangles that mainly consist of amyloid-β (Aβ) and hyperphosphorylated tau aggregates, respectively. Previous studies in mouse models with a targeted knock-out of the microtubule-associated protein tau(Mapt)gene demonstrated that Aβ-driven toxicity is tau-dependent. However, human cellular models with chronic tau lowering remain unstudied.MethodsIn this study, we generated stable tau-depleted human induced pluripotent stem cell (iPSC) isogenic panels from two healthy individuals using CRISPR-Cas9 technology. We then differentiated these iPSCs into cortical neuronsin vitroin co-culture with primary rat cortical astrocytes before conducting electrophysiological and imaging experiments for a wide range of disease-relevant phenotypes. Both AD brain derived and recombinant Aβ were used in this study to elicit toxic responses from the iPSC- derived cortical neurons.ResultsWe showed that tau depletion in human iPSC-derived cortical neurons caused considerable reductions in neuronal activity without affecting synaptic density. We also observed neurite outgrowth impairments in two of the tau-depleted lines used. We found axonal transport of mitochondria, mitochondrial function, and cortical neuron differentiation propensity remained unaffected regardless of tau expression levels. Finally, tau depletion protected neurons from adverse effects mitigating the impact of exogenous Aβ-induced hyperactivity, deficits in retrograde axonal transport of mitochondria, and neurodegeneration.ConclusionsOur study established stable human iPSC isogenic panels with chronic tau depletion from two healthy individuals. Cortical neurons derived from these iPSC lines showed that tau is essential in Aβ-driven hyperactivity, axonal transport deficits, and neurodegeneration, consistent with studies conducted inMapt-/-mouse models. These findings highlight the protective effects of chronic tau lowering strategies in AD pathogenesis and reinforce the potential in clinical settings. The tau-depleted human iPSC models can now be applied at scale to investigate the involvement of tau in disease-relevant pathways and cell types.
Spatial Evolution of Information Dynamics in the Primary Motor Cortex During Reach
Authors: Liang Wei , Papadourakis Vasileios , Hatsopoulos Nicholas G. 
Published: December 2022

AbstractThe primary motor cortex (M1) is known to be spatially organized in terms of muscles and body parts, notwithstanding some overlap. However, the classical view is largely static, neglecting potential representational changes on a fast time scale. To address potential representational dynamics, we probed the mutual information between M1 signals recorded across the cortical sheet and electromyography (EMG) activity from a set of muscles while a macaque monkey performed planar reaches. Here, we demonstrated that the spatial organization of the M1 encoding was in fact quite dynamic throughout the course of a reaching movement such that a given cortical site maximally encoded different muscles at different times. Despite these rapid representational changes, a proximal-to-distal gradient of the upper limb representation was preserved particularly close to movement onset. Representation was most stable close to movement onset, with characteristic topographic maps, possibly serving functional needs. This study bridges the important gap between flexible motor encoding and static motor maps, emphasizing the importance of considering space and time together in motor representation studies.