bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOT1L deletion impairs the development of cortical Parvalbumin-expressing interneurons
Authors: Cheffer Arquimedes , Garcia-Miralles Marta , Maier Esther , Akol Ipek , Franz Henriette , Vedartham Srinivasan Vandana Shree , Vogel Tanja 
Published: January 2023

AbstractThe cortical plate is composed of excitatory and inhibitory neurons, the latter of which originate in the ganglionic eminences. From their origin in the ventral telencephalon, interneuron precursors migrate during embryonic development over some distance to reach their final destination in the cortical plate. The histone methyltransferase DOT1L is necessary for proper cortical plate development and layer distribution of glutamatergic neurons, however, its specific role on cortical interneuron development has not yet been explored. Here, we demonstrate that DOT1L affects interneuron development in a cell-autonomous manner. Deletion ofDot1lin MGE-derived interneuron precursor cells results in an overall reduction and altered distribution of GABAergic interneurons in the cortical plate at postnatal day (P) 0. Furthermore, we observed an altered proportion of GABAergic interneurons in the cortex and striatum at P21 with a significant decrease in Parvalbumin (PVALB)-expressing interneurons. Altogether, our results indicate that reduced numbers of cortical interneurons upon DOT1L deletion results from altered post-mitotic differentiation/maturation.
ZMYM2 controls human transposable element transcription through distinct co-regulatory complexes
Authors: Owen Danielle , Aguilar-Martinez Elisa , Ji Zongling , Li Yaoyong , Sharrocks Andrew D. 
Published: January 2023

AbstractZMYM2 is a zinc finger transcriptional regulator that plays a key role in promoting and maintaining cell identity. It has been implicated in several diseases such as congenital anomalies of the kidney where its activity is diminished and cancer where it participates in oncogenic fusion protein events. ZMYM2 is thought to function through promoting transcriptional repression and here we provide more evidence to support this designation. Here we studied ZMYM2 function in human cells and demonstrate that ZMYM2 is part of distinct chromatin-bound complexes including the established LSD1-CoREST-HDAC1 corepressor complex. We also identify new functional and physical interactions with ADNP and TRIM28/KAP1. The ZMYM2-TRIM28 complex forms in a SUMO-dependent manner and is associated with repressive chromatin. ZMYM2 and TRIM28 show strong functional similarity and co-regulate a large number of genes. However, there are no strong links between ZMYM2-TRIM28 binding events and nearby individual gene regulation. Instead, ZMYM2-TRIM28 appears to regulate genes in a more regionally defined manner within TADs where it can directly regulate co-associated retrotransposon expression. We find that different types of ZMYM2 binding complex associate with and regulate distinct subclasses of retrotransposons, with ZMYM2-ADNP complexes at SINEs and ZMYM2-TRIM28 complexes at LTR elements. We propose a model whereby ZMYM2 acts directly through retrotransposon regulation, which may then potentially affect the local chromatin environment and associated coding gene expression.Genome browser sessionUCSC browser session containing the peak tracks:http://genome.ucsc.edu/cgi-bin/hgTracks?db=hg19&position=chr1:18,078,462-18,084,961&hide=all&hgct_customText=http://bartzabel.ls.manchester.ac.uk/sharrockslab/yaoyong/ZNF198/index_file_hg19_chipSeq_ZMYM2_final.txtOriginal ChIP-seq and ATAC-seq data from U2OS cells can be viewed On ArrayExpress at: E-MTAB-12292 (ADNP and TRIM28 ChIP-seq), E-MTAB-12293 (SUMO ChIP-seq) and E-MTAB-12294 (ATAC-seq)
Identification of diverse antibiotic resistant bacteria in agricultural soil with H218O stable isotope probing and metagenomics
Authors: Hernández Marcela , Roy Shamik , Keevil C. William , Dumont Marc G. 
Published: January 2023

AbstractBackgroundIn this study, we aimed to identify bacteria able to grow in the presence of several antibiotics including the ultra-broad-spectrum antibiotic meropenem in a British agricultural soil, by combining DNA stable isotope probing (SIP) with high throughput sequencing. Soil was incubated with cefotaxime, meropenem, ciprofloxacin and trimethoprim in18O-water. Metagenomes and the V4 region of the 16S rRNA gene from the labelled “heavy” and the unlabelled “light” SIP fractions were sequenced.ResultsAfter incubations, an increase of the 16S rRNA copy numbers in the “heavy” fractions of the treatments with18O-water compared with their controls was detected. The treatments resulted in differences in the community composition of bacteria. Members of the phyla Acidobacteriota (formally Acidobacteria) are highly abundant after two days of incubation with antibiotics. Several Pseudomonadota (formally Proteobacteria) includingStenotrophomonaswere prominent after four days of incubation. Furthermore, a metagenome-assembled genome (MAG-1) from the genusStenotrophomonas(90.7% complete) was retrieved from the heavy fraction. Finally, 11 antimicrobial resistance genes (ARGs) were identified in the unbinned-assembled heavy fractions, and 10 ARGs were identified in MAG-1. On the other hand, only two ARGs from the unbinned-assembled light fractions were identified.ConclusionsThe results indicate that both non-pathogenic soil-dwelling bacteria as well as potential clinical pathogens are present in this agricultural soil, and several ARGs were identified from the labelled communities, but it is still unclear if horizontal gene transfer between these groups can occur.
Membrane-dependent actin polymerization mediated by theLegionella pneumophilaeffector protein MavH
Authors: Zhang Qing , Wan Min , Mao Yuxin 
Published: January 2023

ABSTRACTL. pneumophilapropagates in eukaryotic cells within a specialized niche, theLegionella-containing vacuole (LCV). The infection process is controlled by over 330 effector proteins delivered through the type IV secretion system. In this study, we report that theLegionellaMavH effector harbors a lipid-binding domain that specifically recognizes PI(3)P (phosphatidylinositol 3-phosphate) and localizes to endosomes when ectopically expressed. We show that MavH recruits host actin capping proteins (CP) and actin to the endosome via its CP interacting (CPI) motif and WH2-like actin-binding domain, respectively. In vitro assays revealed that MavH stimulates robust actin polymerization only in the presence of PI(3)P-containing liposomes and the recruitment of CP by MavH negatively regulates F-actin density at the membrane. Furthermore, inL. pneumophila-infected cells, MavH can be detected around the LCV at the very early stage of infection. Together, our results reveal a novel mechanism of membrane-dependent actin polymerization catalyzed by MavH that may play a role at the early stage ofL. pneumophilainfection by regulating host actin dynamics.
Ribonucleotide Reductase Subunit Switching in Hepatoblastoma Drug Response and Relapse
Authors: Brown Anthony , Pan Qingfei , Fan Li , Indersie Emilie , Tian Cheng , Timchenko Nikolai , Li Liyuan , Hansen Baranda S. , Tan Haiyan , Lu Meifen , Peng Junmin , Pruett-Miller Shondra M. , Yu Jiyang , Cairo Stefano , Zhu Liqin 
Published: January 2023

ABSTRACTPrognosis of children with high-risk hepatoblastoma (HB), the most common pediatric liver cancer, remains poor. In this study, we found ribonucleotide reductase (RNR) subunit M2 (RRM2) was one of the key genes supporting cell proliferation in high-risk HB. While standard chemotherapies could effectively suppress RRM2 in HB cells, they induced a significant upregulation of the other RNR M2 subunit,RRM2B. Computational analysis revealed distinct signaling networks RRM2 andRRM2Bwere involved in HB patient tumors, with RRM2 supporting cell proliferation andRRM2Bparticipating heavily in stress response pathways. Indeed,RRM2Bupregulation in chemotherapy-treated HB cells promoted cell survival and subsequent relapse, during whichRRM2Bwas gradually replaced back by RRM2. Combining an RRM2 inhibitor with chemotherapy showed an effective delaying of HB tumor relapse in vivo. Overall, our study revealed the distinct roles of the two RNR M2 subunits and their dynamic switching during HB cell proliferation and stress response.
The effects of repeated intraperitoneal administration of the GABABreceptor agonist baclofen on body weight in rats maintained on a restricted feeding schedule
Authors: Ebenezer Ivor S. 
Published: January 2023

AbstractIt has previously been shown that chronic systemic administration of the GABABagonist, baclofen, reduces body weight in free feeding rats but has no effect on long-term food intake. The present study was conducted to extend these observations by investigating the effects of baclofen on body weight, food intake and water consumption in rats maintained on a restricted feeding schedule. The rats were allowed free access to food for 3 hours each day and injected intraperitoneally (i.p) once daily over a period of 11 days with baclofen (4 mg / kg; n=8) or saline (Control Group; n=8) immediately after each feeding session. Baclofen treatment produced small decreases in food intake on Days 2, 4 and 5 (P<0.05) compared with control animals but there were no differences between the 2 groups on Days 6 to 11. Baclofen did not affect prandial water intake. However, baclofen significantly decreased body weight gain of the animals (F(1,14)= 22.0,P< 0.01) starting 3 days after the initiation of treatment. During the subsequent 9 days both groups received no treatments. However, the “Baclofen Group” continued displaying significant reductions in body weight gain (F(1,14)= 8.47 p<0.01) but there were no significant differences in food and water consumption between the 2 groups of animals. The results of this study indicate that repeated administration of baclofen to food-restricted rats for 11 days reduces body weight and that the effects persist when the drug is withdrawn. While it is possible that the decrease in food intake during the early period of the experiment may have been partly responsible for the reduction in body weight in the baclofen-treated animals, the observation that these rats displayed reduction in body weight during the latter part of the study when there was no significant differences in food intake between the 2 groups, suggests that the drug decreases body weight independently of its effects on food consumption.
Temporal variability and cell mechanics control robustness in mammalian embryogenesis
Authors: Fabrèges Dimitri , Murtra Bernat Corominas , Moghe Prachiti , Kickuth Alison , Ichikawa Takafumi , Iwatani Chizuru , Tsukiyama Tomoyuki , Daniel Nathalie , Gering Julie , Stokkermans Anniek , Wolny Adrian , Kreshuk Anna , Duranthon Véronique , Uhlmann Virginie , Hannezo Edouard , Hiiragi Takashi 
Published: January 2023

AbstractHow living systems achieve precision in form and function despite their intrinsic stochasticity is a fundamental yet open question in biology. Here, we establish a quantitative morphomap of pre-implantation embryogenesis in mouse, rabbit and monkey embryos, which reveals that although blastomere divisions desynchronise passively without compensation, 8-cell embryos still display robust 3D structure. Using topological analysis and genetic perturbations in mouse, we show that embryos progressively change their cellular connectivity to a preferred topology, which can be predicted by a simple physical model where noise and actomyosin-driven compaction facilitate topological transitions lowering surface energy. This favours the most compact embryo packing at the 8- and 16-cell stage, thus promoting higher number of inner cells. Impairing mitotic desynchronisation reduces embryo packing compactness and generates significantly more cell mis-allocation and a lower proportion of inner-cell-mass-fated cells, suggesting that stochasticity in division timing contributes to achieving robust patterning and morphogenesis.
Leveraging genomic redundancy to improve inference and alignment of orthologous proteins
Authors: Singleton Marc , Eisen Michael 
Published: January 2023

AbstractIdentifying protein sequences with common ancestry is a core task in bioinformatics and evolutionary biology. However, methods for inferring and aligning such sequences in annotated genomes have not kept pace with the increasing scale and complexity of the available data. Thus, in this work we implemented several improvements to the traditional methodology that more fully leverage the redundancy of closely related genomes and the organization of their annotations. Two highlights include the application of the more flexiblek-clique percolation algorithm for identifying clusters of orthologous proteins and the development of a novel technique for removing poorly supported regions of alignments with a phylogenetic HMM. In making the latter, we also wrote a fully documented Python package Homomorph that implements standard HMM algorithms and created a set of tutorials to promote its use by a wide audience. We applied the resulting pipeline to a set of 33 annotatedDrosophilagenomes, generating 22,813 orthologous groups and 8,566 high-quality alignments.
The Impact of Species Tree Estimation Error on Cophylogenetic Reconstruction
Authors: Zheng Julia , Nishida Yuya , Okrasińska Alicja , Bonito Gregory M. , Heath-Heckman Elizabeth A.C. , Liu Kevin J. 
Published: January 2023

AbstractJust as a phylogeny encodes the evolutionary relationships among a group of organisms, a cophylogeny represents the coevolutionary relationships among symbiotic partners. Both are widely used to investigate a range of topics in evolutionary biology and beyond. Both are also primarily reconstructed using computational analysis of biomolecular sequence data as well as other biological character data. The most widely used cophylogenetic reconstruction methods utilize an important simplifying assumption: species phylogenies for each set of coevolved taxa are required as input and assumed to be correct. Many theoretical and experimental studies have shown that this assumption is rarely – if ever – satisfied, and the consequences for cophylogenetic studies are poorly understood. To address this gap, we conduct a comprehensive performance study that quantifies the relationship between species tree estimation error and downstream cophylogenetic estimation accuracy. The study includes performance benchmarking usingin silicomodel-based simulations. Our investigation also includes assessments of cophylogenetic reproducibility using genomic sequence datasets sampled from two important models of symbiosis: soil-associated fungi and their endosymbiotic bacteria, and bobtail squid and their bioluminescent bacterial symbionts. Our findings conclusively demonstrate the major impact that upstream phylogenetic estimation error has on downstream cophylogenetic reconstruction quality.
Investigating the Complexity of Gene Co-expression Estimation for Single-cell Data
Authors: Zhang Jiaqi , Singh Ritambhara 
Published: January 2023

AbstractWith the rapid advance of single-cell RNA sequencing (scRNA-seq) technology, understanding biological processes at a more refined single-cell level is becoming possible. Gene co-expression estimation is an essential step in this direction. It can annotate functionalities of unknown genes or construct the basis of gene regulatory network inference. This study thoroughly tests the existing gene co-expression estimation methods on simulation datasets with known ground truth co-expression networks. We generate these novel datasets using two simulation processes that use the parameters learned from the experimental data. We demonstrate that these simulations better capture the underlying properties of the real-world single-cell datasets than previously tested simulations for the task. Our performance results on tens of simulated and eight experimental datasets show that all methods produce estimations with a high false discovery rate potentially caused by high-sparsity levels in the data. Finally, we find that commonly used pre-processing approaches, such as normalization and imputation, do not improve the co-expression estimation. Overall, our benchmark setup contributes to the co-expression estimator development, and our study provides valuable insights for the community of single-cell data analyses.
Systematic Analysis of Network-driven Adaptive Resistance to CDK4/6 and Estrogen Receptor Inhibition using Meta-Dynamic Network Modelling
Authors: Hart Anthony , Shin Sung-Young , Nguyen Lan K. 
Published: January 2023

ABSTRACTDrug resistance inevitably emerges during the treatment of cancer by targeted therapy. Adaptive resistance is a major form of drug resistance, wherein the rewiring of protein signalling networks in response to drug perturbation allows the drug-targeted protein’s activity to recover, despite the continuous presence of the drug, enabling the cells to survive/grow. Simultaneously, molecular heterogeneity enables the selection of drug-resistant cancer clones that can survive an initial drug insult, proliferate, and eventually cause disease relapse. Despite their importance, the link between heterogeneity and adaptive resistance, specifically how heterogeneity influences protein signalling dynamics to drive adaptive resistance, remains poorly understood. Here, we have explored the relationship between heterogeneity, protein signalling dynamics and adaptive resistance through the development of a novel modelling technique coined Meta Dynamic Network (MDN) modelling. We use MDN modelling to characterise how heterogeneity influences the drug-response signalling dynamics of the proteins that regulate early cell cycle progression and demonstrate that heterogeneity can robustly facilitate adaptive resistance associated dynamics for key cell cycle regulators. We determined the influence of heterogeneity at the level of both protein interactions and protein expression and show that protein interactions are a much stronger driver of adaptive resistance. Owing to the mechanistic nature of the underpinning ODE framework, we then identified a full spectrum of subnetworks that drive adaptive resistance dynamics in the key early cell cycle regulators. Finally, we show that single-cell dynamic data supports the validity of our MDN modelling technique and a comparison between our predicted resistance mechanisms and known CDK4/6 and Estrogen Receptor inhibitor resistance mechanisms suggests MDN can be deployed to robustly predict network-level resistance mechanisms for novel drugs and additional protein signalling networks.
Alteration of neural network and hippocampal slice activation through exosomes derived from 5XFAD nasal lavage fluid
Authors: Kim Sang Seong , Jeon Jae Kyong , Ganbat Dulguun , Kim Taewoon , Shin Kyusoon , Hong Sungho , Hong Jong Wook 
Published: January 2023

AbstractExosomes contain various intracellular biomarkers reflecting the condition of cells, organs, and subjects. Under neurodegenerative conditions, they contrive in detrimental neuronal communications leading to the initiation and propagation of neurodegenerative symptoms. Since the exosomes in olfactory fluid are readily accessible to collect in ample amount noninvasively and highly enriched in neural biomarkers, they can be a primary biomarker if we can verify precise pathophysiological information from them. Here we show that exosomes from nasal lavage fluid (NLF) of the neurodegeneration model animal, 5XFAD mice, induce the pathological network activity in neuronal cultures. We separated intact NLF exosomes from the 5XFAD and wild-type mice via a high-efficacy microfluidic system and applied them to the primary cortical neurons and organotypic hippocampal slice cultures (OHSC), whose neuronal activities were monitored by a high-density microelectrode array system. We found that NLF exosomes from 5XFAD mice increased the firing rate of neuronal spikes with augmentation of neuronal connectivity similar to the effect of pathological amyloid beta oligomer treatment. Furthermore, the current source densities, computed from the local field potentials, were elevated in OHSCs incubated with the exosomes, suggesting a pathological shift in synaptic and membrane currents. Those results demonstrate that NLF exosomes from neurodegeneration model can effectively modify neuronal networks and suggest that this property can serve as a functional biomarker for Alzheimer’s disease.
Stereoinversion via alcohol dehydrogenases enables complete catabolism of β-1-type lignin-derived aromatic isomers
Authors: Kato Ryo , Maekawa Kodai , Kobayashi Shota , Hishiyama Shojiro , Katahira Rui , Nambo Miki , Higuchi Yudai , Kuatsjah Eugene , Beckham Gregg T. , Kamimura Naofumi , Masai Eiji 
Published: January 2023

ABSTRACTSphingobiumsp. SYK-6 is an efficient aromatic catabolic bacterium that can consume all four stereoisomers of 1,2-diguaiacylpropane-1,3-diol (DGPD), which is a ring-opened β-1-type dimer. Recently, LdpA-mediated catabolism oferythro-DGPD was reported in SYK-6, but the catabolic pathway forthreo-DGPD was heretofore unknown. Here we elucidated the catabolism ofthreo-DGPD, which proceeds through conversion toerythro-DGPD. Whenthreo-DGPD was incubated with SYK-6, the Cα alcohol groups ofthreo-DGPD (DGPD I and II) were initially oxidized to produce the Cα carbonyl form (DGPD-keto I and II). This initial oxidation step is catalyzed by Cα-dehydrogenases, which belong to the short-chain dehydrogenase/reductase (SDR) family and are involved in the catabolism of β-O-4-type dimers. Analysis of seven candidate genes revealed that NAD+-dependent LigD and LigL are mainly involved in the conversion of DGPD I and II, respectively. Next, we found that DGPD-keto I and II were reduced toerythro-DGPD (DGPD III and IV) in the presence of NADPH. Genes involved in this reduction were sought from Cα-dehydrogenase andldpA-neighboring SDR genes. The gene products of SLG_12690 (ldpC) and SLG_12640 (ldpB) catalyzed the NADPH-dependent conversion of DGPD-keto I to DGPD III and DGPD-keto II to DGPD IV, respectively. Mutational analysis further indicated thatldpCandldpBare predominantly involved in the reduction of DGPD-keto. Together, these results demonstrate that SYK-6 harbors a comprehensive catabolic enzyme system to utilize all four β-1-type stereoisomers through successive oxidation and reduction reactions of the Cα alcohol group ofthreo-DGPD with a net stereoinversion using multiple dehydrogenases.IMPORTANCEIn many catalytic depolymerization processes of lignin polymers, aryl–ether bonds are selectively cleaved, leaving carbon–carbon bonds between aromatic units intact, including dimers and oligomers with β-1 linkages. Therefore, elucidating the catabolic system of β-1-type lignin-derived compounds will aid in the establishment of biological funneling of heterologous lignin-derived aromatic compounds to value-added products. In this work, we found thatthreo-DGPD was converted by successive stereoselective oxidation and reduction at the Cα-position by multiple alcohol dehydrogenases toerythro-DGPD, which is further catabolized. This system is very similar to that developed to obtain enantiopure alcohols from racemic alcohols by artificially combining two enantiocomplementary alcohol dehydrogenases. The results presented here demonstrate that SYK-6 has evolved to catabolize all four stereoisomers of DGPD by incorporating this stereoinversion system into its native β-1-type dimer catabolic system.