bluuebunny/crossref_metadata_2025_split huggingface dataset:
The landscape of ancient human pathogens in Eurasia from the Stone Age to historical times
Authors: Sikora Martin , Canteri Elisabetta , Fernandez-Guerra Antonio , Oskolkov Nikolay , Ågren Rasmus , Hansson Lena , Irving-Pease Evan K. , Mühlemann Barbara , Nielsen Sofie Holtsmark , Scorrano Gabriele , Allentoft Morten E. , Seersholm Frederik Valeur , Schroeder Hannes , Gaunitz Charleen , Stenderup Jesper , Vinner Lasse , Jones Terry C. , Nystedt Bjørn , Parkhill Julian , Fugger Lars , Racimo Fernando , Kristiansen Kristian , Iversen Astrid K. N. , Willerslev Eske 
Published: October 2023

SummaryInfectious diseases have had devastating impacts on human populations throughout history. Still, the origins and past dynamics of human pathogens remain poorly understood1. To create the first spatiotemporal map of diverse ancient human microorganisms and parasites, we screened shotgun sequencing data from 1,313 ancient human remains covering 35,000 years of Eurasian history for ancient DNA deriving from bacteria, viruses, and parasites. We demonstrate the widespread presence of ancient microbial DNA in human remains, identifying over 2,400 individual species hits in 896 samples. We report a wide range of pathogens detected for the first time in ancient human remains, including the food-borne pathogensYersinia enterocoliticaandShigellaspp., the animal-borneLeptospira interrogans, and the malaria-causing parasitePlasmodium vivax. Our findings extend the spatiotemporal range of previously described ancient pathogens such asYersinia pestis, the causative agent of plague,Hepatitis B virus, andBorrelia recurrentis, the cause of louse-borne relapsing fever (LBRF). For LRBF we increase the known distribution from a single medieval genome to 31 cases across Eurasia covering 5,000 years. Grouping the ancient microbial species according to their type of transmission (zoonotic, anthroponotic, sapronotic, opportunistic, and other), we find that most categories are identified throughout the entire sample period, while zoonotic pathogens, which are transmitted from living animals to humans or which have made a host jump into humans from animals in the timeframe of this study, are only detected from ∼6,500 years ago. The incidence of zoonotic pathogens increased in our samples some 1,000 years later before reaching the highest detection rates ∼5,000 years ago, and was associated with a human genetic ancestry component characteristic of pastoralist populations from the Eurasian Steppe. Our results provide the first direct evidence for an epidemiological transition to an increased burden of zoonotic infectious diseases following the domestication of animals2. However, they also reveal that the spread of these pathogens first becomes frequent thousands of years after increased animal-human contact, likely coinciding with the pastoralist migrations from the Eurasian Steppe3,4. This study provides the first spatiotemporal map of past human pathogens using genomic paleoepidemiology, and the first direct evidence for an epidemiological transition of increased zoonotic infectious disease burden after the onset of agriculture, through historical times.
Concurrent encoding of sequence predictability and event-evoked prediction error in unfolding auditory patterns
Authors: Hu Mingyue , Bianco Roberta , Rodriguez Hidalgo Antonio , Chait Maria 
Published: October 2023

AbstractHuman listeners possess an innate capacity to discern patterns within rapidly evolving auditory sequences. Core questions, at the forefront of ongoing research, focus on the mechanisms through which these representations are acquired and whether the brain prioritizes or suppresses predictable sensory signals.Previous work, using fast sequences (tone-pips presented at a rate of 20Hz), revealed sustained response effects that appear to track the dynamic predictability of the sequence. Here we extend the investigation to slower sequences (4Hz), permitting the isolation of responses to individual tones. Stimuli were 50ms tone-pips, ordered into random (RND) and regular (REG; a repeating pattern of 10 frequencies) sequences; Two timing profiles were created: in ‘fast’ sequences tone-pips were presented in direct succession (20 Hz); in ‘slow’ sequences tone-pips were separated by a 200ms silent gap (4 Hz).Naive participants (N=22; both sexes) passively listened to these sequences, while brain responses were recorded using magnetoencephalography (MEG). Results unveiled a heightened magnitude of sustained brain responses in REG when compared to RND patterns. This manifested from three tones after the onset of the pattern repetition, even in the context of slower sequences characterized by extended pattern durations (2500ms). This observation underscores the remarkable implicit sensitivity of the auditory brain to acoustic regularities. Importantly, brain responses evoked by single tones exhibited the opposite pattern - stronger responses to tones in RND compared to REG sequences. The demonstration of simultaneous but opposing sustained and evoked response effects reveals concurrent processes that shape the representation of unfolding auditory patterns.Significance StatementHumans excel at detecting predictable patterns within sound sequences, a process crucial for listening, language processing, and music appreciation. However, questions persist about the underlying neural mechanisms and the specific information monitored by the brain.Our study addresses these questions by analysing magnetoencephalography (MEG) signals from participants exposed to predictable and unpredictable tone-pip patterns. We found that the MEG signal simultaneously captures two crucial aspects of predictability tracking.Firstly, sustained MEG activity, tracking the sequence’s evolution, dynamically assesses pattern predictability, shedding light on how the brain evaluates reliability. Secondly, phasic MEG activity, reflecting responses to individual events, shows reduced activity to predictable tones, aligning with the idea that the brain efficiently encodes and anticipates upcoming events in predictable contexts.
PKCδ is an activator of neuronal mitochondrial metabolism that mediates the spacing effect on memory consolidation
Authors: Comyn Typhaine , Preat Thomas , Pavlowsky Alice , Plaçais Pierre-Yves 
Published: October 2023

AbstractRelevance-based selectivity and high energy cost are two distinct features of long-term memory (LTM) formation that warrant its default inhibition. Spaced repetition of learning is a highly conserved cognitive mechanism that can lift this inhibition. Here, we questioned how the spacing effect integrates experience selection and energy efficiency at the cellular and molecular levels. We showed inDrosophilathat spaced training triggers LTM formation by extending over several hours an increased mitochondrial metabolic activity in neurons of the associative memory center, the mushroom bodies (MBs). We found that this effect is mediated by PKCδ, a member of the so-called ‘novel PKC’ family of enzymes, which uncovers the critical function of PKCδ in neurons as a regulator of mitochondrial metabolism for LTM. Additionally, PKCδ activation and translocation to mitochondria result from LTM-specific dopamine signaling on MB neurons. By bridging experience-dependent neuronal circuit activity with metabolic modulation of memory-encoding neurons, PKCδ signaling binds the cognitive and metabolic constraints underlying LTM formation into a unified gating mechanism.
From head to tail - Atomistic mechanism of long-range coupling from the cytosolic sensor domain to the selectivity filter in TREK K2Pchannels
Authors: Türkaydin Berke , Schewe Marcus , Riel Elena , Schulz Friederike , Biedermann Johann , Baukrowitz Thomas , Sun Han 
Published: October 2023

AbstractThe two-pore domain potassium (K2P) channels TREK-1 and TREK-2 link neuronal excitability to a variety of stimuli including mechanical force, lipids, temperature and phosphorylation. This regulation involves the C-terminus as a polymodal stimulus sensor and the selectivity filter (SF) as channel gate. Using crystallographic up- and down-state structures of TREK-2 as a template for full atomistic molecular dynamics simulations, we reveal that the SF in down-state undergoes inactivation via conformational changes at the S1 ion coordination site, while the up-state structure maintains a stable and conductive SF. This provides an atomistic understanding of the low channel activity previously assigned to the down state, but not evident from the crystal structure. Furthermore, by using (de-)phosphorylation mimics and chemically attaching lipid tethers to the proximal C-terminus (pCt), we confirm the hypothesis that moving the pCt towards the membrane induces the up-state. We also uncover two gating pathways by which movement of the pCt controls the stability (i.e. conductivity) of the filter gate. Together, these findings provide atomistic insights into the SF gating mechanism and the physiological regulation of TREK channels by phosphorylation.
METTL3/MYCN cooperation drives neural crest differentiation and provides therapeutic vulnerability in neuroblastoma
Authors: Thombare Ketan , Vaid Roshan , Pucci Perla , Mendez Akram , Burgos-Panadero Rebeca , Ayyalusamy Ritish , Rehan Aqsa Ali , Baig Mohammad Hassan , Nale Sagar Dattatraya , Bartenhagen Christoph , Dong Jae-June , Fischer Matthias , Turner Suzanne D. , Mondal Tanmoy 
Published: October 2023

AbstractNeuroblastoma (NB) is the most common extracranial childhood cancer, caused by the improper differentiation of developing trunk neural crest cells (tNCC) in the sympathetic nervous system. TheN6-methyladenosine (m6A) epitranscriptomic modification controls post-transcriptional gene expression but the mechanism by which the m6A methyltransferase complex METTL3/METTL14/WTAP is recruited to specific loci remains to be fully characterized. We explored whether the m6A epitranscriptome could fine-tune gene regulation in migrating/differentiating tNCC. We demonstrate that the m6A modification regulates the expression ofHOXgenes in tNCC, thereby contributing to their timely differentiation into sympathetic neurons. Furthermore, we show that posteriorHOXgenes are m6A modified in MYCN-amplified NB with reduced expression. In addition, we provide evidence that sustained overexpression of the MYCN oncogene in tNCC drives METTL3 recruitment to a specific subset of genes including posteriorHOXgenes creating an undifferentiated state. Moreover, METTL3 depletion/inhibition induces DNA damage and differentiation of MYCN overexpressing cells and increases vulnerability to chemotherapeutic drugs in MYCN-amplified patient-derived xenografts (PDX) cells, suggesting METTL3 inhibition could be a potential therapeutic approach for NB.
NEDD4-binding protein 1 suppresses HBV replication by degrading HBV RNAs
Authors: Kobayashi Nobuhiro , Suzuki Saori , Sakamoto Yuki , Suzuki Rigel , Mori Kento , Kosugi Yume , Liang Lihan , Saito Tomoya , Izumi Takuma , Noda Kisho , Okuzaki Daisuke , Kanegae Yumi , Hayashi Sanae , Tanaka Yasuhito , Matsuura Yoshiharu , Takeuchi Osamu , Tamura Tomokazu , Taketomi Akinobu , Fukuhara Takasuke 
Published: October 2023

AbstractChronic infection with hepatitis B virus (HBV) places patients at increased risk for liver cirrhosis and hepatocellular carcinoma. Although nucleos(t)ide analogs are mainly used for the treatment of HBV, they require long-term administration and may lead to the emergence of drug resistant mutants. Therefore, to identify targets for the development of novel anti-HBV drugs, we screened for HBV-suppressive host factors using a plasmid expression library of RNA-binding proteins (RBPs). We screened 132 RBPs using an expression plasmid library by measuring HBV relaxed circular DNA (rcDNA) levels in hepatocellular carcinoma. Our screen identified NEDD4-binding protein 1 (N4BP1) as having an anti-HBV effect. In hepatocellular carcinoma cell lines transfected or infected with HBV, overexpression of N4BP1 decreased rcDNA levels while knockdown or knockout of the gene encoding N4BP1 rescued rcDNA levels. N4BP1 possesses the KH-like and RNase domains and both were required for the anti-HBV effect of N4BP1. Additionally, we measured levels of HBV pregenomic RNA (pgRNA) and covalently closed circular DNA (cccDNA) in the RBP-transfected cells and confirmed that N4BP1 binds pgRNA directly and degraded both the 3.5 kb and 2.4/2.1 kb HBV RNA. In summary, N4BP1 is a newly identified host factor able to counteract HBV production by promoting the degradation of 3.5 kb and 2.1/2.4 kb HBV RNA.ImportanceThere is still a large number of HBV-infected people in the world today because of no curative treatment for HBV infection. In this study, we focused on and screened RNA-binding proteins to identify new host factors which inhibit HBV replication. As a result, we found that NEDD4-binding protein 1 (N4BP1) expression suppresses rcDNA production by promoting the degradation of pregenomic RNA, 2.4kb and 2.1kb HBV RNA. Furthermore, KH-like domain or RNase domain of N4BP1 were involved in this anti-HBV effect. In addition, the N4BP1 levels were lower in HCC resection samples of exacerbated patients, suggesting that individual N4BP1 levels might be related to HCC progression. This novel factor can potentially become a key to new HBV treatments.
Structural insights into the FtsEX-EnvC complex regulation on septal peptidoglycan hydrolysis in Vibrio cholerae
Authors: Hao Aili , Suo Yang , Lee Seok-Yong 
Published: October 2023

SUMMARYDuring bacterial cell division, hydrolysis of septal peptidoglycan (sPG) is crucial for cell separation. This sPG hydrolysis is performed by the enzyme amidases whose activity is regulated by the integral membrane protein complex FtsEX-EnvC. FtsEX is an ATP-binding cassette transporter and EnvC is a long coiled-coiled protein that interacts with and activates the amidases. The molecular mechanism by which the FtsEX-EnvC complex activates amidases remains largely unclear. We present the cryo-electron microscopy structure of the FtsEX-EnvC complex from the pathogenic bacteriaV. cholerae(FtsEX-EnvCVC). FtsEX-EnvCVCin the presence of ADP adopts a distinct conformation where EnvC is “horizontally extended” rather than “vertically extended”. Subsequent structural studies suggest that EnvC can swing between these conformations in space in a nucleotide-dependent manner. Our structural analysis and functional studies suggest that FtsEX-EnvCvc may employ spatial control of EnvC for amidase activation, suggesting species-specific diversity in the FtsEX-EnvC regulation on septal peptidoglycan hydrolysis.
METI: Deep profiling of tumor ecosystems by integrating cell morphology and spatial transcriptomics
Authors: Jiang Jiahui , Liu Yunhe , Qin Jiangjiang , Wu Jingjing , Chen Jianfeng , Pizzi Melissa P. , Segura Rossana L. , Yamashita Kohei , Xu Zhiyuan , Pei Guangsheng , Cho Kyung Serk , Chu Yanshuo , Sinjab Ansam F. , Peng Fuduan , Han Guangchun , Wang Ruiping , Yan Xinmiao , Dai Enyu , Dai Yibo , Li Mingyao , Futreal Andrew , Maitra Anirban , Lazar Alexander , Cheng Xiangdong , Kadara Humam , Ajani Jaffer , Jazaeri Amir A. , Gao Jianjun , Hu Jian , Wang Linghua 
Published: October 2023

AbstractThe recent advance of spatial transcriptomics (ST) technique provides valuable insights into the organization and interactions of cells within the tumor microenvironment (TME). While various analytical tools have been developed for tasks such as spatial clustering, spatially variable gene identification, and cell type deconvolution, most of them are general methods lacking consideration of histological features in spatial data analysis. This limitation results in reduced performance and interpretability of their results when studying the TME. Here, we present a computational framework named,Morphology-Enhanced SpatialTranscriptome Analysis Integrator (METI) to address this gap. METI is an end-to-end framework capable of spatial mapping of both cancer cells and various TME cell components, robust stratification of cell type and transcriptional states, and cell co-localization analysis. By integrating both spatial transcriptomics, cell morphology and curated gene signatures, METI enhances our understanding of the molecular landscape and cellular interactions within the tissue, facilitating detailed investigations of the TME and its functional implications. The performance of METI has been evaluated on ST data generated from various tumor tissues, including gastric, lung, and bladder cancers, as well as premalignant tissues. Across all these tissues and conditions, METI has demonstrated robust performance with consistency.
Yeast eIF2A has a minimal role in translation initiation and uORF-mediated translational controlin vivo
Authors: Gaikwad Swati , Ghobakhlou Fardin , Zhang Hongen , Hinnebusch Alan G. 
Published: October 2023

ABSTRACTInitiating translation of most eukaryotic mRNAs depends on recruitment of methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2) to the small (40S) ribosomal subunit, forming a 43S preinitiation complex (PIC) that attaches to the mRNA and scans the 5’-untranslated region (5’ UTR) for an AUG start codon. Previous studies have implicated mammalian eIF2A in GTP-independent binding of Met-tRNAi to the 40S subunit and its recruitment to specialized mRNAs that do not require scanning, and in initiation at non-AUG start codons, when eIF2 function is attenuated by phosphorylation of its α-subunit during stress. The role of eIF2A in translationin vivois poorly understood however, and it was unknown whether the conserved ortholog in budding yeast can functionally substitute for eIF2. We performed ribosome profiling of a yeast deletion mutant lacking eIF2A and isogenic wild-type (WT) cells in the presence or absence of eIF2α phosphorylation induced by starvation for amino acids isoleucine and valine. Whereas starvation of WT confers changes in translational efficiencies (TEs) of hundreds of mRNAs, theeIF2AΔmutation conferred no significant TE reductions for any mRNAs in non-starved cells, and it reduced the TEs of only a small number of transcripts in starved cells containing phosphorylated eIF2α. We found no evidence that eliminating eIF2A altered the translation of mRNAs containing putative IRES elements, or harboring uORFs initiated by AUG or near-cognate start codons, in non-starved or starved cells. Thus, very few mRNAs (possibly only one) appear to employ eIF2A for Met-tRNAi recruitment in yeast cells, even when eIF2 function is attenuated by stress.
LRP1 Triggers Pro-inflammatory Cell-signaling in Response to Extracellular Tau Independently of the NMDA Receptor
Authors: Azmoon Pardis , Mantuano Elisabetta , Poudel Binita , Zampieri Carlotta , Gonias Steven L. 
Published: October 2023

ABSTRACTIn Alzheimer’s Disease (AD) and other neurodegenerative diseases, microtubule-associated protein Tau forms abnormal intracellular aggregates. The mechanisms by which Tau may promote AD progression remain incompletely understood. Injured and dying neurons release Tau into the extracellular spaces in the CNS. The released Tau may be taken up by receptors in the LDL Receptor gene family, including Low Density Lipoprotein Receptor-related Protein-1 (LRP1), which is expressed by microglia, astrocytes, and neurons. This process may be important for clearing Tau from extracellular spaces but may also promote the seeding of Tau aggregates in new cells. Our laboratory has shown that endocytosis of LRP1 ligands is coupled to the activation of cell-signaling and regulation of inflammation. Notably, different LRP1 ligands can induce either pro-inflammatory or anti-inflammatory responses, depending on the co-receptors that function with LRP1. Here, we demonstrate that in cultured macrophages, microglia, and astrocytes, extracellular Tau induces an LRP1-dependent pro-inflammatory response, characterized by NFκB activation and expression of pro-inflammatory cytokines. Unlike other LRP1 ligands that elicit anti-inflammatory responses, the response to Tau occurs independently of the NMDA receptor. When LRP1 is deleted or silenced, macrophages, microglia, and astrocytes do not respond to Tau, whereas whenGrin1is deleted or the NMDA-R is pharmacologically inhibited, the responses remain unchanged. Because we have evidence that LRP1 in microglia expresses anti-inflammatory activity in response to ligands other than Tau, understanding the role of LRP1 in microglia and astrocytesin vivoin Alzheimer’s Disease and other neuroinflammatory processes is an important future goal.SIGNIFICANCE STATEMENTIn Alzheimer’s Disease and other neurodegenerative diseases, microtubule-associated protein Tau forms abnormal intracellular aggregates that contribute to disease progression. When released extracellularly, Tau binds to the transmembrane receptor LRP1, expressed by diverse cells in the CNS. LRP1 has the unique ability to couple ligand uptake with activation of cell-signaling. We demonstrated that Tau binding to LRP1 activates pro-inflammatory responses in macrophages, microglia, and astrocytes, characterized by NFκB activation and cytokine release. This signaling occurs independently of the NMDA receptor, which distinguishes Tau from other LRP1 ligands. These results define a novel pathway by which extracellular Tau regulates neuroinflammation in Alzheimer’s Disease, providing new therapeutic opportunities that target LRP1 without interfering with NMDA-R functions.
A tRNA-specific function for tRNA methyltransferase Trm10 is associated with a new tRNA quality control mechanism inSaccharomyces cerevisiae
Authors: Bowles Isobel E. , Jackman Jane E. 
Published: October 2023

ABSTRACTInSaccharomyces cerevisiaea single homolog of the tRNA methyltransferase Trm10 performs m1G9 modification on 13 different tRNAs. Here we provide evidence that the m1G9 modification catalyzed byS. cerevisiaeTrm10 plays a biologically important role for one of these tRNA substrates, tRNATrp. Overexpression of tRNATrp(and not any of 38 other elongator tRNAs) rescues growth hypersensitivity of thetrm10Δstrain in the presence of the antitumor drug 5-fluorouracil (5FU). Mature tRNATrpis depleted intrm10Δcells, and its levels are further decreased upon growth in 5FU, while another Trm10 substrate (tRNAGly) is not affected under these conditions. Thus, m1G9 inS. cerevisiaeis another example of a tRNA modification that is present on multiple tRNAs but is only essential for the biological function of one of those species. In addition to the effects of m1G9 on mature tRNATrp, precursor tRNATrpspecies accumulate in the same strains, an effect that is due to at least two distinct mechanisms. The levels of mature tRNATrpare rescued in thetrm10Δmet22Δstrain, consistent with the known role of Met22 in tRNA quality control, where deletion ofmet22causes inhibition of 5’-3’ exonucleases that catalyze tRNA decay. However, none of the known Met22-associated exonucleases appear to be responsible for decay of hypomodified tRNATrp, based on inability of mutants of each enzyme to rescue growth of thetrm10Δstrain in the presence of 5FU. Thus, the surveillance of tRNATrpappears to constitute a distinct tRNA quality control pathway inS. cerevisiae.