bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute appendicitis manifests as two microbiome state types with oral pathogens influencing severity
Authors: Blohs Marcus , Mahnert Alexander , Brunnader Kevin , Flucher Christina , Castellani Christoph , Till Holger , Singer Georg , Moissl-Eichinger Christine 
Published: April 2022

AbstractMounting evidence suggests that acute appendicitis (AA) is not one but two diseases: complicated appendicitis, which is associated with necrosis leading to perforation or periappendicular abscess, and uncomplicated appendicitis, which does not necessarily result in perforation. Even though AA is the most frequent cause of surgery from abdominal pain, little is known about the origins and etiopathogenesis of this disease, much less regarding the different disease types.In this study, we investigated the microbiome of samples from the appendix, rectum and peritoneum of 60 children and adolescents with AA to assess the composition and potential function of bacteria, archaea and fungi. The analysis of the appendix microbial community revealed a shift depending on the severity of the AA. This shift was reflected by two major community state types that represented the complicated and uncomplicated cases. We could demonstrate that complicated, but not uncomplicated, appendicitis is associated with a significant local expansion of oral, bacterial pathogens in the appendix, most strongly influenced by necrotizing Fusobacterium spp., Porphyromonas and Parvimonas. Uncomplicated appendicitis, however, was characterised by gut-associated microbiomes. Our findings support the hypothesis that two disease types exist in AA, which cannot be distinguished beyond doubt using standard clinical characterization methods or by analysis of the patient’s rectal microbiome. An advanced microbiome diagnosis, however, could improve non-surgical treatment of uncomplicated AA.ImportanceWith a lifetime risk of up to 17%, acute appendicitis is one of the most frequent causes of emergency abdominal surgery in westernized countries. Latest literature reports suggests that appendicitis manifests in two disease types: complicated and uncomplicated appendicitis with different, yet unknown, etiopathogenesis.In this study, we investigated the microbial composition (bacteria, archaea and fungi) from 60 children and adolescents that were diagnosed with acute appendicitis. Appendix, rectal and peritoneal samples were analysed using amplicon and metagenomic sequencing. Our results suggest that acute appendicitis manifests in three microbial state types that reflect complicated and uncomplicated appendicitis as well as special cases that are caused by bacterial overgrowth. Strikingly, uncomplicated appendicitis appears to be caused by gut-associated pathogens while complicated appendicitis is driven by oral-associated microbes such as Fusobacterium sp. or Porphyromonas sp. The findings provided in our study are of special interest to understand the etiopathogenesis of both complicated and uncomplicated appendicitis.
Hormones do not make the mole-rat: no steroid hormone signatures of subordinate behavioral phenotypes
Authors: Toor Ilapreet , Faykoo-Martinez Mariela , Edwards Phoebe D. , Boonstra Rudy , Holmes Melissa M. 
Published: April 2022

AbstractIn some cooperatively breeding groups, individuals have distinct behavioral characteristics that are often stable and predictable across time. However, in others, like the eusocial naked mole-rat, evidence for behavioral phenotypes is ambiguous. Here, we study whether the naked mole-rat can be divided into discrete phenotypes and if circulating hormone levels underpin these differences. Naked mole-rat colonies consist of a single breeding female and dozens to hundreds of non-reproductive subordinates. The subordinates can potentially be divided into soldiers, who defend the colony; workers, who maintain it; and dispersers, who want to leave it. We established six colonies de novo, tracked them over three years, and assessed the behavior and hormone levels of the subordinates. We found that soldiers tended to be from earlier litters and were higher ranked compared to workers, whereas dispersers were distributed throughout litters and rankings. There was no difference in estradiol, testosterone, or dehydroepiandrosterone (DHEA) levels amongst phenotypes. Progesterone levels were higher in soldiers but this difference appeared to be driven by a few individuals. Principal component analysis demonstrated that soldiers separated into a discrete category relative to workers/dispersers, with the highest ranked loadings being age, weight, and testosterone levels. However, the higher testosterone in soldiers was correlated with large body size instead of strictly behavioral phenotype. Workers and dispersers have more overlap with each other and no hormonal differences. Thus the behavioral variation in subordinate naked mole-rats is likely not driven by circulating steroid hormone levels but rather stems from alternative neural and/or neuroendocrine mechanisms.
Metabolic compatibility and the rarity of prokaryote endosymbioses
Authors: Libby Eric , Kempes Christopher , Okie Jordan 
Published: April 2022

AbstractThe evolution of the mitochondria was a significant event that gave rise to the eukaryotic lineage and most large complex life. Central to the origins of the mitochondria was an endosymbiosis between prokaryotes. Yet, despite the potential benefits that can stem from a prokaryotic endosymbiosis, their modern occurrence is exceptionally rare. While many factors may contribute to their rarity, we lack methods for estimating the extent to which they constrain the appearance of a prokaryotic endosymbiosis. Here, we address this knowledge gap by examining the role of metabolic compatibility between a prokaryotic host and endosymbiont. We use genome-scale metabolic models from three different databases (AGORA, KBase, and CarveMe) to assess the viability, fitness, and adaptability of potential prokaryotic endosymbioses. We find that while more than half of host-endosymbiont pairings are metabolically viable, the resulting endosymbioses have reduced growth rates compared to their ancestral metabolisms and are unlikely to gain mutations to overcome these fitness differences. In spite of these challenges, we do find that they may be more robust in the face of environmental perturbations at least in comparison with the ancestral host metabolism lineages. Our results provide a critical set of null models and expectations for understanding the forces that shape the structure of prokaryotic life.
Redox-controlled structural reorganization and flavin strain within the ribonucleotide reductase R2b-NrdI complex monitored by serial femtosecond crystallography
Authors: John Juliane , Aurelius Oskar , Srinivas Vivek , Kim In-Sik , Bhowmick Asmit , Simon Philipp S. , Dasgupta Medhanjali , Pham Cindy , Gul Sheraz , Sutherlin Kyle D. , Aller Pierre , Butryn Agata , Orville Allen M. , Cheah Mun Hon , Owada Shigeki , Tono Kensuke , Fuller Franklin D. , Batyuk Alexander , Brewster Aaron S. , Sauter Nicholas K. , Yachandra Vittal K. , Yano Junko , Kern Jan , Lebrette Hugo , Högbom Martin 
Published: April 2022

AbstractRedox reactions are central to biochemistry and are both controlled by and induce protein structural changes. Here we describe structural rearrangements and crosstalk within the Bacillus cereus ribonucleotide reductase R2b-NrdI complex, a di-metal carboxylate- flavoprotein system, as part of the mechanism generating the essential catalytic free radical of the enzyme. Femtosecond crystallography at an X-ray free-electron laser was utilized to obtain structures at room temperature in defined redox states without suffering photoreduction. We show that the flavin in the hydroquinone state is under steric strain in the R2b-NrdI protein complex, presumably tuning its redox potential to promote superoxide generation. Moreover, a binding site in close vicinity to the expected flavin O2-interacton site is observed to be controlled by the redox state of the flavin and linked to the channel proposed to funnel the produced superoxide species from NrdI to the di-manganese site in protein R2b. These specific features are coupled to further structural changes around the R2b- NrdI interaction surface. The mechanistic implications for the control of reactive oxygen species and radical generation in protein R2b are discussed.
A congenital hydrocephalus causing mutation in Trim71 results in stem cell differentiation defects through inhibitingLsd1mRNA translation
Authors: Liu Qiuying , Novak Mariah K. , Pepin Rachel M. , Maschhoff Katharine R. , Chen Xiaoli , Zhang Shaojie , Hu Wenqian 
Published: April 2022

AbstractCongenital hydrocephalus (CH) is a major cause of childhood morbidity. Mono-allelic mutations in Trim71, a conserved stem-cell-specific RNA-binding protein, cause CH, however, molecular basis for pathogenesis mediated by these mutations remains unknown. Here, using mouse embryonic stem cells as a model, we reveal that the mouse R783H mutation (R796H in human) significantly alters Trim71’s mRNA substrate specificity and leads to accelerated stem-cell differentiation and neural lineage commitment. The mutant Trim71, but not the wild-type Trim71, bindsLsd1 (Kdm1a)mRNA and represses its translation. Specific inhibition of this repression or a slight increase of Lsd1 in the mutant cells alleviates the defects in stem cell differentiation and neural lineage commitment. These results determine a functionally relevant target of the CH-causing Trim71 mutant that can potentially be a therapeutic target and provide molecular mechanistic insights into the pathogenesis of this disease.
ProFeatMap: a customizable tool for 2D feature representation of protein sets
Authors: Bich G. , Monsellier E. , Travé G. , Nominé Y. 
Published: April 2022

ABSTRACTSummaryHere, we present ProFeatMap, an intuitive Python-based website allowing to quickly display protein features such as domains, repeats, post-translational modifications location and so forth, into a highly customizable graphical 2D map. Starting from a user-defined protein list, ProFeatMap automatically extracts the main protein features from the Uniprot database. The resulting high-quality maps can help to gain insights, e.g. feature redundancy, that were previously overlooked but which may be useful for the research project. ProFeatMap is freely accessible on the web at: https://profeatmap.pythonanywhere.com/AvailabilitySource code is freely accessible at https://github.com/profeatmap/ProFeatMap under the GPL license.Contactbichg@igbmc.fr, yves.nomine@igbmc.frSupplementary informationdetailed user guide of ProFeatMap
A mitochondrial iron-sensing pathway regulated by DELE1
Authors: Sekine Yusuke , Houston Ryan , Fessler Evelyn , Jae Lucas T , Narendra Derek P , Sekine Shiori 
Published: April 2022

SummaryThe heme-regulated kinase HRI is activated under heme/iron deficient conditions; however, the underlying molecular mechanism is incompletely understood. Here, we show that iron deficiency-induced HRI activation involves a heme-independent mechanism that requires the mitochondrial protein DELE1. Notably, mitochondrial import of DELE1 and its subsequent protein stability are regulated by iron availability. Under steady state conditions, DELE1 is degraded by the mitochondrial matrix-resident protease LONP1 soon after mitochondrial import. Upon iron chelation, DELE1 import is arrested, thereby stabilizing DELE1 on the mitochondrial surface to activate the HRI-mediated integrated stress response (ISR). Moreover, depletion of the mitochondrial ABC transporter ABCB7 that is involved in iron-sulfur cluster (ISC) metabolism markedly abrogates iron deficiency-induced ISR activation, suggesting the possible involvement of ISC-related molecules in this activation. Our findings highlight mitochondrial import regulation of DELE1 as the core component of a previously unrecognized iron monitoring system that connects the mitochondria to the cytosol.
Regulation of inflammation and protection against invasive pneumococcal infection by the long pentraxin PTX3
Authors: Porte Rémi , Silva-Gomes Rita , Theroude Charlotte , Parente Raffaella , Asgari Fatemeh , Sironi Marina , Pasqualini Fabio , Valentino Sonia , Asselta Rosanna , Recordati Camilla , Doni Andrea , Inforzato Antonio , Rodriguez-Gallego Carlos , Obando Ignacio , Colino Elena , Bottazzi Barbara , Mantovani Alberto 
Published: April 2022

AbstractStreptococcus pneumoniae is a major pathogen in children, elderly subjects and immunodeficient patients. PTX3 is a fluid phase pattern recognition molecule (PRM) involved in resistance to selected microbial agents and in regulation of inflammation. The present study was designed to assess the role of PTX3 in invasive pneumococcal infection. In a murine model of invasive pneumococcal infection, PTX3 was strongly induced in non-hematopoietic (particularly, endothelial) cells. The IL-1β/MyD88 axis played a major role in regulation of the Ptx3 gene expression. Ptx3-/- mice were more susceptible to invasive pneumococcal infection. Although high concentrations of PTX3 had opsonic activity in vitro, no evidence of PTX3-enhanced phagocytosis was obtained in vivo. In contrast, Ptx3-deficient mice showed enhanced recruitment of neutrophils and inflammation. Using P-selectin deficient mice, we found that protection against pneumococcus was dependent upon PTX3-mediated regulation of neutrophil inflammation. In humans, PTX3 genetic polymorphisms were associated with invasive pneumococcal infections. Thus, this fluid phase PRM plays an important role in tuning inflammation and resistance against invasive pneumococcal infection.
Identification of microRNAs in the Lyme disease vector Ixodes scapularis
Authors: Kumar Deepak , Downs Latoyia P. , Embers Monica , Flynt Alex , Karim Shahid 
Published: April 2022

AbstractMicroRNAs (miRNAs) are a class of small non-coding RNAs involved in many biological processes, including the immune pathways that control bacterial, parasitic, and viral infections. Pathogens probably modify host miRNAs to facilitate successful infection, so they might be useful targets for vaccination strategies. There are little data on differentially expressed miRNAs in the black- legged tick Ixodes scapularis after infection with Borrelia burgdorferi, the causative agent of Lyme disease in the United States. Small RNA sequencing and qRT-PCR analysis were used to identify and validate differentially-expressed I. scapularis salivary miRNAs. Small RNA-seq yielded 133,465,828 (≥18 nucleotides) and 163,852,135 (≥18 nucleotides) small RNA reads from Borrelia- infected and uninfected salivary glands for downstream analysis using the miRDeep2 algorithm. Two hundred and fifty-four miRNAs were identified across all datasets, 25 of which were high confidence and 51 low confidence known miRNAs. Twenty-three miRNAs were differentially expressed in uninfected and infected salivary glands: 11 were upregulated and 12 were downregulated upon pathogen infection. This study provides new insights into the miRNAs expressed in I. scapularis salivary glands and pave the way for their functional manipulation to prevent or treat B. burgdorferi infection.
Immunogenic cell death in mice expressing caspase-resistant ROCK1 is not replicated by ROCK inhibitors
Authors: Naylor Gregory , Julian Linda , Watson-Bryce Steven , Mullin Margaret , Nibbs Robert J , Olson Michael F 
Published: April 2022

AbstractThe characteristic changes in morphology during apoptosis help facilitate “immunologically-silent” cell death by limiting the release of cellular contents and enabling efficient clearance of apoptotic cell bodies. Caspase-mediated cleavage of the ROCK1 protein kinase results in its constitutive activation, which drives the rapid and forceful contraction of apoptotic cells. We previously showed in Julian et al. [1] that when ROCK1 was mutated to render it caspase-resistant, there was greater liver damage and neutrophil recruitment after acute treatment with the hepatotoxin diethylnitrosamine (DEN). We now show that acute DEN-induced liver damage resulted in greater induction of pro-inflammatory cytokines/chemokines, indicative of immunogenic cell death (ICD), in mice expressing non-cleavable ROCK1 (ROCK1nc). Hepatocellular carcinoma (HCC) tumours in ROCK1nc mice had higher grade steatosis, and more neutrophils and CD8+ T cells relative to mice expressing wild-type ROCK1 (ROCK1wt), indicating that spontaneous tumour cell death also was more immunogenic. Since the induction of ICD has been proposed to be tumour-suppressive, the effects of two structurally distinct pharmacological ROCK inhibitors on HCC tumours was examined. Both fasudil and AT13148 significantly decreased tumour numbers and area, but neither treatment resulted in greater numbers of neutrophils or CD8+ T cells to be recruited. In the context of acute DEN-induced liver damage, AT13148 reduced circulating platelet and lymphocyte numbers, and inhibited the recruitment of dendritic, natural killer and CD8+ T cells to livers. These observations indicate that there is an important role for ROCK1 cleavage to limit immunogenic cell death which was not replicated by systemic administration of pharmacological ROCK inhibitors. As a result, adjuvant administration of ROCK inhibitors with cancer therapeutics would be unlikely to result in therapeutic benefit by inducing ICD to increase anti-tumour immune responses.
HER2 expression defines unique requirements for flotillin and c-Src for EGFR signaling
Authors: Abousawan John , Orofiamma Laura A. , Fairn Gregory D. , Antonescu Costin N. 
Published: April 2022

AbstractThe epidermal growth factor receptor (EGFR) controls many cellular functions. Upon binding its ligand, the receptor undergoes dimerization, phosphorylation, and activation of signals including the phosphatidylinositol-3-kinase (PI3K)-Akt pathway. While some studies indicated that EGFR signaling may be controlled by signal enrichment within membrane raft nanodomains, others have found a limited effect of membrane raft disruption on EGFR signaling, suggesting that specific factor(s) may define context-specific control of EGFR signaling by membrane rafts. Ligand-bound EGFR can homodimerize, or instead undergo heterodimerization with the related receptor HER2 when the latter is expressed. We examined how EGFR signaling in the presence of HER2 distinctly requires membrane raft nanodomains. Induction of HER2 expression altered EGFR signaling duration consistent with EGFR/HER2 heterodimer formation. EGFR and c-Src localized within plasma membrane structures demarked by flotillin, a membrane raft protein, selectively in HER2-expressing cells. Consistently, HER2-expressing cells, but not cells lacking HER2, were dependent on flotillin and c-Src for EGFR signaling leading to Akt activation and cell proliferation. Hence, HER2 expression establishes the requirement of EGFR signaling for flotillin membrane rafts and c-Src, leading to Akt activation.Summary statementThe role of membrane rafts in EGFR signaling may be context-specific. We find that the related receptor HER2 defines unique signaling requirements for EGFR for membrane rafts, flotillin, and c-Src.
Reward Bases: Instantaneous reward revaluation with temporal difference learning
Authors: Millidge Beren , Walton Mark , Bogacz Rafal 
Published: April 2022

AbstractAn influential theory posits that dopaminergic neurons in the mid-brain implement a model-free reinforcement learning algorithm based on temporal difference (TD) learning. A fundamental assumption of this model is that the reward function being optimized is fixed. However, for biological creatures the ‘reward function’ can fluctuate substantially over time depending on the internal physiological state of the animal. For instance, food is rewarding when you are hungry, but not when you are satiated. While a variety of experiments have demonstrated that animals can instantly adapt their behaviour when their internal physiological state changes, under current thinking this requires model-based planning since the standard model of TD learning requires retraining from scratch if the reward function changes. Here, we propose a novel and simple extension to TD learning that allows for the zero-shot (instantaneous) generalization to changing reward functions. Mathematically, we show that if we assume the reward function is a linear combination ofreward basis vectors, and if we learn a value function for each reward basis using TD learning, then we can recover the true value function by a linear combination of these value function bases. This representational scheme allows instant and perfect generalization to any reward function in the span of the reward basis vectors as well as possesses a straightforward implementation in neural circuitry by parallelizing the standard circuitry required for TD learning. We demonstrate that our algorithm can also reproduce behavioural data on reward revaluation tasks, predict dopamine responses in the nucleus accumbens, as well as learn equally fast as successor representations while requiring much less memory.
Hijacking of Cellular Functions by Severe Acute Respiratory Syndrome Coronavirus-2. Permeabilization and Polarization of the Host Lipid Membrane by Viroporins
Authors: Bignon Emmanuelle , Marazzi Marco , Monari Antonio 
Published: April 2022

ABSTRACTAs all viral infections, SARS-CoV-2 acts at multiple levels hijacking fundamental cellular functions and assuring its replication and immune system evasion. In particular, it has been observed that the viral 3’ Open Reading Frame (ORF3a) codes for a hydrophobic protein which embeds in the cellular membrane, where it acts as an ion viroporin and is related to strong inflammatory response. Here we report equilibrium and enhanced sampling molecular dynamic simulation of the SARS-CoV-2 ORF3a in a model lipid bilayer, showing how the protein permeabilizes the lipid membrane, via the formation of a water channel, which in turn assures ion transport. We report the free energy profile for both K+ and Cl- transfer from the cytosol to the extracellular domain. The important role of ORF3a in the viral cycle, and its highly conservation among coronaviruses, may also make it a target of choice for future antiviral development, further justifying the elucidation of its mechanism at the atomistic level.TOC GRAPHICS
Meiotic Nuclear Pore Complex Remodeling Provides Key Insights into Nuclear Basket Organization
Authors: King Grant A. , Wettstein Rahel , Varberg Joseph M. , Chetlapalli Keerthana , Walsh Madison E. , Gillet Ludovic , Hernández-Armenta Claudia , Beltrao Pedro , Aebersold Ruedi , Jaspersen Sue L. , Matos Joao , Ünal Elçin 
Published: April 2022

ABSTRACTNuclear pore complexes (NPCs) are large proteinaceous assemblies that mediate nuclear compartmentalization. NPCs undergo largescale structural rearrangements during mitosis in metazoans and some fungi. However, our understanding of NPC remodeling beyond mitosis remains limited. Using time-lapse fluorescence microscopy, we discovered that NPCs undergo two mechanistically-separable remodeling events during budding yeast meiosis whereby parts or all of the nuclear basket transiently dissociate from the NPC core during meiosis I and II, respectively. Meiosis I detachment, observed for Nup60 and Nup2, is driven by Polo kinase-mediated phosphorylation of Nup60 at its interface with the Y-complex. Subsequent reattachment of Nup60-Nup2 to the NPC core is mediated by a lipid-binding amphipathic helix in Nup60. Preventing Nup60-Nup2 reattachment causes misorganization of the entire nuclear basket in gametes. Strikingly, meiotic nuclear basket remodeling also occurs in the distantly related fission yeast, Schizosaccharomyces pombe. Our study reveals a conserved and developmentally programmed aspect of NPC plasticity, providing key mechanistic insights into nuclear basket organization.SUMMARYKing and Wettstein et al. reveal that nuclear pore complexes undergo two distinct remodeling events during budding yeast meiosis: partial and full nuclear basket detachment. By dissecting the regulation of these events, the study provides mechanistic insights into NPC organization.