bluuebunny/crossref_metadata_2025_split huggingface dataset:
The lung employs an intrinsic surfactant-mediated inflammatory response for viral defense
Authors: Leibel Sandra L. , McVicar Rachael N. , Murad Rabi , Kwong Elizabeth M. , Clark Alex E. , Alvarado Asuka , Grimmig Bethany A. , Nuryyev Ruslan , Young Randee E. , Lee Jamie Casey , Peng Weiqi , Zhu Yanfang Peipei , Griffis Eric , Nowell Cameron J. , Liu Kang , James Brian , Alarcon Suzie , Malhotra Atul , Gearing Linden J. , Hertzog Paul J. , Galapate Cheska Marie , Galenkamp Koen M.O. , Commisso Cosimo , Smith Davey M. , Sun Xin , Carlin Aaron F. , Croker Ben A. , Snyder Evan Y. 
Published: January 2023

AbstractSevere Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causes an acute respiratory distress syndrome (ARDS) that resembles surfactant deficient RDS. Using a novel multi-cell type, human induced pluripotent stem cell (hiPSC)-derived lung organoid (LO) system, validated against primary lung cells, we found that inflammatory cytokine/chemokine production and interferon (IFN) responses are dynamically regulated autonomously within the lung following SARS-CoV-2 infection, an intrinsic defense mechanism mediated by surfactant proteins (SP). Single cell RNA sequencing revealed broad infectability of most lung cell types through canonical (ACE2) and non-canonical (endocytotic) viral entry routes. SARS-CoV-2 triggers rapid apoptosis, impairing viral dissemination. In the absence of surfactant protein B (SP-B), resistance to infection was impaired and cytokine/chemokine production and IFN responses were modulated. Exogenous surfactant, recombinant SP-B, or genomic correction of the SP-B deletion restored resistance to SARS-CoV-2 and improved viability.
Mechanism of assembly, activation and lysine selection by the SIN3B histone deacetylase complex
Authors: Wan Mandy S.M. , Muhammad Reyhan , Koliopoulos Marios G. , Roumeliotis Theodoros I. , Choudhary Jyoti S. , Alfieri Claudio 
Published: January 2023

AbstractHistone deacetylase complexes remove histone lysine acetylation, a key post-translational modification that activates transcription at each gene. Although these complexes are drug targets and crucial regulators of organismal physiology, their structure and mechanisms of action are largely unclear. Here, we present the first structure of a complete human SIN3B histone deacetylase holo-complex with and without a substrate mimic. Remarkably, SIN3B encircles the deacetylase and contacts its allosteric basic patch thereby stimulating catalysis. A SIN3B loop inserts into the catalytic tunnel, rearranges to accommodate the acetyl-lysine moiety and stabilises the substrate for specific deacetylation, which is guided by a substrate receptor subunit. Our findings provide a model of specificity for a main transcriptional regulator conserved from yeast to human and a resource of protein-protein interactions for future drug designs.
Single-molecule displacement mapping unveils sign-asymmetric protein charge effects on intraorganellar diffusion
Authors: Xiang Limin , Yan Rui , Chen Kun , Li Wan , Xu Ke 
Published: January 2023

ABSTRACTUsing single-molecule displacement/diffusivity mapping (SMdM), an emerging super-resolution microscopy method, here we quantify, at nanoscale resolution, the diffusion of a typical fluorescent protein (FP) in the endoplasmic reticulum (ER) and mitochondrion of living mammalian cells. We thus show that the diffusion coefficientsDin both organelles are ~40% of that in the cytoplasm, with the latter exhibiting higher spatial inhomogeneities. Moreover, we unveil that diffusions in the ER lumen and the mitochondrial matrix are markedly impeded when the FP is given positive, but not negative, net charges. Calculation shows most intraorganellar proteins as negatively charged, thus a mechanism to impede the diffusion of positively charged proteins. However, we further identify the ER protein PPIB as an exception with a positive net charge, and experimentally show that the removal of this positive charge elevates its intra-ER diffusivity. We thus unveil a sign-asymmetric protein charge effect on the nanoscale intraorganellar diffusion.
Excitation energy transfer between higher excited states of photosynthetic pigments: 1. Carotenoids facilitate B → Q band conversion in chlorophylls
Authors: Götze Jan P. , Lokstein Heiko 
Published: January 2023

AbstractChlorophylls (Chls) are known for fast, sub-picosecond internal conversion (IC) from ultraviolet/blue absorbing (“B” or “Soret” states) to the energetically lower, red light-absorbing Q states. Consequently, excitation energy transfer (EET) in photosynthetic pigment-protein complexes involving the B states has so far not been considered. We present, for the first time, a theoretical framework for the existence of B-B EET in tightly coupled Chl aggregates, such as photosynthetic pigment-protein complexes. We show that according to a simple Förster resonance energy transport (FRET) scheme, unmodulated B-B EET likely poses an existential threat, in particular the photochemical reaction centers (RCs). This insight leads to so-far undescribed roles for carotenoids (Crts, this article) and Chlb(next article in this series) of possibly primary importance.Here we show that B → Q IC is assisted by the symmetry-allowed Crt state (S2) by using the plant antenna complex CP29 as a model: The sequence is B → S2(Crt, unrelaxed) →S2(Crt, relaxed) → Q. This sequence has the advantage of preventing ~ 39% of Chl-Chl B-B EET, since the Crt S2state is a highly efficient FRET acceptor. The likelihood of CP29 to forward potentially harmful B excitations towards the photosynthetic reaction center (RC) is thus reduced. In contrast to the B band of Chls, most Crt energy donation is energetically located near the Q band, which allows for 74/80% backdonation (from lutein/violaxanthin) to Chls. Neoxanthin, on the other hand, likely donates in the B band region of Chlb, with 76% efficiency. The latter is discussed in more detail in the next article in this series. Crts thus do not only act in their currently proposed photoprotective roles, but also as a crucial building block for any system that could otherwise deliver harmful “blue” excitations to the RCs.
Mapping a brain parasite: occurrence and spatial distribution in fish encephalon
Authors: Born-Torrijos Ana , Beest Gabrielle S. van , Merella Paolo , Garippa Giovanni , Raga Juan Antonio , Montero Francisco E. 
Published: January 2023

AbstractParasites, especially brain-encysting trematodes, can have an impact on host behaviour, facilitating the transmission to next host and completion of the life cycle, but insufficient research has been done on whether specific brain regions are targeted. Using the laboratory modelCardiocephaloides longicollis, the precise distribution of metacercariae in experimentally-infected, wild and farmed fish was mapped. The brain regions targeted by this parasite were explored, also from a histologic perspective, and potential pathologic effects were evaluated. Experimental infections allowed to reproduce the natural infection intensity ofC. longicollis, with four times higher infection intensity at the higher dose (150vs50 cercariae). The observed metacercarial distribution, similar among all fish groups, may reflect a species-specific pattern. Metacercariae occur with highest density in the optic lobe area (primarily infect the periventricular gray zone of optic tectum) and the medulla oblongata, whereas other areas such as the olfactory lobes and cerebellar lobes may be occupied when the more frequently invaded parts of the brain were crowded. Mono- and multicysts (i.e. formed either with a single metacercaria, or with 2 ̶ 25 metacercariae encapsulated together) may be formed depending on the aggregation and timing of metacercariae arrival, with minor host inflammatory response. Larvae ofC. longicolliscolonizing specific brain areas may have an effect on the functions associated with these areas, which are generally related to sensory and motor functions, but are also related to other host fitness traits such as school maintenance or recognition of predators. The detailed information on the extent and distribution ofC. longicollisin fish encephalon sets the ground to understand the effects of brain parasites on fish, but further investigation to establish ifC. longicollis, through purely mechanical damage (e.g., occupation, pressure and displacement), has an actual impact on host behaviour remains to be tested under controlled experimental conditions.
The respiratory syncytial virus surge in Austria, 2022, was caused by lineages present before the COVID-19 pandemic
Authors: Redlberger-Fritz Monika , Springer David N. , Aberle Stephan W. , Camp Jeremy V. , Aberle Judith H. 
Published: January 2023

AbstractIn 2022, Austria experienced a severe respiratory syncytial virus (RSV) epidemic with an earlier-than-usual start and increased numbers of paediatric patients in emergency departments. Nationwide multiyear genomic surveillance revealed that the surge was driven by RSV-B, however genotypes consisted of multiple lineages that were circulating prior to the pandemic.
First virological and pathological study of Göttingen Minipigs with Dippity Pig Syndrome (DPS)
Authors: Jhelum Hina , Grand Nanna , Jacobsen Kirsten Rosenmay , Halecker Sabrina , Salerno Michelle , Prate Robert , Krüger Luise , Kristiansen Yannik , Krabben Ludwig , Möller Lars , Laue Michael , Kaufer Benedikt , Kaaber Kari , Denner Joachim 
Published: January 2023

AbstractDippity Pig Syndrome (DPS) is a well-known but rare complex of clinical signs affecting minipigs, which has not been thoroughly investigated yet. Clinically affected animals show acute appearance of red, exudating lesions across the spine. The lesions are painful, evidenced by arching of the back (dipping), and the onset of clinical symptoms is generally sudden. In order to understand the pathogenesis, histological and virological investigations were performed in affected and unaffected Göttingen Minipigs (GöMPs). The following DNA viruses were screened for using PCR-based methods: Porcine cytomegalovirus (PCMV), which is a porcine roseolovirus (PCMV/PRV), porcine lymphotropic herpesviruses (PLHV-1, PLHV-2, PLHV-3), porcine circoviruses (PCV1, PCV2, PCV3, PCV4), porcine parvovirus 1 (PPV1), and Torque Teno sus virus (TTSuV1, TTSuV2). Screening was also performed for integrated porcine endogenous retroviruses (PERV-A, PERV-B, PERV-C) and recombinant PERV-A/C and their expression as well as for the RNA viruses hepatitis E virus (HEV) and SARS-CoV-2. Eight clinically affected and one unaffected GöMPs were analyzed. Additional unaffected minipigs had been analyzed in the past. The analyzed GöMPs contained PERV-A and PERV-B integrated in the genome, which are present in all pigs and PERV-C, which is present in most, but not all pigs. In one affected GöMPs recombinant PERV-A/C was detected in blood. In this animal a very high expression of PERV mRNA was observed. PCMV/PRV was found in three affected animals, PCV1 was found in three animals with DPS and in the healthy minipig, and PCV3 was detected in two animals with DPS and in the unaffected minipig. Most importantly, in one animal only PLHV-3 was detected. It was found in the affected and unaffected skin, and in other organs. Unfortunately, PLHV-3 could not be studied in all other affected minipigs. None of the other viruses were detected and using electron microscopy, no virus particles were found in the affected skin. This data identified some virus infections in GöMPs with DPS and assign a special role to PLHV-3. Since PCMV/PRV, PCV1, PCV3 and PLHV-3 were also found in unaffected animals, a multifactorial cause of DPS is suggested. However, elimination of the viruses from GöMPs may prevent DPS.
Contribution of circulating host and microbial tryptophan metabolites towards Ah receptor activation
Authors: Morgan Ethan W. , Dong Fangcong , Annalora Andrew , Murray Iain A. , Wolfe Trenton , Erickson Reece , Gowda Krishne , Amin Shantu G. , Petersen Kristina S. , Kris-Etherton Penny M. , Marcus Craig , Walk Seth T. , Patterson Andrew D. , Perdew Gary H. 
Published: January 2023

AbstractThe aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that plays an integral role in homeostatic maintenance by regulating cellular functions such as cellular differentiation, metabolism, barrier function, and immune response. An important but poorly understood class of AHR activators are compounds derived from host and bacterial metabolism of tryptophan. The commensal bacteria of the gut microbiome are major producers of tryptophan metabolites known to activate the AHR, while the host also produces AHR activators through tryptophan metabolism. We used targeted mass spectrometry-based metabolite profiling to determine the presence and metabolic source of these metabolites in the sera of conventional mice, germ-free mice, and humans. Surprisingly, sera concentrations of many tryptophan metabolites are comparable between germ-free and conventional mice. Therefore, many major AHR-activating tryptophan metabolites in mouse sera are produced by the host, despite their presence in feces and mouse cecal contents. AHR activation is rarely studied in the context of a mixture at relevant concentrations, as we present here. The AHR activation potentials of individual and pooled metabolites were explored using cell-based assays, while ligand binding competition assays and ligand docking simulations were used to assess the detected metabolites as AHR agonists. The physiological and biomedical relevance of the identified metabolites was investigated in the context of cell-based models for cancer and rheumatoid arthritis. We present data here that reframe AHR biology to include the presence of ubiquitous tryptophan metabolites, improving our understanding of homeostatic AHR activity and models of AHR-linked diseases.
Evolution of affinity between p53 and MDM2 across the animal kingdom demonstrates high plasticity of motif-mediated interactions
Authors: Mihalic Filip , Åberg Emma , Farkhondehkish Pouria , Theys Niels , Andersson Eva , Jemth Per 
Published: January 2023

ABSTRACTThe interaction between the transcription factor p53 and the ubiquitin ligase MDM2 results in degradation of p53 and is well studied in cancer biology and drug development. Available sequence data suggest that both p53 and MDM2-family proteins are present across the animal kingdom. However, the interacting regions are missing in some animal groups, and it is not clear whether MDM2 interacts with, and regulates p53 in all species. We used phylogenetic analyses and biophysical measurements to examine the evolution of affinity between the interacting protein regions: a conserved 12-residue intrinsically disordered binding motif in the p53 transactivation domain (TAD) and the folded SWIB domain of MDM2. The affinity varied significantly across the animal kingdom. The p53TAD/MDM2 interaction among jawed vertebrates displayed high affinity, in particular for chicken and human proteins (KDaround 0.1 μM). The affinity of the bay mussel p53TAD/MDM2 complex was lower (KD= 15 μM) and those from a placozoan, an arthropod and a jawless vertebrate were very low or non-detectable (KD> 100 μM). Binding experiments with reconstructed ancestral p53TAD/MDM2 variants suggested that a micromolar affinity interaction was present in the ancestral bilaterian animal and was later enhanced in tetrapods while lost in other linages. The different evolutionary trajectories of p53TAD/MDM2 affinity during speciation demonstrate high plasticity of motif-mediated interactions and the potential for rapid adaptation of p53 regulation during times of change. Neutral drift in unconstrained disordered regions may underlie the plasticity and explain the observed low sequence conservation in transactivation domains such as p53TAD.Statement for broader audienceThe protein p53 regulates central cellular processes including cell division and programmed cell death. p53 is regulated by another protein, MDM2, which binds to p53 and marks it for destruction. We measured the interaction between present-day and reconstructed ancient p53 and MDM2 proteins and found a range of binding strengths. Our findings suggest that rapid evolution of the p53/MDM2 interaction facilitates adaptation of p53 regulation during speciation.
Contrasting drivers of abundant phage and prokaryotic communities in tropical, coastal ecosystems across the Isthmus of Panama
Authors: Weinheimer Alaina R. , Aylward Frank O. , Leray Matthieu , Scott Jarrod J. 
Published: January 2023

ABSTRACTPhages, or viruses that infect bacteria and archaea, are ubiquitous and abundant members of Earth’s ecosystems that impact the flow of nutrients, evolution of microbes, and food web dynamics by selectively infecting and killing their prokaryotic hosts. Because phages can only replicate through their hosts, they are inherently linked to processes impacting their hosts’ distribution and susceptibility to infection. Despite these links, phages can also be affected by environmental parameters independent of their hosts, such as pH or salinity which impact cell adsorption or virion degradation. To understand these complex links, in this study, we leverage the unique ecological context of the Isthmus of Panama, which narrowly disconnects the productive Tropical Eastern Pacific (TEP) and Tropical Western Atlantic (TWA) provinces and compare factors that shape active marine phage and prokaryotic communities. Metagenomic sequencing of seawater from mangroves and reefs of both the TEP and TWA coasts of Panama suggest that pronounced environmental gradients, such as along the TEP mangrove rivers, result in common dispersal and physicochemical parameters shaping both prokaryotic and phage community composition and diversity. Conversely, we find that when environmental conditions are relatively similar across adjacent habitats, such as between the mangroves and reefs in the TWA, prokaryotic communities are more influenced by local abiotic conditions while phage communities are shaped more by dispersal. Collectively, this work provides a framework for addressing the co-variability between viruses and their hosts in marine systems and for identifying the different factors that drive consistent versus disparate trends in community shifts, which is essential to inform models of these interactions in biogeochemical cycling.
Intonation Units in spontaneous speech evoke a neural response
Authors: Inbar Maya , Genzer Shir , Perry Anat , Grossman Eitan , Landau Ayelet N. 
Published: January 2023

AbstractSpontaneous speech is produced in chunks called Intonation Units (IUs). IUs are defined by a set of prosodic cues and occur in all human languages. Linguistic theory suggests that IUs pace the flow of information and serve as a window onto the dynamic focus of attention in speech processing. IUs provide a promising and hitherto unexplored theoretical framework for studying the neural mechanisms of communication, thanks to their universality and their consistent temporal structure across different grammatical and socio-cultural conditions. In this article, we identify a neural response unique to the boundary defined by the IU. We measured the EEG of participants who listened to different speakers recounting an emotional life event. We analyzed the speech stimuli linguistically, and modeled the EEG response at word offset using a GLM approach. We find that the EEG response to IU-final words differs from the response to IU-nonfinal words when acoustic boundary strength is held constant. To the best of our knowledge, this is the first time this is demonstrated in spontaneous speech under naturalistic listening conditions, and under a theoretical framework that connects the prosodic chunking of speech, on the one hand, with the flow of information during communication, on the other. Finally, we relate our findings to the body of research on rhythmic brain mechanism in speech processing by comparing the topographical distributions of neural speech tracking in model-predicted and empirical EEG. This qualitative comparison suggests that IU-related neural activity contributes to the previously characterized delta-band neural speech tracking.
Helminth-derived metabolites induce tolerogenic functional, metabolic, and transcriptional signatures in dendritic cells that attenuate experimental colitis
Authors: Malacco Nathalia L. , Michi Aubrey N. , Siciliani Elizabeth , Madrigal Ana G. , Sternlieb Tamara , Fontes Ghislaine , King Irah L. , Cestari Igor , Jardim Armando , Stevenson Mary M. , Lopes Fernando 
Published: January 2023

ABSTRACTInflammatory bowel diseases (IBD) are chronic inflammatory diseases in which abdominal pain, bloody diarrhea, weight loss, and fatigue collectively result in diminished quality of patient life. The disappearance of intestinal helminth infections in Western societies is associated with an increased prevalence of IBD and other immune-mediated inflammatory diseases. Evidence indicates that helminths induce tolerogenic dendritic cells (tolDCs), which promote intestinal tolerance and attenuate intestinal inflammation characteristic of IBD, but the exact mechanism is unclear. Helminth-derived excretory-secretory (HES) products including macromolecules, proteins, and polysaccharides have been shown to modulate the antigen presenting function of DCs with down-stream effects on effector CD4+T cells. Previous studies indicate that DCs in helminth-infected animals induce tolerance to unrelated antigens and DCs exposed to HES display phenotypic and functional features of tolDCs. Here, we identify that nonpolar metabolites (HnpM) produced by a helminth, the murine gastrointestinal nematodeHeligmosomoides polygyrus bakeri(Hpb), induce tolDCs as evidenced by decreased LPS-induced TNF and increased IL-10 secretion and reduced expression of MHC-II, CD86, and CD40. Furthermore, these DCs inhibited OVA-specific CD4+T cell proliferation and induced CD4+Foxp3+regulatory T cells. Adoptive transfer of HnpM-induced tolDCs attenuated DSS-induced intestinal inflammation characteristic of IBD. Mechanistically, HnpM induced metabolic and transcriptional signatures in BMDCs consistent with tolDCs. Collectively, our findings provide groundwork for further investigation into novel mechanisms regulating DC tolerance and the role of helminth secreted metabolites in attenuating intestinal inflammation associated with IBD.Summary Sentence:Metabolites produced byHeligmosomoides polygyrusinduce metabolic and transcriptional changes in DCs consistent with tolDCs, and adoptive transfer of these DCs attenuated DSS-induced intestinal inflammation.
miR-7 controls glutamatergic transmission and neuronal connectivity in a Cdr1as-dependent manner
Authors: Jara Cledi A. Cerda , Kim Seung Joon , Thomas Gwendolin , Farsi Zohreh , Zolotarov Grygoriy , Georgii Elisabeth , Woehler Andrew , Piwecka Monika , Rajewsky Nikolaus 
Published: January 2023

AbstractThe circular RNA (circRNA) Cdr1as is conserved across mammals and highly expressed in neurons, where it directly interacts with microRNA miR-7. However, the biological function of this interaction is unknown. Here, using primary forebrain murine neurons, we demonstrate that stimulating neurons by sustained depolarization rapidly induced two-fold transcriptional up-regulation of Cdr1as and strong post-transcriptional stabilization of miR-7. Cdr1as loss caused doubling of glutamate release from stimulated synapses and increased frequency and duration of local neuronal bursts. Moreover, periodicity of neuronal networks was increased and synchronicity was impaired. Strikingly, these effects were reverted by sustained expression of miR-7 which also cleared Cdr1as molecules from neuronal projections. Consistently, without Cdr1as, transcriptomic changes caused by miR-7 overexpression were stronger (including miR-7-targets down-regulation) and enriched in secretion/synaptic plasticity pathways. Altogether, our results suggest that in forebrain neurons Cdr1as buffers miR-7 activity to control glutamatergic excitatory transmission and neuronal connectivity important for long-lasting synaptic adaptations.