bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microglial phagocytosis mediates long-term restructuring of spinal GABAergic circuits following early life injury
Authors: Xu Yajing , Moulding Dale , Jin Wenanlan , Beggs Simon 
Published: February 2023

AbstractPeripheral injury during the early postnatal period alters the somatosensory system, leading to behavioural hyperalgesia upon re-injury in adulthood. Spinal microglia have been implicated as the cellular mediators of this phenomenon, but the mechanism is unclear. We hypothesised that neonatal injury (1) alters microglial phagocytosis of synapses in the dorsal horn leading to long-term structural changes in neurons, and/or (2) trains microglia, leading to a stronger microglial response after re-injury in adulthood. Using hindpaw surgical incision as a model we showed that microglial density and phagocytosis increased in the dorsal horn region innervated by the hindpaw. Dorsal horn microglia increased engulfment of synapses following injury, with a preference for those expressing the vesicular GABA transporter VGAT and primary afferent A-fibre terminals in neonates. This led to a long-term reduction of VGAT density in the dorsal horn and reduced microglial phagocytosis of VGLUT2 terminals. We also saw an increase in apoptosis following neonatal injury, which was not limited to the dorsal horn suggesting that larger circuit wide changes are happening.In adults, hindpaw incision increased microglial engulfment of predominantly VGAT synapses but did not alter the engulfment of A-fibres. This engulfment was not affected by prior neonatal injury, suggesting that microglial phagocytosis was not trained. These results highlight microglial phagocytosis in the dorsal horn as an important physiological response towards peripheral injury with potential long-term consequences and reveals differences in microglial responses between neonates and adults.
Current Status and Emerging Trends of COVID-19-related Studies in Seven ‘Tropical Medicine’-entitled Journals
Authors: Zhang Xuejuan , Zhong Ziqiao , Luo Peili , Zhu Chune , Huang Ying , Wu Chuanbin , Pan Xin , Huang Zhengwei 
Published: February 2023

AbstractBackgroundCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has created enormous medical and economic burdens on human society. However, the co-existence of COVID-19 and diseases in tropical regions is not taken seriously. To improve the understanding of the current status and trends on crosstalk of COVID-19 and tropical diseases, this paper provided an analysis, from a bibliometric perspective, of the COVID-19-related publications in ‘Tropical Medicine’-entitled journals.MethodsWe used Clarivate Analytics and VOSviewer to analyze 783 publications in seven ‘Tropical Medicine’-entitled journals. Document overview, basic bibliometric characteristics, citation performance, co-authorship, co-citation, bibliographic coupling, and co-occurrence of keywords and terms were summarized in this article.ResultsDocument overview revealed that 76.12% of the related publications were published in open access mode, and basic bibliometric characteristics indicated that the year 2021 was the peak of the number of publications, the documents in the seven journals were unevenly distributed, and ‘article’ was the main publication type. The citation performance analysis elucidated that the documents of interest were frequently cited. The co-authorship analysis showed cooperation networks on the level of region, organization and author. General knowledge of COVID-19 was the overlap of co-citation and bibliographic coupling behavior. Finally, the co-occurrence of keywords and terms revealed the current and emerging hotspots.ConclusionsThe main current research focuses in ‘Tropical Medicine’-entitled journals are the clinical features of COVID-19 patients, and the emerging trends are the hesitancy in making vaccines against SARS-CoV-2 and the circumstance where COVID-19 coexisted with tropical diseases. In summary, this bibliometric analysis of COVID-19-related studies in seven ‘Tropical Medicine’-entitled journals highlights the current research focuses of this field to inspire future studies.
Differentiable Partition Function Calculation for RNA
Authors: Matthies Marco , Krueger Ryan , Torda Andrew , Ward Max 
Published: February 2023

AbstractRibonucleic acid (RNA) is an essential molecule in a wide range of biological functions. In 1990, McCaskill introduced a dynamic programming algorithm for computing the partition function of an RNA sequence. This forward model is widely used for understanding the thermodynamic properties of a given RNA. In this work, we introduce a generalization of McCaskill’s algorithm that is well-defined over continuous inputs and is differentiable. This allows us to tackle the inverse folding problem—designing a sequence with desired equilibrium thermodynamic properties—directly using gradient optimization. This has applications to creating RNA-based drugs such as mRNA vaccines. Furthermore, it allows McCaskill’s foundational algorithm to be incorporated into machine learning pipelines directly since we have made it end-to-end differentiable. This work highlights how principles from differentiable programming can be translated to existing physical models to develop powerful tools for machine learning. We provide a concrete example by implementing an effective and interpretable RNA design algorithm.
Tregs constrain CD8+T cell priming required for curative intratumorally anchored anti-4-1BB immunotherapy
Authors: Palmeri Joseph R. , Lax Brianna M. , Peters Joshua M. , Duhamel Lauren , Stinson Jordan A. , Santollani Luciano , Lutz Emi A. , Pinney William , Bryson Bryan D. , Wittrup K. Dane 
Published: February 2023

AbstractAlthough co-stimulation of T cells with agonist antibodies targeting 4-1BB (CD137) improves antitumor immune responses in preclinical studies, clinical development has been hampered by on-target, off-tumor toxicity. Here, we report the development of a tumor-anchored α4-1BB agonist (α4-1BB-LAIR), which consists of an α4-1BB antibody fused to the collagen binding protein LAIR. While combination treatment with an antitumor antibody (TA99) displayed only modest efficacy, simultaneous depletion of CD4+T cells boosted cure rates to over 90% of mice. We elucidated two mechanisms of action for this synergy: αCD4 eliminated tumor draining lymph node Tregs, enhancing priming and activation of CD8+T cells, and TA99 + α4-1BB-LAIR supported the cytotoxic program of these newly primed CD8+T cells within the tumor microenvironment. Replacement of αCD4 with αCTLA-4, a clinically approved antibody that enhances T cell priming, produced equivalent cure rates while additionally generating robust immunological memory against secondary tumor rechallenge.One Sentence SummaryInhibition of nodal Tregs enhances CD8+T cell priming, improving antitumor responses to collagen-anchored α4-1BB combination therapy.
Fully accessible fitness landscape of oncogene-negative lung adenocarcinoma
Authors: Yousefi Maryam , Andrejka Laura , Winslow Monte M. , Petrov Dmitri A. , Boross Gábor 
Published: February 2023

ABSTRACTCancer genomes are almost invariably complex with genomic alterations cooperating during each step of carcinogenesis. In cancers that lack a single dominant oncogene mutation, cooperation between the inactivation of multiple tumor suppressor genes can drive tumor initiation and growth. Here, we shed light on how the sequential acquisition of genomic alterations generates oncogene-negative lung tumors. We couple tumor barcoding with combinatorial and multiplexed somatic genome editing to characterize the fitness landscapes of three tumor suppressor genes NF1, RASA1, and PTEN, the inactivation of which jointly drives oncogene-negative lung adenocarcinoma initiation and growth. The fitness landscape was surprisingly accessible, with each additional mutation leading to growth advantage. Furthermore, the fitness landscapes remained fully accessible across backgrounds with additional tumor suppressor mutations. These results suggest that while predicting cancer evolution will be challenging, acquiring the multiple alterations required for the growth of oncogene-negative tumors can be facilitated by the lack of constraints on mutational order.
Translational control offurinaby an RNA regulon is essential for heart morphogenesis and cardiac valve function
Authors: Nagorska Agnieszka , Lambert Finnlay , Inman Angus , Toral-Perez Sara , Zaucker Andreas , Gorodkin Jan , Yue Wan , Smutny Michael , Sampath Karuna 
Published: February 2023

AbstractHeart development is a complex process, starting from specification of cardiac precursors and formation of a linear tube to gradual progression to a functional beating organ. For normal heart development, many processes, including asymmetric positioning of the heart along the left-right (L/R) axis, cardiac growth, and cardiac valve morphogenesis must be completed successfully. Although heart development has been studied extensively, the mechanisms that control heart morphogenesis and valve formation are not fully understood. The pro-convertase FurinA is a key protein that functions in heart development in many vertebrates including zebrafish. How FurinA activity is regulated during heart development is not known. Through computational analysis of the zebrafish transcriptome, we identified a short sequence and structure RNA motif in a variant transcript of FurinA harbouring a long 3’untranslated region (3’UTR). The alternative 3’UTRfurinaisoform is expressed at embryonic stages preceding organ positioning. Reporter localization and RNA-binding assays show that thefurina3’UTR forms complexes with the conserved RNA-binding protein and translational repressor Ybx1. Conditional mutant zebrafish embryos affectingybx1show premature and increased Furin reporter protein expression, abnormal cardiac morphogenesis and heart looping defects. Our mutantybx1hearts have an expanded atrioventricular canal, abnormal sino-atrial valves and many mutant embryos show retrograde blood flow from the ventricle to the atrium. This is similar to human heart valve regurgitation patients. Our findings show an essential function for the 3’UTR element/Ybx1 regulon in translational repression of FurinA, revealing a new upstream regulatory mechanism that controls embryonic heart development, and demonstrates theybx1mutant as a model to study cardiac valve development and function.
Mucociliary Clearance Augmenting Drugs Block SARS-Cov-2 Replication in Human Airway Epithelial Cells
Authors: Campos-Gomez Javier , Petty Courtney Fernandez , Mazur Marina , Tang Liping , Solomon George M. , Joseph Reny , Li Qian , Lever Jacelyn E. Peabody , Hussain Shah , Harrod Kevin , Onuoha Ezinwanne , Kim Harrison , Rowe Steven M. 
Published: February 2023

AbstractThe coronavirus disease (COVID-19) pandemic, caused by SARS-CoV-2 coronavirus, is devastatingly impacting human health. A prominent component of COVID-19 is the infection and destruction of the ciliated respiratory cells, which perpetuates dissemination and disrupts protective mucociliary transport (MCT) function, an innate defense of the respiratory tract. Thus, drugs that augment MCT could improve barrier function of the airway epithelium, reduce viral replication and, ultimately, COVID-19 outcomes. We tested five agents known to increase MCT through distinct mechanisms for activity against SARS-CoV-2 infection using a model of human respiratory epithelial cells terminally differentiated in an air/liquid interphase. Three of the five mucoactive compounds tested showed significant inhibitory activity against SARS-CoV-2 replication. An archetype mucoactive agent, ARINA-1, blocked viral replication and therefore epithelial cell injury, thus, it was further studied using biochemical, genetic and biophysical methods to ascertain mechanism of action via improvement of MCT. ARINA-1 antiviral activity was dependent on enhancing the MCT cellular response, since terminal differentiation, intact ciliary expression and motion was required for ARINA-1-mediated anti-SARS-CoV2 protection. Ultimately, we showed that improvement of cilia movement was caused by ARINA-1-mediated regulation of the redox state of the intracellular environment, which benefited MCT. Our study indicates that Intact MCT reduces SARS-CoV-2 infection, and its pharmacologic activation may be effective as an anti-COVID-19 treatment.
Gadusol is a maternally provided sunscreen that protects fish embryos from DNA damage
Authors: Rice Marlen C. , Little Jordan H. , Forrister Dale L. , Machado Julane , Clark Nathan L. , Gagnon James A. 
Published: February 2023

AbstractUltraviolet radiation (UVR) and its deleterious effects on living cells selects for UVR-protective mechanisms. Organisms across the tree of life evolved a variety of natural sunscreens to prevent UVR-induced cellular damage and stress. However, in vertebrates, only melanin is known to act as a sunscreen. Here we demonstrate that gadusol, a transparent compound discovered over 40 years ago in fish eggs, is a maternally provided sunscreen required for survival of embryonic and larval zebrafish exposed to UVR. Mutating an enzyme involved in gadusol biosynthesis increases the formation of cyclobutane pyrimidine dimers, a hallmark of UVB-induced DNA damage. Compared to the contributions of melanin and the chorion, gadusol is the primary sunscreening mechanism in embryonic and larval fish. The gadusol biosynthetic pathway is retained in the vast majority of teleost genomes but is repeatedly lost in species whose young are no longer exposed to UVR. Our data demonstrate that gadusol is a maternally provided sunscreen that is critical for early-life survival in the most species-rich branch of the vertebrate phylogeny.
A new microphysiological system shows hypoxia primes human ISCs for interleukin-dependent rescue of stem cell activity
Authors: Rivera Kristina R. , Bliton R. Jarrett , Burclaff Joseph , Czerwinski Michael J. , Liu Jintong , Trueblood Jessica M. , Hinesley Caroline M. , Breau Keith A , Joshi Shlok , Pozdin Vladimir A. , Yao Ming , Ziegler Amanda L. , Blikslager Anthony T. , Daniele Michael A. , Magness Scott T. 
Published: February 2023

ABSTRACTBackground & AimsHypoxia in the intestinal epithelium can be caused by acute ischemic events or conditions like Inflammatory Bowel Disease (IBD) where immune cell infiltration produces ‘inflammatory hypoxia’, a chronic condition that starves the mucosa of oxygen. Epithelial regeneration after ischemia and IBD suggests intestinal stem cells (ISCs) are highly tolerant to acute and chronic hypoxia; however, the impact of acute and chronic hypoxia on human ISC (hISC) properties have not been reported. Here we present a new microphysiological system (MPS) to investigate how hypoxia affects hISCs isolated from healthy human tissues. We then test the hypothesis that some inflammation-associated interleukins protect hISCs during prolonged hypoxia.MethodshISCs were exposed to <1.0% oxygen in the MPS for 6-, 24-, 48- & 72hrs. Viability, HIF1α response, transcriptomics, cell cycle dynamics, and hISC response to cytokines were evaluated.ResultsThe novel MPS enables precise, real-time control and monitoring of oxygen levels at the cell surface. Under hypoxia, hISCs remain viable until 72hrs and exhibit peak HIF1α at 24hrs. hISCs lose stem cell activity at 24hrs that recovers at 48hrs of hypoxia. Hypoxia increases the proportion of hISCs in G1 and regulates hISC capacity to respond to multiple inflammatory signals. Hypoxia induces hISCs to upregulate many interleukin receptors and hISCs demonstrate hypoxia-dependent cell cycle regulation and increased organoid forming efficiency when treated with specific interleukinsConclusionsHypoxia primes hISCs to respond differently to interleukins than hISCs in normoxia through a transcriptional response. hISCs slow cell cycle progression and increase hISC activity when treated with hypoxia and specific interleukins. These findings have important implications for epithelial regeneration in the gut during inflammatory events.
Bacterial microbiota ofOstreobium, the coral-isolated chlorophyte ectosymbiont, at contrasted salinities
Authors: Massé A. , Detang J. , Duval C. , Duperron S. , Woo A.C. , Domart-Coulon I. 
Published: February 2023

AbstractMicroscopic filaments of the siphonous green algaeOstreobium(Ulvophyceae, Bryopsidales) colonize and dissolve the calcium carbonate skeletons of coral colonies, in shallow-water reef environments of contrasted salinities. Their bacterial composition and plasticity in response to salinity remain unknown. Here, we analyzed the bacteria associated with coral-isolatedOstreobiumstrains from two distinctrbcL lineages, representative of IndoPacific environmental phylotypes, that had been pre-acclimatized (>9months) to three ecologically-relevant reef salinities: 32.9, 35.1 and 40.2 psu. Bacterial phylotypes were visualized at filament scale by CARD-FISH in algal tissue sections, localized to the surface, within filaments or in the algal mucilage.Ostreobium-associated communities, characterized by bacterial 16S rRNA metabarcoding of cultured thalli and corresponding supernatants, were structured by host genotype more than salinity and partly overlapped with those of environmental (Ostreobium-colonized) coral skeletons. Alphaproteobacteria dominated the thalli communities, enriched in Kiloniellaceae or Rhodospirillaceae depending on algal genotype. A small core microbiota composed of 7 ASVs (∼1.5% of thalli ASVs, 19%-36% cumulated proportions), shared by multiple cultures of bothOstreobiumgenotypes and persistent across 3 salinities, included putative intracellular Amoebophilus and Rickettsiales bacteria. This novel knowledge on the taxonomic diversity ofOstreobiumbacterial associates paves the way to functional interaction studies within the coral holobiont.
Single-cell multi-omic topic embedding reveals cell-type-specific and COVID-19 severity-related immune signatures
Authors: Zhou Manqi , Zhang Hao , Bai Zilong , Mann-Krzisnik Dylan , Wang Fei , Li Yue 
Published: February 2023

AbstractThe advent of single-cell multi-omics sequencing technology makes it possible for re-searchers to leverage multiple modalities for individual cells and explore cell heterogeneity. However, the high dimensional, discrete, and sparse nature of the data make the downstream analysis particularly challenging. Most of the existing computational methods for single-cell data analysis are either limited to single modality or lack flexibility and interpretability. In this study, we propose an interpretable deep learning method called multi-omic embedded topic model (moETM) to effectively perform integrative analysis of high-dimensional single-cell multimodal data. moETM integrates multiple omics data via a product-of-experts in the encoder for efficient variational inference and then employs multiple linear decoders to learn the multi-omic signatures of the gene regulatory programs. Through comprehensive experiments on public single-cell transcriptome and chromatin accessibility data (i.e., scRNA+scATAC), as well as scRNA and proteomic data (i.e., CITE-seq), moETM demonstrates superior performance compared with six state-of-the-art single-cell data analysis methods on seven publicly available datasets. By applying moETM to the scRNA+scATAC data in human bone marrow mononuclear cells (BMMCs), we identified sequence motifs corresponding to the transcription factors that regulate immune gene signatures. Applying moETM analysis to CITE-seq data from the COVID-19 patients revealed not only known immune cell-type-specific signatures but also composite multi-omic biomarkers of critical conditions due to COVID-19, thus providing insights from both biological and clinical perspectives.
Bei Mu Gua Lou San facilitates mucus expectoration by increasing surface area and hydration levels of airway mucus in an air-liquid-interface cell culture model of the respiratory epithelium
Authors: Groiss Silvia , Somvilla Ina , Daxböck Christine , Stückler Manuela , Pritz Elisabeth , Brislinger Dagmar 
Published: February 2023

AbstractBei Mu Gua Lou San (BMGLS) is an ancient formulation known for its moisturizing and expectorant properties, but the underlying mechanisms remain unknown. We investigated dose-dependent effects of BMGLS on its rehydrating and mucus-modulating properties using an air-liquid-interface (ALI) cell culture model of the Calu-3 human bronchial epithelial cell line and primary normal human bronchial epithelial cells (NHBE), and specifically focused on quantity and composition of the two major mucosal proteins MUC5AC and MUC5B.ALI cultures were treated with BMGLS at different concentrations over three weeks and evaluated by means of histology, immunostaining and electron microscopy. MUC5AC and MUC5B mRNA levels were assessed and quantified on protein level using an automated image-based approach. Additionally, expression levels of the major mucus-stimulating enzyme 15-lipoxygenase (ALOX15) were evaluated. BMGLS induced dose-dependent morphological changes in NHBE but not Calu-3 ALI cultures that resulted in increased surface area via the formation of herein termed intra-epithelial structures (IES). While cellular rates of proliferation, apoptosis or degeneration remained unaffected, BMGLS caused swelling of mucosal granules, increased the area of secreted mucus, decreased muco-glycoprotein density, and dispensed MUC5AC. Additionally, BMGLS reduced expression levels of MUC5AC, MUC5B and the mucus-stimulating enzyme 15-lipoxygenase (ALOX15).Our studies suggest that BMGLS rehydrates airway mucus while stimulating mucus secretion by increasing surface areas and regulating goblet cell differentiation through modulating major mucus-stimulating pathways.
Detection and quantification of the histone code in the fungal genusAspergillus
Authors: Zhang Xin , Noberini Roberta , Vai Alessandro , Bonaldi Tiziana , Seidl Michael F. , Collemare Jérȏme 
Published: February 2023

AbstractIn eukaryotes, the combination of different histone post-translational modifications (PTMs) – the histone code – impacts the chromatin organization as compact and transcriptionally silent heterochromatin or accessible and transcriptionally active euchromatin. Although specific histone PTMs have been studied in fungi, an overview of histone PTMs and their relative abundance is still lacking. Here, we used mass spectrometry to detect and quantify histone PTMs in germinating spores of three fungal species belonging to three distinct taxonomic sections of the genusAspergillus(Aspergillus niger, Aspergillus nidulans(two strains), andAspergillus fumigatus). We overall detected 23 different histone PTMs, including a majority of lysine methylations and acetylations, and 23 co-occurrence patterns of multiple histone PTMs. Among those, we report for the first time the detection of H3K79me1/2 and H4K5/8/12ac in Aspergilli. Although all three species harbour the same PTMs, we found significant differences in the relative abundance of H3K9me1/2/3, H3K14ac, H3K36me1 and H3K79me1, as well as the co-occurrence of acetylation on both K18 and K23 of histone H3 in a strain-specific manner. Our results provide novel insights about the underexplored complexity of the histone code in filamentous fungi, and its functional implications on genome architecture and gene regulation.HighlightsQuantitative mass spectrometry allows uncovering major histone PTMs.H3K79me1/2 and H4K5/8/12ac are new histone PTMs detected in Aspergilli.The relative abundance of histone PTMs varies in a strain-specific manner.Variation in histone PTM abundance reflects different chromatin status.