bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterologous booster with a novel formulation containing glycosylated trimeric S protein is effective against Omicron
Authors: Bottero Daniela , Rudi Erika , Aispuro Pablo Martin , Zurita Eugenia , Gaillard Emilia , Lopez Ledesma Maria M. Gonzalez , Malito Juan , Stuible Matthew , Ambrosis Nicolas , Durocher Yves , Gamarnik Andrea V. , Wigdorovitz Andrés , Hozbor Daniela 
Published: October 2023

AbstractIn this study, we evaluated the efficacy of a heterologous three-dose vaccination schedule against the Omicron BA.1 SARS-CoV-2 variant infection using a mouse intranasal challenge model. The vaccination schedules tested in this study consisted of a primary series of 2 doses covered by two commercial vaccines: an mRNA-based vaccine (mRNA1273) or a non-replicative vector-based vaccine (AZD1222/ChAdOx1, hereafter referred to as AZD1222). These were followed by a heterologous booster dose using one of the two vaccine candidates previously designed by us: one containing the glycosylated and trimeric spike protein (S) from the ancestral virus (SW-Vac 2μg), and the other from the Delta variant of SARS-CoV-2 (SD-Vac 2μg), both formulated with Alhydrogel as an adjuvant. For comparison purposes, homologous three-dose schedules of the commercial vaccines were used. The mRNA-based vaccine, whether used in heterologous or homologous schedules, demonstrated the best performance, significantly increasing both humoral and cellular immune responses. In contrast, for the schedules that included the AZD1222 vaccine as the primary series, the heterologous schemes showed superior immunological outcomes compared to the homologous 3-dose AZD1222 regimen. For these schemes no differences were observed in the immune response obtained when SW-Vac 2μg or SD-Vac 2μg were used as a booster dose. Neutralizing antibody levels against Omicron BA.1 were low, especially for the schedules using AZD1222. However, a robust Th1 profile, known to be crucial for protection, was observed, particularly for the heterologous schemes that included AZD1222. All the tested schedules were capable of inducing populations of CD4 T effector, memory, and follicular helper T lymphocytes. It is important to highlight that all the evaluated schedules demonstrated a satisfactory safety profile and induced multiple immunological markers of protection. Although the levels of these markers were different among the tested schedules, they appear to complement each other in conferring protection against intranasal challenge with Omicron BA.1 in K18-hACE2 mice. In summary, the results highlight the potential of using the S protein (either ancestral Wuhan or Delta variant)-based vaccine formulation as heterologous boosters in the management of COVID-19, particularly for certain commercial vaccines currently in use.
Spatial heterogeneity in tumor adhesion qualifies collective cell migration
Authors: Prasanna C V S , Jolly Mohit Kumar , Bhat Ramray 
Published: October 2023

AbstractCollective cell migration, a canon of most invasive solid tumors, is an emergent property of the interactions between cancer cells and their surrounding extracellular matrix (ECM). However, tumor populations invariably consist of cells expressing variable levels of adhesive proteins that mediate such interactions, disallowing an intuitive understanding of how tumor invasiveness at a multicellular scale is influenced by spatial heterogeneity of cell-cell and cell-ECM adhesion. Here, we have used a Cellular Potts model-based multiscale computational framework that is constructed on the histopathological principles of glandular cancers. In earlier efforts on homogenous cancer cell populations, this framework revealed the relative ranges of interactions, including cell-cell and cell-ECM adhesion that drove collective, dispersed, and mixed multimodal migrations. Here, we constitute a tumor core of two separate cell subsets showing distinct intra-subset cell-cell or cell-ECM adhesion strengths. These two subsets of cells are arranged to varying extents of spatial intermingling, which we call the heterogeneity index (HI). Our simulations show that for a given two intra-subset cell-cell adhesions for two subsets of cells, low and high inter-subset cell adhesion favors migration of high HI and low HI intermingled populations, respectively. In addition, for the most explored values of cell-ECM adhesion strengths, populations with high HI values collectively migrate better than those with lower HI values. We then asked how spatial migration is regulated by progressively intermingled cellular subsets that were epithelial, i.e., showed high cell-cell but poor cell-ECM adhesion, and mesenchymal, i.e., with reversed adhesion strengths to the former. Here too, inter-subset adhesion plays an important role in contextualizing the proportionate relationship between HI and migration. We also observe an exception to this relationship for cases of heterogeneous cell-ECM adhesion where sub-maximal HI patterns with higher outer localization of cells with stronger ECM adhesion collectively migrate better than their relatively higher HI counterparts. Our simulations also reveal how adhesion heterogeneity qualifies migrative dynamics through collective cellular unjamming, when either cell-cell or -ECM adhesion type is varied but incorporates dispersion when both adhesion types are simultaneously altered.
Microglia shape hippocampal networks but are dispensable for pruning of synapses during development
Authors: Surala Michael , Soso-Zdravkovic Luna , Munro David , Rifat Ali , Ouk Koliane , Vida Imre , Priller Josef , Madry Christian 
Published: October 2023

AbstractMicroglia, the brain-resident macrophages, are believed to sculpt developing neural circuits by eliminating excess synapses in a process called synaptic pruning, removing apoptotic neurons, and promoting neuronal survival. To elucidate the role of microglia during embryonic and postnatal brain development, we used a mouse model deficient in microglia throughout life as a consequence of deletion of the fms-intronic regulatory element (FIRE) in theCsf1rlocus. Surprisingly, young adultCsf1rΔFIRE/ΔFIREmice displayed no changes in excitatory synapse number and spine density of CA1 hippocampal neurons compared toCsf1r+/+littermates. However, CA1 neurons were less excitable, received less CA3 Schaffer collateral-mediated excitatory input and showed altered synaptic properties, but this did not affect novel object recognition. Cytokine profiling indicated an anti-inflammatory state along with increases in ApoE levels and astrocyte reactivity in brains ofCsf1rΔFIRE/ΔFIREmice. Notably, these morphological and functional changes inCsf1rΔFIRE/ΔFIREmice closely resemble the effects of acute microglial depletion in adult mice that had undergone normal development. Thus, our findings challenge the prevailing view that microglia are indispensable for the establishment of neural networks during development.
DRG Explant Model: Elucidating Mechanisms of Oxaliplatin-Induced Peripheral Neuropathy and Identifying Potential Therapeutic Targets
Authors: Du Junwei , Sudlow Leland C. , Luzhansky Igor D. , Berezin Mikhail Y. 
Published: October 2023

ABSTRACTOxaliplatin triggered chemotherapy induced peripheral neuropathy (CIPN) is a common and debilitating side effect of cancer treatment which limits the efficacy of chemotherapy and negatively impacts patients quality of life dramatically. For better understanding the mechanisms of CIPN and screen for potential therapeutic targets, it is critical to have reliablein vitroassays that effectively mirror the neuropathyin vivo. In this study, we established a dorsal root ganglia (DRG) explant model. This model displayed dose-dependent inhibition of neurite outgrowth in response to oxaliplatin, while oxalic acid exhibited no significant impact on the regrowth of DRG. The robustness of this assay was further demonstrated by the inhibition of OCT2 transporter, which facilitates oxaliplatin accumulation in neurons, fully restoring the neurite regrowth capacity. Using this model, we revealed that oxaliplatin triggered a substantial increase of oxidative stress in DRG. Notably, inhibition of TXNIP with verapamil significantly reduced oxidative stress level. Our results demonstrated the use of DRG explants as an efficient model to study the mechanisms of CIPN and screen for potential treatments.
Dynamic intraglomerular neuronal ensembles represent odor identity and concentration
Authors: Loizeau Mathieu , Angelova Alexandra , Cremer Harold , Platel Jean-Claude 
Published: October 2023

AbstractThe olfactory system has been extensively studied from an anatomical and functional point of view, yet how and where certain basic odor characteristics such as identity and concentration are represented in the brain remains poorly understood. The glomerular layer of the olfactory bulb is the first brain region that integrates olfactory signals and enables a topographic representation of odor identity. We investigated this odor encoding at the intraglomerular network level using genetic labeling, in vivo imaging, and computational methods. Our analyses demonstrated that glomerular glutamatergic neurons encode both odor identity and concentration. Furthermore, in vivo structural and functional imaging of sister neurons revealed the emergence of intraglomerular neuronal ensembles governed by odor identity and concentration. These findings revealed a novel network mechanism that enables the simultaneous coding of odor identity and concentration within glomerular modules, suggesting a potential mechanism for odor decorrelation and a new model for odor information processing in the olfactory bulb.One-sentence summaryUnraveling the scent puzzle: Discovery of intraglomerular neuronal ensembles sheds light on odor representation in the brain.
Centriole and transition zone structures in photoreceptor cilia revealed by cryo-electron tomography
Authors: Zhang Zhixian , Moye Abigail , He Feng , Chen Muyuan , Agosto Melina A. , Wensel Theodore G. 
Published: October 2023

AbstractPrimary cilia mediate sensory signaling in multiple organisms and cell types but have structures adapted for specific roles. Structural defects in them lead to devastating diseases known as ciliopathies in humans. Key to their functions are structures at their base: the basal body, the transition zone, the “Y-shaped links” and the “ciliary necklace”. We have used cryo-electron tomography with subtomogram averaging and conventional TEM to elucidate the structures associated with the basal region of the “connecting cilia” of rod outer segments in mouse retina. The longitudinal variations in microtubule (MT) structures and the lumenal scaffold complexes connecting them have been determined, as well as membrane-associated transition zone structures: Y-shaped links connecting MT to the membrane, and ciliary beads connected to them that protrude from the cell surface and form a necklace-like structure. These results represent a clearer structural scaffold onto which molecules, identified genetics, proteomics, and superresolution fluorescence, can be placed in our emerging model of photoreceptor sensory cilia.SummaryCryo-electron tomography and subtomogram averaging reveal new structural features at the base of the light sensing cilia of retinal rods. These include the basal body, the Y-links between axoneme and membrane, and the ciliary necklace of the transition zone.
Epigenetic and physiological alterations in zebrafish subjected to hypergravity
Authors: Salazar Marcela , Joly Silvia , Anglada-Escudé Guillem , Ribas Laia 
Published: October 2023

AbstractGravity is one of the most constant environmental factors across Earth’s evolution and all organisms are adapted to it. Consequently, spatial exploration has captured the interest in studying the biological changes that physiological alterations are caused by gravity. In the last two decades, epigenetics has explained how the environmental cues are able to altered gene functions in the organisms. Although many studies addressed gravity, the underlying biological and molecular mechanisms that are occurred in altered gravity for those epigenetics-related mechanisms, are mostly inexistent. The present study addressed the effects of hypergravity on development, behavior, gene expression, and most importantly, on the epigenetic changes in a world-wide animal model, the zebrafish (Danio rerio). To perform hypergravity experiments, a custom-centrifuge simulating the large diameter centrifuge (100 rpm ∼ 3g) were designed and zebrafish embryos were exposed during 5 days post fertilization (dpf). Results showed a significant decrease of survival at 2 dpf but not significance in the hatching rate. Physiological and morphological alterations including fish position, movement frequency and swimming behavior showed significant changes due to hypergravity. Epigenetic studies showed a significant hypermethylation of the genome of the zebrafish larvae subjected to 5 days of hypergravity. A downregulation of the gene expression of three epigenetic-related genes (dnmt1,dnmt3, andtet1), although not significant, were further observed. Taken altogether, gravity alterations affected biological responses including epigenetics in fish, providing a valuable roadmap of the putative hazards of living beyond Earth.
ABI3 deletion in TgCRND8 mice is associated with reduced amyloid plaque pathology and altered glial response
Authors: Ghaffari Deniz , Griffin Jennifer , St George-Hyslop Peter 
Published: October 2023

AbstractRecent genome-wide association studies (GWAS) have identified several rare coding variants in a cluster of immune-related genes that are significantly associated with Alzheimer’s disease. This includes the risk variant (S209F) inABI3, a gene encoding the Abl Interactor family member 3 protein that is highly expressed in microglia, but little is known about its function in these cells and its association with AD. We have investigated the effects of ABI3 deletion on AD pathological features in the transgenic (Tg) CRND8 APP mouse model by immunofluorescence (IF) staining and confocal microscopy. We have observed that ABI3 expression is localized to microglia in the mouse brain and that the ABI3 immunoreactivity levels are increased in the TgCRND8 mice. The loss of ABI3 leads to a significant reduction of amyloid plaque numbers and size in the 9-month-old TgCRND8 mice. This is also accompanied by a reduced number of microglia clustering around the plaques. On the basis of these observations, we hypothesize that the loss of ABI3 may lead to changes in microglial behavior which directly or indirectly leads to reduced AD pathology in mice.
Multiple origins of dorsal ecdysial sutures in trilobites and their relatives
Authors: Du Kun-sheng , Guo Jin , Losso Sarah R. , Pates Stephen , Li Ming , Chen Ai-lin 
Published: October 2023

AbstractEuarthropods are an extremely diverse phylum in the modern, and have been since their origination in the early Palaeozoic. They grow through moulting the exoskeleton (ecdysis) facilitated by breaking along lines of weakness (sutures). Artiopodans, a group that includes trilobites and their non-biomineralizing relatives, dominated arthropod diversity in benthic communities during the Palaeozoic. Most trilobites – a hyperdiverse group of tens of thousands of species - moult by breaking the exoskeleton along cephalic sutures, a strategy that has contributed to their high diversity during the Palaeozoic. However, the recent description of similar sutures in early diverging non-trilobite artiopodans mean that it is unclear whether these sutures evolved deep within Artiopoda, or convergently appeared multiple times within the group. Here we describe new well-preserved material ofAcanthomeridion, a putative early diverging artiopodan, including hitherto unknown details of its ventral anatomy and appendages revealed through CT scanning, highlighting additional possible homologous features between the ventral plates of this taxon and trilobite free cheeks. We used three coding strategies treating ventral plates as homologous to trilobite free cheeks, to trilobite cephalic doublure, or independently derived. If ventral plates are considered homologous to free cheeks,Acanthomeridionis recovered sister to trilobites however dorsal ecdysial sutures are still recovered at many places within Artiopoda. If ventral plates are considered homologous to doublure or non-homologous, thenAcanthomeridionis not recovered as sister to trilobites, and thus the ventral plates represent a distinct feature to trilobite doublure/free cheeks.
Bioengineered human colon organoids within vivo-like complexity and function
Authors: Mitrofanova Olga , Broguiere Nicolas , Nikolaev Mikhail , Lutolf Matthias P. 
Published: October 2023

SummaryOrganoids and microphysiological systems, such as organs-on-a-chip, have emerged as powerful tools for modeling human gut physiology and diseasein vitro. However, although physiologically relevant, these systems often lack the environmental milieu, spatial organization, cell-type diversity, and maturity necessary for mimicking adult human intestinal mucosa. To instead generate models closely resembling thein vivocell-type composition and spatial compartmentalization, we herein integrated organoid and organ-on-a-chip technology to develop a primary human stem–cell-derived organoid model, called ‘mini-colons’. The luminal access and flow in human mini-colons removes shed cells to greatly enhance tissue longevity and differentiation over physically inaccessible human intestinal organoids that accumulate trapped cellular debris and waste. By establishing a gradient of growth factors, we replicated and sustainedin vivo-like cell fate patterning and concurrent differentiation to secretory cell types and colonocytes. These long-lived human mini-colons contain abundant mucus-producing Goblet cells that lubricate the colonic epithelial lining. The stem and proliferative progenitor cells are also realistically confined to the crypts, facilitating stable homeostatic tissue turnover and preserving tissue integrity for several weeks. Also signifying mini-colonin vivo-like maturation, single-cell RNA sequencing showed emerging mature colonocytes and absorptive BEST4+colonocytes. This methodology could be expanded to generate microtissues derived from the small intestine and incorporate additional microenvironmental components, thus emulating the intricate complexity of the native gut in anin vitrosetting. Our bioengineered human organoids provide a highly accurate, long-lived, functional platform to systematically study human gut physiology and pathology, and for the development of novel therapeutic strategies.
MMPs and NETs are detrimental in human CNS-tuberculosis and MMP inhibition in a mouse model improves survival
Authors: Poh Xuan Ying , Loh Fei Kean , Bai Chen , Chong Hai Tarng , Teo Wei Keat , Hong Jia Mei , Miow Qing Hao , Thong Pei Min , Vilaysane Bryce , Hu Ting Huey , Chhabra Srishti , Wang Yu , Tiong Siew Ching , Fong Siew Moy , Kamihigashi Masako , Rajarethinam Ravisankar , Looi Wen Donq , Cheow Esther Sok Hwee , Bonney Glenn Kunnath , Pakkiri Leroy Sivappiragasam , Drum Chester Lee , Peng Yan Fen , Lee Ming , Tan Char Loo , Ding Cristine Szu Lyn , Lim Tchoyoson Choie Cheio , Yeo Tsin Wen , Tay Joshua K , Vallejo Andres F. , Ong Catherine W M 
Published: October 2023

AbstractDespite anti-tuberculous treatment (ATT), central nervous system tuberculosis (CNS-TB) still cause permanent neurological deficits and death. To identify prognostic factors, we profiled a prospective cohort of tuberculous meningitis (TBM) and non-TBM patients. We determined significantly increased cerebrospinal fluid (CSF) matrix metalloproteinases (MMPs) and neutrophil extracellular traps (NETs) are up-regulated in TBM patients with neuroradiological abnormalities and poor outcomes. To dissect mechanisms, we created a CNS-TB murine model which show neutrophil-rich necrotizing pyogranulomas with MMP-9 and NETs colocalizing, resembling human CNS-TB. Spatial transcriptomic analysis of both human and murine CNS-TB demonstrates a highly-inflamed and neutrophil-rich microenvironment of inflammatory immune responses, extracellular matrix degradation and angiogenesis within CNS-TB granulomas. Murine CNS-TB treated with ATT and MMP inhibitors SB-3CT or doxycycline show significantly suppressed NETs with improved survival. MMP inhibition arms show attenuated inflammation and well-formed blood vessels within granulomas. Adjunctive doxycycline is highly promising to improve CNS-TB outcomes and survival.
Cell-autonomous targeting of arabinogalactan by host immune factors inhibits mycobacterial growth
Authors: Qin Lianhua , Xu Junfang , Chen Jianxia , Wang Sen , Zheng Ruijuan , Cui Zhenling , Liu Zhonghua , Wu Xiangyang , Wang Jie , Huang Xiaochen , Wang Zhaohui , Wang Mingqiao , Pan Rong , Kaufmann Stefan H.E. , Meng Xun , Zhang Lu , Sha Wei , Liu Haipeng 
Published: October 2023

AbstractDeeper understanding of the crosstalk between host cells andMycobacterium tuberculosis(Mtb) provides crucial guidelines for the rational design of novel intervention strategies against tuberculosis (TB). Mycobacteria possess a unique complex cell wall with arabinogalactan (AG) as critical component. AG has been identified as a virulence factor of Mtb which is recognized by host galectin-9. Here we demonstrate that galectin-9 directly inhibited mycobacterial growth through AG-binding property of carbohydrate-recognition domain 2. Furthermore, IgG antibodies with AG specificity were detected in serum of TB patients. Based on the interaction between galectin-9 and AG, we developed monoclonal antibody (mAb) screening assay and identified AG-specific mAbs which profoundly inhibit Mtb growth. Mechanistically, proteomic profiling and morphological characterizations revealed that AG-specific mAbs regulate AG biosynthesis, thereby inducing cell wall swelling. Thus, direct AG-binding by galectin-9 or antibodies contributes to protection against TB. Our findings pave the way for the rational design of novel immunotherapeutic strategies for TB control.
The interpeduncular nucleus blunts the rewarding effect of nicotine
Authors: Jehl Joachim , Ciscato Maria , Vicq Eléonore , Dejean de la Batie Gabrielle , Guyon Nicolas , Mondoloni Sarah , Frangieh Jacinthe , Nguyen Claire , Hardelin Jean-Pierre , Marti Fabio , Corringer Pierre-Jean , Faure Philippe , Mourot Alexandre 
Published: October 2023

SummaryNicotine, by stimulating ventral tegmental area (VTA) dopaminergic neurons, has a rewarding effect that drives tobacco consumption. In turn, the interpeduncular nucleus (IPN) is thought to become activated at high nicotine doses to restrict drug intake. However, the dynamics of the IPN response to nicotine and its impact on the rewarding effect of the drug remain unknown. To address this issue, we have developed a genetically-modified mouse model, in which a “suicide” antagonist of nicotinic acetylcholine receptors (nAChRs) selectively attaches to a designer β4 nAChR subunit. By locally infusing this antagonist in the IPN, we achieved pharmacologically-specific and sustained antagonism of nAChRs containing the β4 subunit. By combining this chemogenetic method within vivoelectrophysiology, we show that even at low doses, nicotine activates and inhibits two different populations of IPN neurons, and that β4-containing nAChRs are only involved in the activation response. Furthermore, blocking the response to nicotine selectively in the IPN increased both the sensitivity of the VTA to the drug and its rewarding effect in a conditioned place preference paradigm. These findings indicate that the IPN is engaged across a large range of nicotine doses and acts as a regulatory brake on the nicotine reward circuit.