bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuroprotective Effects of Naltrexone in a Mouse Model of Post-Traumatic Epilepsy
Authors: Rodriguez Saul , Sharma Shaunik , Tiarks Grant , Peterson Zeru , Jackson Kyle , Thedens Daniel , Wong Angela , Keffala-Gerhard David , Mahajan Vinit B. , Ferguson Polly J. , Newell Elizabeth A. , Glykys Joseph , Nickl-Jockschat Thomas , Bassuk Alexander G.
Published: October 2023

Traumatic Brain Injury (TBI) induces neuroinflammatory responses that can initiate epileptogenesis, which develops into epilepsy. Recently, we identified the anti-convulsive effects of naltrexone, a mu-opioid receptor (MOR) antagonist. While blocking opioid receptors can reduce inflammation, it is unclear if post-TBI epileptogenesis can be prevented by blocking MORs. Here, we tested if naltrexone prevents neuroinflammation and epileptogenesis post-TBI. TBI was induced by a modified Marmarau Weight-Drop (WD) method applied to four-week-old C57BL/6J male mice. Mice were given the pro-convulsant pentylenetetrazol (PTZ) on day two post-injury while telemetry-monitored mice received PTZ on day five. Naltrexone/vehicle treatment started two hours after PTZ. Integrated EEG-video (vEEG) recorded interictal events and spontaneous seizures for three months. Molecular, histological and neuroimaging techniques were used to evaluate neuroinflammation and neurodegeneration both acutely and chronically. Peripheral immune responses were assessed through serum chemokine/cytokine measurements. We observed increases in MOR expression, nitro-oxidative stress, mRNA expression of inflammatory cytokines, microgliosis, neurodegeneration, and white matter damage in the neocortex of TBI mice. vEEG revealed increased interictal events in TBI mice, with 71% developing epilepsy. Naltrexone ameliorated neuroinflammation and neurodegeneration, reduced interictal events and prevented epilepsy, illustrating that naltrexone is a promising drug to prevent TBI-associated neuroinflammation and epileptogenesis in post-traumatic epilepsy.
Activity-dependent survival of odorant receptor neurons in ants
Authors: Sieriebriennikov Bogdan , Sieber Kayli R , Kolumba Olena , Mlejnek Jakub , Jafari Shadi , Yan Hua
Published: October 2023

Olfaction is essential for complex social behavior in eusocial insects. To discriminate complex social cues, ants evolved an expanded number ofodorant receptor(Or) genes. Unlike most insect species, mutations in the obligate odorant co-receptor geneorcolead to loss of ∼80% antennal lobe glomeruli in ants. However, its cellular mechanism remains unclear. Here we demonstrate that this surprising neuronal phenotype results from massive apoptosis of odorant receptor neurons (ORNs) in the mid- to late-stages of pupal development. Further bulk and single-nucleus transcriptome analysis show that, although the majority oforco-expressing ORNs die inorcomutants, a small proportion of them survive: they expressionotropic receptor(Ir) genes that form IR complexes. In addition, we found that someOrgenes are expressed in mechanosensory neurons as well as non-neuronal cells, possibly due to the leaky regulation from nearby non-Orgenes. Our findings suggest that chemosensory receptors are required for activity-dependent survival of developing ORNs in ants.
Multimodal joint deconvolution and integrative signature selection in proteomics
Authors: Pan Yue , Wang Xusheng , Liu Chunyu , Peng Junmin , Li Qian
Published: October 2023

Deconvolution is an efficient approach for detecting cell-type-specific (cs) transcriptomic signals without cellular segmentation. However, this type of methods have not been extended to the proteomics research. Here we present a novel algorithm and tool to dissect bulk proteome by leveraging the information shared between transcriptome-proteome. Our tool first identifies potential cell marker proteins by integrating RNA and protein bulk expression profiles and then jointly quantifies the cell abundance in mixture proteomes without using a reference signature matrix, enabling the downstream analyses such as cs-protein Quantitative Trait Loci (cspQTL) mapping. This new method and the cspQTL analysis are implemented in the R package MIC-SQTL that also provides integrative visualization of bulk multimodal samples, available athttps://bioconductor.org/packages/MICSQTL.
Oral Administration of a specific p300/CBP Lysine Acetyltransferase Activator Induces Synaptic Plasticity and Repairing Spinal Cord Injury
Authors: Singh Akash Kumar , Rai Amrish , Joshi Ila , Reddy Damodara N , Guha Rajdeep , Shukla Shubha , Nazir Aamir , Clement James P , Kundu Tapas K.
Published: October 2023

TTK21 is a small molecule activator of p300/CBP acetyltransferase activity, which upon conjugation with glucose-derived carbon nanosphere (CSP) can efficiently cross the blood-brain barrier and activate histone acetylation in the brain. Its role in adult neurogenesis and retention of long-term spatial memory upon intraperitoneal (IP) administration is well established. In this study, we have successfully demonstrated that CSP-TTK21 can be effectively administered via oral gavage. Using a combination of molecular biology, microscopy, and electrophysiological techniques, we systematically investigated the comparative efficacy of oral administration of CSP and CSP-TTK21 in wild-type mice, evaluating their functional effects in comparison to intraperitoneal (IP) administration. Our findings indicate that CSP-TTK21, when administered orally, induces long-term potentiation in the hippocampus without significantly altering basal synaptic transmission, a response comparable to that achieved through IP injection. Remarkably, in a spinal cord injury model, oral administration of CSP-TTK21 exhibits equivalent efficacy to IP administration. Furthermore, our research demonstrates that oral delivery of CSP-TTK21 leads to improvements in motor functions, histone acetylation dynamics, and increased expression of regeneration associated genes (RAGs) in a spinal injury rat model, mirroring the effectiveness of IP administration. Collectively, these results underscore the potential utility of CSP as an oral drug delivery system, particularly for targeting the neural system.
Kombucha Tea-associated Microbes Remodel Host Metabolic Pathways to Suppress Lipid Accumulation
Authors: DuMez-Kornegay Rachel N. , Morris Alexis J. , Dowen Robert H.
Published: October 2023

The popularity of the ancient, probiotic-rich beverage Kombucha Tea (KT) has surged in part due to its purported health benefits, which include protection against metabolic diseases; however, these claims have not been rigorously tested and the mechanisms underlying host response to the probiotics in KT are unknown. Here, we establish a reproducible method to maintainC. eleganson a diet exclusively consisting of Kombucha Tea-associated microbes (KTM), which mirrors the microbial community found in the fermenting culture. KT microbes robustly colonize the gut of KTM-fed animals and confer normal development and fecundity. Intriguingly, animals consuming KTMs display a marked reduction in total lipid stores and lipid droplet size. We find that the reduced fat accumulation phenotype is not due to impaired nutrient absorption, but rather it is sustained by a programed metabolic response in the intestine of the host. KTM consumption triggers widespread transcriptional changes within core lipid metabolism pathways, including upregulation of a suite of lysosomal lipase genes that are induced during lipophagy. The elevated lysosomal lipase activity, coupled with a decrease in lipid droplet biogenesis, is partially required for the reduction in host lipid content. We propose that KTM consumption stimulates a fasting- like response in theC. elegansintestine by rewiring transcriptional programs to promote lipid utilization. Our results provide mechanistic insight into how the probiotics in Kombucha Tea reshape host metabolism and how this popular beverage may impact human metabolism.
Participant Flow Diagrams for Health Equity in AI Research
Authors: Ellen Jacob G. , Matos João , Viola Martin , Gallifant Jack , Quion Justin , Celi Leo Anthony , Hussein Nebal S. Abu
Published: October 2023

Biases in sample creation can arise at any study phase, including initial patient recruitment, exclusion criteria, input-level exclusion and outcome-level exclusion, and often reflect the underrepresentation or exclusion of demographic groups historically disadvantaged in medical research. The use of non-representative samples to construct clinical algorithms in artificial intelligence (AI) and machine learning (ML) applications may further amplify this selection bias. Building on the “Data Cards” initiative for transparency in AI research, we advocate for the addition of a detailed participant flow diagram for AI studies, emphasizing the need to detail excluded participant demographic characteristics at every study phase. This tracking of excluded participants enhances understanding of potential algorithmic biases before their clinical implementation, and thus deserves to be detailed in any medical AI study. We include both a model for this flow diagram as well as a brief case study explaining how it could be implemented in practice. Through standardized reporting of participant flow diagrams, we can better gauge the potential inequity embedded in AI applications, facilitating more reliable and equitable clinical algorithms.
Enhancing immunotherapy outcomes in glioblastoma through predictive machine learning
Authors: Mestrallet Guillaume
Published: October 2023

Glioblastoma is a highly aggressive cancer associated with a dismal prognosis, with a mere 5% of patients surviving beyond five years post-diagnosis. Current therapeutic modalities encompass surgical intervention, radiotherapy, chemotherapy, and immune checkpoint inhibitors (ICB). However, the efficacy of ICB remains limited in glioblastoma patients, necessitating a proactive approach to anticipate treatment response and resistance.

In this comprehensive study, we conducted a rigorous analysis involving two distinct glioblastoma patient cohorts subjected to PD-1 blockade treatments. Our investigation unveiled that a significant portion, 60%, of patients exhibit persistent disease progression despite ICB intervention. To elucidate the underpinnings of resistance, we characterized the immune profiles of glioblastoma patients with continued cancer progression following anti-PD1 therapy. These profiles revealed multifaceted defects, encompassing compromised macrophage, monocyte, and T follicular helper responses, impaired antigen presentation, aberrant regulatory T cell (Tregs) responses, and heightened expression of immunosuppressive molecules (TGFB, IL2RA, and CD276). Building upon these resistance profiles, we leveraged cutting-edge machine learning algorithms to develop predictive models and accompanying software. This innovative computational tool achieved remarkable success, accurately forecasting the progression status of 82.82% of glioblastoma patients following ICB, based on their unique immune characteristics.

In conclusion, our pioneering approach advocates for the personalization of immunotherapy in glioblastoma patients. By harnessing patient-specific attributes and computational predictions, we offer a promising avenue for the enhancement of clinical outcomes in the realm of immunotherapy. This paradigm shift towards tailored therapies underscores the potential to revolutionize the management of glioblastoma, opening new horizons for improved patient care.
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

In 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

Collective 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

Microglia, 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

Oxaliplatin 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

The 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 summary

Unraveling 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

Primary 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.

Cryo-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

Gravity 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

Recent 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

Euarthropods 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

Organoids 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

Despite 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

Deeper 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

Nicotine, 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.
A Confounder Controlled Machine Learning Approach: Group Analysis and Classification of Schizophrenia and Alzheimer’s Disease using Resting-State Functional Network Connectivity
Authors: Hassanzadeh Reihaneh , Abrol Anees , Pearlson Godfrey , Turner Jessica A. , Calhoun Vince D.
Published: October 2023

Resting-state functional magnetic resonance imaging (rs-fMRI) has increasingly been used to study both Alzheimer’s disease (AD) and schizophrenia (SZ). While most rs-fMRI studies being conducted in AD and SZ compare patients to healthy controls, it is also of interest to directly compare AD and SZ patients with each other to identify potential biomarkers shared between the disorders. However, comparing patient groups collected in different studies can be challenging due to potential confounds, such as differences in the patient’s age, scan protocols, etc. In this study, we compared and contrasted resting-state functional network connectivity (rs-FNC) of 162 patients with AD and late mild cognitive impairment (LMCI), 181 schizophrenia patients, and 315 cognitively normal (CN) subjects. We used confounder-controlled rs-FNC and applied machine learning algorithms (including support vector machine, logistic regression, random forest, and k-nearest neighbor) and deep learning models (i.e., fully-connected neural networks) to classify subjects in binary and three-class categories according to their diagnosis labels (e.g., AD, SZ, and CN). Our statistical analysis revealed that FNC between the following network pairs is stronger in AD compared to SZ: subcortical-cerebellum, subcortical-cognitive control, cognitive control-cerebellum, and visual-sensory motor networks. On the other hand, FNC is stronger in SZ than AD for the following network pairs: subcortical-visual, subcortical-auditory, subcortical-sensory motor, cerebellum-visual, sensory motor-cognitive control, and within the cerebellum networks. Furthermore, we observed that while AD and SZ disorders each have unique FNC abnormalities, they also share some common functional abnormalities that can be due to similar neurobiological mechanisms or genetic factors contributing to these disorders’ development. Moreover, we achieved an accuracy of 85% in classifying subjects into AD and SZ where default mode, visual, and subcortical networks contributed the most to the classification and accuracy of 68% in classifying subjects into AD, SZ, and CN with the subcortical domain appearing as the most contributing features to the three-way classification. Finally, our findings indicated that for all classification tasks, except AD vs. SZ, males are more predictable than females.
Macroevolutionary drivers of morphological disparity in the avian quadrate
Authors: Kuo Pei-Chen , Navalón Guillermo , Benson Roger B. J. , Field Daniel J.
Published: October 2023

In birds, the quadrate bone acts as a hinge between the lower jaw and the skull, playing an important role in cranial kinesis. As such, the evolution of avian quadrate morphology may plausibly be assumed to have been influenced by selective pressures related to feeding ecology. However, variation in quadrate morphology across living birds and its potential relationship with ecology have never been quantitatively characterised. Here, we used three-dimensional geometric morphometrics and phylogenetic comparative methods to quantify morphological variation of the quadrate and its relationship with an array of key ecological features across 200 bird species covering all major extant lineages. We found non-significant associations between quadrate shape and several aspects of feeding and foraging ecology across different scales of phylogenetic comparison. By contrast, allometry and phylogeny exhibit stronger relationships with quadrate shape than other ecological features. We show that the avian quadrate evolves as an integrated unit and exhibits strong associations with the morphologies of neighbouring bones. Our results collectively suggest a macroevolutionary scenario in which the shape of the quadrate evolved jointly with other elements of the avian kinetic system, with the major lineages of birds exploring alternative quadrate morphologies—highlighting the potential diagnostic value of quadrate morphology in investigations of fossil bird systematics.
Ocelli: an open-source tool for the visualization of developmental multimodal single-cell data
Authors: Rutkowski Piotr , Tabaka Marcin
Published: October 2023

The recent expansion of single-cell technologies has enabled simultaneous genome-wide measurements of multiple modalities in the same single cell. The potential to jointly profile such modalities as gene expression, chromatin accessibility, protein epitopes, or multiple histone modifications at single-cell resolution represents a compelling opportunity to study developmental processes at multiple layers of gene regulation. Here, we present Ocelli, a lightweight Python package for scalable visualization and exploration of developmental multimodal single-cell data. The core functionality of Ocelli focuses on diffusion-based modeling of developmental processes. Ocelli addresses common tasks in developmental single-cell data analysis, such as visualization of cells on a low-dimensional embedding that preserves the continuity of the developmental progression of cells, identification of rare and transient cell states, integration with trajectory inference algorithms, and imputation of undetected feature counts. Extensive benchmarking shows that Ocelli outperforms existing methods regarding computational time and quality of the reconstructed low-dimensional representation of developmental data.
Amniotic Fluid Organoids As Personalized Tools For Real-Time Modeling Of The Developing Fetus
Authors: Babosova Olga , Weisz Boaz , Rabinowitz Grace , Avnet Hagai , Shani Hagit , Schwartz Anat , Batsry Linoy , Pardo Noam , Elkan Tal , Stockheim David , Jubany Tammir , Frank Denise D. , Barshack Iris , Dotan Zohar A. , Levin-Klein Rena , Beckerman Pazit , Pleniceanu Oren
Published: October 2023

Despite biomedical advances, major knowledge gaps regarding human development remain, and many developmental disorders lack effective treatment, representing a huge clinical burden. This results from fetuses being largely inaccessible for analysis. Here, we employ fetal cells in human amniotic fluid (AF) to establish personalized fetal kidney and lung organoids (AFKO and AFLO, respectively), recapitulating fetal organs at single-cell resolution. AFKO harbor key fetal kidney cell populations, including nephrogenic, urothelial and stromal, endocytose albumin, and modelPAX2-related anomalies. Strikingly, upon injection into the nephrogenic cortex of human fetal kidney explants, AFKO-derived progenitors integrate into the host progenitor niche and contribute to developing nephrons. AFLO comprise alveolar cells and most airway cell types in a typical pseudostratified structure, upregulate surfactant expression upon corticosteroid treatment, and show functional CFTR channels. Overall, this platform represents a new personalized tool that can be applied to virtually any fetus in real-time, affording unprecedented options in studying development, uncovering mechanisms ofin uteropathologies (e.g., congenital anomalies, infections or chemical teratogens) deciphering the developmental origins of chronic diseases, and tailoring treatments for these pathologies, as well as for prematurity-related complications. Importantly, since AF contains cells from additional tissues (e.g., skin and gastrointestinal tract), and is derived in a procedure already performed in many patients, this platform may well become a broadly applicable tool in fetal medicine.
Transcriptional profiling of peripheral blood mononuclear cells identifies inflammatory phenotypes in ataxia telangiectasia
Authors: Michki Nigel S. , Singer Benjamin D. , Perez Javier V. , Thomas Aaron J. , Natale Valerie , Helmin Kathryn A. , Wright Jennifer , Cheng Leon , Young Lisa R. , Lederman Howard M. , McGrath-Morrow Sharon A.
Published: October 2023

Ataxia telangiectasia (A-T) is an autosomal recessive neurodegenerative disease with widespread systemic manifestations and marked variability in clinical phenotypes. In this study, we sought to determine whether transcriptomic profiling of peripheral blood mononuclear cells defines subsets of individuals with A-T beyond mild and classic phenotypes, enabling identification of novel features for disease classification and treatment response to therapy.

Methods

Participants with stable A-T (n=90) were recruited and compared with unaffected controls (n=15). PBMCs were isolated and bulk RNAseq was performed. Plasma was also isolated in a subset of individuals. Affected individuals were designated mild or classic based onATMmutations and clinical and laboratory features.

Results

People with classic A-T were more likely to be younger and IgA deficient and to have higher alpha-fetoprotein levels and lower % forced vital capacity compared to individuals with mild A-T. In classic A-T, the expression of genes required for V(D)J recombination was lower, and the expression of genes required for inflammatory activity was higher. We assigned inflammatory scores to study participants and found that inflammatory scores were highly variable among people with classic A-T and that higher scores were associated with lowerATMmRNA levels. Using a cell type deconvolution approach, we inferred that CD4+ T cells and CD8+ T cells were lower in number in people with classic A-T. Finally, we showed that individuals with classic A-T exhibit higherSERPINE1(PAI-1) mRNA and plasma protein levels, irrespective of age, and higherFLT4(VEGFR3) andIL6ST(GP130) plasma protein levels compared with mild A-T and controls.

Conclusion

Using an unbiased transcriptomic approach, we identified novel features and developed an inflammatory score to identify subsets of individuals with different inflammatory phenotypes in A-T. Findings from this study could be used to help direct treatment and to track treatment response to therapy.
Data-driven characterization and correction of the orientation dependence of magnetization transfer measures using diffusion MRI
Authors: Karan Philippe , Edde Manon , Gilbert Guillaume , Barakovic Muhamed , Magon Stefano , Descoteaux Maxime
Published: October 2023

Purpose

To characterize the orientation dependence of magnetization transfer (MT) measures in white matter (WM) and propose a first correction method for such measures.

Methods

A characterization method was developed using the fiber orientation obtained from diffusion MRI (dMRI) with diffusion tensor imaging (DTI) and constrained spherical deconvolution (CSD). This allowed for characterization of the orientation dependence of measures in all of WM, regardless of the number of fiber orientation in a voxel. Furthermore, a first correction method was proposed from the results of characterization, aiming at removing said orientation dependence. Both methods were tested on a 20-subject dataset and effects on tractometry results were also evaluated.

Results

Previous results for single-fiber voxels were reproduced and a novel characterization was produced in voxels of crossing fibers, which seems to follow trends consistent with single-fiber results. Unwanted effects of the orientation dependence on MT measures were highlighted, for which the correction method was able to produce improved results.

Conclusion

Encouraging results of corrected MT measures showed the importance of such correction, opening the door for future research on the topic.
Mesoscale Ca2+imaging reveals networks of Purkinje cell dendritic and somatic modulation, with divergent roles of activity versus correlation during behavior
Authors: Streng M.L. , Carter R.E. , Kottke B.W. , Togneri K. , Wasserman E. , Rajendran V. , Kodandaramaiah S. B. , Krook-Magnuson E. , Ebner T.J.
Published: October 2023

A major challenge in cerebellar physiology is determining how the stereotypic, conserved circuitry of the cerebellar cortex, with its dominant parasagittal and transverse architectures, underlies its fundamental computations and contributions to behavior. To interrogate Purkinje cell dynamics at this parasagittal and transverse spatial scale, we implemented a novel approach for awake, chronic, wide-field Ca2+imaging of the cerebellar cortex. We observe two functionally and spatially distinct Purkinje cell networks, reflecting their dendritic and somatic activities, respectively. Both dendritic and somatic networks exhibit bilateral, widespread activation during behavior, but with diverse patterns of spatial correlations occurring primarily along the parasagittal and transverse directions, consistent with the main geometry of the cerebellar cortex. Somatic network correlation dynamics are robustly modulated by prediction errors, and even reflect ultimate behavioral outcomes. These results provide a novel link between cerebellar structure and function, with the correlation dynamics of Purkinje cell activity a key feature.