Fatal neuroinvasion of SARS-CoV-2 in K18-hACE2 mice is partially dependent on hACE2 expression

bioRxiv : the preprint server for biology

2021 Jan 15

Carossino, M;Montanaro, P;O'Connell, A;Kenney, D;Gertje, H;Grosz, KA;Kurnick, SA;Bosmann, M;Saeed, M;Balasuriya, UBR;Douam, F;Crossland, NA;
PMID: 33469581 | DOI: 10.1101/2021.01.13.425144

Animal models recapitulating the distinctive features of severe COVID-19 are critical to enhance our understanding of SARS-CoV-2 pathogenesis. Transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) under the cytokeratin 18 promoter (K18-hACE2) represent a lethal model of SARS-CoV-2 infection. However, the cause(s) and mechanisms of lethality in this mouse model remain unclear. Here, we evaluated the spatiotemporal dynamics of SARS-CoV-2 infection for up to 14 days post-infection. Despite infection and moderate inflammation in the lungs, lethality was invariably associated with viral neuroinvasion and neuronal damage (including spinal motor neurons). Neuroinvasion occurred following virus transport through the olfactory neuroepithelium in a manner that was only partially dependent on hACE2. Interestingly, SARS-CoV-2 tropism was overall neither widespread among nor restricted to only ACE2-expressing cells. Although our work incites caution in the utility of the K18-hACE2 model to study global aspects of SARS-CoV-2 pathogenesis, it underscores this model as a unique platform for exploring the mechanisms of SARS-CoV-2 neuropathogenesis. COVID-19 is a respiratory disease caused by SARS-CoV-2, a betacoronavirus. Here, we show that in a widely used transgenic mouse model of COVID-19, lethality is invariably associated with viral neuroinvasion and the ensuing neuronal disease, while lung inflammation remains moderate.

Adult neural stem cell activation in mice is regulated by the day/night cycle and intracellular calcium dynamics

Cell

2021 Jan 13

Gengatharan, A;Malvaut, S;Marymonchyk, A;Ghareghani, M;Snapyan, M;Fischer-Sternjak, J;Ninkovic, J;Götz, M;Saghatelyan, A;
PMID: 33482084 | DOI: 10.1016/j.cell.2020.12.026

Neural stem cells (NSCs) in the adult brain transit from the quiescent state to proliferation to produce new neurons. The mechanisms regulating this transition in freely behaving animals are, however, poorly understood. We customized in vivo imaging protocols to follow NSCs for several days up to months, observing their activation kinetics in freely behaving mice. Strikingly, NSC division is more frequent during daylight and is inhibited by darkness-induced melatonin signaling. The inhibition of melatonin receptors affected intracellular Ca2+ dynamics and promoted NSC activation. We further discovered a Ca2+ signature of quiescent versus activated NSCs and showed that several microenvironmental signals converge on intracellular Ca2+ pathways to regulate NSC quiescence and activation. In vivo NSC-specific optogenetic modulation of Ca2+ fluxes to mimic quiescent-state-like Ca2+ dynamics in freely behaving mice blocked NSC activation and maintained their quiescence, pointing to the regulatory mechanisms mediating NSC activation in freely behaving animals.

Stem cell-derived CAR T cells traffic to HIV reservoirs in macaques

JCI insight

2021 Jan 11

Barber-Axthelm, IM;Barber-Axthelm, V;Sze, KY;Zhen, A;Suryawanshi, GW;Chen, IS;Zack, JA;Kitchen, SG;Kiem, HP;Peterson, CW;
PMID: 33427210 | DOI: 10.1172/jci.insight.141502

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) with CCR5- donor cells is the only treatment known to cure HIV-1 in patients with underlying malignancy. This is likely due to a donor cell-mediated graft-versus-host effect targeting HIV reservoirs. Allo-HSCT would not be an acceptable therapy for most people living with HIV due to the transplant-related side effects. Chimeric antigen receptor (CAR) immunotherapies specifically traffic to malignant lymphoid tissues (lymphomas) and, in some settings, are able to replace allo-HSCT. Here, we quantified the engraftment of HSC-derived, virus-directed CAR T cells within HIV reservoirs in a macaque model of HIV infection, using potentially novel IHC assays. HSC-derived CAR cells trafficked to and displayed multilineage engraftment within tissue-associated viral reservoirs, persisting for nearly 2 years in lymphoid germinal centers, the brain, and the gastrointestinal tract. Our findings demonstrate that HSC-derived CAR+ cells reside long-term and proliferate in numerous tissues relevant for HIV infection and cancer.

Preliminary RNA-microarray analysis of long non-coding RNA expression in abnormally invasive placenta

Exp Ther Med

2021 Jan 01

Zhang, H;Wu, S;Ye, S;Ma, H;Liu, Z;
PMID: 33235622 | DOI: 10.3892/etm.2020.9445

Long non-coding RNAs (lncRNAs) are reported to have important roles in placental development and function, but the role of lncRNAs in abnormally invasive placenta (AIP) remains elusive. In the present study, the differential expression profiles of lncRNAs were analyzed to identify novel targets for further study of AIP. A total of 10 lncRNAs were chosen for validation by reverse transcription-quantitative PCR. To further determine the functions of dysregulated lncRNAs and their corresponding mRNAs, functional enrichment analysis, coexpression analysis were performed. A total of 329 lncRNAs and 179 mRNAs were identified to be differently expressed between the invasive and control group. Gene ontology analysis revealed that the 10 most significantly enriched functions included upregulated mRNAs and the most significantly enriched term was related to the proteinaceous extracellular matrix (ECM). In the pathway analysis, the two most significantly enriched pathways were the TGF-β signaling pathway for upregulated mRNAs and the pentose phosphate pathway for downregulated mRNAs. Furthermore, for certain dysregulated lncRNAs, their associated mRNAs were also dysregulated. Of note, BMP and activin membrane-bound inhibitor and TGF-β-induced, as the target genes of the TGF-β pathway, were indicated to be closely related to the ECM and invasive placental cells. Their nearby lncRNAs G008916 and vault RNA2-1 were also significantly dysregulated. In conclusion, significant lncRNAs with the potential to serve as biomarkers for AIP were identified.

Resolution of hypereosinophilic syndrome following resection of a schwannoma

The journal of allergy and clinical immunology. In practice

2023 Jan 05

Ware, JM;Folio, LR;Pittaluga, S;Klion, A;Khoury, P;
PMID: 36621605 | DOI: 10.1016/j.jaip.2022.12.028

The technological landscape and applications of single-cell multi-omics

Nature reviews. Molecular cell biology

2023 Jun 06

Baysoy, A;Bai, Z;Satija, R;Fan, R;
PMID: 37280296 | DOI: 10.1038/s41580-023-00615-w

Single-cell multi-omics technologies and methods characterize cell states and activities by simultaneously integrating various single-modality omics methods that profile the transcriptome, genome, epigenome, epitranscriptome, proteome, metabolome and other (emerging) omics. Collectively, these methods are revolutionizing molecular cell biology research. In this comprehensive Review, we discuss established multi-omics technologies as well as cutting-edge and state-of-the-art methods in the field. We discuss how multi-omics technologies have been adapted and improved over the past decade using a framework characterized by optimization of throughput and resolution, modality integration, uniqueness and accuracy, and we also discuss multi-omics limitations. We highlight the impact that single-cell multi-omics technologies have had in cell lineage tracing, tissue-specific and cell-specific atlas production, tumour immunology and cancer genetics, and in mapping of cellular spatial information in fundamental and translational research. Finally, we discuss bioinformatics tools that have been developed to link different omics modalities and elucidate functionality through the use of better mathematical modelling and computational methods.

[Not Available]

Actas dermo-sifiliograficas

2023 Jun 16

Llamas-Velasco, M;Fraga, J;Lario, AR;Catalá, A;Pérez-González, YC;Galván, C;Ruiz-Villaverde, R;Sánchez-Pérez, J;Wiesner, T;Metze, D;
PMID: 37331619 | DOI: 10.1016/j.ad.2023.05.024

Despite the large number of articles published on skin lesions related to COVID-19, clinicopathological correlation has not been performed consistently and immunohistochemistry to demonstrate spike 3 protein expression has not been validated through RT-PCR. We compiled 69 cases of patients with confirmed COVID-19, where skin lesions were clinically and histopathologically studied. Immunohistochemistry (IHC) and RT-PCR was performed in skin biopsies.After a careful review of the cases, 15 were found to be dermatosis not related to COVID-19, while the rest of the lesions could be classified according to their clinical characteristics as vesicular (4), maculopapular eruptions (41), urticariform (9), livedo and necrosis (10) and pernio-like (5). Although histopathological features were similar to previously reported results, we found two previously unreported findings, maculopapular eruptions with squamous eccrine syringometaplasia and neutrophilic epitheliotropism. IHC showed in some cases endothelial and epidermal staining but RT-PCR was negative in all the tested cases. Thus, direct viral involvement could not be demonstrated.Despite presenting the largest series of confirmed COVID-19 patients with histopathologically studied skin manifestations, direct viral involvement was difficult to establish. Vasculopatic and urticariform lesions seem to be those more clearly related to the viral infection, despite IHC or RT-PCR negative results failed to demonstrate viral presence. These findings, as in other dermatological areas, highlight the need of a clinico-pathological correlation to increase knowledge about viral involvement in COVID-19 skin-related lesions.

AT2 Cell-Derived IgA Trapped by the Extracellular Matrix and Promoted Pulmonary Fibrosis

Available at SSRN

2023 May 03

Chen, M;Wang, J;Yuan, M;Long, M;Sun, Y;Wang, S;Luo, W;Zhang, W;Jiang, W;Chao, J;
| DOI: 10.2139/ssrn.4431410

Pulmonary fibrosis is an interstitial lung disease caused by various factors such as exposure to workplace environmental contaminants, drugs, or X-rays. Epithelial cells are among the driving factors of pulmonary fibrosis. Immunoglobulin A (IgA), traditionally thought to be secreted by B cells, is an important immune factor involved in COVID-19 infection and vaccination. In current study, we found lung epithelial cells were involved in IgA secretion which, in turn, promoted pulmonary fibrosis. The spatial transcriptomics and single-cell sequencing suggests that Igha transcripts were highly expressed in the fibrotic lesion areas of lungs from silica-treated mice. Reconstruction of B-cell receptor (BCR) sequences revealed a new cluster of AT2-like epithelial cells with a shared BCR and high expression of genes related to IgA production. Furthermore, the secretion of IgA by AT2-like cells were trapped by extracellular matrix and aggravated pulmonary fibrosis by activating fibroblasts. Targeted blockade of IgA secretion by pulmonary epithelial cells may be a potential strategy for treating pulmonary fibrosis.

Bridging clinic and wildlife care with AI-powered pan-species computational pathology

Nature communications

2023 Apr 26

AbdulJabbar, K;Castillo, SP;Hughes, K;Davidson, H;Boddy, AM;Abegglen, LM;Minoli, L;Iussich, S;Murchison, EP;Graham, TA;Spiro, S;Maley, CC;Aresu, L;Palmieri, C;Yuan, Y;
PMID: 37100774 | DOI: 10.1038/s41467-023-37879-x

Cancers occur across species. Understanding what is consistent and varies across species can provide new insights into cancer initiation and evolution, with significant implications for animal welfare and wildlife conservation. We build a pan-species cancer digital pathology atlas (panspecies.ai) and conduct a pan-species study of computational comparative pathology using a supervised convolutional neural network algorithm trained on human samples. The artificial intelligence algorithm achieves high accuracy in measuring immune response through single-cell classification for two transmissible cancers (canine transmissible venereal tumour, 0.94; Tasmanian devil facial tumour disease, 0.88). In 18 other vertebrate species (mammalia = 11, reptilia = 4, aves = 2, and amphibia = 1), accuracy (range 0.57-0.94) is influenced by cell morphological similarity preserved across different taxonomic groups, tumour sites, and variations in the immune compartment. Furthermore, a spatial immune score based on artificial intelligence and spatial statistics is associated with prognosis in canine melanoma and prostate tumours. A metric, named morphospace overlap, is developed to guide veterinary pathologists towards rational deployment of this technology on new samples. This study provides the foundation and guidelines for transferring artificial intelligence technologies to veterinary pathology based on understanding of morphological conservation, which could vastly accelerate developments in veterinary medicine and comparative oncology.

Small RNA shuffling between murine sperm and their cytoplasmic droplets during epididymal maturation

Developmental cell

2023 Mar 28

Wang, H;Wang, Z;Zhou, T;Morris, D;Chen, S;Li, M;Wang, Y;Zheng, H;Fu, W;Yan, W;
PMID: 37023748 | DOI: 10.1016/j.devcel.2023.03.010

Reports that mouse sperm gain small RNAs from the epididymosomes secreted by epididymal epithelial cells and that these "foreign" small RNAs act as an epigenetic information carrier mediating the transmission of acquired paternal traits have drawn great attention because the findings suggest that heritable information can flow from soma to germ line, thus invalidating the long-standing Weismann's barrier theory on heritable information flow. Using small RNA sequencing (sRNA-seq), northern blots, sRNA in situ hybridization, and immunofluorescence, we detected substantial changes in the small RNA profile in murine caput epididymal sperm (sperm in the head of the epididymis), and we further determined that the changes resulted from sperm exchanging small RNAs, mainly tsRNAs and rsRNAs, with cytoplasmic droplets rather than the epididymosomes. Moreover, the murine sperm-borne small RNAs were mainly derived from the nuclear small RNAs in late spermatids. Thus, caution is needed regarding sperm gaining foreign small RNAs as an underlying mechanism of epigenetic inheritance.

IRX5 promotes DNA damage repair and activation of hair follicle stem cells

Stem cell reports

2023 Apr 07

Chen, JK;Wiedemann, J;Nguyen, L;Lin, Z;Tahir, M;Hui, CC;Plikus, MV;Andersen, B;
PMID: 37084727 | DOI: 10.1016/j.stemcr.2023.03.013

The molecular mechanisms allowing hair follicles to periodically activate their stem cells (HFSCs) are incompletely characterized. Here, we identify the transcription factor IRX5 as a promoter of HFSC activation. Irx5-/- mice have delayed anagen onset, with increased DNA damage and diminished HFSC proliferation. Open chromatin regions form near cell cycle progression and DNA damage repair genes in Irx5-/- HFSCs. DNA damage repair factor BRCA1 is an IRX5 downstream target. Inhibition of FGF kinase signaling partially rescues the anagen delay in Irx5-/- mice, suggesting that the Irx5-/- HFSC quiescent phenotype is partly due to failure to suppress Fgf18 expression. Interfollicular epidermal stem cells also show decreased proliferation and increased DNA damage in Irx5-/-mice. Consistent with a role for IRX5 as a promoter of DNA damage repair, we find that IRX genes are upregulated in many cancer types and that there is a correlation between IRX5 and BRCA1 expression in breast cancer.

Prenatal CFAP53-related laterality defect: case report and review of the literature

The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians

2023 Dec 01

Mastromoro, G;Guadagnolo, D;Novelli, A;Torres, B;Piane, M;Magliozzi, M;Bernardini, L;Ventriglia, F;Pizzuti, A;Petrucci, S;
PMID: 37041101 | DOI: 10.1080/14767058.2023.2201653

Laterality defects include morphological anomalies with impaired left-right asymmetry induction, such as dextrocardia, situs inversus abdominis, situs inversus totalis and situs ambiguus. The different arrangement of major organs is called heterotaxy. We describe for the first time a fetus with situs viscerum inversus and azygos continuation of the inferior vena cava, due to previously unreported variants in compound heterozygosity in the CFAP53 gene, whose product is implied in cilial motility. Prenatal trio exome sequencing was performed with turn-around time during the pregnancy. The fetuses with laterality defects are suitable candidates for prenatal exome sequencing due to the emerging high diagnostic rate of this group of morphological anomalies. A timely molecular diagnosis plays a fundamental role in genetic counseling, regarding couple decisions on the ongoing pregnancy, providing recurrence risks, and in predicting possible respiratory complications due to ciliary dyskinesia.

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sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
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tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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