Acute splanchnic vein thrombosis in patients with COVID-19: a systematic review
Digestive and Liver Disease
Buso, G;Becchetti, C;Berzigotti, A;
| DOI: 10.1016/j.dld.2021.05.021
There is increasing evidence that coronavirus disease 2019 (COVID-19) is associated with a significant risk of venous thromboembolism. While information are mainly available for deep vein thrombosis of the lower limb and pulmonary embolism, scarce data exist regarding acute splanchnic vein thrombosis (SVT) in this setting. PubMed, EMBASE and Google Scholar English-language articles published up to 30 January 2021 on SVT in COVID-19 were searched. Overall, 21 articles reporting equal number of patients were identified. 15 subjects presented with portal vein thrombosis, 11 with mesenteric vein thrombosis, four with splenic vein thrombosis, and two with Budd-Chiari syndrome. Male sex was prevalent (15 patients), and median age was 43 years (range 26–79 years). Three patients had a history of liver disease, while no subject had known myeloproliferative syndrome. Clinical presentation included mainly gastrointestinal symptoms. Anticoagulation was started in 16 patients. Three patients underwent bowel resection. Ten subjects developed gastric or bowel ischemia, seven of whom underwent bowel resection, and four died after SVT diagnosis.
Clinical and research applications of multiplexed immunohistochemistry and in situ hybridization
McGinnis, LM;Ibarra-Lopez, V;Rost, S;Ziai, J;
PMID: 33723864 | DOI: 10.1002/path.5663
Over the past decade, invention and adoption of novel multiplexing technologies for tissues have made increasing impacts in basic and translational research and, to a lesser degree, clinical medicine. Platforms capable of highly multiplexed immunohistochemistry or in situ RNA measurements promise evaluation of protein or RNA targets at levels of plex and sensitivity logs above traditional methods - all with preservation of spatial context. These methods promise objective biomarker quantification, markedly increased sensitivity, and single-cell resolution. Increasingly, development of novel technologies is enabling multi-omic interrogations with spatial correlation of RNA and protein expression profiles in the same sample. Such sophisticated methods will provide unprecedented insights into tissue biology, biomarker science and, ultimately, patient health. However, this sophistication comes at significant cost, requiring extensive time, practical knowledge, and resources to implement. This review will describe the technical features, advantages, and limitations of currently available multiplexed immunohistochemistry and spatial transcriptomic platforms. This article is protected by
Persistent repression of tau in the brain using engineered zinc finger protein transcription factors
Wegmann, S;DeVos, SL;Zeitler, B;Marlen, K;Bennett, RE;Perez-Rando, M;MacKenzie, D;Yu, Q;Commins, C;Bannon, RN;Corjuc, BT;Chase, A;Diez, L;Nguyen, HB;Hinkley, S;Zhang, L;Goodwin, A;Ledeboer, A;Lam, S;Ankoudinova, I;Tran, H;Scarlott, N;Amora, R;Surosky, R;Miller, JC;Robbins, AB;Rebar, EJ;Urnov, FD;Holmes, MC;Pooler, AM;Riley, B;Zhang, HS;Hyman, BT;
PMID: 33741591 | DOI: 10.1126/sciadv.abe1611
Neuronal tau reduction confers resilience against β-amyloid and tau-related neurotoxicity in vitro and in vivo. Here, we introduce a novel translational approach to lower expression of the tau gene MAPT at the transcriptional level using gene-silencing zinc finger protein transcription factors (ZFP-TFs). Following a single administration of adeno-associated virus (AAV), either locally into the hippocampus or intravenously to enable whole-brain transduction, we selectively reduced tau messenger RNA and protein by 50 to 80% out to 11 months, the longest time point studied. Sustained tau lowering was achieved without detectable off-target effects, overt histopathological changes, or molecular alterations. Tau reduction with AAV ZFP-TFs was able to rescue neuronal damage around amyloid plaques in a mouse model of Alzheimer's disease (APP/PS1 line). The highly specific, durable, and controlled knockdown of endogenous tau makes AAV-delivered ZFP-TFs a promising approach for the treatment of tau-related human brain diseases.
SARS-CoV-2 infection aggravates chronic comorbidities of cardiovascular diseases and diabetes in mice
Animal models and experimental medicine
Ma, Y;Lu, D;Bao, L;Qu, Y;Liu, J;Qi, X;Yu, L;Zhang, X;Qi, F;Lv, Q;Liu, Y;Shi, X;Sun, C;Li, J;Wang, J;Han, Y;Gao, K;Dong, W;Liu, N;Gao, S;Xue, J;Wei, Q;Pan, S;Gao, H;Zhang, L;Qin, C;
PMID: 33738432 | DOI: 10.1002/ame2.12155
Cardiovascular diseases (CVDs) and diabetes mellitus (DM) are top two chronic comorbidities that increase the severity and mortality of COVID-19. However, how SARS-CoV-2 alters the progression of chronic diseases remain unclear. We used adenovirus to deliver h-ACE2 to lung to enable SARS-CoV-2 infection in mice. SARS-CoV-2's impacts on pathogenesis of chronic diseases were studied through histopathological, virologic and molecular biology analysis. Pre-existing CVDs resulted in viral invasion, ROS elevation and activation of apoptosis pathways contribute myocardial injury during SARS-CoV-2 infection. Viral infection increased fasting blood glucose and reduced insulin response in DM model. Bone mineral density decreased shortly after infection, which associated with impaired PI3K/AKT/mTOR signaling. We established mouse models mimicked the complex pathological symptoms of COVID-19 patients with chronic diseases. Pre-existing diseases could impair the inflammatory responses to SARS-CoV-2 infection, which further aggravated the pre-existing diseases. This work provided valuable information to better understand the interplay between the primary diseases and SARS-CoV-2 infection.
Distinct subtypes of proprioceptive dorsal root ganglion neurons regulate adaptive proprioception in mice
Wu, H;Petitpré, C;Fontanet, P;Sharma, A;Bellardita, C;Quadros, RM;Jannig, PR;Wang, Y;Heimel, JA;Cheung, KKY;Wanderoy, S;Xuan, Y;Meletis, K;Ruas, J;Gurumurthy, CB;Kiehn, O;Hadjab, S;Lallemend, F;
PMID: 33589589 | DOI: 10.1038/s41467-021-21173-9
Proprioceptive neurons (PNs) are essential for the proper execution of all our movements by providing muscle sensory feedback to the central motor network. Here, using deep single cell RNAseq of adult PNs coupled with virus and genetic tracings, we molecularly identify three main types of PNs (Ia, Ib and II) and find that they segregate into eight distinct subgroups. Our data unveil a highly sophisticated organization of PNs into discrete sensory input channels with distinct spatial distribution, innervation patterns and molecular profiles. Altogether, these features contribute to finely regulate proprioception during complex motor behavior. Moreover, while Ib- and II-PN subtypes are specified around birth, Ia-PN subtypes diversify later in life along with increased motor activity. We also show Ia-PNs plasticity following exercise training, suggesting Ia-PNs are important players in adaptive proprioceptive function in adult mice.
Epithelial expression of Gata4 and Sox2 regulates specification of the squamous-columnar junction via MAPK/ERK signaling in mice
Sankoda, N;Tanabe, W;Tanaka, A;Shibata, H;Woltjen, K;Chiba, T;Haga, H;Sakai, Y;Mandai, M;Yamamoto, T;Yamada, Y;Uemoto, S;Kawaguchi, Y;
PMID: 33495473 | DOI: 10.1038/s41467-021-20906-0
The squamous-columnar junction (SCJ) is a boundary consisting of precisely positioned transitional epithelium between the squamous and columnar epithelium. Transitional epithelium is a hotspot for precancerous lesions, and is therefore clinically important; however, the origins and physiological properties of transitional epithelium have not been fully elucidated. Here, by using mouse genetics, lineage tracing, and organoid culture, we examine the development of the SCJ in the mouse stomach, and thus define the unique features of transitional epithelium. We find that two transcription factors, encoded by Sox2 and Gata4, specify primitive transitional epithelium into squamous and columnar epithelium. The proximal-distal segregation of Sox2 and Gata4 expression establishes the boundary of the unspecified transitional epithelium between committed squamous and columnar epithelium. Mechanistically, Gata4-mediated expression of the morphogen Fgf10 in the distal stomach and Sox2-mediated Fgfr2 expression in the proximal stomach induce the intermediate regional activation of MAPK/ERK, which prevents the differentiation of transitional epithelial cells within the SCJ boundary. Our results have implications for tissue regeneration and tumorigenesis, which are related to the SCJ.
STING controls nociception via type I interferon signalling in sensory neurons
Donnelly, CR;Jiang, C;Andriessen, AS;Wang, K;Wang, Z;Ding, H;Zhao, J;Luo, X;Lee, MS;Lei, YL;Maixner, W;Ko, MC;Ji, RR;
PMID: 33442058 | DOI: 10.1038/s41586-020-03151-1
The innate immune regulator STING is a critical sensor of self- and pathogen-derived DNA. DNA sensing by STING leads to the induction of type-I interferons (IFN-I) and other cytokines, which promote immune-cell-mediated eradication of pathogens and neoplastic cells1,2. STING is also a robust driver of antitumour immunity, which has led to the development of STING activators and small-molecule agonists as adjuvants for cancer immunotherapy3. Pain, transmitted by peripheral nociceptive sensory neurons (nociceptors), also aids in host defence by alerting organisms to the presence of potentially damaging stimuli, including pathogens and cancer cells4,5. Here we demonstrate that STING is a critical regulator of nociception through IFN-I signalling in peripheral nociceptors. We show that mice lacking STING or IFN-I signalling exhibit hypersensitivity to nociceptive stimuli and heightened nociceptor excitability. Conversely, intrathecal activation of STING produces robust antinociception in mice and non-human primates. STING-mediated antinociception is governed by IFN-Is, which rapidly suppress excitability of mouse, monkey and human nociceptors. Our findings establish the STING-IFN-I signalling axis as a critical regulator of physiological nociception and a promising new target for treating chronic pain.
Cranial Suture Regeneration Mitigates Skull and Neurocognitive Defects in Craniosynostosis
Yu, M;Ma, L;Yuan, Y;Ye, X;Montagne, A;He, J;Ho, TV;Wu, Y;Zhao, Z;Sta Maria, N;Jacobs, R;Urata, M;Wang, H;Zlokovic, BV;Chen, JF;Chai, Y;
PMID: 33417861 | DOI: 10.1016/j.cell.2020.11.037
Craniosynostosis results from premature fusion of the cranial suture(s), which contain mesenchymal stem cells (MSCs) that are crucial for calvarial expansion in coordination with brain growth. Infants with craniosynostosis have skull dysmorphology, increased intracranial pressure, and complications such as neurocognitive impairment that compromise quality of life. Animal models recapitulating these phenotypes are lacking, hampering development of urgently needed innovative therapies. Here, we show that Twist1+/- mice with craniosynostosis have increased intracranial pressure and neurocognitive behavioral abnormalities, recapitulating features of human Saethre-Chotzen syndrome. Using a biodegradable material combined with MSCs, we successfully regenerated a functional cranial suture that corrects skull deformity, normalizes intracranial pressure, and rescues neurocognitive behavior deficits. The regenerated suture creates a niche into which endogenous MSCs migrated, sustaining calvarial bone homeostasis and repair. MSC-based cranial suture regeneration offers a paradigm shift in treatment to reverse skull and neurocognitive abnormalities in this devastating disease.
Chasseigneaux S, Moraca Y, Cochois-Guégan V, Boulay AC, Gilbert A, Le Crom S, Blugeon C, Firmo C, Cisternino S, Laplanche JL, Curis E, Declèves X, Saubaméa B.
PMID: 30116021 | DOI: 10.1038/s41598-018-30739-5
Brain mural cells form a heterogeneous family which significantly contributes to the maintenance of the blood-brain barrier and regulation of the cerebral blood flow. Current procedures to isolate them cannot specifically separate their distinct subtypes, in particular vascular smoothmuscle cells (VSMCs) and mid-capillary pericytes (mcPCs), which differ among others by their expression of smooth muscle actin (SMA). We herein describe an innovative method allowing SMA+ VSMCs and SMA- mcPCs to be freshly isolated from the rat cerebral cortex. Using differential RNA-Seq analysis, we then reveal the specific gene expression profile of each subtype. Our results refine the current description of the role of VSMCs in parenchymal cortical arterioles at the molecular level and provide a unique platform to identify the molecular mechanisms underlying the specific functions of mcPCs in the brain vasculature.
Kraiczy, J;McCarthy, N;Malagola, E;Tie, G;Madha, S;Boffelli, D;Wagner, DE;Wang, TC;Shivdasani, RA;
PMID: 37028407 | DOI: 10.1016/j.stem.2023.03.004
Signals from the surrounding niche drive proliferation and suppress differentiation of intestinal stem cells (ISCs) at the bottom of intestinal crypts. Among sub-epithelial support cells, deep sub-cryptal CD81+ PDGFRAlo trophocytes capably sustain ISC functions ex vivo. Here, we show that mRNA and chromatin profiles of abundant CD81- PDGFRAlo mouse stromal cells resemble those of trophocytes and that both populations provide crucial canonical Wnt ligands. Mesenchymal expression of key ISC-supportive factors extends along a spatial and molecular continuum from trophocytes into peri-cryptal CD81- CD55hi cells, which mimic trophocyte activity in organoid co-cultures. Graded expression of essential niche factors is not cell-autonomous but dictated by the distance from bone morphogenetic protein (BMP)-secreting PDGFRAhi myofibroblast aggregates. BMP signaling inhibits ISC-trophic genes in PDGFRAlo cells near high crypt tiers; that suppression is relieved in stromal cells near and below the crypt base, including trophocytes. Cell distances thus underlie a self-organized and polar ISC niche.
Biosensors & bioelectronics
Tian, M;Zhang, R;Li, J;
PMID: 37086563 | DOI: 10.1016/j.bios.2023.115302
In-situ detection provides deep insights into the function of genes and their relationship with diseases by directly visualizing their spatiotemporal behavior. As an emerging in-situ imaging tool, clustered regularly interspaced short palindromic repeats (CRISPR)-mediated bioimaging can localize targets in living and fixed cells. CRISPR-mediated bioimaging has inherent advantages over the gold standard of fluorescent in-situ hybridization (FISH), including fast imaging, cost-effectiveness, and ease of preparation. Existing reviews have provided a detailed classification and overview of the principles of CRISPR-mediated bioimaging. However, the exploitation of potential clinical applicability of this bioimaging technique is still limited. Therefore, analyzing the potential value of CRISPR-mediated in-situ imaging is of great significance to the development of bioimaging. In this review, we initially discuss the available CRISPR-mediated imaging systems from the following aspects: summary of imaging substances, the design and optimization of bioimaging strategies, and factors influencing CRISPR-mediated in-situ detection. Subsequently, we highlight the potential of CRISPR-mediated bioimaging for application in biomedical research and clinical practice. Furthermore, we outline the current bottlenecks and future perspectives of CRISPR-based bioimaging. We believe that this review will facilitate the potential integration of bioimaging-related research with current clinical workflow.
Proceedings of the National Academy of Sciences of the United States of America
He, LN;Chen, S;Yang, Q;Wu, Z;Lao, ZK;Tang, CF;Song, JJ;Liu, XD;Lu, J;Xu, XH;Chen, JJ;Xu, TL;Sun, S;Xu, NJ;
PMID: 36802416 | DOI: 10.1073/pnas.2219952120
Social behavior starts with dynamic approach prior to the final consummation. The flexible processes ensure mutual feedback across social brains to transmit signals. However, how the brain responds to the initial social stimuli precisely to elicit timed behaviors remains elusive. Here, by using real-time calcium recording, we identify the abnormalities of EphB2 mutant with autism-associated Q858X mutation in processing long-range approach and accurate activity of prefrontal cortex (dmPFC). The EphB2-dependent dmPFC activation precedes the behavioral onset and is actively associated with subsequent social action with the partner. Furthermore, we find that partner dmPFC activity is responsive coordinately to the approaching WT mouse rather than Q858X mutant mouse, and the social defects caused by the mutation are rescued by synchro-optogenetic activation in dmPFC of paired social partners. These results thus reveal that EphB2 sustains neuronal activation in the dmPFC that is essential for the proactive modulation of social approach to initial social interaction.
