Chen, Z;Chen, J;Wei, X;Hua, H;Hu, R;Ding, N;Zhang, J;Song, D;Ye, Y;Tang, Y;Ding, Z;Ke, S;
PMID: 34960796 | DOI: 10.3390/v13122527
Porcine epidemic diarrhea virus (PEDV), an enteric coronavirus, causes neonatal pig acute gastrointestinal infection with a characterization of severe diarrhea, vomiting, high morbidity, and high mortality, resulting in tremendous damages to the swine industry. Neither specific antiviral drugs nor effective vaccines are available, posing a high priority to screen antiviral drugs. The aim of this study is to investigate anti-PEDV effects of carbazole alkaloid derivatives. Eighteen carbazole derivatives (No.1 to No.18) were synthesized, and No.5, No.7, and No.18 were identified to markedly reduce the replication of enhanced green fluorescent protein (EGFP) inserted-PEDV, and the mRNA level of PEDV N. Flow cytometry assay, coupled with CCK8 assay, confirmed No.7 and No.18 carbazole derivatives displayed high inhibition effects with low cell toxicity. Furthermore, time course analysis indicated No.7 and No.18 carbazole derivatives exerted inhibition at the early stage of the viral life cycle. Collectively, the analysis underlines the benefit of carbazole derivatives as potential inhibitors of PEDV, and provides candidates for the development of novel therapeutic agents.
Tissue architecture delineates field cancerization in BRAFV600E-induced tumor development
Disease models & mechanisms
Schoultz, E;Johansson, E;Moccia, C;Jakubikova, I;Ravi, N;Liang, S;Carlsson, T;Montelius, M;Patyra, K;Kero, J;Paulsson, K;Fagman, H;Bergo, MO;Nilsson, M;
PMID: 34085700 | DOI: 10.1242/dmm.048887
Cancer cells hijack developmental growth mechanisms but whether tissue morphogenesis and architecture modify tumorigenesis is unknown. Here, we characterized a new mouse model of sporadic thyroid carcinogenesis based on inducible expression of BRAFV600E from the thyroglobulin promoter (TgCreERT2). Spontaneous activation of this Braf-mutant allele due to leaky CRE activity revealed that intrinsic properties of thyroid follicles determined BRAF-mutant cell fate. Papillary thyroid carcinomas developed multicentrically within a normal microenvironment. Each tumor originated from a single follicle that provided a confined space for growth of a distinct tumor type. Lineage tracing revealed oligoclonal tumor development in infancy and early selection of BRAFV600E kinase inhibitor-resistant clones. Somatic mutations were few, non-recurrent, and limited to advanced tumors. Female mice developed larger tumors than males, reproducing the gender difference of human thyroid cancer. These data indicate that BRAFV600E-induced tumorigenesis is spatiotemporally regulated depending on the maturity and heterogeneity of follicles. Moreover, thyroid tissue organization seems to determine whether a BRAF-mutant lineage becomes a cancerized lineage. The sporadic thyroid cancer model provides a new tool to evaluate drug therapy at different stages of tumor evolution.
Mangieri LR, Lu Y, Xu Y, Cassidy RM, Xu Y, Arenkiel BR, Tong Q.
PMID: 29302029 | DOI: 10.1038/s41467-017-02534-9
Abnormal feeding often co-exists with compulsive behaviors, but the underlying neural basis remains unknown. Excessive self-grooming in rodents is associated with compulsivity. Here, we show that optogenetically manipulating the activity of lateral hypothalamus (LH) projections targeting the paraventricular hypothalamus (PVH) differentially promotes either feeding or repetitive self-grooming. Whereas selective activation of GABAergic LH→PVH inputs induces feeding, activation of glutamatergic inputs promotes self-grooming. Strikingly, targeted stimulation of GABAergic LH→PVH leads to rapid and reversible transitions to feeding from induced intense self-grooming, while activating glutamatergic LH→PVH or PVH neurons causes rapid and reversible transitions to self-grooming from voracious feeding induced by fasting. Further, specific inhibition of either LH→PVH GABAergic action or PVH neurons reduces self-grooming induced by stress. Thus, we have uncovered a parallel LH→PVH projection circuit for antagonistic control of feeding and self-grooming through dynamic modulation of PVH neuron activity, revealing a common neural pathway that underlies feeding and compulsive behaviors.
Lu L, Ren Y, Yu T, Liu Z, Wang S, Tan L, Zeng J, Feng Q, Lin R, Liu Y, Guo Q, Luo M
PMID: 31937768 | DOI: 10.1038/s41467-019-14116-y
Navigation requires not only the execution of locomotor programs but also high arousal and real-time retrieval of spatial memory that is often associated with hippocampal theta oscillations. However, the neural circuits for coordinately controlling these important processes remain to be fully dissected. Here we show that the activity of the neuromedin B (NMB) neurons in the nucleus incertus (NI) is tightly correlated with mouse locomotor speed, arousal level, and hippocampal theta power. These processes are reversibly suppressed by optogenetic inhibition and rapidly promoted by optogenetic stimulation of NI NMB neurons. These neurons form reciprocal connections with several subcortical areas associated with arousal, theta oscillation, and premotor processing. Their projections to multiple downstream stations regulate locomotion and hippocampal theta, with the projection to the medial septum being particularly important for promoting arousal. Therefore, NI NMB neurons functionally impact the neural circuit for navigation control according to particular brains states
Liu, HM;Liao, ML;Liu, GX;Wang, LJ;Lian, D;Ren, J;Chi, XT;Lv, ZR;Liu, M;Wu, Y;Xu, T;Wei, JY;Feng, X;Jiang, B;Zhang, XQ;Xin, WJ;
PMID: 37352353 | DOI: 10.1126/sciadv.adg5849
The association between rewarding and drug-related memory is a leading factor for the formation of addiction, yet the neural circuits underlying the association remain unclear. Here, we showed that the interstitial nucleus of the posterior limb of the anterior commissure (IPAC) integrated rewarding and environmental memory information by two different receiving projections from ventral tegmental area (VTA) and nucleus accumbens shell region (NAcSh) to mediate the acquisition of morphine conditioned place preference (CPP). A projection from the VTA GABAergic neurons (VTAGABA) to the IPAC lateral region GABAergic neurons (IPACLGABA) mediated the effect of morphine rewarding, whereas the pathway from NAcSh dopamine receptor 1-expressing neurons (NAcShD1) to the IPAC medial region GABAergic neurons (IPACMGABA) was involved in the acquisition of environmental memory. These findings demonstrated that the distinct IPAC circuits VTAGABA→IPACLGABA and NAcShD1R→IPACMGABA were attributable to the rewarding and environmental memory during the acquisition of morphine CPP, respectively, and provided the circuit-based potential targets for preventing and treating opioid addiction.
He, L;Zhao, W;Zhang, L;Ilango, M;Zhao, N;Yang, L;Guan, Z;
High-quality mouse dorsal root ganglion (DRG) cryostat sections are crucial for proper immunochemistry staining and RNAscope studies in the research of inflammatory and neuropathic pain, itch, as well as other peripheral neurological conditions. However, it remains a challenge to consistently obtain high-quality, intact, and flat cryostat sections onto glass slides because of the tiny sample size of the DRG tissue. So far, there is no article describing an optimal protocol for DRG cryosectioning. This protocol presents a step-by-step method to resolve the frequently encountered difficulties associated with DRG cryosectioning. The presented article explains how to remove the surrounding liquid from the DRG tissue samples, place the DRG sections on the slide facing the same orientation, and flatten the sections on the glass slide without curving up. Although this protocol has been developed for cryosectioning the DRG samples, it can be applied for the cryosectioning of many other tissues with a small sample size.
Zhu, W;Li, J;Wu, Z;Li, H;Zhang, Z;Zhu, X;Sun, M;Dong, S;
PMID: 36726218 | DOI: 10.1111/imm.13629
The reported enterovirus A 71 (EVA71) vaccines and immunoglobin G (IgG) antibodies have no cross-antiviral efficacy against other enterovirus A (EV-A) which caused hand, foot and mouth disease (HFMD). Here we constructed an IgM antibody (20-IgM) based on our previous discovery to address the resistance encountered by IgG-based immunotherapy. Although binding to the same conserved neutralizing epitope within the GH loop of EV-As VP1, the antiviral breath and potency of 20-IgM are still higher than its parental 20-IgG1. The 20-IgM blocks the interaction between the EV-As and its receptors, scavenger receptor class B, member 2 (SCARB2) and Kringle-containing transmembrane protein 1(KREMEN1) of the host cell. The 20-IgM also neutralizes the EV-As at the post-attachment stages, including postattachment neutralization, uncoating and RNA release inhibition after internalization. Mechanistically, the dual blockage effect of 20-IgM is dependent on both a conserved site targeting and high affinity binding. Meanwhile, 20-IgM provides cross-antiviral efficacy in EV-As orally infected neonatal ICR mice. Collectively, 20-IgM and its property exhibit excellent antiviral activity with a dual-blockage inhibitory effect at both the pre- and post-attachment stages. The finding enhances our understanding of IgM-mediated immunity and highlights the potential of IgM subtype antibodies against enterovirus infections.
bioRxiv : the preprint server for biology
Moore, J;Basurto-Lozada, D;Besson, S;Bogovic, J;Brown, EM;Burel, JM;de Medeiros, G;Diel, EE;Gault, D;Ghosh, SS;Gold, I;Halchenko, YO;Hartley, M;Horsfall, D;Keller, MS;Kittisopikul, M;Kovacs, G;Küpcü Yoldaş, A;de la Villegeorges, ALT;Li, T;Liberali, P;Linkert, M;Lindner, D;Lüthi, J;Maitin-Shepard, J;Manz, T;McCormick, M;Mohamed, K;Moore, W;Özdemir, B;Pape, C;Pelkmans, L;Prete, M;Pietzsch, T;Preibisch, S;Rzepka, N;Stirling, DR;Striebel, J;Tischer, C;Toloudis, D;Walczysko, P;Watson, AM;Wong, F;Yamauchi, KA;Bayraktar, O;Haniffa, M;Saalfeld, S;Swedlow, JR;
PMID: 36865282 | DOI: 10.1101/2023.02.17.528834
A growing community is constructing a next-generation file format (NGFF) for bioimaging to overcome problems of scalability and heterogeneity. Organized by the Open Microscopy Environment (OME), individuals and institutes across diverse modalities facing these problems have designed a format specification process (OME-NGFF) to address these needs. This paper brings together a wide range of those community members to describe the format itself - OME-Zarr - along with tools and data resources available today to increase FAIR access and remove barriers in the scientific process. The current momentum offers an opportunity to unify a key component of the bioimaging domain - the file format that underlies so many personal, institutional, and global data management and analysis tasks.
British Journal of Dermatology
Talagas, M;
| DOI: 10.1093/bjd/ljac066/6788796
Sensory neurons innervating the skin are conventionally thought to be the sole transducers of 3 touch, temperature, pain, and itch. However, recent studies have shown that keratinocytes - like 4 Merkel cells - act as sensory transducers, whether for innocuous or noxious mechanical, thermal, 5 or chemical stimuli and communicate with intra-epidermal free nerve endings via chemical 6 synaptic contacts. This paradigm shift leads to the consideration of the whole epidermis as a 7 sensory epithelium. Sensory neurons additionally function as an efferent system. Through the 8 release of neuropeptides in intimate neuro-epidermal contact areas, they contribute to epidermal 9 homeostasis and to the pathogenesis of inflammatory skin diseases. To counteract the dogma 10 regarding neuro-cutaneous interactions, seen exclusively from the perspective of soluble and 11 spreading mediators, this review highlights the essential contribution of the unrecognized 12 anatomical contacts between the sensory neurons and the epidermal cells (keratinocytes, 13 melanocytes, Langerhans cells, and Merkel cells) which serve the reciprocal dialogue between 14 the skin, nervous system, and immune system.
Vignes, H;Vagena-Pantoula, C;Prakash, M;Fukui, H;Norden, C;Mochizuki, N;Jug, F;Vermot, J;
PMID: 35245444 | DOI: 10.1016/j.devcel.2022.02.011
Organ morphogenesis involves dynamic changes of tissue properties while cells adapt to their mechanical environment through mechanosensitive pathways. How mechanical cues influence cell behaviors during morphogenesis remains unclear. Here, we studied the formation of the zebrafish atrioventricular canal (AVC) where cardiac valves develop. We show that the AVC forms within a zone of tissue convergence associated with the increased activation of the actomyosin meshwork and cell-orientation changes. We demonstrate that tissue convergence occurs with a reduction of cell volume triggered by mechanical forces and the mechanosensitive channel TRPP2/TRPV4. Finally, we show that the extracellular matrix component hyaluronic acid controls cell volume changes. Together, our data suggest that multiple force-sensitive signaling pathways converge to modulate cell volume. We conclude that cell volume reduction is a key cellular feature activated by mechanotransduction during cardiovascular morphogenesis. This work further identifies how mechanical forces and extracellular matrix influence tissue remodeling in developing organs.
Parigi, SM;Larsson, L;Das, S;Ramirez Flores, RO;Frede, A;Tripathi, KP;Diaz, OE;Selin, K;Morales, RA;Luo, X;Monasterio, G;Engblom, C;Gagliani, N;Saez-Rodriguez, J;Lundeberg, J;Villablanca, EJ;
PMID: 35149721 | DOI: 10.1038/s41467-022-28497-0
The intestinal barrier is composed of a complex cell network defining highly compartmentalized and specialized structures. Here, we use spatial transcriptomics to define how the transcriptomic landscape is spatially organized in the steady state and healing murine colon. At steady state conditions, we demonstrate a previously unappreciated molecular regionalization of the colon, which dramatically changes during mucosal healing. Here, we identified spatially-organized transcriptional programs defining compartmentalized mucosal healing, and regions with dominant wired pathways. Furthermore, we showed that decreased p53 activation defined areas with increased presence of proliferating epithelial stem cells. Finally, we mapped transcriptomics modules associated with human diseases demonstrating the translational potential of our dataset. Overall, we provide a publicly available resource defining principles of transcriptomic regionalization of the colon during mucosal healing and a framework to develop and progress further hypotheses.
Yu, T;Cazares, O;Tang, AD;Kim, HY;Wald, T;Verma, A;Liu, Q;Barcellos-Hoff, MH;Floor, SN;Jung, HS;Brooks, AN;Klein, OD;
PMID: 35202586 | DOI: 10.1016/j.devcel.2022.01.011
Alternative splicing generates distinct mRNA variants and is essential for development, homeostasis, and renewal. Proteins of the serine/arginine (SR)-rich splicing factor family are major splicing regulators that are broadly required for organ development as well as cell and organism viability. However, how these proteins support adult organ function remains largely unknown. Here, we used the continuously growing mouse incisor as a model to dissect the functions of the prototypical SR family protein SRSF1 during tissue homeostasis and renewal. We identified an SRSF1-governed alternative splicing network that is specifically required for dental proliferation and survival of progenitors but dispensable for the viability of differentiated cells. We also observed a similar progenitor-specific role of SRSF1 in the small intestinal epithelium, indicating a conserved function of SRSF1 across adult epithelial tissues. Thus, our findings define a regulatory mechanism by which SRSF1 specifically controls progenitor-specific alternative splicing events to support adult tissue homeostasis and renewal.
