Modulation of 5-HT release by dynorphin mediates social deficits during opioid withdrawal

Neuron

2022 Sep 29

Pomrenze, MB;Cardozo Pinto, DF;Neumann, PA;Llorach, P;Tucciarone, JM;Morishita, W;Eshel, N;Heifets, BD;Malenka, RC;
PMID: 36202097 | DOI: 10.1016/j.neuron.2022.09.024

Social isolation during opioid withdrawal is a major contributor to the current opioid addiction crisis. We find that sociability deficits during protracted opioid withdrawal in mice require activation of kappa opioid receptors (KORs) in the nucleus accumbens (NAc) medial shell. Blockade of release from dynorphin (Pdyn)-expressing dorsal raphe neurons (DRPdyn), but not from NAcPdyn neurons, prevents these deficits in prosocial behaviors. Conversely, optogenetic activation of DRPdyn neurons reproduced NAc KOR-dependent decreases in sociability. Deletion of KORs from serotonin (5-HT) neurons, but not from NAc neurons or dopamine (DA) neurons, prevented sociability deficits during withdrawal. Finally, measurements with the genetically encoded GRAB5-HT sensor revealed that during withdrawal KORs block the NAc 5-HT release that normally occurs during social interactions. These results define a neuromodulatory mechanism that is engaged during protracted opioid withdrawal to induce maladaptive deficits in prosocial behaviors, which in humans contribute to relapse.

Single-cell/nucleus transcriptomic and muscle pathologies

Transcriptome Profiling

2022 Oct 14

Chemello, F;Sales, G;Cagnin, S;
| DOI: 10.1016/b978-0-323-91810-7.00011-x

Recent years have seen a dramatic improvement in RNA and DNA sequencing technologies allowing the analysis of gene expression and chromatin conformation at the single-cell or nuclei level. This permitted to evidence that cells of the human brain may have different genomes, the different cell types living in a tumor or during its development, and many other biological features, promising significant future biomedical and clinical impacts. In this chapter, we will develop the concept of single-cell or nucleus RNA sequencing discussing methods and applications in the field of muscle pathologies. We will focus on all the three types of muscles: skeletal muscle is particularly important to sustain the body and regulate the metabolism, cardiac muscle is fundamental for blood movement within vessels and oxygen and nutrient distribution, and smooth muscle is involved in the maintenance of blood pressure and in the movement of the bolus within the intestine.

Tlx3 controls the development of C-low threshold mechanoreceptors

Neuroreport

2022 Oct 05

Wang, H;Cao, Z;Jiang, X;Huang, C;Cao, C;Liu, Z;
PMID: 36062515 | DOI: 10.1097/WNR.0000000000001824

Somatosensory information is signaled by primary sensory neurons located in dorsal root ganglia (DRG) or trigeminal ganglia. Type C-low threshold mechanoreceptors (C-LTMRs) are proposed to sense light touch. The differentiation and maturation of C-LTMRs are regulated by multiple transcript factors, including Zfp521 and Runx1. However, the molecular mechanism of C-LTMR development still remains largely unclear. RNA sequencing (RNA-seq) was performed to detect transcriptional changes in Tlx3cko DRGs compared to controls. In situ hybridization and RNAscope were used to verify RNA-seq data. RNA-seq identified 203 up- and 372 downregulated genes in DRG by loss of Tlx3 function. KEGG and Gene ontology analysis indicated that the biological properties and molecular functions were closely associated with neural signal processing and transmitting somatosensory information. In addition, the expression of marker genes of C-LTMRs was significantly decreased in Tlx3 mutants. However, Tlx3cko mice exhibited normal response to static and dynamic touch. Furthermore, Tlx3 was required to regulate the expression of Zfp521 and Runx1. Tlx3, Runx1 and Zfp521 may form a hierarchical regulation pathway to control C-LTMR development.

空间转录组技术在肾脏疾病研究中的应用

肾脏病与透析肾移植杂志

2022 Jan 01

邱丹丹, ;蒋松, ;
| DOI: 10.3969/j.issn.1006-298X.2022.03.011

In the last decade, single cell RNAsequencing (scRNAseq) has made significant advances in obtaining quantitative geneexpression of individual cells and identifying previously uncharacterized cell types and functions. However, scRNAseq technologies have the intrinsic limitation of losing original positional information during tissue dissociation into single cells. Spatial localization of cells in tissue microenvironments is essential to further identify cell types, elucidate the complex celltocell communication and spatial division of labor among cells, and explore the relationship between the tissue microenvironments imbalance and the development and progression of diseases. Tissuelevel systems biology requires obtaining wholegenome expression profiles while retaining the spatial positional information of cells. Spatial transcriptomics emerged at the proper time and developed rapidly in recent years. In this review, we introduced the common techniques of spatial transcriptomics and the integrated applications of spatial transcriptomics with other omics (spatialomics). Finally, we summarized current applications and future opportunities in the field of kidney diseases.

Giant Cell Tumor of Bone Versus Tenosynovial Giant Cell Tumor- Similarities and Differences

International journal of surgical pathology

2022 Jan 31

Kropivšek, L;Pižem, J;Mavčič, B;
PMID: 35098753 | DOI: 10.1177/10668969221076545

Giant cell tumor of bone (GCTB) and tenosynovial giant cell tumor (TGCT) share misleadingly similar names, soft texture and brown color macroscopically, osteoclast-like multinucleated giant cells microscopically and localisation in the musculoskeletal system. However, these two tumor types are biologically and clinically two distinct entities with different natural courses of progression and considerably different modes of surgical and medical treatment. In this article, we provide a detailed update on the similarities and the differences between both tumor types.GCTB is a locally aggressive osteolytic bone tumor, commonly seen in patients in their third decade of life. It usually occurs as a solitary lesion in the meta-epiphyseal region of long bones. It can be diagnosed using plain radiographic imaging, CT radiography or MRI to estimate the tumor extent, soft tissue and joint involvement. GCTB is usually treated with intralesional excision by curettage. Systemically, it can be treated with bisphosphonates and denosumab or radiotherapy.TGCT is a rare, slowly progressing tumor of synovial tissue, affecting the joint, tendon sheath or bursa, mostly seen in middle-aged patients. TGCT is usually not visible on radiographs and MRI is mostly used to enable assessment of potential bone involvement and distinguishing between two TGCT types. Localised TGCT is mostly treated with marginal surgical resection, while diffuse TGCT is optimally treated with total synovectomy and is more difficult to remove. Additionally, radiotherapy, intraarticular injection of radioactive isotopes, anti-TNF-α antibodies and targeted medications may be used.

Palmitic acid conjugation enhances potency of tricyclo-DNA splice switching oligonucleotides

Nucleic acids research

2022 Jan 11

Relizani, K;Echevarría, L;Zarrouki, F;Gastaldi, C;Dambrune, C;Aupy, P;Haeberli, A;Komisarski, M;Tensorer, T;Larcher, T;Svinartchouk, F;Vaillend, C;Garcia, L;Goyenvalle, A;
PMID: 34893881 | DOI: 10.1093/nar/gkab1199

Tricyclo-DNA (tcDNA) is a conformationally constrained oligonucleotide analog that has demonstrated great therapeutic potential as antisense oligonucleotide (ASO) for several diseases. Like most ASOs in clinical development, tcDNA were modified with phosphorothioate (PS) backbone for therapeutic purposes in order to improve their biodistribution by enhancing association with plasma and cell protein. Despite the advantageous protein binding properties, systemic delivery of PS-ASO remains limited and PS modifications can result in dose limiting toxicities in the clinic. Improving extra-hepatic delivery of ASO is highly desirable for the treatment of a variety of diseases including neuromuscular disorders such as Duchenne muscular dystrophy. We hypothesized that conjugation of palmitic acid to tcDNA could facilitate the delivery of the ASO from the bloodstream to the interstitium of the muscle tissues. We demonstrate here that palmitic acid conjugation enhances the potency of tcDNA-ASO in skeletal and cardiac muscles, leading to functional improvement in dystrophic mice with significantly reduced dose of administered ASO. Interestingly, palmitic acid-conjugated tcDNA with a full phosphodiester backbone proved effective with a particularly encouraging safety profile, offering new perspectives for the clinical development of PS-free tcDNA-ASO for neuromuscular diseases.

A Deep Mesencephalic Nucleus Circuit Regulates Licking Behavior

Neuroscience bulletin

2022 Jan 26

Zheng, D;Fu, JY;Tang, MY;Yu, XD;Zhu, Y;Shen, CJ;Li, CY;Xie, SZ;Lin, S;Luo, M;Li, XM;
PMID: 35080731 | DOI: 10.1007/s12264-021-00817-2

Licking behavior is important for water intake. The deep mesencephalic nucleus (DpMe) has been implicated in instinctive behaviors. However, whether the DpMe is involved in licking behavior and the precise neural circuit behind this behavior remains unknown. Here, we found that the activity of the DpMe decreased during water intake. Inhibition of vesicular glutamate transporter 2-positive (VGLUT2+) neurons in the DpMe resulted in increased water intake. Somatostatin-expressing (SST+), but not protein kinase C-δ-expressing (PKC-δ+), GABAergic neurons in the central amygdala (CeA) preferentially innervated DpMe VGLUT2+ neurons. The SST+ neurons in the CeA projecting to the DpMe were activated at the onset of licking behavior. Activation of these CeA SST+ GABAergic neurons, but not PKC-δ+ GABAergic neurons, projecting to the DpMe was sufficient to induce licking behavior and promote water intake. These findings redefine the roles of the DpMe and reveal a novel CeASST-DpMeVGLUT2 circuit that regulates licking behavior and promotes water intake.

BMP4 and WNT signaling interact to promote mouse tracheal mesenchyme morphogenesis

American journal of physiology. Lung cellular and molecular physiology

2021 Dec 01

Bottasso Arias, N;Leesman, L;Burra, K;Snowball, J;Shah, RM;Mohanakrishnan, M;Xu, Y;Sinner, D;
PMID: 34851738 | DOI: 10.1152/ajplung.00255.2021

Tracheobronchomalacia and Complete Tracheal Rings are congenital malformations of the trachea associated with morbidity and mortality for which the etiology remains poorly understood. Epithelial expression of Wls (a cargo receptor mediating Wnt ligand secretion) by tracheal cells is essential for patterning the embryonic mouse trachea's cartilage and muscle. RNA sequencing indicated that Wls differentially modulated the expression of BMP signaling molecules. We tested whether BMP signaling, induced by epithelial Wnt ligands, mediates cartilage formation. Deletion of Bmp4 from respiratory tract mesenchyme impaired tracheal cartilage formation that was replaced by ectopic smooth muscle, recapitulating the phenotype observed after epithelial deletion of Wls in the embryonic trachea. Ectopic muscle was caused in part by anomalous differentiation and proliferation of smooth muscle progenitors rather than tracheal cartilage progenitors. Mesenchymal deletion of Bmp4 impaired expression of Wnt/β-catenin target genes, including targets of WNTsignaling: Notum, and Axin2. In vitro, rBMP4 rescued the expression of Notum in Bmp4 deficient tracheal mesenchymal cells and induced Notum promoter activity via SMAD1/5. RNA sequencing of Bmp4 deficient tracheas identified genes essential for chondrogenesis and muscle development co-regulated by BMP and WNT signaling. During tracheal morphogenesis, WNT signaling induces Bmp4 in mesenchymal progenitors to promote cartilage differentiation and restrict trachealis muscle. In turn, Bmp4 differentially regulates the expression of Wnt/β-catenin targets to attenuate mesenchymal WNT signaling and to further support chondrogenesis.

Oro- and Nasopharyngeal Papillomas with Squamous and Respiratory Features: A Case Series of Schneiderian-Like Papillomas of the Pharynx

Head and neck pathology

2021 Oct 25

Ababneh, EI;Shah, AA;
PMID: 34694538 | DOI: 10.1007/s12105-021-01389-3

There is limited literature detailing the histology of pharyngeal papillomas. Herein, we report our experience with papillomas occurring in the oro-and nasopharynx that have both squamous and respiratory features akin to the sinonasal Schneiderian papilloma. We retrospectively reviewed pharyngeal papillomas that were composed of both squamous and respiratory epithelium received at our institution between 2010 and 2020. Cases of sinonasal papillomas directly extending into the pharynx were excluded. Immunohistochemistry for p16 as well as RNA in situ hybridization to evaluate for 6 low-risk and 18 high-risk HPV genotypes were performed on all cases. Thirteen cases were included. Mean age was 61 with 12 males and 1 female. While often incidentally found, presenting symptoms included globus sensation, hemoptysis, and hoarseness of voice. Histologically, all tumors consisted of squamous and respiratory epithelium with neutrophilic infiltrates arranged in an exophytic/papillary architecture that was reminiscent of the exophytic type of Schneiderian papilloma. Immunohistochemistry for p16 was negative in all papillomas. 85% were positive for low-risk human papillomavirus (HPV) subtypes and all were negative for high-risk HPV subtypes. A well-differentiated, invasive squamous cell carcinoma was associated with two of the cases. Papillomas with squamous and respiratory features similar to the sinonasal exophytic Schneiderian papilloma can arise in the oro- and nasopharynx and like their sinonasal counterparts show an association with HPV. While many in this series were benign, they can be harbingers for invasive squamous cell carcinoma.

Factors modulating the incubation of drug and non-drug craving and their clinical implications

Neuroscience and biobehavioral reviews

2021 Sep 28

Venniro, M;Reverte, I;Ramsey, LA;Papastrat, KM;D'Ottavio, G;Milella, MS;Li, X;Grimm, JW;Caprioli, D;
PMID: 34597716 | DOI: 10.1016/j.neubiorev.2021.09.050

It was suggested in 1986 that cue-induced cocaine craving increases progressively during early abstinence and remains high during extended periods of times. Clinical evidence now supports this hypothesis and that this increase is not specific to cocaine but rather generalize across several drugs of abuse. Investigators have identified an analogous incubation phenomenon in rodents, in which time-dependent increases in cue-induced drug seeking are observed after abstinence from intravenous drug or palatable food self-administration. Incubation of craving is susceptible to variation in magnitude as a function of biological and/or the environmental circumstances surrounding the individual. During the last decade, the neurobiological correlates of the modulatory role of biological (sex, age, genetic factors) and environmental factors (environmental enrichment and physical exercise, sleep architecture, acute and chronic stress, abstinence reinforcement procedures) on incubation of drug craving has been investigated. In this review we summarized the behavioral procedures adopted, the key underlying neurobiological correlates and clinical implications of these studies.

Signature morpho-electric, transcriptomic, and dendritic properties of human layer 5 neocortical pyramidal neurons

Neuron

2021 Sep 15

Kalmbach, BE;Hodge, RD;Jorstad, NL;Owen, S;de Frates, R;Yanny, AM;Dalley, R;Mallory, M;Graybuck, LT;Radaelli, C;Keene, CD;Gwinn, RP;Silbergeld, DL;Cobbs, C;Ojemann, JG;Ko, AL;Patel, AP;Ellenbogen, RG;Bakken, TE;Daigle, TL;Dee, N;Lee, BR;McGraw, M;Nicovich, PR;Smith, K;Sorensen, SA;Tasic, B;Zeng, H;Koch, C;Lein, ES;Ting, JT;
PMID: 34534454 | DOI: 10.1016/j.neuron.2021.08.030

In the neocortex, subcerebral axonal projections originate largely from layer 5 (L5) extratelencephalic-projecting (ET) neurons. The unique morpho-electric properties of these neurons have been mainly described in rodents, where retrograde tracers or transgenic lines can label them. Similar labeling strategies are infeasible in the human neocortex, rendering the translational relevance of findings in rodents unclear. We leveraged the recent discovery of a transcriptomically defined L5 ET neuron type to study the properties of human L5 ET neurons in neocortical brain slices derived from neurosurgeries. Patch-seq recordings, where transcriptome, physiology, and morphology were assayed from the same cell, revealed many conserved morpho-electric properties of human and rodent L5 ET neurons. Divergent properties were often subtler than differences between L5 cell types within these two species. These data suggest a conserved function of L5 ET neurons in the neocortical hierarchy but also highlight phenotypic divergence possibly related to functional specialization of human neocortex.

Specific β-defensins stimulate pruritus through activation of sensory neurons

Journal of Investigative Dermatology

2021 Sep 01

Tseng, P;Hoon, M;
| DOI: 10.1016/j.jid.2021.07.178

Pruritus is a common symptom of dermatological disorders and has a major negative impact of quality of life. Previously, it was suggested that skin derived β-defensin peptides elicit itch through activation of mast cells. Here we investigated, in more detail, the mechanisms by which β-defensins induce itch by defining the receptors activated by these peptides in humans and mice, by establishing their action in vivo, and examining their expression in dermal diseases. We found in psoriasis and atopic dermatitis, elevated expression of DEFB103 is highly correlated with skin lesions. We showed that the peptide encoded by this and related genes activate Mas-related G protein-coupled receptors with different potencies that are related with their charge density. Furthermore, we establish that although these peptides can activate mast cells, they also activate sensory neurons, with the former cells being dispensable for itch reactions in mice. Together our studies highlight that specific β-defensins are likely endogenous pruritogens that can directly stimulate sensory neurons.

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	Description
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
Retired Nomenclature
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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