Neuronal mitochondria transport Pink1 mRNA via synaptojanin 2 to support local mitophagy

Neuron

2022 Feb 19

Harbauer, AB;Hees, JT;Wanderoy, S;Segura, I;Gibbs, W;Cheng, Y;Ordonez, M;Cai, Z;Cartoni, R;Ashrafi, G;Wang, C;Perocchi, F;He, Z;Schwarz, TL;
PMID: 35216662 | DOI: 10.1016/j.neuron.2022.01.035

PTEN-induced kinase 1 (PINK1) is a short-lived protein required for the removal of damaged mitochondria through Parkin translocation and mitophagy. Because the short half-life of PINK1 limits its ability to be trafficked into neurites, local translation is required for this mitophagy pathway to be active far from the soma. The Pink1 transcript is associated and cotransported with neuronal mitochondria. In concert with translation, the mitochondrial outer membrane proteins synaptojanin 2 binding protein (SYNJ2BP) and synaptojanin 2 (SYNJ2) are required for tethering Pink1 mRNA to mitochondria via an RNA-binding domain in SYNJ2. This neuron-specific adaptation for the local translation of PINK1 provides distal mitochondria with a continuous supply of PINK1 for the activation of mitophagy.

Immune landscape of human placental villi using single-cell analysis

Development (Cambridge, England)

2022 Jan 20

Toothaker, JM;Olaloye, O;McCourt, BT;McCourt, CC;Silva, TN;Case, RM;Liu, P;Yimlamai, D;Tseng, G;Konnikova, L;
PMID: 35050308 | DOI: 10.1242/dev.200013

Maintenance of healthy pregnancy is reliant on successful balance between the fetal and maternal immune systems. Although maternal mechanisms responsible have been well studied, those used by the fetal immune system remain poorly understood. Using suspension mass cytometry and various imaging modalities, we report a complex immune system within the mid-gestation (17-23 weeks) human placental villi (PV). Consistent with recent reports in other fetal organs, T cells with memory phenotypes, though rare in abundance, were detected within the PV tissue and vasculature. Moreover, we determined T cells isolated from PV samples may be more proliferative than adult T cells at baseline after T cell receptor (TCR) stimulation. Collectively, we identified multiple subtypes of fetal immune cells within the PV and specifically highlight the enhanced proliferative capacity of fetal PV T cells.

Developmental, Physiological, and Functional Neurobiology of the Inner Ear

Neuromethods

2022 Jan 03

Groves, AK;
| DOI: 10.1007/978-1-0716-2022-9

We use cookies to make sure that our website works properly, as well as some ‘optional’ cookies to personalise content and advertising, provide social media features and analyse how people use our site. By accepting some or all optional cookies you give consent to the processing of your personal data, including transfer to third parties, some in countries outside of the European Economic Area that do not offer the same data protection standards as the country where you live. You can decide which optional cookies to accept by clicking on ‘Manage Settings’, where you can also find more information about how your personal data is processed. Further information can be found in our privacy policy [https://link.springer.com/privacystatement].

Cyclical fate restriction: a new view of neural crest cell fate specification

Development

2021 Nov 15

Kelsh, R;Camargo Sosa, K;Farjami, S;Makeev, V;Dawes, J;Rocco, A;
| DOI: 10.1242/dev.176057

Neural crest cells are crucial in development, not least because of their remarkable multipotency. Early findings stimulated two hypotheses for how fate specification and commitment from fully multipotent neural crest cells might occur, progressive fate restriction (PFR) and direct fate restriction, differing in whether partially restricted intermediates were involved. Initially hotly debated, they remain unreconciled, although PFR has become favoured. However, testing of a PFR hypothesis of zebrafish pigment cell development refutes this view. We propose a novel ‘cyclical fate restriction’ hypothesis, based upon a more dynamic view of transcriptional states, reconciling the experimental evidence underpinning the traditional hypotheses.

The rostromedial tegmental (RMTg) \"brake\" on dopamine and behavior: A decade of progress but also much unfinished work

Neuropharmacology

2021 Aug 22

Jhou, T;
PMID: 34433088 | DOI: 10.1016/j.neuropharm.2021.108763

Between 2005-2009, several research groups identified a strikingly dense inhibitory input to midbrain dopamine neurons in a previously uncharted region posterior to the ventral tegmental area (VTA). This region is now denoted as either the rostromedial tegmental nucleus (RMTg) or the "tail of the VTA" (tVTA), and is recognized to express distinct genetic markers, encode negative "prediction errors" (inverse to dopamine neurons), and play critical roles in behavioral inhibition and punishment learning. RMTg neurons are also influenced by many categories of abused drugs, and may drive some aversive responses to such drugs, particularly cocaine and alcohol. However, despite much progress, many important questions remain about RMTg molecular/genetic properties, diversity of projection targets, and applications to addiction, depression, and other neuropsychiatric disorders.

A midbrain dynorphin circuit promotes threat generalization

Current biology : CB

2021 Aug 11

Fellinger, L;Jo, YS;Hunker, AC;Soden, ME;Elum, J;Juarez, B;Zweifel, LS;
PMID: 34388372 | DOI: 10.1016/j.cub.2021.07.047

Discrimination between predictive and non-predictive threat stimuli decreases as threat intensity increases. The central mechanisms that mediate the transition from discriminatory to generalized threat responding remain poorly resolved. Here, we identify the stress- and dysphoria-associated kappa opioid receptor (KOR) and its ligand dynorphin (Dyn), acting in the ventral tegmental area (VTA), as a key substrate for regulating threat generalization. We identify several dynorphinergic inputs to the VTA and demonstrate that projections from the bed nucleus of the stria terminalis (BNST) and dorsal raphe nucleus (DRN) both contribute to anxiety-like behavior but differentially affect threat generalization. These data demonstrate that conditioned threat discrimination has an inverted "U" relationship with threat intensity and establish a role for KOR/Dyn signaling in the midbrain for promoting threat generalization.

New Latency Reversing Agents for HIV-1 Cure: Insights from Nonhuman Primate Models

Viruses

2021 Aug 06

Bricker, KM;Chahroudi, A;Mavigner, M;
PMID: 34452425 | DOI: 10.3390/v13081560

Antiretroviral therapy (ART) controls human immunodeficiency virus 1 (HIV-1) replication and prevents disease progression but does not eradicate HIV-1. The persistence of a reservoir of latently infected cells represents the main barrier to a cure. "Shock and kill" is a promising strategy involving latency reversing agents (LRAs) to reactivate HIV-1 from latently infected cells, thus exposing the infected cells to killing by the immune system or clearance agents. Here, we review advances to the "shock and kill" strategy made through the nonhuman primate (NHP) model, highlighting recently identified latency reversing agents and approaches such as mimetics of the second mitochondrial activator of caspase (SMACm), experimental CD8+ T cell depletion, immune checkpoint blockade (ICI), and toll-like receptor (TLR) agonists. We also discuss the advantages and limits of the NHP model for HIV cure research and methods developed to evaluate the efficacy of in vivo treatment with LRAs in NHPs.

γδ T cells regulate the intestinal response to nutrient sensing

Science (New York, N.Y.)

2021 Mar 19

Sullivan, ZA;Khoury-Hanold, W;Lim, J;Smillie, C;Biton, M;Reis, BS;Zwick, RK;Pope, SD;Israni-Winger, K;Parsa, R;Philip, NH;Rashed, S;Palm, N;Wang, A;Mucida, D;Regev, A;Medzhitov, R;
PMID: 33737460 | DOI: 10.1126/science.aba8310

The intestine is a site of direct encounter with the external environment and must consequently balance barrier defense with nutrient uptake. To investigate how nutrient uptake is regulated in the small intestine, we tested the effect of diets with different macronutrient compositions on epithelial gene expression. We found that enzymes and transporters required for carbohydrate digestion and absorption were regulated by carbohydrate availability. The "on-demand" induction of this machinery required γδ T cells, which regulated this program through the suppression of interleukin-22 production by type 3 innate lymphoid cells. Nutrient availability altered the tissue localization and transcriptome of γδ T cells. Additionally, transcriptional responses to diet involved cellular remodeling of the epithelial compartment. Thus, this work identifies a role for γδ T cells in nutrient sensing.

Understanding breast cancer heterogeneity through non-genetic heterogeneity

Breast cancer (Tokyo, Japan)

2021 Mar 15

Barzgar Barough, N;Sajjadian, F;Jalilzadeh, N;Shafaei, H;Velaei, K;
PMID: 33723745 | DOI: 10.1007/s12282-021-01237-w

Intricacy in treatment and diagnosis of breast cancer has been an obstacle due to genotype and phenotype heterogeneity. Understanding of non-genetic heterogeneity mechanisms along with considering role of genetic heterogeneity may fill the gaps in landscape painting of heterogeneity. The main factors contribute to non-genetic heterogeneity including: transcriptional pulsing/bursting or discontinuous transcriptions, stochastic partitioning of components at cell division and various signal transduction from tumor ecosystem. Throughout this review, we desired to provide a conceptual framework focused on non-genetic heterogeneity, which has been intended to offer insight into prediction, diagnosis and treatment of breast cancer.

Navigating the cellular landscape in tissue: Recent advances in defining the pathogenesis of human disease

Computational and Structural Biotechnology Journal

2022 Sep 15

Chen, H;Palendira, U;Feng, C;
| DOI: 10.1016/j.csbj.2022.09.005

Over the past decade, our understanding of human diseases has rapidly grown from the rise of single-cell spatial biology. While conventional tissue imaging has focused on visualizing morphological features, the development of multiplex tissue imaging from fluorescence-based methods to DNA- and mass cytometry-based methods has allowed visualization of over 60 markers on a single tissue section. The advancement of spatial biology with a single-cell resolution has enabled the visualization of cell-cell interactions and the tissue microenvironment, a crucial part to understanding the mechanisms underlying pathogenesis. Alongside the development of extensive marker panels which can distinguish distinct cell phenotypes, multiplex tissue imaging has facilitated the analysis of high dimensional data to identify novel biomarkers and therapeutic targets, while considering the spatial context of the cellular environment. This mini-review provides an overview of the recent advancements in multiplex imaging technologies and examines how these methods have been used in exploring pathogenesis and biomarker discovery in cancer, autoimmune and infectious diseases.

Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity

Cell metabolism

2021 Nov 19

Wang, L;Wang, B;Gasek, NS;Zhou, Y;Cohn, RL;Martin, DE;Zuo, W;Flynn, WF;Guo, C;Jellison, ER;Kim, T;Prata, LGPL;Palmer, AK;Li, M;Inman, CL;Barber, LS;Al-Naggar, IMA;Zhou, Y;Kuchel, GA;Meves, A;Tchkonia, T;Kirkland, JL;Robson, P;Xu, M;
PMID: 34813734 | DOI: 10.1016/j.cmet.2021.11.002

Insulin resistance is a pathological state often associated with obesity, representing a major risk factor for type 2 diabetes. Limited mechanism-based strategies exist to alleviate insulin resistance. Here, using single-cell transcriptomics, we identify a small, critically important, but previously unexamined cell population, p21Cip1 highly expressing (p21high) cells, which accumulate in adipose tissue with obesity. By leveraging a p21-Cre mouse model, we demonstrate that intermittent clearance of p21high cells can both prevent and alleviate insulin resistance in obese mice. Exclusive inactivation of the NF-κB pathway within p21high cells, without killing them, attenuates insulin resistance. Moreover, fat transplantation experiments establish that p21high cells within fat are sufficient to cause insulin resistance in vivo. Importantly, a senolytic cocktail, dasatinib plus quercetin, eliminates p21high cells in human fat ex vivo and mitigates insulin resistance following xenotransplantation into immuno-deficient mice. Our findings lay the foundation for pursuing the targeting of p21high cells as a new therapy to alleviate insulin resistance.

The utility of high-risk human papillomavirus in situ hybridization in cytology cell block material from cystic head and neck lesions

Cancer cytopathology

2021 Nov 10

Han, LM;Saunders, TA;Calkins, SM;
PMID: 34758205 | DOI: 10.1002/cncy.22529

Human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV-OPSCC) presents frequently as metastasis in a neck lymph node that may be cystic or necrotic. Fine-needle aspiration (FNA) biopsies are often first-line diagnostic procedures. p16 immunohistochemistry (IHC) is a surrogate marker for high-risk HPV (hrHPV) infection but can be challenging to interpret. This study evaluated the use of hrHPV in situ hybridization (ISH) in cytology cell blocks of cystic neck lesions.Twenty-four FNA cases with cell blocks and surgical correlates were evaluated. p16 IHC and hrHPV ISH were assessed on cell blocks (C-p16 and C-hrHPV ISH), and hrHPV ISH on surgical samples (S-hrHPV ISH). All results were classified as negative, positive, or equivocal.Two cases were excluded because of insufficient tissue on recut. On the basis of C-hrHPV ISH cases, 12 were positive, 5 were negative, and 5 were equivocal. All 12 positive C-hrHPV ISH cases had concordant S-hrHPV ISH with no false positives. Of the 5 negative C-hrHPV ISH cases, 4 had concordant S-hrHPV ISH, and 1 had a discordant S-hrHPV ISH. Of the 5 equivocal C-hrHPV ISH cases, S-hrHPV ISH were both positive and negative. Fourteen cases were equivocal by C-p16; 9 cases were reliably classified by C-hrHPV ISH (5 positive, 4 negative; 64%).C-hrHPV ISH can be reliably used, especially when positive. A negative or equivocal interpretation of C-hrHPV ISH may warrant repeat testing. Compared to C-p16, C-hrHPV ISH is more frequently diagnostic and could be helpful for HPV-OSCC diagnosis and management.

Pages

	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

Search form

Probes for INS

Content for comparison

Gene

Product

Research area

Category

Pages

Advanced Cell Diagnostics

Bio-Techne

Advanced Cell Diagnostics China