Crucial Role of Central Nervous System as a Viral Anatomical Compartment for HIV-1 Infection

Microorganisms

2021 Dec 08

Borrajo, A;Svicher, V;Salpini, R;Pellegrino, M;Aquaro, S;
PMID: 34946138 | DOI: 10.3390/microorganisms9122537

The chronic infection established by the human immunodeficiency virus 1 (HIV-1) produces serious CD4+ T cell immunodeficiency despite the decrease in HIV-1 ribonucleic acid (RNA) levels and the raised life expectancy of people living with HIV-1 (PLWH) through treatment with combined antiretroviral therapies (cART). HIV-1 enters the central nervous system (CNS), where perivascular macrophages and microglia are infected. Serious neurodegenerative symptoms related to HIV-associated neurocognitive disorders (HAND) are produced by infection of the CNS. Despite advances in the treatment of this infection, HAND significantly contribute to morbidity and mortality globally. The pathogenesis and the role of inflammation in HAND are still incompletely understood. Principally, growing evidence shows that the CNS is an anatomical reservoir for viral infection and replication, and that its compartmentalization can trigger the evolution of neurological damage and thus make virus eradication more difficult. In this review, important concepts for understanding HAND and neuropathogenesis as well as the viral proteins involved in the CNS as an anatomical reservoir for HIV infection are discussed. In addition, an overview of the recent advancements towards therapeutic strategies for the treatment of HAND is presented. Further neurological research is needed to address neurodegenerative difficulties in people living with HIV, specifically regarding CNS viral reservoirs and their effects on eradication.

Single-cell analysis reveals androgen receptor regulates the ER-to-Golgi trafficking pathway with CREB3L2 to drive prostate cancer progression

Oncogene

2021 Oct 05

Hu, L;Chen, X;Narwade, N;Lim, MGL;Chen, Z;Tennakoon, C;Guan, P;Chan, UI;Zhao, Z;Deng, M;Xu, X;Sung, WK;Cheung, E;
PMID: 34611310 | DOI: 10.1038/s41388-021-02026-7

Androgen receptor (AR) plays a central role in driving prostate cancer (PCa) progression. How AR promotes this process is still not completely clear. Herein, we used single-cell transcriptome analysis to reconstruct the transcriptional network of AR in PCa. Our work shows AR directly regulates a set of signature genes in the ER-to-Golgi protein vesicle-mediated transport pathway. The expression of these genes is required for maximum androgen-dependent ER-to-Golgi trafficking, cell growth, and survival. Our analyses also reveal the signature genes are associated with PCa progression and prognosis. Moreover, we find inhibition of the ER-to-Golgi transport process with a small molecule enhanced antiandrogen-mediated tumor suppression of hormone-sensitive and insensitive PCa. Finally, we demonstrate AR collaborates with CREB3L2 in mediating ER-to-Golgi trafficking in PCa. In summary, our findings uncover a critical role for dysregulation of ER-to-Golgi trafficking expression and function in PCa progression, provide detailed mechanistic insights for how AR tightly controls this process, and highlight the prospect of targeting the ER-to-Golgi pathway as a therapeutic strategy for advanced PCa.

Subcellular localization of biomolecules and drug distribution by high-definition ion beam imaging

Nature communications

2021 Jul 30

Rovira-Clavé, X;Jiang, S;Bai, Y;Zhu, B;Barlow, G;Bhate, S;Coskun, AF;Han, G;Ho, CK;Hitzman, C;Chen, SY;Bava, FA;Nolan, GP;
PMID: 34330905 | DOI: 10.1038/s41467-021-24822-1

Simultaneous visualization of the relationship between multiple biomolecules and their ligands or small molecules at the nanometer scale in cells will enable greater understanding of how biological processes operate. We present here high-definition multiplex ion beam imaging (HD-MIBI), a secondary ion mass spectrometry approach capable of high-parameter imaging in 3D of targeted biological entities and exogenously added structurally-unmodified small molecules. With this technology, the atomic constituents of the biomolecules themselves can be used in our system as the "tag" and we demonstrate measurements down to ~30 nm lateral resolution. We correlated the subcellular localization of the chemotherapy drug cisplatin simultaneously with five subnuclear structures. Cisplatin was preferentially enriched in nuclear speckles and excluded from closed-chromatin regions, indicative of a role for cisplatin in active regions of chromatin. Unexpectedly, cells surviving multi-drug treatment with cisplatin and the BET inhibitor JQ1 demonstrated near total cisplatin exclusion from the nucleus, suggesting that selective subcellular drug relocalization may modulate resistance to this important chemotherapeutic treatment. Multiplexed high-resolution imaging techniques, such as HD-MIBI, will enable studies of biomolecules and drug distributions in biologically relevant subcellular microenvironments by visualizing the processes themselves in concert, rather than inferring mechanism through surrogate analyses.

Astrocyte-derived CCL7 promotes microglia-mediated inflammation following traumatic brain injury

International immunopharmacology

2021 Jul 19

Xue, J;Zhang, Y;Zhang, J;Zhu, Z;Lv, Q;Su, J;
PMID: 34293712 | DOI: 10.1016/j.intimp.2021.107975

Microglia are immune cells of the central nervous system that mediate neuroinflammation. It is widely known that microglia-mediated inflammation in the brain contribute to the widespread tissue damage and neurological deficits in traumatic brain injury (TBI). However, the mechanisms responsible for this inflammatory response remain elusive. Here, we investigated the role of astrocyte-derived chemokine (C-C motif) ligand 7 (CCL7) in microglial-controlled inflammation following TBI. Our results demonstrated that astrocyte-derived CCL7 induced microglial activation and the release of proinflammatory mediators in the cortex and serum of rats that underwent experimental TBI. Furthermore, CCL7 knockout improved microglia-controlled inflammation, brain morphology and neurological dysfunction following TBI. In vitro, CCL7-siRNA attenuated the LPS-induced expression of pro-inflammatory markers in the co-culture of microglia and astrocytes. Collectively, our findings uncover an important role for astrocyte-derived CCL7 in promoting microglia-mediated inflammation after TBI and suggests CCL7 could serve as a potential therapeutic strategy for attenuating TBI by inhibiting microglial activation.

OMICs, Epigenetics, and Genome Editing Techniques for Food and Nutritional Security

Plants

2021 Jul 12

Gogolev, Y;Ahmar, S;Akpinar, B;Budak, H;Kiryushkin, A;Gorshkov, V;Hensel, G;Demchenko, K;Kovalchuk, I;Mora-Poblete, F;Muslu, T;Tsers, I;Yadav, N;Korzun, V;
| DOI: 10.3390/plants10071423

The incredible success of crop breeding and agricultural innovation in the last century greatly contributed to the Green Revolution, which significantly increased yields and ensures food security, despite the population explosion. However, new challenges such as rapid climate change, deteriorating soil, and the accumulation of pollutants require much faster responses and more effective solutions that cannot be achieved through traditional breeding. Further prospects for increasing the efficiency of agriculture are undoubtedly associated with the inclusion in the breeding strategy of new knowledge obtained using high-throughput technologies and new tools in the future to ensure the design of new plant genomes and predict the desired phenotype. This article provides an overview of the current state of research in these areas, as well as the study of soil and plant microbiomes, and the prospective use of their potential in a new field of microbiome engineering. In terms of genomic and phenomic predictions, we also propose an integrated approach that combines high-density genotyping and high-throughput phenotyping techniques, which can improve the prediction accuracy of quantitative traits in crop species.

Loss of Selenov predisposes mice to extra fat accumulation and attenuated energy expenditure

Redox biology

2021 Jun 17

Chen, LL;Huang, JQ;Wu, YY;Chen, LB;Li, SP;Zhang, X;Wu, S;Ren, FZ;Lei, XG;
PMID: 34167027 | DOI: 10.1016/j.redox.2021.102048

Selenoprotein V (SELENOV) is a new and the least conserved member of the selenoprotein family. Herein we generated Selenov knockout (KO) mice to determine its in vivo function. The KO led to 16-19% increases (P < 0.05) in body weight that were largely due to 54% higher (P < 0.05) fat mass accumulation, compared with the wild-type (WT) controls. The extra fat accumulation in the KO mice was mediated by up-regulations of genes and proteins involved in lipogenesis (Acc, Fas, Dgat, and Lpl; up by 40%-1.1-fold) and down-regulations of lipolysis (Atgl, Hsl, Ces1d, and Cpt1a; down by 36-89%) in the adipose tissues. The KO also decreased (P < 0.05) VO2 consumption (14-21%), VCO2 production (14-16%), and energy expenditure (14-23%), compared with the WT controls. SELENOV and O-GlcNAc transferase (OGT) exhibited a novel protein-protein interaction that explained the KO-induced decreases (P < 0.05) of OGT protein (15-29%), activity (33%), and function (O-GlcNAcylation, 10-21%) in the adipose tissues. A potential cascade of SELENOV-OGT-AMP-activated protein kinase might serve as a central mechanism to link the biochemical and molecular responses to the KO. Overall, our data revealed a novel in vivo function and mechanism of SELENOV as a new inhibitor of body fat accumulation, activator of energy expenditure, regulator of O-GlcNAcylation, and therapeutic target of such related disorders.

LncRNA H19 aggravates intervertebral disc degeneration by promoting the autophagy and apoptosis of nucleus pulposus cells via the miR-139/CXCR4/NF-κB axis

Stem cells and development

2021 May 20

Sun, Z;Tang, X;Wang, H;Sun, H;Chu, P;Sun, L;Tian, J;
PMID: 34015968 | DOI: 10.1089/scd.2021.0009

The etiology of lumbocrural pain is closely related to intervertebral disc degeneration (IDD). Long noncoding RNAs (LncRNAs) serve crucial roles in IDD progression. This study investigated the effect of lncRNA H19 on autophagy and apoptosis of nucleus pulposus cells (NPCs) in IDD. The rat model of IDD was established. Normal NPCs and degenerative NPCs (DNPCs) were cultured in vitro. H19 expression in IDD rat was detected. DNPCs were treated with si-H19 to evaluate autophagy and apoptosis of DNPCs. The binding relationships between H19 and miR-139-3p, and miR-139-3p and CXCR4 were verified. DNPCs were co-transfected si-H19 and miR-139-3p inhibitor. The phosphorylation of NF-κB pathway related p65 in DNPCs was detected. LncRNA H19 was upregulated in IDD rats. Downregulation of H19 inhibited autophagy and apoptosis of DNPCs. LncRNA H19 sponged miR-139-3p to inhibit CXCR4 expression. si-H19 and miR-139-3p inhibitor co-treatment induced autophagy and apoptosis, and enhanced CXCR4 expression. si-H19 decreased p-p65 phosphorylation, while si-H19 and miR-139-3p inhibitor co-treatment partially elevated p-p65 phosphorylation. In conclusion, lncRNA H19 facilitated the autophagy and apoptosis of DNPCs via the miR-139-3p/CXCR4/NF-κB axis, thereby aggravating IDD. This study may offer new insights for the management of IDD.

Next-Generation Digital Histopathology of the Tumor Microenvironment

Genes

2021 Apr 07

Mungenast, F;Fernando, A;Nica, R;Boghiu, B;Lungu, B;Batra, J;Ecker, RC;
PMID: 33917241 | DOI: 10.3390/genes12040538

Progress in cancer research is substantially dependent on innovative technologies that permit a concerted analysis of the tumor microenvironment and the cellular phenotypes resulting from somatic mutations and post-translational modifications. In view of a large number of genes, multiplied by differential splicing as well as post-translational protein modifications, the ability to identify and quantify the actual phenotypes of individual cell populations in situ, i.e., in their tissue environment, has become a prerequisite for understanding tumorigenesis and cancer progression. The need for quantitative analyses has led to a renaissance of optical instruments and imaging techniques. With the emergence of precision medicine, automated analysis of a constantly increasing number of cellular markers and their measurement in spatial context have become increasingly necessary to understand the molecular mechanisms that lead to different pathways of disease progression in individual patients. In this review, we summarize the joint effort that academia and industry have undertaken to establish methods and protocols for molecular profiling and immunophenotyping of cancer tissues for next-generation digital histopathology-which is characterized by the use of whole-slide imaging (brightfield, widefield fluorescence, confocal, multispectral, and/or multiplexing technologies) combined with state-of-the-art image cytometry and advanced methods for machine and deep learning.

Neuromodulation by the immune system: a focus on cytokines

Nature reviews. Immunology

2021 Mar 01

Salvador, AF;de Lima, KA;Kipnis, J;
PMID: 33649606 | DOI: 10.1038/s41577-021-00508-z

Interactions between the immune system and the nervous system have been described mostly in the context of diseases. More recent studies have begun to reveal how certain immune cell-derived soluble effectors, the cytokines, can influence host behaviour even in the absence of infection. In this Review, we contemplate how the immune system shapes nervous system function and how it controls the manifestation of host behaviour. Interactions between these two highly complex systems are discussed here also in the context of evolution, as both may have evolved to maximize an organism's ability to respond to environmental threats in order to survive. We describe how the immune system relays information to the nervous system and how cytokine signalling occurs in neurons. We also speculate on how the brain may be hardwired to receive and process information from the immune system. Finally, we propose a unified theory depicting a co-evolution of the immune system and host behaviour in response to the evolutionary pressure of pathogens.

Brain ethanol metabolism by astrocytic ALDH2 drives the behavioural effects of ethanol intoxication

Nature metabolism

2021 Mar 01

Jin, S;Cao, Q;Yang, F;Zhu, H;Xu, S;Chen, Q;Wang, Z;Lin, Y;Cinar, R;Pawlosky, RJ;Zhang, Y;Xiong, W;Gao, B;Koob, GF;Lovinger, DM;Zhang, L;
PMID: 33758417 | DOI: 10.1038/s42255-021-00357-z

Alcohol is among the most widely used psychoactive substances worldwide. Ethanol metabolites such as acetate, thought to be primarily the result of ethanol breakdown by hepatic aldehyde dehydrogenase 2 (ALDH2), contribute to alcohol's behavioural effects and alcoholism. Here, we show that ALDH2 is expressed in astrocytes in the mouse cerebellum and that ethanol metabolism by astrocytic ALDH2 mediates behavioural effects associated with ethanol intoxication. We show that ALDH2 is expressed in astrocytes in specific brain regions and that astrocytic, but not hepatocytic, ALDH2 is required to produce ethanol-derived acetate in the mouse cerebellum. Cerebellar astrocytic ALDH2 mediates low-dose ethanol-induced elevation of GABA levels, enhancement of tonic inhibition and impairment of balance and coordination skills. Thus, astrocytic ALDH2 controls the production, cellular and behavioural effects of alcohol metabolites in a brain-region-specific manner. Our data indicate that astrocytic ALDH2 is an important, but previously under-recognized, target in the brain to alter alcohol pharmacokinetics and potentially treat alcohol use disorder.

The impact of influenza pulmonary infection and inflammation on vagal bronchopulmonary sensory neurons

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2021 Mar 01

Verzele, NAJ;Chua, BY;Law, CW;Zhang, A;Ritchie, ME;Wightman, O;Edwards, IN;Hulme, KD;Bloxham, CJ;Bielefeldt-Ohmann, H;Trewella, MW;Moe, AAK;Chew, KY;Mazzone, SB;Short, KR;McGovern, AE;
PMID: 33660333 | DOI: 10.1096/fj.202001509R

Influenza A virus (IAV) is rapidly detected in the airways by the immune system, with resident parenchymal cells and leukocytes orchestrating viral sensing and the induction of antiviral inflammatory responses. The airways are innervated by heterogeneous populations of vagal sensory neurons which also play an important role in pulmonary defense. How these neurons respond to IAV respiratory infection remains unclear. Here, we use a murine model to provide the first evidence that vagal sensory neurons undergo significant transcriptional changes following a respiratory IAV infection. RNA sequencing on vagal sensory ganglia showed that IAV infection induced the expression of many genes associated with an antiviral and pro-inflammatory response and this was accompanied by a significant increase in inflammatory cell recruitment into the vagal ganglia. Assessment of gene expression in single-vagal sensory neurons confirmed that IAV infection induced a neuronal inflammatory phenotype, which was most prominent in bronchopulmonary neurons, and also evident in some neurons innervating other organs. The altered transcriptome could be mimicked by intranasal treatment with cytokines and the lung homogenates of infected mice, in the absence of infectious virus. These data argue that IAV pulmonary infection and subsequent inflammation induces vagal sensory ganglia neuroinflammation and this may have important implications for IAV-induced morbidity.

Compromised counterselection by FAS creates an aggressive subtype of germinal center lymphoma

J Exp Med

2021 Mar 01

Razzaghi, R;Agarwal, S;Kotlov, N;Plotnikova, O;Nomie, K;Huang, DW;Wright, GW;Smith, GA;Li, M;Takata, K;Yamadi, M;Yao, C;O'Shea, JJ;Phelan, JD;Pittaluga, S;Scott, DW;Muppidi, JR;
PMID: 33237303 | DOI: 10.1084/jem.20201173

Fas is highly expressed on germinal center (GC) B cells, and mutations of FAS have been reported in diffuse large B cell lymphoma (DLBCL). Although GC-derived DLBCL has better overall outcomes than other DLBCL types, some cases are refractory, and the molecular basis for this is often unknown. We show that Fas is a strong cell-intrinsic regulator of GC B cells that promotes cell death in the light zone, likely via T follicular helper (Tfh) cell-derived Fas ligand. In the absence of Fas, GCs were more clonally diverse due to an accumulation of cells that did not demonstrably bind antigen. FAS alterations occurred most commonly in GC-derived DLBCL, were associated with inferior outcomes and an enrichment of Tfh cells, and co-occurred with deficiency in HVEM and PD-L1 that regulate the Tfh-B cell interaction. This work shows that Fas is critically required for GC homeostasis and suggests that loss of Tfh-mediated counterselection in the GC contributes to lethality in GC-derived lymphoma. This is a work of the U.S. Government and is not subject to

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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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