Intestinal IL-17R Signaling Controls Secretory IgA and Oxidase Balance in Citrobacter rodentium Infection

Journal of immunology (Baltimore, Md. : 1950)

2021 Jan 11

Matsunaga, Y;Clark, T;Wanek, AG;Bitoun, JP;Gong, Q;Good, M;Kolls, JK;
PMID: 33431657 | DOI: 10.4049/jimmunol.2000591

Type 17 cytokines have been strongly implicated in mucosal immunity, in part by regulating the production of antimicrobial peptides. Using a mouse model of Citrobacter rodentium infection, which causes colitis, we found that intestinal IL-17RA and IL-17RC were partially required for control of infection in the colon and IL-17 regulates the production of luminal hydrogen peroxide as well as expression of Tnsf13 Reduced Tnfsf13 expression was associated with a profound defect in generating C. rodentium-specific IgA+ Ab-secreting cells. Taken together, intestinal IL-17R signaling plays key roles in controlling invading pathogens, in part by regulating luminal hydrogen peroxide as well as regulating the generation of pathogen-specific IgA+ Ab-secreting cells.

On the functional relevance of spatiotemporally-specific patterns of experience-dependent long noncoding RNA expression in the brain

RNA biology

2021 Jan 04

Liau, WS;Samaddar, S;Banerjee, S;Bredy, TW;
PMID: 33397182 | DOI: 10.1080/15476286.2020.1868165

The majority of transcriptionally active RNA derived from the mammalian genome does not code for protein. Long noncoding RNA (lncRNA) is the most abundant form of noncoding RNA found in the brain and is involved in many aspects of cellular metabolism. Beyond their fundamental role in the nucleus as decoys for RNA-binding proteins associated with alternative splicing or as guides for the epigenetic regulation of protein-coding gene expression, recent findings indicate that activity-induced lncRNAs also regulate neural plasticity. In this review, we discuss how lncRNAs may exert molecular control over brain function beyond their known roles in the nucleus. We propose that subcellular localization is a critical feature of experience-dependent lncRNA activity in the brain, and that lncRNA-mediated control over RNA metabolism at the synapse serves to regulate local mRNA stability and translation, thereby influencing neuronal function, learning and memory.

The G614 pandemic SARS-CoV-2 variant is not more pathogenic than the original D614 form in adult Syrian hamsters

Virology

2021 Jan 01

Stauft, C;Lien, C;Selvaraj, P;Liu, S;Wang, T;
| DOI: 10.1016/j.virol.2021.01.005

Dynamic tracking of variant frequencies among viruses circulating in the global pandemic has revealed the emergence and dominance of a D614G mutation in the SARS-CoV-2 spike protein. To address whether pandemic SARS-CoV-2 G614 variant has evolved to become more pathogenic, we infected adult hamsters (>10 months old) with two natural SARS-CoV-2 variants carrying either D614 or G614 spike protein to mimic infection of the adult/elderly human population. Hamsters infected by the two variants exhibited comparable viral loads and pathology in lung tissues as well as similar amounts of virus shed in nasal washes. Altogether, our study does not find that naturally circulating D614 and G614 SARS-CoV-2 variants differ significantly in pathogenicity in hamsters.

KDM5D predicts response to docetaxel chemotherapy in metastatic castration resistant prostate cancer patients

Translational Andrology and Urology

2021 Jan 01

Schäfer, G;Bednarova, N;Heidenreich, A;Klocker, H;Heidegger, I;
| DOI: 10.21037/tau-20-1084

Background: The administration of docetaxel chemotherapy is one therapeutic option to delay disease progression and increase overall survival in metastatic castration resistant prostate cancer (mCRPC). However, about 15% of patients are primary resistant to chemotherapy and hence would benefit from an alternative mCRPC treatment. Despite intensive research, there are no robust clinical validated biomarkers to predict mCRPC therapy response. Thus, the aim of the study was to determine KDM5D expression in archival radical prostatectomy specimens of patients medicated with docetaxel at time of mCRPC development in order to correlate KMD5D expression with treatment response. Methods: We used in situ hybridization (ISH) (RNA scope 2.5 HD) to determine KDM5D expression in tissue samples of 28 prostate cancer patients. KDM5D status was correlated to chemotherapy response (PSA and radiographic response). Results: Data revealed that KDM5D is significantly overexpressed in tumor cells (P

Senescent alveolar macrophages promote early-stage lung tumorigenesis

Cancer cell

2023 May 24

Prieto, LI;Sturmlechner, I;Graves, SI;Zhang, C;Goplen, NP;Yi, ES;Sun, J;Li, H;Baker, DJ;
PMID: 37267954 | DOI: 10.1016/j.ccell.2023.05.006

Senescent cells play relevant but context-dependent roles during tumorigenesis. Here, in an oncogenic Kras-driven lung cancer mouse model, we found that senescent cells, specifically alveolar macrophages, accumulate early in neoplasia. These macrophages have upregulated expression of p16INK4a and Cxcr1, are distinct from previously defined subsets and are sensitive to senolytic interventions, and suppress cytotoxic T cell responses. Their removal attenuates adenoma development and progression in mice, indicating their tumorigenesis-promoting role. Importantly, we found that alveolar macrophages with these properties increase with normal aging in mouse lung and in human lung adenocarcinoma in situ. Collectively, our study indicates that a subset of tissue-resident macrophages can support neoplastic transformation through altering their local microenvironment, suggesting that therapeutic interventions targeting senescent macrophages may attenuate lung cancer progression during early stages of disease.

Wound healing, fibroblast heterogeneity, and fibrosis

Cell stem cell

2022 Aug 04

Talbott, HE;Mascharak, S;Griffin, M;Wan, DC;Longaker, MT;
PMID: 35931028 | DOI: 10.1016/j.stem.2022.07.006

Fibroblasts are highly dynamic cells that play a central role in tissue repair and fibrosis. However, the mechanisms by which they contribute to both physiologic and pathologic states of extracellular matrix deposition and remodeling are just starting to be understood. In this review article, we discuss the current state of knowledge in fibroblast biology and heterogeneity, with a primary focus on the role of fibroblasts in skin wound repair. We also consider emerging techniques in the field, which enable an increasingly nuanced and contextualized understanding of these complex systems, and evaluate limitations of existing methodologies and knowledge. Collectively, this review spotlights a diverse body of research examining an often-overlooked cell type-the fibroblast-and its critical functions in wound repair and beyond.

Midbrain Peptidergic Neurons Enable Maternal Nesting

SSRN Electronic Journal

2021 Jul 09

Topilko, T;Diaz, S;Pacheco, C;Verny, F;Deleuze, C;Gaspar, P;Renier, N;
| DOI: 10.2139/ssrn.3878409

Optimizing reproductive fitness in mammalian females requires behavioral adaptations during pregnancy. Maternal preparatory nesting is an essential behavior for the survival of the upcoming litter. Brain-wide immediate early gene mapping in mice evoked by nesting sequences revealed that phases of nest construction strongly activate peptidergic neurons of the Edinger-Westphal nucleus in pregnant mice. Genetic ablation, bidirectional neuromodulation, and in vitro and in vivo activity recordings demonstrated that these neurons are essential to modulate arousal before sleep to promote nesting specifically. We show that these neurons enable the behavioral effects of progesterone on preparatory nesting by modulating a broad network of downstream targets. Overall, our study deciphers the role of midbrain neurons in behavioral adaptations during pregnancy vital for reproductive fitness.

Top-down control of conditioned overconsumption is mediated by insular cortex Nos1 neurons

Cell metabolism

2021 Mar 23

Stern, SA;Azevedo, EP;Pomeranz, LE;Doerig, KR;Ivan, VJ;Friedman, JM;
PMID: 33761312 | DOI: 10.1016/j.cmet.2021.03.001

Associative learning allows animals to adapt their behavior in response to environmental cues. For example, sensory cues associated with food availability can trigger overconsumption even in sated animals. However, the neural mechanisms mediating cue-driven non-homeostatic feeding are poorly understood. To study this, we recently developed a behavioral task in which contextual cues increase feeding even in sated mice. Here, we show that an insular cortex to central amygdala circuit is necessary for conditioned overconsumption, but not for homeostatic feeding. This projection is marked by a population of glutamatergic nitric oxide synthase-1 (Nos1)-expressing neurons, which are specifically active during feeding bouts. Finally, we show that activation of insular cortex Nos1 neurons suppresses satiety signals in the central amygdala. The data, thus, indicate that the insular cortex provides top-down control of homeostatic circuits to promote overconsumption in response to learned cues.

Single-cell RNA-seq analysis reveals compartment-specific heterogeneity and plasticity of microglia

iScience

2021 Mar 01

Zheng, J;Ru, W;Adolacion, J;Spurgat, M;Liu, X;Yuan, S;Liang, R;Dong, J;Potter, A;Potter, S;Chen, K;Chen, R;Varadarajan, N;Tang, S;
| DOI: 10.1016/j.isci.2021.102186

Microglia are ubiquitous central nervous system (CNS)-resident macrophages that maintain homeostasis of neural tissues and protect them from pathogen attacks. Yet, their differentiation in different compartments remains elusive. We performed single-cell RNA-seq to compare microglial subtypes in the cortex and the spinal cord. A multi-way comparative analysis was carried out on samples from C57/BL and HIV gp120 transgenic mice at two, four, and eight months of age. The results revealed overlapping but distinct microglial populations in the cortex and the spinal cord. The differential heterogeneity of microglia in these CNS regions was further suggested by their disparity of plasticity in response to life span progression and HIV-1 pathogenic protein gp120. Our findings indicate that microglia in different CNS compartments are adapted to their local environments to fulfill region-specific biological functions.

In situ cytokine gene expression in early stage of virulent Newcastle disease in chickens

Veterinary pathology

2021 Nov 18

Brown, C;Zhang, J;Pantin-Jackwood, M;Dimitrov, K;Ferreira, HL;Suarez, D;
PMID: 34794360 | DOI: 10.1177/03009858211045945

Selected lymphoid and reproductive tissues were examined from groups of 3-week-old chickens and 62-week-old hens that were inoculated choanally and conjunctivally with 106 EID50 of a virulent Newcastle disease virus (NDV) isolate from the California 2018-2020 outbreak, and euthanized at 1, 2, and 3 days postinfection. In the 3-week-old chickens, immunohistochemistry for NDV and for T and B cell lymphocytes, as well as in situ hybridization for IL-1β, IL-6, IFN-γ, and TNF-α revealed extensive expression of IL-1β and IL-6 in lymphoid tissues, often coinciding with NDV antigen. IFN-γ was only expressed infrequently in the same lymphoid tissues, and TNF-α was rarely expressed. T-cell populations initially expanded but by day 3 their numbers were below control levels. B cells underwent a similar expansion but remained elevated in some tissues, notably spleen, cecal tonsils, and cloacal bursa. Cytokine expression in the 62-week-old hens was overall lower than in the 3-week-old birds, and there was more prolonged infiltration of both T and B cells in the older birds. The strong pro-inflammatory cytokine response in young chickens is proposed as the reason for more severe disease.

Comprehensive BCMA Expression Profiling in Adult Normal Human Brain Suggests a Low Risk of On-target Neurotoxicity in BCMA-targeting Multiple Myeloma Therapy

The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society

2022 Feb 22

Marella, M;Yao, X;Carreira, V;Bustamante, MF;Clark, HB;Jackson, CC;Zudaire, E;Schecter, JM;Glover, TD;Shenton, J;Cornax, I;
PMID: 35193424 | DOI: 10.1369/00221554221079579

B-cell maturation antigen (BCMA) is a target for the treatment of multiple myeloma with cytolytic therapies, such as chimeric antigen receptor T-cells or T-cell redirecting antibodies. To better understand the potential for "on-target/off-tumor" toxicity caused by BCMA-targeting cytolytic therapies in the brain, we investigated normal brain BCMA expression. An immunohistochemistry (IHC) assay using the E6D7B commercial monoclonal antibody was applied to 107 formalin-fixed, paraffin-embedded brain samples (cerebrum, basal ganglia, cerebellum, brainstem; 63 unique donors). Although immunoreactivity was observed in a small number of neurons in brain regions including the striatum, thalamus, midbrain, and medulla, this immunoreactivity was considered nonspecific and not reflective of BCMA expression because it was distinct from the membranous and Golgi-like pattern seen in positive control samples, was not replicated when a different IHC antibody (D6 clone) was used, and was not corroborated by in situ hybridization data. Analysis of RNA-sequencing data from 478 donors in the GTEx and Allen BrainSpan databases demonstrated low levels of BCMA RNA expression in the striatum of young donors with levels becoming negligible beyond 30 years of age. We concluded that BCMA protein is not present in normal adult human brain, and therefore on-target toxicity in the brain is unlikely.

CDK7 and MITF repress a transcription program involved in survival and drug tolerance in melanoma

EMBO reports

2021 Jul 23

Berico, P;Cigrang, M;Davidson, G;Braun, C;Sandoz, J;Legras, S;Vokshi, BH;Slovic, N;Peyresaubes, F;Gene Robles, CM;Egly, JM;Compe, E;Davidson, I;Coin, F;
PMID: 34296805 | DOI: 10.15252/embr.202051683

Melanoma cell phenotype switching between differentiated melanocytic and undifferentiated mesenchymal-like states drives metastasis and drug resistance. CDK7 is the serine/threonine kinase of the basal transcription factor TFIIH. We show that dedifferentiation of melanocytic-type melanoma cells into mesenchymal-like cells and acquisition of tolerance to targeted therapies is achieved through chronic inhibition of CDK7. In addition to emergence of a mesenchymal-type signature, we identify a GATA6-dependent gene expression program comprising genes such as AMIGO2 or ABCG2 involved in melanoma survival or targeted drug tolerance, respectively. Mechanistically, we show that CDK7 drives expression of the melanocyte lineage transcription factor MITF that in turn binds to an intronic region of GATA6 to repress its expression in melanocytic-type cells. We show that GATA6 expression is activated in MITF-low melanoma cells of patient-derived xenografts. Taken together, our data show how the poorly characterized repressive function of MITF in melanoma participates in a molecular cascade regulating activation of a transcriptional program involved in survival and drug resistance in melanoma.

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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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