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Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling in mice

Nature communications

2021 Sep 06

Bisht, K;Okojie, KA;Sharma, K;Lentferink, DH;Sun, YY;Chen, HR;Uweru, JO;Amancherla, S;Calcuttawala, Z;Campos-Salazar, AB;Corliss, B;Jabbour, L;Benderoth, J;Friestad, B;Mills, WA;Isakson, BE;Tremblay, MÈ;Kuan, CY;Eyo, UB;
PMID: 34489419 | DOI: 10.1038/s41467-021-25590-8

Microglia are brain-resident immune cells with a repertoire of functions in the brain. However, the extent of their interactions with the vasculature and potential regulation of vascular physiology has been insufficiently explored. Here, we document interactions between ramified CX3CR1 + myeloid cell somata and brain capillaries. We confirm that these cells are bona fide microglia by molecular, morphological and ultrastructural approaches. Then, we give a detailed spatio-temporal characterization of these capillary-associated microglia (CAMs) comparing them with parenchymal microglia (PCMs) in their morphological activities including during microglial depletion and repopulation. Molecularly, we identify P2RY12 receptors as a regulator of CAM interactions under the control of released purines from pannexin 1 (PANX1) channels. Furthermore, microglial elimination triggered capillary dilation, blood flow increase, and impaired vasodilation that were recapitulated in P2RY12-/- and PANX1-/- mice suggesting purines released through PANX1 channels play important roles in activating microglial P2RY12 receptors to regulate neurovascular structure and function.

Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance

Nature communications

2021 Sep 06

Cui, M;Atmanli, A;Morales, MG;Tan, W;Chen, K;Xiao, X;Xu, L;Liu, N;Bassel-Duby, R;Olson, EN;
PMID: 34489413 | DOI: 10.1038/s41467-021-25653-w

Following injury, cells in regenerative tissues have the ability to regrow. The mechanisms whereby regenerating cells adapt to injury-induced stress conditions and activate the regenerative program remain to be defined. Here, using the mammalian neonatal heart regeneration model, we show that Nrf1, a stress-responsive transcription factor encoded by the Nuclear Factor Erythroid 2 Like 1 (Nfe2l1) gene, is activated in regenerating cardiomyocytes. Genetic deletion of Nrf1 prevented regenerating cardiomyocytes from activating a transcriptional program required for heart regeneration. Conversely, Nrf1 overexpression protected the adult mouse heart from ischemia/reperfusion (I/R) injury. Nrf1 also protected human induced pluripotent stem cell-derived cardiomyocytes from doxorubicin-induced cardiotoxicity and other cardiotoxins. The protective function of Nrf1 is mediated by a dual stress response mechanism involving activation of the proteasome and redox balance. Our findings reveal that the adaptive stress response mechanism mediated by Nrf1 is required for neonatal heart regeneration and confers cardioprotection in the adult heart.

Single-cell transcriptomics of suprachiasmatic nuclei reveal a Prokineticin-driven circadian network

The EMBO journal

2021 Sep 06

Morris, EL;Patton, AP;Chesham, JE;Crisp, A;Adamson, A;Hastings, MH;
PMID: 34487375 | DOI: 10.15252/embj.2021108614

Circadian rhythms in mammals are governed by the hypothalamic suprachiasmatic nucleus (SCN), in which 20,000 clock cells are connected together into a powerful time-keeping network. In the absence of network-level cellular interactions, the SCN fails as a clock. The topology and specific roles of its distinct cell populations (nodes) that direct network functions are, however, not understood. To characterise its component cells and network structure, we conducted single-cell sequencing of SCN organotypic slices and identified eleven distinct neuronal sub-populations across circadian day and night. We defined neuropeptidergic signalling axes between these nodes, and built neuropeptide-specific network topologies. This revealed their temporal plasticity, being up-regulated in circadian day. Through intersectional genetics and real-time imaging, we interrogated the contribution of the Prok2-ProkR2 neuropeptidergic axis to network-wide time-keeping. We showed that Prok2-ProkR2 signalling acts as a key regulator of SCN period and rhythmicity and contributes to defining the network-level properties that underpin robust circadian co-ordination. These results highlight the diverse and distinct contributions of neuropeptide-modulated communication of temporal information across the SCN.

Tick-Borne Encephalitis Virus (TBEV) Infection in Two Horses

Viruses

2021 Sep 06

Conze, TM;Bagó, Z;Revilla-Fernández, S;Schlegel, J;Goehring, LS;Matiasek, K;
PMID: 34578356 | DOI: 10.3390/v13091775

A final diagnosis in a horse with clinical signs of encephalopathy can be challenging despite the use of extensive diagnostics. Clinical signs are often not pathognomonic and need to be interpreted in combination with (specific) laboratory results and epidemiological data of the geographical region of the origin of the case(s). Here we describe the diagnostic pathway of tick-borne encephalitis virus infection in two horses using established molecular diagnostic methods and a novel in situ hybridization technique to differentiate between regionally important/emerging diseases for central Europe: (i) hepatoencephalopathy, (ii) Borna disease virus, and (iii) West Nile virus infections.

Transient acquisition of cross-species infectivity during the evolution of SARS-CoV-2

National Science Review

2021 Sep 04

Chen, Q;Huang, X;Sun, M;Li, R;Gu, H;Tian, Y;Zhang, R;Luo, D;Zhou, C;Zhang, Y;Cao, T;Zhang, N;Deng, Y;Li, X;Qin, C;
| DOI: 10.1093/nsr/nwab167

Laboratory mice are susceptible to infection with the SARS-CoV-2 501Y.V2 variant. (A) Body weight changes in nine-month-old female BALB/c mice infected intranasally with 501Y.V2 or IME-BJ05 at a dose of 1.2 × 104 pfu per mouse. _n_ = 5. (B) Tissue distribution of SARS-CoV-2 sgRNA. Each tissue and serum sample was subjected to viral sgRNA copy analysis by real-time qPCR. The dotted lines denote the detection limit (_n_ = 3). (C) ISH assay for viral RNA in lung tissues from mice infected with 501Y.V2 or treated with PBS (mock) on day 3 post infection. Positive signals are shown in brown. (D) Immunostaining of lung tissues with a SARS-CoV-2 N protein-specific mAb. (E) Gross necropsy and hematoxylin and eosin (H&E) staining of lung tissue sections from mice infected with 501Y.V2 or treated with PBS (mock) on day 3 post infection. (F) Time-resolved frequency distribution of SARS-CoV-2 variants with or without the N501Y mutation (based on the Nextstrain project). The variants with the N501Y mutation are indicated in blue, and mice that can be infected with these variants are shown in an inverted position.

Shifting Gears in Precision Oncology-Challenges and Opportunities of Integrative Data Analysis

Biomolecules

2021 Sep 04

Noh, KW;Buettner, R;Klein, S;
PMID: 34572523 | DOI: 10.3390/biom11091310

For decades, research relating to modification of host immunity towards antitumor response activation has been ongoing, with the breakthrough discovery of immune-checkpoint blockers. Several biomarkers with potential predictive value have been reported in recent studies for these novel therapies. However, with the plethora of therapeutic options existing for a given cancer entity, modern oncology is now being confronted with multifactorial interpretation to devise "the best therapy" for the individual patient. Into the bargain come the multiverse guidelines for established and emerging diagnostic biomarkers, as well as the complex interplay between cancer cells and tumor microenvironment, provoking immense challenges in the therapy decision-making process. Through this review, we present various molecular diagnostic modalities and techniques, such as genomics, immunohistochemistry and quantitative image analysis, which have the potential of becoming powerful tools in the development of an optimal treatment regime when analogized with patient characteristics. We will summarize the underlying complexities of these methods and shed light upon the necessary considerations and requirements for data integration. It is our hope to provide compelling evidence to emphasize on the need for inclusion of integrative data analysis in modern cancer therapy, and thereupon paving a path towards precision medicine and better patient outcomes.

The integrated stress response contributes to tRNA synthetase-associated peripheral neuropathy

Science (New York, N.Y.)

2021 Sep 03

Spaulding, EL;Hines, TJ;Bais, P;Tadenev, ALD;Schneider, R;Jewett, D;Pattavina, B;Pratt, SL;Morelli, KH;Stum, MG;Hill, DP;Gobet, C;Pipis, M;Reilly, MM;Jennings, MJ;Horvath, R;Bai, Y;Shy, ME;Alvarez-Castelao, B;Schuman, EM;Bogdanik, LP;Storkebaum, E;Burgess, RW;
PMID: 34516839 | DOI: 10.1126/science.abb3414

[Figure: see text].

The anti-fibrotic drug pirfenidone inhibits liver fibrosis by targeting the small oxidoreductase glutaredoxin-1

Science advances

2021 Sep 03

Xi, Y;Li, Y;Xu, P;Li, S;Liu, Z;Tung, HC;Cai, X;Wang, J;Huang, H;Wang, M;Xu, M;Ren, S;Li, S;Zhang, M;Lee, YJ;Huang, L;Yang, D;He, J;Huang, Z;Xie, W;
PMID: 34516906 | DOI: 10.1126/sciadv.abg9241

[Figure: see text].

Prrx1b restricts fibrosis and promotes Nrg1-dependent cardiomyocyte proliferation during zebrafish heart regeneration

Development (Cambridge, England)

2021 Sep 03

de Bakker, DEM;Bouwman, M;Dronkers, E;Simões, FC;Riley, PR;Goumans, MJ;Smits, AM;Bakkers, J;
PMID: 34486669 | DOI: 10.1242/dev.198937

Fibroblasts are activated to repair the heart following injury. Fibroblast activation in the mammalian heart leads to a permanent fibrotic scar that impairs cardiac function. In other organisms, like zebrafish, cardiac injury is followed by transient fibrosis and scar-free regeneration. The mechanisms that drive scarring versus scar-free regeneration are not well understood. Here we show that the homeo-box containing transcription factor Prrx1b is required for scar-free regeneration of the zebrafish heart as the loss of Prrx1b results in excessive fibrosis and impaired cardiomyocyte proliferation. Through lineage tracing and single-cell RNA-sequencing we find that Prrx1b is activated in epicardial-derived cells (EPDCs) where it restricts TGF-β ligand expression and collagen production. Furthermore, through combined in vitro experiments in human fetal EPDCs and in vivo rescue experiments in zebrafish, we conclude that Prrx1 stimulates Nrg1 expression and promotes cardiomyocyte proliferation. Collectively, these results indicate that Prrx1 is a key transcription factor that balances fibrosis and regeneration in the injured zebrafish heart.

The Orexigenic Force of Olfactory Palatable Food Cues in Rats

Nutrients

2021 Sep 03

Peris-Sampedro, F;Stoltenborg, I;Le May, MV;Sole-Navais, P;Adan, RAH;Dickson, SL;
PMID: 34578979 | DOI: 10.3390/nu13093101

Environmental cues recalling palatable foods motivate eating beyond metabolic need, yet the timing of this response and whether it can develop towards a less palatable but readily available food remain elusive. Increasing evidence indicates that external stimuli in the olfactory modality communicate with the major hub in the feeding neurocircuitry, namely the hypothalamic arcuate nucleus (Arc), but the neural substrates involved have been only partially uncovered. By means of a home-cage hidden palatable food paradigm, aiming to mimic ubiquitous exposure to olfactory food cues in Western societies, we investigated whether the latter could drive the overeating of plain chow in non-food-deprived male rats and explored the neural mechanisms involved, including the possible engagement of the orexigenic ghrelin system. The olfactory detection of a familiar, palatable food impacted upon meal patterns, by increasing meal frequency, to cause the persistent overconsumption of chow. In line with the orexigenic response observed, sensing the palatable food in the environment stimulated food-seeking and risk-taking behavior, which are intrinsic components of food acquisition, and caused active ghrelin release. Our results suggest that olfactory food cues recruited intermingled populations of cells embedded within the feeding circuitry within the Arc, including, notably, those containing the ghrelin receptor. These data demonstrate the leverage of ubiquitous food cues, not only for palatable food searching, but also to powerfully drive food consumption in ways that resonate with heightened hunger, for which the orexigenic ghrelin system is implicated.

Spatial mapping of the tumor immune microenvironment

Engineering Technologies and Clinical Translation

2021 Sep 03

Wu, Y;Pagacz, J;Emery, S;Kron, S;Lee, S;
| DOI: 10.1016/B978-0-323-90949-5.00009-7

To replace one-size-fits-all cancer immunotherapy with personalized treatment, biomarkers of response and resistance as well as assays to evaluate them in each patient are essential. Among likely determinants of response, the spatial locations and activation states of the immune infiltrate appear critical. Current clinical methods for tissue analysis such as immunohistochemistry are poorly matched to the heterogeneity of the tumor immune microenvironment (TIME). However, multiple tools for analysis of the TIME can now image panels of biomarkers in a single experiment, permit deep profiling to measure dozens of immune features in each sample, and/or facilitate unbiased multiomic analysis at high spatial resolution. Several assays are commercialized with some nearing clinical adoption. In this chapter, we present a broad overview of established and emerging technologies that enable multiplexed detection and spatial mapping of cellular and molecular features of the TIME, highlighting advantages and disadvantages as well as opportunities for future development.

Functional impairment of HIV-specific CD8+ T cells precedes aborted spontaneous control of viremia

Immunity

2021 Sep 02

Collins, DR;Urbach, JM;Racenet, ZJ;Arshad, U;Power, KA;Newman, RM;Mylvaganam, GH;Ly, NL;Lian, X;Rull, A;Rassadkina, Y;Yanez, AG;Peluso, MJ;Deeks, SG;Vidal, F;Lichterfeld, M;Yu, XG;Gaiha, GD;Allen, TM;Walker, BD;
PMID: 34496223 | DOI: 10.1016/j.immuni.2021.08.007

Spontaneous control of HIV infection has been repeatedly linked to antiviral CD8+ T cells but is not always permanent. To address mechanisms of durable and aborted control of viremia, we evaluated immunologic and virologic parameters longitudinally among 34 HIV-infected subjects with differential outcomes. Despite sustained recognition of autologous virus, HIV-specific proliferative and cytolytic T cell effector functions became selectively and intrinsically impaired prior to aborted control. Longitudinal transcriptomic profiling of functionally impaired HIV-specific CD8+ T cells revealed altered expression of genes related to activation, cytokine-mediated signaling, and cell cycle regulation, including increased expression of the antiproliferative transcription factor KLF2 but not of genes associated with canonical exhaustion. Lymphoid HIV-specific CD8+ T cells also exhibited poor functionality during aborted control relative to durable control. Our results identify selective functional impairment of HIV-specific CD8+ T cells as prognostic of impending aborted HIV control, with implications for clinical monitoring and immunotherapeutic strategies.

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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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