Comparison of rhesus and cynomolgus macaques as an infection model for COVID-19

Nature communications

2021 Feb 24

Salguero, FJ;White, AD;Slack, GS;Fotheringham, SA;Bewley, KR;Gooch, KE;Longet, S;Humphries, HE;Watson, RJ;Hunter, L;Ryan, KA;Hall, Y;Sibley, L;Sarfas, C;Allen, L;Aram, M;Brunt, E;Brown, P;Buttigieg, KR;Cavell, BE;Cobb, R;Coombes, NS;Darby, A;Daykin-Pont, O;Elmore, MJ;Garcia-Dorival, I;Gkolfinos, K;Godwin, KJ;Gouriet, J;Halkerston, R;Harris, DJ;Hender, T;Ho, CMK;Kennard, CL;Knott, D;Leung, S;Lucas, V;Mabbutt, A;Morrison, AL;Nelson, C;Ngabo, D;Paterson, J;Penn, EJ;Pullan, S;Taylor, I;Tipton, T;Thomas, S;Tree, JA;Turner, C;Vamos, E;Wand, N;Wiblin, NR;Charlton, S;Dong, X;Hallis, B;Pearson, G;Rayner, EL;Nicholson, AG;Funnell, SG;Hiscox, JA;Dennis, MJ;Gleeson, FV;Sharpe, S;Carroll, MW;
PMID: 33627662 | DOI: 10.1038/s41467-021-21389-9

A novel coronavirus, SARS-CoV-2, has been identified as the causative agent of the current COVID-19 pandemic. Animal models, and in particular non-human primates, are essential to understand the pathogenesis of emerging diseases and to assess the safety and efficacy of novel vaccines and therapeutics. Here, we show that SARS-CoV-2 replicates in the upper and lower respiratory tract and causes pulmonary lesions in both rhesus and cynomolgus macaques. Immune responses against SARS-CoV-2 are also similar in both species and equivalent to those reported in milder infections and convalescent human patients. This finding is reiterated by our transcriptional analysis of respiratory samples revealing the global response to infection. We describe a new method for lung histopathology scoring that will provide a metric to enable clearer decision making for this key endpoint. In contrast to prior publications, in which rhesus are accepted to be the preferred study species, we provide convincing evidence that both macaque species authentically represent mild to moderate forms of COVID-19 observed in the majority of the human population and both species should be used to evaluate the safety and efficacy of interventions against SARS-CoV-2. Importantly, accessing cynomolgus macaques will greatly alleviate the pressures on current rhesus stocks.

SLC6A20 transporter: a novel regulator of brain glycine homeostasis and NMDAR function

EMBO molecular medicine

2021 Jan 11

Bae, M;Roh, JD;Kim, Y;Kim, SS;Han, HM;Yang, E;Kang, H;Lee, S;Kim, JY;Kang, R;Jung, H;Yoo, T;Kim, H;Kim, D;Oh, H;Han, S;Kim, D;Han, J;Bae, YC;Kim, H;Ahn, S;Chan, AM;Lee, D;Kim, JW;Kim, E;
PMID: 33428810 | DOI: 10.15252/emmm.202012632

Glycine transporters (GlyT1 and GlyT2) that regulate levels of brain glycine, an inhibitory neurotransmitter with co-agonist activity for NMDA receptors (NMDARs), have been considered to be important targets for the treatment of brain disorders with suppressed NMDAR function such as schizophrenia. However, it remains unclear whether other amino acid transporters expressed in the brain can also regulate brain glycine levels and NMDAR function. Here, we report that SLC6A20A, an amino acid transporter known to transport proline based on in vitro data but is understudied in the brain, regulates proline and glycine levels and NMDAR function in the mouse brain. SLC6A20A transcript and protein levels were abnormally increased in mice carrying a mutant PTEN protein lacking the C terminus through enhanced β-catenin binding to the Slc6a20a gene. These mice displayed reduced extracellular levels of brain proline and glycine and decreased NMDAR currents. Elevating glycine levels back to normal ranges by antisense oligonucleotide-induced SLC6A20 knockdown, or the competitive GlyT1 antagonist sarcosine, normalized NMDAR currents and repetitive climbing behavior observed in these mice. Conversely, mice lacking SLC6A20A displayed increased extracellular glycine levels and NMDAR currents. Lastly, both mouse and human SLC6A20 proteins mediated proline and glycine transports, and SLC6A20 proteins could be detected in human neurons. These results suggest that SLC6A20 regulates proline and glycine homeostasis in the brain and that SLC6A20 inhibition has therapeutic potential for brain disorders involving NMDAR hypofunction.

Sphingolipid Biology

sphingolipidbiology.com

2021 Jan 01

Guitton, J;Taouis, M;Benomar, Y;Stunff, HL;

During obesity, the adipokine resistin, like saturated fatty acids, lead to an impairment of glucose homeostasis control by the hypothalamus, a risk factor for type 2 diabetes (T2D). We investigate the involvement of hypothalamic de novo ceramide synthesis in resistin-induced neuronal inflammation and insulin resistance which lead, to glucose intolerance. Using the mHypoA mouse hypothalamic cell line, we analyzed the impact of resistin overexposure on expression levels of enzymes driving ceramide biosynthesis. Intracellular ceramide contents were quantified by lipidomic analysis. Myriocin, a pharmacological inhibitor was used to evaluate de novo ceramide synthesis involvement in resistin-induced neuronal inflammation and defect of insulin signaling. In C57BL6J mice we evaluated the impact of resistin intracerebroventricular (ICV) infusion on hypothalamic expression of enzymes involved in ceramide biosynthesis. We studied the impact of serine palmitoyl-transferase 1 (SPT1) hypothalamic invalidation by adenoviral shRNA strategy on neuronal inflammation and glucose intolerance induced by resistin ICV infusion. In mHypoA cells, we show that resistin treatment increases ceramide contents and expression levels of enzymes driving de novo ceramide synthesis. Resistin overexposure induces inflammation and inhibits insulin signaling in a de novo ceramide synthesis-dependent manner. In mice, resistin ICV infusion upregulates hypothalamic gene expression of enzymes driving de novo ceramide biosynthesis. In vivo invalidation of hypothalamic SPT1 counteracts resistin-induced inflammation and prevents glucose intolerance. These findings reveal de novo ceramide synthesis as a new regulatory pathway of neuronal inflammation and insulin resistance that drive resistin-induced glucose intolerance. This pathway may constitute a breakthrough to overcome obesity and T2D occurrence.

Assessment of Treatment-Relevant Immune Biomarkers in Psoriasis and Atopic Dermatitis: Toward Personalized Medicine in Dermatology

The Journal of investigative dermatology

2023 Jun 20

Mortlock, RD;Ma, EC;Cohen, JM;Damsky, W;
PMID: 37341663 | DOI: 10.1016/j.jid.2023.04.005

Immunologically targeted therapies have revolutionized the treatment of inflammatory dermatoses, including atopic dermatitis and psoriasis. Although immunologic biomarkers hold great promise for personalized classification of skin disease and tailored therapy selection, there are no approved or widely used approaches for this in dermatology. This review summarizes the translational immunologic approaches to measuring treatment-relevant biomarkers in inflammatory skin conditions. Tape strip profiling, microneedle-based biomarker patches, molecular profiling from epidermal curettage, RNA in situ hybridization tissue staining, and single-cell RNA sequencing have been described. We discuss the advantages and limitations of each and open questions for the future of personalized medicine in inflammatory skin disease.

The Use of Single Cell RNA-seq and Spatial Transcriptomics in Understanding the Pathogenesis and Treatment of Skin Diseases

JID Innovations

2023 Mar 01

Houser, A;Kazmi, A;Nair, A;Ji, A;
| DOI: 10.1016/j.xjidi.2023.100198

The development of multi-omic profiling tools has rapidly expanded in recent years, along with their use in profiling skin tissues in various contexts, including dermatologic diseases. Among these tools, single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics (ST) have emerged as widely adopted and powerful assays for elucidating key cellular components and their spatial arrangement within skin disease. Here, we review recent biological insights gained from the use of scRNA-seq and ST, and the advantages of combining both, for profiling skin disease, including aberrant wound healing, inflammatory skin diseases, and cancer. We discuss the role of scRNA-seq and ST for improving skin disease treatments and moving towards the goal of achieving precision medicine in dermatology, whereby patients can be optimally matched to treatments that maximize therapeutic response.

A new method for the sampling and preservation of placental specimens in low-resource settings for the identification of P. falciparum and analysis of nucleic acids

Journal of histotechnology

2022 Jun 29

Potoczak, PS;Strassmann, BI;Vincenz, C;
PMID: 35766215 | DOI: 10.1080/01478885.2022.2088191

Collection, preservation, and shipment of histological specimens in low-resource settings is challenging. We present a novel method that achieved excellent preservation of placental specimens from rural Mali by using formalin fixation, ethanol dehydration, and long-term storage in a solar-powered freezer. Sample preservation success was 92%, permitting evaluation of current and past malaria infection, anemia, placental maturity, and inflammation. Using RNAscope hybridization we were able to visualize cell-specific gene expression patterns in the formalin-fixed paraffin-embedded (FFPE) specimens. Additionally, our method entailed mirrored sampling from the two cut faces of a cotyledon, one for the FFPE workflows and the other for storage in RNAlater and RNA-seq.

Sigh Generation in Prebötzinger Complex

SSRN Electronic Journal

2022 May 28

Cui, Y;Bondarenko, E;Thörn Perez, C;Chiu, D;Feldman, J;
| DOI: 10.2139/ssrn.4117921

We elucidated neural mechanisms underlying sighing. Photostimulation of parafacial (pF) neuromedin B ( NMB) or gastrin releasing peptide (GRP) or preBötC NMBR or GRPR neurons elicited ectopic sighs with latency inversely related to time from the preceding endogenous sigh. Of particular note, ectopic sighs could be produced without involvement of these peptides or their receptors in preBötC. Moreover, chemogenetic or optogenetic activation of preBötC SST neurons induced sighing, even in the presence of NMBR or GRPR antagonists. We propose that an increase in the excitability of preBötC NMBR or GRPR neurons not requiring activation of their peptide receptors activates partially overlapping pathways to generate sighs, and that preBötC SST neurons are a downstream element in the sigh generation circuit that converts normal breaths into sighs.

Acute Mesenteric Ischemia in Patients with COVID-19: Review of the literature

Journal of the National Medical Association

2021 Dec 29

Chen, C;Li, YW;Shi, PF;Qian, SX;
PMID: 34973847 | DOI: 10.1016/j.jnma.2021.12.003

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global health emergency. In addition to common respiratory symptoms, some patients with COVID-19 infections may experience a range of extra-pulmonary manifestations, such as digestive system involvement. Patients with COVID-19 have been reported to suffer from acute mesenteric ischemia (AMI) that is associated with disease-related severity and mortality. However, in the context of COVID-19, the exact cause of AMI has yet to be clearly defined. This review provides a comprehensive overview of the available data and elucidates the possible underlying mechanisms linking COVID-19 to AMI, in addition to highlighting therapeutic approaches for clinicians. Finally, given the severe global impact of COVID-19, we emphasize the importance of coordinated vaccination programs.

The Long and the Small Collide: LncRNAs and Small Heterodimer Partner (SHP) in Liver Disease

Molecular and cellular endocrinology

2021 Mar 26

Wu, J;Nagy, LE;Wang, L;
PMID: 33781837 | DOI: 10.1016/j.mce.2021.111262

Long non-coding RNAs (lncRNAs) are a large and diverse class of RNA molecules that are transcribed but not translated into proteins, with a length of more than 200 nucleotides. LncRNAs are involved in gene expression and regulation. The abnormal expression of lncRNAs is associated with disease pathogenesis. Small heterodimer partner (SHP, NR0B2) is a unique orphan nuclear receptor that plays a pivotal role in many biological processes by acting as a transcriptional repressor. In this review, we present the critical roles of SHP and summarize recent findings demonstrating the regulation between lncRNAs and SHP in liver disease.

Genetic deletion of the ghrelin receptor (GHSR) impairs growth and blunts endocrine response to fasting in Ghsr-IRES-Cre mice

Molecular Metabolism

2021 Mar 01

Peris-Sampedro, F;Stoltenborg, I;Le May, M;Zigman, J;Adan, R;Dickson, S;
| DOI: 10.1016/j.molmet.2021.101223

Insertion of the _IRES-Cre_ cassette into the 3’-untranslated region of the _Ghsr_ gene led to a gene-dosage GHSR depletion in the Arc. Whereas heterozygotes remained ghrelin-responsive and more closely resembled wild-types, ghrelin had reduced orexigenic efficacy and failed to induce Arc Fos expression in homozygous littermates. Homozygotes had a lower body weight accompanied by a shorter body length, less fat tissue content, altered bone parameters, and lower insulin-like growth factor-1 levels compared to wild-type and heterozygous littermates. Additionally, both heterozygous and homozygous _Ghsr-IRES-Cre_ mice lacked the usual fasting-induced rise in growth hormone (GH) and displayed an exaggerated drop in blood glucose and insulin compared to wild-types. Unexpectedly, fasting acyl-ghrelin levels were allele-dependently increased.

Temperature and species-dependent regulation of browning in retrobulbar fat

Scientific reports

2021 Feb 04

Rajaii, F;Kim, DW;Pan, J;Mahoney, NR;Eberhart, CG;Qian, J;Blackshaw, S;
PMID: 33542375 | DOI: 10.1038/s41598-021-82672-9

Retrobulbar fat deposits surround the posterior retina and optic nerve head, but their function and origin are obscure. We report that mouse retrobulbar fat is a neural crest-derived tissue histologically and transcriptionally resembles interscapular brown fat. In contrast, human retrobulbar fat closely resembles white adipose tissue. Retrobulbar fat is also brown in other rodents, which are typically housed at temperatures below thermoneutrality, but is white in larger animals. We show that retrobulbar fat in mice housed at thermoneutral temperature show reduced expression of the brown fat marker Ucp1, and histological properties intermediate between white and brown fat. We conclude that retrobulbar fat can potentially serve as a site of active thermogenesis, that this capability is both temperature and species-dependent, and that this may facilitate regulation of intraocular temperature.

Neural mechanisms of comforting: Prosocial touch and stress buffering

Hormones and behavior

2023 Jun 08

Lim, KY;Hong, W;
PMID: 37301130 | DOI: 10.1016/j.yhbeh.2023.105391

Comforting is a crucial form of prosocial behavior that is important for maintaining social unity and improving the physical and emotional well-being of social species. It is often expressed through affiliative social touch toward someone in distress, providing relief for their distressed state. In the face of increasing global distress, these actions are paramount to the continued improvement of individual welfare and the collective good. Understanding the neural mechanisms responsible for promoting actions focused on benefitting others is particularly important and timely. Here, we review prosocial comforting behavior, emphasizing synthesizing recent studies carried out using rodent models. We discuss its underlying behavioral expression and motivations, and then explore both the neurobiology of prosocial comforting in a helper animal and the neurobiology of stress relief following social touch in a recipient as part of a feedback loop interaction.

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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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