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Oral Human Papillomavirus Infection and Head and Neck Squamous Cell Carcinoma in Rural Northwest Cameroon.

SAGE Publications (2019)

2019 Jan 04

Rettig EM, Gooi Z, Bardin R, Bogale M, Rooper L, Acha E, Koch WM.
| DOI: 10.1177/2473974X18818415

Abstract Objective. Oral human papillomavirus (HPV) infection is the precursor for a growing subset of oropharyngeal squamous cell carcinomas (OPSCCs) in the developed world. This study was designed to characterize oral HPV infection and OPSCC in a region with high rates of HPV-driven cervical cancer. Study Design. Cross-sectional cohort study, retrospective case series. Setting. Northwest Cameroon referral hospital. Subjects and Methods. Individuals infected with human immunodeficiency virus attending an outpatient clinic were evaluated for oral HPV infection with oral swabs or rinses that were tested for 51 HPV types. HNSCCs diagnosed and/or treated at the same hospital from 2011 to 2017 were retrospectively reviewed to ascertain demographic and tumor characteristics, and available OPSCCs were tested for HPV. Results. The oral HPV infection study population comprised 101 participants. Most (69%) were female and neversmokers (84%). Participants had median 4 lifetime sexual partners (interquartile range, 3-7; range, 1-100). Five participants (5%) had oral HPV infection; one had 2 HPV types. HPV types detected were HPV68 (n = 2), HPV82 (n = 2), HPV32 (n = 1), and unknown (n = 1). No significant demographic or behavioral differences were detected among individuals with vs without oral HPV infection. OPSCCs comprised just 8% (n = 11) of 131 HNSCCs in the retrospective study population. Two of 7 OPSCCs were HPV positive. Conclusion. The low prevalence of OPSCC observed in northwest Cameroon together with the rarity of oral HPV infection suggests low rates of HPV-driven oropharyngeal carcinogenesis in the region. Future research should examine how geographic differences in oral HPV infection are influenced by cultural norms and affect HPV-OPSCC epidemiology

Single-nucleus and single-cell transcriptomes compared in matched cortical cell types.

PLoS One. 2018 Dec 26;13(12):e0209648.

2018 Dec 26

Bakken TE, Hodge RD, Miller JA, Yao Z, Nguyen TN, Aevermann B, Barkan E, Bertagnolli D, Casper T, Dee N, Garren E, Goldy J, Graybuck LT, Kroll M, Lasken RS, Lathia K, Parry S, Rimorin C, Scheuermann RH, Schork NJ, Shehata SI, Tieu M, Phillips JW, Bernard A, Smith KA, Zeng H, Lein ES, Tasic B.
PMID: 30586455 | DOI: 10.1371/journal.pone.0209648

Transcriptomic profiling of complex tissues by single-nucleus RNA-sequencing (snRNA-seq) affords some advantages over single-cell RNA-sequencing (scRNA-seq). snRNA-seq provides less biased cellular coverage, does not appear to suffer cell isolation-based transcriptional artifacts, and can be applied to archived frozen specimens. We used well-matched snRNA-seq and scRNA-seq datasets from mouse visual cortex to compare cell type detection. Although more transcripts are detected in individual whole cells (~11,000 genes) than nuclei (~7,000 genes), we demonstrate that closely related neuronal cell types can be similarly discriminated with both methods if intronic sequences are included in snRNA-seq analysis. We estimate that the nuclear proportion of total cellular mRNA varies from 20% to over 50% for large and small pyramidal neurons, respectively. Together, these results illustrate the high information content of nuclear RNA for characterization of cellular diversity in brain tissues.

The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy.

Hum Mol Genet. 2019 Jan 2.

2018 Jan 02

Tona R, Chen W, Nakano Y, Reyes LD, Petralia RS, Wang YX, Starost MF, Wafa TT, Morell RJ, Cravedi KD, Hoffmann J, Miyoshi T, Munasinghe JP, Fitzgerald TS, Chudasama Y, Omori K, Pierpaoli C, Banfi B, Dong L, Belyantseva IA, Friedman TB.
PMID: 30602030 | DOI: 10.1093/hmg/ddy445

Epilepsy, deafness, onychodystrophy, osteodystrophy and intellectual disability are associated with a spectrum of mutations of human TBC1D24. The mechanisms underlying TBC1D24-associated disorders and the functions of TBC1D24 are not well understood. Using CRISPR-Cas9 genome editing, we engineered a mouse with a premature translation stop codon equivalent to human S324Tfs*3, a recessive mutation of TBC1D24 associated with early infantile epileptic encephalopathy (EIEE). Homozygous S324Tfs*3 mice have normal auditory and vestibular functions but show an abrupt onset of spontaneous seizures at postnatal day 15 recapitulating human EIEE. The S324Tfs*3 variant is located in an alternatively spliced micro-exon encoding six perfectly conserved amino acids incorporated postnatally into TBC1D24 protein due to a micro-exon utilization switch. During embryonic and early postnatal development, S324Tfs*3 homozygotes produce predominantly the shorter wild-type TBC1D24 protein isoform that omits the six residues encoded by the micro-exon. S324Tfs*3 homozygotes show an abrupt onset of seizures at P15 that correlates with a developmental switch to utilization of the micro-exon. A mouse deficient for alternative splice factor SRRM3 impairs incorporation of the Tbc1d24 micro-exon. Wild-type Tbc1d24 mRNA is abundantly expressed in the hippocampus using RNAscope in situ hybridization. Immunogold electron microscopy using a TBC1D24-specific antibody revealed that TBC1D24 is associated with clathrin-coated vesicles and synapses of hippocampal neurons, suggesting a crucial role of TBC1D24 in vesicle trafficking important for neuronal signal transmission. This is the first characterization of a mouse model of human TBC1D24-associated EIEE that can now be used to screen for antiepileptogenic drugs ameliorating TBCID24 seizure disorders.

Microtubule-Driven Stress Granule Dynamics Regulate Inhibitory Immune Checkpoint Expression in T Cells.

Cell Rep. 2019 Jan 2;26(1):94-107.e7.

2019 Jan 02

Franchini DM, Lanvin O, Tosolini M, Patras de Campaigno E, Cammas A, Péricart S, Scarlata CM, Lebras M, Rossi C, Ligat L, Pont F, Arimondo PB, Laurent C, Ayyoub M, Despas F, Lapeyre-Mestre M, Millevoi S, Fournié JJ.
PMID: 30605689 | DOI: 10.1016/j.celrep.2018.12.014

Despite the clinical success of blocking inhibitory immune checkpoint receptors such as programmed cell death-1 (PD-1) in cancer, the mechanisms controlling the expression of these receptors have not been fully elucidated. Here, we identify a post-transcriptional mechanism regulating PD-1 expression in T cells. Upon activation, the PDCD1 mRNA and ribonucleoprotein complexes coalesce into stress granules that require microtubules and the kinesin 1 molecular motor to proceed to translation. Hence, PD-1 expression is highly sensitive to microtubule or stress granule inhibitors targeting this pathway. Evidence from healthy donors and cancer patients reveals a common regulation for the translation of CTLA4, LAG3, TIM3, TIGIT, and BTLA but not of the stimulatory co-receptors OX40, GITR, and 4-1BB mRNAs. In patients, disproportionality analysis of immune-related adverse events for currently used microtubule drugs unveils a significantly higher risk of autoimmunity. Our findings reveal a fundamental mechanism of immunoregulation with great importance in cancer immunotherapy.

Progress in Brain Cannabinoid CB2 Receptor Research: From Genes to Behavior.

Neurosci Biobehav Rev. 2019 Jan 3.

2018 Jan 03

Jordan CJ, Xi ZX.
PMID: 30611802 | DOI: 10.1016/j.neubiorev.2018.12.026

The type 2 cannabinoid receptor (CB2R) was initially regarded as a peripheral cannabinoid receptor. However, recent technological advances in gene detection, alongside the availability of transgenic mouse lines, indicate that CB2Rs are expressed in both neurons and glial cells in the brain under physiological and pathological conditions, and are involved in multiple functions at cellular and behavioral levels. Brain CB2Rs are inducible and neuroprotective via up-regulation in response to various insults, but display species differences in gene and receptor structures, CB2R expression, and receptor responses to various CB2R ligands. CB2R transcripts also differ between the brain and spleen. In the brain, CB2A is the major transcript isoform, while CB2A and CB2B transcripts are present at higher levels in the spleen. These new findings regarding brain versus spleen CB2R isoforms may in part explain why early studies failed to detect brain CB2R gene expression. Here, we review evidence supporting the expression and function of brain CB2R from gene and receptor levels to cellular functioning, neural circuitry, and animal behavior.

High-throughput single-molecule RNA imaging analysis reveals heterogeneous responses of cardiomyocytes to hemodynamic overload.

J Mol Cell Cardiol. 2019 Jan 3.

2019 Jan 03

Satoh M, Nomura S, Harada M, Yamaguchi T, Ko T, Sumida T, Toko H, Naito AT, Takeda N, Tobita T, Fujita T, Ito M, Fujita K, Ishizuka M, Kariya T, Akazawa H, Kobayashi Y, Morita H, Takimoto E, Aburatani H, Komuro I.
PMID: 30611794 | DOI: 10.1016/j.yjmcc.2018.12.018

Abstract BACKGROUND: The heart responds to hemodynamic overload through cardiac hypertrophy and activation of the fetal gene program. However, these changes have not been thoroughly examined in individual cardiomyocytes, and the relation between cardiomyocyte size and fetal gene expression remains elusive. We established a method of high-throughput single-molecule RNA imaging analysis of in vivo cardiomyocytes and determined spatial and temporal changes during the development of heart failure. METHODS AND RESULTS: We applied three novel single-cell analysis methods, namely, single-cell quantitative PCR (sc-qPCR), single-cell RNA sequencing (scRNA-seq), and single-molecule fluorescence in situ hybridization (smFISH). Isolated cardiomyocytes and cross sections from pressure overloaded murine hearts after transverse aortic constriction (TAC) were analyzed at an early hypertrophy stage (2 weeks, TAC2W) and at a late heart failure stage (8 weeks, TAC8W). Expression of myosin heavy chain β (Myh7), a representative fetal gene, was induced in some cardiomyocytes in TAC2W hearts and in more cardiomyocytes in TAC8W hearts. Expression levels of Myh7 varied considerably among cardiomyocytes. Myh7-expressing cardiomyocytes were significantly more abundant in the middle layer, compared with the inner or outer layers of TAC2W hearts, while such spatial differences were not observed in TAC8W hearts. Expression levels of Myh7 were inversely correlated with cardiomyocyte size and expression levels of mitochondria-related genes. CONCLUSIONS: We developed a new image-analysis pipeline to allow automated and unbiased quantification of gene expression at the single-cell level and determined the spatial and temporal regulation of heterogenous Myh7 expression in cardiomyocytes after pressure overload.

Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis.

Cell Metab. 2018 Dec 28.

2019 Jan 03

Ogrodnik M, Zhu Y, Langhi LGP, Tchkonia T, Krüger P, Fielder E, Victorelli S, Ruswhandi RA, Giorgadze N, Pirtskhalava T, Podgorni O, Enikolopov G, Johnson KO, Xu M, Inman C, Schafer M, Weigl M, Ikeno Y, Burns TC, Passos JF, von Zglinicki T, Kirkland JL, Jurk D.
PMID: 30612898 | DOI: 10.1016/j.cmet.2018.12.008

Cellular senescence entails a stable cell-cycle arrest and a pro-inflammatory secretory phenotype, which contributes to aging and age-related diseases. Obesity is associated with increased senescent cell burden and neuropsychiatric disorders, including anxiety and depression. To investigate the role of senescence in obesity-related neuropsychiatric dysfunction, we used the INK-ATTAC mouse model, from which p16Ink4a-expressing senescent cells can be eliminated, and senolytic drugs dasatinib and quercetin. We found that obesity results in the accumulation of senescent glial cells in proximity to the lateral ventricle, a region in which adult neurogenesis occurs. Furthermore, senescent glial cells exhibit excessive fat deposits, a phenotype we termed “accumulation of lipids in senescence.” Clearing senescent cells from high fat-fed or leptin receptor-deficient obese mice restored neurogenesis and alleviated anxiety-related behavior. Our study provides proof-of-concept evidence that senescent cells are major contributors to obesity-induced anxiety and that senolytics are a potential new therapeutic avenue for treating neuropsychiatric disorders.

In Situ Hybridization Analysis of Long Non-coding RNAs MALAT1 and HOTAIR in Gastroenteropancreatic Neuroendocrine Neoplasms.

Endocr Pathol. 2019 Jan 2.

2019 Jan 02

Chu YH, Hardin H, Eickhoff J, Lloyd RV.
PMID: 30600442 | DOI: 10.1007/s12022-018-9564-1

Recent studies suggest onco-regulatory roles for two long non-coding RNAs (lncRNAs), MALAT1 and HOTAIR, in various malignancies; however, these lncRNAs have not been previously examined in neuroendocrine neoplasms (NENs) of gastroenteropancreatic origins (GEP-NENs). In this study, we evaluated the expressions and prognostic significance of MALAT1 and HOTAIR in 83 cases of GEP-NENs (60 grade 1, 17 grade 2, and 6 grade 3 tumors) diagnosed during the years 2005-2017. Expression levels of MALAT1 and HOTAIR were digitally quantitated in assembled tissue microarray slides labeled by chromogenic in situ hybridization (ISH) using InForm 1.4.0 software. We found diffuse nuclear expression of both HOTAIR and MALAT1 in all primary tumors of GEP-NENs with variable intensities. By multivariate model which adjusted for age and histologic grade, high expression of HOTAIR was associated with lower presenting T and M stages and subsequent development of metastases (P < 0.05). MALAT1 expression was associated with presenting T stage and development of metastases (P < 0.05). In summary, MALAT1 and HOTAIR are commonly expressed in GEP-NENs. High expression of either lncRNA showed grade-independent associations with clinically less aggressive disease.

Preclinical development of an AAV8-hUGT1A1 vector for the treatment of Crigler-Najjar syndrome.

Molecular Therapy - Methods & Clinical Development (2018)

2018 Dec 26

Collaud F, Bortolussi G, Guianvarc’h L, Aronson SJ, Bordet T, Veron P, Charles S, Vidal P, Sola MS, Rundwasser S, Dufour DG, Lacoste F, Luc C, Wittenberghe Lv, Martin S, Le Bec C, Bosma PJ, Muro AF, Ronzitti G, Hebben M, Mingozzi F.
| DOI: 10.1016/j.omtm.2018.12.011

Adeno-associated viruses (AAV) are among the most efficient vectors for liver gene therapy. results obtained in the first hemophilia clinical trials demonstrated the long-term efficacy of this approach in humans, showing efficient targeting of hepatocytes with both self-complementary (sc) and single-stranded (ss) AAV vectors. However, to support clinical development of AAV-based gene therapies, efficient and scalable production processes are needed. In an effort to translate to the clinic an approach of AAV-mediated liver gene transfer to treat Crigler-Najjar (CN) syndrome, we developed a (ss)AAV8 vector carrying the human UDP-glucuronosyltransferase- family 1-member A1 (hUGT1A1) transgene under the control of a liver-specific promoter. We compared our construct with similar (sc)AAV8 vectors expressing hUGT1A1, showing comparable potency in vitro and in vivo. Conversely, (ss)AAV8-hUGT1A1 vectors showed superior yields and product homogeneity compared with their sc counterpart. We then focused our efforts in the scale-up of a manufacturing process of the clinical product (ss)AAV8-hUGT1A1 based on the triple-transfection of human embryonic kidney (HEK) 293 cells grown in suspension. Large-scale production of this vector had characteristics identical to those of small-scale vectors produced in adherent cells. Preclinical studies in animal models of the disease and a good laboratory practice (GLP) toxicology/biodistribution study were also conducted using large scale preparations of vectors. These studies demonstrated long-term safety and efficacy of gene transfer with (ss)AAV8-hUGT1A1 in relevant animal models of the disease, thus supporting the clinical translation of this gene therapy approach for the treatment of CN syndrome.

Organoids from pituitary as a novel research model toward pituitary stem cell exploration.

J Endocrinol. 2018 Nov 1.

2018 Nov 01

Cox B, Laporte E, Vennekens A, Kobayashi H, Nys C, Van Zundert I, Uji-I H, Vercauteren Drubbel A, Beck B, Roose H, Boretto M, Vankelecom H.
PMID: 30475227 | DOI: 10.1530/JOE-18-0462

The pituitary is the master endocrine gland, harboring stem cells of which the phenotype and role remain poorly characterized. Here, we established organoids from mouse pituitary with the aim to generate a novel research model to study pituitary stem cell biology. The organoids originated from the pituitary cells expressing the stem cell marker SOX2, were long-term expandable, displayed a stemness phenotype during expansive culture and showed specific hormonal differentiation ability, although limited, after subrenal transplantation. Application of the protocol to transgenically injured pituitary harboring an activated stem cell population, resulted in more numerous organoids. Intriguingly, these organoids presented with a cystic morphology whereas the organoids from undamaged gland were predominantly dense, and appeared more limited in expandability. Transcriptomic analysis revealed distinct epithelial phenotypes and showed that cystic organoids more resembled the pituitary phenotype, at least to an immature state, and displayed in vitro differentiation, although yet moderate. Organoid characterization further exposed facets of regulatory pathways of the putative stem cells of the pituitary and advanced new injury-activated markers. Taken together, we established a novel organoid research model revealing new insights into the identity and regulation of the putative pituitary stem cells. This organoid model may eventually lead to an interesting tool to decipher pituitary stem cell biology in both healthy and diseased gland.

Overexpression of toll-like receptor 9 correlates with podocyte injury in a murine model of autoimmune membranoproliferative glomerulonephritis.

Autoimmunity. 2018 Dec 28:1-13.

2018 Dec 28

Masum MA, Ichii O, Hosny Ali Elewa Y, Nakamura T, Otani Y, Hosotani M, Kon Y.
PMID: 30592438 | DOI: 10.1080/08916934.2018.1549234

Toll-like receptors (Tlrs) are sensors of danger signals which promote the activation of immune cells and intrinsic renal cells. Podocytes, the intrinsic cells of glomerulus, are continuously exposed to various plasma solutes and danger signals due to their unique location in the glomerulus. Herein, we show that Tlr9 is overexpressed in podocytes and the mechanisms which cause its injury and development of membranoproliferative glomerulonephritis (MPGN) in model BXSB/MpJ-Yaa (Yaa) mice. Yaa mice developed typical lesions of MPGN and showed strong expression of Tlr9 mRNA throughout the glomerulus particularly toward the periphery of the glomerulus. However, BXSB/MpJ (BXSB) mice showed no lesion for MPGN but a very weak expression of Tlr9 mRNA. Relative mRNA expression of Tlr9 and its downstream cytokines, including interleukin 1 beta (Il1b), Il6, interferon gamma (Ifng) and tumour necrosis factor alpha (Tnfa) was markedly increased in glomeruli isolated from Yaa mice. Tlr9 protein expression was almost absent in BXSB mice but intense expression was found in Yaa mice. Podocyte protein expression was normal in BXSB mice but decreased in Yaa mice and colocalized with Tlr9 protein. Furthermore, electron microscopy examination revealed podocyte injury and electron-dense materials in thickened glomerular basement membrane of Yaa mice. Glomerular Tlr9 mRNA expression was significantly correlated with anti-dsDNA antibody, proteinuria, renal function indices (sBUN and sCr), glomerular histopathology indices, downstream factors of Tlr family (Ilb and Tnfa), podocyte injury parameters (p < .05 and p < .01). In conclusion, overexpression of TLR9 correlates with podocyte injury and development of MPGN.

RVFV Infection in Goats by Different Routes of Inoculation.

Viruses. 2018 Dec 12;10(12).

2018 Dec 12

Kroeker AL, Smid V, Embury-Hyatt C, Moffat E, Collignon B, Lung O, Lindsay R, Weingartl H.
PMID: 30545088 | DOI: 10.3390/v10120709

Rift Valley fever virus (RVFV) is a zoonotic arbovirus of the Phenuiviridae family. Infection causes abortions in pregnant animals, high mortality in neonate animals, and mild to severe symptoms in both people and animals. There is currently an ongoing effort to produce safe and efficacious veterinary vaccines against RVFV in livestock to protect against both primary infection in animals and zoonotic infections in people. To test the efficacy of these vaccines, it is essential to have a reliable challenge model in relevant target species, including ruminants. We evaluated two goat breeds (Nubian and LaMancha), three routes of inoculation (intranasal, mosquito-primed subcutaneous, and subcutaneous) using an infectious dose of 10⁷ pfu/mL, a virus strain from the 2006⁻2007 Kenyan/Sudan outbreak and compared the effect of using virus stocks produced in either mammalian or mosquito cells. Our results demonstrated that the highest and longest viremia titers were achieved in Nubian goats. The Nubian breed was also efficient at producing clinical signs, consistent viremia (peak viremia: 1.2 × 10³⁻1.0 × 10⁵ pfu/mL serum), nasal and oral shedding of viral RNA (1.5 × 10¹⁻8 × 10⁶ genome copies/swab), a systemic infection of tissues, and robust antibody responses regardless of the inoculation route. The Nubian goat breed and a needle-free intranasal inoculation technique could both be utilized in future vaccine and challenge studies. These studies are important for preventing the spread and outbreak of zoonotic viruses like RVFV and are supported by the Canadian-led BSL4ZNet network.

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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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