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Transient receptor potential canonical 5 mediates inflammatory mechanical and spontaneous pain in mice

Science translational medicine

2021 May 26

Sadler, KE;Moehring, F;Shiers, SI;Laskowski, LJ;Mikesell, AR;Plautz, ZR;Brezinski, AN;Mecca, CM;Dussor, G;Price, TJ;McCorvy, JD;Stucky, CL;
PMID: 34039739 | DOI: 10.1126/scitranslmed.abd7702

Tactile and spontaneous pains are poorly managed symptoms of inflammatory and neuropathic injury. Here, we found that transient receptor potential canonical 5 (TRPC5) is a chief contributor to both of these sensations in multiple rodent pain models. Use of TRPC5 knockout mice and inhibitors revealed that TRPC5 selectively contributes to the mechanical hypersensitivity associated with CFA injection, skin incision, chemotherapy induced peripheral neuropathy, sickle cell disease, and migraine, all of which were characterized by elevated concentrations of lysophosphatidylcholine (LPC). Accordingly, exogenous application of LPC induced TRPC5-dependent behavioral mechanical allodynia, neuronal mechanical hypersensitivity, and spontaneous pain in naïve mice. Lastly, we found that 75% of human sensory neurons express TRPC5, the activity of which is directly modulated by LPC. On the basis of these results, TRPC5 inhibitors might effectively treat spontaneous and tactile pain in conditions characterized by elevated LPC.

Receptor Activator of NF-κB Mediates Podocyte Injury in Diabetic Nephropathy

Kidney international

2021 May 26

Ke, G;Chen, X;Liao, R;Xu, L;Zhang, L;Zhang, H;Kuang, S;Du, Y;Hu, J;Lian, Z;Dou, C;Zhang, Q;Zhao, X;Zhang, F;Zhu, S;Ma, J;Li, Z;Li, S;He, C;Chen, X;Wen, Y;Feng, Z;Zheng, M;Lin, T;Li, R;Li, B;Dong, W;Chen, Y;Wang, W;Ye, Z;Deng, C;Xiao, H;Xiao, J;Liang, X;Shi, W;Liu, S;
PMID: 34051263 | DOI: 10.1016/j.kint.2021.04.036

Receptor activator of NF-κB (RANK) expression is increased in podocytes of patients with diabetic nephropathy. However, the relevance of RANK to diabetic nephropathy pathobiology remains unclear. Here, to evaluate the role of podocyte RANK in the development of diabetic nephropathy, we generated a mouse model of podocyte-specific RANK depletion (RANK-/-Cre T), and a model of podocyte-specific RANK overexpression (RANK TG), and induced diabetes in these mice with streptozotocin. We found that podocyte RANK depletion alleviated albuminuria, mesangial matrix expansion, and basement membrane thickening, while RANK overexpression aggravated these indices in streptozotocin-treated mice. Moreover, streptozotocin-triggered oxidative stress was increased in RANK overexpression, but decreased in the RANK depleted mice. Particularly, the expression of NADPH oxidase 4, and its obligate partner, P22phox, were enhanced in RANK overexpression, but reduced in RANK depleted mice. In parallel, the transcription factor p65 was increased in the podocyte nuclei of RANK overexpressing mice but decreased in the RANK depleted mice. The relevant findings were largely replicated with high glucose-treated podocytes in vitro. Mechanistically, p65 could bind to the promoter regions of NADPH oxidase 4 and P22phox, and increased their respective gene promoter activity in podocytes, dependent on the levels of RANK. Taken together, these findings suggested that high glucose induced RANK in podocytes and caused the increase of NADPH oxidase 4 and P22phox via p65, possibly together with the cytokines TNF- α, MAC-2 and IL-1 β, resulting in podocyte injury. Thus, we found that podocyte RANK was induced in the diabetic milieu and RANK mediated the development of diabetic nephropathy, likely by promoting glomerular oxidative stress and proinflammatory cytokine production.

A potential role for somatostatin signaling in regulating retinal neurogenesis

Scientific reports

2021 May 26

Weir, K;Kim, DW;Blackshaw, S;
PMID: 34040115 | DOI: 10.1038/s41598-021-90554-3

Neuropeptides have been reported to regulate progenitor proliferation and neurogenesis in the central nervous system. However, these studies have typically been conducted using pharmacological agents in ex vivo preparations, and in vivo evidence for their developmental function is generally lacking. Recent scRNA-Seq studies have identified multiple neuropeptides and their receptors as being selectively expressed in neurogenic progenitors of the embryonic mouse and human retina. This includes Sstr2, whose ligand somatostatin is transiently expressed by immature retinal ganglion cells. By analyzing retinal explants treated with selective ligands that target these receptors, we found that Sstr2-dependent somatostatin signaling induces a modest, dose-dependent inhibition of photoreceptor generation, while correspondingly increasing the relative fraction of primary progenitor cells. These effects were confirmed by scRNA-Seq analysis of retinal explants but abolished in Sstr2-deficient retinas. Although no changes in the relative fraction of primary progenitors or photoreceptor precursors were observed in Sstr2-deficient retinas in vivo, scRNA-Seq analysis demonstrated accelerated differentiation of neurogenic progenitors. We conclude that, while Sstr2 signaling may act to negatively regulate retinal neurogenesis in combination with other retinal ganglion cell-derived secreted factors such as Shh, it is dispensable for normal retinal development.

The role of single-cell sequencing in studying tumour evolution

Faculty reviews

2021 May 26

Mossner, M;Baker, AC;Graham, TA;
PMID: 34131659 | DOI: 10.12703/r/10-49

Tumour evolution is a complex interplay between the acquisition of somatic (epi)genomic changes in tumour cells and the phenotypic consequences they cause, all in the context of a changing microenvironment. Single-cell sequencing offers a window into this dynamic process at the ultimate resolution of individual cells. In this review, we discuss the transformative insight offered by single-cell sequencing technologies for understanding tumour evolution.

Low Grade Papillary Sinonasal (Schneiderian) Carcinoma: A Series of Five Cases of a Unique Malignant Neoplasm with Comparison to Inverted Papilloma and Conventional Nonkeratinizing Squamous Cell Carcinoma

Head and neck pathology

2021 May 26

Saab-Chalhoub, MW;Guo, X;Shi, Q;Chernock, RD;Lewis, JS;
PMID: 34041710 | DOI: 10.1007/s12105-021-01335-3

There have been a few case reports and one small series of low grade papillary sinonasal (Schneiderian) carcinomas (LGPSC) which mimic papillomas but have overtly invasive growth and which occasionally metastasize. We describe the morphologic, clinical, immunohistochemical, and molecular features of five patients with LGPSC compared with eight cases each of inverted papilloma (IP) and conventional nonkeratinizing squamous cell carcinoma (SCC) with papillary growth. All LGPSC were nested with predominantly pushing invasion, no stromal reaction, and frequent surface papillary growth. All consisted of one cell type only, with polygonal cells with round nuclei, no (or limited) cytologic atypia, low mitotic activity, and prominent neutrophilic infiltrate. One patient had slightly more infiltrative bone invasion, another lymphovascular, perineural, and skeletal muscle invasion, and a third nodal metastasis after 17 years. By comparison, IPs had bland cytology, neutrophilic microabscesses, mixed immature squamous, goblet cell, and respiratory epithelium, and extremely low mitotic activity. Nonkeratinizing SCCs had basaloid-appearing cells with nuclear pleomorphism, brisk mitotic activity, and apoptosis. All LGPSC were p63 positive. Mitotic activity and Ki67 indices were significantly higher for LGPSCs than IPs and significantly lower than NKSCCs, while p53 immunohistochemistry in LGPSC was identical to nonkeratinizing SCC and higher than for IP. Sequencing showed all five tumors to harbor a MUC6 mutation, one tumor to harbor CDKN2A and PIK3R1 mutations, and one tumor to harbor a NOTCH1 mutation. All LGPSC lacked EGFR and KRAS mutations and lacked copy number variations of any main cancer genes. At a median follow up of 12 months, two LGPSC recurred locally, and one patient died after massive local recurrences and nodal metastases. LGPSC is a distinct, de novo sinonasal carcinoma that can be differentiated from papillomas by morphology and selected immunohistochemistry.

Highly selective brain-to-gut communication via genetically defined vagus neurons

Neuron

2021 May 25

Tao, J;Campbell, JN;Tsai, LT;Wu, C;Liberles, SD;Lowell, BB;
PMID: 34077742 | DOI: 10.1016/j.neuron.2021.05.004

The vagus nerve innervates many organs, and most, if not all, of its motor fibers are cholinergic. However, no one knows its organizing principles-whether or not there are dedicated neurons with restricted targets that act as "labeled lines" to perform certain functions, including two opposing ones (gastric contraction versus relaxation). By performing unbiased transcriptional profiling of DMV cholinergic neurons, we discovered seven molecularly distinct subtypes of motor neurons. Then, by using subtype-specific Cre driver mice, we show that two of these subtypes exclusively innervate the glandular domain of the stomach where, remarkably, they contact different enteric neurons releasing functionally opposing neurotransmitters (acetylcholine versus nitric oxide). Thus, the vagus motor nerve communicates via genetically defined labeled lines to control functionally unique enteric neurons within discrete subregions of the gastrointestinal tract. This discovery reveals that the parasympathetic nervous system utilizes a striking division of labor to control autonomic function.

Non-productive angiogenesis disassembles Aß plaque-associated blood vessels

Nature communications

2021 May 25

Alvarez-Vergara, MI;Rosales-Nieves, AE;March-Diaz, R;Rodriguez-Perinan, G;Lara-Ureña, N;Ortega-de San Luis, C;Sanchez-Garcia, MA;Martin-Bornez, M;Gómez-Gálvez, P;Vicente-Munuera, P;Fernandez-Gomez, B;Marchena, MA;Bullones-Bolanos, AS;Davila, JC;Gonzalez-Martinez, R;Trillo-Contreras, JL;Sanchez-Hidalgo, AC;Del Toro, R;Scholl, FG;Herrera, E;Trepel, M;Körbelin, J;Escudero, LM;Villadiego, J;Echevarria, M;de Castro, F;Gutierrez, A;Rabano, A;Vitorica, J;Pascual, A;
PMID: 34035282 | DOI: 10.1038/s41467-021-23337-z

The human Alzheimer's disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD.

The gut microbiota regulates hypothalamic inflammation and leptin sensitivity in Western diet-fed mice via a GLP-1R-dependent mechanism

Cell reports

2021 May 25

Heiss, CN;Mannerås-Holm, L;Lee, YS;Serrano-Lobo, J;Håkansson Gladh, A;Seeley, RJ;Drucker, DJ;Bäckhed, F;Olofsson, LE;
PMID: 34038733 | DOI: 10.1016/j.celrep.2021.109163

Mice lacking a microbiota are protected from diet-induced obesity. Previous studies have shown that feeding a Western diet causes hypothalamic inflammation, which in turn can lead to leptin resistance and weight gain. Here, we show that wild-type (WT) mice with depleted gut microbiota, i.e., germ-free (GF) and antibiotic-treated mice, have elevated levels of glucagon-like peptide-1 (GLP-1), are protected against diet-induced hypothalamic inflammation, and have enhanced leptin sensitivity when fed a Western diet. Using GLP-1 receptor (GLP-1R)-deficient mice and pharmacological inhibition of the GLP-1R in WT mice, we demonstrate that intact GLP-1R signaling is required for preventing hypothalamic inflammation and enhancing leptin sensitivity. Furthermore, we show that astrocytes express the GLP-1R, and deletion of the receptor in glial fibrillary acidic protein (GFAP)-expressing cells diminished the antibiotic-induced protection against diet-induced hypothalamic inflammation. Collectively, our results suggest that depletion of the gut microbiota attenuates diet-induced hypothalamic inflammation and enhances leptin sensitivity via GLP-1R-dependent mechanisms.

Monogenic Diabetes and Integrated Stress Response Genes Display Altered Gene Expression in Type 1 Diabetes

Diabetes

2021 May 25

Hiller, H;Beachy, DE;Lebowitz, JJ;Engler, S;Mason, JR;Miller, DR;Kusmarteva, I;Jacobsen, LM;Posgai, AL;Khoshbouei, H;Oram, RA;Schatz, DA;Hattersley, AT;Bodenmiller, B;Atkinson, MA;Nick, HS;Wasserfall, CH;
PMID: 34035041 | DOI: 10.2337/db21-0070

Type 1 diabetes has a multifactorial autoimmune etiology, involving environmental prompts and polygenic predisposition. We hypothesized that pancreata from individuals with and at risk for type 1 diabetes would exhibit dysregulated expression of genes associated with monogenic forms of diabetes caused by non-redundant single-gene mutations. Employing a "monogenetic transcriptomic strategy," we measured the expression of these genes in human type 1 diabetes, autoantibody positive (autoantibody+), and control pancreas tissues using RTqPCR in accordance with the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines. Gene and protein expression were visualized in situ using immunofluorescence, RNAScope, and confocal microscopy. Two-dozen monogenic diabetes genes showed altered expression in human pancreata from individuals with type 1 diabetes versus unaffected controls. Six of these genes also saw dysregulation in pancreata from autoantibody+ persons at increased-risk for type 1 diabetes. As a subset of these genes are related to cellular stress responses, we measured integrated stress response (ISR) genes and identified 20 with altered expression in type 1 diabetes pancreata, including three of the four eIF2α-dependent kinases. Equally intriguing, we observed significant repression of the three arms of the ISR in autoantibody+ pancreata. Collectively, these efforts suggest monogenic diabetes and ISR genes are dysregulated early in the type 1 diabetes disease process and likely contribute to the disorder's pathogenesis.

Relationship of human papillomavirus with seborrheic keratosis of the female genital tract- a case-series and literature review

Histology and histopathology

2021 May 25

Dasgupta, S;van Eersel, R;Morrel, B;van den Munckhof, HAM;de Geus, VA;van der Hoeven, NMA;van de Sandt, MM;Piso-Jozwiak, M;Quint, WGV;van der Avoort, IAM;Koljenović, S;Ewing-Graham, PC;van Kemenade, FJ;
PMID: 34170001 | DOI: 10.14670/HH-18-357

Seborrheic keratoses (SKs) are benign lesions of uncertain etiology, which can develop in both genital and extra-genital locations. For genital SKs, there has been conjecture about the pathogenic role of human papillomavirus (HPV), in view of the frequent association of this virus with genital lesions. In light of the potential consequences on patient management, we investigated the relationship between HPV and SKs of the female genital tract (FGT). For this, we evaluated the current evidence on this relationship by performing an in-depth review of the literature. Furthermore, to add to the evidence on this association, we investigated the presence of HPV in a series of vulvar SKs (n=15), using a novel multimodal approach. This involved whole tissue section-polymerase chain reaction (WTS-PCR) using SPF10-DEIA-LipA25 for HPV detection and genotyping. In addition, immunohistochemistry (IHC) was performed with cellular biomarkers p16 and MIB-1, and viral biomarker E4, to augment HPV-testing. Finally, laser-capture microdissection-PCR (LCM-PCR) was performed to locate HPV to specific lesional cells, and to rule out incidental detection of resident HPV with WTS-PCR. Our findings from the literature review, as well as, the case-series are presented.

Microbial exposure during early human development primes fetal immune cells

Cell

2021 May 25

Mishra, A;Lai, GC;Yao, LJ;Aung, TT;Shental, N;Rotter-Maskowitz, A;Shepherdson, E;Singh, GSN;Pai, R;Shanti, A;Wong, RMM;Lee, A;Khyriem, C;Dutertre, CA;Chakarov, S;Srinivasan, KG;Shadan, NB;Zhang, XM;Khalilnezhad, S;Cottier, F;Tan, ASM;Low, G;Chen, P;Fan, Y;Hor, PX;Lee, AKM;Choolani, M;Vermijlen, D;Sharma, A;Fuks, G;Straussman, R;Pavelka, N;Malleret, B;McGovern, N;Albani, S;Chan, JKY;Ginhoux, F;
PMID: 34077752 | DOI: 10.1016/j.cell.2021.04.039

The human fetal immune system begins to develop early during gestation; however, factors responsible for fetal immune-priming remain elusive. We explored potential exposure to microbial agents in utero and their contribution toward activation of memory T cells in fetal tissues. We profiled microbes across fetal organs using 16S rRNA gene sequencing and detected low but consistent microbial signal in fetal gut, skin, placenta, and lungs in the 2nd trimester of gestation. We identified several live bacterial strains including Staphylococcus and Lactobacillus in fetal tissues, which induced in vitro activation of memory T cells in fetal mesenteric lymph node, supporting the role of microbial exposure in fetal immune-priming. Finally, using SEM and RNA-ISH, we visualized discrete localization of bacteria-like structures and eubacterial-RNA within 14th weeks fetal gut lumen. These findings indicate selective presence of live microbes in fetal organs during the 2nd trimester of gestation and have broader implications toward the establishment of immune competency and priming before birth. Crown

Zika virus induces neuronal and vascular degeneration in developing mouse retina

Acta neuropathologica communications

2021 May 25

Li, Y;Shi, S;Xia, F;Shan, C;Ha, Y;Zou, J;Adam, A;Zhang, M;Wang, T;Liu, H;Shi, PY;Zhang, W;
PMID: 34034828 | DOI: 10.1186/s40478-021-01195-6

Zika virus (ZIKV), a mosquito-borne flavivirus, can cause severe eye disease and even blindness in newborns. However, ZIKV-induced retinal lesions have not been studied in a comprehensive way, mechanisms of ZIKV-induced retinal abnormalities are unknown, and no therapeutic intervention is available to treat or minimize the degree of vision loss in patients. Here, we developed a novel mouse model of ZIKV infection to evaluate its impact on retinal structure. ZIKV (20 plaque-forming units) was inoculated into neonatal wild type C57BL/6J mice at postnatal day (P) 0 subcutaneously. Retinas of infected mice and age-matched controls were collected at various ages, and retinal structural alterations were analyzed. We found that ZIKV induced progressive neuronal and vascular damage and retinal inflammation starting from P8. ZIKV-infected retina exhibited dramatically decreased thickness with loss of neurons, initial neovascular tufts followed by vessel dilation and degeneration, increased microglia and leukocyte recruitment and activation, degeneration of astrocyte network and gliosis. The above changes may involve inflammation and endoplasmic reticulum stress-mediated cell apoptosis and necroptosis. Moreover, we evaluated the efficacy of preclinical drugs and the safety of ZIKV vaccine candidate in this mouse model. We found that ZIKV-induced retinal abnormalities could be blocked by a selective flavivirus inhibitor NITD008 and a live-attenuated ZIKV vaccine candidate could potentially induce retinal abnormalities. Overall, we established a novel mouse model and provide a direct causative link between ZIKV and retinal lesion in vivo, which warrants further investigation of the underlying mechanisms of ZIKV-induced retinopathy and the development of effective therapeutics.

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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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