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TDP-43 and Neurodegeneration

2021 Oct 29

Jaiswal, M;
| DOI: 10.1016/B978-0-12-820066-7.00007-2

Over the years the transactive response DNA-binding protein (TDP-43), a highly conserved 43 kDa nuclear protein, has been acknowledged as a vital protein in brain health and neuropathological disorders such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), Lewy body dementia (LBD), and Parkinson disease (PD). Description of TDP-43 dates back to 1892 when neurologist Arnold Pick first described progressive dementia characterized by atrophy that diverged both clinically and pathophysiologically from AD. In 2006, TDP-43 was identified in ALS and FTD recognized by cytoplasmic inclusions that label ubiquitin (+), whereas tau and α-synuclein stains were negative. Since then, several discoveries have been made which have led to a better understanding of the pathophysiological function of TDP-43 and its intricate links to ALS, FTD, AD, PD, dementia, and few other neurological diseases, all of which shared some common disease mechanisms. In this book chapter, we précis past findings, up-to-date evidence of common physiological function of TDP-43 and the TDP-43 pathobiology witnessed in FTD-TDP, ALS-TDP, and other neurodegenerative diseases such as AD, PD, and LBD. In addition, we deliberate on the accumulating data indicating FTD-TDP and ALS-TDP as two ends of a disease spectrum characterized by a fundamental, main TDP-43 proteinopathy and, thus, contemplate on its implication in precision medicine. Finally, we discuss the status of new advances in TDP-43-associated discovery to neurological practice and care, including the novel prospects to develop better precision diagnostics kits and disease-modifying therapies for ALS-TDP, FTD-TDP, AD, LBD, PD, and other related neurological disorders showing characteristic TDP-43 pathological symptoms.

口咽鳞状细胞癌中人乳头状瘤病毒精准检测研究进展

精准医学杂志

2021 Jan 01

李志鹏, ;范志伟, ;王文龙, ;卜祥斌, ;张凌楠, ;
| DOI: 10.13362/j.pmed.202104024

不同于其他头颈部鳞状细胞癌,人乳头状瘤病毒(HPV)相关口咽鳞状细胞癌(OPSCC)是一类具有不同分子生物学发病机制、危险因素、临床病理特征的特殊疾病。HPV 阳性 OPSCC患者的预后明显优于 HPV 阴性患者,因此 HPV 的检测对 OPSCC的诊断和治疗尤为重要。目前,国内外针对 OPSCC中 HPV 生物分子标志物的检测方法多种多样,但仍然缺乏一个在该领域达成共识的规范化检测标准。本文围绕 OPSCC中 HPV 生物分子标志物的研究现状做一总结,旨在为实验室以及临床上选择适合的生物分子标志物进行 OPSCC诊断提供借鉴。

Visualization of RNA Transcripts in Western Corn Rootworm (Diabrotica virgifera virgifera) and Plants by In Situ Hybridization

Methods in molecular biology (Clifton, N.J.)

2022 Sep 08

Steimel, JP;Hu, X;
PMID: 34495507 | DOI: 10.1007/978-1-0716-1633-8_6

In situ hybridization (ISH) is a methodology by which nucleic acids are detected within fixed tissue samples. Recent advances in detection technology and target recovery have greatly enhanced the technique's ability to detect single mRNA molecules. Here we detail the fixation, paraffin embedding, sectioning, target recovery, and chromogenic detection of an mRNA (DvSSJ1), encoding for a membrane protein associated with the smooth septate junction (SSJ) in Western corn rootworm [Diabrotica virgifera (Dv)]. Further, we demonstrate, the expression of dsRNA of DvSSJ1 in maize root tissues using signal amplification and background suppression technology.

Berbamine inhibits Japanese encephalitis virus (JEV) infection by compromising TPRMLs-mediated endolysosomal trafficking of low-density lipoprotein receptor (LDLR)

Emerging microbes & infections

2021 Dec 01

Huang, L;Li, H;Ye, Z;Xu, Q;Fu, Q;Sun, W;Qi, W;Yue, J;
PMID: 34102949 | DOI: 10.1080/22221751.2021.1941276

Japanese encephalitis virus (JEV), a member of the Flavivirus genus, is an important pathogen that causes human and animal infectious diseases in Asia. So far, no effective antiviral agents are available to treat JEV infection. Here, we found that LDLR is a host factor required for JEV entry. Berbamine significantly decreases the level of LDLR at the plasma membrane by inducing the secretion of LDLR via extracellular vesicles (EVs), thereby inhibiting JEV infection. Mechanistically, berbamine blocks TRPMLs (Ca2+ permeable non-selective cation channels in endosomes and lysosomes) to compromise the endolysosomal trafficking of LDLR. This leads to the increased secretion of LDLR via EVs and the concomitant decrease in its level at the plasma membrane, thereby rendering cells resistant to JEV infection. Berbamine also protects mice from the lethal challenge of JEV. In summary, these results indicate that berbamine is an effective anti-JEV agent by preventing JEV entry.

Characterization of SARS-CoV-2 and host entry factors distribution in a COVID-19 autopsy series

Communications Medicine

2021 Dec 01

Wang, X;Mannan, R;Xiao, L;Abdulfatah, E;Qiao, Y;Farver, C;Myers, J;Zelenka-Wang, S;McMurry, L;Su, F;Wang, R;Pantanowitz, L;Jentzen, J;Wilson, A;Zhang, Y;Cao, X;Chinnaiyan, A;Mehra, R;
| DOI: 10.1038/s43856-021-00025-z

Background SARS-CoV-2 is a highly contagious virus that causes the disease COVID-19. We have recently reported that androgens regulate the expression of SARS-CoV-2 host entry factors ACE2 and TMPRSS2, and androgen receptor (AR) in lung epithelial cells. We also demonstrated that the transcriptional repression of the AR enhanceosome inhibited SARS-CoV-2 infection in vitro. Methods To better understand the various sites of SARS-CoV-2 infection, and presence of host entry factors, we extensively characterized the tissue distribution and localization of SARS-CoV-2 virus, viral replication, and host entry factors in various anatomical sites sampled via autopsy. We applied RNA in-situ-hybridization (RNA-ISH), immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) approaches. We also assessed histopathological changes in SARS-CoV-2 infected tissues. Results We detect SARS-CoV-2 virus and viral replication in pulmonary tissues by RNA-ISH and IHC and a variety of non-pulmonary tissues including kidney, heart, liver, spleen, thyroid, lymph node, prostate, uterus, and colon by qRT-PCR. We observe heterogeneity in viral load and viral cytopathic effects among various organ systems, between individuals and within the same patient. In a patient with a history of kidney transplant and under immunosuppressant therapy, we observe an unusually high viral load in lung tissue by RNA-ISH, IHC and qRT-PCR. SARS-CoV-2 virus is also detected in this patent’s kidney, liver and uterus. We find ACE2, TMPRSS2 and AR expression to overlap with the infection sites. Conclusions This study portrays the impact of dispersed SARS-CoV-2 infection in diverse organ systems, thereby facilitating avenues for systematic therapeutic approaches.

Multi-agent in situ hybridization confirms Ca. Branchiomonas cysticola as a major contributor in complex gill disease in Atlantic salmon

Fish and Shellfish Immunology Reports

2021 Dec 01

Gjessing, M;Spilsberg, B;Steinum, T;Amundsen, M;Austbø, L;Hansen, H;Colquhoun, D;Olsen, A;
| DOI: 10.1016/j.fsirep.2021.100026

Gill diseases may cause high mortalities in farmed Atlantic salmon. In seawater reared fish co-infections involving the epitheliocystis associated bacterium Ca. Branchiomonas cysticola, the microsporidian Desmozoon lepeophtherii, the causative agent of amoebic gill disease Paramoeba perurans and salmon gill poxvirus are common and histopathological lesions may be complex. Here, we report detection of these agents utilising multiplex real-time PCR and link the presence of agents to histopathologically visible gill lesions by in situ hybridisation (ISH) utilising RNAscope™. We show that Ca. Branchiomonas cysticola infections may remain undetected if diagnostic investigations are restricted to histopathology alone. Further, positive in situ labelling of Ca. Branchiomonas cysticola was observed within epitheliocysts, but also in small foci within areas of inflammation and necrosis in which histologically detectable epitheliocysts were not visible. In situ labelling of D. lepeophtherii corresponded well with tissue distribution patterns previously associated with this microsporidian. Salmon gill poxvirus was associated with apoptotic gill epithelial cells, while Ca. Piscichlamydia salmonis could not be associated with pathological changes. The multiplex real-time PCRs utilised were rapid and sensitive diagnostic tools and the results corresponded well with ISH. This study shows that the agents involved in complex gill disease can be linked to lesions using ISH and suggests that Ca. B. cysticola plays a crucial role in the development of gill disease in the farming of salmon in Norway.

Glucagon-like peptide 1 receptor-mediated stimulation of a GABAergic projection from the bed nucleus of the stria terminalis to the hypothalamic paraventricular nucleus

Neurobiology of stress

2021 Nov 01

Povysheva, N;Zheng, H;Rinaman, L;
PMID: 34277897 | DOI: 10.1016/j.ynstr.2021.100363

We previously reported that GABAergic neurons within the ventral anterior lateral bed nucleus of the stria terminalis (alBST) express glucagon-like peptide 1 receptor (GLP1R) in rats, and that virally-mediated "knock-down" of GLP1R expression in the alBST prolongs the hypothalamic-pituitary-adrenal axis response to acute stress. Given other evidence that a GABAergic projection pathway from ventral alBST serves to limit stress-induced activation of the HPA axis, we hypothesized that GLP1 signaling promotes activation of GABAergic ventral alBST neurons that project directly to the paraventricular nucleus of the hypothalamus (PVN). After PVN microinjection of fluorescent retrograde tracer followed by preparation of ex vivo rat brain slices, whole-cell patch clamp recordings were made in identified PVN-projecting neurons within the ventral alBST. Bath application of Exendin-4 (a specific GLP1R agonist) indirectly depolarized PVN-projecting neurons in the ventral alBST and adjacent hypothalamic parastrial nucleus (PS) through a network-dependent increase in excitatory synaptic inputs, coupled with a network-independent reduction in inhibitory inputs. Additional retrograde tracing experiments combined with in situ hybridization confirmed that PVN-projecting neurons within the ventral alBST/PS are GABAergic, and do not express GLP1R mRNA. Conversely, GLP1R mRNA is expressed by a subset of neurons that project into the ventral alBST and were likely contained within coronal ex vivo slices, including GABAergic neurons within the oval subnucleus of the dorsal alBST and glutamatergic neurons within the substantia innominata. Our novel findings reveal potential GLP1R-mediated mechanisms through which the alBST exerts inhibitory control over the endocrine HPA axis.

Implication of folate deficiency in CYP2U1 loss of function

The Journal of experimental medicine

2021 Nov 01

Pujol, C;Legrand, A;Parodi, L;Thomas, P;Mochel, F;Saracino, D;Coarelli, G;Croon, M;Popovic, M;Valet, M;Villain, N;Elshafie, S;Issa, M;Zuily, S;Renaud, M;Marelli-Tosi, C;Legendre, M;Trimouille, A;Kemlin, I;Mathieu, S;Gleeson, JG;Lamari, F;Galatolo, D;Alkouri, R;Tse, C;Rodriguez, D;Ewenczyk, C;Fellmann, F;Kuntzer, T;Blond, E;El Hachimi, KH;Darios, F;Seyer, A;Gazi, AD;Giavalisco, P;Perin, S;Boucher, JL;Le Corre, L;Santorelli, FM;Goizet, C;Zaki, MS;Picaud, S;Mourier, A;Steculorum, SM;Mignot, C;Durr, A;Trifunovic, A;Stevanin, G;
PMID: 34546337 | DOI: 10.1084/jem.20210846

Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders. Understanding of their pathogenic mechanisms remains sparse, and therapeutic options are lacking. We characterized a mouse model lacking the Cyp2u1 gene, loss of which is known to be involved in a complex form of these diseases in humans. We showed that this model partially recapitulated the clinical and biochemical phenotypes of patients. Using electron microscopy, lipidomic, and proteomic studies, we identified vitamin B2 as a substrate of the CYP2U1 enzyme, as well as coenzyme Q, neopterin, and IFN-α levels as putative biomarkers in mice and fluids obtained from the largest series of CYP2U1-mutated patients reported so far. We also confirmed brain calcifications as a potential biomarker in patients. Our results suggest that CYP2U1 deficiency disrupts mitochondrial function and impacts proper neurodevelopment, which could be prevented by folate supplementation in our mouse model, followed by a neurodegenerative process altering multiple neuronal and extraneuronal tissues.

Expression of immunoglobulin constant domain genes in neurons of the mouse central nervous system

Life science alliance

2021 Nov 01

Scheurer, L;Das Gupta, RR;Saebisch, A;Grampp, T;Benke, D;Zeilhofer, HU;Wildner, H;
PMID: 34433614 | DOI: 10.26508/lsa.202101154

General consensus states that immunoglobulins are exclusively expressed by B lymphocytes to form the first line of defense against common pathogens. Here, we provide compelling evidence for the expression of two heavy chain immunoglobulin genes in subpopulations of neurons in the mouse brain and spinal cord. RNA isolated from excitatory and inhibitory neurons through ribosome affinity purification revealed Ighg3 and Ighm transcripts encoding for the constant (Fc), but not the variable regions of IgG3 and IgM. Because, in the absence of the variable immunoglobulin regions, these transcripts lack the canonical transcription initiation site used in lymphocytes, we screened for alternative 5' transcription start sites and identified a novel 5' exon adjacent to a proposed promoter element. Immunohistochemical, Western blot, and in silico analyses strongly support that these neuronal transcripts are translated into proteins containing four Immunoglobulin domains. Our data thus demonstrate the expression of two Fc-encoding genes Ighg3 and Ighm in spinal and supraspinal neurons of the murine CNS and suggest a hitherto unknown function of the encoded proteins.

Reduced activity of intestinal surface Na+/H+ exchanger NHE3 is a key factor for induction of diarrhea after PEDV infection in neonatal piglets

Virology

2021 Nov 01

Song, Z;Yan, T;Ran, L;Niu, Z;Zhang, Y;Kan, Z;Xu, S;Zhang, S;Zhang, J;Zou, H;Lei, C;
PMID: 34464882 | DOI: 10.1016/j.virol.2021.08.011

Porcine epidemic diarrhea virus (PEDV; family Coronaviridae, genus Alphacoronavirus) causes acute diarrhea and vomiting, dehydration, and high mortality in neonatal piglets. Despite extensive research focusing on the pathogenesis of PEDV infection, the molecular pathogenesis of PEDV-induced diarrhea in piglets remains unclear. Na+/H+ exchanger 3 (NHE3), the main exchanger of electroneutral sodium in intestinal epithelial cells, is closely associated with the occurrence of diarrhea. To date, there is no study on whether diarrhea caused by PEDV infection is related to the activity of NHE3. In the present study, it was found that the expression level of cell membrane protein NHE3 significantly decreased after PEDV infection, whereas the total level of protein expression was not significantly changed. The Na+/H+ transport rate and the mRNA abundance of NHE3 decreased; the NHE3 activity decreased gradually with increasing infection time. In vivo, after PEDV infection of newborn piglets, rupture of intestinal villi and interstitial degeneration of intestinal epithelial cells in different intestinal segments were observed by hematoxylin-eosin staining. Immunohistochemical and immunofluorescence methods were used to observe the decreased expression of NHE3 protein on the membrane of intestinal epithelial cells in the jejunum and ileum. Taken together, these data indicate that PEDV infection reduces NHE3 activity in intestinal epithelial cells, hindering Na+ transport and thus causing diarrhea.

Sex in the Nucleus Accumbens: ΔFosB, Addiction, and Affective States

Biological psychiatry

2021 Oct 15

Cadet, JL;
PMID: 34556203 | DOI: 10.1016/j.biopsych.2021.08.002

Autocrine and paracrine effects of a novel podocyte gene, RARRES1

Kidney international

2021 Oct 01

Chen, A;Lee, K;He, JC;
PMID: 34556297 | DOI: 10.1016/j.kint.2021.07.008

Retinoic acid receptor responder protein 1 (RARRES1) has been identified as a novel gene for the regulation of podocyte function, and its expression is increased in glomerular disease and associated with disease progression. Increased expression of RARRES1 in podocytes leads to apoptosis through an autocrine effect. Möller-Hackbarth et al. recently found that RARRES1 expression is increased in the endothelial cells in some diseased kidneys to promote podocyte injury, likely through a paracrine effect.

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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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