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Advances in our understanding of nematode ion channels as potential anthelmintic targets

International Journal for Parasitology: Drugs and Drug Resistance

2021 Dec 01

Choudhary, S;Kashyap, S;Martin, R;Robertson, A;
| DOI: 10.1016/j.ijpddr.2021.12.001

Ion channels are specialized multimeric proteins that underlie cell excitability. These channels integrate with a variety of neuromuscular and biological functions. In nematodes, the physiological behaviors including locomotion, navigation, feeding and reproduction, are regulated by these protein entities. Majority of the antinematodal chemotherapeutics target the ion channels to disrupt essential biological functions. Here, we have summarized current advances in our understanding of nematode ion channel pharmacology. We review cys-loop ligand gated ion channels (LGICs), including nicotinic acetylcholine receptors (nAChRs), acetylcholine-chloride gated ion channels (ACCs), glutamate-gated chloride channels (GluCls), and GABA (γ-aminobutyric acid) receptors, and other ionotropic receptors (transient receptor potential (TRP) channels and potassium ion channels). We have provided an update on the pharmacological properties of these channels from various nematodes. This article catalogs the differences in ion channel composition and resulting pharmacology in the phylum Nematoda. This diversity in ion channel subunit repertoire and pharmacology emphasizes the importance of pursuing species-specific drug target research. In this review, we have provided an overview of recent advances in techniques and functional assays available for screening ion channel properties and their application.

An Enriched Environment Reduces Chronic Stress-Induced Visceral Pain Through Modulating Microglial Activity in the Central Nucleus of the Amygdala

American journal of physiology. Gastrointestinal and liver physiology

2021 Dec 08

Yuan, T;Orock, A;Greenwood-Van Meerveld, B;
PMID: 34877892 | DOI: 10.1152/ajpgi.00307.2021

Cognitive behavioral therapy (CBT) improves the quality of life for patients with brain-gut disorders, however, the underlying mechanisms of CBT remain to be explored. Previously we showed that environmental enrichment (EE), an experimental paradigm that mirrors positive behavioral intervention, ameliorates chronic stress-induced visceral hypersensitivity in a rodent model via mechanisms involving altered activity in the central nucleus of amygdala (CeA). In the present study, we investigated whether microglia-mediated synaptic plasticity in the CeA is a potential mechanism underlying the protective effects of EE against stress-induced visceral hypersensitivity. We sterotaxically implanted corticosterone (CORT) micropellets onto the dorsal margin of the CeA shown previously to induce colonic hypersensitivity. Animals were housed in EE cages or standard cages for 14 days following CORT implantation. Visceral sensitivity was assessed via visceromotor behavioral response to colorectal distension. Microglial morphology, microglia-mediated synaptic engulfment and the expression of synaptic pruning-related signals C1q, C3 and C3R were measured using immunofluorescence and RNAscope assay. We found that housing CORT implanted rats in EE cages for 14 days attenuated visceral hypersensitivity in both male and female rats as compared to control rats maintained in standard housing. EE reduced CORT-induced microglial remodeling and microglia-mediated synaptic pruning with reduced C1q and CR3, but not C3, expression. Our data suggest that exposure to EE is sufficient to ameliorate stress-induced visceral pain via reducing amygdala microglia-modulated neuronal plasticity.

Molecular mechanisms in IL-1β-mediated decorin production by decidual cells

Molecular human reproduction

2021 Nov 27

Halari, CD;Renaud, SJ;Lala, PK;
PMID: 34915564 | DOI: 10.1093/molehr/gaab068

Decorin, a small leucine-rich proteoglycan produced by decidual cells restrains trophoblast differentiation, migration and invasiveness of extra-villous trophoblast cells. Decidual overproduction of decorin is associated with preeclampsia, and elevated decorin levels in maternal plasma are a predictive biomarker of preeclampsia. Furthermore, decorin plays an autocrine role in maturation of human endometrial stromal cells into decidual cells. Thus, a balanced decorin production by the decidua is critical for healthy pregnancy. However, the molecular mechanisms regulating decorin production by the decidua are unclear. Interleukin-1 beta is an inflammation-associated multi-functional cytokine, and is reported to induce decidualization in primates. Hence, the present study was designed: (i) to test if exogenous Interleukin-1 beta stimulated decorin production by human endometrial stromal cells; and if so, (ii) to identify the cellular source of Interleukin-1 beta in first trimester decidual tissue; (iii) to identify the downstream molecular partners in Interleukin-1 beta mediated decorin production by human endometrial stromal cells. Results revealed that (i) amongst multiple pro-inflammatory cytokines tested, Interleukin-1 beta alone stimulated decorin production by these cells; (ii) both macrophages and decidual cells in first trimester decidua produced Interleukin-1 beta; (iii) Interleukin-1 beta mediated decorin production was dependent on Interleukin-1 receptor activation, followed by activation and nuclear translocation of nuclear factor kappa B and its binding to the decorin promoter. These results reveal that Interleukin-1 beta plays a novel role in inducing decorin production by human endometrial stromal cells by activating nuclear factor kappa B.

Baiting out a full length sequence from unmapped RNA-seq data

BMC genomics

2021 Nov 27

Li, D;Huang, Q;Huang, L;Wen, J;Luo, J;Li, Q;Peng, Y;Zhang, Y;
PMID: 34837950 | DOI: 10.1186/s12864-021-08146-4

As a powerful tool, RNA-Seq has been widely used in various studies. Usually, unmapped RNA-seq reads have been considered as useless and been trashed or ignored.We develop a strategy to mining the full length sequence by unmapped reads combining with specific reverse transcription primers design and high throughput sequencing. In this study, we salvage 36 unmapped reads from standard RNA-Seq data and randomly select one 149 bp read as a model. Specific reverse transcription primers are designed to amplify its both ends, followed by next generation sequencing. Then we design a statistical model based on power law distribution to estimate its integrality and significance. Further, we validate it by Sanger sequencing. The result shows that the full length is 1556 bp, with insertion mutations in microsatellite structure.We believe this method would be a useful strategy to extract the sequences information from the unmapped RNA-seq data. Further, it is an alternative way to get the full length sequence of unknown cDNA.

Intrauterine Fetal Demise After Uncomplicated COVID-19: What Can We Learn from the Case?

Viruses

2021 Dec 19

Babal, P;Krivosikova, L;Sarvaicova, L;Deckov, I;Szemes, T;Sedlackova, T;Palkovic, M;Kalinakova, A;Janega, P;
PMID: 34960815 | DOI: 10.3390/v13122545

SARS-CoV-2 infection in pregnant women can lead to placental damage and transplacental infection transfer, and intrauterine fetal demise is an unpredictable event.A 32-year-old patient in her 38th week of pregnancy reported loss of fetal movements. She overcame mild COVID-19 with positive PCR test 22 days before. A histology of the placenta showed deposition of intervillous fibrinoid, lympho-histiocytic infiltration, scant neutrophils, clumping of villi, and extant infarctions. Immunohistochemistry identified focal SARS-CoV-2 nucleocapsid and spike protein in the syncytiotrophoblast and isolated in situ hybridization of the virus' RNA. Low ACE2 and TMPRSS2 contrasted with strong basigin/CD147 and PDL-1 positivity in the trophoblast. An autopsy of the fetus showed no morphological abnormalities except for lung interstitial infiltrate, with prevalent CD8-positive T-lymphocytes and B-lymphocytes. Immunohistochemistry and in situ hybridization proved the presence of countless dispersed SARS-CoV-2-infected epithelial and endothelial cells in the lung tissue. The potential virus-receptor protein ACE2, TMPRSS2, and CD147 expression was too low to be detected.Over three weeks' persistence of trophoblast viral infection lead to extensive intervillous fibrinoid depositions and placental infarctions. High CD147 expression might serve as the dominant receptor for the virus, and PDL-1 could limit maternal immunity in placental tissue virus clearance. The presented case indicates that the SARS-CoV-2 infection-induced changes in the placenta lead to ischemia and consecutive demise of the fetus. The infection of the fetus was without significant impact on its death. This rare complication of pregnancy can appear independently to the severity of COVID-19's clinical course in the pregnant mother.

Antiviral Activities of Carbazole Derivatives against Porcine Epidemic Diarrhea Virus In Vitro

Viruses

2021 Dec 16

Chen, Z;Chen, J;Wei, X;Hua, H;Hu, R;Ding, N;Zhang, J;Song, D;Ye, Y;Tang, Y;Ding, Z;Ke, S;
PMID: 34960796 | DOI: 10.3390/v13122527

Porcine epidemic diarrhea virus (PEDV), an enteric coronavirus, causes neonatal pig acute gastrointestinal infection with a characterization of severe diarrhea, vomiting, high morbidity, and high mortality, resulting in tremendous damages to the swine industry. Neither specific antiviral drugs nor effective vaccines are available, posing a high priority to screen antiviral drugs. The aim of this study is to investigate anti-PEDV effects of carbazole alkaloid derivatives. Eighteen carbazole derivatives (No.1 to No.18) were synthesized, and No.5, No.7, and No.18 were identified to markedly reduce the replication of enhanced green fluorescent protein (EGFP) inserted-PEDV, and the mRNA level of PEDV N. Flow cytometry assay, coupled with CCK8 assay, confirmed No.7 and No.18 carbazole derivatives displayed high inhibition effects with low cell toxicity. Furthermore, time course analysis indicated No.7 and No.18 carbazole derivatives exerted inhibition at the early stage of the viral life cycle. Collectively, the analysis underlines the benefit of carbazole derivatives as potential inhibitors of PEDV, and provides candidates for the development of novel therapeutic agents.

Decreased Fetal Movements: A Sign of Placental SARS-CoV-2 Infection with Perinatal Brain Injury

Viruses

2021 Dec 15

Favre, G;Mazzetti, S;Gengler, C;Bertelli, C;Schneider, J;Laubscher, B;Capoccia, R;Pakniyat, F;Ben Jazia, I;Eggel-Hort, B;de Leval, L;Pomar, L;Greub, G;Baud, D;Giannoni, E;
PMID: 34960786 | DOI: 10.3390/v13122517

Neonatal COVID-19 is rare and mainly results from postnatal transmission. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, can infect the placenta and compromise its function. We present two cases of decreased fetal movements and abnormal fetal heart rhythm 5 days after mild maternal COVID-19, requiring emergency caesarean section at 29 + 3 and 32 + 1 weeks of gestation, and leading to brain injury. Placental examination revealed extensive and multifocal chronic intervillositis, with intense cytoplasmic positivity for SARS-CoV-2 spike antibody and SARS-CoV-2 detection by RT-qPCR. Vertical transmission was confirmed in one case, and both neonates developed extensive cystic peri-ventricular leukomalacia.

The Bank Vole (Clethrionomys glareolus)-Small Animal Model for Hepacivirus Infection

Viruses

2021 Dec 03

Röhrs, S;Begeman, L;Straub, BK;Boadella, M;Hanke, D;Wernike, K;Drewes, S;Hoffmann, B;Keller, M;Drexler, JF;Drosten, C;Höper, D;Kuiken, T;Ulrich, RG;Beer, M;
PMID: 34960690 | DOI: 10.3390/v13122421

Many people worldwide suffer from hepatitis C virus (HCV) infection, which is frequently persistent. The lack of efficient vaccines against HCV and the unavailability of or limited compliance with existing antiviral therapies is problematic for health care systems worldwide. Improved small animal models would support further hepacivirus research, including development of vaccines and novel antivirals. The recent discovery of several mammalian hepaciviruses may facilitate such research. In this study, we demonstrated that bank voles (Clethrionomys glareolus) were susceptible to bank vole-associated Hepacivirus F and Hepacivirus J strains, based on the detection of hepaciviral RNA in 52 of 55 experimentally inoculated voles. In contrast, interferon α/β receptor deficient C57/Bl6 mice were resistant to infection with both bank vole hepaciviruses (BvHVs). The highest viral genome loads in infected voles were detected in the liver, and viral RNA was visualized by in situ hybridization in hepatocytes, confirming a marked hepatotropism. Furthermore, liver lesions in infected voles resembled those of HCV infection in humans. In conclusion, infection with both BvHVs in their natural hosts shares striking similarities to HCV infection in humans and may represent promising small animal models for this important human disease.

The Role of Male Reproductive Organs in the Transmission of African Swine Fever—Implications for Transmission

Viruses

2021 Dec 24

Roszyk, H;Franzke, K;Breithaupt, A;Deutschmann, P;Pikalo, J;Carrau, T;Blome, S;Sehl-Ewert, J;
| DOI: 10.3390/v14010031

African swine fever (ASF) has evolved from an exotic animal disease to a threat to global pig production. An important avenue for the wide-spread transmission of animal diseases is their dissemination through boar semen used for artificial insemination. In this context, we investigated the role of male reproductive organs in the transmission of ASF. Mature domestic boars and adolescent wild boars, inoculated with different ASF virus strains, were investigated by means of virological and pathological methods. Additionally, electron microscopy was employed to investigate in vitro inoculated sperm. The viral genome, antigens and the infectious virus could be found in all gonadal tissues and accessory sex glands. The viral antigen and viral mRNAs were mainly found in mononuclear cells of the respective tissues. However, some other cell types, including Leydig, endothelial and stromal cells, were also found positive. Using RNAScope, p72 mRNA could be found in scattered halo cells of the epididymal duct epithelium, which could point to the disruption of the barrier. No direct infection of spermatozoa was observed by immunohistochemistry, or electron microscopy. Taken together, our results strengthen the assumption that ASFV can be transmitted via boar semen. Future studies are needed to explore the excretion dynamics and transmission efficiency.

AZD1222 (ChAdOx1 nCov-19): A Single-Dose biodistribution study in mice

Vaccine

2021 Dec 02

Stebbings, R;Armour, G;Pettis, V;Goodman, J;
PMID: 34865878 | DOI: 10.1016/j.vaccine.2021.11.028

Biodistribution studies of adenovirus-based vaccines support their clinical development by evaluating their spread and persistence following in vivo administration. AZD1222 (ChAdox1 nCov-19) is a replication-deficient non-human adenovirus-vectored vaccine for coronavirus disease 2019. In this nonclinical study, the biodistribution of AZD1222 was assessed in mice for 29 days following intramuscular injection. Results show that AZD1222 was safe and well tolerated, with a spread that was largely confined to administration sites and the proximal sciatic nerve, with low levels observed in sites that are involved in rapid clearance of particulates by the reticuloendothelial system. Accordingly, levels of AZD1222 decreased from Day 2 to Day 29, indicating clearance. There were no quantifiable levels of AZD1222 in the blood, brain, spinal cord, and reproductive tissue, suggesting a lack of widespread or long-term distribution of AZD1222 vector DNA throughout the body following its administration.

Angiotensin II infusion results in both hypertension and increased AMPA GluA1 signaling in hypothalamic paraventricular nucleus of male but not female mice

Neuroscience

2022 Jan 01

Wang, G;Woods, C;Johnson, M;Milner, T;Glass, M;
| DOI: 10.1016/j.neuroscience.2021.12.041

The hypothalamic paraventricular nucleus (PVN) plays a key role in hypertension, however the signaling pathways that contribute to the adaptability of the PVN during hypertension are uncertain. We present evidence that signaling at the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) GluA1 receptor subunit contributes to increased blood pressure in a model of neurogenic hypertension induced by 14-day slow-pressor angiotensin II (AngII) infusion in male mice. It was found that AngII hypertension was associated with an increase in plasma membrane affiliation of GluA1, but decreased GluA2, in dendritic profiles of PVN neurons. The increased plasma membrane GluA1 was paralleled by the results of whole-cell current clamping experiments, which showed heightened AMPA currents in PVN neurons from AngII-infused male mice. The inhibition of heightened AMPA currents was blocked by 1-Naphthyl acetyl spermine trihydrochloride, pointing to the involvement of GluA2-lacking GluA1 receptors in the elevated AMPA signaling in PVN neurons. A further functional role for GluA1 signaling in the PVN was demonstrated by the attenuated hypertensive response following silencing of GluA1 in the PVN of AngII-infused mice. In female mice, AngII-infusion did not impact blood pressure. In addition, AngII was not associated with alterations in transcription or plasma membrane localization of GluA1 in females. Posttranslational modifications that increase the plasma membrane localization of AMPA GluA1 and heighten the rapid signaling actions of glutamate in PVN neurons may serve as a molecular substrate underlying sex differences in hypertension.

High mobility group AT-hook 2 regulates osteoblast differentiation and facial bone development

Biochemical and biophysical research communications

2021 Dec 27

Negishi, T;Mihara, N;Chiba, T;D'Armiento, J;Chada, K;Maeda, M;Igarashi, M;Imai, K;
PMID: 34973532 | DOI: 10.1016/j.bbrc.2021.12.093

The mutation and deletion of high mobility group AT-hook 2 (Hmga2) gene exhibit skeletal malformation, but almost nothing is known about the mechanism. This study examined morphological anomaly of facial bone in Hmga2-/- mice and osteoblast differentiation of pre-osteoblast MC3T3-E1 cells with Hmga2 gene knockout (A2KO). Hmga2-/- mice showed the size reduction of anterior frontal part of facial bones. Hmga2 protein and mRNA were expressed in mesenchymal cells at ossification area of nasal bone. A2KO cells differentiation into osteoblasts after reaching the proliferation plateau was strongly suppressed by alizarin red and alkaline phosphatase staining analyses. Expression of osteoblast-related genes, especially Osterix, was down-regulated in A2KO cells. These results demonstrate a close association of Hmga2 with osteoblast differentiation of mesenchymal cells and bone growth. Although future studies are needed, the present study suggests an involvement of Hmga2 in osteoblast-genesis and bone growth.

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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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