C1q and SRPX2 regulate microglia mediated synapse elimination during early development in the visual thalamus but not the visual cortex

Glia

2021 Nov 11

Cong, Q;Soteros, BM;Huo, A;Li, Y;Tenner, AJ;Sia, GM;
PMID: 34762332 | DOI: 10.1002/glia.24114

The classical complement cascade mediates synapse elimination in the visual thalamus during early brain development. However, whether the primary visual cortex also undergoes complement-mediated synapse elimination during early visual system development remains unknown. Here, we examined microglia-mediated synapse elimination in the visual thalamus and the primary visual cortex of early postnatal C1q and SRPX2 knockout mice. In the lateral geniculate nucleus, deletion of C1q caused a persistent decrease in synapse elimination and microglial synapse engulfment, while deletion of SRPX2 caused a transient increase in the same readouts. In the C1q-SRPX2 double knockout mice, the C1q knockout phenotypes were dominant over the SRPX2 knockout phenotypes, a result which is consistent with SRPX2 being an inhibitor of C1q. We found that genetic deletion of either C1q or SRPX2 did not affect synapse elimination or microglial engulfment of synapses in layer 4 of the primary visual cortex in early brain development. Together, these results show that the classical complement pathway regulates microglia-mediated synapse elimination in the visual thalamus but not the visual cortex during early development of the central nervous system.

ABERRANT WNT SIGNALING INDUCES COMEDO-LIKE CHANGES IN THE MURINE UPPER HAIR FOLLICLE

The Journal of investigative dermatology

2021 Dec 17

Shang, W;Quan Tan, AY;van Steensel, MAM;Lim, X;
PMID: 34929175 | DOI: 10.1016/j.jid.2021.11.034

Stem cell proliferation and differentiation must be carefully balanced to support tissue maintenance and growth. Defective stem cell regulation may underpin diseases in many organs, including the skin. Lrig1-expressing stem cells residing in the HF junction zone (JZ) support sebaceous gland (SG) homeostasis. An emerging hypothesis from observations in both mouse and human holds that imbalances in key stem cell regulatory pathways such as Wnt signaling may lead to abnormal fate determination of these Lrig1+ve cells. They accumulate and form cystic structures in the JZ that are similar to the comedones found in human acne. To test the possible involvement of Wnt signals in this scenario, we used the Lrig1-CreERT2 mouse line to modulate Wnt signaling in JZ stem cells. We observed that persistent activation of Wnt signaling leads to JZ cyst formation with associated SG atrophy. The cysts strongly express stem cell markers and can be partially reduced by all-trans retinoic acid treatment as well as by Hedgehog signaling inhibition. Conversely, loss of Wnt signaling leads to enlargement of JZ, infundibulum and SGs. These data implicate abnormal Wnt signaling in the generation of mouse pathologies that resemble human acne and respond to acne treatments.

Crk and Crkl have shared functions in neural crest cells for cardiac outflow tract septation and vascular smooth muscle differentiation

Human molecular genetics

2021 Oct 23

Shi, L;Racedo, SE;Diacou, A;Park, T;Zhou, B;Morrow, BE;
PMID: 34686881 | DOI: 10.1093/hmg/ddab313

CRK and CRKL encode cytoplasmic adaptors that contribute to the etiology of congenital heart disease. Neural crest cells (NCCs) are required for cardiac outflow tract (OFT) septation and aortic arch formation. The roles of Crk/Crkl in NCCs during mouse cardiovascular development remains unknown. To test this, we inactivated Crk and/or Crkl in NCCs. We found that the loss of Crk, rather than Crkl, in NCCs resulted in double outlet right ventricle, while loss of both Crk/Crkl in NCCs resulted in severe defects with earlier lethality due to failed OFT septation and severe dilation of the pharyngeal arch arteries (PAAs). We found that these defects are due to altered cell morphology resulting in reduced localization of NCCs to the OFT and failed integrity of the PAAs, along with reduced expression of Integrin signaling genes. Further, molecular studies identified reduced differentiation of vascular smooth muscle cells that may in part be due to altered Notch signaling. Additionally, there is increased cellular stress that leads to modest increase in apoptosis. Overall, this explains the mechanism for the Crk/Crkl phenotype.

TNF-Related Apoptosis-Inducing Ligand (TRAIL) Loss in Canine Mammary Carcinoma

Veterinary and comparative oncology

2021 Aug 23

Kim, SH;Seung, BJ;Bae, MK;Lim, HY;Cho, SH;Sur, JH;
PMID: 34423555 | DOI: 10.1111/vco.12767

Escaping apoptosis is a hallmark of cancer. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a central molecule that regulates the extrinsic apoptotic pathway, has been widely investigated in human oncology; however, investigations focusing on the endogenous expression of TRAIL in canine tumors are lacking. Therefore, we aimed to examine the expression of endogenous TRAIL in canine mammary tumors and analyzed its correlation to downstream molecules Fas-associated death domain protein (FADD) and caspase-3, and to the apoptotic index. A total of 147 samples, classified as normal mammary gland (n = 9), mammary adenoma (n = 30), low-grade carcinoma (n = 42), and high-grade carcinoma (n = 66) were included in the immunohistochemical analyses, and 43 samples with sufficient levels of RNA were analyzed via RNA in situ hybridization and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. In immunohistochemistry, TRAIL protein expression was significantly decreased in high-grade carcinoma compared to those in normal mammary gland and adenoma, with similar downregulation of TRAIL mRNA expression. Also, FADD and caspase-3 expression positively correlated with TRAIL expression. However, the apoptotic index was paradoxically elevated in high-grade tumors. Overall, these results suggest that loss of TRAIL accompanied by dysregulation of TRAIL-induced extrinsic apoptotic pathway molecules could affect malignant progression of canine mammary tumors.This article is protected by

Localization and genotyping of canine papillomavirus in canine inverted papillomas

Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc

2021 Jul 31

Orlandi, M;Mazzei, M;Vascellari, M;Melchiotti, E;Zanardello, C;Verin, R;Albanese, F;Necci, F;Pazzini, L;Lazzarini, G;Abramo, F;
PMID: 34338089 | DOI: 10.1177/10406387211035799

Numerous canine papillomaviruses (CPVs) have been identified (CPV1-23). CPV1, 2, and 6 have been associated with inverted papillomas (IPs). We retrieved 19 IPs from 3 histopathology archives, and evaluated and scored koilocytes, inclusion bodies, giant keratohyalin granules, cytoplasmic pallor, ballooning degeneration, and parakeratosis. IHC targeting major capsid proteins of PV was performed, and CPV genotyping was achieved by PCR testing. Tissue localization of CPV DNA and RNA was studied by chromogenic and RNAscope in situ hybridization (DNA-CISH, RNA-ISH, respectively). IPs were localized to the limbs (50%), trunk (30%), and head (20%), mainly as single nodules (16 of 19). In 15 of 19 cases, immunopositivity was detected within the nuclei in corneal and subcorneal epidermal layers. PCR revealed CPV1 in 11 IPs and CPV2 DNA in 3 IPs. Overall, 14 of 17 cases were positive by both DNA-CISH and RNA-ISH, in accord with PCR results. A histologic score >5 was always obtained in cases in which the viral etiology was demonstrated by IHC, DNA-CISH, and RNA-ISH. IHC and molecular approaches were useful to ascertain the viral etiology of IPs. Although IHC is the first choice for diagnostic purposes, ISH testing allows identification of PV type and the infection phase. RNA-ISH seems a promising tool to deepen our understanding of the pathogenesis of different PV types in animal species.

FGFR signaling and endocrine resistance in breast cancer: Challenges for the clinical development of FGFR inhibitors

Biochimica et biophysica acta. Reviews on cancer

2021 Jul 22

Servetto, A;Formisano, L;Arteaga, CL;
PMID: 34303787 | DOI: 10.1016/j.bbcan.2021.188595

Fibroblast growth factors (FGFs) and their receptors (FGFRs) have been extensively investigated in solid malignancies, representing an attractive therapeutic target. In breast cancer, especially in estrogen receptor positive (ER+) subtype, FGFR signaling aberrations have been reported to contribute to proliferation, dedifferentiation, metastasis and drug resistance. However, clinical trials evaluating the use of FGFR inhibitors in breast cancer have had disappointing results. The different biological properties of distinct FGFR alterations and lack of established patient selection criteria, in addition to the early use of non-selective inhibitors, are possible reasons of this failure. Herein, we review the current knowledge regarding the role of FGFR signaling in endocrine resistance in breast cancer. We will also summarize the results from the clinical development of FGFR inhibitors in breast cancer, discussing future challenges to identify the correct cohorts of patients to enroll in trials testing FGFR inhibitors.

ORAL MUCOSAL LESIONS IN PATIENTS FROM CLINICS OF THE SCHOOL OF DENTISTRY, UNIVERSITY OF ANTIOQUIA, MEDELLÍN, COLOMBIA

Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology

2021 Jul 01

Álvarez Gómez, G;Rodríguez Montoya, G;López, A;Saldarriaga, A;Alzate, M;Muñoz, L;
| DOI: 10.1016/j.oooo.2021.03.039

Background To our knowledge, there are no studies in Colombia that describe the frequency of oral mucosal lesions. Only the ENSAB IV evaluated potentially malignant lesions and lesions associated with a removable prosthesis. Objective The aim of this study was to determine the frequency of oral mucosal lesions and their risk indicators in patients attending clinics of the School of Dentistry, University of Antioquia. Methods Structured interviews, clinical examination, and a biopsy, if deemed necessary, were conducted in a nonprobabilistic sample of 539 patients. Results Eight hundred forty mucosal lesions were found in 409 patients (75.9%). The average age was 35.26 years (SD = 23.4); 69.7% of patients were female. The most frequent lesions were exfoliative cheilitis (17.4%), frictional keratosis (15.4%), and vascular lesions (11.5%). In exploring the relationship between the number of lesions and sociodemographic characteristics and habits, a correlation was found with age (P = .001), use of removable appliances (P = .042), type of appliance (P = .001), and the variable “you have seen or felt something in your mouth” (P = .004). Conclusions The most frequent lesions in this study were exfoliative cheilitis. There was a low percentage of potentially malignant disorders, and no malignant lesions were found. In the teaching programs of dentistry and even to establish the diagnosis of presumption, it is necessary to know the frequency of lesions of the oral mucosa in the region.

Distribution and persistence of atypical porcine pestivirus in experimentally inoculated pigs

Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc

2021 Jun 02

Buckley, AC;Falkenberg, SM;Palmer, MV;Arruda, PH;Magstadt, DR;Schwartz, KJ;Gatto, IR;Neill, JD;Arruda, BL;
PMID: 34078182 | DOI: 10.1177/10406387211022683

Atypical porcine pestivirus (APPV) is a cause of congenital tremors (CTs) in piglets and has been found in swine populations around the globe. Although systemic distribution of the virus has been reported, there is limited information regarding viral localization at the cellular level and distribution at the tissue level. We collected multiple tissues from 2-d-old piglets (n = 36) born to sows inoculated at 45 or 62 d of gestation with APPV via 3 simultaneous routes: intravenous, intranasal, and directly in amniotic vesicles. In addition, 2 boars from APPV-inoculated sows with CT were raised and euthanized when 11 mo old. In situ hybridization performed on tissue samples from piglets demonstrated a broad and systemic distribution of viral RNA including endothelial cells, fibroblasts, and smooth muscle. Labeling in tissues was more pronounced in piglet tissues compared to boars, with the notable exception of diffuse labeling of the cerebellum in boars. Presence of APPV in boar tissues well after resolution of clinical signs suggests persistence of APPV similar to other pestiviruses.

Parafacial neurons in the human brainstem express specific markers for neurons of the retrotrapezoid nucleus

The Journal of comparative neurology

2021 May 19

Levy, J;Droz-Bartholet, F;Achour, M;Facchinetti, P;Parratte, B;Giuliano, F;
PMID: 34008871 | DOI: 10.1002/cne.25191

The retrotrapezoid nucleus (RTN) is a hub for respiratory chemoregulation in the mammal brainstem that integrates chemosensory information from peripheral sites and central relays. Chemosensitive neurons of the RTN express specific genetic and molecular determinants, which have been used to identify RTN precise location within the brainstem of rodents and nonhuman primates. Based on a comparative approach, we hypothesized that among mammals, neurons exhibiting the same specific molecular and genetic signature would have the same function. The co-expression of preprogalanin (PPGAL) and SLC17A6 (VGluT2) mRNAs with duplex in situ hybridization has been studied in formalin fixed paraffin-embedded postmortem human brainstems. Two specimens were processed and analyzed in line with RTN descriptions in adult rats and macaques. Double-labeled PPGAL+/SLC17A6+ neurons were only identified in the parafacial region of the brainstem. These neurons were found surrounding the nucleus of the facial nerve, located ventrally to the nucleus VII on caudal sections, and slightly more dorsally on rostral sections. The expression of neuromedin B (NMB) mRNA as a single marker of chemosensitive RTN neurons has not been confirmed in humans. The location of the RTN in human adults is provided. This should help to develop investigation tools combining anatomic high-resolution imaging and respiratory functional investigations to explore the pathogenic role of the RTN in congenital or acquired neurodegenerative diseases.

Long Noncoding RNA NEAT1: A Potential Biomarker in the Progression of Laryngeal Squamous Cell Carcinoma

ORL; journal for oto-rhino-laryngology and its related specialties

2021 Apr 08

Wang, P;Li, QY;Sun, YN;Wang, JT;Liu, M;
PMID: 33831864 | DOI: 10.1159/000515228

Laryngeal squamous cell carcinoma (LSCC) is diverse in its natural history and responsiveness to treatments. There is an urgent need to generate candidate biomarkers for the stratification and individualization of treatment to avoid overtreatment or inadequate treatment. Long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been identified as an oncogenic gene in multiple human tumors entitles, and dysregulation of NEAT1 was tightly linked to carcinogenesis and cancer progression. One hundred two paraffin samples of LSCC patients were collected. Furthermore, in situ hybridization (ISH), Kaplan-Meier, and MTT were used to analyze the relationship between NEAT1 and the progress of LSCC. In this study, ISH revealed that NEAT1 was strongly expressed in the nucleus. The increased expression of NEAT1 was correlated with T grade, neck nodal metastasis, clinical stage, drinking history, or smoking history of LSCC. The Kaplan-Meier analysis indicated that patients with higher NEAT1 expression had a worse overall survival in LSCC patients. In addition, NEAT1 knockdown significantly inhibited the growth of LSCC cells. Together, these results suggested that NEAT1 involved in the progress of LSCC and might act as a tumor oncogenic gene. This study provides a potential new marker and target for gene therapy in the treatment of LSCC.

Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness

Journal of the American Society of Nephrology : JASN

2021 Apr 02

Schlingmann, KP;Renigunta, A;Hoorn, EJ;Forst, AL;Renigunta, V;Atanasov, V;Mahendran, S;Barakat, TS;Gillion, V;Godefroid, N;Brooks, AS;Lugtenberg, D;Lake, J;Debaix, H;Rudin, C;Knebelmann, B;Tellier, S;Rousset-Rouvière, C;Viering, D;deBaaij, JHF;Weber, S;Palygin, O;Staruschenko, A;Kleta, R;Houillier, P;Bockenhauer, D;Devuyst, O;Vargas-Poussou, R;Warth, R;Zdebik, AA;Konrad, M;
PMID: 33811157 | DOI: 10.1681/ASN.2020111587

The transepithelial transport of electrolytes, solutes, and water in the kidney is a well-orchestrated process involving numerous membrane transport systems. Basolateral potassium channels in tubular cells not only mediate potassium recycling for proper Na+,K+-ATPase function but are also involved in potassium and pH sensing. Genetic defects in KCNJ10 cause EAST/SeSAME syndrome, characterized by renal salt wasting with hypokalemic alkalosis associated with epilepsy, ataxia, and sensorineural deafness. A candidate gene approach and whole-exome sequencing determined the underlying genetic defect in eight patients with a novel disease phenotype comprising a hypokalemic tubulopathy with renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness. Electrophysiologic studies and surface expression experiments investigated the functional consequences of newly identified gene variants. We identified mutations in the KCNJ16 gene encoding KCNJ16, which along with KCNJ15 and KCNJ10, constitutes the major basolateral potassium channel of the proximal and distal tubules, respectively. Coexpression of mutant KCNJ16 together with KCNJ15 or KCNJ10 in Xenopus oocytes significantly reduced currents. Biallelic variants in KCNJ16 were identified in patients with a novel disease phenotype comprising a variable proximal and distal tubulopathy associated with deafness. Variants affect the function of heteromeric potassium channels, disturbing proximal tubular bicarbonate handling as well as distal tubular salt reabsorption.

NLRP3 inflammasome induces CD4+ T cell loss in chronically HIV-1-infected patients

The Journal of clinical investigation

2021 Mar 15

Zhang, C;Song, JW;Huang, HH;Fan, X;Huang, L;Deng, JN;Tu, B;Wang, K;Li, J;Zhou, MJ;Yang, CX;Zhao, QW;Yang, T;Wang, LF;Zhang, JY;Xu, RN;Jiao, YM;Shi, M;Shao, F;Sékaly, RP;Wang, FS;
PMID: 33720048 | DOI: 10.1172/JCI138861

Chronic HIV-1 infection is generally characterized by progressive CD4+ T cell depletion due to direct and bystander death that is closely associated with persistent HIV-1 replication and an inflammatory environment in vivo. The mechanisms underlying the loss of CD4+ T cells in patients with chronic HIV-1 infection are incompletely understood. In this study, we simultaneously monitored caspase-1 and caspase-3 activation in circulating CD4+ T cells, which revealed that pyroptotic and apoptotic CD4+ T cells are distinct cell populations with different phenotypic characteristics. Levels of pyroptosis and apoptosis in CD4+ T cells were significantly elevated during chronic HIV-1 infection, and decreased following effective antiretroviral therapy. Notably, the occurrence of pyroptosis was further confirmed by elevated gasdermin D activation in lymph nodes of HIV-1-infected individuals. Mechanistically, caspase-1 activation closely correlated with the inflammatory marker expression and was shown to occur through NLRP3 inflammasome activation driven by virus-dependent and/or -independent ROS production, while caspase-3 activation in CD4+ T cells was more closely related to T cell activation status. Hence, our findings show that NLRP3-dependent pyroptosis plays an essential role in CD4+ T cell loss in HIV-1-infected patients and implicate pyroptosis signaling as a target for anti-HIV-1 treatment.

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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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