Prenatal CFAP53-related laterality defect: case report and review of the literature

The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians

2023 Dec 01

Mastromoro, G;Guadagnolo, D;Novelli, A;Torres, B;Piane, M;Magliozzi, M;Bernardini, L;Ventriglia, F;Pizzuti, A;Petrucci, S;
PMID: 37041101 | DOI: 10.1080/14767058.2023.2201653

Laterality defects include morphological anomalies with impaired left-right asymmetry induction, such as dextrocardia, situs inversus abdominis, situs inversus totalis and situs ambiguus. The different arrangement of major organs is called heterotaxy. We describe for the first time a fetus with situs viscerum inversus and azygos continuation of the inferior vena cava, due to previously unreported variants in compound heterozygosity in the CFAP53 gene, whose product is implied in cilial motility. Prenatal trio exome sequencing was performed with turn-around time during the pregnancy. The fetuses with laterality defects are suitable candidates for prenatal exome sequencing due to the emerging high diagnostic rate of this group of morphological anomalies. A timely molecular diagnosis plays a fundamental role in genetic counseling, regarding couple decisions on the ongoing pregnancy, providing recurrence risks, and in predicting possible respiratory complications due to ciliary dyskinesia.

Molecular mechanisms of cardiac complications associated with COVID-19

Biophysical Journal

2023 Feb 01

Reiken, S;Dridi, H;Sittenfeld, L;Liu, Y;Marks, A;
| DOI: 10.1016/j.bpj.2022.11.1388

The COVID-19 pandemic has had a devastating global impact, resulting in over 5,000,000 deaths. In the United States alone, over 1,000,000 individuals have died from COVID-19. Cardiovascular complications of COVID-19 include arrhythmias, heart failure, and myocardial infarction and COVID-19 has differentially impacted racial and ethnic groups. Ethnic minority groups, including African Americans and Hispanics, have a higher risk of COVID-19 hospitalization and death, independent of their socioeconomic, lifestyle and health-related factors. Our data indicate substantial proteomic remodeling of cardiac tissues from SARS-CoV-2 infected mice including upregulation of arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy and dilated cardiomyopathy pathways. Markers of collagen deposition were significantly enriched in the COVID-19 group and confirmed by Masson’s trichrome staining in the hearts of SARS-CoV-2 infected mice. Inflammatory cell infiltration, rupture of cardiomyocytes and significantly increased thrombotic events were also observed. Cardiac tissues of COVID-19 patients exhibited oxidative stress, inflammatory and adrenergic signaling, and calcium dyshomeostasis. Furthermore, we have observed posttranslational modifications of cardiac RyR2 calcium release channels from human COVID-19 hearts including increased PKA phosphorylation and oxidation of RyR2 known as the “leaky phenotype” of these channels. These biochemical changes correlated with the cardiomyopathic pathways activation identified by whole cell proteomic analyses in the hACE2 mouse model of COVID-19.

Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology

2023 Feb 27

Caprini, E;D'Agnese, G;Brennan, PA;Rahimi, S;
PMID: 36847112 | DOI: 10.1111/jop.13419

The increase of the incidence of Human Papilloma Virus (HPV) dependent oropharyngeal squamous cell carcinoma (OPSCC) is alarming, although we have greatly progressed in the classification and staging of this disease. We now know that OPSCC-HPV+ is a sub-type of head and neck squamous cell carcinoma with favourable prognosis and good response to therapy that needs a proper system of classification and staging. Thus, in routine practice it is essential to test patients for the presence of HPV. The most popular technique to assess HPV status is immunohistochemistry on biopsy samples with p16, which is an excellent surrogate for high-risk HPV infection. Another highly sensitive and specific tissue-based technique for the detection of HPV is RNAscope In Situ Hybridization (ISH) that has a prohibitive cost, limiting its use in routine practice. Radiomic is an artificial intelligence based non-invasive method of computational analysis of computed tomography, magnetic resonance imaging, positron emission tomography, and ultrasound images. A growing body of evidence suggest that radiomics is able to characterise and detect early relapse after treatment, and enable development of tailored therapy of HPV-positive OPSCC. In this review, we summarise the last findings of radiomic applied to HPV-associated OPSCC.This article is protected by

Distinct biogenesis pathways may have led to functional divergence of the human and Drosophila Arglu1 sisRNA

EMBO reports

2022 Dec 19

Chan, SN;Pek, JW;
PMID: 36533631 | DOI: 10.15252/embr.202154350

Stable intronic sequence RNAs (sisRNAs) are stable, long noncoding RNAs containing intronic sequences. While sisRNAs have been found across diverse species, their level of conservation remains poorly understood. Here we report that the biogenesis and functions of a sisRNA transcribed from the highly conserved Arglu1 locus are distinct in human and Drosophila melanogaster. The Arglu1 genes in both species show similar exon-intron structures where the intron 2 is orthologous and positionally conserved. In humans, Arglu1 sisRNA retains the entire intron 2 and promotes host gene splicing. Mechanistically, Arglu1 sisRNA represses the splicing-inhibitory activity of ARGLU1 protein by binding to ARGLU1 protein and promoting its localization to nuclear speckles, away from the Arglu1 gene locus. In contrast, Drosophila dArglu1 sisRNA forms via premature cleavage of intron 2 and represses host gene splicing. This repression occurs through a local accumulation of dARGLU1 protein and inhibition of telescripting by U1 snRNPs at the dArglu1 locus. We propose that distinct biogenesis of positionally conserved Arglu1 sisRNAs in both species may have led to functional divergence.

Safety De-risking Approaches for Advanced Modalities

pharmafocusasia.com

2022 Jan 01

Gaskin, P;Singh, P;

Artificial intelligence (AI) is now a powerful tool which can be applied to significantly improve the safety de-risking process early in discovery, with AI-driven pipelines of biotechs expanding at a very fast rate. Data from screening studies with DNA-encoded libraries together with high throughput in silico data are screened through AI-enabled computational platforms. These platforms leverage a wide range of in vitro and in vivo models and along with computational predictive models to help identify targets, predicting ‘druggable’ characteristics and target selectivity of molecules from a vast space. In terms of safety, AI can also be used to predict potential interactions and by leveraging publicly available data or proprietary databases can predict potential on- and off-target safety liabilities. A major advantage of AI systems is that they include an active learning loop, referred to as machine learning, which helps to improve the accuracy of prediction and to identify advanceable lead series or candidate molecules leading to a very high success rate, which improves as more data is gathered. Critically AI can also be used to screen billions of molecules virtually, reducing costs and resource requirements and improving the discovery process by more efficient use of molecular biology, public and private databases and other resources.

Unravelling the landscape of skin cancer through single-cell transcriptomics

Translational oncology

2022 Oct 17

Srivastava, A;Bencomo, T;Das, I;Lee, CS;
PMID: 36257209 | DOI: 10.1016/j.tranon.2022.101557

The human skin is a complex organ that forms the first line of defense against pathogens and external injury. It is composed of a wide variety of cells that work together to maintain homeostasis and prevent disease, such as skin cancer. The exponentially rising incidence of skin malignancies poses a growing public health challenge, particularly when the disease course is complicated by metastasis and therapeutic resistance. Recent advances in single-cell transcriptomics have provided a high-resolution view of gene expression heterogeneity that can be applied to skin cancers to define cell types and states, understand disease evolution, and develop new therapeutic concepts. This approach has been particularly valuable in characterizing the contribution of immune cells in skin cancer, an area of great clinical importance given the increasing use of immunotherapy in this setting. In this review, we highlight recent skin cancer studies utilizing bulk RNA sequencing, introduce various single-cell transcriptomics approaches, and summarize key findings obtained by applying single-cell transcriptomics to skin cancer.

S3.3c Alveolar macrophage-mediated host resistance against Aspergillus fumigatus

Medical Mycology

2022 Sep 20

Obar, J;
| DOI: 10.1093/mmy/myac072.s3.3c

S3.3 Innate immune responses to pathogenic fungi, September 21, 2022, 4:45 PM - 6:15 PM Alveolar macrophages (AlvMφ) reside on the luminal surface of the airways serving as the primary phagocyte within the airways of the lungs where they act as immune sentinel cells sensing and responding to microbial and environmental exposures. In this role, AlvMφ must be able to respond in a manner that is appropriate to the threat posed which has been hypothesized to occur through sensing microbial vitality and/or patterns of pathogenesis. It is well-established that AlvMφ interact with phagocytose and respond to A. fumigatus, but their role in host resistance against A. fumigatus is currently controversial. Here I will discuss the role of AlvMφ play in orchestrating a robust and effective antifungal innate immune response to mediate A. fumigatus clearance. AlvMφ orchestrate the protective innate immune response against A. fumigatus by sensing live fungal conidia using the cytosolic RNA-sensing MDA5 receptor to initiate the host protective type I and type III interferon response in both mice and humans. The activation of MDA5/MAVS signaling appears to be mediated by both fungal dsRNA-dependent and fungal dsRNA-independent mechanisms. Thus, AlvMφ serve as a central hub for regulating and tuning the antifungal immune response within the respiratory tract.

Consensus guidelines on the construct validity of rodent models of restless legs syndrome

Disease models & mechanisms

2022 Aug 01

Salminen, AV;Clemens, S;García-Borreguero, D;Ghorayeb, I;Li, Y;Manconi, M;Ondo, W;Rye, D;Siegel, JM;Silvani, A;Winkelman, JW;Allen, RP;Ferré, S;International Restless Legs Syndrome Study Group (IRLSSG), ;
PMID: 35946581 | DOI: 10.1242/dmm.049615

Our understanding of the causes and natural course of restless legs syndrome (RLS) is incomplete. The lack of objective diagnostic biomarkers remains a challenge for clinical research and for the development of valid animal models. As a task force of preclinical and clinical scientists, we have previously defined face validity parameters for rodent models of RLS. In this article, we establish new guidelines for the construct validity of RLS rodent models. To do so, we first determined and agreed on the risk, and triggering factors and pathophysiological mechanisms that influence RLS expressivity. We then selected 20 items considered to have sufficient support in the literature, which we grouped by sex and genetic factors, iron-related mechanisms, electrophysiological mechanisms, dopaminergic mechanisms, exposure to medications active in the central nervous system, and others. These factors and biological mechanisms were then translated into rodent bioequivalents deemed to be most appropriate for a rodent model of RLS. We also identified parameters by which to assess and quantify these bioequivalents. Investigating these factors, both individually and in combination, will help to identify their specific roles in the expression of rodent RLS-like phenotypes, which should provide significant translational implications for the diagnosis and treatment of RLS.

Microglia-derived PDGFB promotes neuronal potassium currents to suppress basal sympathetic tonicity and limit hypertension

Immunity

2022 Jul 12

Bi, Q;Wang, C;Cheng, G;Chen, N;Wei, B;Liu, X;Li, L;Lu, C;He, J;Weng, Y;Yin, C;Lin, Y;Wan, S;Zhao, L;Xu, J;Wang, Y;Gu, Y;Shen, XZ;Shi, P;
PMID: 35863346 | DOI: 10.1016/j.immuni.2022.06.018

Although many studies have addressed the regulatory circuits affecting neuronal activities, local non-synaptic mechanisms that determine neuronal excitability remain unclear. Here, we found that microglia prevented overactivation of pre-sympathetic neurons in the hypothalamic paraventricular nucleus (PVN) at steady state. Microglia constitutively released platelet-derived growth factor (PDGF) B, which signaled via PDGFRα on neuronal cells and promoted their expression of Kv4.3, a key subunit that conducts potassium currents. Ablation of microglia, conditional deletion of microglial PDGFB, or suppression of neuronal PDGFRα expression in the PVN elevated the excitability of pre-sympathetic neurons and sympathetic outflow, resulting in a profound autonomic dysfunction. Disruption of the PDGFBMG-Kv4.3Neuron pathway predisposed mice to develop hypertension, whereas central supplementation of exogenous PDGFB suppressed pressor response when mice were under hypertensive insult. Our results point to a non-immune action of resident microglia in maintaining the balance of sympathetic outflow, which is important in preventing cardiovascular diseases.

miR-181b targets semaphorin 3A to mediate TGF-β-induced endothelial-mesenchymal transition related to atrial fibrillation

The Journal of clinical investigation

2022 Jul 01

Lai, YJ;Tsai, FC;Chang, GJ;Chang, SH;Huang, CC;Chen, WJ;Yeh, YH;
PMID: 35775491 | DOI: 10.1172/JCI142548

Atrial fibrosis is an essential contributor to atrial fibrillation (AF). It remains unclear whether atrial endocardial endothelial cells (AEECs) that undergo endothelial-mesenchymal transition (EndMT) are among the sources of atrial fibroblasts. We studied human atria, TGF-β-treated human AEECs, cardiac-specific TGF-β-transgenic mice, and heart failure rabbits to identify the underlying mechanism of EndMT in atrial fibrosis. Using isolated AEECs, we found that miR-181b was induced in TGF-β-treated AEECs, which decreased semaphorin 3A (Sema3A) and increased EndMT markers, and these effects could be reversed by a miR-181b antagomir. Experiments in which Sema3A was increased by a peptide or decreased by a siRNA in AEECs revealed a mechanistic link between Sema3A and LIM-kinase 1/phosphorylated cofilin (LIMK/p-cofilin) signaling and suggested that Sema3A is upstream of LIMK in regulating actin remodeling through p-cofilin. Administration of the miR-181b antagomir or recombinant Sema3A to TGF-β-transgenic mice evoked increased Sema3A, reduced EndMT markers, and significantly decreased atrial fibrosis and AF vulnerability. Our study provides a mechanistic link between the induction of EndMT by TGF-β via miR-181b/Sema3A/LIMK/p-cofilin signaling to atrial fibrosis. Blocking miR-181b and increasing Sema3A are potential strategies for AF therapeutic intervention.

VMHvllCckar cells dynamically control female sexual behaviors over the reproductive cycle

Neuron

2022 Jul 21

Yin, L;Hashikawa, K;Hashikawa, Y;Osakada, T;Lischinsky, JE;Diaz, V;Lin, D;
PMID: 35896109 | DOI: 10.1016/j.neuron.2022.06.026

Sexual behavior is fundamental for the survival of mammalian species and thus supported by dedicated neural substrates. The ventrolateral part of ventromedial hypothalamus (VMHvl) is an essential locus for controlling female sexual behaviors, but recent studies revealed the molecular complexity and functional heterogeneity of VMHvl cells. Here, we identify the cholecystokinin A receptor (Cckar)-expressing cells in the lateral VMHvl (VMHvllCckar) as the key controllers of female sexual behaviors. The inactivation of VMHvllCckar cells in female mice diminishes their interest in males and sexual receptivity, whereas activating these cells has the opposite effects. Female sexual behaviors vary drastically over the reproductive cycle. In vivo recordings reveal reproductive-state-dependent changes in VMHvllCckar cell spontaneous activity and responsivity, with the highest activity occurring during estrus. These in vivo response changes coincide with robust alternation in VMHvllCckar cell excitability and synaptic inputs. Altogether, VMHvllCckar cells represent a key neural population dynamically controlling female sexual behaviors over the reproductive cycle.

Prss29 Cre recombinase mice are useful to study adult uterine gland function

Genesis (New York, N.Y. : 2000)

2022 Jul 22

Kelleher, AM;Allen, CC;Davis, DJ;Spencer, TE;
PMID: 35866844 | DOI: 10.1002/dvg.23493

All mammalian uteri contain glands in their endometrium that develop only or primarily after birth. In mice, those endometrial glands govern post implantation pregnancy establishment via regulation of blastocyst implantation, stromal cell decidualization, and placental development. Here, we describe a new uterine glandular epithelium (GE) specific Cre recombinase mouse line that is useful for the study of uterine gland function during pregnancy. Utilizing CRISPR-Cas9 genome editing, Cre recombinase was inserted into the endogenous serine protease 29 precursor (Prss29) gene. Both Prss29 mRNA and Cre recombinase activity was specific to the GE of the mouse uterus following implantation, but was absent from other areas of the female reproductive tract. Next, Prss29-Cre mice were crossed with floxed forkhead box A2 (Foxa2) mice to conditionally delete Foxa2 specifically in the endometrial glands. Foxa2 was absent in the glands of the post-implantation uterus, and Foxa2 deleted mice exhibited complete infertility after their first pregnancy. These results establish that Prss29-Cre mice are a valuable resource to elucidate and explore the functions of glands in the adult uterus.

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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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