Generation of a genetically encoded voltage indicator MARINA reporter human iPS cell line using Cas9 (VULSCi002-A-2).

Fluorescent protein-based Genetically Encoded Voltage Indicators (GEVI) offer a remarkable system for high-throughput screening of membrane potential phenotypes. The GEVI MARINA is a derivative from ArcLight, which conversely to ArcLight increases its fluorescence intensity alongside depolarization. Here we created knock-in reporter human iPS cell lines carrying the MARINA reporter using SpCas9 programmable nuclease and characterize a heterozygous clone.

Proof-of-Concept for Long-Term Human Endometrial Epithelial Organoids in Modeling Menstrual Cycle Responses.

Endometrial disorders, such as infertility and endometriosis, significantly impact reproductive health, thus necessitating better models to study endometrial function. Current in vitro models fail to replicate the complexity of the human endometrium throughout the entire menstrual cycle. This study aimed to assess the physiological response of human endometrial organoids (hEOs) to in vitro hormonal treatments designed to mimic the hormonal fluctuations of the menstrual cycle.

Transcriptomic profiling of the oocyte-cumulus-granulosa cell complex from estrogen receptor β knockout mice.

Objective: To study the role of estrogen receptor β in follicle development and maturation and the response to gonadotropin stimulation aiming at superovulation.

Design: Experimental study and transcriptomic analysis.

Setting: Karolinka Institutet, medical university.

CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice.

The brain-specific enzyme CYP46A1 controls cholesterol turnover by converting cholesterol into 24-hydroxycholesterol (24OH). Dysregulation of brain cholesterol turnover and reduced levels are observed in Alzheimer's disease (AD). In this study, we report that overexpression in aged female mice leads to enhanced estrogen signaling in the hippocampus and improved cognitive functions.

Loss of ERβ in Aging LXRαβ Knockout Mice Leads to Colitis.

Liver X receptors (LXRα and LXRβ) are oxysterol-activated nuclear receptors that play key roles in cholesterol homeostasis, the central nervous system, and the immune system. We have previously reported that LXRαβ-deficient mice are more susceptible to dextran sodium sulfate (DSS)-induced colitis than their WT littermates, and that an LXR agonist protects against colitis in mice mainly via the regulation of the immune system in the gut. We now report that both LXRα and LXRβ are expressed in the colonic epithelium and that in aging LXRαβ mice there is a reduction in the intensity of goblet cells, mucin (MUC2), TFF3, and estrogen receptor β (ERβ) levels.

ERβ in Granulosa Cell Tumors and Its Clinical Potential.

Granulosa cell tumors (GCTs) are rare ovarian tumors comprising an adult and a juvenile subtype. They have a generally good prognosis, but the survival rate drastically declines in patients with late-stage or recurring tumors. Due to the rarity of GCTs, the tumor type is largely understudied and lacks a specific treatment strategy.

Harnessing the reverse cholesterol transport pathway to favor differentiation of monocyte-derived APCs and antitumor responses.

Lipid and cholesterol metabolism play a crucial role in tumor cell behavior and in shaping the tumor microenvironment. In particular, enzymatic and non-enzymatic cholesterol metabolism, and derived metabolites control dendritic cell (DC) functions, ultimately impacting tumor antigen presentation within and outside the tumor mass, dampening tumor immunity and immunotherapeutic attempts. The mechanisms accounting for such events remain largely to be defined.

Neuroprotection against Aminochrome Neurotoxicity: Glutathione Transferase M2-2 and DT-Diaphorase.

Glutathione is an important antioxidant that plays a crucial role in the cellular protection against oxidative stress and detoxification of electrophilic mutagens, and carcinogens. Glutathione transferases are enzymes catalyzing glutathione-dependent reactions that lead to inactivation and conjugation of toxic compounds, processes followed by subsequent excretion of the detoxified products. Degeneration and loss of neuromelanin-containing dopaminergic neurons in the nigrostriatal neurons generally involves oxidative stress, neuroinflammation, alpha-synuclein aggregation to neurotoxic oligomers, mitochondrial dysfunction, protein degradation dysfunction, and endoplasmic reticulum stress.

Astrocytes protect dopaminergic neurons against aminochrome neurotoxicity.

Astrocytes protect neurons by modulating neuronal function and survival. Astrocytes support neurons in several ways. They provide energy through the astrocyte-neuron lactate shuttle, protect neurons from excitotoxicity, and internalize neuronal lipid droplets to degrade fatty acids for neuronal metabolic and synaptic support, as well as by their high capacity for glutamate uptake and the conversion of glutamate to glutamine.

Expression of Sex Hormone Receptor and Immune Response Genes in Peripheral Blood Mononuclear Cells During the Menstrual Cycle.

Sex hormones are known to interact with the immune system on multiple levels but information on the types of sex hormone receptors (SHR) and their expression levels in immune cells is scarce. Estrogen, testosterone and progesterone are all considered to interact with the immune system through their respective cell receptors (ERα and ERβ including the splice variant ERβ2, AR and PGR). In this study expression levels of SHR genes in peripheral blood mononuclear cells (PBMCs) and cell subsets (CD4 and CD8 T-cells, CD56 NK-cells, CD14 monocytes and CD19 B-cells) were analyzed using standard manual qPCR or a qPCR array (TLDA).

Estrogen receptors and the aging brain.

The female sex hormone estrogen has been ascribed potent neuroprotective properties. It signals by binding and activating estrogen receptors that, depending on receptor subtype and upstream or downstream effectors, can mediate gene transcription and rapid non-genomic actions. In this way, estrogen receptors in the brain participate in modulating neural differentiation, proliferation, neuroinflammation, cholesterol metabolism, synaptic plasticity, and behavior.

Loss of liver X receptor β in astrocytes leads to anxiety-like behaviors via regulating synaptic transmission in the medial prefrontal cortex in mice.

Astrocytes are integral components of synaptic transmission, and their dysfunction leads to neuropsychiatric disorders such as anxiety and depression. Liver X receptor β (LXRβ) is expressed in astrocytes, and LXRβ global knockout mice shows impaired synaptic formation. In order to define the role of LXRβ in astrocytes, we used a conditional Cre-loxP system to specifically remove LXRβ from astrocytes.

Corrigendum to "Blood hormones and torque teno virus in peripheral blood mononuclear cells" [Heliyon 6 (11) (2020) e05535].

[This corrects the article DOI: 10.1016/j.heliyon.

Estrogen receptor beta and neural development.

The female sex hormone estradiol (E2, 17β-estradiol) has important functions in the developing brain. In addition to regulating sexual differentiation of the brain, E2 participates in the development of brain areas involved in functions unrelated to reproduction, such as cognition. E2 signals mainly thorough two estrogen receptors; estrogen receptor alpha (ERα) and beta (ERβ).

Hematopoietic stem cell- and induced pluripotent stem cell-derived CAR-NK cells as reliable cell-based therapy solutions.

Hematopoietic stem cell- (HSC) and induced pluripotent stem (iPS) cell-derived natural killer (NK) cells containing engineered functions, such as chimeric antigen receptors (CAR), offer great promise for the treatment of seemingly incurable oncological malignancies. Today, some of the main challenges of CAR cell-based therapeutics are the long manufacturing time and safety of the cell sources used. Additional challenges include avoiding graft vs host disease (GVHD) and cytokine release syndrome (CRS).

Cellular Trafficking of Glutathione Transferase M2-2 Between U373MG and SHSY-S7 Cells is Mediated by Exosomes.

The enzyme glutathione transferase M2-2, expressed in human astrocytes, increases its expression in the presence of aminochrome and catalyzes the conjugation of aminochrome, preventing its toxic effects. Secretion of the enzyme glutathione transferase M2-2 from U373MG cells, used as a cellular model for astrocytes, has been reported, and the enzyme is taken up by neuroblastoma SYSH-S7 cells and provide protection against aminochrome. The present study provides evidence that glutathione transferase M2-2 is released in exosomes from U373MG cells, thereby providing a means for intercellular transport of the enzyme.

Generation of nonviral integration-free human iPS cell line KISCOi001-A from normal human fibroblasts, under defined xeno-free and feeder-free conditions.

KISCOi001-A is a healthy feeder-free and fully characterized human induced pluripotent stem (iPS) cell line cultured under xeno-free and defined conditions. The cell line is generated from normal human foreskin fibroblasts with non-integrating episomal plasmid vectors encoding OCT4, SOX2, KLF4, NANOG, LIN28, nontransforming L-MYC and dominant negative p53. The generated iPS cells are transgene-free and their pluripotency is confirmed by the expression of stem cell markers and capacity to differentiate into the cells of ectoderm, endoderm and mesoderm while their identity and karyotype stability is confirmed with Genomic assays.

Blood hormones and torque teno virus in peripheral blood mononuclear cells.

Men and women respond differently to infectious diseases. Women show less morbidity and mortality, partially due to the differences in sex hormone levels which can influence the immune response. Torque teno virus (TTV) is non-pathogenic and ubiquitously present in serum from a large proportion (up to 90%) of adult humans with virus levels correlating with the status of the host immune response.

Generation of an all-exon Esr2 deleted mouse line: Effects on fertility.

Estrogen receptor beta (ERβ), encoded by the Esr2 gene, is one of two nuclear receptors that mediate the functions of the steroid hormone estradiol. The binding of estradiol to the receptor results in enhanced transcription of many genes that have estrogen response elements in promoter or enhancer regions. Several genetically modified mouse lines with mutations or deletions of exons in the Esr2 gene have been developed and results from analysis of these are not completely consistent, especially regarding ERβ's role in fertility.

Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene.

Disagreements about the phenotype of estrogen receptor β (ERβ) knockout mouse, created by removing the DNA-binding domain of the ERβ gene or interruption of the gene with a neocassette (Oliver Smithies ERβ knockout mice [ERβ]), prompted us to create an ERβ knockout mouse by deleting the ERβ gene with the use of CRISPR/Cas9 technology. We confirmed that the ERβ gene was eliminated from the mouse genome and that no ERβ mRNA or protein was detectable in tissues of this mouse. Overall the phenotype of the ventral prostate (VP) and mammary gland (MG) in ERβ mice was similar to, but more severe than, that in the ERβmice.

Sex Stratified Treatment of Neurological Disorders: Challenges and Perspectives.

Despite the obvious sex differences in many of the most common neuropsychiatric and neurodegenerative disorders, males and females are still often treated the same from a clinical perspective. Why is that? The simple answer is that there is still too little known about this very complex matter. Sex hormone signaling, genetic sex, sex-biased comorbidities, and social gender perceptions all interact, making discrimination between the impacts of each of these factors hard to evaluate.

Motor Function Deficits in the Estrogen Receptor Beta Knockout Mouse: Role on Excitatory Neurotransmission and Myelination in the Motor Cortex.

Background: Male estrogen receptor beta (ERβ) knockout (BERKO) mice display anxiety and aggression linked to, among others, altered serotonergic signaling in the basolateral amygdala and dorsal raphe, impaired cortical radial glia migration, and reduced GABAergic signaling. The effects on primary motor cortex (M1 cortex) and locomotor activity as a consequence of ERβ loss have not been investigated.

Objective: The aim of this study was to determine whether locomotor activity is altered as a consequence of the changes in the M1 cortex.

Citalopram attenuates social behavior deficits in the BTBR TItpr3/J mouse model of autism.

Autism spectrum disorder (ASD) is diagnosed by two core symptoms: impaired social communication and the presence of repetitive, stereotyped behaviors and/or restricted interests. Alterations in serotonergic signaling are involved in the genesis of ASD. Selective serotonin reuptake inhibitors (SSRIs) have been reported to reduce repetitive behaviors and rescue social deficits in ASD mouse models and patients.