•Viral pandemics have been associated with an increased incidence of schizophrenia.•Maternal immune activation models have provided support for this association.•SARS-CoV-2 has been associated with ...neuropsychiatric symptoms, may be neurotropic.•It remains unclear whether SARS-CoV-2 is associated with direct vertical transmission.•It is plausible that SARS-CoV-2 exposure in utero may increase risk for schizophrenia later in life.
The SARS-CoV-2 virus has emerged as a striking 21st century pandemic. Communities across the globe have experienced significant infection rates and widespread psychosocial stress and trauma, leading to calls for increased allocation of resources for mental health screening and treatment. In addition to the burden of psychosocial stress, there is increasing evidence of direct viral neuroinvasion of the central nervous system through physical contact with the nasal mucosa. In a parallel fashion, there is a significant body of ongoing research related to the risk of in utero viral transmission and the resulting neurodevelopmental impact in the fetus. Aberrant neurodevelopment secondary to viral transmission has previously been related to the later development of psychosis, schizophrenia, and schizophrenia spectrum disorders, generating the hypothesis that this population of individuals exposed to SARS-CoV-2 may see an increased incidence in future decades. We discuss the current understanding of the possible neurotropism and vertical transmission of SARS-CoV-2, and relate this to the history of viral pandemics to better understand the relationship of viral infection, aberrant immune response and neurodevelopment, and the risk for schizophrenia disorder.
Abstract
Circadian regulation of nuclear receptors in peripheral tissues is important in the timing of key physiological processes. However few studies have examined circadian regulation of estrogen ...receptor alpha (ERa) protein in cancer or normal tissues, and no studies have evaluated ERα phosphorylation during the circadian cycle. In addition to transcription, protein turnover and posttranslational modifications are important regulatory mechanisms in the circadian control of protein function. ERα protein is important in regulation of the peripheral clock proteins Period (PER), Cryptochrome (CRY), CLOCK, and brain and muscle arnt-like protein-1 (BMAL1). Several key ERα phosphorylation sites, serine 118 and serine 167, important in regulating ERα function contain consensus sequences for two kinases, casein kinase 1 and 2 (CK1, CK2), that regulate the peripheral clock proteins levels. The present study examined ERα protein levels and phosphorylation in human and rat mammary carcinoma cells following entrainment by 50% serum shock that results in circadian oscillation of clock genes in vitro. In human MCF-7 breast cancer cells, ERα protein levels exhibited circadian regulation after serum shock with an approx. 60% decrease at 4 hours, recovery to baseline level or above at 16 hours, and a 30% decline from baseline at 24 hours. Estradiol treatment resulted in a longer sustained suppression of ERα protein levels. Rat MAT mammary carcinoma cells exhibited a similar circadian regulation of ERα protein following serum shock. In MCF-7 cells, serine 118 phosphorylation was elevated 2-7 fold 4 hours after serum shock with a subsequent return to baseline levels by 12 hours. Estradiol treatment resulted in a more robust circadian cycle of serine 118 phosphorylation of up to 40 fold with peaks occurring between 4-8 hours and at 16-24 hours. A reverse phosphorylation pattern occurred for serine 167 phosphorylation. Serum shock resulted in a single induction up to 23 fold of serine 167 phosphorylation at 8-12 hours that was suppressed by estradiol. In rat MAT cells, serum shock resulted in circadian oscillation of serine 167 phosphorylation up to 3 fold with peaks at 8 and 20 hours that was similar when cells were treated with estradiol. For both MCF-7 cells and MAT cells, it was noted that peak levels of ERa protein and ERα phosphorylation were out of phase. Estradiol induction of cyclin D1 and c-myc mRNA demonstrated functional ERα signaling following serum shock. These data demonstrate a very significant circadian regulation of ERα protein levels and ERα phosphorylation in mammary carcinoma cells following entrainment by serum shock that likely contribute to time-dependent effects on peripheral clock function and ERα signaling in mammary cancer.A.Y. and Y.Z. contributed equally to this work.
Citation Format: Alix Youngblood, Yifang Zhang, Murali Anbalagan, Dawei Tian, Brian G. Rowan. Circadian regulation of estrogen receptor alpha protein and phosphorylation in mammary carcinoma cells. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1822.
A 29-year-old man with chronic portal venous thrombosis resulting in portal biliopathy required stenting of his common bile duct (CBD) and underwent a transjugular intrahepatic portosystemic shunt ...(TIPS) procedure to decrease portal pressures. He later presented with abdominal pain in the setting of prolonged CBD stent placement and was found to have air within his TIPS stent with a fistula on endoscopic retrograde cholangiopancreatography between his fully covered CBD stent and bare metal TIPS stent. There was concern that further intervention would lead to an air embolus. We suggest that when multiple stents are indicated, stent selection with close monitoring is critical.
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