Deciphering the Molecular Mechanisms of Orai1-dependent Entosis in Cancer Development and SEPTINs Cleavage-mediated Ciliary Defects in Coronavirus Infection

Department of Biological SciencesThe cytoskeleton is a complex network of protein filaments that plays a crucial role in maintaining cell shape, organizing cellular components, and coordinating various cellular processes. This study aimed to explore the regulation of the cytoskeleton in the context of cancer development and investigate the mechanism underlying cytoskeletal defects during virus infection. It provides insights into the pathogenesis of various disease and identify potential therapeutic targets. In the first part, I described the regulation mechanism of cytoskeleton during cancer development, specifically in the context of Entosis. Entosis is a non-apoptotic cell death process that forms characteristic cell-in-cell structures in cancers, killing invading cells. Intracellular Ca2+ dynamics are essential for cellular processes, including actomyosin contractility, migration, and autophagy. However, the significance of Ca2+ and Ca2+ channels participating in entosis are unclear. Here, I showed that intracellular Ca2+ signaling regulates entosis via SEPTIN-Orai1-Ca2+/CaM-MLCK-actomyosin axis. Intracellular Ca2+ oscillations in entotic cells showed spatiotemporal variations during engulfment, mediated by Orai1 Ca2+ channels in plasma membranes. SEPTIN controlled polarized distribution of Orai1 for local MLCK activation, resulting in MLC phosphorylation and actomyosin contraction, leading to internalization of invasive cells. Ca2+ chelators and SEPTIN, Orai1, and MLCK inhibitors suppressed entosis. This study identified potential targets for treating entosis-associated tumors, showed that Orai1 is an entotic Ca2+ channel that provides essential Ca2+ signaling, and shed light on the molecular mechanism underlying entosis that involves SEPTIN filaments, Orai1, and MLCK. In the second part, I explored the mechanism underlying cytoskeletal defects during virus infection, focusing on their implications in ciliopathy. Coronaviruses target ciliate cells causing the loss of cilia, acute rhinorrheas, and other ciliopathies. The loss of ciliary function may help the virus infect, replicate, and spread. However, the molecular mechanisms by which coronaviruses cause ciliary defects are still unclear. Herein I demonstrate how coronavirus infection and SARS-CoV-2 3CL protease induce cilia dysfunction by targeting a host protein septin that is required for the structure and function of cilia. Further, I demonstrate that coronaviruses and 3CL protease lead to the cleavage of several septin proteins (SEPT2, 6, and 9), producing cleaved obstructive fragments. Furthermore, ectopic expression of cleaved SEPT2 fragments shows defective ciliogenesis, disoriented septin filaments, and ablated Sonic Hedgehog (SHH) signaling in a protease activity-dependent manner. I present that the 3CLpro inhibitors are potent and prevent abnormal ciliary structures and SHH signaling. These results provide useful insights into the general mechanisms underlying ciliary defects caused by coronaviruses, which in turn facilitate virus spread and prove that preclinical and clinical 3CL protease inhibitors may prove useful as therapeutics for treating ciliary defects of coronaviruses.clos

Quality of Life Differences between Younger and Older Breast Cancer Patients

Purpose: This study was designed to investigate quality of life (QOL) differences between younger (<50 years) and older (≥50 years) breast cancer survivors and to determine the unique effect of age on QOL after adjusting age-correlated variables. Methods: One thousand two hundred fifty patients were enrolled. Clinicopatholgical and social parameters were reviewed and Functional Assessment of Cancer Therapy-Breast cancer instrument (FACT-B) and the Ladder of Life scale were used to measure the QOL. Among 1,250 eligible patients, 1,094 patients completed the questionnaire and were used for analysis. Chi-square test, t-test and a series of multiple regression analyses were conducted to verify age-related differences in QOL between two groups and to evaluate the unique contribution of age variable on QOL of breast cancer patients. Results: Significant socio-demographic and clinical differences existed based on age categories, includin

Acupuncture Enhances the Synaptic Dopamine Availability to Improve Motor Function in a Mouse Model of Parkinson's Disease

Parkinson's disease (PD) is caused by the selective loss of dopaminergic neurons in the substantia nigra (SN) and the depletion of striatal dopamine (DA). Acupuncture, as an alternative therapy for PD, has beneficial effects in both PD patients and PD animal models, although the underlying mechanisms therein remain uncertain. The present study investigated whether acupuncture treatment affected dopamine neurotransmission in a PD mouse model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found that acupuncture treatment at acupoint GB34 improved motor function with accompanying dopaminergic neuron protection against MPTP but did not restore striatal dopamine depletion. Instead, acupuncture treatment increased dopamine release that in turn, may lead to the enhancement of dopamine availability in the synaptic cleft. Moreover, acupuncture treatment mitigated MPTP-induced abnormal postsynaptic changes, suggesting that acupuncture treatment may increase postsynaptic dopamine neurotransmission and facilitate the normalization of basal ganglia activity. These results suggest that the acupuncture-induced enhancement of synaptic dopamine availability may play a critical role in motor function improvement against MPTP

Fulminant and Fatal Multiple Organ Failure in a 12-Year-Old Boy With Mycoplasma pneumoniae Infection

Mycoplasma pneumoniae (Mp) is a unique pathogen that causes not only pulmonary but also extrapulmonary manifestations that must be rapidly diagnosed. A 12-year-old boy, with no relevant medical history, presented with fever, severe epigastric pain, and vomiting. Laboratory findings showed fulminant and cholestatic hepatitis, hemolytic anemia, thrombocytopenia, acute kidney injury, disseminated intravascular coagulopathy, acute myocardial infarction, and rhabdomyolysis. His clinical condition rapidly deteriorated during intubation and continuous renal replacement therapy. Despite intensive treatment, he did not recover. We report a case of fulminant and fatal multiple organ failure in a previously healthy boy with Mp infection, describing the possible pathomechanisms of multiple organ failure involved in the disease

Environmental and dietary exposure of perfluorooctanoic acid and perfluorooctanesulfonic acid in the Nakdong River, Korea

This study performed the first environmental and dietary exposure assessment to explore plant uptake of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) from agricultural soil and irrigation water in the Nakdong River delta, South Korea. Annual average concentrations of total PFOA and PFOS ranged from 0.026 to 0.112 µg L−1 (irrigation water), and from 0.818 to 1.364 µg kg−1 (soil), respectively. PFOA and PFOS hotspots were identified downstream of the Nakdong River and were influenced by seasonal climatic variations. The observed average biennial concentration of the sum of PFOA and PFOS decreased in irrigation water, from 0.112 µg L−1 in 2013 to 0.026 µg L−1 in 2015, suggests that the 2013 Persistent Organic Pollutants Control Act may have helped to reduce levels of PFAS at this location. This study calculated some of the highest plant uptake factors reported to date, with values ranging from 0.962 in green onions to < 0.004 in plums. Leafy vegetables and rice are important components of the Korean diet; these groups had the largest contribution to the estimated dietary intake of PFOA and PFOS, which was calculated at 0.449 and 0.140 ng kg −1bw day−1, respectively. This corresponded to 66.4% for PFOA and 7.9% for PFOS of the EFSA reference dose (RfD). The dietary intake of PFOA and PFOS from crops alone did not exceed the RfD. However, when the estimated daily intake (EDI) from other sources such as tap water, meat, fish, dairy, and beverages was included in the exposure risk assessment, both of the EDIs to PFOA and PFOS exceeded the RfDs, indicating that there may be a risk to human health. This study concludes that consumption of crops might, therefore, be a significant and underappreciated pathway for human exposure to PFAS

A Comparative Study of Anxiety, Pain and Maternal-fetal Attachment between Women who became Pregnant after Infertility Treatment and became Pregnant Naturally

PURPOSE: This study was a comparative study to understand the levels of anxiety, pain and maternal-fetal attachment between women who became pregnant after infertility treatment and became pregnant naturally. METHODS: This study used a comparative survey design. Data were collected by 50 couples of natural pregnancy and of who became pregnant after infertility treatment who visited delivery room in C Medical hospital, Seoul. These couples were to have first baby, and cervix dilatation of women was less than 3 cm regardless of diagnosis. RESULTS: The score of anxiety of infertile women was significantly higher than that of naturally pregnant women; however, that of spouses showed no difference. The pain score for infertile women was significantly higher in both the active and transition phases. Pain scores that reported by their spouses did not show differences in either phase. The score of maternal-fetal attachment showed no difference between two groups of women. CONCLUSION: The result showed the importance of nursing intervention to reduce women&apos;s anxiety and pain, through both antenatal-childbirth education programs and assertive nursing interventions. It is necessary to develop and evaluate new intervention which would be more effective for reducing pain and anxiety for couples who became pregnant after infertility treatment

From Peripheral to Central: The Role of ERK Signaling Pathway in Acupuncture Analgesia

Despite accumulating evidence of the clinical effectiveness of acupuncture, its mechanism remains largely unclear. We assume that molecular signaling around the acupuncture needled area is essential for initiating the effect of acupuncture. To determine possible bio-candidates involved in the mechanisms of acupuncture and investigate the role of such bio-candidates in the analgesic effects of acupuncture, we conducted 2 stepwise experiments. First, a genome-wide microarray of the isolated skin layer at the GB34-equivalent acupoint of C57BL/6 mice 1 hour after acupuncture found that a total of 236 genes had changed and that extracellular signal–regulated kinase (ERK) activation was the most prominent bio-candidate. Second, in mouse pain models using formalin and complete Freund adjuvant, we found that acupuncture attenuated the nociceptive behavior and the mechanical allodynia; these effects were blocked when ERK cascade was interrupted by the mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) inhibitor U0126 (.8 μg/μL). Based on these results, we suggest that ERK phosphorylation following acupuncture needling is a biochemical hallmark initiating the effect of acupuncture including analgesia

Shared psychological characteristics that are linked to aggression between patients with Internet addiction and those with alcohol dependence

Background : Internet addiction (IA) is considered as one of behavioral addictions. Although common neurobiological mechanisms have been suggested to underlie behavioral addiction and substance dependence, few studies have directly compared IA with substance dependence, such as alcohol dependence (AD). Methods : We compared patients with IA, AD, and healthy controls (HC) in terms of the Five Factor Model of personality and with regard to impulsiveness, anger expression, and mood to explore psychological factors that are linked to aggression. All patients were treatment-seeking and had moderate-to-severe symptoms. Results : The IA and AD groups showed a lower level of agreeableness and higher levels of neuroticism, impulsivity, and anger expression compared with the HC group, which are characteristics related to aggression. The addiction groups showed lower levels of extraversion, openness to experience, and conscientiousness and were more depressive and anxious than the HCs, and the severity of IA and AD symptoms was positively correlated with these types of psychopathology. Conclusions : IA and AD are similar in terms of personality, temperament, and emotion, and they share common characteristics that may lead to aggression. Our findings suggest that strategies to reduce aggression in patients with IA are necessary and that IA and AD are closely related and should be dealt with as having a close nosological relationship.This work was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (HI12C-0113-020013).Peer Reviewe