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We do not yet understand exactly how corticosteroids attenuate hyperinflammatory responses and alleviate high-risk coronavirus disease 2019 (COVID-19). We aimed to reveal the molecular mechanisms of hyperinflammation in COVID-19 and the anti-inflammatory effects of corticosteroids in patients with high-risk COVID-19. We performed single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from three independent COVID-19 cohorts: cohort 1 was used for comparative analysis of high-risk and low-risk COVID-19 (47 PBMC samples from 28 patients), cohort 2 for longitudinal analysis during COVID-19 (57 PBMC samples from 15 patients), and cohort 3 for investigating the effects of corticosteroid treatment in patients with high-risk COVID-19 (55 PBMC samples from 13 patients). PBMC samples from healthy donors (12 PBMC samples from 12 donors) were also included. Cohort 1 revealed a significant increase in the proportion of monocytes expressing the long noncoding RNAs NEAT1 and MALAT1 in high-risk patients. Cohort 2 showed that genes encoding inflammatory chemokines and their receptors were upregulated during aggravation, whereas genes related to angiogenesis were upregulated during improvement. Cohort 3 demonstrated downregulation of interferon-stimulated genes (ISGs), including STAT1, in monocytes after corticosteroid treatment. In particular, unphosphorylated STAT-dependent ISGs enriched in monocytes from lupus patients were selectively downregulated by corticosteroid treatment in patients with high-risk COVID-19. Corticosteroid treatment suppresses pathologic interferon responses in monocytes by downregulating STAT1 in patients with high-risk COVID-19. Our study provides insights into the mechanisms underlying COVID-19 aggravation and improvement and the effects of corticosteroid treatment.

Hypertriglyceridemia, a symptom of elevated triglyceride level in the blood, is a potent risk factor for cardiovascular and metabolic disorders. Among the numerous treatments to regulate circulating triglyceride levels, fibrates are widely used to treat hypertriglyceridemia, although they also have side effects such as hepatotoxicity and gallstone formation. In the present study, we aimed to investigate the blood triglyceride-lowering effects of a naturally fermented green tea extract (NFGT) and the underlying mechanisms on hypertriglyceridemia in vitro and in vivo models. NFGT suppressed the expression of lipogenic genes, while augmented expression of fatty acid oxidation-related genes in cultured cells, leading to the significant decrease of intracellular triglyceride content. NFGT treated group in fructose-induced hypertriglyceridemic rat model significantly decreased plasma and hepatic triglyceride, which was accompanied by an increase in excretion of fecal fat. Taken together, we propose that NFGT could be potentially a novel functional ingredient to prevent or treat hypertriglyceridemia.

Two fundamental elements of pre-implantation embryogenesis are cells’ intrinsic self-organization program and their developmental plasticity, which allows embryos to compensate for alterations in cell position and number; yet, these elements are still poorly understood. To be able to decipher these features, we established culture conditions that enable the two fates of blastocysts’ extraembryonic lineages—the primitive endoderm and the trophectoderm—to coexist. This plasticity emerges following the mechanisms of the first lineage segregation in the mouse embryo, and it manifests as an extended potential for extraembryonic chimerism during the pre-implantation embryogenesis. Moreover, this shared state enables robust assembly into higher-order blastocyst-like structures, thus combining both the cell fate plasticity and self-organization features of the early extraembryonic lineages.

This study aimed to improve the quality of ultrasound images by modeling an algorithm using a non-local means (NLM) noise-reduction approach to achieve precise quality control and accurate diagnosis of thyroid nodules. An ATS-539 multipurpose phantom was used to scan the dynamic range and gray-scale measurement regions, which are most closely related to the noise level. A convex-type 3.5-MHz frequency probe is used for scanning according to ATS regulations. In addition, ultrasound images of human thyroid nodules were obtained using a linear probe. An algorithm based on the NLM noise-reduction approach was modeled based on the intensity and relative distance of adjacent pixels in the image, and conventional filtering methods for image quality improvement were designed as a comparison group. When the NLM algorithm was applied to the image, the contrast-to-noise ratio and coefficient of variation values improved by 28.62% and 19.54 times, respectively, compared with those of the noisy images. In addition, the image improvement efficiency of the NLM algorithm was superior to that of conventional filtering methods. Finally, the applicability of the NLM algorithm to human thyroid images using a high-frequency linear probe was validated. We demonstrated the efficiency of the proposed algorithm in ultrasound images and the possibility of capturing improved images in the dynamic range and gray-scale region for quality control parameters.

The blood-brain barrier (BBB) limits the entry of leukocytes and potentially harmful substances from the circulation into the central nervous system (CNS). While BBB defects are a hallmark of many neurological disorders, the cellular heterogeneity at the neurovascular interface, and the mechanisms governing neuroinflammation are not fully understood.Through single-cell RNA sequencing of non-neuronal cell populations of the murine cerebral cortex during development, adulthood, ageing, and neuroinflammation, we identify reactive endothelial venules, a compartment of specialized postcapillary endothelial cells that are characterized by consistent expression of cell adhesion molecules, preferential leukocyte transmigration, association with perivascular macrophage populations, and endothelial activation initiating CNS immune responses. Our results provide novel insights into the heterogeneity of the cerebral vasculature and a useful resource for the molecular alterations associated with neuroinflammation and ageing.

While previous studies have suggested that snoring may be associated with depressive symptoms and suicidality in adults and preschool children, there have been no investigations in non-clinical adolescent populations. This study aimed to demonstrate the association between snoring and depressive symptoms/suicidality in adolescents. This survey study recruited 8530 students (grades 7–11) and examined depressive symptoms, suicidality, snoring frequency, daytime sleepiness, sleep duration, and presence of insomnia by questionnaires. Correlation analyses, multiple linear regression analyses and mediation analyses were performed to determine the association between snoring frequency and depressive symptoms/suicidality. The study population included 8080 students (16.73 ± 1.09 years old). Snoring frequency was positively correlated with depressive symptoms and suicidality. Snoring frequency was associated with depressive symptoms and suicidality when adjusted for age and sex, and the association remained significant after additionally adjusting for sleep duration, insomnia, and daytime sleepiness. When depressive symptoms were included as a predictor of suicidality, snoring frequency showed no significant predictive value. Mediation analysis confirmed that depressive symptoms mediate the association between snoring frequency and suicidality. Our findings suggest that self-reported complaints of snoring are associated with increased depressive symptoms and suicidality in adolescents independently of sleep duration, insomnia, and daytime sleepiness, and the connection between snoring and suicidality is mediated by depressive symptoms. These data underscore the importance of identifying snorers among adolescents and screening for depression and suicidal ideation in this population.

Antipsychotic agents are clinically utilized to treat schizophrenia and other mental disorders. These drugs induce neurological and metabolic side effects, but their influence on blood vessels remains largely unknown. Here, we show that haloperidol, one of the most frequently prescribed antipsychotic agents, induces vascular defects in bone marrow. Acute haloperidol treatment results in vascular dilation that is specific to hematopoietic organs. This vessel dilation is associated with disruption of hematopoiesis and hematopoietic stem/progenitor cells (HSPCs), both of which are reversible after haloperidol withdrawal. Mechanistically, haloperidol treatment blocked the secretion of vascular endothelial growth factor A (VEGF-A) from HSPCs. Genetic blockade of VEGF-A secretion from hematopoietic cells or inhibition of VEGFR2 in endothelial cells result in similar vessel dilation in bone marrow during regeneration after irradiation and transplantation. Conversely, VEGF-A gain of function rescues the bone marrow vascular defects induced by haloperidol treatment and irradiation. Our work reveals an unknown effect of antipsychotic agents on the vasculature and hematopoiesis with potential implications for drug application in clinic.

Trillions of microorganisms reside in the hosts' gut. Since diverse activities of gut microbiota affect the hosts' health status, maintenance of gut microbiota is important for maintaining human health. Green tea (GT) has multiple beneficial effects on energy metabolism with antiobesity, antidiabetic, and hypolipidemic properties. As GT contains a large amount of bioactive ingredients (e.g., catechins), which can be metabolized by microorganisms, it would be feasible that consumption of GT may cause compositional changes in gut microbiota, and that the changes in gut microbiota would be associated with the beneficial effects of GT. In this study, we demonstrated that consumption of GT extract relieves high-fat diet-induced metabolic abnormalities. Interestingly, GT administration significantly encouraged the growth of Akkermansia muciniphila (Akkermansia), a beneficial microorganism to relieve obesity and related metabolic disorders. Finally, we found that epigallocatechin gallate is the component of GT that stimulates the growth of Akkermansia. According to these data, we propose that GT could be a prebiotic agent for Akkermansia to treat metabolic syndromes.

Background: Panax ginseng Meyer (Araliaceae) is a highly valued medicinal plant in Asian regions, especially in Korea, China, and Japan. Chemical and biological studies on P. ginseng have focused primarily on its roots, whereas the seeds remain poorly understood. This study explores the phytochemical and biological properties of compounds from P. ginseng seeds. Methods: P. ginseng seeds were extracted with methanol, and 16 compounds were isolated using various chromatographic methods. The chemical structures of the isolates were determined by spectroscopic data. Antiinflammatory activities were evaluated for triterpene and steroidal saponins using lipopolysaccharide-stimulated RAW264.7 macrophages and THP-1 monocyte leukemia cells. Results: Phytochemical investigation of P. ginseng seeds led to the isolation of a novel triterpene saponin, pseudoginsenoside RT8, along with 15 known compounds. Pseudoginsenoside RT8 exhibited more potent antiinflammatory activity than the other saponins, attenuating lipopolysaccharide-mediated induction of proinflammatory genes such as interleukin-1β, interleukin-6, inducible nitric oxide synthase, cyclooxygenase-2, and matrix metalloproteinase-9, and suppressed reactive oxygen species and nitric oxide generation in a dose-dependent manner. Conclusion: These findings indicate that pseudoginsenoside RT8 has a pharmaceutical potential as an antiinflammatory agent and that P. ginseng seeds are a good natural source for discovering novel bioactive molecules. Keywords: Antiinflammatory activity, Panax ginseng seeds, Pseudoginsenoside RT8

In adult mammalian bone marrow (BM), vascular endothelial cells and perivascular reticular cells control the function of haematopoietic stem and progenitor cells (HSPCs). During fetal development, the mechanisms regulating the de novo haematopoietic cell colonization of BM remain largely unknown. Here, we show that fetal and adult BM exhibit fundamental differences in cellular composition and molecular interactions by single cell RNA sequencing. While fetal femur is largely devoid of leptin receptor-expressing cells, arterial endothelial cells (AECs) provide Wnt ligand to control the initial HSPC expansion. Haematopoietic stem cells and c-Kit+ HSPCs are reduced when Wnt secretion by AECs is genetically blocked. We identify Wnt2 as AEC-derived signal that activates β-catenin-dependent proliferation of fetal HSPCs. Treatment of HSPCs with Wnt2 promotes their proliferation and improves engraftment after transplantation. Our work reveals a fundamental switch in the cellular organization and molecular regulation of BM niches in the embryonic and adult organism.

Takotsubo syndrome (TTS) is an acute, stress-induced cardiomyopathy that occurs predominantly in women after extreme physical and/or emotional stress. To date, our understanding of the molecular basis for TTS remains unknown and, consequently, specific therapies are lacking. Myocardial infiltration of monocytes and macrophages in TTS has been documented in clinical studies. However, the functional importance of these findings remains poorly understood. Here, we show that a single high dose of isoproterenol (ISO) in mice induced a TTS-like cardiomyopathy phenotype characterized by female predominance, severe cardiac dysfunction, and robust myocardial infiltration of macrophages. Single-cell RNA-Seq studies of myocardial immune cells revealed that TTS-like cardiomyopathy is associated with complex activation of innate and adaptive immune cells in the heart, and macrophages were identified as the dominant immune cells. Global macrophage depletion (via clodronate liposome administration) or blockade of macrophage infiltration (via a CCR2 antagonist or in CCR2-KO mice) resulted in recovery of cardiac dysfunction in ISO-challenged mice. In addition, damping myeloid cell activation by HIF1α deficiency or exposure to the immunomodulatory agent bortezomib ameliorated ISO-induced cardiac dysfunction. Collectively, our findings identify macrophages as a critical regulator of TTS pathogenesis that can be targeted for therapeutic gain.

It is widely recognized that inflammation plays a critical role in cardiac hypertrophy and heart failure. However, clinical trials targeting cytokines have shown equivocal effects indicating the need for a deeper understanding of the precise role of inflammation and inflammatory cells in heart failure.Leukocytes from human subjects and a rodent model of heart failure were characterized by a marked reduction in expression of KLF2 mRNA. Using a mouse model of Angiotensin II-induced non-ischemic cardiac dysfunction, we showed that neutrophils played an essential role in the pathogenesis and progression of heart failure. Mechanistically, chronic Angiotensin II infusion activated a neutrophil KLF2-NETosis pathway that triggered sporadic thrombosis in small myocardial vessels leading to myocardial hypoxia, cell death, and hypertrophy. Conversely, targeting neutrophils, NETs or thrombosis ameliorated these pathological changes and preserved cardiac dysfunction. KLF2 regulated neutrophil activation in response to Angiotensin II at the molecular level, partly through the crosstalk with HIF1 signaling.Taken together, our data implicate neutrophil-mediated immunothrombotic dysregulation as a critical pathogenic mechanism leading to cardiac hypertrophy and heart failure. This neutrophil KLF2-NETosis-thrombosis mechanism underlying chronic heart failure can be exploited for therapeutic gain by therapies targeting neutrophils, NETosis, or thrombosis.

It is very important to use effective parameters in the treatment plan of breast cancer patients in TomoDirect (TD)-three-dimensional conformal radiation therapy (TD-3DCRT). The objective of this study was to compare the radiation treatment plans to the parameters (jaw width and jaw mode) of TD-3DCRT for left-breast cancer. This study was conducted using the phantom, the jaw mode (fixed and dynamic) and field width (2.5 cm and 5.0 cm) were controlled to compare the TD-3DCRT treatment plans. There was small difference in the conformity index (CI) and homogeneity index (HI) values for target according to the jaw mode for each field width. As a result of observation in terms of dose, treatment time and unnecessary damage to surrounding normal organs could be minimized when dynamic jaw with a field width of 5.0 cm was used. In conclusion, we verified that the use of dynamic jaws and 5.0 cm field width was effective in left-breast cancer radiotherapy plan using TD-3DCRT.

This paper presented an efficient multiband FSK signals with direct sequence spread spectrum for maintaining covertness and performance. In aspect to covertness, direct sequence spread spectrum method, which multiplying by PN codes whose rate is much higher than that of data sequence, is employed. In aspect to performance, we applied multiband, turbo equalization, and weighting algorithm. Underwater acoustic communication experiments were conducted in the lake. In the lake experimental results, we confirmed that the performance was improved as the number of bands and chips are increased. Furthermore, the performance of multiband was improved when the proposed weighting algorithm was applied.

The multi-band UWAS communication techniques are effective in terms of performance and throughput efficiency. However, the multi-band configuration in a particular band affects the output from the entire bands. This problem can be solved through a receiving end that analyzes error rates of each band. In this paper, we proposed an estimation BER algorithm which get the reliability of received data to set the weighting value to each band. Therefore, we analyzed the efficiency of multi-band transmission scheme with estimation BER and 3 [dB] performance gain is obtained.

Little is known regarding structural brain changes in traumatized refugees and the association with psychopathology. In the present study, the cortical thickness in North Korean refugees and the association with psychological symptoms were explored. North Korean refugees with lifetime post-traumatic stress disorder (PTSD group, n = 27), trauma-exposed North Korean refugees without lifetime PTSD (trauma-exposed control (TEC) group, n = 23), and healthy South Korean controls without traumatic experiences (HC group, n = 51) completed questionnaires assessing depression, anxiety, somatization, and PTSD symptoms. The cortical thickness was measured by magnetic resonance imaging (MRI) using FreeSurfer. Age- and sex-adjusted cortical thickness of the right medial prefrontal cortex (mPFC) was greater in the TEC group than in the HC group. However, significant differences were not observed between the PTSD and HC groups. Increased right mPFC thickness was significantly correlated with less anxiety and somatization after controlling for age and sex in the TEC group, but not in the PTSD or HC groups. North Korean refugees who did not develop PTSD after trauma showed increased right mPFC thickness, which was associated with less severe psychiatric symptoms. These findings indicate that increased mPFC thickness might have helped to reduce PTSD and psychiatric symptoms after trauma, and likely reflects resilience achieved by potentially enhancing emotional regulation in the mPFC.

Lactobacillus plantarum shows high intraspecies diversity species, and has one of the largest genome sizes among the lactobacilli. It is adapted to diverse environments and provides a promising potential for various applications. The aim of the study was to investigate the safety and probiotic properties of 18 L. plantarum strains isolated from fermented food products, green tea, and insects. For preliminary safety evaluation the L. plantarum strains were tested for their ability to produce hemolysin and biogenic amines and for their antibiotic resistance. Based on preliminary safety screening, four strains isolated from green tea showed antibiotic resistance below the cut-off MIC values suggested by EFSA, and were selected out of the 18 strains for more detailed studies. Initial selection of strains with putative probiotic potential was determined by their capacity to survive in the human GIT using an in vitro simulation model, and for their adhesion to human Caco-2/TC-7 cell line. Under simulated GIT conditions, all four L. plantarum strains isolated from green tea showed higher survival rates than the control (L. plantarum subsp. plantarum ATCC 14917). All studied strains were genetically identified by 16S rRNA gene sequencing and confirmed to be L. plantarum. In addition, whole-genome sequence analysis of L. plantarum strains APsulloc 331261 and APsulloc 331263 from green tea was performed, and the outcome was compared with the genome of L. plantarum strain WCFS1. The genome was also annotated, and genes related to virulence factors were searched for. The results suggest that L. plantarum strains APsulloc 331261 and APsulloc 331263 can be considered as potential beneficial strains for human and animal applications.

Green tea is reported to exert beneficial effects on metabolic disorders through the regulation of lipid metabolism. On the contrary, fermented food products have been introduced to improve human health by modulating immune response and energy metabolism. To maximize health benefit, we applied fermentation processing to green tea. Fermented green tea extract (FGT) inhibited adipogenesis and lipogenesis in cultured adipocytes, whereas it augmented mRNA expression of fatty acid oxidation-related genes in differentiated myocytes. In diet-induced obese mice, FGT blunted body weight and fat mass gain by 69.7% and 56.7%, respectively. FGT also improved circulating triglyceride concentrations by 32.6%. Similar to in vitro results, FGT suppressed lipogenesis and promoted lipid catabolism in peripheral tissues. In addition, FGT administration modulated the composition of certain gut microbiota which are associated with obesity and related metabolic disorders. Among the various components of FGT, gallocatechin gallate is suggested to mediate the effect of FGT on lipid metabolism. Taken together, we propose FGT as a novel functional food to benefit human health by controlling adiposity and lipid metabolism.

G protein–coupled receptor 182 (GPR182) has been shown to be expressed in endothelial cells; however, its ligand and physiological role has remained elusive. We found GPR182 to be expressed in microvascular and lymphatic endothelial cells of most organs and to bind with nanomolar affinity the chemokines CXCL10, CXCL12, and CXCL13. In contrast to conventional chemokine receptors, binding of chemokines to GPR182 did not induce typical downstream signaling processes, including Gq- and Gi-mediated signaling or β-arrestin recruitment. GPR182 showed relatively high constitutive activity in regard to β-arrestin recruitment and rapidly internalized in a ligand-independent manner. In constitutive GPR182-deficient mice, as well as after induced endothelium-specific loss of GPR182, we found significant increases in the plasma levels of CXCL10, CXCL12, and CXCL13. Global and induced endothelium-specific GPR182-deficient mice showed a significant decrease in hematopoietic stem cells in the bone marrow as well as increased colony-forming units of hematopoietic progenitors in the blood and the spleen. Our data show that GPR182 is a new atypical chemokine receptor for CXCL10, CXCL12, and CXCL13, which is involved in the regulation of hematopoietic stem cell homeostasis., Proceedings of the National Academy of Sciences of the United States of America, 118 (17), ISSN:0027-8424, ISSN:1091-6490

Local signals provided by cells in specialized niche microenvironments regulate stem cell behaviour in many different organs and species. In adult mammalian bone marrow (BM), leptin receptor-positive (LepR+) reticular cells express secreted factors that control the function of haematopoietic stem and progenitor cells (HSPCs). During fetal development, the developing skeletal system is colonized by c-Kit+ haematopoietic cells de novo after a transient phase of liver haematopoiesis. The cellular and molecular mechanisms regulating de novo haematopoietic cell colonization and expansion remain largely unknown. Here, we report that fetal and adult BM exhibit fundamental differences both in terms of cellular composition and molecular interactions by single cell RNA sequencing (scRNA-seq) analysis. While LepR+ reticular cells are almost completely absent in fetal femur, arterial endothelial cells (AECs) are a source of signals controlling the initial HSPC expansion during BM development. Long-term haematopoietic stem cells (HSCs) and other c-Kit+ HSPCs are reduced when Wnt ligand secretion by AECs is genetically blocked. We identify Wnt2 as an AEC-derived signal that directly activates β-catenin dependent proliferation of fetal HSPCs. Treatment of HSPCs ex vivo with Wnt2 promotes their proliferation and improves engraftment in vivo after transplantation. Our work reveals a fundamental switch in the cellular organization and molecular regulation of BM niches in the embryonic and adult organism.

In this paper, we verify the performance of the equalizer and phase-locked loop (PLL) operating jointly for channel time variability in underwater acoustic communications. We apply the decision feedback equalizer in order to eliminate channel multipath and PLL to phase rotation due to Doppler effects. In the PLL, a decision-directed tan−1 type phase detector is adopted. As shown in previous papers, it is difficult to make PLL to be steady state because of time-varying ISI occurred by multipath. Also, the phase rotation incurs the equalizer tap rotation. Therefore, we can see that the two subsystems of equalizer and PLL complement each other perfectly. Another issue is the convergence speed; how quickly we can make the joint equalizer and PLL to be stable state within the preamble period (known data). In order to verify the performance, the sea experiments were conducted in the condition of moving transmitter. The transmitted signal is modulated by using PSK and consists of five burst frames that are composed of preamble of PN code and random data. As a result, if we use the initial multipath value and Doppler frequency offset, we can make the joint equalizer and PLL to be the steady state more quickly.