Spatiotemporal alterations in the brain oscillations of Arctic explorers.

BACKGROUND: The limited understanding of the physiology and psychology of polar expedition explorers has prompted concern over the potential cognitive impairments caused by exposure to extreme environmental conditions. Prior research has demonstrated that such stressors can negatively impact cognitive function, sleep quality, and behavioral outcomes. Nevertheless, the impact of the polar environment on neuronal activity remains largely unknown. METHODS: In this study, we aimed to investigate spatiotemporal alterations in brain oscillations of 13 individuals (age range: 22 - 48 years) who participated in an Arctic expedition. We utilized electroencephalography (EEG) to record cortical activity before and during the Arctic journey, and employed standardized low resolution brain electromagnetic tomography to localize changes in alpha, beta, theta, and gamma activity. RESULTS: Our results reveal a significant increase in the power of theta oscillations in specific regions of the Arctic, which differed significantly from pre-expedition measurements. Furthermore, microstate analysis demonstrated a significant reduction in the duration of microstates (MS) D and alterations in the local synchrony of the frontoparietal network. CONCLUSION: Overall, these findings provide novel insights into the neural mechanisms underlying adaptation to extreme environments. These findings have implications for understanding the cognitive consequences of polar exploration and may inform strategies to mitigate potential neurological risks associated with such endeavors. Further research is warranted to elucidate the long-term effects of Arctic exposure on brain function.

Dual human iPSC-derived cardiac lineage cell-seeding extracellular matrix patches promote regeneration and long-term repair of infarcted hearts.

Human pluripotent stem cell-derived cardiovascular progenitor cells (hCVPCs) and cardiomyocytes (hCMs) possess therapeutic potential for infarcted hearts; however, their efficacy needs to be enhanced. Here we tested the hypotheses that the combination of decellularized porcine small intestinal submucosal extracellular matrix (SIS-ECM) with hCVPCs, hCMs, or dual of them (Mix, 1:1) could provide better therapeutic effects than the SIS alone, and dual hCVPCs with hCMs would exert synergic effects in cardiac repair. The data showed that the SIS patch well supported the growth of hCVPCs and hCMs. Epicardially implanted SIS-hCVPC, SIS-hCM, or SIS-Mix patches at 7-day post-myocardial infarction significantly ameliorated functional worsening, ventricular dilation and scar formation at 28- and 90-day post-implantation in C57/B6 mice, whereas the SIS only mildly improved function at 90-day post-implantation. Moreover, the SIS and SIS-cell patches improved vascularization and suppressed MI-induced cardiomyocyte hypertrophy and expression of Col1 and Col3, but only the SIS-hCM and the SIS-Mix patches increased the ratio of collagen III/I fibers in the infarcted hearts. Further, the SIS-cell patches stimulated cardiomyocyte proliferation via paracrine action. Notably, the SIS-Mix had better improvements in cardiac function and structure, engraftments, and cardiomyocyte proliferation. Proteomic analysis showed distinct biological functions of exclusive proteins secreted from hCVPCs and hCMs, and more exclusive proteins secreted from co-cultivated hCVPCs and hCMs than mono-cells involving in various functional processes essential for infarct repair. These findings are the first to demonstrate the efficacy and mechanisms of mono- and dual-hCVPC- and hCM-seeding SIS-ECM for repair of infarcted hearts based on the side-by-side comparison.

The analysis of the characteristics of imported COVID-19 cases from January to April in 2020: a cross-sectional study.

Background: Since the first case reported in December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an outbreak of coronavirus disease 2019 (COVID-19) worldwide. The global case count continued to rise and the WHO declared a Public Health Emergency of International Concern (PHEIC), causing a growing risk of imported COVID-19 infection. This study aimed to provide descriptive and quantitative epidemiological characteristics of imported COVID-19 cases in China. Methods: This cross-sectional study examined all imported COVID-19 cases in Mainland China from 22 January to 21 April 2020. Ratios, Median and percentile were used for descriptive analysis. Spearman's correlation analysis was performed between daily new imported cases in Mainland China and the country of origin. The chi-square test was used to evaluate the difference between home quarantine and compulsory centralized quarantine on native transmission. Results: A total of 1,610 cases of COVID-19 were imported from 49 countries to 27 provincial administrative regions in China; 79.8% were from European countries and the United States of America (the USA). Before 29 March 2020, the imported cases were mainly from the USA (27.7%) and United Kingdom (UK; 42.6%). After 29 March 2020, the daily newly imported cases from Russia rapidly grew. After 12 April 2020, the number of daily newly imported cases gradually decreased and remained at a low level (12±7 cases per day). Airport entry was encouraged, and ground border crossing was limited. Among the 1,610 cases, 54.0% were in the asymptomatic incubation period on arrival in Mainland China. Conclusions: The transmissions by imported COVID-19 were gradually and effectively curbed in Mainland China, despite a disproportionally high number of cases worldwide. Entry screening measures must be implemented universally to all inbound travelers at a point of entry or targeted to specific travel routes or to specific travelers. Compulsory centralized quarantine should be recommended in the prevention of the imported COVID-19 epidemic.

Asiatic acid alleviates ischemic myocardial injury in mice by modulating mitophagy- and glycophagy-based energy metabolism.

Myocardial infarction (MI) causes disturbances in myocardial energy metabolism, ultimately leading to a poor prognosis. Cytosolic glycogen autophagy (glycophagy) and mitochondrial autophagy (mitophagy) are upregulated in MI to optimize energy metabolism but to a limited extent. Asiatic acid (AA), a pentacyclic triterpene derived from the traditional Chinese herb Centella asiatica, displays anti-inflammatory, antioxidant, and antiapoptotic activities. AA has been found to alleviate focal cerebral and liver ischemic injury by reversing mitochondrial dysfunction. In this study, we investigated whether AA exerted cardioprotective effects against MI by activating glycophagy and mitophagy to improve the energy balance. In vitro cardioprotective effects were examined in neonatal mouse cardiomyocytes subjected to oxygen-glucose deprivation for 12 h. Treatment with AA (2-50 µM) significantly increased cell viability and improved the energy metabolism evidenced by increased ATP level and phosphocreatine/ATP ratio. In vivo cardioprotective effects were studied in a mouse model of MI. Administration of AA (5-125 mg·kg-1·d-1, ig) significantly reduced infarct size and ischemic myocardial injury, and improved cardiac function. AA treatment also promoted mitophagy and relieved mitochondrial edema evidenced by increased number of mitophagosomes in ischemic myocardium in vivo and increased mitochondria-light chain 3 (LC3)-II colocalization in ODG-treated cardiomyocytes in vitro. Mitophagy activation was accompanied by activation of the AMPK signaling pathway. Knockdown of AMPK abolished AA-activated mitophagy. Furthermore, we showed that glycophagy was upregulated in OGD cardiomyocytes evidenced by increased starch binding domain protein 1 (STBD1)-GABA type A receptor-associated protein-like 1(GABARAPL1) interaction and extracellular acidification rate, whereas AA treatment further promoted glycophagy accompanied by PI3K/Akt activation. PI3K inhibitor LY294002 or Akt inhibitor GSK690693 blocked the effects of AA on glycophagy and glycolysis. Finally, simultaneous inhibition of glycophagy and mitophagy abolished the cardioprotective effects and energy regulation of AA. These results demonstrate that AA protects ischemic cardiomyocytes by modulating glycophagy- and mitophagy-based energy metabolism through the PI3K/Akt and AMPK pathways.

Generation of a laminopathies-specific iPSC line EHTJUi005-A-3 with homozygous knockout of the LMNA gene by CRISPR/Cas9 technology.

LAMIN A/C, encoded by the LMNA gene, supports the normal structure of the cell nucleus and regulates the connection between the nucleus and the cytoskeleton as a component of the nucleus envelope. The loss of expression and function of the LMNA gene would lead to the occurrence of congenital muscular dystrophy and Emery-Dreifuss muscular dystrophy which are collectively named as laminopathies. Here, we report a human induced pluripotent stem cell (iPSC) line (EHTJUi005-A-3) generated from a wild iPSC (EHTJUi005-A) with homozygous knockout of the gene LMNA through CRISPR/Cas9. This iPSC line provides a useful research model for studying laminopathies disease.

CRISPR/Cas9 mediated generation of a iPSC line EHTJUi005-A-1 with homozygous knockout of the SUV39H1 gene.

SUV39H1 is a histone methyltransferase involve numerous biological processes, including of aging, embryo development, tumor growth and mitosis via catalysis of dimethylation and trimethylation of lysine 9 of histone H3. Here we report a human induced pluripotent stem cell line (EHTJUi005-A-1) which is generated from a wildtype human iPSC previously established in our laboratory, and this iPSC has a homozygous knockout of 8 bp in Exon 2 of SUV39H1. This iPSC model provides a valuable resource to study epigenetic regulation in extensive biological processes as mentioned above.

An induced pluripotent stem cell line (EHTJUi003-A) generated from a neonate with c.1377delC mutation in the gene MYBPC3 causing hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant heart disease. An induced pluripotent stem cell line (EHTJUi003-A) was generated from umbilical cord blood mononuclear cells (UCBMCs) of a female neonate with heterozygous mutation of p.L460Wfs (c.1377delC) in the MYBPC3 gene. This iPSC model offers a very valuable resource to study the pathological mechanism of HCM in vitro.

An induced pluripotent stem cell line (EHTJUi004-A) generated from a neonate with c.4683_4684delCT:p.Leu1563fs mutation in the gene DSP causing Familial Arrhythmogenic Right Ventricular Dysplasia (ARVD).

Familial Arrhythmogenic Right Ventricular Dysplasia (ARVD) is a primary cardiomyopathy characterized by the abnormality of the right ventricular muscle. ARVD may be life-threatening due to the induction of paroxysmal refractory ventricular tachycardia or supraventricular arrhythmia. A human induced pluripotent stem cell line (EHTJUi004-A) was generated from human umbilical cord blood mononuclear cells (UCBMCs) of a female neonate with heterozygous mutation of p.Leu1563fs (c.4683_4684delCT) in the DSP gene. This iPS cell line resource provides an ideal in vitro model to study the pathological mechanism of ARVD.

An induced pluripotent stem cell line (EHTJUi002-A) derived from a neonate with c.678G>A mutation in the gene FZD4 causing exudative vitreoretinopathy.

Familial exudative vitreoretinopathy (FEVR) is an autosomal dominant genetic disease. An induced pluripotent stem cell line (EHTJUi002-A) was generated from umbilical cord blood mononuclear cells (UCBMCs) of a neonate with heterozygous mutation of p.W226X(c.678G>A) in the FZD4 gene. This iPSC model offers a very valuable resource to study the pathological mechanism of FEVR in vitro.

An evaluation of pitavastatin for the treatment of hypercholesterolemia.

INTRODUCTION: Statins are the first line of therapy to reduce low-density lipoprotein cholesterol (LDL-C) in order to decrease cardiovascular events. Pitavastatin is the latest statin to be introduced to the market. Areas covered: In this article, the authors review the efficacy, safety, and tolerability of pitavastatin. The authors also review a recent cardiovascular outcome study. Expert opinion: Pitavastatin produces dose-dependent reductions in LDL-C at lower doses than other statins. The maximum approved dose of 4 mg reduces LDL-C by about 40-49% in different patient groups and is equivalent to atorvastatin 20 mg in this effect. Pitavastatin undergoes minimal metabolism so drug-drug interactions are less likely than with many other statins, but it can interact with some drugs that inhibit drug transporters. Compared with other statins, it has been associated with greater increases in high-density lipoprotein cholesterol and it was found to be less likely to cause new onset diabetes. In a recent study in Japanese patients with stable coronary artery disease, pitavastatin 4 mg was more effective than pitavastatin 1 mg in reducing cardiovascular events. Therefore, the highest dose may be preferred in high-risk patients.

Berberine promotes nerve regeneration through IGFR­mediated JNK­AKT signal pathway.

Berberine presents therapeutic ability for various central nervous system disorders, including Alzheimer's disease and cerebral ischemia. The present study investigated the role of berberine in nerve regeneration and analyzed the potential mechanism mediated by berberine in hippocampal pyramidal neurons. Reverse transcription­quantitative poylmerase chain reaction, western blot, TUNEL assay and immunofluorescence were used to analyze the therapeutic effects of berberine on nerve regeneration. Berberine treatment increased growth and viability of hippocampal pyramidal neurons. Berberine treatment inhibited apoptosis of hippocampal pyramidal neurons and increased apoptosis regulator Bcl­2 and Bcl­w expression. Neuroinflammation of tumor necrosis factor α, interleukin (IL)1ß, IL6 levels and autophagy­related proteins microtubule­associated proteins 1A/1B light chain 3B, autophagy related 16 like 1 and autophagy related 7 were downregulated by berberine treatment in hippocampal pyramidal neurons. Notably, study has found that berberine increased insulin-like growth factor receptor (IGFR) and decreased c­Jun N­terminal kinase (JNK) and protein kinase B (AKT) expression in hippocampal pyramidal neurons. IGFR antagonist abolished berberine­increased growth of hippocampal pyramidal neurons. In conclusion, these results indicate that berberine can promote nerve regeneration through IGFR­mediated JNK­AKT signal pathway.

Metformin transporter pharmacogenomics: insights into drug disposition-where are we now?

INTRODUCTION: Metformin is recommended as first-line treatment for type 2 diabetes (T2D) by all major diabetes guidelines. With appropriate usage it is safe and effective overall, but its efficacy and tolerability show considerable variation between individuals. It is a substrate for several drug transporters and polymorphisms in these transporter genes have shown effects on metformin pharmacokinetics and pharmacodynamics. Areas covered: This article provides a review of the current status of the influence of transporter pharmacogenomics on metformin efficacy and tolerability. The transporter variants identified to have an important influence on the absorption, distribution, and elimination of metformin, particularly those in organic cation transporter 1 (OCT1, gene SLC22A1), are reviewed. Expert opinion: Candidate gene studies have shown that genetic variations in SLC22A1 and other drug transporters influence the pharmacokinetics, glycemic responses, and gastrointestinal intolerance to metformin, although results are somewhat discordant. Conversely, genome-wide association studies of metformin response have identified signals in the pharmacodynamic pathways rather than the transporters involved in metformin disposition. Currently, pharmacogenomic testing to predict metformin response and tolerability may not have a clinical role, but with additional data from larger studies and availability of safe and effective alternative antidiabetic agents, this is likely to change.

Betulin inhibits lipopolysaccharide/D-galactosamine-induced acute liver injury in mice through activating PPAR-γ.

Betulin is a phenolic flavonoid which has been reported to possess a mass of pharmacological properties, especially anti-inflammatory activity. The purpose of this study was to explore the protective effects and possible mechanism of betulin against lipopolysaccharide/D-galactosamine (LPS/D-Gal)-induced acute liver injury. D-Gal and LPS were intraperitoneally injected to develop acute liver injury animal model. Betulin (2, 4 or 8 mg/kg) were given 1 h before LPS/D-Gal instillation. Liver tissues and plasma samples were collected 9 h after LPS/D-Gal were given. The results indicated that betulin dramatically decreased liver pathologic changes, myeloperoxidase (MPO) activity, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Simultaneously, the levels of interleukin (IL-1ß) and tumor necrosis factor (TNF-α) in serum and liver tissues were both attenuated by betulin. Besides, betulin suppressed NF-κB pathway activation in a dose-dependently manner. Betulin increased the expression of PPAR-γ in a dose-dependent manner. In conclusion, all these results revealed that betulin could possess potential therapeutic effect for LPS/D-Gal-induced acute liver injury.

Photoreductive dissolution of schwertmannite induced by oxalate and the mobilization of adsorbed As(V).

Schwertmannite (Sch), a poorly crystalline iron mineral, shows high sorption capacity to As(V). In this study, the effects of UV irradiation and oxalate on the dissolution of pure Sch, Sch with adsorbed As(V) [Sch*-As(V)] and subsequent mobilization of As(V) were investigated at pH 3.0. Under UV irradiation, the dissolved Fe(II) took the majority of the total dissolved Fe during the dissolution of Sch and Sch*-As(V). In the presence of oxalate, Fe(III)-oxalate complexes formed on Sch [or Sch*-As(V)] could be converted into Fe(II)-oxalate by photo-generated electrons under UV illumination, and more total dissolved Fe produced compared to that without oxalate. In the dark, total dissolved Fe reached the maximum value (42.64 mg L-1 for Sch) rapidly and existed as Fe(III) predominately. In addition, UV irradiation has almost no effect on the mobilization of As(V) in Sch*-As(V) in the absence of oxalate. However, in the presence of oxalate, UV irradiation resulted in the mobilization of As(V) declined by 14-36.5 times compared to that in the dark. This study enhanced our understanding on the mobilization of As(V), and UV irradiation could contribute to the immobilization of As(V) on Sch in the aquatic environments containing oxalate.

The extent of liver injury determines hepatocyte fate toward senescence or cancer.

It is well known that induction of hepatocyte senescence could inhibit the development of hepatocellular carcinoma (HCC). Until now, it is still unclear how the degree of liver injury dictates hepatocyte senescence and carcinogenesis. In this study, we investigated whether the severity of injury determines cell fate decisions between hepatocyte senescence and carcinogenesis. After testing of different degrees of liver injury, we found that hepatocyte senescence is strongly induced in the setting of severe acute liver injury. Longer-term, moderate liver injury, on the contrary did not result into hepatocyte senescence, but led to a significant incidence of HCC instead. In addition, carcinogenesis was significantly reduced by the induction of severe acute injury after chronic moderate liver injury. Meanwhile, immune surveillance, especially the activations of macrophages, was activated after re-induction of senescence by severe acute liver injury. We conclude that severe acute liver injury leads to hepatocyte senescence along with activating immune surveillance and a low incidence of HCC, whereas chronic moderate injury allows hepatocytes to proliferate rather than to enter into senescence, and correlates with a high incidence of HCC. This study improves our understanding in hepatocyte cell fate decisions and suggests a potential clinical strategy to induce senescence to treat HCC.

A technology developed from concept of acupuncture and meridian system, the clinical effect of BIOCERAMIC resonance on psychological related sleep disturbance with findings on questionnaire, EEG and fMRI.

Under the concept of meridian channels that belongs to traditional Chinese medicine, BIOCERAMIC Resonance (BR) has already been applied to many clinical medical research projects with functions mimicking of traditional acupuncture. Forty-five patients were recruited with chronic sleep disorders; 36 patients were given, applied to the device with BIOCERAMIC material and sound rhythm on chest skin surface; 9 patients were included as controls. All study participants completed a sleep pattern and quality of life questionnaire (assessment on psychological and physical causes of sleep disturbances), which was repeated before, during and after treatment. Electroencephalograph (EEG) recordings were analyzed before, during and after treatment. Functional MRI (fMRI) was also used for demonstration of BR effect for another 8 candidates. During the first 3 days of treatment, sleep quality improved in all 36 patients especially to psychological reasons; in 91.7% (33/36) treatment was associated with an elevation in the beta spectrum of the EEG (at 15-27 Hz). The result of fMRI found corresponding cerebral and cerebellar areas of activation and deactivation. BIOCERAMIC Resonance can improve sleep disorder due to psychological causes, with transient alter brain wave activity and functional activation on specific locations of brain.