Heliox Protects SH-SY5Y Cells from Oxygen-Glucose Deprivation/Reperfusion-Induced Ferroptosis.

BACKGROUND: Heliox shows protective effects against acute focal ischemia-reperfusion injury in the brain. However, further research is needed to unveil the intricate molecular mechanisms involved. Determining how heliox affects ferroptosis caused by oxygen-glucose deprivation/reoxygenation (OGD/R) in SH-SY5Y cells as well as the underlying mechanism was the goal of the current work. METHODS: With the use of 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA), JC-1, and methyl thiazolyl tetrazolium, we assessed the survival, reactive oxygen species (ROS), and mitochondrial membrane potential in SH-SY5Y cells after they had been exposed to OGD/R and heliox. The expression of molecules associated with ferroptosis and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway was analyzed using quantitative polymerase chain reaction (PCR) and immunoblotting, while malondialdehyde (MDA), oxidized glutathione disulfide (GSSG), ferrous ion (Fe2+), and reduced glutathione (GSH) levels were evaluated using biochemical kits. RESULTS: OGD/R treatment reduced the GSH to GSSG ratio; the potential of the mitochondrial membrane; the expression of the proteins GSH, SLC7A11, and glutathione peroxidase 4 (GPX4); and the ability of SH-SY5Y cells to survive. In contrast, OGD/R treatment increased the expression of cyclooxygenase-2 (COX2), ACSL4, and ferritin heavy chain 1 (FTH1) proteins, the production of MDA and GSSG, and the levels of ROS and Fe2+. However, heliox effectively mitigated all these OGD/R-induced effects. Furthermore, in OGD/R-treated SH-SY5Y cells, heliox administration stimulated the PI3K/AKT pathway while suppressing the nuclear factor-κB (NF-κB) pathway. When MK-2206, an AKT inhibitor, was applied concurrently to the cells, these outcomes were reversed. CONCLUSIONS: Heliox prevents OGD/R from causing ferroptosis in SH-SY5Y cells by activating the PI3K/AKT pathway. This suggests a promising therapeutic potential for heliox use in the management of ischemia/reperfusion injury.

Preferred Conformation-Guided Discovery of Potent and Orally Active HIF Prolyl Hydroxylase 2 Inhibitors for the Treatment of Anemia.

In this work, we discovered a novel series of prolyl hydroxylase 2 (PHD2) inhibitors with improved metabolic properties based on a preferred conformation-guided drug design strategy. Piperidinyl-containing linkers with preferred metabolic stability were designed to match the dihedral angle of the desired docking conformation in the PHD2 binding site with the lowest energy conformation. Based on the piperidinyl-containing linkers, a series of PHD2 inhibitors with high PHD2 affinity and favorable druggability were obtained. Remarkably, compound 22, with an IC50 of 22.53 nM toward PHD2, significantly stabilized hypoxia-inducible factor α (HIF-α) and upregulated the expression of erythropoietin (EPO). Furthermore, oral administration of 22 dose-dependently stimulated erythropoiesis in vivo. Preliminary preclinical studies showed that 22 has good pharmacokinetic properties and an excellent safety profile, even at 10 times the efficacious dose (200 mg/kg). Taken together, these results indicate that 22 is a promising candidate for anemia treatment.

Therapeutic Hypothermia Inhibits Hypoxia-Induced Cardiomyocyte Apoptosis Via the MiR-483-3p/Cdk9 Axis.

Background Therapeutic hypothermia has a beneficial effect on cardiac function after acute myocardial infarction, but the exact mechanism is still unclear. Recent research has suggested that microRNAs participate in acute myocardial infarction to regulate cardiomyocyte survival. This study aimed to explore the ability of hypothermia-regulated microRNA-483-3p (miR-483-3p) to inhibit hypoxia-induced myocardial infarction. Methods and Results Primary cardiomyocytes were cultured under hypoxia at 32 °C to mimic therapeutic hypothermia, and the differentially expressed microRNAs were determined by RNA sequencing. Therapeutic hypothermia recovered hypoxia-induced increases in apoptosis, decreases in ATP levels, and decreases in miR-483-3p expression. Overexpression of miR-483-3p exhibited effects similar to those of therapeutic hypothermia on hypoxia in the treatment of cardiomyocytes to associate with maintaining the mitochondrial membrane potential, and cyclin-dependent kinase 9 (Cdk9) was identified as a target gene with downregulated expression by miR-483-3p. Knockdown of Cdk9 also promoted cardiac survival, ATP production, and mitochondrial membrane potential stability under hypoxia. In vivo, the expression of miR-483-3p and Cdk9 was tested in the cardiac tissue of the mice with acute myocardial infarction, and the expression of miR-483-3p decreased and Cdk9 increased in the region of myocardial infarction. However, miR-483-3p was overexpressed with lentivirus, which suppressed apoptosis, infarct size (miR-483-3p, 22.00±4.04% versus negative control, 28.57±5.44%, P<0.05), and Cdk9 expression to improve cardiac contractility. Conclusions MiR-483-3p antagonizes hypoxia, leading to cardiomyocyte injury by targeting Cdk9, which is a new mechanism of therapeutic hypothermia.

Plasma metabolomic profiling reflects the malnourished and chronic inflammatory state in recessive dystrophic epidermolysis bullosa.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a hereditary blistering disorder characterized by skin fragility, chronic inflammation, malnutrition, and fibrosis. Metabolomics is an emerging investigative field that helps elucidate disease pathophysiology and identify biomarkers. However, previous metabolomic studies in RDEB are limited. OBJECTIVE: To investigate the plasma metabolomic profiles in RDEB patients. METHODS: We recruited 10 RDEB patients and 10 age-/gender-matched healthy controls. Peripheral blood samples were collected and plasma metabolomic profiling was performed by LC-MS/MS analysis. MS data processing and compound identification were executed by MS-DIAL. Enrichment analysis was performed by MetaboAnalyst 5.0. RESULTS: Metabolomic analyses demonstrated that most amino acid levels were downregulated in RDEB patients, and the extent of insufficiency correlated with clinical severity. Several metabolites were dysregulated in RDEB, including glutamine and glutamate metabolism, tryptophan-to-kynurenine ratio, phenylalanine-to-tyrosine ratio, and succinate accumulation. LIMITATIONS: The study was limited by small case numbers and the unrepresentativeness of a single time-point blood sample. CONCLUSION: Our study demonstrated the altered metabolomic profiles in RDEB, reflecting the disease severity, the chronic inflammatory and malnourished status, while the fibrotic signatures were not evident.

Programmed Exercise Attenuates Familial Hypertrophic Cardiomyopathy in Transgenic E22K Mice via Inhibition of PKC-α/NFAT Pathway.

Familial hypertrophic cardiomyopathy (FHCM), an autosomal dominant disease, is caused by mutations in genes encoding cardiac sarcomeric proteins. E22K, a mutation in the myosin regulatory light chain sarcomere gene, is associated with the development of FHCM. However, the molecular mechanisms by which E22K mutation promotes septal hypertrophy are still elusive. The hypertrophic markers, including beta-myosin heavy chain, atrial natriuretic peptide and B-type natriuretic peptide, were upregulated, as detected by fluorescence quantitative PCR. The gene expression profiles were greatly altered in the left ventricle of E22K mutant mice. Among these genes, nuclear factor of activated T cells (NFAT) and protein kinase C-alpha (PKC-α) were upregulated, and their protein expression levels were also verified to be elevated. The fibrosis markers, such as phosphorylated Smad and transforming growth factor beta receptor, were also elevated in transgenic E22K mice. After receiving 6 weeks of procedural exercise training, the expression levels of PKC-α and NFAT were reversed in E22K mouse hearts. In addition, the expression levels of several fibrosis-related genes such as transforming growth factor beta receptor 1, Smad4, and alpha smooth muscle actin in E22K mouse hearts were also reversed. Genes that associated with cardiac remodeling such as myocyte enhancer factor 2C, extracellular matrix protein 2 and fibroblast growth factor 12 were reduced after exercising. Taken together, our results indicate that exercise can improve hypertrophy and fibrosis-related indices in transgenic E22K mice via PKC-α/NFAT pathway, which provide new insight into the prevention and treatment of familial hypertrophic cardiomyopathy.

Brain network effects by continuous theta burst stimulation in mal de débarquement syndrome: simultaneous EEG and fMRI study.

Objective. Heterogeneous clinical responses to treatment with non-invasive brain stimulation are commonly observed, making it necessary to determine personally optimized stimulation parameters. We investigated neuroimaging markers of effective brain targets of treatment with continuous theta burst stimulation (cTBS) in mal de débarquement syndrome (MdDS), a balance disorder of persistent oscillating vertigo previously shown to exhibit abnormal intrinsic functional connectivity.Approach.Twenty-four right-handed, cTBS-naive individuals with MdDS received single administrations of cTBS over one of three stimulation targets in randomized order. The optimal target was determined based on the assessment of acute changes after the administration of cTBS over each target. Repetitive cTBS sessions were delivered on three consecutive days with the optimal target chosen by the participant. Electroencephalography (EEG) was recorded at single-administration test sessions of cTBS. Simultaneous EEG and functional MRI data were acquired at baseline and after completion of 10-12 sessions. Network connectivity changes after single and repetitive stimulations of cTBS were analyzed.Main results.Using electrophysiological source imaging and a data-driven method, we identified network-level connectivity changes in EEG that correlated with symptom responses after completion of multiple sessions of cTBS. We further determined that connectivity changes demonstrated by EEG during test sessions of single administrations of cTBS were signatures that could predict optimal targets.Significance.Our findings demonstrate the effect of cTBS on resting state brain networks and suggest an imaging-based, closed-loop stimulation paradigm that can identify optimal targets during short-term test sessions of stimulation.ClinicalTrials.gov Identifier:NCT02470377.

The Wnt Signaling Pathway in Diabetic Nephropathy.

Diabetic nephropathy (DN) is a serious kidney-related complication of both type 1 and type 2 diabetes mellitus (T1DM, T2DM) and the second major cause of end-stage kidney disease. DN can lead to hypertension, edema, and proteinuria. In some cases, DN can even progress to kidney failure, a life-threatening condition. The precise etiology and pathogenesis of DN remain unknown, although multiple factors are believed to be involved. The main pathological manifestations of DN include mesangial expansion, thickening of the glomerular basement membrane, and podocyte injury. Eventually, these pathological manifestations will lead to glomerulosclerosis, thus affecting renal function. There is an urgent need to develop new strategies for the prevention and treatment of DN. Existing evidence shows that the Wnt signaling cascade plays a key role in regulating the development of DN. Previous studies focused on the role of the Wnt canonical signaling pathway in DN. Subsequently, accumulated evidence on the mechanism of the Wnt non-canonical signaling indicated that Wnt/Ca2+ and Wnt/PCP also have essential roles in the progression of DN. In this review, we summarize the specific mechanisms of Wnt signaling in the occurrence and development of DN in podocyte injury, mesangial cell injury, and renal fibrosis. Also, to elucidate the significance of the Wnt canonical pathway in the process of DN, we uncovered evidence supporting that both Wnt/PCP and Wnt/Ca2+ signaling are critical for DN development.

Mitochondrial DNA Depletion Syndrome and Its Associated Cardiac Disease.

Mitochondria is a ubiquitous, energy-supplying (ATP-based) organelle found in nearly all eukaryotes. It acts as a "power plant" by producing ATP through oxidative phosphorylation, providing energy for the cell. The bioenergetic functions of mitochondria are regulated by nuclear genes (nDNA). Mitochondrial DNA (mtDNA) and respiratory enzymes lose normal structure and function when nuclear genes encoding the related mitochondrial factors are impaired, resulting in deficiency in energy production. Massive generation of reactive oxygen species and calcium overload are common causes of mitochondrial diseases. The mitochondrial depletion syndrome (MDS) is associated with the mutations of mitochondrial genes in the nucleus. It is a heterogeneous group of progressive disorders characterized by the low mtDNA copy number. TK2, FBXL4, TYPM, and AGK are genes known to be related to MDS. More recent studies identified new mutation loci associated with this disease. Herein, we first summarize the structure and function of mitochondria, and then discuss the characteristics of various types of MDS and its association with cardiac diseases.

Amplitude of fNIRS Resting-State Global Signal Is Related to EEG Vigilance Measures: A Simultaneous fNIRS and EEG Study.

Recently, functional near-infrared spectroscopy (fNIRS) has been utilized to image the hemodynamic activities and connectivity in the human brain. With the advantage of economic efficiency, portability, and fewer physical constraints, fNIRS enables studying of the human brain at versatile environment and various body positions, including at bed side and during exercise, which complements the use of functional magnetic resonance imaging (fMRI). However, like fMRI, fNIRS imaging can be influenced by the presence of a strong global component. Yet, the nature of the global signal in fNIRS has not been established. In this study, we investigated the relationship between fNIRS global signal and electroencephalogram (EEG) vigilance using simultaneous recordings in resting healthy subjects in high-density and whole-head montage. In Experiment 1, data were acquired at supine, sitting, and standing positions. Results found that the factor of body positions significantly affected the amplitude of the resting-state fNIRS global signal, prominently in the frequency range of 0.05-0.1 Hz but not in the very low frequency range of less than 0.05 Hz. As a control, the task-induced fNIRS or EEG responses to auditory stimuli did not differ across body positions. However, EEG vigilance plays a modulatory role in the fNIRS signals in the frequency range of less than 0.05 Hz: resting-state sessions of low EEG vigilance measures are associated with high amplitudes of fNIRS global signals. Moreover, in Experiment 2, we further examined the epoch-to-epoch fluctuations in concurrent fNIRS and EEG data acquired from a separate group of subjects and found a negative temporal correlation between EEG vigilance measures and fNIRS global signal amplitudes. Our study for the first time revealed that vigilance as a neurophysiological factor modulates the resting-state dynamics of fNIRS, which have important implications for understanding and processing the noises in fNIRS signals.

Value of plasma homocysteine to predict stroke, cardiovascular diseases, and new-onset hypertension: A retrospective cohort study.

The influences of hyperhomocysteinemia on cardiovascular diseases (CVDs), stroke and new-onset hypertension are unclear. The aim of the study is to explore the associations of homocysteine levels with stroke, CVDs, and new-onset hypertension in Chinese individuals.This retrospective cohort study included outpatients and inpatients from the Department of Geriatrics at Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine from January to December 2000. They were divided based on their homocysteine (Hcy) levels in 2000: Q1 (<10 µmol/L), Q2 (10-15 µmol/L), and Q3 (>15 µmol/L) and according to whether they had hypertension at baseline. Information about stroke, mortality and major adverse cardiac events, and newly onset hypertension was gathered in December each year until 2017. The effects of Hcy levels on the risk for stroke and CVDs among all patients, and new-onset hypertension among patients without hypertension at baseline were evaluated.After adjustment for confounders, compared with the Q1 group (Hcy <10 µmol/L), when the Hcy increased to 10 to 15 µmol/L, the risks for stroke, CVDs, and new-onset hypertension significantly increased, and the hazard ratio and 95% confidence interval were 2.02 (1.35-3.05, P = .001), 2.22 (1.32-3.76, P = .003), and 7.20 (4.52-11.48, P < .001), respectively. Hcy improved the predictive capability of traditional risk factors for stroke. The optimal cut-off value of Hcy for predicting stroke was 13.4 µmol/L (sensitivity: 70.9%, specificity: 62.2%).Hcy 10 to 15 µmol/L is significantly associated with the risks for stroke, mortality and major adverse cardiac events, and hypertension. The best cut-off point of Hcy for predicting stroke is 13.4 µmol/L.

Mixotrophic Ochromonas Addition Improves the Harmful Microcystis-Dominated Phytoplankton Community in In Situ Microcosms.

Driven by global warming and eutrophication, outbreaks of cyanobacterial blooms have severely impacted ecosystem stability and water safety. Of the organisms used to control cyanobacteria, protozoa can highly resist cyanotoxins, efficiently control cyanobacterial populations, and show considerably different feeding strategies from those of metazoans. Thus, protozoa have great potential to control harmful cyanobacteria and improve phytoplankton composition in eutrophic waters. To evaluate the actual effects of protozoa in controlling cyanobacteria and improving the phytoplankton community structure in the field, an in situ microcosm study was performed using a flagellate Ochromonas gloeopara that ingests Microcystis. Results showed that adding Ochromonas reduced the cyanobacterial populations and increased the chlorophyte and diatom proportions. Furthermore, the species richness and diversity of the phytoplankton community were enhanced in microcosms with Ochromonas. Additionally, there was a gradual increase in the chlorophyte population in the unicellular Microcystis control, while Ochromonas addition significantly accelerated the replacement of dominant species. This study was the first to show the practical effects of protozoa on controlling cyanobacteria in the field, highlighting that a reduction in in situ cyanobacteria via protozoa can improve the phytoplankton community structure, dredge the toxic cyanobacteria-dominated microbial food web, and mitigate harmful cyanobacteria risks in fresh waters.

Whole-brain electrophysiological functional connectivity dynamics in resting-state EEG.

OBJECTIVE: Functional connectivity (FC) dynamics have been studied in functional magnetic resonance imaging (fMRI) data, while it is largely unknown in electrophysiological data, e.g. EEG. APPROACH: The present study proposed a novel analytic framework to study spatiotemporal dynamics of FC (dFC) in resting-state human EEG data, including independent component analysis, cortical source imaging, sliding-window correlation analysis, and k-means clustering. MAIN RESULTS: Our results confirm that major fMRI intrinsic connectivity networks (ICNs) can be successfully reconstructed from EEG using our analytic framework. Prominent spatial and temporal variability were revealed in these ICNs. The mean dFC spatial patterns of individual ICNs resemble their corresponding static FC (sFC) patterns but show fewer cross-talks among distinct ICNs. Our investigation unveils evidences of time-domain variations in individual ICNs comparable to their mean FC level in terms of magnitude. The major contributors to these variations are from the frequency below 0.0156 Hz, in the similar range of FC dynamics from fMRI data. Among different ICNs, larger temporal variabilities are observed in the frontal attention and auditory/visual ICNs, while sensorimotor, salience, and default model networks showed less. Our analytic framework for the first time revealed quasi-stable states within individual EEG ICNs, with various strengths or spatial patterns that were reliably detected at both group and individual levels. These states all together reveal a more complete picture of EEG ICNs: (1) quasi-stable state spatial patterns as a whole for each EEG ICN are more consistent with the corresponding fMRI ICN in terms of the bilateral distribution and multi-nodes structure; (2) EEG ICNs reveal more transient patterns about within-ICN between-node communications than fMRI ICNs. SIGNIFICANCE: The present findings highlight the fact that rich temporal and spatial dynamics exist in ICN that can be detected from EEG data. Future studies might extend investigations towards spectral dynamics of EEG ICNs.

Non-toxic and toxic Microcystis aeruginosa reduce the tolerance of Daphnia pulex to low calcium in different degrees: Based on the changes in the key life-history traits.

Calcium decline and cyanobacterial blooms pose a serious threat to the crustacean zooplankton Daphnia, which has a high demand for calcium. In the present study, we exposed two different clones of Daphnia pulex to different combinations of calcium concentrations (0.1, 0.5, 1.0, 5.0, 10.0 mg L-1) and food types (100% Chlorella; 80% Chlorella and 20% non-toxic Microcystis; 80% Chlorella and 20% toxic Microcystis) for 16 days, recorded the key life-history traits, and then used an exponential rise function to fit the traits. Results showed toxic Microcystis and low calcium together negatively affected the survival, development, and reproduction of Daphnia. The negative effect of non-toxic Microcystis and low calcium only affected the development and reproduction. The survival time and reproductive performance increased exponentially with increasing calcium concentration and then approached an asymptotic maximum. Both non-toxic and toxic Microcystis reduced the asymptotic maximum of the reproductive performance. The rising rate at which they reached the asymptotes differed significantly among the three food types; i.e., the reproductive performance of Daphnia was affected in a wider range of calcium concentrations under bad food quality. The findings indicated that Microcystis impaired the tolerance of Daphnia to low calcium, which may cause serious consequences in freshwater ecosystems.

Microcystis aeruginosa affects the inducible anti-predator responses of Ceriodaphnia cornuta.

Cyanobacterial blooms are an increasing problem in a more eutrophic world. It is still a challenge to fully understand the influence of cyanobacteria on the interactions between predator and prey at higher trophic levels. The present study was mainly undertaken to understand the inducible anti-predator responses of cladocerans while using cyanobacteria as part of food. Specifically speaking, we focused on the anti-predator strategies of Ceriodaphnia cornuta in response to different predators (fish and Chaoborus larvae) under food with different proportions of Microcystis aeruginosa. The morphological (i.e., body size and the induction of horns) and life history traits (e.g., time to first reproduction, offspring number, and survival time) responses were measured under different proportions of M. aeruginosa (i.e., 0%, 20%, 40%, 60%, 80%, and 100%). Our results showed that both the life history and the inducible anti-predator responses of C. cornuta were significantly affected by different concentrations of M. aeruginosa. Specifically, lower concentrations of Microcystis (20%-60%) can significantly promote the horns induction under Chaoborus predation risks, and higher Microcystis concentrations (60%-100%) tend to enhance reproduction in response to fish predation risks, such as larger body size, decreased time to first reproduction, and increased total offspring number. Additionally, an increasing concentration of M. aeruginosa decreased the ability of C. cornuta to reverse horns when predation risks removed. Our findings indicated that cyanobacteria affecting life history traits and the subsequent indirect effects on anti-predator responses in cladocerans could impact the interactions between predator and prey at higher trophic levels and may consequently contribute to shaping the structure of the community in a cyanobacteria bloom area.

Daphnia enhances relative reproductive allocation in response to toxic microcystis: Changes in the performance of parthenogenetic and sexual reproduction.

Eutrophication and warming lead to frequent occurrence of cyanobacterial blooms, which significantly impact on zooplankton. Freshwater zooplankton Daphnia adopts two distinct ways of reproduction: asexual (parthenogenetic) reproduction for rapidly reproducing many offspring in favorable environment and sexual reproduction for producing resting eggs as seed bank to survive in harsh environments. Daphnia pulex has worse performance in growth and reproduction under the exposure to toxic cyanobacteria Microcystis aeruginosa and tends to allocate less energy to reproduction in the case of insufficient food. However, the relative reproductive allocation strategy (energy allocation) of D. pulex individuals exposed to toxic M. aeruginosa is still unclear. Here we tested the relative reproductive performance of D. pulex fed on solely Chlorella pyrenoidosa (high quality food) or Chlorella mixed with toxic M. aeruginosa (low quality food), based on the parthenogenetic reproduction (life-history experiments) and sexual reproduction (population experiments). The results showed that under low quality food conditions, D. pulex reproduced fewer offspring which were also smaller and thus led to a reduced absolute output in parthenogenetic reproduction, but produced ephippia in the same size and quantity compared to those cultured under high quality food conditions. However, as the body size of maternal D. pulex cultured under low quality food conditions decreased, the relative reproductive allocation significantly increased in both parthenogenetic and sexual reproduction, compared to those cultured under high quality food conditions. In conclusion, D. pulex tend to allocate relatively more energy to reproduction under Microcystis conditions, which is a reasonable strategy for it to decentralize the risks from low-quality food.

Effect of HIF-1α/miR-10b-5p/PTEN on Hypoxia-Induced Cardiomyocyte Apoptosis.

Background Few reports have addressed the mechanism by which microRNA miR-10b-5p regulates post-myocardial infarction (post-MI) cardiomyocyte apoptosis under hypoxic conditions. Methods and Results C57BL/6 mice underwent surgical ligation of the left anterior descending artery to create an MI or ischemia/reperfusion animal model. The expression of miR-10b-5p, PTEN (phosphatase and tensin homolog), and HIF-1α (hypoxia-inducible factor 1α) was detected in infarct border zone tissues at various time points. After precordial injections of the negative control or miR-10b-5p, overexpression lentiviruses were made in the areas surrounding the MI sites at 1 week, and myocardial infarct size, cardiac function, and cardiomyocyte apoptosis were examined. A miR-10b-5p mimic was transfected into primary mouse cardiomyocytes to analyze its effects on cardiomyocyte apoptosis and PTEN expression. Meanwhile, PTEN as a target of miR-10b-5p was verified via luciferase reporter gene assays. Cotransfection of miR-10b-5 and PTEN verified the relationship between miR-10b-5 and PTEN. Under hypoxic stress, the expression of HIF-1α and miR-10b-5p was examined. The results showed that miR-10b-5p expression was markedly reduced in the infarct border zone. Overexpression of miR-10b-5p in the murine model of MI significantly reduced MI size, improved cardiac function, and inhibited apoptosis. Overexpression of miR-10b-5p in vitro antagonized hypoxia-induced cardiomyocyte apoptosis and specifically inhibited the expression of the apoptosis-related gene PTEN, but overexpression of PTEN weakened these effects. We also found that hypoxia-induced accumulation of HIF-1α resulted in decreased expression of miR-10b-5p. Interfering with the activation of the HIF-1α signaling pathway promoted Pri-miR-10b and miR-10b-5p expression and inhibited PTEN expression. Conclusions MicroRNA miR-10b-5p antagonizes hypoxia-induced cardiomyocyte apoptosis, indicating that miR-10b-5p may serve as a potential future clinical target for the treatment of MI.

Combined effects of ZnO nanoparticles and toxic Microcystis on life-history traits of Daphnia magna.

Rise in cyanobacterial blooms and massive discharge of nanoparticles (NPs) in aquatic ecosystems cause zooplankton to be exposed in toxic food and NPs simultaneously, which may impact on zooplankton interactively. Therefore, the present study focused on assessing the combined effects of different ZnO NPs levels (0, 0.10, 0.15, 0.20 mg L-1) and different proportions of toxic Microcystis (0%, 10%, 20%, 30%) in the food on a model zooplankton, Daphnia magna. The results showed that both toxic Microcystis and ZnO NPs significantly delayed the development of D. magna to maturation, but there was no significant interaction between the two factors on the times to maturation except the body length at maturation. Both ZnO NPs and toxic Microcystis also significantly decreased the number of neonates in the first brood, total offspring, and number of broods per female, and there was a significant interaction between ZnO NPs and food composition on the reproductive performance of D. magna. Specifically, presence of toxic Microcystis reduced the gap among the effects of different ZnO NPs concentrations on the reproductive performance of D. magna. When the ZnO NPs concentration was at 0.15 mg L-1, the gap of the reproductive performance among different proportions of toxic Microcystis also tended to be narrow. Similar phenomenon also occurred in mortality. Such results suggested that low concentration of ZnO NPs and toxic Microcystis can mutually attenuate their harmful effects on D. magna, which has significantly implications in appropriately assessing the ecotoxicological effects of emerging pollutants in a complex food conditions.

Combined Search for a Lorentz-Violating Force in Short-Range Gravity Varying as the Inverse Sixth Power of Distance.

Precision measurements of the inverse-square law via experiments on short-range gravity provide sensitive tests of Lorentz symmetry. A combined analysis of data from experiments at the Huazhong University of Science and Technology and Indiana University sets simultaneous limits on all 22 coefficients for Lorentz violation correcting the Newton force law as the inverse sixth power of distance. Results are consistent with no effect at the level of 10^{-12} m^{4}.

Genistein ameliorated obesity accompanied with adipose tissue browning and attenuation of hepatic lipogenesis in ovariectomized rats with high-fat diet.

Estrogen deficiency in postmenopausal women is linked to the higher prevalence of obesity, type 2 diabetes and metabolic syndromes. Development of beige adipocytes (browning of WAT) increases energy expenditure and could be a promising strategy for obesity management. This study aimed to investigate the effects of phytoestrogen genistein (GEN) on white adipose tissue (WAT) inflammation, browning and hepatic lipogenesis in ovariectomized rats with high-fat diet (HFD) and further explore the underlying mechanism. Female Wistar rats received ovariectomy (Ovx) and HFD (45% fat) and then were administered with 17ß-estradiol (E2, 3 times/week, subcutaneously) or GEN (15 mg/kg or 30 mg/kg, gavage, once daily) for 4 weeks. Administration of GEN decreased Ovx-induced body weight gain and adiposity and improved insulin sensitivity as well as increased insulin signaling p-IRS1 and p-AKT in retroperitoneal WAT. Adipocyte hypertrophy and production of proinflammatory cytokines MCP-1, TNF-α and IL-6 were reduced by GEN. It also suppressed the activation of NF-κB pathway evidenced by attenuation of p65 and phospho-IκB levels. Additionally, GEN elevated myokine irisin and promoted WAT browning by increasing UCP-1, PRDM-16, PGC-1α and CIDEA proteins and Ppargc1a, Ucp-1 and Tbx-1 mRNA in inguinal WAT which is associated with up-regulation of nuclear estrogen receptor-α. Plasma levels of triglyceride and cholesterol were reduced by GEN treatment accompanied with inhibition of lipogenic proteins (p-ACC, SREBP-1, FAS and CD36) in the liver. Long-term treatment with GEN attenuated estrogen-deficiency-induced obesity, WAT inflammation and hepatic lipogenesis and promoted the induction of WAT browning. It may provide a promising approach to prevent obesity during menopause.

Multimodal Imaging of Repetitive Transcranial Magnetic Stimulation Effect on Brain Network: A Combined Electroencephalogram and Functional Magnetic Resonance Imaging Study.

Repetitive transcranial magnetic stimulation (rTMS) has been increasingly used to treat many neurological and neuropsychiatric disorders. However, the clinical response is heterogeneous mainly due to our inability to predict the effect of rTMS on the human brain. Our previous investigation based on functional magnetic resonance imaging (fMRI) suggested that neuroimaging-guided navigation for rTMS could be informed by understanding connectivity patterns that correlate with treatment response. In this study, 20 individuals with a balance disorder called Mal de Debarquement Syndrome completed high-density resting-state electroencephalogram (EEG) and fMRI recordings before and after 5 days of rTMS stimulation over both dorsolateral prefrontal cortices. Based on temporal independent component analysis of source-level EEG data, large-scale electrophysiological resting-state networks were reconstructed and connectivity values in each individual were quantified both before and after treatment. Our results show that high-density, resting-state EEG can reveal connectivity changes in brain networks after rTMS that correlate with symptom changes. The connectivity changes measured by EEG were primarily superficial cortical areas that correlate with previously shown default mode network changes revealed by fMRI. Further, higher baseline EEG connectivity values in the primary visual cortex were predictive of symptom reduction after rTMS. Our findings suggest that multimodal EEG and fMRI measures of brain networks can be biomarkers that correlate with the treatment effect of rTMS. Since EEG is compatible with rTMS, real-time navigation based on an EEG neuroimaging marker may augment rTMS optimization.