The ketogenic diet does not improve cardiac function and blunts glucose oxidation in ischemic heart failure.

AIMS: Cardiac energy metabolism is perturbed in ischemic heart failure and is characterized by a shift from mitochondrial oxidative metabolism to glycolysis. Notably, the failing heart relies more on ketones for energy than a healthy heart, an adaptive mechanism that improves the energy-starved status of the failing heart. However, whether this can be implemented therapeutically remains unknown. Therefore, our aim was to determine if increasing ketone delivery to the heart via a ketogenic diet can improve the outcomes of heart failure. METHODS: C57BL/6J male mice underwent either a sham surgery or permanent left anterior descending (LAD) coronary artery ligation surgery to induce heart failure. After 2 weeks, mice were then treated with either a control diet or a ketogenic diet for 3 weeks. Transthoracic echocardiography was then carried out to assess in vivo cardiac function and structure. Finally, isolated working hearts from these mice were perfused with appropriately 3H or 14C labelled glucose (5 mM), palmitate (0.8 mM), and ß-hydroxybutyrate (0.6 mM) to assess mitochondrial oxidative metabolism and glycolysis. RESULTS: Mice with heart failure exhibited a 56% drop in ejection fraction which was not improved with a ketogenic diet feeding. Interestingly, mice fed a ketogenic diet had marked decreases in cardiac glucose oxidation rates. Despite increasing blood ketone levels, cardiac ketone oxidation rates did not increase, probably due to a decreased expression of key ketone oxidation enzymes. Furthermore, in mice on the ketogenic diet no increase in overall cardiac energy production was observed, and instead there was a shift to an increased reliance on fatty acid oxidation as a source of cardiac energy production. This resulted in a decrease in cardiac efficiency in heart failure mice fed a ketogenic diet. CONCLUSIONS: We conclude that the ketogenic diet does not improve heart function in failing hearts, due to ketogenic diet-induced excessive fatty acid oxidation in the ischemic heart and a decrease in insulin-stimulated glucose oxidation.

Mitochondrial fatty acid oxidation is the major source of cardiac adenosine triphosphate production in heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is a prevalent disease worldwide. While it is well established that alterations of cardiac energy metabolism contribute to cardiovascular pathology, the precise source of fuel used by the heart in HFpEF remains unclear. The objective of this study was to define the energy metabolic profile of the heart in HFpEF. METHODS AND RESULTS: Eight-week-old C57BL/6 male mice were subjected to a '2-Hit' HFpEF protocol [60% high-fat diet (HFD) + 0.5 g/L of Nω-nitro-L-arginine methyl ester]. Echocardiography and pressure-volume loop analysis were used for assessing cardiac function and cardiac haemodynamics, respectively. Isolated working hearts were perfused with radiolabelled energy substrates to directly measure rates of fatty acid oxidation, glucose oxidation, ketone oxidation, and glycolysis. HFpEF mice exhibited increased body weight, glucose intolerance, elevated blood pressure, diastolic dysfunction, and cardiac hypertrophy. In HFpEF hearts, insulin stimulation of glucose oxidation was significantly suppressed. This was paralleled by an increase in fatty acid oxidation rates, while cardiac ketone oxidation and glycolysis rates were comparable with healthy control hearts. The balance between glucose and fatty acid oxidation contributing to overall adenosine triphosphate (ATP) production was disrupted, where HFpEF hearts were more reliant on fatty acid as the major source of fuel for ATP production, compensating for the decrease of ATP originating from glucose oxidation. Additionally, phosphorylated pyruvate dehydrogenase levels decreased in both HFpEF mice and human patient's heart samples. CONCLUSION: In HFpEF, fatty acid oxidation dominates as the major source of cardiac ATP production at the expense of insulin-stimulated glucose oxidation.

Stimulating cardiac glucose oxidation lessens the severity of heart failure in aged female mice.

Heart failure is a prevalent disease worldwide. While it is well accepted that heart failure involves changes in myocardial energetics, what alterations that occur in fatty acid oxidation and glucose oxidation in the failing heart remains controversial. The goal of the study are to define the energy metabolic profile in heart failure induced by obesity and hypertension in aged female mice, and to attempt to lessen the severity of heart failure by stimulating myocardial glucose oxidation. 13-Month-old C57BL/6 female mice were subjected to 10 weeks of a 60% high-fat diet (HFD) with 0.5 g/L of Nω-nitro-L-arginine methyl ester (L-NAME) administered via drinking water to induce obesity and hypertension. Isolated working hearts were perfused with radiolabeled energy substrates to directly measure rates of myocardial glucose oxidation and fatty acid oxidation. Additionally, a series of mice subjected to the obesity and hypertension protocol were treated with a pyruvate dehydrogenase kinase inhibitor (PDKi) to stimulate cardiac glucose oxidation. Aged female mice subjected to the obesity and hypertension protocol had increased body weight, glucose intolerance, elevated blood pressure, cardiac hypertrophy, systolic dysfunction, and decreased survival. While fatty acid oxidation rates were not altered in the failing hearts, insulin-stimulated glucose oxidation rates were markedly impaired. PDKi treatment increased cardiac glucose oxidation in heart failure mice, which was accompanied with improved systolic function and decreased cardiac hypertrophy. The primary energy metabolic change in heart failure induced by obesity and hypertension in aged female mice is a dramatic decrease in glucose oxidation. Stimulating glucose oxidation can lessen the severity of heart failure and exert overall functional benefits.

Amlodipine rescues advanced iron overload cardiomyopathy in hemojuvelin knockout murine model: Clinical implications.

Background: Iron overload cardiomyopathy (IOC) is a major co-morbidity of genetic hemochromatosis and secondary iron overload with limited therapeutic options. We aim to investigate mechanisms of rescue action of amlodipine in the murine model of iron overload, characterize changes in human cardiac tissue due to IOC, and compare them to the changes in the animal model of IOC. Methods and results: As an animal model, we used male hemojuvelin knockout (HJVKO) mice, which lacked hemojuvelin (a co-receptor protein for hepcidin expression). The mice were fed a high-iron diet from 4 weeks to 1 year of age. As a rescue, iron-fed mice received the Ca2+ channel blocker, amlodipine, from 9 to 12 months. Iron overload resulted in systolic and diastolic dysfunctions and changes in the cardiac tissue similar to the changes in the explanted human heart with IOC. An IOC patient (ß-thalassemia) with left-ventricular ejection fraction (LVEF) 25% underwent heart transplantation. The murine model and the explanted heart showed intra-myocyte iron deposition, fibrosis, hypertrophy, oxidative stress, remodeling of Ca2+ cycling proteins, and metabolic kinases typical of heart failure. Single-myocyte contractility and Ca2+ release were diminished in the murine model. The amlodipine-treated group exhibited normalization of cellular function and reversed fibrosis, hypertrophy, oxidative stress, and metabolic remodeling. We also report a clinical case of primary hemochromatosis successfully treated with amlodipine. Conclusions: The aged HJVKO murine model on the iron-rich diet reproduced many features of the human case of IOC. The use of amlodipine in the murine model and clinical case reversed IOC remodeling, demonstrating that amlodipine is effective adjuvant therapy for IOC.

Low-intensity focused ultrasound ameliorates depression-like behaviors associated with improving the synaptic plasticity in the vCA1-mPFC pathway.

It is of great social significance and clinical value to explore new effective treatments for depression. Low-intensity focused ultrasound stimulation (LIFUS) has been indicated to have notable neuroprotective effects on depression. However, little is known about how different strategies of LIFUS affect the therapeutic effect. Therefore, the purpose of this study is to investigate whether the effects of LIFUS on depression-like behaviors are associated with the intensity and the underlying mechanisms. We established the depression rats model using the chronic unpredictable stress (CUS) and applied the LIFUS with high/low intensity (Ispta = 500 and 230 mW/cm2, respectively) to the left medial prefrontal cortex (mPFC) after CUS. We found that two intensities of LIFUS both could significantly improve depression-like behaviors to a comparable degree. We further found that theta oscillation synchronization and synaptic functional plasticity in the hippocampal vCA1-mPFC pathway were significantly improved by chronic LIFUS which mainly due to the alternation of synaptic structural plasticity and the expression of post-synaptic proteins in the mPFC. These results suggest that LIFUS ameliorates the depression-like behaviors associated with improving the synaptic plasticity in the vCA1-mPFC pathway. Our study provides preclinical evidence and a theoretical basis for applying LIFUS for depression treatment.

Myocardial Iron Deficiency and Mitochondrial Dysfunction in Advanced Heart Failure in Humans.

Background Myocardial iron deficiency (MID) in heart failure (HF) remains largely unexplored. We aim to establish defining criterion for MID, evaluate its pathophysiological role, and evaluate the applicability of monitoring it non-invasively in human explanted hearts. Methods and Results Biventricular tissue iron levels were measured in both failing (n=138) and non-failing control (NFC, n=46) explanted human hearts. Clinical phenotyping was complemented with comprehensive assessment of myocardial remodeling and mitochondrial functional profiles, including metabolic and oxidative stress. Myocardial iron status was further investigated by cardiac magnetic resonance imaging. Myocardial iron content in the left ventricle was lower in HF versus NFC (121.4 [88.1-150.3] versus 137.4 [109.2-165.9] µg/g dry weight), which was absent in the right ventricle. With a priori cutoff of 86.1 µg/g d.w. in left ventricle, we identified 23% of HF patients with MID (HF-MID) associated with higher NYHA class and worsened left ventricle function. Respiratory chain and Krebs cycle enzymatic activities were suppressed and strongly correlated with depleted iron stores in HF-MID hearts. Defenses against oxidative stress were severely impaired in association with worsened adverse remodeling in iron-deficient hearts. Mechanistically, iron uptake pathways were impeded in HF-MID including decreased translocation to the sarcolemma, while transmembrane fraction of ferroportin positively correlated with MID. Cardiac magnetic resonance with T2* effectively captured myocardial iron levels in failing hearts. Conclusions MID is highly prevalent in advanced human HF and exacerbates pathological remodeling in HF driven primarily by dysfunctional mitochondria and increased oxidative stress in the left ventricle. Cardiac magnetic resonance demonstrates clinical potential to non-invasively monitor MID.

Low-Intensity Focused Ultrasound Stimulation Ameliorates Working Memory Dysfunctions in Vascular Dementia Rats via Improving Neuronal Environment.

Working memory impairment is one of the remarkable cognitive dysfunctions induced by vascular dementia (VD), and it is necessary to explore an effective treatment. Recently, low-intensity focused ultrasound stimulation (LIFUS) has been found notable neuroprotective effects on some neurological diseases, including VD. However, whether it could ameliorate VD-induced working memory impairment was still not been clarified. The purpose of this study was to address this issue and the underlying mechanism. We established VD rat model using the bilateral common carotid artery occlusion (BCCAO) and applied the LIFUS (center frequency = 0.5 MHz; Ispta = 500 mW/cm2, 10 mins/day) to bilateral medial prefrontal cortex (mPFC) for 2 weeks since 2 weeks after the surgery. The main results showed that the LIFUS could significantly improve the performance of VD rats in the specific working memory tasks (delayed nonmatch-to-sample task and step-down task), which might be associated with the improved synaptic function. We also found the improvement in the cerebral blood flow (CBF) and reduced neuroinflammation in mPFC after LIFUS treatment indicated by the inhibition of Toll-like receptor (TLR4)/nuclear factor kappa B (NF-κB) pathway and the decrease of proinflammatory cytokines. The amelioration of CBF and neuroinflammation may promote the living environment of the neurons in VD which then contribute to the survival of neurons and the improvement in synaptic function. Taken together, our findings indicate that LIFUS targeted mPFC can effectively ameliorate reward-based spatial working memory and fear working memory dysfunctions induced by VD via restoring the living environment, survivability, and synaptic functions of the neurons in mPFC of VD rats. This study adds to the evidence that LIFUS could become a promising and non-invasive treatment strategy for the clinical treatment of central nervous system diseases related to cognitive impairments in the future.

Natural History of a Mouse Model Overexpressing the Dp71 Dystrophin Isoform.

Dystrophin is a 427 kDa protein that stabilizes muscle cell membranes through interactions with the cytoskeleton and various membrane-associated proteins. Loss of dystrophin as in Duchenne muscular dystrophy (DMD) causes progressive skeletal muscle weakness and cardiac dysfunction. Multiple promoters along the dystrophin gene (DMD) give rise to a number of shorter isoforms. Of interest is Dp71, a 71 kDa isoform implicated in DMD pathology by various animal and patient studies. Strong evidence supporting such a role for Dp71, however, is lacking. Here, we use del52;WT mice to understand how Dp71 overexpression affects skeletal and cardiac muscle phenotypes. Apart from the mouse Dmd gene, del52;WT mice are heterozygous for a full-length, exon 52-deleted human DMD transgene expected to only permit Dp71 expression in muscle. Thus, del52;WT mice overexpress Dp71 through both the human and murine dystrophin genes. We observed elevated Dp71 protein in del52;WT mice, significantly higher than wild-type in the heart but not the tibialis anterior. Moreover, del52;WT mice had generally normal skeletal muscle but impaired cardiac function, exhibiting significant systolic dysfunction as early as 3 months. No histological abnormalities were found in the tibialis anterior and heart. Our results suggest that Dp71 overexpression may have more detrimental effects on the heart than on skeletal muscles, providing insight into the role of Dp71 in DMD pathogenesis.

Loss of TIMP4 (Tissue Inhibitor of Metalloproteinase 4) Promotes Atherosclerotic Plaque Deposition in the Abdominal Aorta Despite Suppressed Plasma Cholesterol Levels.

[Figure: see text].

Barth syndrome-related cardiomyopathy is associated with a reduction in myocardial glucose oxidation.

Heart failure presents as the leading cause of infant mortality in individuals with Barth syndrome (BTHS), a rare genetic disorder due to mutations in the tafazzin (TAZ) gene affecting mitochondrial structure and function. Investigations into the perturbed bioenergetics in the BTHS heart remain limited. Hence, our objective was to identify the potential alterations in myocardial energy metabolism and molecular underpinnings that may contribute to the early cardiomyopathy and heart failure development in BTHS. Cardiac function and myocardial energy metabolism were assessed via ultrasound echocardiography and isolated working heart perfusions, respectively, in a mouse model of BTHS [doxycycline-inducible Taz knockdown (TazKD) mice]. In addition, we also performed mRNA/protein expression profiling for key regulators of energy metabolism in hearts from TazKD mice and their wild-type (WT) littermates. TazKD mice developed hypertrophic cardiomyopathy as evidenced by increased left ventricular anterior and posterior wall thickness, as well as increased cardiac myocyte cross-sectional area, though no functional impairments were observed. Glucose oxidation rates were markedly reduced in isolated working hearts from TazKD mice compared with their WT littermates in the presence of insulin, which was associated with decreased pyruvate dehydrogenase activity. Conversely, myocardial fatty acid oxidation rates were elevated in TazKD mice, whereas no differences in glycolytic flux or ketone body oxidation rates were observed. Our findings demonstrate that myocardial glucose oxidation is impaired before the development of overt cardiac dysfunction in TazKD mice, and may thus represent a pharmacological target for mitigating the development of cardiomyopathy in BTHS.NEW & NOTEWORTHY Barth syndrome (BTHS) is a rare genetic disorder due to mutations in tafazzin that is frequently associated with infantile-onset cardiomyopathy and subsequent heart failure. Although previous studies have provided evidence of perturbed myocardial energy metabolism in BTHS, actual measurements of flux are lacking. We now report a complete energy metabolism profile that quantifies flux in isolated working hearts from a murine model of BTHS, demonstrating that BTHS is associated with a reduction in glucose oxidation.

Membrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis.

Plasma low-density lipoprotein (LDL) is primarily cleared by LDL receptor (LDLR). LDLR can be proteolytically cleaved to release its soluble ectodomain (sLDLR) into extracellular milieu. However, the proteinase responsible for LDLR cleavage is unknown. Here we report that membrane type 1-matrix metalloproteinase (MT1-MMP) co-immunoprecipitates and co-localizes with LDLR and promotes LDLR cleavage. Plasma sLDLR and cholesterol levels are reduced while hepatic LDLR is increased in mice lacking hepatic MT1-MMP. Opposite effects are observed when MT1-MMP is overexpressed. MT1-MMP overexpression significantly increases atherosclerotic lesions, while MT1-MMP knockdown significantly reduces cholesteryl ester accumulation in the aortas of apolipoprotein E (apoE) knockout mice. Furthermore, sLDLR is associated with apoB and apoE-containing lipoproteins in mouse and human plasma. Plasma levels of sLDLR are significantly increased in subjects with high plasma LDL cholesterol levels. Thus, we demonstrate that MT1-MMP promotes ectodomain shedding of hepatic LDLR, thereby regulating plasma cholesterol levels and the development of atherosclerosis.

Modulation of bone formation and resorption using a novel zoledronic acid loaded gelatin nanoparticles integrated porous titanium scaffold: an in vitro and in vivo study.

Osteoporotic bone defects are a major challenge in clinics for bone regeneration. With the condition of osteoporosis, excessive bone absorption and impaired osteogenesis result in unexpectedly long healing procedures for defects. In order to simultaneously enhance bone formation and reduce bone resorption, a polydopamine-coated porous titanium scaffold was designed, to be integrated with anti-catabolic drug zoledronic acid nanoparticles (ZOL loaded gelatin NPs), which was able to achieve a local sustained release of ZOL as expected. The in vitro study demonstrated that extracts of the composite scaffolds would stimulate osteoblast differentiation; they also inhibited osteoclastogenesis at a ZOL loading concentration of 50 µmol l-1. In the subsequent in vivo study, the composite scaffolds were implanted into ovariectomy-induced osteoporotic rabbits suffering from femoral condyles defects. The results indicated that the composite scaffolds without ZOL loaded gelatin NPs only induced callus formation, mainly at the interface margin between the implant and bone, whereas the composite scaffolds with ZOL loaded gelatin NPs were capable of further enhancing osteogenesis and bone growth into the scaffolds. Moreover, the research proved that the promoting effect was optimal at a ZOL loading concentration of 50 µmol l-1. In summary, the present research indicated that a new type of porous titanium scaffold integrated with ZOL loaded gelatin NPs inherited a superior biocompatibility and bone regeneration capability. It would be an optimal alternative for the reconstruction of osteoporosis-related defects compared to a traditional porous titanium implant; in other words, the new type of scaffold offers a new effective and practical procedure option for patients suffering from osteoporotic bone defects.

Low-Frequency Pulsed Magnetic Field Improves Depression-Like Behaviors and Cognitive Impairments in Depressive Rats Mainly via Modulating Synaptic Function.

Transcranial magnetic stimulation (TMS) has shown great promise as a medical treatment of depression. The effectiveness of TMS treatment at high frequency has been well investigated; however, low-frequency TMS in depression treatment has rarely been investigated in depression-induced cognitive deficits. Herein, this study was carried out to assess the possible modulatory role of low-frequency pulsed magnetic field (LFPMF) on reversing cognitive impairment in a model of depression induced by chronic unpredictable stress (CUS). Wistar rats were randomly allocated into four groups as follows: a control group (CON), a control applied with LFPMF (CON + LFPMF), a CUS group, and a CUS treated with LFPMF (CUS + LFPMF) group. During 8 weeks of CUS, compared to those in the CON group, animals not only gained less weight but also exhibited anhedonia, anxiety, and cognitive decline in behavioral tests. After 2-week treatment of LFPMF, a 20 mT, 1 Hz magnetic stimulation, it reversed the impairment of spatial cognition as well as hippocampal synaptic function including long-term potentiation and related protein expression. Thus, LFPMF has shown effectively improvements on depressant behavior and cognitive dysfunction in CUS rats, possibly via regulating synaptic function.

Apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs.

Abdominal aortic aneurysm (AAA) remains the second most frequent vascular disease with high mortality but has no approved medical therapy. We investigated the direct role of apelin (APLN) in AAA and identified a unique approach to enhance APLN action as a therapeutic intervention for this disease. Loss of APLN potentiated angiotensin II (Ang II)-induced AAA formation, aortic rupture, and reduced survival. Formation of AAA was driven by increased smooth muscle cell (SMC) apoptosis and oxidative stress in Apln-/y aorta and in APLN-deficient cultured murine and human aortic SMCs. Ang II-induced myogenic response and hypertension were greater in Apln-/y mice, however, an equivalent hypertension induced by phenylephrine, an α-adrenergic agonist, did not cause AAA or rupture in Apln-/y mice. We further identified Ang converting enzyme 2 (ACE2), the major negative regulator of the renin-Ang system (RAS), as an important target of APLN action in the vasculature. Using a combination of genetic, pharmacological, and modeling approaches, we identified neutral endopeptidase (NEP) that is up-regulated in human AAA tissue as a major enzyme that metabolizes and inactivates APLN-17 peptide. We designed and synthesized a potent APLN-17 analog, APLN-NMeLeu9-A2, that is resistant to NEP cleavage. This stable APLN analog ameliorated Ang II-mediated adverse aortic remodeling and AAA formation in an established model of AAA, high-fat diet (HFD) in Ldlr-/- mice. Our findings define a critical role of APLN in AAA formation through induction of ACE2 and protection of vascular SMCs, whereas stable APLN analogs provide an effective therapy for vascular diseases.

PI3Kα Pathway Inhibition With Doxorubicin Treatment Results in Distinct Biventricular Atrophy and Remodeling With Right Ventricular Dysfunction.

Background Cancer therapies inhibiting PI 3Kα (phosphoinositide 3-kinase-α)-dependent growth factor signaling, including trastuzumab inhibition of HER 2 (Human Epidermal Growth Factor Receptor 2), can cause adverse effects on the heart. Direct inhibition of PI 3Kα is now in clinical trials, but the effects of PI 3Kα pathway inhibition on heart atrophy, remodeling, and function in the context of cancer therapy are not well understood. Method and Results Pharmacological PI 3Kα inhibition and heart-specific genetic deletion of p110α, the catalytic subunit of PI 3Kα, was characterized in conjunction with anthracycline (doxorubicin) treatment in female murine models. Biventricular changes in heart morphological characteristics and function were analyzed, with molecular characterization of signaling pathways. Both PI 3Kα inhibition and anthracycline therapy promoted heart atrophy and a combined effect of distinct right ventricular dilation, dysfunction, and cardiomyocyte remodeling in the absence of pulmonary arterial hypertension. Congruent findings of right ventricular dilation and dysfunction were seen with pharmacological and genetic suppression of PI 3Kα signaling when combined with doxorubicin treatment. Increased p38 mitogen-activated protein kinase activation was mechanistically linked to heart atrophy and correlated with right ventricular dysfunction in explanted failing human hearts. Conclusions PI 3Kα pathway inhibition promotes heart atrophy in mice. The right ventricle is specifically at risk for dilation and dysfunction in the setting of PI 3K inhibition in conjunction with chemotherapy. Inhibition of p38 mitogen-activated protein kinase is a proposed therapeutic target to minimize this mode of cardiotoxicity.

Effects of Gastrin-releasing Peptide on Hippocampal Neural Networks in Vascular Dementia Rats.

Gastrin-releasing peptide (GRP) has been confirmed to exhibit a variety of physiological functions in the brain and play a role in many neurological diseases. Our previous research found that GRP could restore the impaired synaptic plasticity and the spatial learning and memory impairments induced by vascular dementia (VD). However, the specific mechanisms of GRP affecting hippocampus, especially the effects on the neuronal oscillations were still poorly understood. In this study, we examined the effects of GRP on the changes of the interactions between theta and gamma oscillations in the hippocampal CA3-CA1 pathway of VD rats and explored the potential electrophysiological mechanism. To this purpose, local field potentials (LFPs) simultaneously collected from hippocampal CA3 and CA1 were measured by the power spectrum, phase synchronization, phase-phase coupling (PPC) and phase-amplitude coupling (PAC). We found that GRP substantially restored the phase synchronization of the theta and gamma oscillations. The GRP also significantly improved the strength of theta-gamma cross-frequency coupling (including theta-gamma PPC and theta-gamma PAC) in the CA3-CA1 network. The results indicated that GRP could alleviate the changes of neural activities in hippocampal CA3-CA1 pathway induced by VD. This might be an electrophysiological mechanism for GRP preventing cognitive impairments induced by VD.

Analysis and Classification for Single-Trial EEG Induced by Sequential Finger Movements.

In recent years, motor imagery-based BCIs (MI-BCIs) controlled various external devices successfully, which have great potential in neurological rehabilitation. In this paper, we designed a paradigm of sequential finger movements and utilized spatial filters for feature extraction to classify single-trial electroencephalography (EEG) induced by finger movements of left and right hand. Ten healthy subjects participated the experiment. The analysis of EEG patterns showed significant contralateral dominance. We investigated how data length affected the classification accuracy. The classification accuracy was improved with the increase of the keystrokes in one trial, and the results were 87.42%, 91.21%, 93.08% and 93.59% corresponding to single keystroke, two keystrokes, three keystrokes and four keystrokes. This study would be helpful to improve the decoding efficiency and optimize the encoding method of motor-related EEG information.

PI3Kα-regulated gelsolin activity is a critical determinant of cardiac cytoskeletal remodeling and heart disease.

Biomechanical stress and cytoskeletal remodeling are key determinants of cellular homeostasis and tissue responses to mechanical stimuli and injury. Here we document the increased activity of gelsolin, an actin filament severing and capping protein, in failing human hearts. Deletion of gelsolin prevents biomechanical stress-induced adverse cytoskeletal remodeling and heart failure in mice. We show that phosphatidylinositol (3,4,5)-triphosphate (PIP3) lipid suppresses gelsolin actin-severing and capping activities. Accordingly, loss of PI3Kα, the key PIP3-producing enzyme in the heart, increases gelsolin-mediated actin-severing activities in the myocardium in vivo, resulting in dilated cardiomyopathy in response to pressure-overload. Mechanical stretching of adult PI3Kα-deficient cardiomyocytes disrupts the actin cytoskeleton, which is prevented by reconstituting cells with PIP3. The actin severing and capping activities of recombinant gelsolin are effectively suppressed by PIP3. Our data identify the role of gelsolin-driven cytoskeletal remodeling in heart failure in which PI3Kα/PIP3 act as negative regulators of gelsolin activity.

Modulation of Low-Frequency Pulsed Magnetic Field on Hippocampal Neural Oscillation in Depression Rats.

Transcranial magnetic stimulation (TMS), as a non-invasive brain stimulation technique, has been approved for some medication-resistant depression by the United States Food and Drug Administration. However, the majority of these studies have focused on the effects of high-frequency TMS, and little is known about low-frequency TMS in depression treatment. Furthermore, the potential electroneurophysiology mechanisms of TMS on the improvement of and function of the brain remain poorly understood. In the present study, a depression rat model was established by chronic unpredictable stress (CUS). Rats were exposed to low-frequency pulsed magnetic field (LFPMF) (1Hz, 20mT) for 14 days, one hour per day, then elevated plus-maze test was assessed and local field potentials (LFPs) in hippocampus were recorded. In order to analyze LFPs, sample entropy was calculated to make complexity analysis, while phase locked value and phase-amplitude coupling modulation index were used to figure out the correlation of oscillations. Our data showed that LFPMF significantly relieved CUS-induced depression-behaviors and improved the undesirable changes of the identical-frequency synchronization and theta-gamma phase-amplitude coupling in CUS rats. These findings indicated that the antidepressive-like effects of LFPMF might be associated with the LFPMF-induced improvement in neural oscillation.

Evaluation of an artificial vertebral body fabricated by a tantalum-coated porous titanium scaffold for lumbar vertebral defect repair in rabbits.

Tantalum (Ta)-coated porous Ti-6A1-4V scaffolds have better bioactivity than Ti-6A1-4V scaffolds; however, their bioperformance as an artificial vertebral body (AVB) is unknown. In the present study, we combined a Ta-coated Ti-6A1-4V scaffold with rabbit bone marrow stromal cells (BMSCs) for tissue-engineered AVB (TEAVB) construction and evaluated the healing and fusion efficacy of this scaffold in lumbar vertebral defects after corpectomy in rabbits. The results showed that BMSCs on the surface of the Ta-coated Ti scaffolds proliferated better than BMSCs on Ti scaffolds. Histomorphometry showed better bone formation when using Ta-coated TEAVBs than that with Ti TEAVBs at both 8 and 12 weeks after implantation. In addition, the vertical and rotational stiffness results showed that, compared with uncoated TEAVBs, Ta-coated TEAVBs enhanced rabbit lumbar vertebral defect repair. Our findings demonstrate that Ta-coated TEAVBs have better healing and fusion efficacy than Ti TEAVBs in rabbit lumbar vertebral defects, which indicates their good prospects for clinical application.