Glutamine is an essential nutrient that regulates energy production, redox homeostasis, and signaling in cancer cells. Despite the importance of glutamine in mitochondrial metabolism, the ...mitochondrial glutamine transporter has long been unknown. Here, we show that the SLC1A5 variant plays a critical role in cancer metabolic reprogramming by transporting glutamine into mitochondria. The SLC1A5 variant has an N-terminal targeting signal for mitochondrial localization. Hypoxia-induced gene expression of the SLC1A5 variant is mediated by HIF-2α. Overexpression of the SLC1A5 variant mediates glutamine-induced ATP production and glutathione synthesis and confers gemcitabine resistance to pancreatic cancer cells. SLC1A5 variant knockdown and overexpression alter cancer cell and tumor growth, supporting an oncogenic role. This work demonstrates that the SLC1A5 variant is a mitochondrial glutamine transporter for cancer metabolic reprogramming.
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•The SLC1A5 variant is a mitochondrial glutamine transporter•The SLC1A5 variant has a mitochondrial targeting sequence•Hypoxia controls SLC1A5 variant expression through HIF-2α•The SLC1A5 variant mediates mitochondrial glutamine metabolism in cancer
Despite the importance of glutamine in cancer metabolism, the mitochondrial glutamine transporter has long been unknown. Yoo et al. show that a variant of SLC1A5 has a mitochondrial targeting signal for mitochondrial localization and is induced by HIF-2α. SLC1A5 variant knockdown suppressed cancer cell growth, supporting an oncogenic role.
Recent studies of functional or effective connectivity in the brain have reported that motor-related brain regions were activated during motor execution and motor imagery, but the relationship ...between motor and cognitive areas has not yet been completely understood. The objectives of our study were to analyze the effective connectivity between motor and cognitive networks in order to define network dynamics during motor execution and motor imagery in healthy individuals. Second, we analyzed the differences in effective connectivity between correct and incorrect responses during motor execution and imagery using dynamic causal modeling (DCM) of electroencephalography (EEG) data.
Twenty healthy subjects performed a sequence of finger tapping trials using either motor execution or motor imagery, and the performances were recorded. Changes in effective connectivity between the primary motor cortex (M1), supplementary motor area (SMA), premotor cortex (PMC), and dorsolateral prefrontal cortex (DLPFC) were estimated using dynamic causal modeling. Bayesian model averaging with family-level inference and fixed-effects analysis was applied to determine the most likely connectivity model for these regions.
Motor execution and imagery showed inputs to distinct brain regions, the premotor cortex and the supplementary motor area, respectively. During motor execution, the coupling strength of a feedforward network from the DLPFC to the PMC was greater than that during motor imagery. During motor imagery, the coupling strengths of a feedforward network from the PMC to the SMA and of a feedback network from M1 to the PMC were higher than that during motor execution. In imagined movement, although there were connectivity differences between correct and incorrect task responses, each motor imagery task that included correct and incorrect responses showed similar network connectivity characteristics. Correct motor imagery responses showed connectivity from the PMC to the DLPFC, while the incorrect responses had characteristic connectivity from the SMA to the DLPFC.
These findings provide an understanding of effective connectivity between motor and cognitive areas during motor execution and imagery as well as the basis for future connectivity studies for patients with stroke.
•Chitin nano fibrils (CNF) were extracted from crab shell chitin by acid hydrolysis, high speed homogenization and sonication.•CNF offered the high crystalline structure to enhance the mechanical ...properties of carrageenan biopolymer.•Homogeneous distribution of CNF in carrageenan was observed and transparent films were obtained.•Carrageenan/CNF films showed antibacterial activity against L. monocytogenes.
Present study illustrates the preparation of chitin nanofibrils (CNF) reinforced carrageenan nanocomposite films by the solution-casting technique. CNF was prepared by acid hydrolysis of chitin, followed by high speed homogenization and sonication. FTIR result demonstrated that the chemical structure of chitin had not changed after acid hydrolysis. However, the crystalinity of CNF was found to be higher than chitin. The crystallite size of chitin and CNF was 4.73 and 6.27nm, respectively. The char content at 600°C of chitin (19.2%) was lower than the CNF (25%). The carrageenan/CNF composite films were smooth and flexible and the CNF was dispersed uniformly in the carrageenan polymer matrix. The tensile strength and modulus of carrageenan film were increased significantly (p<0.05) after CNF reinforcement with up to 5 wt%, however, elongation at break, water vapor permeability, and transparency decreased slightly. Carrageenan/CNF nanocomposite films showed strong antibacterial activity against a Gram-positive food-borne pathogen, Listeria monocytogenes.
Summary
Globally, infection by seasonal influenza viruses causes 3–5 million cases of severe illness and 290,000–650,000 respiratory deaths each year. Various influenza vaccines, including ...inactivated split‐ and subunit‐type, recombinant and live attenuated vaccines, have been developed since the 1930s when it was discovered that influenza viruses could be cultivated in embryonated eggs. However, the protection rate offered by these vaccines is rather low, especially in very young children and the elderly. In this review, we describe the history of influenza vaccine development, the immune responses induced by the vaccines and the adjuvants applied. Further, we suggest future directions for improving the effectiveness of influenza vaccines in all age groups. This includes the development of an influenza vaccine that induces a balanced T helper cell type 1 and type 2 immune responses based on the understanding of the immune system, and the development of a broad‐spectrum influenza vaccine that can increase effectiveness despite antigen shifts and drifts, which are characteristics of the influenza virus. A brighter future can be envisaged if the development of an adjuvant that is safe and effective is realized.
•Feasibility of three-class fNIRS–BCI demonstrated.•Classification of fNIRS signals corresponding to three different brain activities.•Motor and prefrontal cortex activities ...used.•Intentionally-generated cognitive tasks as inputs.
Functional near-infrared spectroscopy (fNIRS) is an optical imaging method that can be used for a brain-computer interface (BCI). In the present study, we concurrently measure and discriminate fNIRS signals evoked by three different mental activities, that is, mental arithmetic (MA), right-hand motor imagery (RI), and left-hand motor imagery (LI). Ten healthy subjects were asked to perform the MA, RI, and LI during a 10s task period. Using a continuous-wave NIRS system, signals were acquired concurrently from the prefrontal and the primary motor cortices. Multiclass linear discriminant analysis was utilized to classify MA vs. RI vs. LI with an average classification accuracy of 75.6% across the ten subjects, for a 2–7s time window during the a 10s task period. These results demonstrate the feasibility of implementing a three-class fNIRS-BCI using three different intentionally-generated cognitive tasks as inputs.
To test whether autologous modified mesenchymal stem cells (MSCs) improve recovery in patients with chronic major stroke.
In this prospective, open-label, randomized controlled trial with blinded ...outcome evaluation, patients with severe middle cerebral artery territory infarct within 90 days of symptom onset were assigned, in a 2:1 ratio, to receive preconditioned autologous MSC injections (MSC group) or standard treatment alone (control group). The primary outcome was the score on the modified Rankin Scale (mRS) at 3 months. The secondary outcome was to further demonstrate motor recovery.
A total of 39 and 15 patients were included in the MSC and control groups, respectively, for the final intention-to-treat analysis. Mean age of patients was 68 (range 28-83) years, and mean interval between stroke onset to randomization was 20.2 (range 5-89) days. Baseline characteristics were not different between groups. There was no significant difference between the groups in the mRS score shift at 3 months (
= 0.732). However, secondary analyses showed significant improvements in lower extremity motor function in the MSC group compared to the control group (change in the leg score of the Motricity Index,
= 0.023), which was notable among patients with low predicted recovery potential. There were no serious treatment-related adverse events.
IV application of preconditioned, autologous MSCs with autologous serum was feasible and safe in patients with chronic major stroke. MSC treatment was not associated with improvements in the 3-month mRS score, but we did observe leg motor improvement in detailed functional analyses.
This study provides Class III evidence that autologous MSCs do not improve 90-day outcomes in patients with chronic stroke.
NCT01716481.
Stem cell-based therapy is a promising approach to repair brain damage after stroke. This study was conducted to investigate changes in neuroimaging measures using stem cell-based therapy in patients ...with ischemic stroke.
In this prospective, open-label, randomized controlled trial with blinded outcome evaluation, patients with severe middle cerebral artery territory infarct were assigned to the autologous mesenchymal stem cell (MSC) treatment or control group. Of 54 patients who completed the intervention, 31 for the MSC and 13 for the control groups were included in this neuroimaging analysis. Motor function was assessed before the intervention and 90 days after randomization using the Fugl-Meyer assessment scale. Neuroimaging measures included fractional anisotropy values of the corticospinal tract and posterior limb of the internal capsule from diffusion tensor magnetic resonance imaging and strength of connectivity, efficiency, and density of the motor network from resting-state functional magnetic resonance imaging.
For motor function, the improvement ratio of the Fugl-Meyer assessment score was significantly higher in the MSC group compared with the control group. In neuroimaging, corticospinal tract and posterior limb of the internal capsule fractional anisotropy did not decrease in the MSC group but significantly decreased at 90 days after randomization in the control group. Interhemispheric connectivity and ipsilesional connectivity significantly increased in the MSC group. Change in interhemispheric connectivity showed a significant group difference.
Stem cell-based therapy can protect corticospinal tract against degeneration and enhance positive changes in network reorganization to facilitate motor recovery after stroke. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01716481.
In animal models of stroke, behavioral assessments could be complemented by a variety of neuroimaging studies to correlate them with recovery and better understand mechanisms of improvement after ...stem cell therapy. We evaluated morphological and connectivity changes after treatment with human mesenchymal stem cells (hMSCs) in a rat stroke model, through quantitative measurement of T2-weighted images and diffusion tensor imaging (DTI). Transient middle cerebral artery occlusion rats randomly received PBS (PBS-only), FBS cultured hMSCs (FBS-hMSCs), or stroke patients' serum cultured hMSCs (SS-hMSCs). Functional improvement was assessed using a modified neurological severity score (mNSS). Quantitative analyses of T2-weighted ischemic lesion and ventricular volume changes were performed. Brain microstructure/connectivity changes were evaluated in the ischemic recovery area by DTI-derived microstructural indices such as relative fractional anisotropy (rFA), relative axial diffusivity (rAD), and relative radial diffusivity (rRD), and relative fiber density (rFD) analyses. According to mNSS results, the SS-hMSCs group showed the most prominent functional improvement. Infarct lesion volume of the SS-hMSCs group was significantly decreased at 2 weeks when compared to the PBS-only groups, but there were no differences between the FBS-hMSCs and SS-hMSCs groups. Brain atrophy was significantly decreased in the SS-hMSCs group compared to the other groups. In DTI, rFA and rFD values were significantly higher and rRD value was significant lower in the SS-hMSCs group and these microstructure/connectivity changes were correlated with T2-weighted morphological changes. T2-weighted volume alterations (ischemic lesion and brain atrophy), and DTI microstructural indices and rFD changes, were well matched with the results of behavioral assessment. These quantitative MRI measurements could be potential outcome predictors of functional recovery after treatment with stem cells for stroke.
Assessment of functional independence and residual disability is very important for measuring treatment outcome after stroke. The modified Rankin Scale (mRS) and the modified Barthel Index (MBI) are ...commonly used scales to measure disability or dependence in activities of daily living (ADL) of stroke survivors. Lack of consensus regarding MBI score categories has caused confusion in interpreting stroke outcomes. The purpose of this study was to identify the optimal corresponding MBI and modified Rankin scale (mRS) grades for categorization of MBI. The Korean versions of the MBI (K-MBI) and mRS were collected from 5,759 stroke patients at 3 months after onset of stroke. The sensitivity and specificity were calculated at K-MBI score cutoffs for each mRS grade to obtain optimally corresponding K-MBI scores and mRS grades. We also plotted receiver operating characteristic (ROC) curves of sensitivity and specificity and determined the area under the curve (AUC). The K-MBI cutoff points with the highest sum of sensitivity and specificity were 100 (sensitivity 0.940; specificity 0.612), 98 (sensitivity 0.904; specificity 0.838), 94 (sensitivity 0.885; specificity 0.937), 78 (sensitivity 0.946; specificity, 0.973), and 55 (sensitivity 937; specificity 0.986) for mRS grades 0, 1, 2, 3, and 4, respectively. From this result, the K-MBI cutoff score range for each mRS grade can be obtained. For mRS grade 0, the K-MBI cutoff score is 100, indicating no associated score range. For mRS grades 1, 2, 3, 4, and 5, the K-MBI score ranges is from 99 to 98, 97 to 94, 93 to 78, 77 to 55, and under 54, respectively.The AUC for the ROC curve was 0.791 for mRS grade 0, 0.919 for mRS grade 1, 0.970 for mRS grade 2, 0.0 for mRS grade 3, and 0.991 for mRS grade 4. The K-MBI cutoff score ranges for representing mRS grades were variable; mRS grades 0, 1, and 2 had narrow K-MBI score ranges, while mRS grades 3, 4, and 5 exhibited broad K-MBI score ranges. mRS grade seemed to sensitively differentiate mild residual disability of stroke survivors, whereas K-MBI provided more specific information of the functional status of stroke survivors with moderate to severe residual impairment.
Objective: Our study aimed to predict the Fugl-Meyer assessment (FMA) upper limb using network properties during motor imagery using electroencephalography (EEG) signals. Methods: The subjects ...performed a finger tapping imagery task according to consecutive cues. We measured the weighted phase lag index (wPLI) as functional connectivity and directed transfer function (DTF) as causal connectivity in healthy controls and stroke patients. The network properties based on the wPLI and DTF were calculated. We predicted the FMA upper limb using partial least squares regression. Results: A higher DTF in the mu band was observed in stroke patients than in healthy controls. Notably, the difference in local properties at node F3 was negatively correlated with motor impairment in stroke patients. Finally, using significant network properties based on the wPLI and DTF, we predicted motor impairments using the FMA upper limb with a root-mean-square error of 1.68 (<inline-formula><tex-math notation="LaTeX">R^{2}</tex-math></inline-formula> = 0.97). This outperformed the state-of-the-art predictors. Conclusion: These findings demonstrate that network properties based on functional and causal connectivity were highly associated with motor function in stroke patients. Significance: Our network properties can help calculate the predictor of motor impairments in stroke rehabilitation and provide insight into the neural correlates related to motor function based on EEG after reorganization induced by stroke.
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