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1.
Mol Ther ; 28(1): 217-234, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31551137

RESUMO

Adult mammalian brains have largely lost neuroregeneration capability except for a few niches. Previous studies have converted glial cells into neurons, but the total number of neurons generated is limited and the therapeutic potential is unclear. Here, we demonstrate that NeuroD1-mediated in situ astrocyte-to-neuron conversion can regenerate a large number of functional new neurons after ischemic injury. Specifically, using NeuroD1 adeno-associated virus (AAV)-based gene therapy, we were able to regenerate one third of the total lost neurons caused by ischemic injury and simultaneously protect another one third of injured neurons, leading to a significant neuronal recovery. RNA sequencing and immunostaining confirmed neuronal recovery after cell conversion at both the mRNA level and protein level. Brain slice recordings found that the astrocyte-converted neurons showed robust action potentials and synaptic responses at 2 months after NeuroD1 expression. Anterograde and retrograde tracing revealed long-range axonal projections from astrocyte-converted neurons to their target regions in a time-dependent manner. Behavioral analyses showed a significant improvement of both motor and cognitive functions after cell conversion. Together, these results demonstrate that in vivo cell conversion technology through NeuroD1-based gene therapy can regenerate a large number of functional new neurons to restore lost neuronal functions after injury.

2.
Med Sci Monit ; 25: 9585-9593, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31838483

RESUMO

BACKGROUND The aim of this study was to investigate whether patients with basal ganglia stroke and patients with pontine stroke have different types of functional connectivity (FC) alterations in the early chronic phase. MATERIAL AND METHODS We included 14 patients with pontine stroke, 17 patients with basal ganglia stroke, and 20 well-matched healthy controls (HCs). All of them underwent resting-state functional magnetic resonance imaging (rs-fMRI) scanning. The independent component analysis (ICA) approach was applied to extract information regarding the default-mode network (DMN), including anterior DMN (aDMN) and posterior DMN (pDMN) components and the sensorimotor network (SMN). RESULTS Compared with HCs, patients with basal ganglia stroke exhibited significantly reduced FC in the left precuneus of the pDMN, right supplementary motor area (SMA), and right superior frontal gyrus (SFG) of the SMN. Additionally, FC in the left medial prefrontal gyrus (MFG) of the aDMN, right precuneus and right posterior cingulate cortex (PCC) of the pDMN, and left middle cingulate gyrus (mid-CC) of the SMN decreased in patients with pontine stroke. CONCLUSIONS The different patterns of FC damage in patients with basal ganglia stroke and patients with pontine stroke in the early chronic phase may provide a new method for investigating lesion-induced network plasticity.

3.
Nat Commun ; 10(1): 5569, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31804489

RESUMO

Quantum technology relies on proper hardware, enabling coherent quantum state control as well as efficient quantum state readout. In this regard, wide-bandgap semiconductors are an emerging material platform with scalable wafer fabrication methods, hosting several promising spin-active point defects. Conventional readout protocols for defect spins rely on fluorescence detection and are limited by a low photon collection efficiency. Here, we demonstrate a photo-electrical detection technique for electron spins of silicon vacancy ensembles in the 4H polytype of silicon carbide (SiC). Further, we show coherent spin state control, proving that this electrical readout technique enables detection of coherent spin motion. Our readout works at ambient conditions, while other electrical readout approaches are often limited to low temperatures or high magnetic fields. Considering the excellent maturity of SiC electronics with the outstanding coherence properties of SiC defects, the approach presented here holds promises for scalability of future SiC quantum devices.

4.
Mediators Inflamm ; 2019: 2343867, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31814799

RESUMO

The most common postoperative complication after reconstructive surgery is flap necrosis. Adipose-derived stem cells (ADSCs) and their secretomes are reported to mediate skin repair. This study was designed to investigate whether conditioned media from ADSCs (ADSC-CM) protects ischemia/reperfusion- (I/R-) induced injury in skin flaps by promoting cell proliferation and increasing the number of hair follicles. The mouse flap model of ischemia was ligating the long thoracic vessels for 3 h, followed by blood reperfusion. ADSC-CM was administered to the flaps, and their survival was observed on postoperative day 5. ADSC-CM treatment led to a significant increase in cell proliferation and the number of hair follicles. IL-6 levels in the lysate and CM from ADSCs were significantly higher than those from Hs68 fibroblasts. Furthermore, a strong decrease in cell proliferation and the number of hair follicles was observed after treatment with IL-6-neutralizing antibodies or si-IL-6-ADSC. In addition, ADSC transplantation increased flap repair, cell proliferation, and hair follicle number in I/R injury of IL-6-knockout mice. In conclusion, IL-6 secreted from ADSCs promotes the survival of I/R-induced flaps by increasing cell proliferation and the number of hair follicles. ADSCs represent a promising therapy for preventing skin flap necrosis following reconstructive and plastic surgery.

5.
Surg Endosc ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792689

RESUMO

BACKGROUND: The aims of the present study were to (1) analyse preoperative computed tomography (CT) parameters, (2) investigate whether obesity and CT parameters affect surgical outcomes in patients undergoing LESS lateral retroperitoneal adrenalectomy, and (3) further establish the optimal cutoff point of CT parameters for tolerable operating time. METHODS: Between January 2010 and August 2016, patients who underwent LESS adrenalectomy through the retroperitoneal approach in our hospitals were included. Patients' demographic data, preoperatively measured CT parameters (the depth and horizontal width to the adrenal gland in the axial view of abdominal CT, the vertical height in the coronal view of CT, and the angle of the depth and horizontal width), and intraoperative (operative time and blood loss) and postoperative (hospital stay and complications) parameters were retrospectively reviewed. Linear regression was performed to determine factors that potentially affect surgical outcomes. RESULTS: In 116 patients, depth was the only CT parameter associated with surgical outcomes. Large depth (P = 0.005; 95% CI 1.739-9.256) and high BMI (P = 0.012; 95% CI 0.357-2.851) were factors significantly associated with longer operative time. The area under the ROC curve for the depth was 0.69 (P = 0.002), and the cutoff point 10.48 cm may be the tolerable operating time. CONCLUSIONS: Our results suggest a depth limit of 10.48 cm for the optimal prediction of operating time less than 90 min; although obese patients and deeper adrenal glands had longer operative time, LESS adrenalectomy could be performed in the obese patients without increased blood loss, prolonged hospital stay, or increased pain.

7.
J Headache Pain ; 20(1): 116, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31856703

RESUMO

BACKGROUND: Resting-state functional magnetic resonance imaging (fMRI) has confirmed disrupted visual network connectivity in migraine without aura (MwoA). The thalamus plays a pivotal role in a number of pain conditions, including migraine. However, the significance of altered thalamo-visual functional connectivity (FC) in migraine remains unknown. The goal of this study was to explore thalamo-visual FC integrity in patients with MwoA and investigate its clinical significance. METHODS: Resting-state fMRI data were acquired from 33 patients with MwoA and 22 well-matched healthy controls. After identifying the visual network by independent component analysis, we compared neural activation in the visual network and thalamo-visual FC and assessed whether these changes were linked to clinical characteristics. We used voxel-based morphometry to determine whether functional differences were dependent on structural differences. RESULTS: The visual network exhibited significant differences in regions (bilateral cunei, right lingual gyrus and left calcarine sulcus) by inter-group comparison. The patients with MwoA showed significantly increased FC between the left thalami and bilateral cunei and between the right thalamus and the contralateral calcarine sulcus and right cuneus. Furthermore, the neural activation of the left calcarine sulcus was positively correlated with visual analogue scale scores (r = 0.319, p = 0.043), and enhanced FC between the left thalamus and right cuneus in migraine patients was negatively correlated with Generalized Anxiety Disorder scores (r = - 0.617, p = 0.005). CONCLUSION: Our data suggest that migraine distress is exacerbated by aberrant feedback projections to the visual network, playing a crucial role in migraine physiological mechanisms. The current study provides further insights into the complex scenario of migraine mechanisms.

8.
Aging (Albany NY) ; 11(22): 10684-10696, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31754082

RESUMO

There have been an increasing number of functional magnetic resonance imaging (fMRI) reports on brain abnormalities in mild traumatic brain injury (mTBI) at different phases. However, the neural bases and cognitive impairment after acute mTBI are unclear. This study aimed to identify brain functional hubs and connectivity abnormalities in acute mTBI patients and their correlations with deficits in cognitive performance. Within seven days after brain injury, mTBI patients (n=55) and age-, sex-, and educational -matched healthy controls (HCs) (n=41) underwent resting-state fMRI scans and cognitive assessments. We derived functional connectivity (FC) strength of the whole-brain network using degree centrality (DC) and performed Granger causality analysis (GCA) to analyze causal connectivity patterns in acute mTBI. Compared with HCs, acute mTBI patients had significantly decreased network centrality in the left middle frontal gyrus (MFG). Additionally, acute mTBI showed decreased inflows from the left MFG to bilateral middle temporal gyrus (MTG), left medial superior frontal gyrus (mSFG), and left anterior cingulate cortex (ACC). Correlation analyses revealed that changes in network centrality and causal connectivity were associated with deficits in cognitive performance in mTBI. Our findings may help to provide a new perspective for understanding the neuropathophysiological mechanism of acute cognitive impairment after mTBI.

10.
Nano Lett ; 19(10): 7173-7180, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31532999

RESUMO

Color centers with long-lived spins are established platforms for quantum sensing and quantum information applications. Color centers exist in different charge states, each of them with distinct optical and spin properties. Application to quantum technology requires the capability to access and stabilize charge states for each specific task. Here, we investigate charge state manipulation of individual silicon vacancies in silicon carbide, a system which has recently shown a unique combination of long spin coherence time and ultrastable spin-selective optical transitions. In particular, we demonstrate charge state switching through the bias applied to the color center in an integrated silicon carbide optoelectronic device. We show that the electronic environment defined by the doping profile and the distribution of other defects in the device plays a key role for charge state control. Our experimental results and numerical modeling evidence that control of these complex interactions can, under certain conditions, enhance the photon emission rate. These findings open the way for deterministic control over the charge state of spin-active color centers for quantum technology and provide novel techniques for monitoring doping profiles and voltage sensing in microscopic devices.

11.
Leukemia ; 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462739

RESUMO

Fcγ receptor (FcγR) signalling in monocyte derived macrophages from chronic lymphocytic leukaemia (CLL) patients is poorly understood. This signalling pathway is the key determinant of the ability of the macrophages to respond to therapeutic antibodies in current clinical use for CLL. Muted FcγR signalling activity accompanies disease progression and results in resistance to therapeutic antibodies. The molecular mechanisms controlling FcγR signalling and resistance are unknown. Here, we demonstrate that the class I phosphoinositide 3-kinase (PI3K) catalytic subunit p110δ is essential for CLL-derived macrophages to respond to therapeutic antibodies. Inhibition of p110δ in the macrophages reduces FcγR-mediated antibody immune responses. Surprisingly, our studies indicated that FcγR downstream signalling is independent of SYK and BTK activity. Thus, we show that FcγR antibody responses occur via a previously unidentified p110δ-dependent pathway, which is independent of the previously described SYK/BTK activation pathway. These data provide novel insights into the effectors of antibody responses. Our data also provide mechanistic insights into therapy resistance in CLL.

12.
Brain Imaging Behav ; 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31270776

RESUMO

Presbycusis, associated with a diminished quality of life characterized by bilateral sensorineural hearing loss at high frequencies, has become an increasingly critical public health problem. This study aimed to identify directed functional connectivity (FC) of the hippocampus in patients with presbycusis and to explore the causes if the directed functional connections of the hippocampus were disrupted. Presbycusis patients (n = 32) and age-, sex-, and education-matched healthy controls (n = 40) were included in this study. The seed regions of bilateral hippocampus were selected to identify directed FC in patients with presbycusis using Granger causality analysis (GCA) approach. Correlation analyses were conducted to detect the associations of disrupted directed FC of hippocampus with clinical measures of presbycusis. Compared to healthy controls, decreased directed FC between inferior parietal lobule, insula, right supplementary motor area, middle temporal gyrus and hippocampus were detected in presbycusis patients. Furthermore, a negative correlation between TMB score and the decline of directed FC from left inferior parietal lobule to left hippocampus (r = -0.423, p = 0.025) and from right inferior parietal lobule to right hippocampus (r = -0.516, p = 0.005) were also observed. The decreased directed functional connections of the hippocampus were detected in patients with presbycusis, which was associated with specific cognitive performance. This study mainly emphasizes the crucial role of hippocampus in presbycusis and will enhance our understanding of the neuropathological mechanisms of presbycusis.

14.
Brain Imaging Behav ; 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31183773

RESUMO

Aberrant functional connectivity of brain networks has been demonstrated in migraine sufferers. Functional magnetic resonance imaging (fMRI) may illustrate altered connectivity in patients suffering from migraine without aura (MwoA). Here, we applied a seed-based approach based on limbic regions to investigate disrupted functional connectivity between spontaneous migraine attacks. Resting-state fMRI data were obtained from 28 migraine patients without aura and 23 well-matched healthy controls (HC). The functional connectivity of the limbic system was characterized using a seed-based whole-brain correlation method. The resulting functional connectivity measurements were assessed for correlations with other clinical features. Neuropsychological data revealed significantly increased connectivity between the limbic system (bilateral amygdala and right hippocampus) and left middle occipital gyrus (MOG), and a positive correlation was revealed between disease duration and connective intensity of the left amygdala and the ipsilateral MOG. There was decreased functional connectivity between the right amygdala and contralateral orbitofrontal cortex (OFC). In addition, resting-state fMRI showed that, compared to HC, patients without aura had significant functional connectivity consolidation between the bilateral hippocampus and cerebellum, and a negative correlation was detected between scores on the headache impact test (HIT) and connectivity intensity of the right hippocampus and bilateral cerebellum. There was decreased functional connectivity between the left hippocampus and three brain areas, encompassing the bilateral inferior parietal gyri (IPG) and contralateral supplementary motor area (SMA). There were no structural differences between the two groups. Our data suggest that migraine patients have disrupted limbic functional connectivity to pain-related regions of the modulatory and encoding cortices, which are associated with specific clinical characteristics. Disturbances of resting-state functional connectivity may play a key role in neuropathological features, perception and affection of migraine. The current study provides further insights into the complex scenario of migraine mechanisms. .

15.
Curr Med Sci ; 39(3): 349-355, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31209802

RESUMO

Peptides play crucial roles in various physiological and pathological processes. Consequently, the investigation of peptide-based drugs is a highlight in the research and development of new drugs. However, natural peptides are not always ideal choices for clinical application due to their limited number and sometimes cytotoxicity to normal cells. Aiming to gain stronger or specific or novel biological effects and overcome the disadvantages of natural peptides, artificial hybrid peptides have been designed by combining the sequence of two or more different peptides with varied biological functions. Compared to natural peptides, hybrid peptides have shown better therapeutic potentials against bacteria, tumors, and metabolic diseases. In this review, design strategies, structure features and recent development of hybrid peptides are summarized; future directions for the research and development of hybrid peptide drugs are also discussed.


Assuntos
Peptídeos Catiônicos Antimicrobianos/síntese química , Antineoplásicos/síntese química , Peptídeos Penetradores de Células/biossíntese , Hipoglicemiantes/síntese química , Engenharia de Proteínas/métodos , Proteínas Recombinantes de Fusão/biossíntese , Antibacterianos/síntese química , Antibacterianos/uso terapêutico , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Antineoplásicos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Peptídeos Penetradores de Células/genética , Peptídeos Penetradores de Células/uso terapêutico , Citotoxinas/síntese química , Citotoxinas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Desenho de Drogas , Humanos , Hipoglicemiantes/uso terapêutico , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/fisiopatologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/uso terapêutico
17.
Brain Imaging Behav ; 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31250263

RESUMO

The value of fluid-attenuated inversion recovery vascular hyperintensity (FVH)-diffusion-weighted imaging (DWI)mismatch in predicting outcome with acute stroke is unclear. We assessed the association between FVH-DWI mismatch and functional outcome in patients with acute stroke patients receiving endovascular therapy. FVH-DWI mismatch, DWI volume, the functional outcome at 3 months (modified Rankin scale; mRS) and other clinical data were collected for 59 acute stroke patients receiving MRI within 6 h before endovascular therapy. Statistical analysis was performed to predict functional outcome after stroke. Patients with FVH-DWI mismatch (n = 39) had a higher FVH score (p = 0.038), smaller DWI volume (p = 0.007), higher American Society of Interventional and Therapeutic Neuroradiology (ASITN) (p = 0.043), higher interval time of ASITN (p = 0.038), and better functional outcome (p = 0.010) than patients with no FVH-DWI mismatch (n = 20). The good functional outcome group (n = 32) had a higher FVH score (p = 0.028), smaller DWI volume (p = 0.003) and higher ASITN grade (p = 0.043) than the poor functional outcome group (n = 27). Multivariable logistic analysis demonstrated that DWI volume (OR, 1.031; 95% CI, 1.005-1.058; P = 0.021) and FVH-DWI mismatch (OR, 14.311; 95% CI, 2.670-76.703; P = 0.002) were independently associated with functional outcome. Assessing DWI volume and FVH-DWI mismatch in acute stroke patients might be useful for predicting functional outcome after stroke.

18.
Eur J Radiol ; 114: 69-75, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31005180

RESUMO

PURPOSE: Mild traumatic brain injury is known to have frequent cognitive impairment. Accumulating evidence is pointing to the malfunctioning of the substantia nigra (SN) as an important factor for head trauma. However, it remains unknown whether changes in the SN-based resting state functional connectivity following mTBI at acute stage and its relationship with cognitive function. MATERIALS AND METHODS: 58 patients with mTBI and 30 age-, gender-, and years of education-matched healthy controls were enrolled in the current study. All of participants received resting state functional magnetic resonance imaging as well as neuropsychological assessment. The resting state functional MR imaging data were analyzed by using a standard seed-based whole-brain correlation method to characterize SN resting state networks. Student t tests were used to perform comparisons. The association between SN resting state networks and performance on neuropsychological measures was also investigated in patients with mTBI by using Pearson rank correlation. RESULTS: Patients with mTBI at acute stage exhibited reduced left SN-based functional connectivity with right insula and caudate and increased left SN-based functional connectivity with left precuneus and left middle occipital gyrus, and reduced right SN-based functional connectivity with left insula. Increased functional connectivity of left precuneus was negatively associated with neurocognitive functions as well (r = -0.266; P = 0.049). CONCLUSION: The present study indicated that patients with acute mTBI suffer from disruption in their SN resting state networks. Moreover, abnormal functional connectivity significantly correlated with cognitive function. Taking together, these results may better improve our understanding of the neuropathological mechanism underlying the neurocognitive symptoms associated with acute mTBI.


Assuntos
Concussão Encefálica/fisiopatologia , Mapeamento Encefálico/métodos , Disfunção Cognitiva/patologia , Imagem por Ressonância Magnética , Substância Negra/patologia , Adulto , Concussão Encefálica/complicações , Concussão Encefálica/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Substância Negra/diagnóstico por imagem
19.
J Cell Biochem ; 120(8): 13881-13892, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30983000

RESUMO

Bone marrow stromal cells (BMSCs) are a unique population of multipotent cells that exhibit pluripotent properties to a certain extent and are significantly heterogeneous in terms of the cell population. We isolate a small cell subpopulation from bovine BMSCs, bovine small stem cells (bSSCs), and herein characterize their properties. The bSSCs are smaller in size and express nuclear Oct-4 and other pluripotency markers. In addition, when cultured in suspension conditions, bSSCs form three-dimensional spheres and display a strong capability for self-renewal and differentiation into cells from three germ layers. Notably, bSSCs display neural features with Sox1 and Pax6 expression. Using bSSCs as donor nuclear cells for somatic cell nuclear transfer, we further demonstrate that the developmental potential of cloned embryos in vitro is significantly increased. Our study identifies a new bovine bone marrow stromal cell-derived stem cell subtype that could have broad importance for developmental biology as well as great potential for regenerative medicine.

20.
Nat Commun ; 10(1): 1954, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31028260

RESUMO

Scalable quantum networking requires quantum systems with quantum processing capabilities. Solid state spin systems with reliable spin-optical interfaces are a leading hardware in this regard. However, available systems suffer from large electron-phonon interaction or fast spin dephasing. Here, we demonstrate that the negatively charged silicon-vacancy centre in silicon carbide is immune to both drawbacks. Thanks to its 4A2 symmetry in ground and excited states, optical resonances are stable with near-Fourier-transform-limited linewidths, allowing exploitation of the spin selectivity of the optical transitions. In combination with millisecond-long spin coherence times originating from the high-purity crystal, we demonstrate high-fidelity optical initialization and coherent spin control, which we exploit to show coherent coupling to single nuclear spins with ∼1 kHz resolution. The summary of our findings makes this defect a prime candidate for realising memory-assisted quantum network applications using semiconductor-based spin-to-photon interfaces and coherently coupled nuclear spins.

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