The astrocyte water channel aquaporin‐4 (AQP4) regulates extracellular space (ECS) K+ concentration (K+e) and volume dynamics following neuronal activation. Here, we investigated how AQP4‐mediated ...changes in K+e and ECS volume affect the velocity, frequency, and amplitude of cortical spreading depression (CSD) depolarizations produced by surface KCl application in wild‐type (AQP4+/+) and AQP4‐deficient (AQP4−/−) mice. In contrast to initial expectations, both the velocity and the frequency of CSD were significantly reduced in AQP4−/− mice when compared with AQP4+/+ mice, by 22% and 32%, respectively. Measurement of K+e with K+‐selective microelectrodes demonstrated an increase to ∼35 mM during spreading depolarizations in both AQP4+/+ and AQP4−/− mice, but the rates of K+e increase (3.5 vs. 1.5 mM/s) and reuptake (t1/2 33 vs. 61 s) were significantly reduced in AQP4−/− mice. ECS volume fraction measured by tetramethylammonium iontophoresis was greatly reduced during depolarizations from 0.18 to 0.053 in AQP4+/+ mice, and 0.23 to 0.063 in AQP4−/− mice. Analysis of the experimental data using a mathematical model of CSD propagation suggested that the reduced velocity of CSD depolarizations in AQP4−/− mice was primarily a consequence of the slowed increase in K+e during neuronal depolarization. These results demonstrate that AQP4 effects on K+e and ECS volume dynamics accelerate CSD propagation. GLIA 2015;63:1860–1869
Main Points
The velocity and frequency of CSD depolarizations were significantly reduced in AQP4‐/‐ mice compared to AQP4+/+ mice.
The kinetics of increase in extracellular space K+ during CSD and the clearance of K+ following CSD were significantly reduced in AQP4‐/‐ mice.
Malignant metastatic melanoma (MM) is the most lethal of all skin cancers, but detailed mechanisms for regulation of melanoma metastasis are not fully understood. Here, we demonstrated that ...developmentally regulated GTP‐binding protein 2 (DRG2) is required for the growth of primary tumors and for metastasis. DRG2 expression was significantly increased in MM compared with primary melanoma (PM) and dysplastic nevi. A correlation between DRG2 expression and poor disease‐specific survival in melanoma patients was also identified. Furthermore, inhibition of DRG2 suppressed the binding of Hypoxia‐inducible factor 1α to the VEGF‐A promoter region, expression of vascular endothelial growth factor (VEGF)‐A, and formation of endothelial cell tubes. In experimental mice, DRG2 depletion inhibited the growth of PM and lung metastases and increased survival. These results identify DRG2 as a critical regulator of VEGF‐A expression and of growth of PMs and lung metastases.
Hypoxia‐inducible factor 1 (HIF‐1) activates transcription of VEGF under hypoxic conditions. Under normal oxygen conditions, HIF‐1α is first hydroxylated and undergoes ubiquitin‐dependent degradation. However, under hypoxic conditions, HIF‐1α is stabilized, translocates to the nucleus, and induces expression of vascular endothelial growth factor‐A, a key regulator of tumor angiogenesis. In this study, we demonstrated that developmentally regulated GTP‐binding protein 2 is required for nuclear translocation of HIF‐1 and thus for the growth of primary melanomas and lung metastases.
Cell membrane water permeability is an important determinant of epithelial fluid secretion, tissue swelling, angiogenesis, tumor spread and other biological processes. Cellular water channels, ...aquaporins, are important drug targets. Water permeability is generally measured from the kinetics of cell volume change in response to an osmotic gradient. Here, we developed a microfluidic platform in which cells expressing a cytoplasmic, volume-sensing fluorescent dye are rapidly subjected to an osmotic gradient by solution mixing inside a ~0.1 nL droplet surrounded by oil. The solution mixing time was <10 ms. Osmotic water permeability was deduced from a single, time-integrated fluorescence image of an observation area in which the time after mixing was determined through spatial position. Water permeability was accurately measured in aquaporin-expressing erythrocytes with half-times for osmotic equilibration down to <50 ms. Compared with conventional water permeability measurements using costly stopped-flow instrumentation, the microfluidic platform here utilizes sub-microliter blood sample volume, does not suffer from mixing artifacts, and replaces challenging kinetic measurements by single image capture using a standard laboratory fluorescence microscope.
To investigate the visual/anatomical outcome of diabetic macular edema (DME) patients lost to follow-up (LTFU) for more than 1 year during intravitreal anti-VEGF treatment. A retrospective review of ...182 treatment-naïve DME patients was performed. Among them, we identified patients LTFU for more than 1 year during anti-VEGF treatment. Visual acuity and anatomic outcomes at the first visit, last visit before being LTFU, return visit, and after re-treatment were analyzed and compared with those of DME patients with regular follow-up. Patients who had continuous follow-up visits were assigned to the control group. Sixty patients (33%) with DME were LTFU for more than 1 year during anti-VEGF treatment. Multivariate analysis revealed that the ratio of male (p = 0.004), diabetes mellitus (DM) duration less than 5 years (p = 0.015), and poor early anatomic response (p = 0.012) were higher compared to the control group. Eighteen patients returned to the clinic and received re-treatment. After re-treatment with anti-VEGF, central subfield thickness (CST) was significantly improved to the CST of before LTFU. However, visual acuity did not recover to the level before LTFU (0.63 ± 0.26 vs. 0.45 ± 0.28, p = 0.003). About thirty percent of DME patients were LTFU for more than 1 year. Permanent visual loss was observed in these LTFU patients. Patients with a high risk of LTFU such as male, early DM, and poor response after initial injections should be treated more aggressively to improve the visual outcomes.
In this study, we numerically investigated the effects of design parameters, such as the strut geometry or diffusion angle, on the performance of an industrial turbine exhaust diffuser. Turbine ...exhaust diffusers are commonly used to change the kinetic energy of exhaust gases from the outlet of turbine stages into the static pressure. The turbine exhaust diffuser investigated in this work consisted of an annular diffuser with five identical struts equally spaced around the front circumference and a conical diffuser with a hub extension at the rear. Four design parameters were considered and several values for each parameter were tested in this study. The aerodynamic performances of the studied diffusers were evaluated according to their pressure recovery coefficients and rates of total pressure loss. Contours for the velocity, pressure, and entropy increase were plotted and compared for the various diffuser shapes. The numerical results showed that the strut thickness and the axially swept angle of the strut significantly influence the aerodynamic performance of the turbine exhaust diffuser, whereas the strut lean angle and the diffuser hade angle are less important.
Assessing recurrent laryngeal nerve invasion is crucial for the accurate staging of thyroid cancer. This, in turn, determines the extent of surgery or whether active surveillance is appropriate. ...Ultrasonography is useful in diagnosing extrathyroidal extension to adjacent structures. However, preoperative ultrasound cannot definitely exclude recurrent laryngeal nerve invasion or identify the entire course of the recurrent laryngeal nerve to the thyroid gland. Therefore, it is important to understand the ultrasound features that are most likely to be associated with the gross involvement of the recurrent laryngeal nerve.
Leptin links peripheral adiposity and the central nervous system (CNS) to regulate cardiometabolic physiology. Within the CNS, leptin receptor-expressing cells are a counterpart to circulating ...leptin, and leptin receptor-mediated neural networks modulate the output of neuroendocrine and sympathetic nervous activity to balance cardiometabolic homeostasis. Therefore, disrupted CNS leptin signaling is directly implicated in the development of metabolic diseases, such as hypertension, obesity, and type 2 diabetes. Independently, maternal leptin also plays a central role in the development and growth of the infant during gestation. Accumulating evidence points to the dynamic maternal leptin environment as a predictor of cardiometabolic fate in their offspring as it is directly associated with infant metabolic parameters at birth. In postnatal life, the degree of serum leptin is representative of the level of body adiposity/weight, a driving factor for cardiometabolic alterations, and therefore, the levels of blood leptin through the CNS mechanism, in a large part, are a strong determinant for future cardiometabolic fate. The current review focuses on highlighting and discussing recent updates for temporal dissection of leptin-associated programing of future cardiometabolic fate throughout the entire life.
On-demand NW light sources in a photonic integrated circuit (PIC) have faced several practical challenges. Here, we report on an all-graphene-contact, electrically pumped, on-demand transferrable NW ...source that is fabricated by implementing an all-graphene-contact approach in combination with a highly accurate microtransfer printing technique. A vertically p-i-n-doped top-down-fabricated semiconductor NW with optical gain structures is electrically pumped through the patterned multilayered graphene contacts. Electroluminescence (EL) spectroscopy results reveal that the electrically driven NW device exhibits strong EL emission between the contacts and displays waveguiding properties. Further, a single NW device is precisely integrated into an existing photonic waveguide to perform light coupling and waveguiding experiments. Three-dimensional numerical simulation results show a good agreement with experimental observations. We believe that our all-graphene-contact approach is readily applicable to various micro/nanostructures and devices, which facilitates stable electrical operation and thus extends their practical applicability in compact integrated circuits.
A growing body of evidence shows that hypothalamic inflammation is an important factor in the initiation of obesity. In particular, reactive gliosis accompanied by inflammatory responses in the ...hypothalamus are pivotal cellular events that elicit metabolic abnormalities. In this study, we examined whether MyD88 signaling in hypothalamic astrocytes controls reactive gliosis and inflammatory responses, thereby contributing to the pathogenesis of obesity.
To analyze the role of astrocyte MyD88 in obesity pathogenesis, we used astrocyte-specific Myd88 knockout (KO) mice fed a high-fat diet (HFD) for 16 weeks or injected with saturated free fatty acids. Astrocyte-specific gene expression in the hypothalamus was determined using real-time PCR with mRNA purified by the Ribo-Tag system. Immunohistochemistry was used to detect the expression of glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, phosphorylated signal transducer and activator of transcription 3, and α-melanocyte-stimulating hormone in the hypothalamus. Animals' energy expenditure was measured using an indirect calorimetry system.
The astrocyte-specific Myd88 KO mice displayed ameliorated hypothalamic reactive gliosis and inflammation induced by injections of saturated free fatty acids and a long-term HFD. Accordingly, the KO mice were resistant to long-term HFD-induced obesity and showed an improvement in HFD-induced leptin resistance.
These results suggest that MyD88 in hypothalamic astrocytes is a critical molecular unit for obesity pathogenesis that acts by mediating HFD signals for reactive gliosis and inflammation.
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