Investigation of drop geometry at free-falling process depending on volume of dozing

Present work performs experimental investigation of the changes in the geometric shape of the drop in terms of its free-falling, depending on the conditions of drop formation on dispenser. It was found that volume and velocity of drop formation on dispenser are the factors affecting the geometric shape of the drop in terms of its free-falling

STRADα deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice

Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) is a rare human autosomalrecessive disorder characterized by abnormal brain development, cognitive disability, and intractable epilepsy. It is caused by homozygous deletions of STE20-related kinase adaptor α (STRADA). The underlying pathogenic mechanisms of PMSE and the role of STRADA in cortical development remain unknown. Here, we found that a human PMSE brain exhibits cytomegaly, neuronal heterotopia, and aberrant activation of mammalian target of rapamycin complex 1 (mTORC1) signaling. STRADα normally binds and exports the protein kinase LKB1 out of the nucleus, leading to suppression of the mTORC1 pathway. We found that neurons in human PMSE cortex exhibited abnormal nuclear localization of LKB1. To investigate this further, we modeled PMSE in mouse neural progenitor cells (mNPCs) in vitro and in developing mouse cortex in vivo by knocking down STRADα expression. STRADα-deficient mNPCs were cytomegalic and showed aberrant rapamycin-dependent activation of mTORC1 in association with abnormal nuclear localization of LKB1. Consistent with the observations in human PMSE brain, knockdown of STRADα in vivo resulted in cortical malformation, enhanced mTORC1 activation, and abnormal nuclear localization of LKB1. Thus, we suggest that the aberrant nuclear accumulation of LKB1 caused by STRADα deficiency contributes to hyperactivation of mTORC1 signaling and disruption of neuronal lamination during corticogenesis, and thereby the neurological features associated with PMSE

Early Progenitor Cell Marker Expression Distinguishes Type II From Type I Focal Cortical Dysplasias

Type I and type II focal cortical dysplasias (FCDs) exhibit distinct histopathologic features that suggest different pathogenic mechanisms. Type I FCDs are characterized by mild laminar disorganization and hypertrophic neurons, whereas type II FCDs exhibit dramatic laminar disorganization and cytomegalic cells (balloon cells). Both FCD types are associated with intractable epilepsy; therefore, identifying cellular or molecular differences between these lesion types that explains the histologic differences could provide new diagnostic and therapeutic insights. Type II FCDs express nestin, a neuroglial progenitor protein that is modulated in vitro by the stem cell proteins c-Myc, sex-determining region Y-box 2 (SOX2), and Octamer-4 (Oct-4) after activation of mammalian target of rapamycin complex 1 (mTORC1). Because mTORC1 activation has been demonstrated in type II FCDs, we hypothesized that c-Myc, SOX2, and Oct-4 expression would distinguish type II from type I FCDs. In addition, we assayed the expression of progenitor cell proteins forkhead box G1 (FOXG1), Kruppel-like factor 4 (KLF4), Nanog, and SOX3. Differential expression of 7 stem cellproteins and aberrant phosphorylation of 2 mTORC1 substrates, S6 and S6 kinase 1 proteins, clearly distinguished type II from type I FCDs (n = 10 each). Our results demonstrate new potential pathogenic pathways in type II FCDs and suggest biomarkers for diagnostic pathology in resected epilepsy specimen

STRADα deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice

Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) is a rare human autosomal-recessive disorder characterized by abnormal brain development, cognitive disability, and intractable epilepsy. It is caused by homozygous deletions of STE20-related kinase adaptor α (STRADA). The underlying pathogenic mechanisms of PMSE and the role of STRADA in cortical development remain unknown. Here, we found that a human PMSE brain exhibits cytomegaly, neuronal heterotopia, and aberrant activation of mammalian target of rapamycin complex 1 (mTORC1) signaling. STRADα normally binds and exports the protein kinase LKB1 out of the nucleus, leading to suppression of the mTORC1 pathway. We found that neurons in human PMSE cortex exhibited abnormal nuclear localization of LKB1. To investigate this further, we modeled PMSE in mouse neural progenitor cells (mNPCs) in vitro and in developing mouse cortex in vivo by knocking down STRADα expression. STRADα-deficient mNPCs were cytomegalic and showed aberrant rapamycin-dependent activation of mTORC1 in association with abnormal nuclear localization of LKB1. Consistent with the observations in human PMSE brain, knockdown of STRADα in vivo resulted in cortical malformation, enhanced mTORC1 activation, and abnormal nuclear localization of LKB1. Thus, we suggest that the aberrant nuclear accumulation of LKB1 caused by STRADα deficiency contributes to hyperactivation of mTORC1 signaling and disruption of neuronal lamination during corticogenesis, and thereby the neurological features associated with PMSE

Chorus-driven resonant scattering of diffuse auroral electrons in nondipolar magnetic fields

We perform a comprehensive analysis of resonant scattering of diffuse auroral electrons by oblique nightside chorus emissions present along a field line with an equatorial crossing of 6 R(E) at 00: 00 MLT, using various nondipolar Tsyganenko magnetic field models. Bounce-averaged quasi-linear diffusion coefficients are evaluated for both moderately and actively disturbed geomagnetic conditions using the T89, T96, and T01s models. The results indicate that inclusion of nondipolar magnetic field leads to significant changes in bounce-averaged rates of both pitch angle and momentum diffusion for 200 eV to 10 keV plasma sheet electrons. Compared to the results using a dipole field, the rates of pitch angle diffusion obtained using the Tsyganenko models are enhanced at all resonant pitch angles for 200 eV electrons. In contrast, for 500 eV to 10 keV electrons the rates of pitch angle scattering are enhanced at intermediate and/or high pitch angles but tend to be considerably lower near the loss cone, thus reducing the precipitation loss compared to that in a dipole field. Upper band chorus acts as the dominant cause for scattering loss of 200 eV to 2 keV electrons, while lower band chorus scattering prevails for 5-10 keV electrons, consistent with the results using the dipole model. The first-order cyclotron resonance and the Landau resonance are mainly responsible for the net scattering rates of plasma sheet electrons by oblique chorus waves and also primarily account for the differences in bounce-averaged diffusion coefficients introduced by the use of Tsyganenko models. As the geomagnetic activity increases, the differences in scattering rates compared to the dipole results increase accordingly. Nonnegligible differences also occur particularly at high pitch angles for the diffusion rates between the Tsyganenko models, showing an increase with geomagnetic activity level and a dependence on the discrepancy between the Tsyganenko model fields. The strong dependence of bounce-averaged quasi-linear scattering rates on the adopted global magnetic field model and geomagnetic activity level demonstrates that realistic magnetic field models should be incorporated into future modeling efforts to accurately quantify the role of magnetospheric chorus in driving the diffuse auroral precipitation and the formation of electron pancake distributions

Enhanced Epidermal Growth Factor, Hepatocyte Growth Factor, and Vascular Endothelial Growth Factor Expression in Tuberous Sclerosis Complex

Epidermal growth factor (EGF), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) regulate angiogenesis and cell growth in the developing brain. EGF, HGF, and VEGF modulate the activity of the mammalian target of rapamycin (mTOR) cascade, a pathway regulating cell growth that is aberrantly activated in tuberous sclerosis complex (TSC). We hypothesized that expression of EGF, HGF, VEGF, and their receptors EGFR, c-Met, and Flt-1, respectively, would be altered in TSC. We show by cDNA array and immunohistochemical analysis that EGF, EGFR, HGF, c-Met, and VEGF, but not Flt-1, mRNA, and protein expression was up-regulated in Tsc1 conditional knockout (Tsc1GFAPCKO) mouse cortex. Importantly, these alterations closely predicted enhanced expression of these proteins in tuber and subependymal giant cell astrocytoma (SEGA) specimens in TSC. Expression of EGF, EGFR, HGF, c-Met, and VEGF protein, as well as hypoxia inducible factor-1α, a transcription factor that regulates VEGF levels and is also modulated by mTOR cascade activity, was enhanced in SEGAs (n = 6) and tubers (n = 10) from 15 TSC patients. Enhanced expression of these growth factors and growth factor receptors in human SEGAs and tubers and in the Tsc1GFAPCKO mouse may account for enhanced cellular growth and proliferation in tubers and SEGAs and provides potential target molecules for therapeutic development in TSC