Paroxysmal dyskinesias (PDs) are a group of episodic movement disorders with marked variability in clinical manifestation and potential association with epilepsy. PRRT2 has been identified as a ...causative gene for PDs, but the phenotypes and inheritance patterns of PRRT2 mutations need further clarification. In this study, 10 familial and 21 sporadic cases with PDs and PDs‐related phenotypes were collected. Genomic DNA was screened for PRRT2 mutations by direct sequencing. Seven PRRT2 mutations were identified in nine (90.0%) familial cases and in six (28.6%) sporadic cases. Five mutations are novel: two missense mutations (c.647C>G/p.Pro216Arg and c.872C>T/p.Ala291Val) and three truncating mutations (c.117delA/p.Val41TyrfsX49, c.510dupT/p.Leu171SerfsX3 and c.579dupA/p.Glu194ArgfsX6). Autosomal dominant inheritance with incomplete penetrance was observed in most of the familial cases. In the sporadic cases, inheritance was heterogeneous including recessive inheritance with compound heterozygous mutations, inherited mutations with incomplete parental penetrance and de novo mutation. Variant phenotypes associated with PRRT2 mutations, found in 36.0% of the affected cases, included febrile convulsions, epilepsy, infantile non‐convulsive seizures (INCS) and nocturnal convulsions (NC). All patients with INCS or NC, not reported previously, displayed abnormalities on electroencephalogram (EEG). No EEG abnormalities were recorded in patients with classical infantile convulsions and paroxysmal choreoathetosis (ICCA)/paroxysmal kinesigenic dyskinesia (PKD). Our study further confirms that PRRT2 mutations are the most common cause of familial PDs, displaying both dominant and recessive inheritance. Epilepsy may occasionally occur in ICCA/PKD patients with PRRT2 mutations. Variant phenotypes INCS or NC differ from classical ICCA/PKD clinically and electroencephalographically. They have some similarities with, but not identical to epilepsy, possibly represent an overlap between ICCA/PKD and epilepsy.
Seven PRRT2 mutations (including five novel mutations) in 15 cases (or families) with paroxysmal dyskinesias (PDs) and PDs‐related phenotypes were detected, which extended the spectrum of PRRT2 mutations and provided the evidence that PRRT2 was the causative gene in most familial PDs. The heterogeneity in inheritance patterns of PRRT2 mutations, including autosomal recessive inheritance with compound heterozygous PRRT2 mutations, was identified. Variant phenotypes associated with PRRT2 mutations and EEG abnormalities were reported, including infantile non‐convulsion seizures and nocturnal convulsions that were not reported previously
Ethanol induced CTA response varied as a function of age, strain and ethanol dose.
The development of molecular machines requires new building blocks which are easy to characterize and visualize to realize a complexity comparable to their natural counterparts such as biological ...enzymes. Furthermore, with the desire to build functional nanobots capable of navigating living organisms, it is necessary that the building blocks show mobility even in the solid state. Herein we report a system which is emissive in the amorphous state but is non‐fluorescent in the crystalline state due to the formation of extensive π‐π interactions. This dual nature could be exploited for easy visualization of its solid‐state molecular rearrangement. The emission of the amorphous film was quenched as the molecules spontaneously formed π‐π interactions even in the solid state. Scratching the non‐emissive film destroyed the interactions and restored the emission of the film. The emission quickly disappeared with an average lifetime of 20 s as the compound reformed the π‐network even at room temperature.
Beacons lit by molecular motion: Intermolecular forces drive the formation of π‐π interactions even in the solid state. Shear forces/scratching disrupt the interactions, turning on emission. The quenched π‐π‐interactions quickly reform even in a film, allowing the visualization of the molecular motions. Theoretical calculations show that the formation of π‐interactions is highly favorable and driving this motion.
Massively parallel sequencing of DNA molecules in the plasma of pregnant women has been shown to allow accurate and noninvasive prenatal detection of fetal trisomy 21. However, whether the sequencing ...approach is as accurate for the noninvasive prenatal diagnosis of trisomy 13 and 18 is unclear due to the lack of data from a large sample set. We studied 392 pregnancies, among which 25 involved a trisomy 13 fetus and 37 involved a trisomy 18 fetus, by massively parallel sequencing. By using our previously reported standard z-score approach, we demonstrated that this approach could identify 36.0% and 73.0% of trisomy 13 and 18 at specificities of 92.4% and 97.2%, respectively. We aimed to improve the detection of trisomy 13 and 18 by using a non-repeat-masked reference human genome instead of a repeat-masked one to increase the number of aligned sequence reads for each sample. We then applied a bioinformatics approach to correct GC content bias in the sequencing data. With these measures, we detected all (25 out of 25) trisomy 13 fetuses at a specificity of 98.9% (261 out of 264 non-trisomy 13 cases), and 91.9% (34 out of 37) of the trisomy 18 fetuses at 98.0% specificity (247 out of 252 non-trisomy 18 cases). These data indicate that with appropriate bioinformatics analysis, noninvasive prenatal diagnosis of trisomy 13 and trisomy 18 by maternal plasma DNA sequencing is achievable.
Two experiments were conducted to study the effects of development and delayed feed access on ghrelin expression in neonatal chickens. In experiment 1, ghrelin levels in ad libitum-fed chickens were ...assessed from hatching (0 h) to 120 h. Ghrelin mRNA expression increased after hatching and reached peak levels at 24 h; levels were 1.8-fold higher compared to those at 0 h. Afterward, ghrelin expression decreased consistently throughout the later experimental period, and at 120 h, it was only 16.0% of 0 h levels. The density of ghrelin immunopositive cells in the proventriculus and plasma ghrelin levels decreased slightly from hatching to 48 h and later increased slowly until the end of the experimental period. In a follow-up study, chickens were assigned randomly into 2 groups after hatching, a control group (C, fed ad libitum) and a delayed feeding group (F+SF, 72-h fast period, subsequently fed ad libitum). Delayed feed access for 72 h up-regulated ghrelin mRNA expression significantly in the proventriculus (P < 0.05) to 2.1-fold higher levels compared to the control, while the density of ghrelin immunopositive cells and the plasma ghrelin level decreased (P < 0.05) to 28.4% and 64.8% of the control, respectively. After the onset of feeding, the ghrelin mRNA expression in the delayed feeding group was decreased but still higher than that of the control (P < 0.05). The density of ghrelin immunopositive cells and the plasma ghrelin level climbed quickly and all returned to the control level with a supply of food for 48 h. These results suggest that the onset of feeding in neonatal chickens stimulated an increase in ghrelin peptide levels and that ghrelin peptide levels increased with age. Neonatal chickens respond to food deprivation in a different way than do young and adult chickens.
Summary
Chronic hepatitis B (CHB) patients with higher hepatitis B virus (HBV) load (higher viral load HVL, HBV DNA ≥1 × 107 copies/mL) require antiviral therapy, but data for evaluating the ...long‐term outcome of this therapy with antiviral agents remain limited. We comparatively evaluated the efficacy and the safety of nucleoside analogues in 179 noncirrhotic CHB patients with HVL over 5 years. The HBeAg‐positive (n = 104) or HBeAg‐negative (n = 75) patients were treated consecutively with telbivudine (LdT, n = 88) or entecavir (ETV, n = 91) and evaluated for viral response, drug resistance and safety. HBV DNA, viral serology, biochemistries, HBV mutation and off‐therapy relapse were determined. The cumulative rates of HBV DNA negativity were 86.4% and 94.5% for LdT and ETV at year 5, respectively. The rates of early viral response (EVR, HBV DNA <103 copies/mL at month 6) under LdT and ETV treatments were 58.0% and 34.1%, respectively (P < .05). Hepatitis B e antigen (HBeAg) and Hepatitis B surface antigen (HBsAg) loss‐seroconversions were 47.7% and 18.2% on LdT and 16.5% and 2.2% on ETV (P < .01). Eighteen patients (age 28.2 ± 3.1) experienced HBsAg loss‐seroconversion, followed by 33 ± 4.6 month off‐therapy without a relapse. Viral mutations and serum creatine kinase elevation were 9.1% and 8.0% on LdT, but only 1.1% and 0% on ETV. Both LdT and ETV suppressed HBV replication in HVL CHB patients within 5 years. LdT therapy achieved a higher EVR, HBeAg and HBsAg seroconversion, especially in the younger patients, whereas ETV caused lower drug resistance and fewer adverse events. This finding might help to identify the optimal treatment for CHB patients with HVL.
Direct measurements of the phase separation relative humidity (RH) and morphology of aerosol particles consisting of liquid organic and aqueous inorganic domains are presented. Single droplets of ...mixed phase composition are captured in a gradient force optical trap, and the evolving size, refractive index (RI), and morphology are characterized by cavity-enhanced Raman spectroscopy. Starting at a RH above the phase separation RH, the trapped particle is dried to lower RH and the transition to a phase-separated structure is inferred from distinct changes in the spectroscopic fingerprint. In particular, the phase separation RHs of droplets composed of aqueous solutions of polyethylene glycol (PEG-400)/ammonium sulfate and a mixture of C6-diacids/ammonium sulfate are probed, inferring the RH from the RI of the droplet immediately prior to phase separation. The observed phase separation RHs occur at RH marginally higher (at most 4%) than reported in previous measurements made from studies of particles deposited on hydrophobic surfaces by brightfield imaging. Clear evidence for the formation of phase-separated droplets of core–shell morphology is observed, although partially engulfed structures can also be inferred to form. Transitions between the different spectroscopic signatures of phase separation suggest that fluctuations in morphology can occur. For droplets that are repeatedly cycled through the phase separation RH, the water activity at phase separation is found to be remarkably reproducible (within ±0.0013) and is the same for the 1-phase to 2-phase transition and the 2-phase to 1-phase transition. By contrast, larger variation between the water activities at phase separation is observed for different droplets (typically ±0.02).
Organ-specific colonization suggests that specific cell–cell recognition is essential. Yet, very little is known about this particular interaction. Moreover, tumor cell lodgement requires binding ...under shear stress, but not static, conditions. Here, we successfully isolate the metastatic populations of cancer stem/tumor-initiating cells (M-CSCs). We show that the M-CSCs tether more and roll slower than the non-metastatic (NM)-CSCs, thus resulting in the preferential binding to the peritoneal mesothelium under ascitic fluid shear stress. Mechanistically, this interaction is mediated by P-selectin expressed by the peritoneal mesothelium. Insulin-like growth factor receptor-1 carrying an uncommon non-sulfated sialyl-Lewisx (sLex) epitope serves as a distinct P-selectin binding determinant. Several glycosyltransferases, particularly α1,3-fucosyltransferase with rate-limiting activity for sLex synthesis, are highly expressed in M-CSCs. Tumor xenografts and clinical samples corroborate the relevance of these findings. These data advance our understanding on the molecular regulation of peritoneal metastasis and support the therapeutic potential of targeting the sLex-P-selectin cascade.Tumor cell in the peritoneum are often exposed to shear forces generated by ascitic flow during metastasis. Here, the authors show that metastatic cancer stem cells tether more and roll slower than the non-metastatic counterparts, and that sialyl-Lewisx -P-selectin axis mediates peritoneal metastasis.
Formation of thaw loss cannot generally be avoided when meat is frozen and then thawed. Explanations have mainly focused on the damage to muscle fibers resulting from ice crystallization and the ...freezing-induced denaturation of myofibrillar proteins, the latter of which has, however, not received much research focus. This review discusses the relationship between myofibrillar protein denaturation and water-holding capacity of meat in freezing-thawing with the aim to improve the understanding the relative importance of protein denaturation in the formation of thaw loss. The contribution of decreased pH and high ionic strength in the unfrozen water in freezing is emphasized and we hypothesize that these two factors are causing protein denaturation and conformational changes within muscle fibers, and consequently loss of water-holding capacity. Slow freezing produces more thaw loss than fast freezing, and this is discussed here in relation to the impacts on myofibrillar protein denaturation induced by the freezing rate.
Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis and vitamin D metabolism. In patients with acute kidney injury (AKI), FGF23 levels rise rapidly after onset of AKI and are ...associated with AKI progression and increased mortality. In mouse models of AKI, excessive rise in FGF23 levels is accompanied by a moderate increase in FGF23 expression in bone. We examined the folic acid-induced AKI (FA-AKI) mouse model to determine whether other organs contribute to the increase in plasma FGF23 and assessed the vitamin D axis as a possible trigger for increased
gene expression. Twenty-four hours after initiation of FA-AKI, plasma intact FGF23 and 1,25(OH)
D were increased and kidney function declined. FA-treated mice developed renal inflammation as shown by increased
and
mRNA expression.
mRNA expression was 5- to 15-fold upregulated in thymus, spleen and heart of FA-treated mice, respectively, but only 2-fold in bone. Ectopic renal
mRNA expression was also detected in FA-AKI mice. Plasma FGF23 and
mRNA expression in thymus, spleen, heart, and bone strongly correlated with renal
mRNA expression. Furthermore,
mRNA expression was upregulated in spleen, thymus and heart and strongly correlated with
mRNA expression in the same organ. In conclusion, the rapid rise in plasma FGF23 in FA-AKI mice is accompanied by increased
mRNA expression in multiple organs and increased
expression in extra osseous tissues together with increased plasma 1,25(OH)
D and inflammation may trigger the rise in FGF23 in FA-AKI.
Material erosion under a multiphase flow is a very complex process influenced by many parameters. Understanding physical mechanisms and establishing governing laws for predicting the erosion rate are ...of great importance to alleviate or even avoid erosion damage in engineering applications. In this paper, we perform a combined numerical and experimental study to understand how the evolution of material surface induced by erosion can inversely affect the multiphase flow characteristics and erosion mechanisms on the surface. A water–sand erosion test-rig system is used to obtain the surface profiles, erosion rates and surface patterns of stainless steel under a water–sand multiphase flow. A multiphase flow model and an erosion model are combined to obtain the flow profile, erosion rate and erosion pattern. To gain insights into the multiphase flow and erosion mechanism changes due to the surface evolution induced by the erosion process, we take the surface profiles obtained from our testing samples at different stages of experiments to create geometry models for our numerical simulations. The numerical results are in good agreement with experimental results for erosion rate and erosion pattern as well as erosion mechanism. Through systematic numerical simulations, we clearly reveal the detailed changes in multiphase flow characteristics and erosion mechanisms arising from the surface evolution. The present work shows that the erosion process is very sensitive to the change of the test sample surface resulting from the change in erosion mechanism, highlighting the need to include the surface evolution in erosion modeling.
•A combined numerical–experimental study was performed to studyerosion process.•Water–sand erosion test-rig was used to obtain surface profiles and erosion rates.•Sample geometry models in simulations were created from measurement profiles.•Flow characteristics and erosion mechanism changes due to the surface evolution.•It is necessary to include the surface evolution in the erosion numerical modeling.
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