RNF213 was recently reported as a susceptibility gene for moyamoya disease (MMD). Our aim was to clarify the correlation between the RNF213 genotype and MMD phenotype.
The entire coding region of the ...RNF213 gene was sequenced in 204 patients with MMD, and corresponding variants were checked in 62 pairs of parents, 13 mothers and 4 fathers of the patients, and 283 normal controls. Clinical information was collected. Genotype-phenotype correlations were statistically analyzed.
The c.14576G>A variant was identified in 95.1% of patients with familial MMD, 79.2% of patients with sporadic MMD, and 1.8% of controls, thus confirming its association with MMD, with an odds ratio of 259 and p < 0.001 for either heterozygotes or homozygotes. Homozygous c.14576G>A was observed in 15 patients but not in the controls and unaffected parents. The incidence rate for homozygotes was calculated to be >78%. Homozygotes had a significantly earlier age at onset compared with heterozygotes or wild types (median age at onset 3, 7, and 8 years, respectively). Of homozygotes, 60% were diagnosed with MMD before age 4, and all had infarctions as the first symptom. Infarctions at initial presentation and involvement of posterior cerebral arteries, both known as poor prognostic factors for MMD, were of significantly higher frequency in homozygotes than in heterozygotes and wild types. Variants other than c.14576G>A were not associated with clinical phenotypes.
The homozygous c.14576G>A variant in RNF213 could be a good DNA biomarker for predicting the severe type of MMD, for which early medical/surgical intervention is recommended, and may provide a better monitoring and prevention strategy.
Background
Oscillatory activities observed in multiple regions are closely associated with the experience of pain. Specifically, oscillatory activities within the theta‐ and beta‐frequency bands, ...observed in the left dorsolateral prefrontal cortex (DLPFC), have been implicated in pain perception among healthy individuals and those with chronic pain. However, their physiological significance remains unclear.
Methods
We explored the modulation of pain perception in healthy individuals by theta‐ and beta‐band transcranial alternating current stimulation (tACS) over the left DLPFC and examined the relationship between the modulation effect and magnitude of the electric field elicited by tACS in the left DLPFC using computational simulation.
Results
Our findings revealed that both theta‐ and beta‐tACS increased the heat pain threshold during and after stimulation. Notably, the simulated electric field magnitude in the left DLPFC exhibited an inverted U‐shaped relationship with the pain modulation effect for theta‐tACS.
Conclusions
Our study findings suggested that there would be an optimal electric field strength to produce a high analgesic effect for theta‐tACS.
Significance
The application of theta‐ and beta‐tACS interventions targeting the left DLPFC might facilitate the treatment of chronic pain. Furthermore, the attainment of effective pain modulation via theta‐tACS over the DLPFC warrants the use of optimal stimulus intensity.
Contexte
: Nous avons précédemment développé un modèle de douleur centrale post-AVC (DCPA) chez le macaque et confirmé l’implication d’une activité accrue du cortex insulaire postérieur (CIP) et du ...cortex somatosensoriel secondaire (SII) dans l’allodynie mécanique, observée en cas de DCPA, en associant une inactivation pharmacologique de ces régions corticales et des techniques d’imagerie. Cependant, on ne sait pas si cette inactivation joue un rôle dans l’hyperalgésie thermique. Par conséquent, en utilisant ce modèle de macaque, nous avons examiné les réponses comportementales aux stimuli thermiques après une inactivation pharmacologique du CIP/SII.
Méthodes
: Une DCPA a été créée chez deux macaques en induisant des lésions hémorragiques unilatérales dans le noyau ventral postérolatéral du thalamus, par injection de collagénase. Pour évaluer la perception de la douleur, la latence de retrait des mains à des stimuli thermiques de 37, 45, 50, 52 et 55 °C a été mesurée. Quelques semaines après l’induction de la lésion, une inactivation pharmacologique des CIP/SII par micro-injection de muscimol a été réalisée. L’effet de l’inactivation sur la latence de retrait a été évalué par comparaison avec la latence de retrait après injection de placebo.
Résultats
: Quelques semaines après l’induction des lésions thalamiques, on observe une réduction des latences de retrait à la stimulation thermique (< 50 °C) de la main controlatérale de l’emplacement de la lésion chez les deux macaques, indiquant l’apparition d’une hyperalgésie thermique. Lorsque les CIP/SII sont inactivés par lemuscimol, les latences de retrait à des stimuli thermiques de 50 et 52 °C sont significativement augmentées par rapport à celles après injection de placebo.
Conclusion
: Nos données soulignent qu’une activité accrue dans les CIP/SII après lésion thalamique peut contribuer à une douleur anormale en réponse à de multiples modalités et que la modulation de cette activité peut être une approche thérapeutique pour l’hyperalgésie thermique.
Signification
: La DCPA est causée par des lésions cérébrales du système somatosensoriel et se caractérise par une allodynie mécanique ou une hyperalgésie thermique. Il a été démontré que l’inactivation pharmacologique de l’activité des CIP/SII a un effet analgésique sur l’allodynie mécanique ; cependant, l’efficacité de cette inactivation pour réduire l’hyperalgésie thermique n’était pas claire. Dans ce travail, en utilisant deux macaques, nous avons démontré que l’inactivation de ces régions corticales réduit l’hypersensibilité aux stimuli thermiques. Ce résultat souligne qu’une activité accrue des CIP/SII peut contribuer à une douleur anormale en réponse à de multiples modalités.
Background
: We previously established a macaque model of central post-stroke pain (CPSP) and confirmed the involvement of increased activity of the posterior insular cortex (PIC) and secondary somatosensory cortex (SII) to somatosensory stimuli in mechanical allodynia by a combination of imaging techniques with local pharmacological inactivation. However, it is unclear whether the same intervention would be effective for thermal hyperalgesia. Therefore, using the macaque model, we examined behavioral responses to thermal stimuli following pharmacological inactivation of the PIC/SII.
Methods
: Two CPSP model macaques were established based on collagenase-induced unilateral hemorrhagic lesions in the ventral posterolateral nucleus of the thalamus. To evaluate pain perception, withdrawal latencies to thermal stimuli of 37, 45, 50, 52, and 55 °C to hands were measured. Several weeks after the lesion induction, pharmacological inactivation of the PIC/SII by microinjection of muscimol was performed. The effect of inactivation on withdrawal latency was assessed by comparison with withdrawal latency after vehicle injection.
Results
: Several weeks after induction of the thalamic lesions, both macaques demonstrated a reduction in withdrawal latencies to thermal stimulation (< 50 °C) on the contralesional hand, indicating the occurrence of thermal hyperalgesia. When the PIC/SII was inactivated by muscimol, the withdrawal latencies to thermal stimuli of 50 °C and 52 °C were significantly increased compared to those after vehicle injection.
Conclusion
: Our data emphasize that increased activity in the PIC/SII after appearance of thalamic lesions can contribute to abnormal pain of multiple modalities, and the modulation of PIC/SII activity may be a therapeutic approach for thermal hyperalgesia.
Significance
: CPSP is caused by stroke lesions in the sensory system and characterized by mechanical allodynia or thermal hyperalgesia. Inactivation of the PIC/SII has an analgesic effect on mechanical allodynia; however, it is not clear whether the same intervention could reduce thermal hyperalgesia. Here, using the macaque model, we demonstrated that inactivation of these cortices reduces hypersensitivity to thermal stimuli. This result emphasizes that increased PIC/SII activity can contribute to abnormal pain of multiple modalities.
Human papillomaviruses (HPVs) are the causative agents of a number of human cancers, of which cervical cancer is the most important. This occurs following persistent infection with a limited number ...of viral subtypes and is characterized by continued expression of the viral E6 and E7 oncoproteins. A unique characteristic of the cancer-causing HPV types is the presence of a PDZ recognition motif on the carboxy terminus of the E6 oncoprotein. Through this motif, E6 directs the proteasome-mediated degradation of cellular proteins involved in the regulation of cell polarity and in cell proliferation control. These include components of the Scrib and Par polarity complexes, as well as a number of other PDZ domain-containing substrates. Thus, PVs are now providing novel insights into the functioning of many of these cellular proteins, and into which of these functions, in particular, are relevant for maintaining normal cellular homeostasis. In this review, we discuss the biological consequences of papillomaviral targeting of these cell polarity regulators, both with respect to the viral life cycle and, most importantly, to the development of HPV-induced malignancy.
Human papillomavirus vaccines are being introduced worldwide and are expected to reduce the incidence of cervical cancer. Here we report a cross-sectional study using a validated human papillomavirus ...genotyping method to reveal the human papillomavirus prevalence and genotype distribution in Japanese women with cervical intraepithelial neoplasia Grade 2/3 and invasive cervical cancer.
Cervical exfoliated cells were collected from 647 patients with abnormal cervical histology (cervical intraepithelial neoplasia Grade 2, n = 164; cervical intraepithelial neoplasia Grade 3, n = 334; and invasive cervical cancer, n = 149), and subjected to the PGMY-PCR-based genotyping assay. The association between human papillomavirus infection and lesion severity was calculated using a prevalence ratio.
Overall, the prevalence of human papillomavirus deoxyribonucleic acid was 96.3% in cervical intraepithelial neoplasia Grade 2, 98.8% in cervical intraepithelial neoplasia Grade 3 and 88.0% in invasive cervical cancer (97.8% in squamous cell carcinoma and 71.4% in adenocarcinoma). The three most prevalent types were as follows: human papillomavirus 16 (29.3%), human papillomavirus 52 (27.4%) and human papillomavirus 58 (22.0%) in cervical intraepithelial neoplasia Grade 2; human papillomavirus 16 (44.9%), human papillomavirus 52 (26.0%) and human papillomavirus 58 (17.4%) in cervical intraepithelial neoplasia Grade 3; and human papillomavirus 16 (47.7%), human papillomavirus 18 (23.5%) and human papillomavirus 52 (8.7%) in invasive cervical cancer. The prevalence ratio of human papillomavirus 16 was significantly higher in cervical intraepithelial neoplasia Grade 3 compared with cervical intraepithelial neoplasia Grade 2 (prevalence ratio, 1.62; 95% confidence interval, 1.26-2.13) and in squamous cell carcinoma compared with cervical intraepithelial neoplasia Grade 3 (prevalence ratio, 1.55; 95% confidence interval, 1.25-1.87). Multiple infections decreased from cervical intraepithelial neoplasia Grade 2/3 (38.4/29.6%) to invasive cervical cancer (14.1%), whereas co-infections with human papillomavirus 16/52/58 were found in cervical intraepithelial neoplasia Grade 2/3.
The results of this study provide pre-vaccination era baseline data on human papillomavirus type distribution in Japanese women and serve as a reliable basis for monitoring the future impact of human papillomavirus vaccination in Japan.
The cell polarity regulator, human Scribble (hScrib), is a potential tumour suppressor whose loss is a frequent event in late-stage cancer development. Little is yet known about the mode of action of ...hScrib, although recent reports suggest its role in the regulation of cell signalling. In this study we show that hScrib is a direct regulator of extracellular signal-regulated kinase (ERK). In human keratinocytes, loss of hScrib results in elevated phospho-ERK levels and concomitant increased nuclear translocation of phospho-ERK. We also show that hScrib interacts with ERK through two well-conserved kinase interaction motif (KIM) docking sites, both of which are also required for ERK-induced phosphorylation of hScrib on two distinct residues. Although wild-type hScrib can downregulate activation of ERK and oncogenic Ras co-transforming activity, an hScrib mutant that lacks the carboxy terminal KIM docking site has no such effects. These results provide a clear mechanistic explanation of how hScrib can regulate ERK signalling and begin to explain how loss of hScrib during cancer development can contribute to disease progression.
The purpose of this study is to conduct the techno economical study of PC-Diesel power system based on renewable energy available locally in a remote island. This research is a case study for Miangas ...island which is the border island between Indonesia and Philipines. It is located in Talaud Island regency of North Sulawesi province of Indonesia. The monthly average daily radiation in Miangas island is 5.52 kWh/m2.The research methods used are data collection and data analysis using software HOMER. Based on the simulation result, the techno economic study of PV-Diesel power plant system based on energy demand in Miangas island can be obtained. The Cost of Energy (COE), Net Present Cost (NPC) and operating cost for proposed hybrid PV-Diesel power generation can be assessed for the design power systems uses Canadian solar Max Power C56x-325P of 150 KW PV, 18 string of Surette 6CS25P, Diesel Generator 50 kW and converter Magnum MS4448PAE 25 kW. The annual electricity production from the PV Diesel system for Miangas island is 309.589 kWh in which 80.7% electricity comes from PV, 19.3% electricity comes from diesel with the 109.063 kWh excess electricity. The cost of generating electrical energy in the term of cost of energy (COE), Net Present Cost (NPC) and operating cost are 0.318 US$/kWh, 719.673 US$ and 36.857 US$ respectively.
DBC1/KIAA1967 (deleted in breast cancer 1) is a putative tumour-suppressor gene cloned from a heterozygously deleted region in breast cancer specimens. Caspase-dependent processing of DBC1 promotes ...apoptosis, and depletion of endogenous DBC1 negatively regulates p53-dependent apoptosis through its specific inhibition of SIRT1. Hereditary breast and ovarian cancer susceptibility gene product BRCA1, by binding to the promoter region of SIRT1, is a positive regulator of SIRT1 expression.
A physical interaction between DBC1 and BRCA1 was investigated both in vivo and in vitro. To determine the pathophysiological significance of DBC1, its role as a transcriptional factor was studied.
We found a physical interaction between the amino terminus of DBC1 and the carboxyl terminus of BRCA1, also known as the BRCT domain. Endogenous DBC1 and BRCA1 form a complex in the nucleus of intact cells, which is exported to the cytoplasm during ultraviolet-induced apoptosis. We also showed that the expression of DBC1 represses the transcriptional activation function of BRCT by a transient expression assay. The expression of DBC1 also inhibits the transactivation of the SIRT1 promoter mediated by full-length BRCA1.
These results revealed that DBC1 may modulate the cellular functions of BRCA1 and have important implications in the understanding of carcinogenesis in breast tissue.
Eu0.5La0.5FBiS2-xSex is a new BiS2-based superconductor system. In Eu0.5La0.5FBiS2-xSex, electron carriers are doped to the BiS2 layer by the substitution of Eu by La. Bulk superconductivity in this ...system is induced by increasing the in-plane chemical pressure, which is controlled by the Se concentration (x). In this study, we have analysed the crystal structure of Eu0.5La0.5FBiS2-xSex using synchrotron powder diffraction and the Rietveld refinement. The precise determination of the structural parameters and thermal factors suggest that the emergence of bulk superconductivity in Eu0.5La0.5FBiS2-xSex is achieved by the enhanced in-plane chemical pressure and the decrease in in-plane disorder.
PDF
