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CRISPR-Cas9-mediated leptin (Lep) knockout (KO) mice exhibited prominent phenotypes for constipation, even though they were not compared with other model animals. This study compared the stool excretion, gastrointestinal motility, histological structure, mucin secretion, and enteric nerve function in Lep KO and high fat diet (HFD)-treated mice to determine if there were differences in their phenotypes for constipation. Most obesity phenotypes, including fat weight, adipocyte size, expression of lipolytic proteins (HSL, perilipin, and ATGL), and glucose concentrations, were detected similarly in the Lep KO and HFD-treated mice. They showed a similar decrease in the excretion parameters, including the stool number, weight, and water content, while the same pattern was detected in the gastrointestinal motility and intestinal length. A similar decrease in the mucosal layer thickness, muscle thickness, ability for mucin secretion, and expression of water channel (aquaporin 3 and 8) genes was detected in the mid-colon of the Lep KO and HFD-treated mice, but the alteration rate in some levels was greater in the HFD-treated group than the Lep KO mice. On the other hand, the levels of c-kit, nNOS, NSE, and PGP9.5 expression for the enteric neurons and intestitial cells of Cajal (ICC) were remarkably lower in the mid-colon of the HFD-treated mice than in the Lep KO mice, but the level of most proteins in both groups remained lower than those in the control group. A similar alteration pattern in the expression of muscarinic acetylcholine receptors (mAChRs) and serotonin receptors was detected in the Lep KO and HFD-treated mice. These results suggest that most phenotypes for obesity-induced constipation were similarly detected in the Lep KO and HFD-treated mice, but there was a difference in the regulatory function of the enteric nervous system (ENS). [ABSTRACT FROM AUTHOR]

During mammalian evolution, the Myodural Bridges (MDB) have been shown to be highly conserved anatomical structures. However, the putative physiological function of these structures remains unclear. The MDB functionally connects the suboccipital musculature to the cervical spinal dura mater, while passing through the posterior atlanto-occipital and atlanto-axial interspaces. MDB transmits the tensile forces generated by the suboccipital muscles to the cervical dura mater. Moreover, head movements have been shown to be an important contributor to human CSF circulation. In the present study, a 16-week administration of a Myostatin-specific inhibitor, ACE-031, was injected into the suboccipital musculature of rats to establish an experimental animal model of hyperplasia of the suboccipital musculature. Using an optic fiber pressure measurement instrument, the present authors observed a significant increase in intracranial pressure (ICP) while utilizing the hyperplasia model. In contrast, surgically severing the MDB connections resulted in a significant decrease in intracranial pressure. Thus, these results indicated that muscular activation of the MDB may affect CSF circulation, suggesting a potential functional role of the MDB, and providing a new research perspective on CSF dynamics. [ABSTRACT FROM AUTHOR]

Lumbar spinal stenosis (LSS), one of the most commonly reported spinal disorders, can cause loss of sensation and dyskinesia. In currently used animal models of LSS, the spinal cord is covered entirely with a silicone sheet, or block-shaped silicone is inserted directly into the spinal canal after laminectomy. However, the effects of differences between these implant materials have not been studied. We assessed the degree of damage and locomotor function of an LSS model in Sprague-Dawley rats using silicone blocks of varying hardness (70, 80, and 90 kPa) implanted at the L4 level. In sham rats, the spinal cord remained intact; in LSS rats, the spinal cord was increasingly compressed by the mechanical pressure of the silicone blocks as hardness increased. Inflammatory cells were not evident in sham rats, but numerous inflammatory cells were observed around the implanted silicone block in LSS rats. CD68+ cell quantification revealed increases in the inflammatory response in a hardness-dependent manner in LSS rats. Compared with those in sham rats, proinflammatory cytokine levels were significantly elevated in a hardness-dependent manner, and locomotor function was significantly decreased, in LSS rats. Overall, this study showed that hardness could be used as an index to control the severity of nerve injury induced by silicone implants. [ABSTRACT FROM AUTHOR]

Background and aims: Knowledge of the proper dry weight plays a critical role in the efficiency of dialysis and the survival of hemodialysis patients. Recently, bioimpedance spectroscopy(BIS) has been widely used for set dry weight in hemodialysis patients. However, BIS is often misrepresented in clinical healthy weight. In this study, we tried to predict the clinically proper dry weight (DWCP) using machine learning for patient's clinical information including BIS. We then analyze the factors that influence the prediction of the clinical dry weight. Methods: As a retrospective, single center study, data of 1672 hemodialysis patients were reviewed. DWCP data were collected when the dry weight was measured using the BIS (DWBIS). The gap between the two (GapDW) was calculated and then grouped and analyzed based on gaps of 1 kg and 2 kg. Results: Based on the gap between DWBIS and DWCP, 972, 303, and 384 patients were placed in groups with gaps of <1 kg, ≧1kg and <2 kg, and ≧2 kg, respectively. For less than 1 kg and 2 kg of GapDW, It can be seen that the average accuracies for the two groups are 83% and 72%, respectively, in usign XGBoost machine learning. As GapDW increases, it is more difficult to predict the target property. As GapDW increase, the mean values of hemoglobin, total protein, serum albumin, creatinine, phosphorus, potassium, and the fat tissue index tended to decrease. However, the height, total body water, extracellular water (ECW), and ECW to intracellular water ratio tended to increase. Conclusions: Machine learning made it slightly easier to predict DWCP based on DWBIS under limited conditions and gave better insights into predicting DWCP. Malnutrition-related factors and ECW were important in reflecting the differences between DWBIS and DWCP. [ABSTRACT FROM AUTHOR]

Recent studies have evidenced that the anatomical structure now known as the myodural bridge (MDB) connects the suboccipital musculature to the cervical spinal dura mater (SDM). In humans, the MDB passes through both the posterior atlanto-occipital and the posterior atlanto-axial interspaces. The existence of the MDB in various mammals, including flying birds (Rock pigeons and Gallus domesticus) has been previously validated. Gentoo penguins are marine birds, able to make 450 dives per day, reaching depths of up to 660 feet. While foraging, this penguin is able to reach speeds of up to 22 miles per hour. Gentoo penguins are also the world's fastest diving birds. The present study was therefore carried out to investigate the existence and characteristics of the MDB in Gentoo penguin (Pygoscelis papua), a non-flying, marine bird that can dive. For this study, six Gentoo penguin specimens were dissected to observe the existence and composition of their MDB. Histological staining was also performed to analyze the anatomic relationships and characteristic of the MDB in the Gentoo penguin. In this study, it was found that the suboccipital musculature in the Gentoo penguin consists of the rectus capitis dorsalis minor (RCDmi) muscle and rectus capitis dorsalis major (RCDma) muscle. Dense connective tissue fibers were observed connecting these two suboccipital muscles to the spinal dura mater (SDM). This dense connective tissue bridge consists of primarily type I collagen fibers. Thus, this penguin's MDB appears to be analogous to the MDB previously observed in humans. The present study evidences that the MDB not only exists in penguins but it also has unique features that distinguishes it from that of flying birds. Thus, this study advances the understanding of the morphological characteristics of the MDB in flightless, marine birds. [ABSTRACT FROM AUTHOR]

To investigate the role of tannin-enriched extracts of Ecklonia cava (TEE) on the regulation of oxidative balance and laxative activity in chronic constipation, we investigated alterations after exposure to TEE, on constipation phenotypes, muscarinic cholinergic regulation, and oxidative stress responses in the transverse colons of SD rats with loperamide (Lop)-induced constipation. This extract contains high levels of total condensed tannin content (326.5 mg/g), and exhibited high inhibitory activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals. TEE treatment induced significant improvements in reactive oxygen species (ROS) production, superoxide dismutase (SOD) expression and nuclear factor erythroid 2-related factor 2 (Nrf2) phosphorylation in primary smooth muscles of rat intestine cells (pRISMCs) and transverse colon of constipation model. Also, Lop+TEE treated groups showed alleviated outcomes for the following: most stool parameters, gastrointestinal transit, and intestine length were remarkably recovered; a similar recovery pattern was observed in the histopathological structure, mucin secretion, water channel expression and gastrointestinal hormones secretion in the transverse colon; expressions of muscarinic acetylcholine receptors M2/M3 (mAChR M2/M3) and their mediators on muscarinic cholinergic regulation were significantly recovered. Taken together, these results provide the first evidence that TEE stimulates oxidative stress modulation and muscarinic cholinergic regulation when exerting its laxative effects in chronic constipation models. [ABSTRACT FROM AUTHOR]

A higher levodopa dose is a strong risk factor for levodopa-induced dyskinesia (LID) in patients with Parkinson's disease (PD). However, levodopa dose can change during long-term medication. We explored the relationship between levodopa dose and time to onset of LID using longitudinal multicenter data. Medical records of 150 patients who were diagnosed with de novo PD and treated with levodopa until onset of LID were collected. Levodopa dose were assessed as the dose at 6 months from levodopa initiation and rate of dose increase between 6 months and onset of LID. The groups with earlier LID onset had higher levodopa and levodopa-equivalent dose at the first 6 months of treatment and rapid increase in both levodopa and levodopa-equivalent dose. Multivariable linear regression models revealed that female sex, severe motor symptom at levodopa initiation, and higher rate of increase in both levodopa and levodopa-equivalent dose were significantly associated with early onset of LID. The present results demonstrated that rapid increase in levodopa dose or levodopa-equivalent dose is associated with early onset of LID. [ABSTRACT FROM AUTHOR]

Congenital amusia, commonly known as tone deafness, is a lifelong impairment of music perception and production. It remains a question of debate whether the impairments in musical domain observed in congenital amusia are paralleled in other non-musical perceptual abilities. Using behavioral measures in two experiments, the current study explored face perception and memory in congenital amusics. Both congenital amusics and matched controls performed a face perception task (Experiment 1) and an old/novel object memory task (for both faces and houses, Experiment 2). The results showed that the congenital amusic group had significantly slower reaction times than that in matched control group when identifying whether two faces presented together were the same or different. For different face-pairs, the deficit was greater for upright faces compared with inverted faces. For object memory task, the congenital amusic group also showed worse memory performance than the control group. The results of the present study suggest that the impairment attributed to congenital amusia is not only limited to music, but also extends to visual perception and visual memory domain. [ABSTRACT FROM AUTHOR]

Eating disorders comorbid with depression are an established risk factor for suicide. In this study, we aimed to determine the effects of binge eating (BE) symptoms on suicidality and related clinical characteristics in major depressive disorder (MDD). A total of 817 community participants with MDD were included. We compared two groups (with and without lifetime BE symptoms). The MDD with BE group was subdivided into a frequent BE (FBE) subgroup (BE symptoms greater than twice weekly) and any BE (ABE) subgroup (BE symptoms greater than twice weekly). The MDD with BE group comprised 142 (17.38%) patients. The FBE and ABE subgroups comprised 75 (9.18%) and 67 (8.20%) patients, respectively. Comorbid alcohol use disorder, anxiety disorder, post-traumatic stress disorder (PTSD) and history of suicide attempt were significantly more frequent in the MDD with BE group than MDD without BE group. Sexual trauma was also reported more frequently in MDD with BE group. No significant differences were observed between the ABE and FBE subgroups. Multivariate logistic regression revealed an association of suicide attempt with BE symptoms and sexual trauma. Structural equation modeling showed that sexual trauma increased BE (β = 0.337, P <0.001) together with alcohol use (β = 0.185, P <0.001) and anxiety (β = 0.299, p<0.001), which in turn increased suicide attempt (β = 0.087, p = 0.011). BE symptoms were associated with suicide attempt in MDD after adjusting for other factors associated with suicidality. BE symptoms also moderated an association between suicide attempt and sexual trauma. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease. For patients with localized PDAC, surgery is the best option, but with a median survival of less than 2 years and a difficult and prolonged postoperative course for most, there is an urgent need to better identify patients who have the most aggressive disease. Methods and Findings: We analyzed the gene expression profiles of primary tumors from patients with localized compared to metastatic disease and identified a six-gene signature associated with metastatic disease. We evaluated the prognostic potential of this signature in a training set of 34 patients with localized and resected PDAC and selected a cut-point associated with outcome using X-tile. We then applied this cut-point to an independent test set of 67 patients with localized and resected PDAC and found that our signature was independently predictive of survival and superior to established clinical prognostic factors such as grade, tumor size, and nodal status, with a hazard ratio of 4.1 (95% confidence interval [CI] 1.7-10.0). Patients defined to be high-risk patients by the six-gene signature had a 1-year survival rate of 55% compared to 91% in the low-risk group. Conclusions: Our six-gene signature may be used to better stage PDAC patients and assist in the difficult treatment decisions of surgery and to select patients whose tumor biology may benefit most from neoadjuvant therapy. The use of this six-gene signature should be investigated in prospective patient cohorts, and if confirmed, in future PDAC clinical trials, its potential as a biomarker should be investigated. Genes in this signature, or the pathways that they fall into, may represent new therapeutic targets., Introduction Pancreatic ductal adenocarcinoma (PDAC), comprising over 90% of all pancreatic cancers, remains a lethal disease with an estimated 232,000 new cases, 227,000 deaths per year worldwide, and a less [...]

Purpose: Internet addiction (IA) is defined as a psychological dependence on the internet, regardless of the type of activities once logged on, and previous studies have focused on adolescents and young adults. The aim of this study was to investigate the association between suicide attempts and sleep among community-dwelling adults with IA. Methods: The Young’s Internet Addiction Test (IAT), the Korean version of the Composite International Diagnostic Interview (K-CIDI) and a suicide questionnaire were used in this cross-sectional multistage, cluster sampling population-based study. A total of 3212 adults aged 18–64 years were interviewed face-to-face, and they had been randomly selected through a one-person-per-household method. Results: Of the 3212 adults, 204 were assessed as having IA (6.35%). Adults with IA were younger, and more frequently male, unmarried, and unemployed, and had poorer sleep quality than adults without IA (32.8% vs. 19.8%), whereas there was no significant difference in the absolute duration of sleep between the two groups. Adults with IA showed more frequent difficulty initiating and maintaining sleep, non-restorative sleep, daytime functional impairment, and duration of sleep more than 10 hours on weekdays than adults without IA. IA with poor sleep quality was significantly associated with lifetime suicide attempts (AOR = 3.34, 95% CI 1.38–8.05) after adjusting for demographic covariates. Adults with IA who had more sleep problems showed more severe IA, especially those who experienced a previous suicidal attempt. Among mental disorders, IA with poor sleep quality was significantly associated with anxiety disorder and overall psychiatric disorders. Conclusions: Among adults with IA, poor sleep quality was found to be associated with more severe IA and lifetime suicide attempt. [ABSTRACT FROM AUTHOR]

In acute ischemic stroke, blood pressure (BP) tends to rise initially and fall to a baseline level within 24–48 hours. Previous studies reported several different effects of BPs during acute ischemic stroke on clinical outcomes, which was partly due to the different time intervals from stroke onset to BP measurement. All patients with acute ischemic stroke (onset ≤3 hours) who lived independently before the stroke, were consecutively enrolled for a 62-month period. BPs at 0, 12, and 24 hours after admission were collected. A favorable outcome was defined as a modified Rankin Scale (mRS) score 0–2 at discharge. For different standards of BP management, patients were grouped and analyzed according to intravenous (IV) tissue plasminogen activator (tPA) treatment and favorable outcome. Among the 446 enrolled patients, 227 patients underwent IV tPA treatment and 216 had mRS score 0–2 at discharge. Patients with favorable outcomes had lower initial NIH Stroke Scale (NIHSS) scores, less frequent progressive neurological deficits, and lower systolic BP (SBP) 12 and 24 hours after admission than patients with unfavorable outcomes, regardless of whether they underwent tPA treatment or not (p <0.05). The BP decreased over a period of 24 hours after admission. In logistic regression analysis, the independent variables associated with favorable outcome were the initial NIHSS score, a progressive neurological deficit, a previous stroke, and the SBP 24 hours after admission in the patients who underwent tPA treatment and the initial NIHSS score and a progressive neurological deficit in the patients who did not undergo tPA treatment (p <0.05). The SBPs at 12 and 24 hours after admission were lower in acute stroke patients with favorable outcomes than in the other patients, regardless of whether the patients underwent tPA therapy and the SBP at 24 hours was an independent predictor of favorable outcomes among the patients who underwent tPA treatment. [ABSTRACT FROM AUTHOR]

Several epidemiological studies have demonstrated the reciprocal relationship between the development of cancer and Parkinson’s disease (PD). However, the possible mechanisms underlying this relationship remain unclear. To identify this relationship, we first compared lung tumor growth in parkin knockout (KO) mice and wild-type (WT) mice. Parkin KO mice showed decreased lung tumor growth and increased expression of p21, a cell cycle arrester, as compared with WT mice. We also found that parkin interacts with p21, resulting in its degradation; however, parkin KO, knockdown, as well as mutation (R275W or G430D) reduced the degradation of p21. We investigated whether parkin KO increases the association of p21 with proliferating cell nuclear antigen (PCNA) or CDK2 by reducing p21 degradation, and, thus, arresting the cell cycle. The interaction between p21 and PCNA or CDK2 was also enhanced by parkin knockdown, and this increased interaction induced sub G0/G1 arrest, leading to cell death. Therefore, our data indicate that parkin KO reduces the development of lung tumors via cell cycle arrest by blocking the degradation of p21. These findings suggest that PD could be associated with lower lung cancer incidence. [ABSTRACT FROM AUTHOR]

Depressive symptoms are related to abnormalities in the autonomic nervous system (ANS), and physiological signals that can be used to measure and evaluate such abnormalities have previously been used as indicators for diagnosing mental disorder, such as major depressive disorder (MDD). In this study, we investigate the feasibility of developing an objective measure of depressive symptoms that is based on examining physiological abnormalities in individuals when they are experiencing mental stress. To perform this, we recruited 30 patients with MDD and 31 healthy controls. Then, skin conductance (SC) was measured during five 5-min experimental phases, comprising baseline, mental stress, recovery from the stress, relaxation, and recovery from the relaxation, respectively. For each phase, the mean amplitude of the skin conductance level (MSCL), standard deviations of the SCL (SDSCL), slope of the SCL (SSCL), mean amplitude of the non-specific skin conductance responses (MSCR), number of non-specific skin conductance responses (NSCR), and power spectral density (PSD) were evaluated from the SC signals, producing 30 parameters overall (six features for each phase). These features were used as input data for a support vector machine (SVM) algorithm designed to distinguish MDD patients from healthy controls based on their physiological responses. Statistical tests showed that the main effect of task was significant in all SC features, and the main effect of group was significant in MSCL, SDSCL, SSCL, and PSD. In addition, the proposed algorithm achieved 70% accuracy, 70% sensitivity, 71% specificity, 70% positive predictive value, 71% negative predictive value in classifying MDD patients and healthy controls. These results demonstrated that it is possible to extract meaningful features that reflect changes in ANS responses to various stimuli. Using these features, detection of MDD was feasible, suggesting that SC analysis has great potential for future diagnostics and prediction of depression based on objective interpretation of depressive states. [ABSTRACT FROM AUTHOR]

Objective: By identifying pregnancy-related risk factors for endometrial neoplasia, women’s risk of developing this disease after childbirth can be predicted and high-risk women can be screened for early detection. Methods: Study data from women who gave birth in Korea in 2007 were collected from the Korea National Health Insurance (KNHI) claims database between 2007 and 2015. The adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the development of endometrial neoplasia were estimated by multivariate Cox proportional hazards models. Results: Data from 386,614 women were collected for this study. By 2015, 3,370 women from the initial cohort had been diagnosed with endometrial neoplasia secondary to delivery. Multivariate Cox proportional hazards regression revealed that preeclampsia (HR 1.55, 95% CI 1.29, 1.86), advanced maternal age (≥ 35; HR 1.52, 95% CI 1.39, 1.66), multifetal pregnancy (HR 1.81, 95% CI 1.46, 2.23), multiparity (HR 1.16, 95% CI 1.08, 1.24), cesarean section (HR 1.15, 95% CI 1.07, 1.23) and delivery of a large-for-gestational-age infant (HR 1.19, 95% CI 1.02, 1.39) were independent risk factors for future endometrial neoplasia. The risk for endometrial neoplasia increased as the number of risk factors increased (risk factors ≥3: HR 2.11, 95% CI 1.86–2.40). Conclusion: This study showed that six pregnancy-related factors—advanced maternal age, multiparity, multifetal pregnancy, cesarean section, delivery of a large-for-gestational-age infant, and preeclampsia—are positively correlated with future development of endometrial neoplasia, including endometrial hyperplasia or cancer. Close observation and surveillance are warranted to enable early diagnosis of endometrial diseases, including endometrial cancer after pregnancy in high-risk women. However, due to unavailability of clinical information, many clinical/epidemiological factors can become confounders. Further research is needed on factors associated with the risk of endometrial neoplasia. [ABSTRACT FROM AUTHOR]

Neurons require a nearly constant supply of ATP. Glucose is the predominant source of brain ATP, but the direct effects of prolonged glucose deprivation on neuronal viability and function remain unclear. In sparse rat hippocampal microcultures, neurons were surprisingly resilient to 16 h glucose removal in the absence of secondary excitotoxicity. Neuronal survival and synaptic transmission were unaffected by prolonged removal of exogenous glucose. Inhibition of lactate transport decreased microculture neuronal survival during concurrent glucose deprivation, suggesting that endogenously released lactate is important for tolerance to glucose deprivation. Tandem depolarization and glucose deprivation also reduced neuronal survival, and trace glucose concentrations afforded neuroprotection. Mass cultures, in contrast to microcultures, were insensitive to depolarizing glucose deprivation, a difference attributable to increased extracellular lactate levels. Removal of local astrocyte support did not reduce survival in response to glucose deprivation or alter evoked excitatory transmission, suggesting that on-demand, local lactate shuttling is not necessary for neuronal tolerance to prolonged glucose removal. Taken together, these data suggest that endogenously produced lactate available globally in the extracellular milieu sustains neurons in the absence of glucose. A better understanding of resilience mechanisms in reduced preparations could lead to therapeutic strategies aimed to bolster these mechanisms in vulnerable neuronal populations. [ABSTRACT FROM AUTHOR]

Vitamin D is a secosteroid hormone with many varied functions including regulation of blood calcium levels, cell proliferation, immunity, and reproduction in mammals. Vitamin D is activated by 25-hydroxylase (CYP2R1) and 1-alpha-hydroxylase (CYP27B1) and is degraded by 24-hydroxylase (CYP24A1). Vitamin D is transported by vitamin D-binding protein (group-specific component, GC) through the bloodstream and regulates cellular actions by binding to vitamin D receptor (VDR). In this study, we determined the expression and regulation of vitamin D-related molecules and the role of vitamin D at the maternal-conceptus interface in pigs. Vitamin D-metabolizing enzymes CYP2R1, CYP27B1, and CYP24A1, vitamin D binding protein GC, and vitamin D receptor VDR were expressed in the endometrium in a pregnancy stage-specific manner as well as in conceptus and chorioallantoic tissues during pregnancy. VDR protein was localized to endometrial and trophoblastic cells. Concentrations of calcitriol, the active form of vitamin D, in the endometrial tissues were higher during early pregnancy than in mid- to late pregnancy, while plasma concentrations of calcitriol were highest during late pregnancy. Furthermore, calcitriol affected the expression of several genes related to conceptus implantation, vitamin D metabolism, calcium ion regulation, PG metabolism, and calcium-binding proteins in endometrial tissue explants. These results show that CYP2R1, CYP27B1, CYP24A1, GC, and VDR were expressed at the maternal-conceptus interface, endometrial calcitriol levels were regulated during pregnancy, and calcitriol modulated the expression of endometrial genes, suggesting that calcitriol may play an important role in the establishment and maintenance of pregnancy by regulating endometrial function in pigs. [ABSTRACT FROM AUTHOR]

In the last two decades, many studies have focused on the muscles and dense connective tissues located in the suboccipital region. Our study investigated the existence of the second terminations originating from the suboccipital muscles, and the relationship between the variable types of the To Be Named Ligament (TBNL). Anatomical dissection was performed on 35 head-neck specimens. The existence of the second terminations of the suboccipital muscles was confirmed and various types of the TBNL were observed in this study. The second terminations originated from multiple suboccipital muscles including the rectus capitis posterior minor (RCPmi), rectus capitis posterior major (RCPma) and obliquus capitis inferior (OCI) muscles, merged and terminated at the TBNL. The overall incidence of the second terminations of the suboccipital muscles was 34.29% and it varied among the various suboccipital muscle origins. 28.57% of the second terminations originated from the RCPma; 11.43% was from the RCPmi and 8.57% was from the OCI. Furthermore, there was a significant relationship between the existence of second terminations and the particular type of the TBNL. 95% of the arcuate type of the TBNL was accompanied with the second terminations which attached to their turning part, whereas only 10% of all the radiate type of the TBNL was accompanied with the second terminations. This study for the first time described the second terminations originating from multiple suboccipital muscles and demonstrated the relationship with the various types of the TBNL. We speculated that the second terminations maintain the arcuate TBNL and transfer tensile forces to the Myodural Bridge (MDB), thereby modulating the physiological functions of the MDB. [ABSTRACT FROM AUTHOR]

Because synonymy treatment traditionally relies on morphological judgments, it usually causes many problems in species delimitation and in the biodiversity catalogue. For example, Diplopterygium simulans, which belongs to the Gleicheniaceae family, has been considered to be synonymous with D. glaucum or D. giganteum based mainly on the morphology of its pinna rachis and blade. In the absence of molecular evidence, these revisions remain doubtful. DNA barcoding, which is considered to be a powerful method for species-level identification, was employed to assess the genetic distance among 9 members of the Diplopterygium genus. The results indicate that D. simulans is an independent species rather than a synonymy of D. glaucum or D. giganteum. Moreover, phylogenetic analysis uncovered the sisterhood of D. simulans and D. cantonense, which is supported by their geographical distributions and morphological traits. Incorrect synonymy treatment is prevalent in the characterization of biological diversity, and our study proposes a convenient and effective method for validating synonym treatments and discovering cryptic species. [ABSTRACT FROM AUTHOR]

Recent studies have identified that the myodural bridge (MDB) between the rectus capitis posterior minor (RCPmi) and the cervical spinal dura mater in the posterior atlanto-occipital interspace in humans. And it was supposed that the MDB may play essential physiological roles. As a result, the MDB is possibly a highly conserved structure in the evolution of mammals. However, there is little confirmative description about the existence of the MDB in marine mammals. The objective of this study was to explore the existence and the fiber property of the MDB in the Neophocaena phocaenoides. Six cadavers of the Neophocaena phocaenoides with formalin fixation were used in this study. One was used for head and neck CT scanning and three-dimensional (3D) reconstruction and suboccipital region dissection, two were for sectional observation by P45 plastinated sheets of head and neck, and three were for histological analysis of suboccipial structures. This is the first study to demonstrate the existence of the MDB in the aquatic mammals. The rectus capitis dorsal minor (RCDmi) originated from the inferior border of the occiput and inserted into the cervical spinal dura mater. At the ventral aspect of the RCDmi, the MDB directly extended through the posterior atlanto-occipital interspace and connected with the cervical spinal dura mater which was consisted of type Ⅰ collagen. In addition, the dorsal atlanto-occipital membrane was not found in the Neophocaena phocaenoides. The tendinous myodural bridge extended from the RCDmi to the spinal dura mater through the posterior atlanto-occipital interspace in the Neophocaena phocaenoides. [ABSTRACT FROM AUTHOR]

The rainbow tradeoff is an algorithm for inverting one-way functions that is widely used in practice to recover passwords from unsalted password hashes. An auxiliary technique referred to as checkpoints can be applied to the rainbow tradeoff to reduce the time taken for these inversions. Working out a rigorous theory that can explain and predict the effects of this technique involves delicate manipulations of the random function and is thus a challenging task. In this work, we compare three existing theoretical analyses of the checkpoint technique. We first demonstrate that the claims made by the three works are incompatible with each other. We then carry out experiments designed to highlight these incompatibilities, obtaining experimental evidences that show just one of the three analyses to be correct. Finally, we discuss the obscure theoretical errors made by the two inadequate analyses. [ABSTRACT FROM AUTHOR]

Several natural products containing tannins are used as traditional medicines for treatment of constipation; however, their pharmacological mechanism is not well understood. The laxative effects of gallotannin-enriched extract isolated from Galla Rhois (GEGR) were investigated using a constipation model induced by loperamide (Lop) injection. After analysis for antioxidant activity of GEGR, alterations in the excretion parameters, histological structure, mucin secretion, and related protein levels were measured in the transverse colon of Sprague Dawley (SD) rats with Lop-induced constipation following treatment with 250, 500 and 1,000 mg/ml of GEGR. The number and weight of feces increased significantly by 48–79% and 128–159%, respectively, in the Lop+GEGR treated group relative to the Lop+vehicle treated group, while food intake and water consumption were maintained at a constant level. The thickness of mucosa, muscle and flat luminal surface, as well as the number of goblet cells and crypt of lieberkuhn were enhanced in the Lop+GEGR treated group. Moreover, mucin secretion increased significantly in a dose dependent manner in the Lop+GEGR treated group. Furthermore, the downstream signaling pathway of the muscarinic acetylcholine receptors (mAChR) M2 and M3 was recovered by GEGR treatment, although the expression level varied. The levels of Gα expression and inositol triphosphate (IP3) concentration were also recovered in the Lop+GEGR treated group relative to the Lop+vehicle treated group. The results of the present study provide strong evidence that tannins distributed in various medicinal plants are important candidates for improving chronic constipation induced by Lop treatment in animal models. [ABSTRACT FROM AUTHOR]

Functional neuroimaging for the dopamine transporter (DAT) is used to distinguish drug-induced parkinsonism (DIP) from subclinical Parkinson’s disease (PD). Although DIP patients who show a normal DAT image are expected to recover completely, some do not. We investigated whether these patients showed changes in striatal DAT activity using semi-quantitative analysis of 18F-FP-CIT PET data. DIP patients with visually normal DAT images were selected from medical records. The subjects were classified as patients who recovered partially (PR) or completely within 12 months (CR). The 18F-FP-CIT uptake in each striatal subregion was compared between the CR and the PR groups. In total, 41 and 9 patients of the CR and PR groups were assessed, respectively. The two patient groups were comparable in terms of clinical characteristics including age, sex, and severity of parkinsonism. From semi-quantitative analysis of the PET image, the PR patients showed a relatively lower ligand uptake in the ventral striatum, the anterior putamen and the posterior putamen compared with the CR patients. This result suggests that persistent DIP in patients with visually normal DAT imaging may be associated with subtle decrement of DAT activity. [ABSTRACT FROM AUTHOR]

Microtubule stabilizing agents (MTSA) are known to inhibit vascular smooth muscle cell (VSMC) proliferation and migration, and effectively reduce neointimal hyperplasia and restenosis. Epothilones (EPOs), non-taxane MTSA, have been found to be effective in the inhibition of VSMC proliferation and neointimal formation by cell cycle arrest. However, effect of EPOs on apoptosis in hyper-proliferated VSMCs as a possible way to reduce neointimal formation and its action mechanism related to VSMC viability has not been suited yet. Thus, the purposes of the present study was to investigate whether EPOs are able to inhibit neointimal formation by inducing apoptosis within the region of neointimal hyperplasia in balloon-injured rat carotid artery, as well as underlying action mechanism. Treatment of EPO-B and EPO-D significantly induced apoptotic cell death and mitotic catastrophe in hyper-proliferated VSMCs, resulting in cell growth inhibition. Further, EPOs significantly suppressed VSMC proliferation and induced apoptosis by activation of p53-dependent apoptotic signaling pathway, Bax/cytochrome c/caspase-3. We further demonstrated that the local treatment of carotid arteries with EPOs potently inhibited neointimal lesion formation by induction of apoptosis in rat carotid injury model. Our findings demonstrate a potent anti-neointimal hyperplasia property of EPOs by inducing p53-depedent apoptosis in hyper-proliferated VSMCs. [ABSTRACT FROM AUTHOR]

ALS-8112 is the parent molecule of ALS-8176, a first-in-class nucleoside analog prodrug effective in the clinic against respiratory syncytial virus (RSV) infection. The antiviral activity of ALS-8112 is mediated by its 5'-triphosphate metabolite (ALS-8112-TP, or 2'F-4'ClCH2-cytidine triphosphate) inhibiting the RNA polymerase activity of the RSV L-P protein complex through RNA chain termination. Four amino acid mutations in the RNA-dependent RNA polymerase (RdRp) domain of L (QUAD: M628L, A789V, L795I, and I796V) confer in vitro resistance to ALS-8112-TP by increasing its discrimination relative to natural CTP. In this study, we show that the QUAD mutations specifically recognize the ClCH2 group of ALS-8112-TP. Among the four mutations, A789V conferred the greatest resistance phenotype, which was consistent with its putative position in the active site of the RdRp domain. AZ-27, a non-nucleoside inhibitor of RSV, also inhibited the RdRp activity, with decreased inhibition potency in the presence of the Y1631H mutation. The QUAD mutations had no effect on the antiviral activity of AZ-27, and the Y1631H mutation did not significantly increase the discrimination of ALS-8112-TP. Combining ALS-8112 with AZ-27 in vitro resulted in significant synergistic inhibition of RSV replication. Overall, this is the first mechanistic study showing a lack of cross-resistance between mutations selected by different classes of RSV polymerase inhibitors acting in synergy, opening the door to future potential combination therapies targeting different regions of the L protein. [ABSTRACT FROM AUTHOR]

The focus of this study is the anti-cancer effects of Cudrania tricuspidata stem (CTS) extract on cervical cancer cells. The effect of CTS on cell viability was investigated in HPV-positive cervical cancer cells and HaCaT human normal keratinocytes. CTS showed significant dose-dependent cytotoxic effects in cervical cancer cells. However, there was no cytotoxic effect of CTS on HaCaT keratinocytes at concentrations of 0.125–0.5 mg/mL. Based on this cytotoxic effect, we demonstrated that CTS induced apoptosis by down-regulating the E6 and E7 viral oncogenes. Apoptosis was detected by DAPI staining, annexin V-FITC/PI staining, cell cycle analysis, western blotting, RT-PCR, and JC-1 staining in SiHa cervical cancer cells. The mRNA expression levels of extrinsic pathway molecules such as Fas, death receptor 5 (DR5), and TNF-related apoptosis-inducing ligand (TRAIL) were increased by CTS. Furthermore, CTS treatment activated caspase-3/caspase-8 and cleavage of poly (ADP-ribose) polymerase (PARP). However, the mitochondrial membrane potential and expression levels of intrinsic pathway molecules such as Bcl-2, Bcl-xL, Bax, and cytochrome C were not modulated by CTS. Taken together, these results indicate that CTS induced apoptosis by activating the extrinsic pathway, but not the intrinsic pathway, in SiHa cervical cancer cells. These results suggest that CTS can be used as a modulating agent in cervical cancer. [ABSTRACT FROM AUTHOR]

This study aimed to clarify changes in the prevalence of rheumatic diseases in Shantou, China, in the past 3 decades and validate whether stair-climbing is a risk factor for knee pain and knee osteoarthritis (KOA). The World Health Organization-International League Against Rheumatism Community Oriented Program for Control of Rheumatic Diseases (COPCORD) protocol was implemented. In all, 2337 adults living in buildings without elevators and 1719 adults living in buildings with elevators were surveyed. The prevalence of rheumatic pain at any site and in the knee was 15.7% and 10.2%, respectively; both types of pain had a significantly higher incidence in residents of buildings without elevators than was reported by people who lived in buildings with elevators (14.9% vs. 10.6% and 11.32% vs. 8.82%, respectively) (both P < 0.0001). The prevalence of rheumatic pain in the neck, lumbar spine, shoulder, elbow, and foot was 5.6%, 4.5%, 3.1%, 1.4%, and 1.8%, respectively; these findings were similar to the data from the 1987 rural survey, but were somewhat lower than data reported in the urban and suburban surveys of the 1990s, with the exception of neck and lumbar pain. The prevalence of KOA, gout, and fibromyalgia was 7.10%, 1.08%, and 0.07%, respectively, and their prevalence increased significantly compared with those in previous studies from the 20th century. There were no significant differences in the prevalence of rheumatoid arthritis (RA) (0.35%) or ankylosing spondylitis (AS) (0.31%) compared to that reported in prior surveys. The prevalence of KOA was higher in for residents of buildings without elevators than that in those who had access to elevators (16–64 years, 5.89% vs. 3.95%, P = 0.004; 16->85 years, 7.64% vs. 6.26%, P = 0.162). The prevalence of RA and AS remained stable, whereas that of KOA, gout, and fibromyalgia has increased significantly in Shantou, China, during the past 3 decades. Stair-climbing might be an important risk factor for knee pain and KOA. [ABSTRACT FROM AUTHOR]

To find environmental variables (EVs) shaping the ecological niche of the archaeal phylum Thaumarchaeota in terrestrial environments, we determined the abundance of Thaumarchaeota in various soil samples using real-time PCR targeting thaumarchaeotal 16S rRNA gene sequences. We employed our previously developed primer, THAUM-494, which had greater coverage for Thaumarchaeota and lower tolerance to nonthaumarchaeotal taxa than previous Thaumarchaeota-directed primers. The relative abundance estimates (RVs) of Thaumarchaeota (RTHAUM), Archaea (RARCH), and Bacteria (RBACT) were subjected to a series of statistical analyses. Redundancy analysis (RDA) showed a significant (p < 0.05) canonical relationship between RVs and EVs. Negative causal relationships between RTHAUM and nutrient level–related EVs were observed in an RDA biplot. These negative relationships were further confirmed by correlation and regression analyses. Total nitrogen content (TN) appeared to be the EV that affected RTHAUM most strongly, and total carbon content (TC), which reflected the content of organic matter (OM), appeared to be the EV that affected it least. However, in the path analysis, a path model indicated that TN might be a mediator EV that could be controlled directly by the OM. Additionally, another path model implied that water content (WC) might also indirectly affect RTHAUM by controlling ammonium nitrogen (NH4+-N) level through ammonification. Thus, although most directly affected by NH4+-N, RTHAUM could be ultimately determined by OM content, suggesting that Thaumarchaeota could prefer low-OM or low-WC conditions, because either of these EVs could subsequently result in low levels of NH4+-N in soil. [ABSTRACT FROM AUTHOR]

To characterize the changes in global gene expression in the distal colon of constipated SD rats in response to the laxative effects of aqueous extracts of Liriope platyphylla (AEtLP), including isoflavone, saponin, oligosaccharide, succinic acid and hydroxyproline, the total RNA extracted from the distal colon of AEtLP-treated constipation rats was hybridized to oligonucleotide microarrays. The AEtLP treated rats showed an increase in the number of stools, mucosa thickness, flat luminal surface thickness, mucin secretion, and crypt number. Overall, compared to the controls, 581 genes were up-regulated and 216 genes were down-regulated by the constipation induced by loperamide in the constipated rats. After the AEtLP treatment, 67 genes were up-regulated and 421 genes were down-regulated. Among the transcripts up-regulated by constipation, 89 were significantly down-regulated and 22 were recovered to the normal levels by the AEtLP treatment. The major genes in the down-regulated categories included Slc9a5, klk10, Fgf15, and Alpi, whereas the major genes in the recovered categories were Cyp2b2, Ace, G6pc, and Setbp1. On the other hand, after the AEtLP treatment, ten of these genes down-regulated by constipation were up-regulated significantly and five were recovered to the normal levels. The major genes in the up-regulated categories included Serpina3n, Lcn2 and Slc5a8, whereas the major genes in the recovered categories were Tmem45a, Rerg and Rgc32. These results indicate that several gene functional groups and individual genes as constipation biomarkers respond to an AEtLP treatment in constipated model rats. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) causes severe lower respiratory tract infections, yet no vaccines or effective therapeutics are available. ALS-8176 is a first-in-class nucleoside analog prodrug effective in RSV-infected adult volunteers, and currently under evaluation in hospitalized infants. Here, we report the mechanism of inhibition and selectivity of ALS-8176 and its parent ALS-8112. ALS-8176 inhibited RSV replication in non-human primates, while ALS-8112 inhibited all strains of RSV in vitro and was specific for paramyxoviruses and rhabdoviruses. The antiviral effect of ALS-8112 was mediated by the intracellular formation of its 5'-triphosphate metabolite (ALS-8112-TP) inhibiting the viral RNA polymerase. ALS-8112 selected for resistance-associated mutations within the region of the L gene of RSV encoding the RNA polymerase. In biochemical assays, ALS-8112-TP was efficiently recognized by the recombinant RSV polymerase complex, causing chain termination of RNA synthesis. ALS-8112-TP did not inhibit polymerases from host or viruses unrelated to RSV such as hepatitis C virus (HCV), whereas structurally related molecules displayed dual RSV/HCV inhibition. The combination of molecular modeling and enzymatic analysis showed that both the 2'F and the 4'ClCH2 groups contributed to the selectivity of ALS-8112-TP. The lack of antiviral effect of ALS-8112-TP against HCV polymerase was caused by Asn291 that is well-conserved within positive-strand RNA viruses. This represents the first comparative study employing recombinant RSV and HCV polymerases to define the selectivity of clinically relevant nucleotide analogs. Understanding nucleotide selectivity towards distant viral RNA polymerases could not only be used to repurpose existing drugs against new viral infections, but also to design novel molecules. [ABSTRACT FROM AUTHOR]

The annual suicide rate in South Korea is the highest among the developed countries. Paraquat is a highly lethal herbicide, commonly used in South Korea as a means for suicide. We have studied the effect of the 2011 paraquat prohibition on the national suicide rate and method of suicide in South Korea. We obtained the monthly suicide rate from 2005 to 2013 in South Korea. In our analyses, we adjusted for the effects of celebrity suicides, and economic, meteorological, and seasonal factors on suicide rate. We employed change point analysis to determine the effect of paraquat prohibition on suicide rate over time, and the results were verified by structural change analysis, an alternative statistical method. After the paraquat prohibition period in South Korea, there was a significant reduction in the total suicide rate and suicide rate by poisoning with herbicides or fungicides in all age groups and in both genders. The estimated suicide rates during this period decreased by 10.0% and 46.1% for total suicides and suicides by poisoning of herbicides or fungicides, respectively. In addition, method substitution effect of paraquat prohibition was found in suicide by poisoning by carbon monoxide, which did not exceed the reduction in the suicide rate of poisoning with herbicides or fungicides. In South Korea, paraquat prohibition led to a lower rate of suicide by paraquat poisoning, as well as a reduction in the overall suicide rate. Paraquat prohibition should be considered as a national suicide prevention strategy in developing and developed countries alongside careful observation for method substitution effects. [ABSTRACT FROM AUTHOR]

Suggestive associations of suicide with air pollutant concentrations have been reported. Recognizing regional and temporal variability of pollutant concentrations and of suicide, we undertook a detailed meta-analysis of completed suicides in relation to 5 major pollutants over 6 years in the 16 administrative regions of the Republic of Korea, while also controlling for other established influences on suicide rates. Of the 5 major pollutants examined, ozone concentrations had a powerful association with suicide rate, extending back to 4 weeks. Over the range of 2 standard deviations (SD) around the annual mean ozone concentration, the adjusted suicide rate increased by an estimated 7.8% of the annual mean rate. Particulate matter pollution also had a significant effect, strongest with a 4-week lag, equivalent to 3.6% of the annual mean rate over the same 2 SD range that approximated the half of annual observed range. These results strongly suggest deleterious effects of ozone and particulate matter pollution on the major public health problem of suicide. [ABSTRACT FROM AUTHOR]

Few studies have been conducted specifically on the dense connective tissue located in the posterior medial part of the cervical epidural space. This study was undertaken to examine the presence of this connection between the cervical dura mater and the posterior wall of spinal canal at the level of C1–C2. 30 head-neck specimens of Chinese adults were used. Gross dissection was performed on the suboccipital regions of the 20 specimens. Having been treated with the P45 plastination method, 10 specimens were sliced (9 sagittal and 1 horizontal sections). As a result, a dense fibrous band was identified in the nuchal ligament of 29 specimens (except for one horizontal section case). This fascial structure arose from the tissue of the posterior border of the nuchal ligament and then projected anteriorly and superiorly to enter the atlantoaxial interspace. It was termed as to be named ligament (TBNL). In all 30 specimens the existence of a fibrous connection was found between the posterior aspect of the cervical dura mater and the posterior wall of the spinal canal at the level of the atlas to the axis. This fibrous connection was identified as vertebrodural ligament (VDL). The VDL was mainly subdivided into three parts, and five variations of VDL were identified. These two structures, TBNL and VDL, firmly link the posterior aspect of cervical dura mater to the rear of the atlas-axis and the nuchal region. According to these findings, the authors speculated that the movements of the head and neck are likely to affect the shape of the cervical dural sleeve via the TBNL and VDL. It is hypothesized that the muscles directly associated with the cervical dural sleeve, in the suboccipital region, may work as a pump providing an important force required to move the CSF in the spinal canal. [ABSTRACT FROM AUTHOR]

Based on comparative phylogenetic analysis of 16S rRNA gene sequences deposited in an RDP database, we constructed a local database of thaumarchaeotal 16S rRNA gene sequences and developed a novel PCR primer specific for the archaeal phylum Thaumarchaeota. Among 9,727 quality-filtered (chimeral-checked, size >1.2 kb) archaeal sequences downloaded from the RDP database, 1,549 thaumarchaeotal sequences were identified and included in our local database. In our study, Thaumarchaeota included archaeal groups MG-I, SAGMCG-I, SCG, FSCG, RC, and HWCG-III, forming a monophyletic group in the phylogenetic tree. Cluster analysis revealed 114 phylotypes for Thaumarchaeota. The majority of the phylotypes (66.7%) belonged to the MG-I and SCG, which together contained most (93.9%) of the thaumarchaeotal sequences in our local database. A phylum-directed primer was designed from a consensus sequence of the phylotype sequences, and the primer’s specificity was evaluated for coverage and tolerance both in silico and empirically. The phylum-directed primer, designated THAUM-494, showed >90% coverage for Thaumarchaeota and <1% tolerance to non-target taxa, indicating high specificity. To validate this result experimentally, PCRs were performed with THAUM-494 in combination with a universal archaeal primer (ARC917R or 1017FAR) and DNAs from five environmental samples to construct clone libraries. THAUM-494 showed a satisfactory specificity in empirical studies, as expected from the in silico results. Phylogenetic analysis of 859 cloned sequences obtained from 10 clone libraries revealed that >95% of the amplified sequences belonged to Thaumarchaeota. The most frequently sampled thaumarchaeotal subgroups in our samples were SCG, MG-I, and SAGMCG-I. To our knowledge, THAUM-494 is the first phylum-level primer for Thaumarchaeota. Furthermore, the high coverage and low tolerance of THAUM-494 will make it a potentially valuable tool in understanding the phylogenetic diversity and ecological niche of Thaumarchaeota. [ABSTRACT FROM AUTHOR]

There is accumulating evidence that virus-like particles (VLPs) recombinantly produced in Saccharomyces cerevisiae (S. cerevisiae) are characterized by low structural stability, and that this is associated with reduced antigenicity and immunogenicity. However, little attention has been devoted to methods of improving the quality of the VLPs. Here, we investigated the effect of carbon source concentration in the medium on the antigenicity and immunogenicity of human papillomavirus (HPV) type 16 L1 VLPs expressed in S. cerevisiae from the galactose promoter. Media containing 2, 4, 6, and 8% carbon source, composed of both glucose and galactose in equal proportion, were used. VLP antigenicity was enhanced in cultures grown on media with 6 or 8% carbon source, compared to those from cultures with less than 6% carbon source. Moreover, the VLPs obtained from these cultures induced higher anti-HPV16 L1 IgG titers and neutralizing antibody titers in immunized mice than those purified from cultures with less than 6% carbon source. Our results indicate that the concentration of the carbon source in the medium plays a crucial role in determining the antigenicity and immunogenicity of HPV type16 L1 VLPs. [ABSTRACT FROM AUTHOR]

Thiacremonone (2, 4-dihydroxy-2, 5-dimethyl-thiophene-3-one) is an antioxidant substance as a novel sulfur compound generated from High-Temperature-High-Pressure-treated garlic. Peroxiredoxin 6 (PRDX6) is a member of peroxidases, and has glutathione peroxidase and calcium-independent phospholipase A2 (iPLA2) activities. Several studies have demonstrated that PRDX6 stimulates lung cancer cell growth via an increase of glutathione peroxidase activity. A docking model study and pull down assay showed that thiacremonone completely fits on the active site (cys-47) of glutathione peroxidase of PRDX6 and interacts with PRDX6. Thus, we investigated whether thiacremonone inhibits cell growth by blocking glutathione peroxidase of PRDX6 in the human lung cancer cells, A549 and NCI-H460. Thiacremonone (0–50 μg/ml) inhibited lung cancer cell growth in a concentration dependent manner through induction of apoptotic cell death accompanied by induction of cleaved caspase-3, -8, -9, Bax, p21 and p53, but decrease of xIAP, cIAP and Bcl2 expression. Thiacremonone further inhibited glutathione peroxidase activity in lung cancer cells. However, the cell growth inhibitory effect of thiacremonone was not observed in the lung cancer cells transfected with mutant PRDX6 (C47S) and in the presence of dithiothreitol and glutathione. In an allograft in vivo model, thiacremonone (30 mg/kg) also inhibited tumor growth accompanied with the reduction of PRDX6 expression and glutathione peroxidase activity, but increased expression of cleaved caspase-3, -8, -9, Bax, p21 and p53. These data indicate that thiacremonone inhibits tumor growth via inhibition of glutathione peroxidase activity of PRDX6 through interaction. These data suggest that thiacremonone may have potentially beneficial effects in lung cancer. [ABSTRACT FROM AUTHOR]

PiggyBac is a prevalent transposon system used to deliver transgenes and functionally explore the mammalian untouched genomic territory. The important features of piggyBac transposon are the relatively low insertion site preference and the ability of seamless removal from genome, which allow its potential uses in functional genomics and regenerative medicine. Efforts to increase its transposition efficiency in mammals were made through engineering the corresponding transposase (PBase) codon usage to enhance its expression level and through screening for mutant PBase variants with increased enzyme activity. To improve the safety for its potential use in regenerative medicine applications, site-specific transposition was achieved by using engineered zinc finger- and Gal4-fused PBases. An excision-prone PBase variant has also been successfully developed. Here we describe the construction of a nucleolus-predominant PBase, NP-mPB, by adding a nucleolus-predominant (NP) signal peptide from HIV-1 TAT protein to a mammalian codon-optimized PBase (mPB). Although there is a predominant fraction of the NP-mPB-tGFP fusion proteins concentrated in the nucleoli, an insertion site preference toward nucleolar organizer regions is not detected. Instead a 3–4 fold increase in piggyBac transposition efficiency is reproducibly observed in mouse and human cells. [ABSTRACT FROM AUTHOR]

We identified a novel neuroprotective compound, 1-methoxyoctadecan-1-ol, from Uncaria sinensis (Oliv.) Havil and investigated its effects and mechanisms in primary cortical neurons and in a photothrombotic ischemic model. In primary rat cortical neurons against glutamate-induced neurotoxicity, pretreatment with 1-methoxyoctadecan-1-ol resulted in significantly reduced neuronal death in a dose-dependent manner. In addition, treatment with 1-methoxyoctadecan-1-ol resulted in decreased neuronal apoptotic death, as assessed by nuclear morphological approaches. To clarify the neuroprotective mechanism of 1-methoxyoctadecan-1-ol, we explored the downstream signaling pathways of N-methyl-D-aspartate receptor (NMDAR) with calpain activation. Treatment with glutamate leads to early activation of NMDAR, which in turn leads to calpain-mediated cleavage of striatal-enriched protein tyrosine phosphatase (STEP) and subsequent activation of p38 mitogen activated protein kinase (MAPK). However, pretreatment with 1-methoxyoctadecan-1-ol resulted in significantly attenuated activation of GluN2B-NMDAR and a decrease in calpain-mediated STEP cleavage, leading to subsequent attenuation of p38 MAPK activation. We confirmed the critical role of p38 MAPK in neuroprotective effects of 1-methoxyoctadecan-1-ol using specific inhibitor SB203580. In the photothrombotic ischemic injury in mice, treatment with 1-methoxyoctadecan-1-ol resulted in significantly reduced infarct volume, edema size, and improved neurological function. 1-methoxyoctadecan-1-ol effectively prevents cerebral ischemic damage through down-regulation of calpain-mediated STEP cleavage and activation of p38 MAPK. These results suggest that 1-methoxyoctadecan-1-ol showed neuroprotective effects through down-regulation of calpain-mediated STEP cleavage with activation of GluN2B-NMDAR, and subsequent alleviation of p38 MAPK activation. In addition, 1-methoxyoctadecan-1-ol might be a useful therapeutic agent for brain disorder such as ischemic stroke. [ABSTRACT FROM AUTHOR]

Xylitol has been used as a substitute for sugar to prevent cavity-causing bacteria, and most studies have focused on its benefits in dental care. Meanwhile, the constituents of red ginseng (RG) are known to be effective in ameliorating the symptoms of influenza virus infection when they are administered orally for 14 days. In this study, we investigated the effect of dietary xylitol on influenza A virus infection (H1N1). We designed regimens containing various fractions of RG (RGs: whole extract, water soluble fraction, saponin and polysaccharide) and xylitol, and combination of xylitol with the RG fractions. Mice received the various combinations orally for 5 days prior to lethal influenza A virus infection. Almost all the mice died post challenge when xylitol or RGs were administered separately. Survival was markedly enhanced when xylitol was administered along with RGs, pointing to a synergistic effect. The effect of xylitol plus RG fractions increased with increasing dose of xylitol. Moreover, dietary xylitol along with the RG water soluble fraction significantly reduced lung virus titers after infection. Therefore, we suggest that dietary xylitol is effective in ameliorating influenza-induced symptoms when it is administered with RG fractions, and this protective effect of xylitol should be considered in relation to other diseases. [ABSTRACT FROM AUTHOR]

Background: Recent studies have suggested that essential tremor (ET) is a more complex and heterogeneous clinical entity than initially thought. In the present study, we assessed the pattern of cortical thickness and diffusion tensor white matter (WM) changes in patients with ET according to the response to propranolol to explore the pathogenesis underlying the clinical heterogeneity of ET. Methods: A total of 32 patients with drug naive ET were recruited prospectively from the Movement Disorders outpatient clinic. The patients were divided into a propranolol-responder group (n = 18) and a non-responder group (n = 14). We analyzed the pattern of cortical thickness and diffusion tensor WM changes between these two groups and performed correlation analysis between imaging and clinical parameters. Results: There were no significant differences in demographic characteristics, general cognition, or results of detailed neuropsychological tests between the groups. The non-responder group showed more severe cortical atrophy in the left orbitofrontal cortex and right temporal cortex relative to responders. However, the responders exhibited significantly lower fractional anisotropy values in the bilateral frontal, corpus callosal, and right parietotemporal WM compared with the non-responder group. There were no significant clusters where the cortical thickness or WM alterations were significantly correlated with initial tremor severity or disease duration. Conclusions: The present data suggest that patients with ET have heterogeneous cortical thinning and WM alteration with respect to responsiveness to propranolol, suggesting that propranolol responsiveness may be a predictive factor to determine ET subtypes in terms of neuroanatomical heterogeneity. [ABSTRACT FROM AUTHOR]

Background: The acute effects of grape polyphenols on endothelial function in adults are inconsistent. Here, we performed meta-analyses to determine these acute effects as measured by flow-mediated dilation (FMD). Methods: Trials were searched in PubMed, Embase and the Cochrane Library database. Summary estimates of weighted mean differences (WMDs) and 95% CIs were obtained by using random-effects models. Meta-regression and subgroup analyses were performed to identify the source of heterogeneity. The protocol details of our meta-analysis have been submitted to the PROSPERO register and our registration number is CRD42013004157. Results: Nine studies were included in the present meta-analyses. The results showed that the FMD level was significantly increased in the initial 120 min after intake of grape polyphenols as compared with controls. Meta-regression and subgroup analyses were performed and showed that a health status was the main effect modifier of the significant heterogeneity. Subgroups indicated that intake of grape polyphenols could significantly increase FMD in healthy subjects, and the increased FMD appeared to be more obviously in subjects with high cardiovascular risk factors. Moreover, the peak effect of grape polyphenols on FMD in healthy subjects was found 30 min after ingestion, which was different from the effect in subjects with high cardiovascular risk factors, in whom the peak effect was found 60 min after ingestion. Conclusions: Endothelial function can be significantly improved in healthy adults in the initial 2 h after intake of grape polyphenols. The acute effect of grape polyphenols on endothelial function may be more significant but the peak effect is delayed in subjects with a smoking history or coronary heart disease as compared with the healthy subjects. [ABSTRACT FROM AUTHOR]