Molecular insights into the effect of graphene packing on mechanical behaviors of graphene reinforced cis-1,4-polybutadiene polymer nanocomposites.
Through united-atom molecular dynamics simulations, we build a series of graphene (GP) reinforced cis-1,4-polybutadiene (cis-PB) models with two novel GP structures, intercalated and stacked GP structures, to investigate the effect of different GP packing patterns on the chain structure, chain dynamics, uniaxial tension and visco-elastic behaviors, and correlate the microscopic mechanism with macroscopic mechanical properties. Simulation results show that the interlayer polymer chains in the void of intercalated GPs are strongly confined, leading to higher bond orientation of polymer chains during the stretch process compared with monodisperse systems. And due to this restriction effect, intercalated systems exhibit higher tensile stress under large tensile strain. For stacked systems, the interaction within GP layers and the orientation of the whole stacked GP structure play dominant roles in mechanical and visco-elastic properties. Furthermore, from the results that stacked systems have higher tensile stress and intercalated systems exhibit a higher storage modulus, we can conclude that the GP-GP interaction makes greater contribution than the GP-PB interaction and the chain confinement effect to the tensile behavior, whereas the restriction and orientation of polymer chains become more crucial factors than the GP-GP interaction under shear conditions. This work may provide rational means to tune the mechanical and visco-elastic properties of GP reinforced polymer nanocomposites.


What is sphincter of Oddi dysfunction?
Ever since its description approximately 100 years ago, the sphincter of Oddi has been surrounded by controversy. First, whether it indeed existed, second, whether it had a significant physiological role in man and more recently whether abnormalities in its function give rise to a clinical syndrome. Data from animal and human studies, using sensitive techniques, have helped define the physiological role of the sphincter of Oddi, and more recent studies are determining the factors which control sphincter of Oddi function. These studies support Oddi's original description that the sphincter has a major role in the control of flow of bile and pancreatic juice into the duodenum, and equally importantly helps prevent the reflux of duodenal contents into the biliary and pancreatic ductal systems. The controversy of whether abnormalities in sphincter of Oddi motility result in clinical syndromes has not been totally resolved. Part of the difficulty has been inability to document normal and hence abnormal function of the sphincter. With the emergence of endoscopic biliary manometry as a sensitive and reproducible technique, however, the motility of the human sphincter of Oddi has come under closer scrutiny and allowed definition of possible disorders. We have used the term sphincter of Oddi dysfunction to define manometric abnormalities in patients who present with signs and symptoms consistent with a biliary or pancreatic ductal origin. Based on the manometry, we have subdivided the dysfunction into two groups; a group characterised by a stenotic pattern - that is, raised sphincter basal pressure - and a second group having a dyskinetic pattern - that is, paradoxical response to cholecystokinin injection, rapid contraction frequency, high percentage of retrograde contractions, or short periods of raised basal percentage of retrograde contractions, or short periods of raised basal pressure. It is apparent from the mamometry but also from the clinical data that the patients are a heterogeneous group and thus any therapy would need to be tailored for each patient and abnormality. The most recent therapeutic data suggest that patients with the stenotic pattern on manometry respond to division of the sphincter, however, those patients with the dyskinetic manometric pattern show no significant effect after sphincterotomy. Further prospective trials evaluating therapeutic options are under way and their results are eagerly awaited.


Letrozole in the treatment of breast cancer.
Over the last 30 years the role of tamoxifen in breast cancer treatment has been progressively expanded by clinical investigation to encompass the entire spectrum of disease from cancer chemoprevention to palliation of advanced disease. The primacy of tamoxifen for these indications in postmenopausal women is now under challenge by the selective aromatase inhibitors, a class of endocrine agent that induces oestrogen deprivation rather than oestrogen receptor blockade. This review considers the biochemical, pharmacological and clinical properties of the nonsteroidal aromatase inhibitor letrozole. This agent is superior to tamoxifen for the treatment of metastatic breast cancer, a finding that suggests that letrozole may ultimately eclipse tamoxifen for other indications, including chemoprevention. Further clinical investigation will be necessary to establish the risks and benefits of letrozole versus tamoxifen for each new indication, with adjuvant therapy being the next in line. The object of this review is to provide a reference source on the biochemical, pharmacological and clinical properties of letrozole for clinicians to consider both established and future indications.


Proapoptotic BAX and BAK regulate the type 1 inositol trisphosphate receptor and calcium leak from the endoplasmic reticulum.
Proapoptotic BCL-2 family members BAX and BAK are required for the initiation of mitochondrial dysfunction during apoptosis and for maintaining the endoplasmic reticulum (ER) Ca(2+) stores necessary for Ca(2+)-dependent cell death. Conversely, antiapoptotic BCL-2 has been shown to decrease Ca(2+) concentration in the ER. We found that Bax(-/-)Bak(-/-) double-knockout (DKO) cells have reduced resting ER Ca(2+) levels because of increased Ca(2+) leak and an increase in the Ca(2+)-permeable, hyperphosphorylated state of the inositol trisphosphate receptor type 1 (IP3R-1). The ER Ca(2+) defect of DKO cells is rescued by RNA interference reduction of IP3R-1, supporting the argument that this channel regulates the increased Ca(2+) leak in these cells. BCL-2 and IP3R-1 physically interact at the ER, and their binding is increased in the absence of BAX and BAK. Moreover, knocking down BCL-2 decreases IP3R-1 phosphorylation and ER Ca(2+) leak rate in the DKO cells. These findings support a model in which BCL-2 family members regulate IP3R-1 phosphorylation to control the rate of ER Ca(2+) leak from intracellular stores.


Electroconvulsive therapy in adolescents with intellectual disability and severe self-injurious behavior and aggression: a retrospective study.
Efficacious intervention for severe, treatment-refractory self-injurious behavior and aggression (SIB/AGG) in children and adolescents with intellectual disability and concomitant psychiatric disorders remains a complex and urgent issue. The aim of this study is to assess the efficacy of electroconvulsive therapy (ECT) on severe and treatment-resistant SIB/AGG in young people with intellectual disability and current psychiatric disorder. We reviewed the charts of all patients (N = 4) who received ECT in the context of SIB/AGG with resistance to behavioral interventions, milieu therapy and pharmacotherapy from 2007 to 2011. We scored the daily rate of SIB/AGG per patient for each hospital day. Inter rater reliability was good (intraclass correlations = 0.91). We used a mixed generalized linear model to assess whether the following explanatory variables (time, ECT) influenced the course of SIB/AGG over time, the dependant variable. The sample included two girls and two boys. The mean age at admission was 13.8 years old [range 12-14]. The patients had on average 19 ECT sessions [range 16-26] and one patient received maintenance ECT. There was no effect of time before and after ECT start. ECT was associated with a significant decrease in SIB/AGG scores (p < 0.001): mean aggression score post-ECT was half the pre-ECT value. ECT appears beneficial in severe, treatment-resistant SHBA in adolescents with intellectual disability.


A comprehensive census of microbial diversity in hot springs of Tengchong, Yunnan Province China using 16S rRNA gene pyrosequencing.
The Rehai and Ruidian geothermal fields, located in Tengchong County, Yunnan Province, China, host a variety of geochemically distinct hot springs. In this study, we report a comprehensive, cultivation-independent census of microbial communities in 37 samples collected from these geothermal fields, encompassing sites ranging in temperature from 55.1 to 93.6°C, in pH from 2.5 to 9.4, and in mineralogy from silicates in Rehai to carbonates in Ruidian. Richness was low in all samples, with 21-123 species-level OTUs detected. The bacterial phylum Aquificae or archaeal phylum Crenarchaeota were dominant in Rehai samples, yet the dominant taxa within those phyla depended on temperature, pH, and geochemistry. Rehai springs with low pH (2.5-2.6), high temperature (85.1-89.1°C), and high sulfur contents favored the crenarchaeal order Sulfolobales, whereas those with low pH (2.6-4.8) and cooler temperature (55.1-64.5°C) favored the Aquificae genus Hydrogenobaculum. Rehai springs with neutral-alkaline pH (7.2-9.4) and high temperature (>80°C) with high concentrations of silica and salt ions (Na, K, and Cl) favored the Aquificae genus Hydrogenobacter and crenarchaeal orders Desulfurococcales and Thermoproteales. Desulfurococcales and Thermoproteales became predominant in springs with pH much higher than the optimum and even the maximum pH known for these orders. Ruidian water samples harbored a single Aquificae genus Hydrogenobacter, whereas microbial communities in Ruidian sediment samples were more diverse at the phylum level and distinctly different from those in Rehai and Ruidian water samples, with a higher abundance of uncultivated lineages, close relatives of the ammonia-oxidizing archaeon "Candidatus Nitrosocaldus yellowstonii", and candidate division O1aA90 and OP1. These differences between Ruidian sediments and Rehai samples were likely caused by temperature, pH, and sediment mineralogy. The results of this study significantly expand the current understanding of the microbiology in Tengchong hot springs and provide a basis for comparison with other geothermal systems around the world.


Predictors and timing of recanalization in intracranial carotid artery and siphon dissection: an ultrasound follow-up study.
Intra- and extracranial internal carotid artery dissections (ICD) are two different pathological conditions. Extracranial dissection is considered to be among the most frequent causes of stroke in the young and the segment generally reopens in 2 out of 3 cases, completely or partially, within 6 months. Intracranial ICD (IICD) is considered a rare occurrence in stroke and, accordingly, there are few systematic published data. However, it is a clinically significant condition that may cause severely disabling ischemic stroke or subarachnoid hemorrhage. In the past, sole availability of invasive imaging methods for its detection may have induced an underreporting. The aim of the study was to analyze ultrasound findings, timing and predictors of recanalization in patients with IICD. IICD acute patients admitted to our Stroke Unit were submitted to carotid sonographic seriated monitoring, daily for the 1st week after symptom onset, at day 14, at month 1 and every 3 months thereafter up to a follow-up of 4 years. Contrast carotid ultrasound was performed in patients with persistent occlusion after month 1. Fourteen acute patients with IICD were enrolled. Extracranial internal carotid patency was observed in 8 patients at first ultrasound scans; all of these showed complete intracranial recanalization within the 1st week and oral anticoagulants were withdrawn after 6 months. Conversely, in 6 patients retrograde extracranial internal carotid thrombosis was immediately observed, since the first ultrasound scans. In 4 of these the occlusion persisted after 4 years while 2 of them had only a partial recanalization, with evidence at contrast ultrasound of still late remodeling processes in the extracranial thrombus up to 2 years after the first observation; for this reason, in these 2 patients anticoagulation was not discontinued, while in the 4 patients with persistent, stable, occlusion, therapy was suspended 1 year after the diagnosis. Identification of the site of dissection - i.e. extra- versus intracranial - is fundamental in clinical studies for outcome and prognosis evaluation. Carotid ultrasound strict surveillance is important to monitor eventual recanalization in patients with ICD, even in a late phase. Retrograde internal carotid thrombosis seems to be correlated with persistent occlusion and partial recanalization. Remodeling of thrombotic material in the internal carotid artery may, however, continue for up to 2 years. In these cases, contrast ultrasound evidence of thrombus morphological changes may support the decision to continue anticoagulation.


Bootstrapping least-squares estimates in biochemical reaction networks.
The paper proposes new computational methods of computing confidence bounds for the least-squares estimates (LSEs) of rate constants in mass action biochemical reaction network and stochastic epidemic models. Such LSEs are obtained by fitting the set of deterministic ordinary differential equations (ODEs), corresponding to the large-volume limit of a reaction network, to network's partially observed trajectory treated as a continuous-time, pure jump Markov process. In the large-volume limit the LSEs are asymptotically Gaussian, but their limiting covariance structure is complicated since it is described by a set of nonlinear ODEs which are often ill-conditioned and numerically unstable. The current paper considers two bootstrap Monte-Carlo procedures, based on the diffusion and linear noise approximations for pure jump processes, which allow one to avoid solving the limiting covariance ODEs. The results are illustrated with both in-silico and real data examples from the LINE 1 gene retrotranscription model and compared with those obtained using other methods.


Nonlinear dynamics of superparamagnetic beads in a traveling magnetic-field wave.
The nonlinear dynamic behavior of superparamagnetic beads exposed to a periodic array of micromagnets and an external rotating field is simulated as a function of the relative size of the bead with respect to the micromagnet size and the strength of the external field relative to the pole density of the substrate. For large bead sizes, it is confirmed that the motion of the beads corresponds to the dynamics of an overdamped nonlinear harmonic oscillator. For lower bead sizes, additional subharmonic locking effects are observed along with the emergence of bounded orbits. These results qualitatively support previous experimental investigations of traveling-wave magnetophoresis and provide guidelines for achieving nearly infinite separation resolution between differently sized beads.


The Green, Amber, Red Delineation of Risk and Need (GARDIAN) management system: a pragmatic approach to optimizing heart health from primary prevention to chronic disease management.
A sustained epidemic of cardiovascular disease and related risk factors is a global phenomenon contributing significantly to premature deaths and costly morbidity. Preventative strategies across the full continuum of life, from a population to individual perspective, are not optimally applied. This paper describes a simple and adaptable 'traffic-light' system we have developed to systematically perform individual risk and need delineation in order to 'titrate' the intensity and frequency of healthcare intervention in a cost-effective manner. The GARDIAN (Green Amber Red Delineation of Risk and Need) system is an individual assessment of risk and need that modulates the frequency and intensity of future healthcare intervention. Individual assessment of risk and need for ongoing intervention and support is determined with reference to three domains: (1) clinical stability, (2) gold-standard management, and (3) a broader, holistic assessment of individual circumstance. This can be applied from a primary prevention, secondary prevention, or chronic disease management perspective. Our experience with applying and validating GARDIAN to titrate healthcare resources according to need has been extensive to date, with >5000 individuals profiled in a host of clinical settings. A series of clinical randomized trials will determine the impact of the GARDIAN system on important indices of healthcare utilization and health status. The GARDIAN model to delineating risk and need for varied intensity of management shows strong potential to cost effectively improve health outcomes for both individuals at risk of heart disease and those with established heart disease.


Viewpoints: feeding mechanics, diet, and dietary adaptations in early hominins.
Inference of feeding adaptation in extinct species is challenging, and reconstructions of the paleobiology of our ancestors have utilized an array of analytical approaches. Comparative anatomy and finite element analysis assist in bracketing the range of capabilities in taxa, while microwear and isotopic analyses give glimpses of individual behavior in the past. These myriad approaches have limitations, but each contributes incrementally toward the recognition of adaptation in the hominin fossil record. Microwear and stable isotope analysis together suggest that australopiths are not united by a single, increasingly specialized dietary adaptation. Their traditional (i.e., morphological) characterization as "nutcrackers" may only apply to a single taxon, Paranthropus robustus. These inferences can be rejected if interpretation of microwear and isotopic data can be shown to be misguided or altogether erroneous. Alternatively, if these sources of inference are valid, it merely indicates that there are phylogenetic and developmental constraints on morphology. Inherently, finite element analysis is limited in its ability to identify adaptation in paleobiological contexts. Its application to the hominin fossil record to date demonstrates only that under similar loading conditions, the form of the stress field in the australopith facial skeleton differs from that in living primates. This observation, by itself, does not reveal feeding adaptation. Ontogenetic studies indicate that functional and evolutionary adaptation need not be conceptually isolated phenomena. Such a perspective helps to inject consideration of mechanobiological principles of bone formation into paleontological inferences. Finite element analysis must employ such principles to become an effective research tool in this context.


Social Support, Sexual Violence, and Transactional Sex Among Female Transnational Migrants to South Africa.
To examine the relationship between sexual violence and transactional sex and assess the impact of social support on this relationship among female transnational migrants in Cape Town, South Africa. In 2012 we administered a behavioral risk factor survey using respondent-driven sampling to transnational migrant women aged between 16 and 39 years, born outside South Africa, living in Cape Town, and speaking English, Shona, Swahili, Lingala, Kirundi, Kinyarwanda, French, or Somali. Controlling for study covariates, travel-phase sexual violence was positively associated with engagement in transactional sex (adjusted prevalence ratio [APR] = 1.38; 95% confidence interval [CI] = 1.07, 1.77), and social support was shown to be a protective factor (APR = 0.84; 95% CI = 0.75, 0.95). The interaction of experienced sexual violence during migration and social support score was APR = 0.85 (95% CI = 0.66, 1.10). In the stratified analysis, we found an increased risk of transactional sex among the low social support group (APR = 1.56; 95% CI = 1.22, 2.00). This relationship was not statistically significant among the moderate or high social support group (APR = 1.04; 95% CI = 0.58, 1.87). Programs designed to strengthen social support may reduce transactional sex among migrant women after they have settled in their receiving communities.


Translationally invariant colloidal crystal templates.
We show that dynamic, feed-back controlled optical traps, whose positions depend on the instantaneous local configuration of particles in a pre-determined way, can stabilise colloidal particles in finite lattices of any given symmetry. Unlike in a static template, the crystal so formed is invariant under uniform translations and retains all possible zero energy modes. We demonstrate this in silico by stabilising the unstable two-dimensional square lattice in a model soft solid with isotropic interactions.


X-Point-Position-Dependent Intrinsic Toroidal Rotation in the Edge of the TCV Tokamak.
Edge intrinsic rotation was investigated in Ohmic L-mode discharges on the Tokamak à Configuration Variable, scanning the major radial position of the X point, R(X). Edge rotation decreased linearly with increasing R(X), vanishing or becoming countercurrent for an outboard X point, in agreement with theoretical expectations. The core rotation profile shifted fairly rigidly with the edge rotation, changing the central rotation speed by more than a factor of two. Core rotation reversals had little effect on the edge rotation velocity. Edge rotation was modestly more countercurrent in unfavorable than favorable ∇B shots.


Effect of a dental cream containing amorphous cream phosphate complexes on white spot lesion regression assessed by laser fluorescence.
To investigate and compare the effects of a dental cream containing complexes of casein phosphoprotein-amorphous calcium phosphate (CPP-ACP) and fluoride mouthwashes on the regression of white spot lesions (WSL). The study group consisted of 26 healthy adolescents (mean age 14.6 years) exhibiting 60 teeth with 152 visible WSL sites on incisors and canines immediately after debonding of fixed orthodontic appliances. After bracket removal, professional tooth cleaning and drying, a visual scoring (0-4) and laser fluorescence (LF) readings were carried out. The patients were randomly assigned to two different treatment protocols with the aim of remineralising the lesions: A) daily topical applications of a dental cream containing CPP-ACP (Topacal) for 3 months followed by a 3-month period of daily toothbrushing with fluoridated dentifrice, or B) daily 0.05% sodium fluoride mouthwash combined with fluoridated dentifrice for 6 months. The registrations were repeated after 1, 3, 6 and 12 months and follow-up data were compared with baseline with aid of chi-square and paired t-tests. A significant improvement of the clinical WSL-scores was found over time in both groups, but there was a statistically significant difference (p < 0.01) concerning the number of sites that totally disappeared after 12 months in favour of the CPP-ACP regime, 63% compared with 25% respectively. The clinical registrations were mirrored by a statistically significant decrease (p < 0.05) in the LF readings at the 6- and 12-month follow-ups compared with baseline. No significant differences were displayed between the groups. Clinical scoring and LF assessment suggested that both regimens could promote regression of WSL after debonding of fixed orthodontic appliances. The visual evaluation suggested an aesthetically more favourable outcome of the amorphous calcium phosphate treatments.


The atropine factor in pharmacologic stress echocardiography. Echo Persantine (EPIC) and Echo Dobutamine International Cooperative (EDIC) Study Groups.
This study sought to compare, head to head, the two most popular pharmacologic stress echocardiographic tests--dipyridamole and dobutamine--with state of the art protocols in a large multicenter prospective study. In the continuing quest for ideal diagnostic accuracy, pharmacologic stress echocardiography has quickly moved over the years from low to high dose regimens and is currently performed with atropine coadministration. Dobutamine (up to 40 microgram/kg body weight per min) plus atropine (up to 1 mg over 4 h) and dipyridamole (up to 0.84 mg/kg per min over 10 h) plus atropine (up to 1 mg over 4 h) stress echocardiography was performed on different days, in random order and within 1 week in 360 patients with chest pain syndrome. Thirteen different echocardiographic laboratories, all fulfilling quality control criteria for stress echocardiographic reading, contributed to the study. No major complications occurred during either test. The test was interrupted before achievement of predetermined end points for limiting side effects in 37 dobutamine-atropine and 7 dipyridamole-atropine stress echocardiographic studies (feasibility 90% vs. 98%, p < 0.01). Diagnostic accuracy was assessed in a subset of 110 patients with no obvious rest dyssynergy (akinesia or dyskinesia) who underwent coronary angiography independently of test results and within 1 week of testing. Significant coronary artery disease (> or = 50% diameter reduction in at least one major coronary vessel by quantitative coronary angiography) was found in 92 patients. Sensitivity for detection of coronary artery disease was 84% (77 of 92) for dobutamine-atropine and 82% (75 of 92) for dipyridamole-atropine stress echocardiography (p = NS), with a specificity of 89% (16 of 18) for dobutamine-atropine and 94% (17 of 18) for dipyridamole-atropine stress echocardiography (p = NS). A significant correlation was present between peak wall motion score index during dipyridamole-atropine and dobutamine-atropine stress echocardiography (r = 0.83, p < 0.0001). Dobutamine-atropine and dipyridamole-atropine stress echocardiography are safe and feasible, although submaximal studies are more frequent with dobutamine. The two stresses have comparable accuracy in the detection of angiographically assessed coronary artery disease, although dobutamine is marginally more sensitive and dipyridamole marginally more specific. Stratification of the ischemic response in the space domain is also comparable with the two stresses.


The Relationship between Insecure Attachment to Depression: Mediating Role of Sleep and Cognitive Reappraisal.
Previously, we have shown that neuromodulators are important factors in stress-induced emotional disorders, such as depression, for example, serotonin is the major substance for depression. Many psychological studies have proved that depression is due to insecure attachment. In addition, sleep is a major symptom of depression. Furthermore, serotonin is the substrate for both sleep and depression. To explore the role of sleep in the relationships between insecure attachment and depression, we investigated 755 college students with Close Relationship Inventory, Emotion Regulation Questionnaire, Self-rated Depression Scale, and Pittsburgh Sleep Quality Index. The results showed that (1) insecure attachment positively predicted poor sleep quality; (2) sleep quality partially affected depression, possibly due the same stress neuromodulators such as norepinephrine and cortisol; and (3) cognitive reappraisal moderated the mediating path leading from attachment anxiety to poor sleep quality. These findings highlight the moderating role of cognitive reappraisal in the effects of attachment anxiety on sleep quality and finally on depression. In conclusion, sleep quality links attachment anxiety and emotional disorders.


Ganoderic acid A potentiates the antioxidant effect and protection of mitochondrial membranes and reduces the apoptosis rate in primary hippocampal neurons in magnesium free medium.
Ganoderma lucidum extracts have shown antiepileptic effects in in vivo and in vitro studies. In this work, primary hippocampal neurons cultured in magnesium-free medium were used to study the neuroprotective effects of ganoderic acid A and B (GA-A and GA-B) on superoxide dismutase (SOD) activity and mitochondrial membrane potential, to improve our understanding of their antiepileptic effect. The activity of SOD was determined by the xanthine oxidase assay, the variations of mitochondrial membrane potential and cell apoptosis were measured by JC-1 fluorescent staining and flow cytometry. It was found that the SOD activity and mitochondrial membrane potential (118.84 U/mg protein and 244.08 Δψm) of the epileptic hippocampal neurons were significantly lower than control values (135.95 U/mg protein and 409.81 Δψm), associated with an increase of cell apoptosis (31.88% vs. 8.84%). These circumstances can be improved by treatment of GA-A/GA-B (for SOD, 127.15±3.82 / 120.52±4.30 U/mg protein; for membrane potential (Δψm), 372.35 / 347.28; and for cell apoptosis (%), 14.93 / 20.52). Results indicated that GA-A significantly improved SOD activity, while both GA-A/GA-B tranquillized the mitochondrial membrane potential of hippocampal neurons, and thereby protected these neurons by inhibiting apoptosis.


Perrault syndrome with neurological features in a compound heterozygote for two TWNK mutations: overlap of TWNK-related recessive disorders.
Perrault syndrome is a rare autosomal recessive disorder that is characterized by the association of sensorineural hearing impairment and ovarian dysgenesis in females, whereas males have only hearing impairment. In some cases, patients present with a diversity of neurological signs. To date, mutations in six genes are known to cause Perrault syndrome, but they do not explain all clinically-diagnosed cases. In addition, the number of reported cases and the spectra of mutations are still small to establish conclusive genotype-phenotype correlations. Affected siblings from family SH19, who presented with features that were suggestive of Perrault syndrome, were subjected to audiological, neurological and gynecological examination. The genetic study included genotyping and haplotype analysis for microsatellite markers close to the genes involved in Perrault syndrome, whole-exome sequencing, and Sanger sequencing of the coding region of the TWNK gene. Three siblings from family SH19 shared similar clinical features: childhood-onset bilateral sensorineural hearing impairment, which progressed to profound deafness in the second decade of life; neurological signs (spinocerebellar ataxia, polyneuropathy), with onset in the fourth decade of life in the two females and at age 20 years in the male; gonadal dysfunction with early cessation of menses in the two females. The genetic study revealed two compound heterozygous pathogenic mutations in the TWNK gene in the three affected subjects: c.85C>T (p.Arg29*), previously reported in a case of hepatocerebral syndrome; and a novel missense mutation, c.1886C>T (p.Ser629Phe). Mutations segregated in the family according to an autosomal recessive inheritance pattern. Our results further illustrate the utility of genetic testing as a tool to confirm a tentative clinical diagnosis of Perrault syndrome. Studies on genotype-phenotype correlation from the hitherto reported cases indicate that patients with Perrault syndrome caused by TWNK mutations will manifest neurological signs in adulthood. Molecular and clinical characterization of novel cases of recessive disorders caused by TWNK mutations is strongly needed to get further insight into the genotype-phenotype correlations of a phenotypic continuum encompassing Perrault syndrome, infantile-onset spinocerebellar ataxia, and hepatocerebral syndrome.


Fungal and bacterial utilization of organic substrates depends on substrate complexity and N availability.
There is growing evidence of a direct relationship between microbial community composition and function, which implies that distinct microbial communities vary in their functional properties. The aim of this study was to determine whether differences in initial substrate utilization between distinct microbial communities are due to the activities of certain microbial groups. We performed a short-term experiment with beech forest soils characterized by three different microbial communities (winter and summer community, and a community from a tree-girdling plot). We incubated these soils with different (13) C-labelled substrates with or without inorganic N addition and analyzed microbial substrate utilization by (13) C-phospholipid fatty acid (PLFA) analysis. Our results revealed that the fate of labile C (glucose) was similar in the three microbial communities, despite differences in absolute substrate incorporation between the summer and winter community. The active microbial community involved in degradation of complex C substrates (cellulose, plant cell walls), however, differed between girdling and control plots and was strongly affected by inorganic N addition. Enhanced N availability strongly increased fungal degradation of cellulose and plant cell walls. Our results indicate that fungi, at least in the presence of a high N supply, are the main decomposers of polymeric C substrates.


News on the molecular regulation and function of hepatic low-density lipoprotein receptor and LDLR-related protein 1.
Clearing of atherogenic lipoprotein particles by the liver requires hepatic low-density lipoprotein receptor (LDLR) and LDLR-related protein 1 (LRP1). This review highlights recent studies that have expanded our understanding of the molecular regulation and metabolic functions of LDLR and LRP1 in the liver. Various proteins orchestrate the intracellular trafficking of LDLR and LRP1. After internalization, the receptors are redirected via recycling endosomes to the cell surface. Several new endocytic proteins that facilitate the endosomal trafficking of LDLR and consequently the clearance of circulating LDL cholesterol have recently been reported. Mutations in some of these proteins cause hypercholesterolemia in human. In addition, LRP1 controls cellular cholesterol efflux by modulating the expression of ABCA1 and ABCG1, and hepatic LRP1 protects against diet-induced hepatic insulin resistance and steatosis through the regulation of insulin receptor trafficking. LDLR and LRP1 have prominent roles in cellular and organismal cholesterol homeostasis. Their functioning, including their trafficking in the cell, is controlled by numerous proteins. Comprehensive studies into the molecular regulation of LDLR and LRP1 trafficking have advanced our fundamental understanding of cholesterol homeostasis, and these insights may lead to novel therapeutic strategies for atherosclerosis, hyperlipidemia and insulin resistance in the future.


p53 mutations in human lung tumors.
Mutation of one p53 allele and loss of the normal p53 allele [loss of heterozygosity (LOH)] occur in many tumors including lung cancers. These alterations apparently contribute to development of cancer by interfering with the tumor suppressor activity of p53. We directly sequenced amplified DNA in the mutational hot spots (exons 4-8) of p53 in DNA samples from 40 lung cancers. Most (31 of 40) samples were preselected for LOH in the region of p53. We detected 23 p53 mutations within these exons in 22 lung cancers; no p53 mutations were found in normal tissue of the patients. One-half of the mutations were G to T transversions on the nontranscribed strand, consistent with mutagenesis by tobacco smoke. Mutations of C to A on the nontranscribed strand, which would result from G to T mutations on the transcribed strand, were detected only in one sample. Three of 23 mutations were nonsense mutations; to date, nonsense mutations of p53 have not been reported in lung cancer. Mutation of this p53-coding region was detected in 20 of 27 small cell lung cancer samples, representing a 70% occurrence. Mutation of the p53 gene is apparently very frequent in small cell lung cancers. When LOH in the p53 region could be determined, complete concordance occurred between a sample having both a p53 mutation and LOH in the region of p53 (18 of 18 samples). Twelve samples of lung cancer had LOH in the region of p53, but the samples had no detectable p53 mutations, suggesting either alterations outside the known mutational hot spots of p53 or alterations of another unidentified tumor suppressor gene in the region of p53.


A New Schizophrenia Model: Immune Activation is Associated with the Induction of Different Neurotoxic Products which Together Determine Memory Impairments and Schizophrenia Symptom Dimensions.
Recently, we reported that stable-phase schizophrenia is characterized by two interrelated symptom dimensions: PHEMN (psychotic, hostility, excitation, mannerism and negative symptoms); and DAPS (depressive, anxiety and physio-somatic symptoms) and that Major Neuro-Cognitive psychosis (MNP) is the full-blown phenotype of schizophrenia (largely overlapping with deficit schizophrenia). Herein we examined the effects of immune activation in association with tryptophan catabolite (TRYCAT) patterning and memory disorders on PHEMN/DAPS dimensions and MNP. Serum levels of macrophage inflammatory protein-1 (MIP-1), soluble interleukin (IL)-1 receptor antagonist (sIL-1RA), IL-10, eotaxin, IgA/IgM responses to TRYCATs, and Consortium to Establish a Registry for Alzheimer's disease (CERAD) tests were assessed in 40 controls and 80 schizophrenia patients. Schizophrenia and MNP were predicted by significantly increased levels of IL-10, eotaxin and TRYCATs. A large part of variance in both PHEMN/DAPS symptom dimensions (42.8%) was explained by cytokine levels and TRYCATs combined. The MIP+sIL-1RA+IL-10 composite score and eotaxin explained each around on the basis of 19% of the variance in symptom dimensions, and approximately 18% of memory deficits. Moreover, MIP+sIL-1RA+IL-10 was significantly associated with elevations in picolinic acid, xanthurenic acid and 3-OH-kynurenine. Partial Least Squares path modeling shows that highly significant effects of MIP+sIL-1RA+IL-10 on symptomatology are mediated by the effects of noxious TRYCATs on memory deficits. Current findings indicate that in schizophrenia, immune activation may underpin activation of indoleamine-2,3-dioxygenase and kynurenine monooxygenase, while impairments in episodic and semantic memory may be caused by the neurotoxic effects of TRYCATs and eotaxin. The combined effects of immune activation, eotaxin and memory defects determine to a large extent, PHEMN/DAPS symptoms and the MNP phenotype. These findings indicate that schizophrenia phenomenology is largely mediated by multiple neuro-immune pathways and that immune activation, increased production of eotaxin and neurotoxic TRYCATs (picolinic acid, xanthurenic acid and 3-HOkynurenine) are new drug targets in schizophrenia and MNP.


Excess prevalence of Pneumocystis carinii pneumonia in patients treated for lymphoma with combination chemotherapy.
A significantly greater prevalence of interstitial pulmonary infiltrates and Pneumocystis carinii pneumonitis occurred on one arm of a randomized study comparing ProMACE-CytaBOM (prednisone, methotrexate with leucovorin, doxorubicin, cyclophosphamide, etoposide; cytarabine, bleomycin, vincristine, methotrexate with leucovorin) to ProMACE-MOPP (ProMACE, mechlorethamine, vincristine, prednisone, procarbazine) chemotherapy in patients with lymphoma. Of the 37 patients receiving ProMACE-CytaBOM, 13 (35.1%) developed an interstitial pulmonary infiltrate compared with 3 of 32 (9.4%) patients receiving ProMACE-MOPP (p2 = 0.02). Of the 13 patients receiving ProMACE-CytaBOM who had infiltrates, open lung biopsy in 7 showed P. carinii; 5 others had clinically suspected P. carinii pneumonia, and 1 had blastomycosis. No patient receiving ProMACE-MOPP had documented or suspected P. carinii pneumonia. Of patients with infiltrates, 3 of 13 on ProMACE-CytaBOM but 0 of 3 on ProMACE-MOPP died. Two other patients on ProMACE-CytaBOM who had P. carinii pneumonia died. Groups did not differ in predisposing risk factors or patient history. The exact cause for the increased prevalence of P. carinii infection in patients receiving ProMACE-CytaBOM was not ascertained. These data emphasize that new drug regimens may lead to unanticipated complications.


Cognitive-Behavioral Therapy for College Students With ADHD: Temporal Stability of Improvements in Functioning Following Active Treatment.
Objective: This study examined the extent to which college students with ADHD continued to benefit from a cognitive-behavioral therapy (CBT) program beyond the active phase of treatment. Method: In successive cohorts over a 4-year period, a total of 88 college students with well-defined ADHD received CBT in an open clinical trial format that included active treatment and maintenance phases delivered across two consecutive semesters. Results: Immediately following active treatment, participants displayed statistically significant reductions in ADHD symptoms, improvements in executive functioning, and declines in anxiety and depression symptoms. Although grade point average did not improve significantly, there were statistically significant increases in the number of credit hours that participants attempted and earned across active treatment. Improvements in symptom severity, executive functioning, and educational functioning remained stable 5 to 7 months after active treatment concluded. Conclusion: Findings from this study support the use of CBT interventions for college students with ADHD.


Diffusion-weighted MR imaging of the brain: value of differentiating between extraaxial cysts and epidermoid tumors.
This study demonstrates the use of diffusion-weighted MR imaging in improving the specificity of the diagnosis of extraaxial brain tumors. Three surgically proved lesions (one arachnoid cyst and two epidermoid tumors) and two nonsurgically proved lesions (arachnoid and ependymal cysts) were evaluated with T1- and T2-weighted spin-echo studies followed by intravoxel incoherent motion (IVIM) MR imaging. The IVIM images of the lesions were displayed as an apparent diffusion coefficient (ADC) image obtained at 0.65 G/cm (maximum gradient b value = 100 sec/mm2) and compared with external oil and water phantoms. The ADC of arachnoid cysts was similar to stationary water whereas the ADC of epidermoid tumors was similar to brain parenchyma, indicating the solid nature and the slower diffusion rate of the epidermoid tumors. Cisternal CSF demonstrated uniformly high ADC, primarily because of bulk flow, which enhanced image contrast. Improved delineation of postsurgical changes was also possible. Our preliminary results show that diffusion-weighted MR imaging can be useful in distinguishing between arachnoid cysts and epidermoid tumors.


Visualization of pelvic floor reflex and voluntary contractions.
Visualization of the geometric deformation and associated displacement patterns of tubular abdominal organs to mechanical stimuli provides a quantitative measure that is useful in modeling their elastic properties. The origin of the stimulus may be the result of direct and voluntary muscle contraction or in response to a triggered reflex activity. Using trans-perineal 2D ultrasound imaging we examined the characteristics of deformation and displacement of these organs in response to voluntary activity, contraction, straining, and fast reflex responses to stimuli such as coughing. The relative time sequence in movement was examined by serially segmenting the outline of these structures and mapping their temporal characteristics.


Exploring the Factors Affecting the Mechanical Properties of 2D Hybrid Organic-Inorganic Perovskites.
Mechanical stability of hybrid organic-inorganic perovskites (HOIPs) is essential to achieve long-term durable HOIP-based devices. While HOIPs in two-dimensional (2D) form offer numerous options in the structure and composition to tune their mechanical properties, little is known about the structure-mechanical-property relationship in this family of materials. Here, we investigated a series of 2D lead halide HOIPs by nanoindentation to explore the impact of critical factors controlling the properties of both the organic and inorganic layers on the materials' out-of-plane mechanical performance. We find that the lead-halide bond in the inorganic framework can significantly influence the mechanical properties of 2D Ruddlesden-Popper (RP) HOIPs with n = 1. Like 3D HOIPs, stronger lead-halide bond strength leads to a higher Young's modulus in these 2D HOIPs, i.e., E⊥Cl ≳ E⊥Br > E⊥I. In contrast, the hardness of 2D RP HOIPs follows a trend of HBr2D > HCl2D > HI2D, which is different from that found in 3D HOIPs, probably due to the combined effects from the Pb-X bond strength and inorganic framework structural change (e.g., symmetry and distortion). We further show that the interface between the organic layers in 2D HOIPs can be an effective route to engineer the materials' mechanical properties. Replacing the weak CH3-CH3 van der Waals forces by covalent bonds or phenyl-phenyl interactions in the interface can lead to a much stiffer and harder 2D HOIPs. Finally, we discover that the mechanical performance of 2D HOIPs with linear aliphatic diammonium spacer molecules is affected by the two basic structural parameters, i.e., the thicknesses of the organic and inorganic layers, in a similar way compared to that of 2D RP HOIPs with linear aliphatic monoammonium spacer molecules. A thinner organic layer and a thicker inorganic layer can result in 2D HOIPs with larger elastic modulus and hardness values. Our results offer intriguing insights into the structure-property relationship of 2D HOIPs from a mechanical perspective, providing guidelines and inspirations to achieve material design with required mechanical properties for applications.


Mutations that affect membrane receptor for LDL are useful for studying normal receptor function.
Low-density lipoprotein (LDL), the major plasma cholesterol transport protein, is taken up by cells through a receptor-mediated process. After internalization through specialized segments of the cell surface called coated pits, the LDL is degraded in the lysosome and the released cholesterol is used by cells to meet various metabolic needs. The discovery of the LDL receptor and the studies of its function have provided new insights into both the biochemical aspects of cholesterol metabolism and the cell biology of receptor-mediated endocytosis. Of paramount importance in all of these studies has been the availability of human cells that express one or more allelic mutations that affect the function of the LDL receptor. These mutations have been valuable for assessing normal receptor function. Just as important, these mutations have been used as a reference point in the development of various cytochemical and biochemical techniques for studying receptor activity.


Nurse-delivered sleep restriction therapy in primary care for adults with insomnia disorder: a mixed-methods process evaluation.
Sleep restriction therapy (SRT) is a behavioural therapy for insomnia. To conduct a process evaluation of a randomised controlled trial comparing SRT delivered by primary care nurses plus a sleep hygiene booklet with the sleep hygiene booklet only for adults with insomnia disorder. A mixed-methods process evaluation in a general practice setting. Semi-structured interviews were conducted in a purposive sample of patients receiving SRT, the practice nurses who delivered the therapy, and also GPs or practice managers at the participating practices. Qualitative data were explored using framework analysis, and integrated with nurse comments and quantitative data, including baseline Insomnia Severity Index score and serial sleep efficiency outcomes to investigate the relationships between these. In total, 16 patients, 13 nurses, six practice managers, and one GP were interviewed. Patients had no previous experience of behavioural therapy, needed flexible appointment times, and preferred face-to-face consultations; nurses felt prepared to deliver SRT, accommodating patient concerns, tailoring therapy, and negotiating sleep timings despite treatment complexity and delays between training and intervention delivery. How the intervention produced change was explored, including patient and nurse interactions and patient responses to SRT. Difficulties maintaining SRT, negative attitudes towards treatment, and low self-efficacy were highlighted. Contextual factors, including freeing GP time, time constraints, and conflicting priorities for nurses, with suggestions for alternative delivery options, were raised. Participants who found SRT a positive process showed improvements in sleep efficiency, whereas those who struggled did not. SRT was successfully delivered by practice nurses and was generally well received by patients, despite some difficulties delivering and applying the intervention in practice.


Temporal aspects of the visuotactile congruency effect.
We report an experiment designed to investigate the temporal dynamics of the visuotactile crossmodal congruency effect. Vibrotactile targets were presented randomly to the index finger (top side of a hand-held cube) or thumb (bottom side) of either hand while visual distractors were presented randomly from one of the same four possible locations. The stimulus onset asynchrony (SOA) between the vibrotactile target and the visual distractor was varied on a trial-by-trial basis. Participants made speeded discrimination responses regarding the elevation of the vibrotactile targets (i.e., upper versus lower) while trying to ignore the visual distractors. The largest crossmodal congruency effects (defined as the difference in performance between incongruent and congruent elevation distractor trials) were obtained when the visual distractor preceded the vibrotactile target by 50-100 ms, although significant effects were also reported when the distractor followed the target by as much as 100 ms. These results are discussed in terms of the conjoint influence of response competition, crossmodal perceptual interactions (i.e., the ventriloquism effect), and exogenous spatial attention on the crossmodal congruency effect. The distinct temporal signatures of each of these effects are also highlighted.


Masseteric-facial nerve neurorrhaphy: results of a case series.
OBJECTIVE Facial palsy is a well-known functional and esthetic problem that bothers most patients and affects their social relationships. When the time between the onset of paralysis and patient presentation is less than 18 months and the proximal stump of the injured facial nerve is not available, another nerve must be anastomosed to the facial nerve to reactivate its function. The masseteric nerve has recently gained popularity over the classic hypoglossus nerve as a new motor source because of its lower associated morbidity rate and the relative ease with which the patient can activate it. The aim of this work was to evaluate the effectiveness of masseteric-facial nerve neurorrhaphy for early facial reanimation. METHODS Thirty-four consecutive patients (21 females, 13 males) with early unilateral facial paralysis underwent masseteric-facial nerve neurorrhaphy in which an interpositional nerve graft of the great auricular or sural nerve was placed. The time between the onset of paralysis and surgery ranged from 2 to 18 months (mean 13.3 months). Electromyography revealed mimetic muscle fibrillations in all the patients. Before surgery, all patients had House-Brackmann Grade VI facial nerve dysfunction. Twelve months after the onset of postoperative facial nerve reactivation, each patient underwent a clinical examination using the modified House-Brackmann grading scale as a guide. RESULTS Overall, 91.2% of the patients experienced facial nerve function reactivation. Facial recovery began within 2-12 months (mean 6.3 months) with the restoration of facial symmetry at rest. According to the modified House-Brackmann grading scale, 5.9% of the patients had Grade I function, 61.8% Grade II, 20.6% Grade III, 2.9% Grade V, and 8.8% Grade VI. The morbidity rate was low; none of the patients could feel the loss of masseteric nerve function. There were only a few complications, including 1 case of postoperative bleeding (2.9%) and 2 local infections (5.9%), and a few patients complained about partial loss of sensitivity of the earlobe or a small area of the ankle and foot, depending on whether great auricular or sural nerves were harvested. CONCLUSIONS The surgical technique described here seems to be efficient for the early treatment of facial paralysis and results in very little morbidity.


GI domain-mediated association of the eukaryotic initiation factor 2alpha kinase GCN2 with its activator GCN1 is required for general amino acid control in budding yeast.
In response to the starvation of a single amino acid, the budding yeast Saccharomyces cerevisiae activates numerous genes involved in various amino acid biosynthetic pathways, all of which are under the control of transcription factor GCN4. This general amino acid control response is based on de-repressed translation of GCN4 mRNA, which is induced by the activation of the eIF2alpha kinase, GCN2. Although it is known that in vivo activation of GCN2 requires GCN1, the mode of GCN1 action remains to be elucidated at the molecular level. Here, we show that GCN2 interacts with GCN1 via the GI domain, a novel protein-binding module that occurs at the N terminus; mutations to conserved residues of this domain abolish its binding to GCN1. Furthermore, the yeast cells with GCN2 defective in interaction with GCN1 fail to display general control response. A similar phenotype is observed in cells overexpressing the GI domain of GCN2 or its target region on GCN1. Thus, GI domain-mediated association of GCN2 to GCN1 is required for general amino acid control. This finding provides the first insight into the molecular mechanism for the activation of GCN2 by GCN1.


Effects of antipsychotic medications on appetite, weight, and insulin resistance.
Although clozapine, olanzapine, and other atypical antipsychotic drugs (APDs) have fewer extrapyramidal side effects, they have serious metabolic side effects such as substantial weight gain, intra-abdominal obesity, and type 2 diabetes mellitus. Given that most patients with mental disorders face chronic, even life-long, treatment with APDs, the risks of weight gain/obesity and other metabolic symptoms are major considerations for APD maintenance treatment. This review focuses on the effects of APDs on weight gain, appetite, insulin resistance, and glucose dysregulation, and the relevant underlying mechanisms that may be help to prevent and treat metabolic side effects caused by APD therapy.


Visualization and quantification of glycolipid polarity dynamics in the plasma membrane of the mammalian spermatozoon.
Seminolipid (sulphogalactosylalkylacylglycerol), the glycolipid that is specific for mammalian germ cells, is located exclusively in the outer leaflet of the sperm plasma membrane. In this study the lateral distribution of seminolipid on sperm heads has been investigated by indirect immunofluorescence labelling and detection with digital imaging fluorescence microscopy. In freshly ejaculated sperm cells this glycolipid was present primarily at the apical ridge subdomain of the plasma membrane of the sperm head. After binding the sperm cells to zona-coated coverslips seminolipid migrated, in 40 minutes, from the apical ridge to the equatorial subdomain of the plasma membrane. A similar redistribution of seminolipid was observed during capacitation of sperm cells in vitro induced by Ca2+ or bovine serum albumin. Comparable migration of seminolipid was also found after prolonged storage of ejaculated sperm cells, albeit at a much slower rate. Addition of arylsulphatase A, an enzyme present in seminal plasma that desulphates seminolipid, significantly enhanced the migration of seminolipid during storage of sperm cells. Its breakdown product desulphoseminolipid (galactosylalkylacylglycerol) appeared highly specifically at the equatorial segment. The measured fluorescence intensity over the sperm head surface correlated linearly with the spatial probe distribution as was checked by fluorescence lifetime imaging microscopy. This paper demonstrates and quantifies for the first time the polarity of seminolipid on the surface of the sperm cell and the dynamic alterations that occur in this polarity during post-ejaculatory events.


Four-dimensional microscope- integrated optical coherence tomography to enhance visualization in glaucoma surgeries.
We report the first use of swept-source microscope-integrated optical coherence tomography (SS-MIOCT) capable of live four-dimensional (4D) (three-dimensional across time) imaging intraoperatively to directly visualize tube shunt placement and trabeculectomy surgeries in two patients with severe open-angle glaucoma and elevated intraocular pressure (IOP) that was not adequately managed by medical intervention or prior surgery. We performed tube shunt placement and trabeculectomy surgery and used SS-MIOCT to visualize and record surgical steps that benefitted from the enhanced visualization. In the case of tube shunt placement, SS-MIOCT successfully visualized the scleral tunneling, tube shunt positioning in the anterior chamber, and tube shunt suturing. For the trabeculectomy, SS-MIOCT successfully visualized the scleral flap creation, sclerotomy, and iridectomy. Postoperatively, both patients did well, with IOPs decreasing to the target goal. We found the benefit of SS-MIOCT was greatest in surgical steps requiring depth-based assessments. This technology has the potential to improve clinical outcomes.


Identification and induction of cytochromes P450, P450IIE1 and P450IA1 in rabbit bone marrow.
A number of drugs and xenobiotics which require metabolic activation to reactive metabolites by cytochrome P450 are toxic to hemopoietic tissue. In the present study we used immunoblot analysis and specific catalytic activities to identify two isozymes of cytochrome P450 (P450IIE1 and P450IA1) in rabbit bone marrow microsomal preparations. P450IIB1, P450IIC1, P450IIIA6 and P450IA2 were below detectable levels using immunoblot analysis. P450IIE1 was present at a concentration of 0.0065 nmol/mg of microsomal protein in marrow microsomes from untreated rabbits, and it was induced 12.9-fold by acetone treatment. The change in the P450IIE1 apoprotein determined immunochemically in bone marrow microsomes after acetone treatment was paralleled by a 9.4-fold increase in benzene hydroxylation, a P450IIE1-dependent activity. Aroclor 1254 pretreatment induced P450IA1 in marrow microsomes 11-fold to a specific content of about 0.025 nmol/mg of microsomal protein. 7-Ethoxyresorufin deethylation, a P450IA1-dependent activity, was induced 15.7-fold by Aroclor 1254 treatment. The increases in the enzymic activities are consistent with an increase in catalytically competent holoenzymes. The presence of these two isozymes in bone marrow could result in the metabolic activation of compounds in the bone marrow producing toxic metabolites at the site of toxicity.


Inoculation of Tomato Spotted Wilt Virus into Cotton.
Tomato spotted wilt virus (TSWV) is an economically important virus of many crops throughout the world. Cotton, Gossypium hirsutum L., has previously been demonstrated to be susceptible to TSWV (1). During the fall of 1996, cotton was assayed as a potential host of TSWV, as it is an important early season host of thrips vectors of TSWV. Four commercial cotton varieties (DP 20, DP 52, DP 5409, and HS 46) were screened for susceptibility to four isolates of TSWV: two from tobacco, one from pineapple, and one from dahlia. Greenhouse-grown plants in the first true leaf stage were inoculated mechanically. Mean percent infection ranged from 20 to 33% (x = 27%) across all cotton varieties screened against all virus isolates 21 days post-inoculation. TSWV was recovered through mechanical inoculation from double antibody sandwich-enzyme-linked immunosorbent assay (DAS ELISA) positive cotton leaves in 83% of indicator plants, Emilia sonchifolia (L.) DC. ex Wight. Individual cotton plants testing TSWV ELISA positive were held for an additional 28 days with 4% of these again testing virus positive. The four cotton varieties were tested in the cotyledon, one-leaf, and four-leaf stages for susceptibility to tobacco thrips, Frankliniella fusca Hinds, transmission of one TSWV isolate from tobacco. First instar thrips were obtained from an avirulent colony. Mean percent infection among all varieties assayed was 10, 63, and 5%, respectively, for the three developmental stages. Cotton appears to be most susceptible in the one-leaf developmental stage with potential to serve as a source for TSWV spread to other crops. Reference: (1) G. L. Schuster and R. S. Haliwell. Plant Dis. 78:100, 1994.


Depression among Asian-American Adults in the Community: Systematic Review and Meta-Analysis.
In this systematic review, we provide an overview of the literature on depression among Asian-Americans and explore the possible variations in depression prevalence estimates by methodological and demographic factors. Six databases were used to identify studies reporting a prevalence estimate for depression in Asian-American adults in non-clinical settings. Meta-analysis was used to calculate pooled estimates of rates of depression by assessment type. Statistical heterogeneity was assessed for subgroup analyses by gender, age, ethnicity, and other participant characteristics. A total of 58 studies met the review criteria (n = 21.731 Asian-American adults). Heterogeneity across the studies was considerably high. The prevalence of major depression assessed via standardized clinical interviews ranged between 4.5% and 11.3%. Meta-analyses revealed comparable estimated prevalence rates of depression as measured by the Center for Epidemiologic Studies Depression Scale (35.6%, 95% CI 27.6%-43.7%) and the Geriatric Depression Scale (33.1%, 95% CI 14.9%-51.3%). Estimates varied by Asian racial/ethnic group and other participant characteristics. Estimates of depression among special populations, which included maternity, caregivers, and homosexuals, were significantly higher than estimates obtained from other samples (58.8% vs 29.3%, p = .003). Estimates of depression among Korean and Filipino-Americans were similar (33.3%-34.4%); however, the estimates were twice as high as those for Chinese-Americans (15.7%; p = .012 for Korean, p = .049 for Filipino). There appears to be wide variability in the prevalence rates of depression among Asian-Americans in the US. Practitioners and researchers who serve Asian-American adults need to be sensitive to the potential diversity of the expression of depression and treatment-seeking across Asian-American subgroups. Public health policies to increase Asian-American access to mental health care, including increased screening, are necessary. Further work is needed to determine whether strategies to reduce depression among specific Asian racial/ethnic groups is warranted.


Cancer beliefs in cancer survivors, cancer relatives and persons with no cancer experience.
Aims: Negative cancer beliefs have been associated with late stage at cancer diagnosis. High levels of negative cancer beliefs have been found among individuals with low socioeconomic position and ethnic minority women, but the impact of cancer experience on cancer beliefs is unexamined. The aim of this study was to examine whether cancer beliefs are associated with cancer experience. Methods: This was a cross-sectional population-based study. Telephone interviews of 2992 Danish residents (30+) were carried out using the Awareness and Beliefs about Cancer Measure (ABC). Respondents reported whether they or someone close had been diagnosed with cancer and whether they agreed/disagreed with three positively and three negatively framed cancer beliefs. Results: Respondents with someone close diagnosed was reference group. Compared with these, respondents with no cancer experience (RRadj=0.91, 95% CI=0.84-0.98) or who had had cancer themselves (RRadj=0.87, 0.77-0.98) were less likely to believe that cancer treatment is worse than the cancer itself, and respondents with no cancer experience were less likely to believe that a diagnosis of cancer is a death sentence (RRadj=0.83, 0.70-0.98), but more likely to report that they did not want to know if they had cancer (RRadj=1.31, 1.01-1.71). Conclusions: The results suggest that cancer beliefs are sensitive to cancer experience. This is an important addition to previous results focusing on the association between cancer beliefs and static factors such as socioeconomic position and ethnicity. Since cancer beliefs may determine health-related behaviour, it is important that negative cancer beliefs are addressed and possibly reframed in population-based interventions.


Novelty helmet use and motorcycle rider fatality.
To compare the risk of fatal injury across helmet types among collision-involved motorcyclists. We used data from a cohort of motorcyclists involved in police-reported traffic collisions. Eighty-four law enforcement agencies in California collected detailed information on helmet and rider characteristics during collision investigations in June 2012 through July 2013. Multiply-adjusted risk ratios were estimated with log-binomial regression. The adjusted fatal injury risk ratio for novelty helmets was 1.95 (95% CI 1.11-3.40, p 0.019), comparing novelty helmets with full-face helmets. The risk ratios for modular, open-face, and half-helmets, compared with full-face helmets, were not significant. A more complete understanding of the inadequacy of novelty helmets can be used in educational and law enforcement countermeasures to improve helmet use among motorcycling populations in California and other US states. Law enforcement approaches to mitigating novelty helmet use would seem attractive given that novelty helmets can be visually identified by law enforcement officers with sufficient training.


Plant foods, antioxidants, and prostate cancer risk: findings from case-control studies in Canada.
Epidemiological data on most cancer sites suggest that consumption of plant foods, which contain high levels of antioxidants, might slow or prevent the appearance of cancer. We used data from three case-control studies to test this hypothesis. The total study population consisted of 617 incident cases of prostate cancer and 636 population controls from Ontario, Quebec, and British Columbia. Dietary information was collected by an in-person interview with a detailed quantitative dietary history. Unconditional logistic regression analyses were performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs). A decreasing, statistically significant association was found with increasing intakes of green vegetables (OR = 0.54, 95% CI = 0.40-0.71 for 4th quartile), tomatoes (OR = 0.64, 95% CI = 0.45-0.91), beans/lentils/nuts (OR = 0.69, 95% CI = 0.53-0.91), and cruciferous vegetables (OR = 0.69, 95% CI = 0.52-0.91 for 3rd quartile). Higher intakes of fruit were associated with higher ORs (OR = 1.51, 95% CI = 1.14-2.01 for 4th quartile), an effect that was seen for total fruit and citrus fruit, as well as for all other noncitrus fruits. Among the grains, refined-grain bread intake was associated with a decrease in risk (OR = 0.65 for 4th quartile), whereas whole-grain breakfast cereals were associated with a higher risk for prostate cancer. Of all the antioxidant nutrients studied, the ORs were higher with higher intakes of cryptoxanthin (OR = 1.44, 95% CI = 1.09-1.89 for 4th quartile). Exposure to certain dietary components of plant origin, which are potentially modifiable, indicates the theoretical scope for reducing the risk from prostate cancer. Future experimental studies or trials are warranted for further understanding.


Caffeic Acid Phenethyl Ester Inhibits UV-Induced MMP-1 Expression by Targeting Histone Acetyltransferases in Human Skin.
Caffeic acid phenethyl ester (CAPE), a naturally occurring bioactive compound, displays anti-inflammatory, anti-carcinogenic, and anti-microbial effects. However, the effect of CAPE on skin photoaging is unknown. Herein, we investigated the inhibitory effect of CAPE against ultraviolet (UV) irradiation-mediated matrix metalloproteinase (MMP)-1 expression and its underlying molecular mechanism. CAPE treatment suppressed UV-induced MMP-1 levels in both human dermal fibroblasts (HDF) and human skin tissues. While CAPE did not display any significant effects against the upstream regulatory pathways of MMP-1, CAPE was capable of reversing UV-mediated epigenetic modifications. CAPE suppressed UV-induced acetyl-histone H3 (Lys9) as well as total lysine acetylation in HDF cells. Similarly, CAPE also attenuated UV-induced lysine acetylations in human skin tissues, suggesting that the CAPE-mediated epigenetic alterations can be recapitulated in ex vivo conditions. CAPE was found to attenuate UV-induced histone acetyltransferase (HAT) activity in HDF. Notably, CAPE was able to directly inhibit the activity of several HATs including p300, CREP-binding protein (CBP), and p300/CBP-associated factor (PCAF), further confirming that CAPE can function as an epigenetic modulator. Thus, our study suggests that CAPE maybe a promising agent for the prevention of skin photoaging via targeting HATs.


Ugonin J improves metabolic disorder and ameliorates nonalcoholic fatty liver disease by regulating the AMPK/AKT signaling pathway.
Closely associated with visceral obesity, hepatic steatosis resulting from non-alcoholic fatty liver disease (NAFLD) exacerbates insulin resistance. Developing effective drugs to treat NAFLD is imperative. Here, we investigated the pharmacological mechanism of ugonin J (UJ) in controlling metabolic disorder and ameliorating NAFLD pathophysiology in diet-induced obese mice. The effects of UJ were assessed in 5-week-old C57BL/6 J mice fed a high-fat diet (HFD) for 12 weeks. UJ treatment averted HFD-induced body weight gain by reducing fat deposition in adipose tissues and reduced HFD-induced hyperlipidemia and hepatic inflammation. UJ also improved HFD-induced glucose tolerance and insulin resistance. Moreover, the mode of action of UJ was analyzed in palmitate (PA)-induced steatotic human HuS-E/2 hepatocytes and in hyperglycemia-simulating rat BRIN-BD11 pancreatic β cells. In PA-induced steatotic human hepatocytes, UJ treatment promoted lipid clearance via pAMPK, pACC and CPT-1 upregulation and SREBP-1c downregulation. Interestingly, UJ upregulated Akt activity in hepatocytes and increased insulin secretion from β cells in acute insulin secretion tests. Taken together, UJ improved adipocyte hypertrophy, hyperinsulinemia, hyperglycemia, hyperlipidemia and fat deposition in livers. UJ also reduced fatty acid accumulation by modulating key metabolic regulators. Our findings demonstrated the therapeutic potential of UJ for the treatment of NAFLD and diet-induced metabolic disorders.


Phenytoin affects metabolism of free fatty acids and nucleotides in rat cerebral ischemia.
We investigated the effects of phenytoin on the rate of enzymatic release of free fatty acids and on the levels of energy metabolites and nucleoside phosphates in ischemic brain. Phenytoin (10 mg/kg i.v.) was administered 30 minutes before the onset of ischemia induced in 30 male Wistar rats by occluding the basilar and both common carotid arteries. The rats' brains were frozen in situ after 0, 5, or 30 minutes of ischemia or 10, 30, or 60 minutes of recirculation following 30 minutes of ischemia (n = 5 at each time). Nucleoside triphosphate levels were higher in the phenytoin-treated rats than in corresponding untreated rats at each time during and after ischemia. Phenytoin significantly attenuated the accumulation of lactate and free fatty acids (arachidonic acid and stearic acid) during ischemia and accelerated their recovery during recirculation. These results suggest that phenytoin has favorable protective effects on ischemic brain and that phenytoin may inhibit calcium-mediated phenomena, especially the inositol cycle, in cerebral ischemia.


Assessment of ability/disability in patients treated with chronic thalamic stimulation for tremor.
Chronic thalamic stimulation (CTS) has a documented good effect on tremor in patients with Parkinson's disease (PD) and essential tremor (ET). This study evaluates whether the alleviation of impairment, i.e., tremor, translates into improvement of the patient's ability in performing instrumental activities of daily living (IADL). Thirteen patients were assessed with an occupational therapy tool called Assessment of Motor and Process Skills (AMPS). This observation-based scale rates the patient's motor and process skills needed to perform a given task. The evaluations were done at a mean of 13 months after surgery in the patient's home, and included assessments of IADL with the CTS activated and switched off, respectively. The results showed that most patients improved to variable degrees in their IADL ability when the thalamic stimulation was on. The improvement was more marked in patients operated on for tremor of their dominant hand. The improvement concerned mainly the skill items related to the patients' abilities of coordination, calibration, endurance, and accommodation during IADL task performance. The authors concluded that for some patients with tremor, CTS can improve independence in domestic activities of daily living.


Differential Expression and Significance of PD-L1, IDO-1, and B7-H4 in Human Lung Cancer.
To determine the expression level, associations, and biological role of PD-L1, IDO-1, and B7-H4 in non-small cell lung cancer (NSCLC). Using multiplexed quantitative immunofluorescence (QIF), we measured the levels of PD-L1, IDO-1, B7-H4, and different tumor-infiltrating lymphoycte (TIL) subsets in 552 stages I-IV lung carcinomas from two independent populations. Associations between the marker levels, TILs, and major clinicopathologic variables were determined. Validation of findings was performed using mRNA expression data from The Cancer Genome Atlas (TCGA) and in vitro stimulation of lung adenocarcinoma A549 cells with IFNγ and IL10. PD-L1 was detected in 16.9% and 21.8% of cases in each population. IDO-1 was expressed in 42.6% and 49.8%; and B7-H4 in 12.8% and 22.6% of cases, respectively. Elevated PD-L1 and IDO-1 were consistently associated with prominent B- and T-cell infiltrates, but B7-H4 was not. Coexpression of the three protein markers was infrequent, and comparable results were seen in the lung cancer TCGA dataset. Levels of PD-L1 and IDO-1 (but not B7-H4) were increased by IFNγ stimulation in A549 cells. Treatment with IL10 upregulated B7-H4 but did not affect PD-L1 and IDO-1 levels. PD-L1, IDO-1, and B7-H4 are differentially expressed in human lung carcinomas and show limited co-expression. While PD-L1 and IDO-1 are associated with increased TILs and IFNγ stimulation, B7-H4 is not. The preferential expression of discrete immune evasion pathways in lung cancer could participate in therapeutic resistance and support design of optimal clinical trials. Clin Cancer Res; 23(2); 370-8. ©2016 AACR.


Acm1 contributes to nuclear positioning by inhibiting Cdh1-substrate interactions.
The anaphase-promoting complex (APC) is tightly regulated during cell division, often by pseudosubstrate binding to its coactivators Cdh1 and Cdc20. Budding yeast Acm1 is a Cdh1 pseudosubstrate inhibitor whose biological function is unknown. We show here that cells lacking Acm1 have defects in nuclear positioning and spindle morphology during mitosis. However, Cdh1 substrates are not destabilized in the absence of Acm1 and expression of inactive Cdh1 mutants that retain substrate binding is sufficient for the acm1 phenotype. We conclude that Acm1 is not required to inhibit APC(Cdh1) activity but rather prevents untimely Cdh1-substrate interactions. We further provide evidence suggesting that the substrate primarily responsible for the acm1 phenotype is the bud neck-localized kinase, Hsl1. Our results imply that at least some coactivator-substrate interactions require regulation. Several unrelated APC pseudosubstrates have been identified in diverse eukaryotes and their ability to simultaneously inhibit enzymatic activity and substrate binding may partly explain why this regulatory mechanism has been selected repeatedly during evolution.


Mucosal mast cells. II. Effects of anti-allergic compounds on histamine secretion by isolated intestinal mast cells.
Functional mast cells have been isolated from the lamina propria of the small intestine of rats infected with the nematode Nippostrongylus brasiliensis. The cells released histamine on challenge with specific antigen, anti-rat IgE, concanavalin A, and calcium ionophores but were less responsive than peritoneal mast cells (MMC) from the same animals. Intestinal mucosa mast cells (PMC) were refractory to the action of the basic secretagogues peptide 401 from bee venom and compound 48/80. The anti-allergic compounds disodium cromoglycate (less than or equal to 10(-3) M), AH 9679 (less than or equal to 10(-4) M), and theophylline (less than or equal to 10(-2)) did not inhibit antigen-induced histamine secretion by MMC, although these compounds were effective against PMC. In contrast, doxantrazole (10(-5) to 10(-3) M) inhibited the secretion of histamine from both MMC and PMC in a comparable dose-dependent fashion. Thus, we have established that mast cells from different sites are functionally heterogeneous not only in their response to various stimuli for histamine secretion, but also in their responses to different pharmacologic modulators of secretion. It cannot be assumed that anti-allergic compounds effective against mast cells in one tissue site or organ will be equally efficacious against mast cells in other sites. The extent of this functional heterogeneity must be established, and its investigation may provide new insights into the biochemical events involved in mast cell secretion.


6-Bicycloaryl substituted (S)- and (R)-5,6-dihydro-2H-pyran-2-ones: asymmetric synthesis, and anti-proliferative properties.
(R)-Goniothalamin, is a member of styryl lactones, possesses selective cytotoxicity against cancer cell lines. In this work, replacement of styryl substituent with 2-naphthyl and 3-quinoyl gave new analogues which may have less conformational changes compared to the lead compound. Anti-proliferative tests indicated that 2-naphthyl substituted (R)-5,6-dihydro-2H-pyran-2-one has slightly better cytotoxicity than (R)-goniothalamin. To clarify the effect of 2-naphthyl substituent additional aryl substituted (R)-5,6-dihydro-2H-pyran-2-ones have been synthesized enantioselectively and tested against PC-3 and MCF-7 cell lines.


A novel in vitro and numerical analysis of shear-induced drug release from extended-release tablets in the fed stomach.
To design an in vitro apparatus that could simulate the in vivo range of surface shear stresses relevant for the human stomach under fed conditions. Computer simulations were combined with in vitro experiments to quantify tablet erosion rate vs. surface shear stress. From two separate computer models, of tablets in the fed stomach and of tablets in vitro, we first estimated the intragastric range of surface stress and Reynolds number (Re), and then designed a dissolution apparatus and parameter space to replicate the in vivo conditions. The in vitro tablet erosion was determined by a new rotating beaker apparatus that provided predictable surface shear on tablets. Tablet mass erosion rates were measured for two different extended-release tablets at a range of in vivo relevant surface shear stresses obtained by varying viscosity of test media and rotation rate of the beaker. Mass erosion rate and surface shear were found to be highly correlated. Erosion rate increased with surface shear more rapidly at "low" stresses (<35 dyne/cm2) independent of tablet material. At higher surface stress, erosion was strongly material dependent. Shear force effects on drug release from matrix tablets relevant for fed state are for the first time possible to predict by in vitro dissolution testing.


Ca2+ homeostasis and fast-type sarcoplasmic reticulum Ca(2+)-ATPase expression in L6 muscle cells. Role of thyroid hormone.
The effect of thyroid hormone (L-tri-iodothyronine; T3) on the cytosolic free Ca2+ concentration ([Ca2+]i) in L6 myotubes was studied at rest and during activation to explore the possible mediating role of [Ca2+]i in the T3-induced net synthesis of fast-type sarcoplasmic reticulum (SR) Ca(2+)-ATPase. The mean [Ca2+]i at rest was approx. 115 nM in myoblasts, control myotubes and T3-treated myotubes. Therefore it is unlikely that the T3-induced elevation of Ca(2+)-ATPase levels is mediated by [Ca2+]i changes. To investigate the influence of the 4-fold higher Ca(2+)-ATPase levels in T3-treated myotubes (compared with controls) on [Ca2+]i, interventions with caffeine (10 mM) and a high extracellular K+ concentration ([K+]o) (30 mM) were applied which initially mobilize Ca2+ predominantly from the SR. The results showed a lower (caffeine) or not significantly different (high [K+]o) increase in [Ca2+]i in T3-treated myotubes compared with controls. No rise in [Ca2+]i was found in myoblasts with caffeine or high [K+]o. The role of [Ca2+]i in the regulation of Ca(2+)-ATPase levels was investigated by varying [Ca2+]i through exposure of cells to different concentrations of extracellular Ca2+ (0.2-1.8 mM) and ionomycin (0.1-0.25 microM). At subnormal [Ca2+]i (55 nM) the T3-induced net synthesis of Ca(2+)-ATPase was virtually abolished, and at supranormal [Ca2+]i (195 nM) it was greatly depressed. Intermediate stimulation of net Ca(2+)-ATPase synthesis was found at [Ca2+]i of 95 and 165 nM, with an optimum at approx. 125 nM. Similar but less pronounced effects were found for the basal Ca(2+)-ATPase levels. In contracting primary rat myotubes, Ca(2+)-ATPase levels were significantly lower than in tetrodotoxin-arrested myotubes. The same results were obtained in the presence of T3. Since the mean [Ca2+]i in contracting cells is higher than in resting cells, these data agree with those obtained in the L6 cells with ionomycin. A major conclusion of this study is the existence of a [Ca2+]i optimum, near resting levels, for the expression of the fast-type Ca(2+)-ATPase in the L6 muscle cell line.


Thermoelectric Performance of Na-Doped GeSe.
Recently, hole-doped GeSe materials have been predicted to exhibit extraordinary thermoelectric performance owing largely to extremely low thermal conductivity. However, experimental research on the thermoelectric properties of GeSe has received less attention. Here, we have synthesized polycrystalline Na-doped GeSe compounds, characterized their crystal structure, and measured their thermoelectric properties. The Seebeck coefficient decreases with increasing Na content up to x = 0.01 due to an increase in the hole carrier concentration and remains roughly constant at higher concentrations of Na, consistent with the electrical resistivity variation. However, the electrical resistivity is large for all samples, leading to low power factors. Powder X-ray diffraction and scanning electron microscopy/energy-dispersive spectrometry results show the presence of a ternary impurity phase within the GeSe matrix for all doped samples, which suggests that the optimal carrier concentration cannot be reached by doping with Na. Nevertheless, the lattice thermal conductivity and carrier mobility of GeSe is similar to those of polycrystalline samples of the leading thermoelectric material SnSe, leading to quality factors of comparable magnitude. This implies that GeSe shows promise as a thermoelectric material if a more suitable dopant can be found.


Monoclonal Antibodies with Neutralizing Activity and Fc-Effector Functions against the Machupo Virus Glycoprotein.
Machupo virus (MACV), the causative agent of Bolivian hemorrhagic fever (BHF), is a New World arenavirus that was first isolated in Bolivia from a human spleen in 1963. Due to the lack of a specific vaccine or therapy, this virus is considered a major risk to public health and is classified as a category A priority pathogen by the U.S. National Institutes of Health. In this study, we used DNA vaccination against the MACV glycoprotein precursor complex (GPC) and murine hybridoma technology to generate 25 mouse monoclonal antibodies (MAbs) against the GPC of MACV. Out of 25 MAbs, five were found to have potent neutralization activity in vitro against a recombinant vesicular stomatitis virus expressing MACV GPC (VSV-MACV) as well as against authentic MACV. Furthermore, the five neutralizing MAbs exhibited strong antibody-dependent cellular cytotoxicity (ADCC) activity in a reporter assay. When tested in vivo using VSV-MACV in a Stat2-/- mouse model, three MAbs significantly lowered viral loads in the spleen. Our work provides valuable insights into epitopes targeted by neutralizing antibodies that could be potent targets for vaccines and therapeutics and shed light on the importance of effector functions in immunity against MACV.IMPORTANCE MACV infections are a significant public health concern and lead to high case fatality rates. No specific treatment or vaccine for MACV infections exist. However, cases of Junin virus infection, a related virus, can be treated with convalescent-phase serum. This indicates that a MAb-based therapy for MACV could be effective. Here, we describe several MAbs that neutralize MACV and could be used for this purpose.


Anti-Ulcer Efficacy of Soluble Epoxide Hydrolase Inhibitor TPPU on Diclofenac-Induced Intestinal Ulcers.
Proton pump inhibitors such as omeprazole (OME) reduce the severity of gastrointestinal (GI) ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs) but can also increase the chance of dysbiosis. The aim of this study was to test the hypothesis that preventive use of a soluble epoxide hydrolase inhibitor (sEHI) such as TPPU can decrease NSAID-induced ulcers by increasing anti-inflammatory epoxyeicosatrienoic acids (EETs). Dose- [10, 30, and 100 mg/kg, by mouth (PO)] and time-dependent (6 and 18 hours) ulcerative effects of diclofenac sodium (DCF, an NSAID) were studied in the small intestine of Swiss Webster mice. Dose-dependent effects of TPPU (0.001-0.1 mg/kg per day for 7 days, in drinking water) were evaluated in DCF-induced intestinal toxicity and compared with OME (20 mg/kg, PO). In addition, the effect of treatment was studied on levels of Hb in blood, EETs in plasma, inflammatory markers such as myeloperoxidase (MPO) in intestinal tissue homogenates, and tissue necrosis factor-α (TNF-α) in serum. DCF dose dependently induced ulcers that were associated with both a significant (P < 0.05) loss of Hb and an increase in the level of MPO and TNF-α, with severity of ulceration highest at 18 hours. Pretreatment with TPPU dose dependently prevented ulcer formation by DCF, increased the levels of epoxy fatty acids, including EETs, and TPPU's efficacy was comparable to OME. TPPU significantly (P < 0.05) reversed the effect of DCF on the level of Hb, MPO, and TNF-α Thus sEHI might be useful in the management of NSAID-induced ulcers.


Sirt1 mediates the effect of the heme oxygenase inducer, cobalt protoporphyrin, on ameliorating liver metabolic damage caused by a high-fat diet.
Heme oxygenase 1 (HO-1)-mediated increases in adiponectin, ameliorate the deleterious effects of obesity and metabolic syndrome; however, the effect of HO-1 on hepatic lipid metabolism remains elusive. The aim of this study is to evaluate the role of HO-1 in hepatic lipid metabolism. Functional studies were performed using C57BL/6J (WT) mice and Sirt1 liver specific mutant (Sirt1-deficient) mice. The molecular mechanism was explored in primary hepatocytes and mouse liver. Chronic exposure to high-fat diet (HFD) induced hepatic steatosis in WT mice. Treatment of WT mice on HFD with cobalt protoporphyrin (CoPP), an inducer of HO-1 activity, decreased body weight and visceral fat content, reduced intracellular hepatic triglyceride and serum total cholesterol concentrations, and decreased liver lipid droplet formation. Compared with WT mice, the administration of CoPP to Sirt1-deficient mice on HFD increased visceral fat content, and slightly promoted liver lipid droplet formation. CoPP improved glucose tolerance and insulin sensitivity in WT mice on HFD, but compromised insulin sensitivity in Sirt1-deficient mice on HFD. Furthermore, CoPP-induced Sirt1 expression and decreased sterol regulatory element binding protein 1c (SREBP-1c) expression in WT mice on HFD. However, CoPP promoted SREBP-1c expression in Sirt1-deficient hepatocytes, which was reversed by a protein tyrosine phosphatase 1b inhibitor. Additionally, while the administration of CoPP to WT mice on HFD improved antioxidant and anti-inflammatory states, these CoPP-mediated effects were abolished in Sirt1-deficient mice. Sirt1 mediates the effect of CoPP on ameliorating liver metabolic damage caused by HFD.


Regulation of p53 expression, phosphorylation and subcellular localization by a G-protein-coupled receptor.
G-protein-coupled receptors (GPCRs) have been extremely successful drug targets for a multitude of diseases from heart failure to depression. This superfamily of cell surface receptors have not, however, been widely considered as a viable target in cancer treatment. In this study we show that a classical G(q/11)-coupled GPCR, the M(3)-muscarinic receptor, was able to regulate apoptosis through receptors that are endogenously expressed in the human neuroblastoma cell line, SH-SY5Y, and when ectopically expressed in Chinese hamster ovary (CHO) cells. Stimulation of the M(3)-muscarinic receptor was shown to inhibit the ability of the DNA-damaging chemotherapeutic agent, etoposide, from mediating apoptosis. This protective response in CHO cells correlated with the ability of the receptor to regulate the expression levels of p53. In contrast, stimulation of endogenous muscarinic receptors in SH-SY5Y cells did not regulate p53 expression but rather was able to inhibit p53 translocation to the mitochondria and p53 phosphorylation at serine 15 and 37. This study suggests the possibility that a GPCR can regulate the apoptotic properties of a chemotherapeutic DNA-damaging agent by regulating the expression, subcellular trafficking and modification of p53 in a manner that is, in part, dependent on the cell type.


Y90 Radioembolization Significantly Prolongs Time to Progression Compared With Chemoembolization in Patients With Hepatocellular Carcinoma.
Conventional transarterial chemoembolization (cTACE) is used to treat patients with hepatocellular carcinoma (HCC). Radioembolization is a minimally invasive procedure that involves implantation of radioactive micron-sized particles loaded with yttrium-90 (Y90) inside the blood vessels that supply a tumor. We performed a randomized, phase 2 study to compare the effects of cTACE and Y90 radioembolization in patients with HCC. From October 2009 through October 2015, we reviewed patients with HCC of all Barcelona Clinic Liver Cancer (BCLC) stages for eligibility. Of these, 179 patients with BCLC stages A or B met our enrollment criteria and were candidates for cTACE or Y90 therapy. Patients were assigned randomly to groups that received Y90 therapy (n = 24; 50% Child-Pugh A) or cTACE (n = 21; 71% Child-Pugh A). The primary outcome was time to progression (TTP), evaluated by intention-to-treat analysis. Secondary outcomes included safety, rate of response (based on tumor size and necrosis criteria), and Kaplan-Meier survival time. We performed inverse probability of censoring weighting and competing risk analyses. Patients in the Y90 radioembolization group had significant longer median TTP (>26 mo) than patients in the cTACE group (6.8 mo; P = .0012) (hazard ratio, 0.122; 95% confidence interval [CI], 0.027-0.557; P = .007). This was confirmed by competing risk and inverse probability of censoring weighting analyses accounting for transplantation or death. A significantly greater proportion of patients in the cTACE group developed diarrhea (21%) than in the Y90 group (0%; P = .031) or hypoalbuminemia (58% in the cTACE group vs 4% in the Y90 group; P < .001). Similar proportions of patients in each group had a response to therapy, marked by necrosis (74% in the cTACE group vs 87% in the Y90 group) (P = .433). The median survival time, censored to liver transplantation, was 17.7 months for the cTACE group (95% CI, 8.3-not calculable) vs 18.6 months for the Y90 group (95% CI, 7.4-32.5) (P = .99). In a randomized phase 2 study of patients with HCC of BCLC stages A or B, we found Y90 radioembolization to provide significantly longer TTP than cTACE. Y90 radioembolization provides better tumor control and could reduce drop-out from transplant waitlists. ClinicalTrials.gov no. NCT00956930.


Optimal Protocols in Quantum Annealing and Quantum Approximate Optimization Algorithm Problems.
Quantum annealing (QA) and the quantum approximate optimization algorithm (QAOA) are two special cases of the following control problem: apply a combination of two Hamiltonians to minimize the energy of a quantum state. Which is more effective has remained unclear. Here we analytically apply the framework of optimal control theory to show that generically, given a fixed amount of time, the optimal procedure has the pulsed (or "bang-bang") structure of QAOA at the beginning and end but can have a smooth annealing structure in between. This is in contrast to previous works which have suggested that bang-bang (i.e., QAOA) protocols are ideal. To support this theoretical work, we carry out simulations of various transverse field Ising models, demonstrating that bang-anneal-bang protocols are more common. The general features identified here provide guideposts for the nascent experimental implementations of quantum optimization algorithms.


Randomized comparison of low-dose versus standard-dose praziquantel therapy in treatment of urinary tract morbidity due to Schistosoma haema tobium infection.
At present, anthelmintic therapy with praziquantel at a dose of 40 mg/kg of body weight is the recommended treatment for control of urinary tract morbidity caused by Schistosoma haematobium. Although this standard regimen is effective, drug cost may represent a significant barrier to implementation of large-scale schistosomiasis control programs in developing areas. Previous comparison trials have established that low-dose (20-30 mg/kg) praziquantel regimens can effectively suppress the intensity of S. haematobium infection in endemic settings. However, the efficacy of these low-dose regimens in controlling infection-related morbidity has not been determined in a randomized field trial. The present random allocation study examined the relative efficacy of a 20 mg/kg dose versus a 40 mg/kg dose of praziquantel in control of hematuria and bladder and renal abnormalities associated with S. haematobium infection in an endemic area of Coast Province, Kenya. After a nine-month observation period, the results indicated an advantage to the standard 40 mg/kg praziquantel dose in terms of reduction of infection prevalence and hematuria after therapy (P < 0.01 and P < 0.005, respectively). However, the two treatment groups were equally effective in reducing structural urinary tract morbidity detected on ultrasound examination. We conclude that in certain settings, a 20 mg/kg dose of praziquantel may be sufficient in providing control of morbidity due to urinary schistosomiasis in population-based treatment programs.


Carbonic anhydrase-related protein CA10 is an evolutionarily conserved pan-neurexin ligand.
Establishment, specification, and validation of synaptic connections are thought to be mediated by interactions between pre- and postsynaptic cell-adhesion molecules. Arguably, the best-characterized transsynaptic interactions are formed by presynaptic neurexins, which bind to diverse postsynaptic ligands. In a proteomic screen of neurexin-1 (Nrxn1) complexes immunoisolated from mouse brain, we identified carbonic anhydrase-related proteins CA10 and CA11, two homologous, secreted glycoproteins of unknown function that are predominantly expressed in brain. We found that CA10 directly binds in a cis configuration to a conserved membrane-proximal, extracellular sequence of α- and β-neurexins. The CA10-neurexin complex is stable and stoichiometric, and results in formation of intermolecular disulfide bonds between conserved cysteine residues in neurexins and CA10. CA10 promotes surface expression of α- and β-neurexins, suggesting that CA10 may form a complex with neurexins in the secretory pathway that facilitates surface transport of neurexins. Moreover, we observed that the Nrxn1 gene expresses from an internal 3' promoter a third isoform, Nrxn1γ, that lacks all Nrxn1 extracellular domains except for the membrane-proximal sequences and that also tightly binds to CA10. Our data expand the understanding of neurexin-based transsynaptic interaction networks by providing further insight into the interactions nucleated by neurexins at the synapse.


Mitochondrial phylogeny reveals intraspecific variation in Peronospora effusa, the spinach downy mildew pathogen.
Since about two hundred years, downy mildew caused by Peronospora effusa is probably the most economically important disease of spinach (Spinacia oleracea). However, there is no information on the global phylogeographic structure of the pathogen and thus it is unclear whether a single genotype occurs worldwide or whether some local genetic variation exists. To investigate the genetic variability of this pathogen, a sequence analysis of two partial mitochondrial DNA genes, cox2 and nad1, was carried out. Thirty-three specimens of Peronospora effusa from four continents were analyzed, including samples from Australia, China, Japan, Korea, Mexico, Russia, Sweden, and the USA. Despite the potential anthropogenic admixture of genotypes, a phylogeographic pattern was observed, which corresponds to two major groups, an Asian/Oceanian clade and another group, which includes American/European specimens. Notably, two of six Japanese specimens investigated did not belong to the Asian/Oceanian clade, but were identical to three of the specimens from the USA, suggestive of a recent introduction from the USA to Japan. As similar introduction events may be occurring as a result of the globalised trade with plant and seed material, a better knowledge of the phylogeographic distribution of pathogens is highly warranted for food security purposes.