The effect of glucose added to the dialysis fluid on blood pressure, blood glucose, and quality of life in hemodialysis patients: a placebo-controlled crossover study.
Risk for hypoglycemia increases during hemodialysis sessions. The compensatory homeostatic response to hypoglycemia may increase the risk for abnormal blood pressure regulation. The purpose is to determine blood pressure and blood glucose levels and variability in these variables during dialysis with and without glucose in the dialysis fluid. In a randomized, placebo-controlled, unblinded, crossover study of 44 hemodialysis patients, 34 patients without diabetes and 10 patients with diabetes were allocated to treatment with and without glucose in the dialysis fluid during two 10-week periods. Blood pressure and blood glucose levels were determined 5 to 8 times at each dialysis session during both periods. Quality of life was estimated by using the 36-Item Short-Form Health Survey questionnaire at the end of both treatment periods. With glucose in the dialysis fluid, blood pressure was significantly lower (systolic, 144 +/- 20 versus 149 +/- 21 mm Hg; P < 0.003; diastolic, 73 +/- 10 versus 76 +/- 10 mm Hg; P < 0.001), blood glucose level was higher (125 +/- 25 versus 110 +/- 26 mg/dL [6.96 +/- 1.36 versus 6.08 +/- 1.47 mmol/L]; P < 0.001), and quality of life was the same. Variations in systolic and diastolic blood pressures and blood glucose levels were the same during both treatments. In the subgroup of patients with diabetes, variation in blood glucose levels decreased significantly with glucose in the dialysis fluid (mean, 30 versus 37 mg/dL [1.66 versus 2.03 mmol/L]; P = 0.008). Systolic and diastolic blood pressures decreased with glucose in the dialysis fluid in patients with chronic renal failure, presumably because of insulin-induced vasodilatation in patients without diabetes. Blood glucose level regulation improved in the diabetic subgroup, and blood glucose levels were not greater in patients with diabetes with glucose in the dialysis water. Quality of life was not changed.


Above Room Temperature Organic Ferroelectrics: Diprotonated 1,4-Diazabicyclo[2.2.2]octane Shifts between Two 2-Chlorobenzoates.
A pure organic single crystal, [H2dabco]·[2CB]2 ([H2dabco](2+) = diprotonated 1,4-diazabicyclo[2.2.2]octane, 2CB(-) = 2-chlorobenzoate), which undergoes a ferroelectric-to-paraelectric phase transition above room temperature (∼323 K upon heating), was prepared and characterized. This ferroelectric crystal possesses a distinctive supramolecular architecture composed of discrete H-bonded trimeric units (two 2CB(-) anions bridged by one [H2dabco](2+) cation through N-H···O hydrogen bond interactions). In the paraelectric phase, the [H2dabco](2+) cation is rotationally disordered and lies at the symmetric center of the trimer. Upon cooling, it is frozen in an ordered state and deviates toward a 2CB(-) anion at one end along the H-bond. The collective displacement of the cations leads to a polarization of the single crystal along the crystallographic c axis, which is confirmed by the temperature dependence of the second harmonic generation and spontaneous polarization. A significant increase in the phase transition temperature of the deuterated analogue suggests that the proton plays an important role in the ferroelectric phase transition.


Generalized mastocytosis in a foal, resembling urticaria pigmentosa of man.
A newborn foal with multiple, nodular, cutaneous lesions containing mast cells and with mast cell accumulations in bone marrow was observed for 1 year. Cutaneous nodules grew to several centimeters in size, ulcerated, and regressed. Only a few healed nodules remained when the foal was 1 year old. The disease was considered to be similar to urticaria pigmentosa of man.


Clinical Efficacy of an Arthroscopic Surgery in Open Wedge High Tibial Osteotomy.
Few studies have identified the effects of arthroscopic surgery on the clinical outcomes when open wedge high tibial osteotomy (OWHTO) and arthroscopic surgery were performed together. The purpose of this study was to evaluate the clinical efficacy of arthroscopic surgery in patients who had varus osteoarthritic knee and were treated with OWHTO combined with arthroscopic surgery. Among the 98 knees (88 patients) who underwent OWHTO between January 2008 and March 2013, 79 knees (71 patients) with more than 2 years of follow-up were reviewed retrospectively. The patients were divided into two groups: Group 1 (24 knees) underwent only OWHTO and Group 2 (55 knees) underwent OWHTO combined with arthroscopic surgery. For clinical evaluation, the range of motion (ROM), pain visual analog scale, Knee Society knee score, Knee Society function score, and complication were used. For radiologic evaluation, Kellgren-Lawrence grade, mechanical femorotibial angle, and posterior tibial slope were used. The average follow-up period was 29.1 months. Group 2 showed a significant increase in the ROM at the last follow-up (133.2 ± 6.0 degrees) compared with the preoperative time point (128.3 ± 7.7 degrees) (p < 0.001). In the comparison of radiologic parameters between Groups 1 and 2, there was no significant difference. In the minimum 24-month follow-up, when OWHTO combined with arthroscopic surgery was performed, arthroscopic surgery helped increase the ROM of patients with mechanical symptoms. However, the amount of the ROM increase of 4.9 degrees was of unknown clinical significance.


Rethinking the regulatory framework for tobacco control in New Zealand.
Tobacco is a particularly unusual consumer product in that it is highly addictive, kills over half its long-term users, and is a major cause of premature death and health inequalities in New Zealand. We therefore examined the place of regulatory frameworks in advancing tobacco control, and suggest the formation of a Government Tobacco Authority. Such an authority could enable the Government to specify the design of tobacco products (to maximise harm reduction), to eliminate the marketing for profit of branded products, and to appropriately control the introduction of alternative nicotine delivery devices or less hazardous alternative tobacco products. As the authority could be funded through levies on the tobacco industry, it has the potential advantage of delivering major population health gains while costing the taxpayer nothing.


Selective photoinactivation of Candida albicans in the non-vertebrate host infection model Galleria mellonella.
Candida spp. are recognized as a primary agent of severe fungal infection in immunocompromised patients, and are the fourth most common cause of bloodstream infections. Our study explores treatment with photodynamic therapy (PDT) as an innovative antimicrobial technology that employs a nontoxic dye, termed a photosensitizer (PS), followed by irradiation with harmless visible light. After photoactivation, the PS produces either singlet oxygen or other reactive oxygen species (ROS) that primarily react with the pathogen cell wall, promoting permeabilization of the membrane and cell death. The emergence of antifungal-resistant Candida strains has motivated the study of antimicrobial PDT (aPDT) as an alternative treatment of these infections. We employed the invertebrate wax moth Galleria mellonella as an in vivo model to study the effects of aPDT against C. albicans infection. The effects of aPDT combined with conventional antifungal drugs were also evaluated in G. mellonella. We verified that methylene blue-mediated aPDT prolonged the survival of C. albicans infected G. mellonella larvae. The fungal burden of G. mellonella hemolymph was reduced after aPDT in infected larvae. A fluconazole-resistant C. albicans strain was used to test the combination of aPDT and fluconazole. Administration of fluconazole either before or after exposing the larvae to aPDT significantly prolonged the survival of the larvae compared to either treatment alone. G. mellonella is a useful in vivo model to evaluate aPDT as a treatment regimen for Candida infections. The data suggests that combined aPDT and antifungal therapy could be an alternative approach to antifungal-resistant Candida strains.


Hematologic, plasma protein, and biochemical profiles of brown pelicans (Pelecanus occidentalis).
To establish hematologic and biochemical reference values for the brown pelican (Pelecanus occidentalis). 31 captive, healthy, but permanently disabled pelicans and 35 wild-caught, healthy pelicans from a rehabilitation facility on the east coast of Florida. Samples of venous blood were collected from each pelican, and hematologic, plasma biochemical, and electrophoretic protein analyses were performed. Student t-tests were used to compare blood values between captive versus wild-caught, adult male versus adult female, and adult versus juvenile pelicans. Hematologic and electrophoretic values were similar between male and female, adult and juvenile, and captive and wild-caught pelicans. Significant sex differences existed for plasma calcium and triglyceride concentrations. Plasma concentrations of calcium, cholesterol, and CO2 content differed between captive and wild-caught adults. No significant differences were found between wild-caught adult and juvenile pelicans. Our plasma biochemical results are similar to those of other brown pelicans and confamilial species. Additional studies on seabirds are encouraged, as age, sex, reproductive status, feeding habits, and captivity are important variables for health assessment in this and other aquatic species.


Modulation of the central memory and Tr1-like regulatory T cells in multiple sclerosis patients responsive to interferon-beta therapy.
Interferon-beta is used to reduce disease activity in multiple sclerosis, but its action is incompletely understood, individual treatment response varies among patients, and biological markers predicting clinical benefits have yet to be identified. Since it is known that multiple sclerosis patients have a deficit of the regulatory T-cell subsets, we investigated whether interferon-beta therapy induced modifications of the two main categories of regulatory T cells (Tregs), natural and IL-10-secreting inducible Tr1 subset, in patients who are biologically responsive to the therapy. T-cell phenotype was determined by flow cytometry, while real-time PCR was used to evaluate interferon-beta bioactivity through MxA determination, and to measure the RNA for IL-10 and CD46 molecule in peripheral blood mononuclear cells stimulated with anti-CD46 and anti-CD3 monoclonal antibodies, which are known to expand a Tr1-like population. Interferon-beta induced a redistribution of natural Treg subsets with a shift of naive Tregs towards the 'central memory-like' Treg population that expresses the CCR7 molecule required for the in vivo suppressive activity. Furthermore, in a subgroup of treated patients, the CD46/CD3 co-stimulation, probably through the Tr1-like subset modulation, increased the production of RNA for IL-10 and CD46. The same group showed a lower median EDSS score after two years of therapy. The selective increase of 'central memory-like' subset and the involvement of the Tr1-like population may be two of the mechanisms by which interferon-beta achieves its beneficial effects. The quantification of RNA for IL-10 and CD46 could be used to identify patients with a different response to interferon-beta therapy.


Magnetic resonance imaging of feline hippocampal necrosis.
The clinical, neuropathologic, and magnetic resonance (MR) imaging features in four cats with necrosis of the hippocampus and piriform lobe are described. All cats had acute generalized seizures and behavioral changes including aggression, salivation, polyphagia, and disorientation. Routine hematologic, serum chemistry, and cerebrospinal fluid analyses were normal. MR imaging abnormalities were restricted to the area of the hippocampus and piriform lobe. The lesions were T2-hyperintense, T1-hypointense, and were characterized by various degrees of contrast enhancement. Lesions were consistent with necrotizing encephalitis. Two cats were euthanized and underwent postmortem examination within a week after MR imaging due to the lack of response to antiepileptic drug therapy and progressive encephalopathy [corrected] The remaining two cats lived for about four months and were then euthanized because of persistent behavioral and neurologic signs; only one of these cats underwent postmortem examination with histopathologic examination. Histopathological findings were typical of severe, diffuse, bilateral symmetric necrosis, and degeneration of neurons in the hippocampus and piriform lobe, but an etiologic agent was not apparent. This apparently unique feline syndrome, now reported in Switzerland and Italy, has no known cause at this time.


Associations of the MCM6-rs3754686 proxy for milk intake in Mediterranean and American populations with cardiovascular biomarkers, disease and mortality: Mendelian randomization.
Controversy persists on the association between dairy products, especially milk, and cardiovascular diseases (CVD). Genetic proxies may improve dairy intake estimations, and clarify diet-disease relationships through Mendelian randomization. We meta-analytically (n ≤ 20,089) evaluated associations between a lactase persistence (LP) SNP, the minichromosome maintenance complex component 6 (MCM6)-rs3754686C>T (nonpersistence>persistence), dairy intake, and CVD biomarkers in American (Hispanics, African-American and Whites) and Mediterranean populations. Moreover, we analyzed longitudinal associations with milk, CVD and mortality in PREDIMED), a randomized Mediterranean diet (MedDiet) intervention trial (n = 7185). The MCM6-rs3754686/MCM6-rs309180 (as proxy), LP-allele (T) was strongly associated with higher milk intake, but inconsistently associated with glucose and lipids, and not associated with CVD or total mortality in the whole population. Heterogeneity analyses suggested some sex-specific associations. The T-allele was associated with higher CVD and mortality risk in women but not in men (P-sex interaction:0.005 and 0.032, respectively), mainly in the MedDiet group. However, milk intake was not associated with CVD biomarkers, CVD or mortality either generally or in sub-groups. Although MCM6-rs3754686 is a good milk intake proxy in these populations, attributing its associations with CVD and mortality in Mediterranean women to milk is unwarranted, as other factors limiting the assumption of causality in Mendelian randomization may exist.


[Hepatoblastoma cells producing alpha-fetoprotein: morphometric, immunohistochemical and electron microscopic studies].
Morphometric, immunohistochemical, and electron-microscopic studies were undertaken in an attempt to identify the types of hepatoblastoma cellular elements responsible for the synthesis of alpha-fetoprotein (AFP), and to see how they may relate to serum AFP levels and the metastatic spread and prognosis of the hepatoblastoma. Morphometric studies of 21 hepatoblastomas with statistical treatment of the results revealed a moderately strong reliable correlation of the AFP serum titer with the volume ratio of embryonal tumor cells and with that of those tumor elements of endodermal hepatic diverticulum which are similar to the latter cells with regard to degree of differentiation. Also, a consistent, reliable negative correlation was demonstrated between serum AFP titer and the volume of fetal hepatoblastoma cells. The volume ratio of stromal elements was found to be subject to chance variations and not to correlate with serum AFP level. Immunohistochemical and electron-microscopic studies confirmed the morphometric findings and showed AFP synthesis to be effected by poorly differentiated hepatoblastoma cells--by endodermal hepatic diverticulum elements at first and by embryonal and intermediate tumor cells later--and to decrease as the liver tumor cells differentiate further. It is concluded that a high serum AFP level is, generally, an indication that the hepatoblastoma is an extensive one and consists of poorly differentiated cells so that the prognosis is unfavorable.


The antimicrobial peptide LL-37 activates innate immunity at the airway epithelial surface by transactivation of the epidermal growth factor receptor.
Antimicrobial peptides produced by epithelial cells and neutrophils represent essential elements of innate immunity, and include the defensin and cathelicidin family of antimicrobial polypeptides. The human cathelicidin cationic antimicrobial protein-18 is an antimicrobial peptide precursor predominantly expressed in neutrophils, and its active peptide LL-37 is released from the precursor through the action of neutrophil serine proteinases. LL-37 has been shown to display antimicrobial activity against a broad spectrum of microorganisms, to neutralize LPS bioactivity, and to chemoattract neutrophils, monocytes, mast cells, and T cells. In this study we show that LL-37 activates airway epithelial cells as demonstrated by activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and increased release of IL-8. Epithelial cell activation was inhibited by the MAPK/ERK kinase (MEK) inhibitors PD98059 and U0126, by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478, by blocking anti-EGFR and anti-EGFR-ligand Abs, and by the metalloproteinase inhibitor GM6001. These data suggest that LL-37 transactivates the EGFR via metalloproteinase-mediated cleavage of membrane-anchored EGFR-ligands. LL-37 may thus constitute one of the mediators by which neutrophils regulate epithelial cell activity in the lung.


GA-based fuzzy reinforcement learning for control of a magnetic bearing system.
This paper proposes a TD (temporal difference) and GA (genetic algorithm)-based reinforcement (TDGAR) learning method and applies it to the control of a real magnetic bearing system. The TDGAR learning scheme is a new hybrid GA, which integrates the TD prediction method and the GA to perform the reinforcement learning task. The TDGAR learning system is composed of two integrated feedforward networks. One neural network acts as a critic network to guide the learning of the other network (the action network) which determines the outputs (actions) of the TDGAR learning system. The action network can be a normal neural network or a neural fuzzy network. Using the TD prediction method, the critic network can predict the external reinforcement signal and provide a more informative internal reinforcement signal to the action network. The action network uses the GA to adapt itself according to the internal reinforcement signal. The key concept of the TDGAR learning scheme is to formulate the internal reinforcement signal as the fitness function for the GA such that the GA can evaluate the candidate solutions (chromosomes) regularly, even during periods without external feedback from the environment. This enables the GA to proceed to new generations regularly without waiting for the arrival of the external reinforcement signal. This can usually accelerate the GA learning since a reinforcement signal may only be available at a time long after a sequence of actions has occurred in the reinforcement learning problem. The proposed TDGAR learning system has been used to control an active magnetic bearing (AMB) system in practice. A systematic design procedure is developed to achieve successful integration of all the subsystems including magnetic suspension, mechanical structure, and controller training. The results show that the TDGAR learning scheme can successfully find a neural controller or a neural fuzzy controller for a self-designed magnetic bearing system.


An anti-human recombinant tumor necrosis factor alpha (TNF alpha) monoclonal antibody recognizes an epitope in feline TNF alpha.
It is likely that the murine response to human recombinant TNF alpha (hrTNF alpha) may generate antibodies (Ab) to epitopes present in TNF alpha from other species. Here, we demonstrate that F5 anti-hrTNF alpha monoclonal antibody (mAb) recognizes feline TNF alpha while E8 anti-hrTNF alpha mAb failed to do so. In order to demonstrate that E8 and F5 mAb recognize different epitopes in the hrTNF alpha molecule, a constant concentration of E8 and variable concentrations of F5 were incubated with solid phase bound hrTNF alpha. Binding of E8 and F5 to hrTNF alpha was determined with anti-mu and gamma chain specific Ab. F5 bound equally to hrTNF alpha in the presence or absence of E8 and the same amount of E8 bound to hrTNF alpha, in spite of the presence of F5. When using the E8 and F5 mAb for capturing the TNF alpha from the equine, canine, feline and bovine species, in supernatants of an ex vivo lipopolysaccharide (LPS)-stimulated whole blood cell culture, we only detected the feline TNF alpha by F5 mAb (p = 0.001). By a cytotoxic assay on L929 fibroblasts, we indeed demonstrated the feline TNF alpha production after the LPS stimulus. In an inhibition assay, the human and feline cytokines competed for F5, although the inhibition of native human TNF alpha binding to F5 was significant but only about 20% (p = 0.001). In conclusion, most likely the F5 anti-hrTNF alpha mAb recognizes an epitope in feline TNF alpha. Its immunomodulatory potential in the feline model remains to be studied.


Phospholipase A2 enzymes and the risk of atherosclerosis.
Certain members of the phospholipase A(2) superfamily of enzymes have established causal involvement in atherosclerosis, thus at least two groups of this family of enzymes have been considered potential candidates for the prevention of cardiovascular events. Recently completed experimental animal studies, human biomarker data, vascular imaging studies, and genome-wide atherosclerosis studies provide the rationale for proceeding with clinical outcome trials directed at inhibition of secretory phospholipase A(2) and lipoprotein-associated phospholipase A(2). A clinical trial with the sPLA(2) inhibitor varespladib methyl was recently terminated, while clinical trials with the Lp-PLA(2) inhibitor darapladib are being conducted in coronary heart disease patients. This article reviews the available experimental animal and human trial evidence that serve as the basis for the development of these two classes of phospholipase A(2) inhibitors.


Bacterial community dynamics across developmental stages of fungal fruiting bodies.
Increasing evidence suggest that bacteria form diverse communities in various eukaryotic hosts, including fungi. However, little is known about their succession and the functional potential at different host development stages. Here we examined the effect of fruiting body parts and developmental stages on the structure and potential function of fungus-associated bacterial communities. Using high-throughput sequencing, we characterized bacterial communities and their associated potential functions in fruiting bodies from ten genera belonging to four major mushroom-forming orders and three different developmental stages of a model host species Cantharellus cibarius. Our results demonstrate that bacterial community structure differs between internal and external parts of the fruiting body but not between inner tissues. The structure of the bacterial communities showed significant variation across fruiting body developmental stages. We provide evidence that certain functional groups, such as those related to nitrogen fixation, persist in fruiting bodies during the maturation, but are replaced by putative parasites/pathogens afterwards. These data suggest that bacterial communities inhabiting fungal fruiting bodies may play important roles in their growth and development.


The 20 item prosopagnosia index (PI20): relationship with the Glasgow face-matching test.
The 20 item prosopagnosia index (PI20) was recently developed to identify individuals with developmental prosopagnosia. While the PI20's principal purpose is to aid researchers and clinicians, it was suggested that it may serve as a useful screening tool to identify people with face recognition difficulties in applied settings where face matching is a critical part of their occupation. Although the PI20 has been validated using behavioural measures of face recognition, it has yet to be validated against a measure of face-matching ability that is more representative of applied settings. In this study, the PI20 was therefore administered with the Glasgow face-matching test (GFMT). A strong correlation was observed between PI20 and GFMT scores, providing further validation for the PI20, indicating that it is likely to be of value in applied settings.


Gene organization and transcription of duplicated MBP genes of myelin deficient (shi(mld)) mutant mouse.
A hereditary dysmyelinating mutation, named myelin deficient (shi(mld)), is characterized by reduced expression of myelin basic protein (MBP). In shi(mld), the MBP gene is duplicated and its reduced expression is mainly determined by the level of mRNA. We have characterized the structure and function of the promoter regions of the duplicated MBP genes in shi(mld). Among the lambda clones containing promoter regions of the duplicated MBP genes in shi(mld), one (gene 1) had the same restriction enzyme pattern as that in control mice, but another (gene 2) had a rearrangement on a distal part of the promoter. A 712-bp nucleotide sequence upstream of the first exons of both of the duplicated MBP genes of shi(mld) was completely consistent with that of the control. Promoter activities of 1.3-kb 5'-flanking regions from respective genes of shi(mld) measured by in vitro run-off assay using HeLa whole-cell extracts were indistinguishable from that of the control MPB gene. Chromosomal mapping by in situ hybridization suggested that the duplicated MBP genes were located closely to each other at the distal part of chromosome 18. A recombinational event including the inversion seemed to have occurred within gene 1 and its possible relationship to the reduced expression of MBP is discussed.


Modification of Association of Cystatin C With Kidney and Cardiovascular Outcomes by Obesity.
Cystatin C-based estimated glomerular filtration rate (eGFRcys) has stronger associations with adverse clinical outcomes than creatinine-based eGFR (eGFRcr). Obesity may be associated with higher cystatin C levels, independent of kidney function, but it is unknown whether obesity modifies associations of eGFRcys with kidney and cardiovascular outcomes. Cohort study. 27,249 US adults in the Reasons for Geographic and Racial Differences in Stroke Study. eGFRcys, eGFRcr, waist circumference, and body mass index (BMI). All-cause mortality, kidney failure, incident atherosclerotic cardiovascular disease (ASCVD), and incident heart failure (HF). Multivariable Cox and Fine-Gray models with multiplicative interaction terms were constructed to investigate whether waist circumference quartiles or BMI categories modified associations of eGFRcys with risks of 4 clinical outcomes. Participants had a mean age of 65 years; 54% were women, 41% were Black, and 21% had an eGFRcys<60mL/min/1.73m2. The baseline prevalence of abdominal obesity (waist circumference≥88cm for women or≥102cm for men) was 48% and obesity was 38%. In multivariable adjusted analyses, each 15mL/min/1.73m2 lower eGFRcys was associated with higher HR and 95% CI of mortality in each waist circumference quartile (first quartile, 1.19 [1.15-1.24]; second quartile, 1.22 [1.18-1.26]; third quartile, 1.20 [1.16-1.24]; fourth quartile, 1.19 [1.15-1.23]) as well as within each BMI category (BMI<24.9: 1.21 [1.17-1.25]; BMI 25.0-29.9: 1.21 [1.18-1.25]; BMI 30.0-34.9: 1.20 [1.16-1.25]; BMI≥35: 1.17, [1.12-1.22]). Neither waist circumference nor BMI modified the association of eGFRcys with mortality, kidney failure, incident ASCVD, or incident HF (all Pinteraction>0.05). Included only Black and White persons in the United States. Obesity did not modify the association of eGFRcys with all-cause mortality, kidney failure, incident ASCVD, or incident HF. Among individuals with obesity, cystatin C may be used to provide eGFR-based risk prognostication for adverse outcomes. Cystatin C is increasingly used in clinical practice to estimate kidney function, and cystatin C-based eGFR (eGFRcys) may be used to determine risk for adverse clinical outcomes. Adiposity may increase serum levels of cystatin C, independent of kidney function. This cohort study investigated whether associations of eGFRcys with adverse kidney and cardiovascular outcomes are modified by measures of obesity, waist circumference, and body mass index. We found that obesity does not modify associations of eGFRcys with 4 clinical outcomes and conclude that among individuals with obesity, cystatin C may be used to provide eGFR-based risk prognostication for adverse outcomes.


[Biochemical characteristics of functionally active actin-like protein from liver mitochondria].
The actin-like protein with a molecular weight of 42 kDa was obtained from the preparation of freshly isolated mitochondria of the rat liver using the method of immobilized DNAse affinity chromatography. The inhibitory ability of the isolated protein with respect to pancreatic DNAse I was the same as that of muscular actin. The native structure of the mitochondria protein is confirmed by the data of spectral analysis and its ability to globular-fibrillar transformation with an increased ionic strength of the solution. The polymerization ability as well as a stimulating effect of the actin-like protein of mitochondria on the ATPase activity of myosin is much less pronounced as compared to actin of skeletal muscles.


Near-infrared photoimmunotherapy: a comparison of light dosing schedules.
Near infrared photoimmunotherapy (NIR-PIT) is a newly-developed cancer therapy in which a monoclonal antibody is conjugated to a near-infrared photoabsorber, IR700 to form an antibody photoabsorber conjugate (APC). After the APC binds to cancer cells expressing the cognate antigen, exposure to NIR light results in rapid, highly selective necrotic cell death of the cancer cells with minimal off-target effects. Several hours after NIR-PIT, the tumor vessels become supraphysiologically permeable and circulating APC can therefore readily leak into the already-treated tumor space where it can bind with viable cancer cells that is called super-enhanced permeability and retention effect. The presence of the SUPR effect after NIR-PIT has prompted regimens in which there is a repeat exposure of NIR light 24 hours after the initial NIR-PIT to take advantage of the leakage of additional APC deeper into the tumor. However, this post-treatment APC penetration was fully induced within 3 hours, therefore, it is possible that repeated exposures of NIR light could be administered much earlier than 24 hours and still produce the same effects. To test this idea, we compared several modes of delivering additional doses of light after initial NIR-PIT. We found that repeated exposures of NIR light starting 3 hours after initial NIR-PIT produced equal or superior results to more delayed exposures of NIR light. This finding has practical implications of an easy-to-perform regimen as repeated light exposures could be performed during a single day rather than extending the procedure over two days which is the current recommendation.


Breast cancer in Ardabil province in the north-west of Iran: an epidemiological study.
Breast cancer accounts for about 26% of all newly diagnosed cancers in women aged 20 to 59 years. As part of a basic program for cancer control, the present cross sectional descriptive study was conducted with the objective of determining the epidemiology of breast cancer in Ardabil province during 2003-2010. Necessary information on 469 recorded cases of breast cancer in the registry were collected by check list from patient's files and then analyzed by statistical methods with SPSS.16 software. Some 455 of the patients (97%) were female, 329 (70.1%) residing in Ardabil. The mean age was 46.8 ± 13.6 and most were in the age group of 40 - 60. The most prevalent pathologic form was infiltrative ductal carcinoma with 316 cases (67.4%), the largest proportion being grade II (30.6%), but very many belonged to grades III and IV (40.5%). Breast cancer in Ardabil province appeared to slightly increase over the period studied. The results were similar to other places in Asia. With regard to this, more widespread studies are required to determine factors influencing the prevalence at low age and also how to promote early detection.


A three-dimensional model of RNase P in the hyperthermophilic archaeon Pyrococcus horikoshii OT3.
Ribonuclease P (RNase P) is an endoribonuclease involved in maturation of the 5'-end of tRNA. We found previously that RNase P in the hyperthermophilic archaeon Pyrococcus horikoshii OT3 consists of a catalytic RNase P RNA (PhopRNA) and five protein cofactors designated PhoPop5, PhoRpp21, PhoRpp29, PhoRpp30, and PhoRpp38. The crystal structures of the five proteins have been determined, a three-dimensional (3-D) model of PhopRNA has been constructed, and biochemical data, including protein-RNA interaction sites, have become available. Here, this information was combined to orient the crystallographic structures of the proteins relative to their RNA binding sites in the PhopRNA model. Some alterations were made to the PhopRNA model to improve the fit. In the resulting structure, a heterotetramer composed of PhoPop5 and PhoRpp30 bridges helices P3 and P16 in the PhopRNA C-domain, thereby probably stabilizing a double-stranded RNA structure (helix P4) containing catalytic Mg2+ ions, while a heterodimer of PhoRpp21 and PhoRpp29 locates on a single-stranded loop connecting helices P11 and P12 in the specificity domain (S-domain) in PhopRNA, probably forming an appropriate conformation of the precursor tRNA (pre-tRNA) binding site. The fifth protein PhoRpp38 binds each kink-turn (K-turn) motif in helices P12.1, P12.2, and P16 in PhopRNA. Comparison of the structure of the resulting 3-D model with that of bacterial RNase P suggests transition from RNA-RNA interactions in bacterial RNase P to protein-RNA interactions in archaeal RNase P. The proposed 3-D model of P. horikoshii RNase P will serve as a framework for further structural and functional studies on archaeal, as well as eukaryotic, RNase Ps.


Beyond the Benefits of Assistance Dogs: Exploring Challenges Experienced by First-Time Handlers.
The purpose of this study was to explore first time handlers' experiences when working with an assistance dog (AD). Interviewees included seven first time AD handlers and 14 other individuals close to these handlers, including family members, carers and AD instructors. Semi-structured interviews were conducted six months and one year after each handler received their AD. Interview questions were informed by the Thriving Through Relationships theory of social support and previous interviews with the participants. Inductive content analysis corroborated previous findings regarding the benefits that ADs provide. In addition, four factors were revealed to substantially influence the challenges handlers experienced when learning to utilize their dog. These included the handlers' medical conditions, cognitive ability and social environment, and dog-related factors. Organizations would benefit from considering these factors in their operational processes.


Analgesic use before and after oral anticoagulant initiation--a population-based study in Finland.
Due to potential drug-drug interactions and subsequent bleeding risk, analgesic use should be reviewed when an oral anticoagulant is initiated. The aim of this study was to compare use of non-steroidal anti-inflammatory drugs (NSAIDs) and other analgesics before and after oral anticoagulant initiation. All individuals who initiated warfarin, dabigatran, or rivaroxaban between January 2012 and September 2013 were identified from the Finnish Prescription Register. Prevalence of analgesic use during 3 months after oral anticoagulant initiation was compared to analgesic use during 4 months before initiation. Analgesics included were NSAIDs, paracetamol, paracetamol in doses ≥ 2 g/day, tramadol, and other opioids. Conditional logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI). In total, 54,025 initiated warfarin, 16,894 rivaroxaban, and 1569 dabigatran. The odds of NSAID use decreased among warfarin initiators (odds ratio (OR) 0.10; 95% confidence interval (CI) 0.09-0.10); 2.6% used NSAID after initiation. In contrast, the odds of NSAID use increased among rivaroxaban (OR 3.56; 95% CI 3.37-3.75) and dabigatran initiators (OR 1.44; 95% CI 1.16-1.78). The proportions using NSAIDs after the initiation were 69 and 32%, respectively. However, NSAID use decreased among dabigatran initiators with confirmed atrial fibrillation (OR 0.46; 95% CI 0.23-0.92) and among rivaroxaban initiators with a daily dose of ≥ 15 mg (OR 0.28; 95% CI 0.19-0.40). The use of NSAIDs decreases extensively among warfarin initiators which is encouraging. However, the use of NSAIDs increases among rivaroxaban and dabigatran initiators. This is a concern as the bleeding risk may increase due to potential pharmacodynamic interactions.


Undiagnosed Hypertension in a Workplace: The Case of a Logistics Company in Gauteng, South Africa.
A large proportion of the population with hypertension remains undiagnosed, untreated, or inadequately treated, contributing to the rising burden of cardiovascular diseases in South Africa. A workplace may either mitigate or accentuate the risk factors for hypertension. A cross sectional study was conducted to determine the prevalence of undiagnosed hypertension and associated factors among 312 employees in a Logistics Company, South Africa. A modified, validated, self-administered WHO STEPwise questionnaire was used to collect data on demography, lifestyle factors, anthropometry and blood pressure (BP). Hypertension was defined at BP ≥ 140/90 mmHg. Data was analysed using STATA 14. Mean age of employees was 40 ± 10 years, with a 50% prevalence of undiagnosed hypertension. No significant association was observed between occupation and undiagnosed hypertension, except for high prevalence of undiagnosed hypertension among truck drivers and van assistants (43%), and general workers (27%), having higher odds of increased waist-to-height ratio. Hypertension was associated with age (OR = 2.3, 95%CI; 1.21-4.27), alcohol use (AOR = 1.8, 95%CI; 1.05-2.93), waist circumference (AOR = 2.3, 95%CI; 1.29-4.07) and waist-to-height-ratio (AOR = 3.7, 95%CI; 1.85-7.30). Improved and effective workplace health programs and policies are necessary for management of undiagnosed hypertension among employees. Longitudinal studies on mediation of occupation in association of demographic and lifestyle factors with hypertension in workplaces are needed.


Assaying epigenome functions of PRMTs and their substrates.
Among the widespread and increasing number of identified post-translational modifications (PTMs), arginine methylation is catalyzed by the protein arginine methyltransferases (PRMTs) and regulates fundamental processes in cells, such as gene regulation, RNA processing, translation, and signal transduction. As epigenetic regulators, PRMTs play key roles in pluripotency, differentiation, proliferation, survival, and apoptosis, which are essential biological programs leading to development, adult homeostasis but also pathological conditions including cancer. A full understanding of the molecular mechanisms that underlie PRMT-mediated gene regulation requires the genome wide mapping of each player, i.e., PRMTs, their substrates and epigenetic marks, methyl-marks readers as well as interaction partners, in a thorough and unambiguous manner. However, despite the tremendous advances in high throughput sequencing technologies and the numerous efforts from the scientific community, the epigenomic profiling of PRMTs as well as their histone and non-histone substrates still remains a big challenge owing to obvious limitations in tools and methodologies. This review will summarize the present knowledge about the genome wide mapping of PRMTs and their substrates as well as the technical approaches currently in use. The limitations and pitfalls of the technical tools along with conventional approaches will be then discussed in detail. Finally, potential new strategies for chromatin profiling of PRMTs and histone substrates will be proposed and described.


System-size corrections for self-diffusion coefficients calculated from molecular dynamics simulations: The case of CO2, n-alkanes, and poly(ethylene glycol) dimethyl ethers.
Molecular dynamics simulations were carried out to study the self-diffusion coefficients of CO2, methane, propane, n-hexane, n-hexadecane, and various poly(ethylene glycol) dimethyl ethers (glymes in short, CH3O-(CH2CH2O)n-CH3 with n = 1, 2, 3, and 4, labeled as G1, G2, G3, and G4, respectively) at different conditions. Various system sizes were examined. The widely used Yeh and Hummer [J. Phys. Chem. B 108, 15873 (2004)] correction for the prediction of diffusion coefficient at the thermodynamic limit was applied and shown to be accurate in all cases compared to extrapolated values at infinite system size. The magnitude of correction, in all cases examined, is significant, with the smallest systems examined giving for some cases a self-diffusion coefficient approximately 15% lower than the infinite system-size extrapolated value. The results suggest that finite size corrections to computed self-diffusivities must be used in order to obtain accurate results.


PRMT5 mediates FoxO1 methylation and subcellular localization to regulate lipophagy in myogenic progenitors.
Development is regulated by various factors, including protein methylation status. While PRMT5 is well known for its roles in oncogenesis by mediating symmetric di-methylation of arginine, its role in normal development remains elusive. Using Myod1Cre to drive Prmt5 knockout in embryonic myoblasts (Prmt5MKO), we dissected the role of PRMT5 in myogenesis. The Prmt5MKO mice are born normally but exhibit progressive muscle atrophy and premature death. Prmt5MKO inhibits proliferation and promotes premature differentiation of embryonic myoblasts, reducing the number and regenerative function of satellite cells in postnatal mice. Mechanistically, PRMT5 methylates and destabilizes FoxO1. Prmt5MKO increases the total FoxO1 level and promotes its cytoplasmic accumulation, leading to activation of autophagy and depletion of lipid droplets (LDs). Systemic inhibition of autophagy in Prmt5MKO mice restores LDs in myoblasts and moderately improves muscle regeneration. Together, PRMT5 is essential for muscle development and regeneration at least partially through mediating FoxO1 methylation and LD turnover.


SIR DYNAMICS WITH ECONOMICALLY DRIVEN CONTACT RATES.
The susceptible-infected-recovered (SIR) model has greatly evidenced epidemiology despite its apparent simplicity. Most applications of the SIR framework use a form of nonlinear incidence to describe the number of new cases per instant. We adapt theorems to analyze the stability of SIR models with a generalized nonlinear incidence structure. These theorems are then applied to the case of standard incidence and incidence resulting from adaptive behavioral response based on epidemiological-economic theory. When adaptive behavior is included in the SIR model multiple equilibria and oscillatory epidemiological dynamics can occur over a greater parameter space. Our analysis, based on the epidemiological-economic incidence, provides new insights into epidemics as complex adaptive systems, highlights important nonlinearities that lead to complex behavior, and provides mechanistic motivation for a shift away from standard incidence, and outlines important areas of research related to the complex-adaptive dynamics of epidemics.


Merger in Eivissan Catalan: an acoustic analysis of the vowel systems of young native speakers.
The vowel system of Catalan has been the focus of many studies, though work on the varieties spoken on the island of Eivissa (Ibiza) are scarce, with a single mention of the possible merger of the mid back vowels /o, ɔ/ (Torres Torres, Marià. 1983. Aspectes del vocalisme tònic eivissenc. Eivissa 14. 22-23). The present article provides the first acoustic analysis of the vowel inventory of 25 young native speakers of Eivissan Catalan, with a focus on the realisations of stressed /ə, ɛ/, and the back mid vowels /o, ɔ/. We employed Pillai scores (Hay, Jennifer, Paul Warren & Katie Drager. 2006. Factors influencing speech perception in the context of a merger-in-progress. Journal of Phonetics 34. 458-484) to compare the possibly merged pairs /ə, ɛ/ and /o, ɔ/ to the fully-contrasting neighbouring pairs /e, ɛ/ and /o, u/. Our results show that all participants had considerable overlap of stressed /ə/ and /ɛ/, and all but one had considerable overlap of the back mid vowels, while the fully contrastive pairs (/e, ɛ/ and /o, u/) showed almost no overlap.


[Spectrum-effect relationship of Moutan cortex against lipopolysaccharide-induced acute lung injury].
This research is to study the relationship between HPLC fingerprints of Moutan Cortex, Paeoniae Radix Rubra and Paeoniae Radix Alba and their activity on lipopolysaccharide-induced acute lung injury. HPLC fingerprints of each extract of Moutan Cortex,Paeoniae Radix Rubra and Paeoniae Radix Alba were established by an optimized HPLC-MS method. The activities of all samples against protein and tumor necrosis a factor were tested by the model of lipopolysaccharide-induced acute lung injury. The possible relationship between HPLC-MS fingerprints and the activitieswere deduced by the Partial least squares regression analysis method. Samples were analyzed by HPLC-MS/MS to identify the major peaks. The results showed that each sample had some effect on acute lung injury. Four components with a lager contribution rate of efficacy were calculated by the research of spectrum-effect relationship. Moutan Cortex exhibited good activity on acute lung injury, and gallic acid, paeoniflorin, galloylpaeoniflorin and paeonol were the main effective components.


Inclisiran in patients with prior myocardial infarction: A post hoc pooled analysis of the ORION-10 and ORION-11 Phase 3 randomised trials.
Among patients with prior myocardial infarction (MI), the risk of future ischaemic cardiovascular events is increased, and intensive lipid-lowering therapy (LLT) is indicated to achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals. Here, the efficacy and safety of inclisiran, a small interfering ribonucleic acid, were evaluated in patients with or without prior MI from the pooled ORION-10 and ORION-11 Phase 3 trials. Patients (n = 2636) were randomised 1:1 to receive 284 mg inclisiran (300 mg inclisiran sodium) or placebo on Day 1, Day 90, and 6-monthly thereafter over 18 months, along with background oral LLT, including statins. Of these, 1643 (62.3%) patients had an MI prior to randomisation, stratified as recent (>3 months to <1 year) or remote (≥1 year), and 993 (37.7%) patients were without a prior MI. The percentage change in LDL-C from baseline and safety were assessed. Baseline characteristics were well balanced across the treatment arms and MI strata. The mean (95% confidence interval) placebo-corrected LDL-C reductions from baseline to Day 510 with inclisiran were 52.6% (40.1, 65.1), 50.4% (47.0, 53.8), and 51.6% (47.4, 55.9) for recent, remote, and no prior MI, respectively. Corresponding time-adjusted LDL-C reductions were 50.0% (41.4, 58.7), 52.2% (49.8, 54.7), and 51.2% (48.1, 54.2). In each MI stratum, treatment-emergent adverse events (TEAEs) at the injection site (all mild to moderate) were observed more in inclisiran-treated patients than placebo, without an excess of other TEAEs. Inclisiran provided effective and consistent LDL-C lowering, irrespective of MI status.


Neural transfer learning for assigning diagnosis codes to EMRs.
Electronic medical records (EMRs) are manually annotated by healthcare professionals and specialized medical coders with a standardized set of alphanumeric diagnosis and procedure codes, specifically from the International Classification of Diseases (ICD). Annotating EMRs with ICD codes is important for medical billing and downstream epidemiological studies. However, manually annotating EMRs is both time-consuming and error prone. In this paper, we explore the use of convolutional neural networks (CNNs) for automatic ICD coding. Because many codes occur infrequently, CNN performance is inhibited. Therefore, we propose supplementing EMR data with PubMed indexed biomedical research abstracts through neural transfer learning. Transfer learning is the process of "transferring" knowledge acquired from one task (the source task) to a different (target) task. For the source task, we train a CNN to predict medical subject headings (MeSH) using 1.6 million PubMed indexed biomedical abstracts. For the target task, we train a CNN on 71,463 real-world EMRs collected from the University of Kentucky (UKY) medical center to predict ICD diagnosis codes. We introduce a simple, yet effective, transfer learning methodology which avoids forgetting knowledge gained from the source task. Compared to our prior work using EMRs from the UKY medical center, we improve both the micro and macro F-scores by more than 8%. Likewise, compared to other transfer learning methods, our approach results in nearly 2% improvement in macro F-score. We show that transfer learning can improve CNN performance for EMR coding in the presence of data sparsity issues. Furthermore, we find that our proposed transfer learning approach outperforms other methods with respect to macro F-score. Finally, we analyze how transfer learning impacts codes with respect to code frequency. We find that we achieve greater improvement on infrequent codes compared to improvements in most frequent codes.


Plasma membrane calcium-ATPase isoform four distribution changes during corneal epithelial wound healing.
Plasma Membrane Calcium-ATPases (PMCAs) are integral membrane proteins essential to the control of intracellular Ca2+ concentration. In humans, four genes encode PMCA proteins termed PMCA1-PMCA4. PMCA4 is the major PMCA isoform expressed in human corneal epithelium (hCE); however, little is known about its role. The present study documented expression of PMCA4 in rabbit CE (rbCE) and followed the distribution of PMCA4 during CE wound healing in a rabbit (rb) model. Reverse transcriptase PCR using PMCA4 isoform gene-specific primers that flanked alternative splice site A was used to examine the presence of PMCA4 mRNA in rbCE. Protein expression was assessed by immunoblotting using panPMCA- and PMCA4-specific antibodies. Immunocytochemistry was employed to examine PMCA immunolocalization in frozen, formaldehyde-fixed sections of control and wounded rb corneas. In wound healing studies, circular, 6-mm diameter corneal wounds were produced in the central CE using the n-heptanol technique. The distribution of PMCA4 in CE was examined by immunohistochemical staining of frozen sections using PMCA4 isoform-specific antibody at 6-, 24-, 36-, and 48 h post-injury. siRNA(PMCA4) was used to transfect telomerase-immortalized human corneal epithelial (hTCEpi) cells. Cell cultures were wounded 48 h after transfection, and the wound area was measured at 0 h and at 3 h intervals post-wounding. Direct sequencing of PCR DNAs documented the presence of PMCA4 transcripts in rbCE and showed that the splice variant at site A was PMCA4x. Immunoblot analysis for PMCA4 detected an intense band at approximately 160 kDa and a faint band at approximately 142 kDa. Immunohistochemistry with the panPMCA antibody demonstrated strong immunoreactivity (IR) in all layers of uninjured rbCE. Immunohistochemistry with a PMCA4-specific antibody demonstrated a similar pattern of intense IR along the plasma membrane of cells in all layers of CE, except for the notable absence of PMCA4 IR along the basal cell membranes adjacent to the stroma. The pattern of PMCA4 IR changed following wound healing. During the lag phase of corneal epithelial wound healing, PMCA4 IR was seen mostly on apical plasma membranes of basal cells near the wound margin, with little staining of basal plasma membranes. During the migration phase (24 h), PMCA4 IR was found mostly on basal cell membranes adjacent to the stroma. At 6 h and 24 h following wounding, PMCA4 IR of the cytoplasm was increased compared to control eyes. After closure of the denuded area and stratification, PMCA4 IR was again primarily found along the apical and lateral plasma membranes of basal cells and was again absent from basal cell membranes adjacent to the stroma; PMCA4 IR of the cytoplasm was also similar to that observed in control eyes. siRNA(PMCA4) transfected hTCEpi cells failed to seal the wound area, whereas wounds in control cultures transfected with a scrambled construct were completed healed. PMCA4 is strongly expressed in rabbit CE and its immunolocalization exhibits marked changes in distribution during the wound healing process. Knockdown of PMCA4 expression in hTCEpi cells decreases wound healing. Present findings suggest that PMCA4 redistribution could function as one factor in mediating calcium-regulated events necessary for cell migration in regenerating CE.


Novel single nucleotide polymorphisms of the bovine methyltransferase 3b gene and their association with meat quality traits in beef cattle.
DNA methylation is essential for adipose deposition in mammals. We screened SNPs of the bovine DNA methyltransferase 3b (DNMT3b) gene in Snow Dragon beef, a commercial beef cattle population in China. Nine SNPs were found in the population and three of six novel SNPs were chosen for genotyping and analyzing a possible association with 16 meat quality traits. The frequencies of the alleles and genotypes of the three SNPs in Snow Dragon beef were similar to those in their terminal-paternal breed, Wagyu. Association analysis disclosed that SNP1 was not associated with any of the traits; SNP2 was significantly associated with lean meat color score and chuck short rib score, and SNP3 had a significant effect on dressing percentage and back-fat thickness in the beef population. The individuals with genotype GG for SNP2 had a 25.7% increase in lean meat color score and a 146% increase in chuck short rib score, compared with genotype AA. The cattle with genotype AG for SNP3 had 35.7 and 24% increases in dressing percentage and 28.8 and 29.2% increases in back-fat thickness, compared with genotypes GG and AA, respectively. Genotypic combination analysis revealed significant interactions between SNP1 and SNP2 and between SNP2 and SNP3 for the traits rib-eye area and live weight. We conclude that there is considerable evidence that DNMT3b is a determiner of beef quality traits.


m6A-express: uncovering complex and condition-specific m6A regulation of gene expression.
N6-methyladenosine (m6A) is the most abundant form of mRNA modification and controls many aspects of RNA metabolism including gene expression. However, the mechanisms by which m6A regulates cell- and condition-specific gene expression are still poorly understood, partly due to a lack of tools capable of identifying m6A sites that regulate gene expression under different conditions. Here we develop m6A-express, the first algorithm for predicting condition-specific m6A regulation of gene expression (m6A-reg-exp) from limited methylated RNA immunoprecipitation sequencing (MeRIP-seq) data. Comprehensive evaluations of m6A-express using simulated and real data demonstrated its high prediction specificity and sensitivity. When only a few MeRIP-seq samples may be available for the cellular or treatment conditions, m6A-express is particularly more robust than the log-linear model. Using m6A-express, we reported that m6A writers, METTL3 and METTL14, competitively regulate the transcriptional processes by mediating m6A-reg-exp of different genes in Hela cells. In contrast, METTL3 induces different m6A-reg-exp of a distinct group of genes in HepG2 cells to regulate protein functions and stress-related processes. We further uncovered unique m6A-reg-exp patterns in human brain and intestine tissues, which are enriched in organ-specific processes. This study demonstrates the effectiveness of m6A-express in predicting condition-specific m6A-reg-exp and highlights the complex, condition-specific nature of m6A-regulation of gene expression.


A distinct neurocognitive profile: unipolar mania.
Despite a growing number of studies reporting patients with a history of mania without depression have several socio-demographic and clinical differences than bipolar disorder patients, unipolar mania is recognized as bipolar I disorder in the most commonly used classification systems. Studies showing that unipolar mania is a separate clinical entity are insufficient in number, and to the best of our knowledge, there has been no study investigating the neuropsychological differences in this area. The aim of this study is to evaluate the neurocognitive differences between unipolar mania, bipolar I disorder and healthy controls, and to reveal the underlying neurocognitive differences. Cambridge Neuropsychological Test Automated Battery was applied to 18 unipolar mania, 19 bipolar I disorder patients and 21 healthy controls matched for age, sex and education levels. Unipolar mania group had worse performance regarding visual memory and executive functions, and had specific social cognition deficits compared to both bipolar I disorder and healthy control groups. The results of our study indicate that unipolar mania might have unique neurocognitive differences compared to bipolar I disorder, which might support the hypothesis that unipolar mania is a distinct neurocognitive disorder within bipolar spectrum disorders.


Qing Dai attenuates nonsteroidal anti-inflammatory drug-induced mitochondrial reactive oxygen species in gastrointestinal epithelial cells.
Treatments with nonsteroidal anti-inflammatory drugs (NSAIDs) have increased the number of patients with gastrointestinal complications. Qing Dai has been traditionally used in Chinese herbal medicine for various inflammatory diseases such as ulcerative colitis. We previously reported that Qing Dai suppressed inflammations by scavenging reactive oxygen species (ROS) in ulcerative colitis patients. Thus, Qing Dai can attenuate the production of ROS, which play an important role in NSAID-induced gastrointestinal injuries. In this study, we aimed to elucidate whether Qing Dai decreased mitochondrial ROS production in NSAID-treated gastrointestinal cells by examining cellular injury, mitochondrial membrane potentials, and ROS production with specific fluorescent indicators. We also performed electron paramagnetic resonance measurement in isolated mitochondria with a spin-trapping reagent (CYPMPO or DMPO). Treatments with indomethacin and aspirin induced cellular injury and mitochondrial impairment in the gastrointestinal cells. Under these conditions, mitochondrial alterations were observed on electron microscopy. Qing Dai prevented these complications by suppressing ROS production in gastrointestinal cells. These results indicate that Qing Dai attenuated the ROS production from the NSAID-induced mitochondrial alteration in the gastrointestinal epithelial cells. Qing Dai treatment may be considered effective for the prevention NSAID-induced gastrointestinal injury.


Social Representations of Urinary Incontinence in Caregivers and General Population: A Focus Group Study.
Urinary incontinence (UI) is a major public health problem. Although trivialized, it affects nearly 9% of the world's population and its prevalence increases with age. It affects many people living in nursing homes. In the literature, there is a lot of information on its symptoms, risk factors and therapeutic approaches, but its social representations are rarely studied. The objective of this qualitative focus-group study is to understand the social representations of urinary incontinence of caregivers of institutionalized elderly people, but also of the general population. Seven focus groups were organized with 41 participants. The data collected were analyzed both manually and using Atlas.Ti software. For caregivers and the general population, urinary incontinence remains a misunderstood and disturbing subject: judged as too intimate, embarrassing, and shameful, it is even considered uninteresting by those who are not affected, with some going so far as to make fun of those affected. It is also represented as a real difficulty for relationships: it can be a source of conflict, but also of questioning by the role of caregiver. However, it is also represented as a means of increasing the empowerment of the residents concerned, thanks to the choice of their means of protection. This study has enabled us to gain a deeper understanding of the social representations of caregivers and the general population on urinary incontinence in the elderly, but also to highlight the various preventive and educational actions that could be taken to improve the management of this health problem. It is part of a larger research program that aims at understanding the representations of urinary incontinence of caregivers, the general population, but also of course, of residents in nursing homes and their carers.


Neurodevelopmental outcomes after staged palliation for hypoplastic left heart syndrome.
The goal was to determine the relative effects of underlying genetic factors and current management strategies on neurodevelopmental disabilities among one-year old survivors of palliation for hypoplastic left heart syndrome. Children who underwent staged reconstruction for hypoplastic left heart syndrome and variants were assessed at 1 year of age by using a neuromuscular examination and the Bayley Scales of Infant Development II, which provide the Mental Development Index and the Psychomotor Development Index. The effects of perioperative, operative, and genetic variables on developmental scores were evaluated. The median birth weight was 3.3 kg (range: 2.1-4.5 kg). Eight-three patients (94%) underwent multiple operations with cardiopulmonary bypass during the first year of life (median: 2 operations). Seven patients (8%) required extracorporeal membrane oxygenation. Twenty-five patients (28%) had a confirmed or suspected genetic syndrome. At 1 year of age, the neuromuscular examination results were abnormal or suspect for 57 patients (65%). The median Mental Development Index score was 90, and 10 patients (11%) had scores of <70 (2 SDs below the general population mean). The median Psychomotor Development Index score was 73, and 42 patients (48%) had scores of <70. In multivariate analyses, younger gestational age, the presence of a genetic syndrome, and the need for preoperative intubation had significant negative effects on neurodevelopmental outcomes. No association was found with operative factors, including duration of deep hypothermic circulatory arrest. At 1 year of age, there was a significant incidence of neurodevelopmental disabilities in children with hypoplastic left heart syndrome and variants; motor scores were particularly concerning. Many children had suspected or confirmed genetic syndromes, which negatively affected neurodevelopmental outcomes. Surgical variables did not affect neurologic outcomes.


A survey for arboviral antibodies in sera of humans and animals in Lombok, Republic of Indonesia.
Sera were collected from humans, cattle, horses, goats, ducks, chickens, wild birds, bats and rats in Lombok, Indonesia, and were tested by haemagglutination inhibition (HI) for antibodies to JE, ZIKA, CHIK and RR. Selected sera were tested by microneutralization tests for antibodies to the following viruses: JE, ZIKA, MVE, TMU, LGT, KUN, SEP, DEN-2, CHIK, RR, GET, SIN, BUN, BAT and BAK. Human sera had JE HI antibody in 135 (30%) of 446 tested. Neutralization tests indicated that DEN-2, ZIKA, TMU, KUN and SEP may have caused flavivirus infections. Antibodies to other arboviruses tested for were not found. HI and neutralization tests on animal sera indicated possible flavivirus infections with JE, MVE, KUN and SEP, and also that infections with BAT and BUN had occurred among domestic animals. No neutralizing antibodies were found for alphaviruses or other viruses used in the tests.


Three cases with de novo 6q imbalance and variable prenatal phenotype.
We describe two families in which three fetuses had a de novo 6q imbalance and abnormal phenotypes. We determined the boundaries and the parental origin of the chromosomal alterations by segregation analysis using a panel of short tandem repeats (STRs) located on 6q. Cases 1 and 2 (family A) were two sibs with 6q imbalance involving different regions. Case 1 was a female fetus with arthrogryposis, who had a complex rearrangement resulting in two deleted regions (6q22 and 6q25.1-q25.2) and a duplication of 6q23-q25.1. This latter imbalance was reported previously and is associated with joint contractures and short neck, also present in this fetus. The sib (case 2) had intrauterine growth restriction (IUGR) and agenesis of the ductus venosus. This male died shortly after birth; postnatal karyotype and molecular investigations showed a 6q21 de novo deletion. Case 3 (family B) had a prenatally detected deletion of 6q14-q16. Autopsy of the fetus documented minor facial anomalies and contractures of the limbs. All rearrangements were de novo and of paternal origin. Our data and the consistent number of cases of de novo 6q alterations previously reported suggest that chromosome arm 6q could be prone to rearrangements resulting in heterogeneous phenotypes. In family A, chromosome 6q imbalances involving different chromosomal regions were present in two consecutive pregnancies. In such cases counseling should suggest the impossibility of excluding recurrence of a chromosomal imbalance, and should discuss the option of early prenatal diagnosis in subsequent pregnancies.


Incorporating directivity in the Fourier pseudospectral time-domain method using spherical harmonics.
The pseudospectral time-domain method (PSTD) provides an efficient way to solve the linear acoustics equations. With regards to acoustic modeling and auralization, source directivity as well as head-related directivity have a clear influence on the perceived sound field and have to be included in computations. In this paper directive sources are implemented in the time-domain method PSTD. First, a given frequency dependent source directivity is decomposed onto spherical harmonic functions. The directive source is then implemented through spatial distributions in PSTD that relate to the spherical harmonic functions, and time-dependent functions are assigned to the spatial distributions in order to obtain the frequency content of the directivity. Since any directivity function can be expressed as a summation of series of spherical harmonics, the approach can be used to model any type of directive source. For the evaluation of the method, a directivity function was designed analytically and then modeled in PSTD. Octave band analysis was performed and results show a good agreement between the analytical and simulated directivity. A distance related error was observed. However, for distances above 17.5 grid cells from the source center the average error was small (<0.9 dB) at all octave-bands.


Social Brain Activation and Connectivity in Autism Spectrum Disorders: An Electroencephalogram Study of Jigsaw Puzzle Solving.
Autism spectrum disorder requires early detection and treatment. Thus, we developed a method to obtain reliable neurophysiological biomarkers to assist in diagnosing autism. This method includes a simple but typical jigsaw puzzle that allows participants to play and interact with each other. While playing this game, brain signals of the participants were observed and analyzed. The patients with autism were found to have differences in the time range of some event-related potential, such as P300 and N400. Altered patterns of function connectivity were also found in delta frequency bands in the patients while interacting with other people. Working around patients' capabilities, the jigsaw puzzle game was designed as easy to complete; this caused fewer mismatch conditions. The result suggested that these patterns are promising neurophysiological biomarker to assist doctors in social cognitive assessment in autism.Clinical Relevance-This study demonstrated the possibility of using hyperscanning technique for social cognitive assessment of autism spectrum disorder.


Effects of exercise training on neuromuscular junction morphology and pre- to post-synaptic coupling in young and aged rats.
The objective of this study was to determine whether pre- to post-synaptic coupling of the neuromuscular junction (NMJ) could be maintained in the face of significant morphological remodeling brought about by exercise training, and whether aging altered this capacity. Eighteen young adult (8 mo) and eighteen aged (24 mo) Fischer 344 rats were randomly assigned to either endurance trained (treadmill running) or untrained control conditions resulting in four groups (N=9/group). After the 10-week intervention rats were euthanized and hindlimb muscles were surgically removed, quickly frozen at approximate resting length and stored at -85°C. The plantaris and EDL muscles were selected for study as they have different functions (ankle extensor and ankle flexor, respectively) but both are similarly and overwhelmingly comprised of fast-twitch myofibers. NMJs were stained with immunofluorescent procedures and images were collected with confocal microscopy. Each variable of interest was analyzed with a 2-way ANOVA with main effects of age and endurance training; in all cases significance was set at P⩽0.05. Results showed that no main effects of aging were detected in NMJs of either the plantaris or the EDL. Similarly, endurance training failed to alter any synaptic parameters of EDL muscles. The same exercise stimulus in the plantaris however, resulted in significant pre- and post-synaptic remodeling, but without altering pre- to post-synaptic coupling of the NMJs. Myofiber profiles of the same plantaris and EDL muscles were also analyzed. Unlike NMJs, myofibers displayed significant age-related atrophy in both the plantaris and EDL muscles. Overall, these results confirm that despite significant training-induced reconfiguration of NMJs, pre- to post-synaptic coupling remains intact underscoring the importance of maintaining proper apposition of neurotransmitter release and binding sites so that effective nerve to muscle communication is assured.


Probing the interaction of nanoparticles with small molecules in real time via quartz crystal microbalance monitoring.
Despite extensive advances in the field of molecular recognition, the real-time monitoring of small molecule binding to nanoparticles (NP) remains a challenge. To this end, we report on a versatile approach, based on quartz crystal microbalance with dissipation monitoring, for the stepwise in situ quantification of gold nanoparticle (AuNPs) immobilisation and subsequent uptake and release of binding partners. AuNPs stabilised by thiol-bound ligand shells of prescribed chemical composition were densely immobilised onto gold surfaces via dithiol linkers. The boronate ester formation between salicylic acid derivatives in solution and boronic acids in the AuNP ligand shell was then studied in real time, revealing a drastic effect of both ligand architecture and Lewis base concentration on the interaction strength. The binding kinetics were analysed with frequency response modelling for a thorough comparison of binding parameters including relaxation time as well as association rate constant. The results directly mirror those from previously reported in-depth studies using nuclear magnetic resonance spectroscopy. By achieving quantitative characterisation of selective binding of analytes with molecular weight below 300 Da, this new method enables rapid, low cost, rational screening of AuNP candidates for molecular recognition.


A multi-omics view of the complex mechanism of vascular calcification.
Vascular calcification is a high incidence and high risk disease with increasing morbidity and high mortality, which is considered the consequence of smooth muscle cell transdifferentiation initiating the mechanism of accumulation of hydroxyl calcium phosphate. Vascular calcification is also thought to be strongly associated with poor outcomes in diabetes and chronic kidney disease. Numerous studies have been accomplished; however, the specific mechanism of the disease remains unclear. Development of the genome project enhanced the understanding of life science and has entered the post-genomic era resulting in a variety of omics techniques used in studies and a large amount of available data; thus, a new perspective on data analysis has been revealed. Omics has a broader perspective and is thus advantageous over a single pathway analysis in the study of complex vascular calcification mechanisms. This paper reviews in detail various omics studies including genomics, proteomics, transcriptomics, metabolomics and multiple group studies on vascular calcification. Advances and deficiencies in the use of omics to study vascular calcification are presented in a comprehensive view. We also review the methodology of the omics studies and omics data analysis and processing. In addition, the methodology and data processing presented here can be applied to other areas. An omics landscape perspective across the boundaries between genomics, transcriptomics, proteomics and metabolomics is used to examine the mechanisms of vascular calcification. The perspective combined with various technologies also provides a direction for the subsequent exploration of clinical significance.


Modulation of retinoic acid receptor alpha activity by lysine methylation in the DNA binding domain.
Metabolic labeling and detection with a methylated lysine-specific antibody confirm lysine methylation of RAR alpha in mammalian cells. We previously reported Lys (347) trimethylation of mouse retinoic acid receptor alpha (RAR alpha) in the ligand binding domain (LBD) that affected ligand sensitivity of the dissected LBD. Here we report two monomethylated residues, Lys (109) and Lys (171) identified by LC-ESI-MS/MS in the DNA binding domain (DBD) and the hinge region, which affect retinoic acid (RA) sensitivity, coregulator interaction and heterodimerization with retinoid X receptor (RXR) in the context of the full-length protein. Constitutive negative mutation at Lys (109), but not Lys (171), reduces RA-dependent activation. Methylation at Lys (109) plays a more dominant role than trimethylation at Lys (347) in terms of RA activation of the full-length receptor. Lys (109) is located in a homologous sequence (CEGC K GFFRRS) of the DBD in RARs and is conserved in the nuclear receptor superfamily even across the species boundary. This study uncovers a potential role for monomethylation at Lys (109) in coordinating the synergy between DBD and LBD for ligand-dependent activation of RAR alpha.


Pre-implant magnetic resonance and transrectal ultrasound imaging in high-dose-rate prostate brachytherapy: comparison of prostate volumes, craniocaudal extents, and contours.
The purpose of this study was to compare the prostate contours drawn by two radiation oncologists and one radiologist on magnetic resonance (MR) and transrectal ultrasound (TRUS) images. TRUS intra- and inter-fraction variability as well as TRUS vs. MR inter-modality and inter-operator variability were studied. Thirty patients affected by localized prostate cancer and treated with interstitial high-dose-rate (HDR) prostate brachytherapy at the National Cancer Institute in Milan were included in this study. Twenty-five patients received an exclusive two-fraction (14 Gy/fraction) treatment, while the other 5 received a single 14 Gy fraction as a boost after external beam radiotherapy. The prostate was contoured on TRUS images acquired before (virtual US) and after (real US) needle implant by two radiation oncologists, whereas on MR prostate was independently contoured by the same radiation oncologists (MR1, MR2) and by a dedicated radiologist (MR3). Absolute differences of prostate volumes (│ΔV│) and craniocaudal extents (│Δdz│) were evaluated. The Dice's coefficient (DC) was calculated to quantify spatial overlap between MR contours. Significant difference was found between Vvirtual and Vlive (p < 0.001) for the first treatment fractions and between VMR1 and VMR2 (p = 0.043). Significant difference between cranio-caudal extents was found between dzvirtual and dzlive (p < 0.033) for the first treatment fractions, between dzvirtual of the first treatment fractions and dzMR1 (p < 0.001) and between dzMR1 and dzMR3 (p < 0.01). Oedema might be responsible for some of the changes in US volumes. Average DC values resulting from the comparison MR1 vs. MR2, MR1 vs. MR3 and MR2 vs. MR3 were 0.95 ± 0.04 (range, 0.82-0.99), 0.87 ± 0.04 (range, 0.73-0.91) and 0.87 ± 0.04 (range, 0.72-0.91), respectively. Our results demonstrate the importance of a multiprofessional approach to TRUS-guided HDR prostate brachytherapy. Specific training in MR and US prostate imaging is recommended for centers that are unfamiliar with HDR prostate brachytherapy.


The prognostic advantage of preoperative intratumoral injection of OK-432 for gastric cancer patients.
To investigate, by a multi-institutional randomized trial, the prognostic significance of the augmentation of tumour-infiltrating lymphocytes (TILs) by preoperative intratumoral injection of OK-432 (OK-432 it), a bacterial biological response modifier, in patients with gastric cancer. The 10-year survival and disease-free survival were examined and analysis of the factors showing survival benefit was performed. 370 patients who had undergone curative resection of gastric cancer were enrolled in this study and followed up for 10 years postoperatively. Patients were randomized into either an OK-432 it group or a control group. Ten Klinishe Einheit (KE) of OK-432 was endoscopically injected at 1 to 2 weeks before the operation in the OK-432 it group. Both groups received the same adjuvant chemoimmunotherapy consisting of a bolus injection of mitomycin C (0.4 mg kg(-1) i.v.) and administration of tegafur and OK-432 from postoperative day 14 up to 1 year later. Tegafur (600 mg day(-1)) was given orally and OK-432 (5 KE/2 weeks) was injected intradermally for a maintenance therapy. The TILs grades in resected tumour specimens and presence of metastasis and metastatic pattern in dissected lymph nodes were examined. Multivariate analysis was performed to determine the efficacy of OK-432 it on prognostic factors. All patients were followed up for 10 years. The overall 5- and 10-year survival rates and disease-free survival rates of the OK-432 it group were not significantly higher than those of the control group. However, OK-432 it significantly increased the 5- and 10-year survival rates of patients with stage IIIA + IIIB, moderate lymph node metastasis (pN2), and positive TILs. OK-432 it was most effective at prolonging the survival of patients who had both positive TILs and lymph node metastasis. The OK-432 it group with positive TILs showed a significant decrease in metastatic lymph node frequency and in the number of lymph node micro- metastatic foci when compared to the control group. This study showed that only one time preoperative OK-432 it, particularly when it triggers TILs, is effective for reduction of regional lymph node metastasis. OK-432 it probably acts partly by eliminating micro-metastatic foci in lymph nodes. Preoperative intratumoral injection of OK-432 is technically very easy and has no serious adverse effects, so it is a promising form of neoadjuvant immunotherapy for advanced gastric cancer.


Growth and role of the corpus luteum throughout delayed gestation in the potoroo, Potorous tridactylus.
The growth cycle of the corpus luteum (CL) of the potoroo is similar to that of other macropodids. During delayed gestation, the post-partum CL remains quiescent until it is reactivated by removal of the sucking pouch young. The CL then undergoes a period of growth, rapid from Day 6 until Day 12, followed by a gradual decline from Day 21 to Day 27. Excision of the CL before Day 6 of pregnancy either inhibited embryonic development or failed to support it. Excision of the CL between 6 and 21 days after removal of pouch young did not prevent embryos developing to full term but interfered with parturition. Excision on Day 25 after removal of pouch young allowed birth but impaired lactation, neonates dying within 2 days. By Day 27, the CL appeared to be no longer essential for embryonic development, birth or neonate survival. It is suggested that the CL of the potoroo is required for a slightly greater proportion of pregnancy than in most larger kangaroos because the birth canal must be prepared before each parturition.


Excessive remifentanil during total intravenous anesthesia is associated with increased risk of pain after robotic thyroid surgery.
The widespread use of remifentanil during total intravenous anesthesia (TIVA) has raised concerns about the risk of postoperative remifentanil-associated pain. Although a recent meta-analysis suggests that remifentanil-associated pain is unlikely to occur in patients with TIVA because of the protective effect of co-administered propofol, the evidence is not conclusive. We retrospectively assessed 635 patients who received robotic thyroid surgery under TIVA to evaluate the risk of remifentanil-associated pain. Postoperative pain was evaluated using 11-point numeric rating scale (NRS). Time dependent Cox proportional hazards regression analysis was used to determine the risk factors of treatment-requiring pain (NRS > 4) during the first 48 postoperative hours. Postoperative pain rapidly decreased, and treatment-requiring pain remained in 12.8% (81 out of 635) of patients at 48 hours postoperatively. After adjusting for the time-dependent analgesic consumption, intraoperative use of remifentanil > 0.2 mcg/kg/min was a positive predictor of postoperative pain with a hazard ratio of 1.296 (95% C.I., 1.014-1.656, P = 0.039) during 48 hours after surgery. In conclusion, excessive use of remifentanil during TIVA was associated with increased risk of pain after robotic thyroid surgery. Prospective trials are required to confirm these results and determine whether decreasing remifentanil consumption below the threshold can reduce postoperative pain.


Ethanol-regulated genes that contribute to ethanol sensitivity and rapid tolerance in Drosophila.
Increased ethanol intake, a major predictor for the development of alcohol use disorders, is facilitated by the development of tolerance to both the aversive and pleasurable effects of the drug. The molecular mechanisms underlying ethanol tolerance development are complex and are not yet well understood. To identify genetic mechanisms that contribute to ethanol tolerance, we examined the time course of gene expression changes elicited by a single sedating dose of ethanol in Drosophila, and completed a behavioral survey of strains harboring mutations in ethanol-regulated genes. Enrichment for genes in metabolism, nucleic acid binding, olfaction, regulation of signal transduction, and stress suggests that these biological processes are coordinately affected by ethanol exposure. We also detected a coordinate up-regulation of genes in the Toll and Imd innate immunity signal transduction pathways. A multi-study comparison revealed a small set of genes showing similar regulation, including increased expression of 3 genes for serine biosynthesis. A survey of Drosophila strains harboring mutations in ethanol-regulated genes for ethanol sensitivity and tolerance phenotypes revealed roles for serine biosynthesis, olfaction, transcriptional regulation, immunity, and metabolism. Flies harboring deletions of the genes encoding the olfactory co-receptor Or83b or the sirtuin Sir2 showed marked changes in the development of ethanol tolerance. Our findings implicate novel roles for these genes in regulating ethanol behavioral responses.


The nuclear autoantigen La/SS-associated antigen B: one gene, three functional mRNAs.
Transcription of the gene encoding for the nuclear autoantigen La resulted in three mRNA forms. A promoter switching combined with an alternative splicing pathway replaced exon 1 with either exon 1' or exon 1'. The exon 1' donor splice site was located 4 nts downstream of the exon 1' donor splice site. All three La mRNA forms were expressed in all the tissues analysed including peripheral blood lymphocytes, liver, fetal spleen, cultured primary endothelial cells, and mouse LTA cell lines permanently transfected with the human La gene. Both the exons 1' and 1' had unusual structures. They contained GC-rich regions and an oligo(U)-tail of 23 uridine residues. Moreover, they encoded for three open reading frames upstream of the La protein reading frame. In spite of this unusual structure, when exon 1' or exon 1' La mRNAs were expressed in transfected mouse LTA cells, both La mRNAs were translated to nuclear La protein, indicating that all La mRNA forms are functional mRNAs.


Evidence that the beta-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of abeta by zinc.
Abeta binds Zn(2+), Cu(2+), and Fe(3+) in vitro, and these metals are markedly elevated in the neocortex and especially enriched in amyloid plaque deposits of individuals with Alzheimer's disease (AD). Zn(2+) precipitates Abeta in vitro, and Cu(2+) interaction with Abeta promotes its neurotoxicity, correlating with metal reduction and the cell-free generation of H(2)O(2) (Abeta1-42 > Abeta1-40 > ratAbeta1-40). Because Zn(2+) is redox-inert, we studied the possibility that it may play an inhibitory role in H(2)O(2)-mediated Abeta toxicity. In competition to the cytotoxic potentiation caused by coincubation with Cu(2+), Zn(2+) rescued primary cortical and human embryonic kidney 293 cells that were exposed to Abeta1-42, correlating with the effect of Zn(2+) in suppressing Cu(2+)-dependent H(2)O(2) formation from Abeta1-42. Since plaques contain exceptionally high concentrations of Zn(2+), we examined the relationship between oxidation (8-OH guanosine) levels in AD-affected tissue and histological amyloid burden and found a significant negative correlation. These data suggest a protective role for Zn(2+) in AD, where plaques form as the result of a more robust Zn(2+) antioxidant response to the underlying oxidative attack.


A silicon-based widely tunable short-wave infrared optical parametric oscillator.
We demonstrate a synchronously pumped optical parametric oscillator (OPO) based on parametric gain in a silicon-on-insulator photonic wire. We exploit the highly nonlinear broadband response of the photonic wire to achieve broadband single-pass amplification up to 54 dB. This allows us to construct an OPO that is tunable across a 75 nm-wide band near 2075 nm, when pumped by a picosecond pulse train at 2175 nm. Additionally we demonstrate broadband tuning across 150 nm by varying the pump wavelength and exploiting the higher order dispersion characteristics of the silicon photonic wire.


Daily light sensitivity rhythm in a rodent.
Single 10-minute light periods can cause a phase shift in the rhythm of the daily locomotor activity of flying squirrels otherwise maintained in constant darkness. A daily rhythm of sensitivity to these standard light periods was found.


Lamarckian Evolution of Simulated Modular Robots.
We study evolutionary robot systems where not only the robot brains but also the robot bodies are evolvable. Such systems need to include a learning period right after 'birth' to acquire a controller that fits the newly created body. In this paper we investigate the possibility of bootstrapping infant robot learning through employing Lamarckian inheritance of parental controllers. In our system controllers are encoded by a combination of a morphology dependent component, a Central Pattern Generator (CPG), and a morphology independent part, a Compositional Pattern Producing Network (CPPN). This makes it possible to transfer the CPPN part of controllers between different morphologies and to create a Lamarckian system. We conduct experiments with simulated modular robots whose fitness is determined by the speed of locomotion, establish the benefits of inheriting optimized parental controllers, shed light on the conditions that influence these benefits, and observe that changing the way controllers are evolved also impacts the evolved morphologies.


Ultrafast UV-induced photoisomerization of intramolecularly H-bonded symmetric β-diketones.
In photoinduced molecular reaction dynamics, the effects of electronic charge redistribution can lead to multiple pathways that are determined by the nature of the initial structures involved and the environment the molecule of interest is studied in. The β-diketones are a common example of this complexity. They show keto-enol tautomerism that is almost totally shifted toward the enolic form. However, compared to the gas phase, the photochemistry proceeds completely differently by virtue of the solvent environment for these compounds, which are used in commercial sunscreen agents due to a high absorption in the ultraviolet (UV) and fast deactivation processes. We disclose these dynamics by investigating three symmetrical β-diketones in various solvents. To observe these effects on an ultrafast time scale directly in the UV spectral region where the relevant electronic transitions take place, we have developed and employed femtosecond transient absorption with detection capability in the deep UV. Our studies confirm that electronic excitation of the chelated enol form does not lead to any ultrafast photochemistry other than proton transfer followed by rotamerization. The formation of the nonchelated conformers takes place on a picosecond time scale through a dark state, whereas the recovery to the stable chelated enol form is a comparably slow process.


Heritage-culture images disrupt immigrants' second-language processing through triggering first-language interference.
For bicultural individuals, visual cues of a setting's cultural expectations can activate associated representations, switching the frames that guide their judgments. Research suggests that cultural cues may affect judgments through automatic priming, but has yet to investigate consequences for linguistic performance. The present studies investigate the proposal that heritage-culture cues hinder immigrants' second-language processing by priming first-language structures. For Chinese immigrants in the United States, speaking to a Chinese (vs. Caucasian) face reduced their English fluency, but at the same time increased their social comfort, effects that did not occur for a comparison group of European Americans (study 1). Similarly, exposure to iconic symbols of Chinese (vs. American) culture hindered Chinese immigrants' English fluency, when speaking about both culture-laden and culture-neutral topics (study 2). Finally, in both recognition (study 3) and naming tasks (study 4), Chinese icon priming increased accessibility of anomalous literal translations, indicating the intrusion of Chinese lexical structures into English processing. We discuss conceptual implications for the automaticity and adaptiveness of cultural priming and practical implications for immigrant acculturation and second-language learning.


Chemical modification of the multitarget neuroprotective compound fisetin.
Many factors are implicated in age-related central nervous system (CNS) disorders, making it unlikely that modulating only a single factor will provide effective treatment. Perhaps a better approach is to identify small molecules that have multiple biological activities relevant to the maintenance of brain function. Recently, we identified an orally active, neuroprotective, and cognition-enhancing molecule, the flavonoid fisetin, that is effective in several animal models of CNS disorders. Fisetin has direct antioxidant activity and can also increase the intracellular levels of glutathione (GSH), the major endogenous antioxidant. In addition, fisetin has both neurotrophic and anti-inflammatory activity. However, its relatively high EC(50) in cell based assays, low lipophilicity, high topological polar surface area (tPSA), and poor bioavailability suggest that there is room for medicinal chemical improvement. Here we describe a multitiered approach to screening that has allowed us to identify fisetin derivatives with significantly enhanced activity in an in vitro neuroprotection model while at the same time maintaining other key activities.


Urban-rural differences in the association between access to healthcare and health outcomes among older adults in China.
Studies have shown that inadequate access to healthcare is associated with lower levels of health and well-being in older adults. Studies have also shown significant urban-rural differences in access to healthcare in developing countries such as China. However, there is limited evidence of whether the association between access to healthcare and health outcomes differs by urban-rural residence at older ages in China. Four waves of data (2005, 2008/2009, 2011/2012, and 2014) from the largest national longitudinal survey of adults aged 65 and older in mainland China (n = 26,604) were used for analysis. The association between inadequate access to healthcare (y/n) and multiple health outcomes were examined-including instrumental activities of daily living (IADL) disability, ADL disability, cognitive impairment, and all-cause mortality. A series of multivariate models were used to obtain robust estimates and to account for various covariates associated with access to healthcare and/or health outcomes. All models were stratified by urban-rural residence. Inadequate access to healthcare was significantly higher among older adults in rural areas than in urban areas (9.1% vs. 5.4%; p < 0.01). Results from multivariate models showed that inadequate access to healthcare was associated with significantly higher odds of IADL disability in older adults living in urban areas (odds ratio [OR] = 1.58-1.79) and rural areas (OR = 1.95-2.30) relative to their counterparts with adequate access to healthcare. In terms of ADL disability, we found significant increases in the odds of disability among rural older adults (OR = 1.89-3.05) but not among urban older adults. Inadequate access to healthcare was also associated with substantially higher odds of cognitive impairment in older adults from rural areas (OR = 2.37-3.19) compared with those in rural areas with adequate access to healthcare; however, no significant differences in cognitive impairment were found among older adults in urban areas. Finally, we found that inadequate access to healthcare increased overall mortality risks in older adults by 33-37% in urban areas and 28-29% in rural areas. However, the increased risk of mortality in urban areas was not significant after taking into account health behaviors and baseline health status. Inadequate access to healthcare was significantly associated with higher rates of disability, cognitive impairment, and all-cause mortality among older adults in China. The associations between access to healthcare and health outcomes were generally stronger among older adults in rural areas than in urban areas. Our findings underscore the importance of providing adequate access to healthcare for older adults-particularly for those living in rural areas in developing countries such as China.


[An evaluation of the impact of cardiovascular disease prevention in Portugal (1980-1996). A longitudinal Gompertzian analysis of mortality].
The behaviour of cardiovascular diseases has suffered important modifications in recent years. There have been increases in mortality and morbidity in some countries while others have seen stabilization and even reduction. In the countries where we have observed a reduction in cardiovascular mortality, the reasons are multiple: efficacy of prevention measures; improvement of environmental conditions; increase in survival; and competitiveness with other causes of death. In order to ascertain whether a certain tendency is real or fictitious, we need to use techniques that allow the evaluation of the true evolution, to study the effect of environmental factors (not genetic) and the variability of internal resistance (vitality) to disease. Based on the longitudinal Gompertzian analysis of mortality for ischemic heart disease (IHD) and cerebrovascular disease (CVD) between 1980 and 1996, it was possible to observe a reduction in mortality for both causes, which was more obvious in the case of CHD, and that the impact of the improvement in environmental conditions (not genetic) was higher in CVD versus IHD. The prevention of CVD was more efficient in men (42.8% vs 29.7%) than in women, while in IHD the most efficient prevention was 20.6% in women versus 14.9% in men, comparing the data of 1996 and 1980. During this period, the environmental influences (not genetic) were responsible for the reduction in mortality for IHD in 2.7% of men and 4.3% of women, while in CVD we observed a reduction in mortality of 7.5% in men and 4.5% in women.


Er3+-doped YbPO4 up-conversion porous nanospheres for UCL/CT bimodal imaging in vivo and chemotherapy.
The combined use nanotechnology and medical technologies holds great promise for the development and improvement of various theranostic media. Here, based on a facile hydrothermal method, polyethyleneimine (PEI) functionalized YbPO4:Er up-conversion porous nanospheres (UCPSs) were fabricated, which combined the capabilities of up-conversion luminescence (UCL)/X-ray computed tomography (CT) bimodal imaging and drug delivery. The resulting hydrophilic PEI functionalized YbPO4:Er UCPSs (PEI-UCPSs) showed uniform morphology and high crystallinity. Moreover, PEI-UCPSs possessed high drug loading capacity because of their large specific surface area, which was confirmed by the Brunauer-Emmett-Teller (BET) experiment. Cellular experiments indicated that the PEI-UCPSs had low cytotoxicity and confirmed the performance of the pH-mediated cancer targeting of PEI-UCPSs@DOX. Importantly, because of the ideal UCL property and high CT contrast both in vitro and in vivo, YbPO4:Er PEI-UCPSs could be used as an optical probe and a contrast agent for optical and CT imaging, forming a promising platform for simultaneous bioimaging and drug delivery.