Scope for regulation of cigarette smoke toxicity: the case for including charcoal filters.
To compare the emissions toxicity of two manufactured cigarette brands, one with and one without a charcoal filter, in the light of manufacturers' laboratory research findings on the properties of charcoal filters. Emissions of Mild Seven charcoal filter brands, regular (labelled '12 mg tar') and Light (labelled '9 mg tar') purchased in 2004, were compared with those of Holiday Extra-mild brand (9 mg tar, acetate filter), purchased in 2002. All emissions were tested under intensive machine smoking conditions by Labstat International Inc., Kitchener, Ontario. The Mild Seven brands contained a small amount of charcoal, its black granules visible against the white acetate filter. The charcoal filter in the brands tested did not reduce toxicity to the extent expected, though they gave significantly lower emissions for the respiratory-toxicants acrolein (14%-17% lower, p 'less than and equal to' 0.01) and formaldehyde (26-37% lower, p 'less than and equal to' 0.01). Reductions were not significant for acetaldehyde, and actually higher for hydrogen cyanide. Overall, estimated cardiovascular-respiratory toxicity was not reduced, whether based on toxicant emissions or the toxicant to nicotine ratios. Of the packet labels, neither tar yield (mg) nor the descriptors 'mild', 'light', or 'extra-mild', or 'charcoal filter' for these three brands was associated with any reduction of the combined respiratory--and cardiovascular toxicity of mainstream smoke, as measured by leading toxicants tested by the intensive method. Previously secret documents from cigarette companies, including British American Tobacco, reported reductions of 75%-80% in hydrogen cyanide, acetaldehyde, acrolein, and formaldehyde in mainstream smoke from addition of charcoal to the filter. We estimated that an effective charcoal filter could reduce a brand's overall relative toxicity score for identifiable toxicant by over 40%. Since 1965, major cigarette firms have known from their chemists that many smoke toxicants, including hydrogen cyanide and acrolein, were removable by manufacturing the cigarette with a charcoal filter. To this day, few brands have charcoal filters. The best known, Mild Seven, contained a token charcoal filter only. In neither Japan nor New Zealand did this brand lower cardiovascular toxicant emissions in smoke. In the Smoke-free Environments Act, Government has the power to lower smoke emissions by regulation, but no regulations are in place. The Act does not give power to add filters to cigarettes, but does give power to lower smoke emissions to the level attainable by using a charcoal filter, which could reduce smoke emission toxicity to a large extent. Regulation to require effective charcoal filters is now long overdue.


The value of stereotactic biopsy in improving survival and quality of life for malignant brain glioma patients.
The purpose of the study was to investigate possible differences in the survival and outcome of malignant brain glioma patients when treated by two different methods of surgery. During a 3-year period, 32 glioma patients underwent surgery and oncological protocol afterwards. The patients were divided into two groups according to the surgical method applied. The case group comprised 11 patients in whom a stereotactic biopsy was performed, while the control group consisted of21 patients who were operated on by radical surgery (craniotomy and maximal reduction of the tumor mass). All survived patients were clinically examined at follow-ups (one year and 2 years following the surgery). The monitored variables for both groups were the tumor pathohistology (the tumor type), the survival rate (time between surgery and follow-up), and the outcome assessed by The Extended Glasgow Outcome Scale. Data statistical analysis was done to compare various investigated variables in two different groups of patients. The majority of patients treated by a stereotactic biopsy survived for more than 2 years following the procedure. The great part of patients treated by radical surgery died or was severely disabled at follow-up examination. The survival and outcome for the patients in whom a stereotactic biopsy was performed were notably better comparing to the patients who were treated by radical surgery. Consequently, it appears that a stereotactic biopsy is surgical option for primary treatment of selected patients with malignant brain glioma when the survival and quality of life are concerned.


Prediction of BMI traits in the Chinese population based on the gut metagenome.
Identifying individual characteristics based on trace evidence left at a crime scene is crucial in forensic identification. Microbial communities found in fecal traces have high individual specificity and could serve as potential markers for forensic characterization. Previous research has established that predicting body type based on the relative abundance of the gut microbiome is relatively accurate. However, the long-term stability and high individual specificity of the gut microbiome are closely linked to changes at the genome level of the microbiome. No studies have been conducted to deduce body shape from genetic traits. Therefore, in this study, the vital role of gut bacterial community characteristics and genetic traits in predicting body mass index (BMI) was investigated using gut metagenomic data from a healthy Chinese population. Regarding the gut microbial community, the underweight group displayed increased α-diversity in comparison to the other BMI groups. There were significant differences in the relative abundances of 19 species among these three BMI groups. The BMI prediction model, based on the 31 most significant species, showed a goodness of fit (R2) of 0.56 and a mean absolute error (MAE) of 2.09 kg/m2. The overweight group exhibited significantly higher α-diversity than the other BMI groups at the level of gut microbial genes. Furthermore, there were significant variations observed in the single-nucleotide polymorphism (SNP) density of 732 contigs between these three BMI groups. The BMI prediction model, reliant on the 62 most contributing contigs, exhibited a model R2 of 0.72 and an MAE of 1.56 kg/m2. The model predicting body type from 44 contigs correctly identified the body type of 93.55% of the study participants. Based on metagenomic data from a healthy Chinese population, we demonstrated the potential of genetic traits of gut bacteria to predict an individual's BMI. The findings of this study suggest the effectiveness of a novel method for determining the body type of suspects in forensic applications using the genetic traits of the gut microbiome and holds great promise for forensic individual identification.


Visual outcome and contrast sensitivity after photorefractive keratectomy in low to moderate myopia: wavefront-optimized versus conventional methods.
To compare visual outcomes and contrast sensitivity after wavefront-optimized or conventional photorefractive keratectomy (PRK) in myopic patients with or without astigmatism. Vanak Eye Surgery Center, Tehran, Iran. Comparative case series. Patients with low to moderate myopia with or without astigmatism were allocated into 2 groups. The study group was treated with wavefront-optimized PRK (Allegretto Wave Eye-Q software version 2.020 default treatment) and the control group, with conventional PRK (Technolas 217z). In all cases, treatments were bilateral and performed with the same device. Baseline and 3-month postoperative measures were uncorrected and corrected distance visual acuities, manifest refraction, and contrast sensitivity. Each group comprised 66 eyes. The mean preoperative spherical equivalent refraction improved from -2.99 diopters (D) ± 1.02 (SD) preoperatively to -0.08 ± 0.26 D 3 months postoperatively in the study group and from -2.66 ± 0.95 D to 0.01 ± 0.30 D, respectively, in the control group. In both groups, the postoperative mesopic and photopic contrast sensitivity decreased significantly at most spatial frequencies. The postoperative decrease in contrast sensitivity in both groups was comparable except at spatial frequencies of 3 cycles per degree (cpd) under mesopic conditions and 12 cpd under photopic conditions, frequencies at which the control group had a greater reduction. Visual acuity and refractive error outcomes were similar in both treatment groups. After 3 months, mesopic and photopic contrast sensitivity were significantly decreased in both groups; the reduction in the 2 groups was almost comparable. No author has a financial or proprietary interest in any material or method mentioned.


Characteristics of rural elderly people who bypass local pharmacies.
The bypassing of local pharmacies by consumers is an indicator of limited accessibility and, possibly, compromised quality of rural pharmacy services. The objective of this study was to identify the characteristics of rural consumers who bypassed local pharmacies for their medication needs. The sample was derived from the Texas Tech 5000, a longitudinal survey in West Texas, and pharmacy data from the Texas State Board of Pharmacy. The sample included 1062 people aged 65 or older who lived in rural counties and had at least one community pharmacy in town. Bivariate and multivariate analyses were performed to investigate the demographic, financial, nonfinancial, prescription and over-the-counter drug use, and health characteristics that were associated with the probabilities of the subjects' using local community pharmacies, nonlocal community pharmacies, and mail-order pharmacies. In the sample, 70.8%, 13.7%, and 15.5% of elderly people primarily used local pharmacies, nonlocal pharmacies, and mail-order pharmacies, respectively. The oldest subjects, women subjects, subjects with no employer-provided or other federal insurance, subjects who had a regular doctor, and subjects living within city limits and in areas with a higher density of community pharmacies had lower probabilities of choosing nonlocal pharmacies over local pharmacies. Insurance coverage for prescriptions was one of the most important determinants in choosing mail-order pharmacies over local community pharmacies. Additional research is warranted to further understand the choices made by older people, as well as by younger people who use medications. In particular, further investigation of the potential differences between services provided by rural-community, urban-community, and mail-order pharmacies is needed to identify other reasons for bypassing local pharmacies.


Secondary contact between Lycaeides idas and L. melissa in the Rocky Mountains: extensive admixture and a patchy hybrid zone.
Studies of hybridization have increased our understanding of the nature of species boundaries, the process of speciation, and the effects of hybridization on the evolution of populations and species. In the present study we use genetic and morphological data to determine the outcome and consequences of secondary contact and hybridization between the butterfly species Lycaeides idas and L. melissa in the Rocky Mountains. Admixture proportions estimated from structure and geographical cline analysis indicate L. idas and L. melissa have hybridized extensively in the Rocky Mountains and that reproductive isolation was insufficient to prevent introgression for much of the genome. Geographical patterns of admixture suggest that hybridization between L. idas and L. melissa has led to the formation of a hybrid zone. The hybrid zone is relatively wide, given estimates of dispersal for Lycaeides butterflies, and does not show strong evidence of cline concordance among characters. We believe the structure of the Lycaeides hybrid zone might be best explained by the patchy distribution of Lycaeides, local extinction and colonization of habitat patches, environmental variation and weak overall selection against hybrids. We found no evidence that hybridization in the Rocky Mountains has resulted in the formation of independent hybrid species, in contrast to the outcome of hybridization between L. idas and L. melissa in the Sierra Nevada. Finally, our results suggest that differences in male morphology between L. idas and L. melissa might contribute to isolation, or perhaps even that selection has favoured the spread of L. melissa male genitalia alleles.


HIV, syphilis infection, and sexual practices among transgenders, male sex workers, and other men who have sex with men in Jakarta, Indonesia.
To establish the prevalence of HIV, syphilis, and sexual risk behaviour among three groups of men who have sex with men in Jakarta, Indonesia, and to investigate sexual links between these men and broader heterosexual populations. Anonymous, cross sectional surveys among community recruited transgender and male sex workers and self recognised men who have sex with men (MSM) were undertaken in mid-2002 in Jakarta, Indonesia. Places where transgender and male sex workers sell sex and where men go to meet non-commercial male sex partners were mapped. Probability samples were selected for the sex worker populations, while a mixed probability and convenience sample was drawn for self recognised MSM. Blood was drawn for HIV and syphilis serology and community interviewers administered a standardised questionnaire. HIV prevalence was 22% among transgender sex workers, 3.6% among male sex workers, and 2.5% among self recognised MSM, and syphilis prevalence was 19.3%, 2.0% and 1.1% respectively. 59.3% of transgender sex workers and 64.8% of male sex workers reported recent unprotected anal intercourse with clients, and 53.1% of other MSM reported unprotected anal sex with male partners. Some 54.4% of male sex workers and 18.3% of other MSM reported female partners in the preceding year. HIV has reached substantial levels among transgender sex workers, and is not negligible in other MSM groups. Risk behaviour is high in all subpopulations, and bisexual behaviour is common, meaning the threat of a wider epidemic is substantial. Prevention programmes targeting male-male sex are needed to reduce this threat.


Improvement of in vitro-transcribed amber suppressor tRNAs toward higher suppression efficiency in wheat germ extract.
In vitro-transcribed, unmodified, and non-aminoacylated amber suppressor tRNAs that are recognized by natural aminoacyl-tRNA synthetase were improved toward higher suppression efficiency in batch-mode cell-free translation in wheat germ extract. The suppression efficiency of the suppressor obtained through four sequence optimization steps (anticodon alteration of natural tRNAs (the first generation); chimerization of the efficient suppressors in the first generation; investigation and optimization of the effective parts in the second generation; combination of the optimized parts in the third generation) and by the terminal tuning was approximately 60%, which was 2.4-fold higher than that of the best suppressor in the first generation. In addition, an eRF1 aptamer further increased the efficiency up to 85%. This highly efficient suppression system also functioned well in a dialysis-based large-scale protein synthesis.


[Effects of Haikun Shenxi on expression of platelet-derived growth factor-B and mRNA in renal tissue of rats with adriamycin nephropathy].
To investigate the effects of Haikun Shenxi on the expression of platelet-derived growth factor-BB (PDGF-BB) and mRNA in renal tissue of rats with adriamycin nephropathy. Rat model was established by unilateral nephrectomy and injecting adriamycin intraperitoneally. The adriamycin-induced nephrotic rats were randomly divided into 6 groups: normal group, sham operation group, model group, lotensin treatment group, Haikun Shenxi low and high dose treatment groups (0.77, 0.08 mg x kg(-1). Ten weeks later, the 24 hour urine protein and blood biochemistry examinations and renal pathologic changes were observed, and the expression of PDGF-BB and mRNA was measured using immunohistochemical method. Compared with model group, proteinuria and the levels of serum creatinine (Scr) , urea nitrogen (BUN) were decreased obviously in both Haikun Shenxi low and high dose groups. The expression of PDGF-BB and mRNA was mostly presented in cytoplasm of renal tubular epithelial cells and mesangial area, and it could be reduced significantly after treatment (P < 0. 05). The level of PDGF-BB and mRNA is high in renal tissue of adriamycin-induced nephrotic rats. This progress could be effectively inhibited by Haikun Shenxi and the mechanism may be that it can control the excessive expression of PDGF-BB and mRNA.


A painless erythematous swelling of the external ear as a manifestation of Lyme disease: a case report.
Lyme disease is the most common tick-borne illness in the USA, Canada, and Europe. Clinical manifestations vary greatly, with localized skin findings functioning as early signs of the disease, followed by disseminated disease. The rarest dermatologic presentation of Lyme is a borrelial lymphocytoma, occurring distinctly in Europe and caused typically by Borrelia afzelii. We report a case of a Caucasian 5-year-old European-American boy with slowly progressing, painless edema and erythema of his right pinna. Travel history revealed significant exposure to ticks during a recent trip to Eastern Europe. Laboratory testing for Borrelia burgdorferi demonstrated mixed positivity. He was treated with a 21-day course of amoxicillin, with complete resolution of symptoms and no sign of secondary Lyme disease. Borrelial lymphocytoma is a rare manifestation of Lyme disease in North America, although not uncommon in Europe. Diagnosis is made by the presence of a painless erythematous swelling typically found on the ear lobe, nipples, or testes. Laboratory tests are available but with low sensitivity, therefore, a high index of suspicion is necessary for a clinical diagnosis to be made. Treatment for isolated borrelial lymphocytoma is doxycycline 4 mg/kg up to 100 mg twice daily, whereas for children less than 8 years of age amoxicillin 50 mg/kg divided three times daily, for 3-4 weeks, is preferred.


Detection of chromosomal aberrations in renal tumors: a comparative study of conventional cytogenetics and virtual karyotyping with single-nucleotide polymorphism microarrays.
-Renal epithelial neoplasms have characteristic chromosomal imbalances, and we have shown previously that virtual karyotypes derived from single-nucleotide polymorphism microarrays can be performed on formalin-fixed, paraffin-embedded tissue. -To perform a direct comparison of virtual and conventional karyotypes to evaluate concordance of results. -Twenty archival formalin-fixed, paraffin-embedded tumor samples with preexisting, conventional cytogenetic results were analyzed with Affymetrix 10K 2.0 or 250K Nsp single-nucleotide polymorphism microarrays. -Nineteen samples yielded adequate virtual karyotypes for interpretation. Eight samples showed complete agreement between the 2 techniques, and 8 samples showed partial agreement. The disease-defining lesions (eg, loss of 3p for clear cell carcinoma) were identified in all 19 cases by virtual karyotypes and in 15 cases by conventional karyotypes. Virtual and conventional karyotypic findings were concordant in the identification of these disease-defining lesions in 86% (13 of 15) of cases. In 3 cases, virtual karyotypes identified lesions consistent with the morphologic diagnosis, whereas the conventional karyotypes were unsuccessful because of insufficient tumor representation or stromal overgrowth. Two cases with acquired uniparental disomy were identified by single-nucleotide polymorphism arrays, and 5 cases with translocations were identified by conventional karyotype. -Our results show that both techniques are able to identify the characteristic chromosomal abnormality for renal tumor subtypes in most cases. Discrepancies can be explained by inherent limitations of each technique, inadequate tumor sampling, and tumor heterogeneity. We conclude that virtual karyotyping is a robust alternative to conventional cytogenetics for the evaluation of chromosomal anomalies in formalin-fixed, paraffin-embedded tissues from renal epithelial neoplasms.


Imaging T-lymphocytes in inflammatory diseases: a nuclear medicine approach.
Increasing interest and research efforts have been made in search of specific radiolabelled probes for imaging different immune cells (including T-lymphocytes) in inflammation and infection. This has led to early detection of lymphocyte infiltration, and the deepening of our understanding of pathogenesis of immune mediated diseases. In-vivo imaging of T-lymphocytes with radiolabelled specific probes may provide an important piece of information about inflammatory lesions, which could be very important to understand the molecular mechanism of action of any drug and/or their effect on the microenvironment of the immune system of the body. The present review focuses on radiolabelled T-lymphocytes and different monoclonal antibodies, peptides, cytokines, chemokine used for scintigraphic imaging of T-lymphocytes and their subsets.


Effect of Ligand Aromaticity on Cyclohexane and Benzene Sorption in IRMOFs: A Computational Study.
A series of four isoreticular MOFs (IRMOF-1, -10, -14, and -16) were selected for a computational investigation of the effect of ligand aromaticity on the adsorption capacity of an aromatic VOC (benzene) compared to its nonaromatic analog (cyclohexane). The affinity of the adsorbates was evaluated by calculating Henry's constants and adsorption enthalpies. It has been evidenced that while KH values decrease with ligand elongation (IRMOF-10 and -16), inserting a pyrene core into the MOF structure (IRMOF-14) increases both the cyclohexane and benzene adsorption efficiency by ∼290 and 54%, respectively. To elucidate host-guest interactions, we sought to locate preferential adsorption sites in MOF structures for the two VOCs studied by using the GCMC method. It appears that benzene interacts with the metal center (Zn4O clusters) and most of the ligand while cyclohexane tends to localize preferentially only near the Zn4O clusters. Coadsorption isotherms (equimolar mixture of benzene and cyclohexane) demonstrated the preferential adsorption of cyclohexane due to the stronger affinity for the MOF structure. On the other hand, for other isoreticular structures, the ligand elongation leads to a shift of the adsorption curve of cyclohexane caused by pore size increase and therefore less interactions with the walls. This phenomenon is counterbalanced in the case of IRMOF-14 due to stronger interactions between the cyclohexane and pyrene groups. The present results thus open perspectives in the design of promising MOF candidates for high-performing separation and sorption/detection of hydrocarbon VOCs.


Maturation of pancreatic beta-cell function in the fetal horse during late gestation.
At birth, the endocrine pancreas becomes more directly involved in the control of glycaemia than in utero. However, compared with other tissues, relatively little is known about the maturational changes that occur in the fetal endocrine pancreas in preparation for extrauterine life. This study examined the pancreatic beta-cell response to exogenous administration of glucose and arginine in fetal horses with respect to their gestational age and concentration of cortisol, the hormone responsible for prepartum maturation of other fetal tissues. Glucose administration had no effect on fetal insulin secretion between 175 and 230 days of gestation but evoked a rapid insulin response in fetuses closer to term (290-327 days). In late gestation, the beta-cell response was more rapid and greater in magnitude in fetuses with basal cortisol levels higher than 15 ng/ml than in those with lower cortisol values at the time of glucose administration. The fetal beta-cell response to arginine was unaffected by the rise in fetal plasma cortisol towards term. These findings show that there are maturational changes in pancreatic beta-cell function in fetal horses as cortisol levels rise close to term. Primarily, these prepartum maturational changes were in the mechanisms of glucose-stimulated insulin secretion, which would enable the beta cells to regulate glycaemia at the higher glucose levels observed postnatally.


Involvement of the mirror neuron system in blunted affect in schizophrenia.
Blunted affect is a relatively enduring schizophrenic symptom and its presence brings about poor functioning and outcomes. Functional impairment in the mirror neuron system which is involved in both motor execution and imitation may be a neural basis of blunted affect, but it is not proved yet. Fifteen patients with schizophrenia and 16 healthy controls performed the facial expression task during functional magnetic resonance imaging. The task was to reproduce facial expressions in response to the face or word stimuli for happiness, sadness, and meaningless expression. Brain activities during facial expressions in patients compared with controls and their relationship with affective flattening were analyzed. Compared to controls, patients exhibited decreased activity in the widespread dorsal frontal regions and increased activity in the ventral frontal and subcortical regions. Patients also demonstrated significant negative correlation of the severity of affective flattening with activities in the mirror neuron system, such as the premotor cortex, motor cortex, and inferior parietal lobule. Emotional expression in patients with schizophrenia may be related to hypoactivity of the dorsal system and hyperactivity of the ventral system. An imbalance of these two systems may contribute to blunted affect. Directly addressing blunted affect using emotional expression provides a new perspective that functional disturbance of the mirror neuron system may play an important role in manifestation of blunted affect in schizophrenia.


Amphetamine decreases the expression and acquisition of appetitive conditioning but increases the acquisition of anticipatory responding over a trace interval.
The effects of amphetamine on selective learning were tested in a trace conditioning procedure, in which the informativeness of the conditioned stimulus (CS) (noise) was manipulated through the introduction of a time interval before the delivery of the unconditioned stimulus (UCS) (food). The results showed that d-amphetamine (0.5 and 1.5 mg/kg) impaired both the expression (Experiment 1b) and acquisition (Experiment 2) of appetitive conditioning. This was true for both trace and contiguously conditioned groups. The effects of the 0.5 mg/kg dose of d-amphetamine were not attributable to general motor (measured pre-CS) or motivational (measured post-UCS) effects of the drug. Moreover, the same pattern of effects (impaired appetitive conditioning, irrespective of the trace interval between CS and UCS) was confirmed in drug-free extinction tests. By contrast to the general depression in the acquisition and expression of associative learning observed under amphetamine, the 0.5 mg/kg dose promoted the acquisition of anticipatory responses made later in the trace interval (in Experiment 2 but, again, not the expression of previous conditioning in Experiment 1b). This suggests a dissociable effect of low-dose d-amphetamine on learning about the temporal relationship between CS and UCS.


Cost effectiveness of couple counselling to enhance infant HIV-1 prevention.
Data collected in the years 2001--2003 from an antenatal clinic in Nairobi, Kenya, were used to assess the benefit of couple counselling and test it as a way of increasing the uptake of interventions in the prevention of mother-to-child transmission of HIV-1. Among 2833 women enrolled, 311 (11%) received couple pretest counselling and 2100 (74%) accepted HIV-1 testing. Among those tested 314 (15%) were HIV-1 seropositive. We incorporated these and other data from the cohort study into a spreadsheet-based model and costs associated with couple counselling were compared with individual counselling in a theoretical cohort of 10,000 women. Voluntary couple counselling and testing (VCT), although more expensive, averted a greater number of infant infections when compared with individual VCT. Cost per disability-adjusted life year was similar to that of individual VCT. Sensitivity analyses found that couple VCT was more cost-effective in scenarios with increased uptake of couple counselling and higher HIV-1 prevalence.


Life's Experiences of Middle-aged Divorced Women with Higher Education and Profession.
Today, an increasing number of divorce is shifting family forms and gender role practices. The purpose of this qualitative study was to understand life's experiences of middle-aged divorced women with higher education and profession lives in Korea. For this study, 6 middle-aged divorced women with similar backgrounds were recruited from December 2013 to June 2014, using in-depth individual interviews. Data analysis was performed using Giorgi's phenomenological methodology. Individual interviews revealed the following 15 meaning of themes and 5 themes. 1) A woman considering herself to be ashamed that she has not lived an ordinary life. 2) The destiny of a woman not having a fortune. 3) An exhilarated mood like a teenage girl's 4) Suppressing an instinctive desire of sex. 5) Being a mother as a woman head of household. This study provides deep understanding of middle-aged divorced women with higher levels of education and professional lives of women who experienced difficult times and overcame their problems. Based on the results of this study, nursing strategies for enhancing quality of life need to be created and implemented for all professional women by Korean community networking gradually.


Heavy episodic drinking and sensation seeking in adolescents as predictors of harmful driving and celebrating behaviors: implications for prevention.
Effectiveness of strategies to counter injurious risk-taking in adolescents depends on the degree to which behaviors are modifiable or intrinsic to a sensation-seeking personality. Alcohol consumption is often targeted because it is seen as a modifiable determinant. This study sought to clarify the relative importance of engagement in heavy episodic drinking (HED) independently of sensation-seeking tendency (SS), as a predictor of potentially harmful (and protective) behaviors. A written survey was administered to students aged 15-17 years in 40 high schools in New South Wales (NSW), Australia to measure HED, SS, and harmful and protective behaviors associated with drug and alcohol use, driving, and celebrating. Of 2705 respondents, 60% reported HED, 36% failed to wear a seatbelt, 23% rode with an alcohol-impaired driver, 23% rode with a drug-impaired driver and 9% had been alcohol impaired while driving. Two-thirds (65%) had engaged in harmful behaviors and 99% had engaged in protective behaviors while celebrating. SS, gender, income, and age were significant predictors of HED. HED and SS were significant, independent predictors of every harmful or protective behavior. HED had the greatest effect on harmful celebrating behaviors, riding with an alcohol-impaired acquaintance, and riding with a drug-impaired driver. HED had a stronger effect than SS, for alcohol-impaired driving, riding with an alcohol-impaired acquaintance, riding with a drug-impaired driver, and harmful celebrating behaviors. The vast majority of adolescents who are low to average sensation seekers may benefit from population-based prevention strategies emphasizing that decisions leading to harmful outcomes are more likely if they engage in HED.


Knockdown of SQLE promotes CD8+ T cell infiltration in the tumor microenvironment.
Cholesterol biosynthesis and metabolism are critical aspects that shape the process of tumor development and associated microenvironmental conditions owing to the ability of cholesterol to drive tumor growth and invasion. Squalene Epoxidase (SQLE) is the second rate-limiting enzyme involved in the synthesis of cholesterol. The functional role of SQLE within the tumor microenvironment, however, has yet to be established. Here we show that SQLE is distinctively expressed across most types of cancer, and the expression level is highly correlated with tumor mutation burden and microsatellite instability. Accordingly, SQLE was identified as a prognostic risk factor in cancer patients. In addition, we observed a negative correlation between SQLE expression and immune cell infiltration across multiple cancers, and murine xenograft model further confirmed that SQLE knockdown was associated with enhanced intratumoral CD8+ T cell infiltration. Using next-generation sequencing, we identified 410 genes distinctively expressed in tumors exhibiting SQLE inhibition. KEGG and GO analysis further verified that SQLE altered the immune response in the tumor microenvironment. Furthermore, we found that the metabolism and translation of proteins is the main binding factor with SQLE. Our findings ascertain that SQLE is a potential target in multiple cancers and suppressing SQLE establishes an essential mechanism for shaping tumor microenvironment.


Dietary patterns in french home-living older adults: Results from the PRAUSE study.
The aim of the present study was to provide descriptive dietary patterns of home-living older adults, and to examine their association with sociodemographic and 'diet-related' variables, and health and psychological factors. Dietary patterns were analyzed using separately cluster analysis for men (N=151,Mage=72.72, SD=8.80, range=56-97) and women (N=251, Mage=76.74, SD=9.95, range=55-97) in 402 older adults aged 55 years and over. Cluster analyses showed four distinct dietary profiles for each gender. In older men, the four distinct dietary clusters were associated with any differences in sociodemographic and 'diet-related' variables, cognitive function, and health and psychological factors. Likewise, in older women, the four distinct dietary clusters were associated with any differences in sociodemographic and 'diet-related' variables'. However in older women, results showed that the cluster 1 "high fish-fruit-vegetable" was associated with a better cognitive function, a better self-rated health and no depressive symptoms, whereas cluster 3 "moderate ready meals" was associated with cognitive decline, slight depression, and poor perceived health. Results emphasize the interest to take into consideration health and psychological factors associated with dietary patterns to better target the vulnerability of individuals and enable an effective prevention.


Analysis of nonlinear gene expression progression reveals extensive pathway and age-specific transitions in aging human brains.
Several recent gene expression studies identified hundreds of genes that are correlated with age in brain and other tissues in human. However, these studies used linear models of age correlation, which are not well equipped to model abrupt changes associated with particular ages. We developed a computational algorithm for age estimation in which the expression of each gene is treated as a dichotomized biomarker for whether the subject is older or younger than a particular age. In addition, for each age-informative gene our algorithm identifies the age threshold with the most drastic change in expression level, which allows us to associate genes with particular age periods. Analysis of human aging brain expression datasets from three frontal cortex regions showed that different pathways undergo transitions at different ages, and the distribution of pathways and age thresholds varies across brain regions. Our study reveals age-correlated expression changes at particular age points and allows one to estimate the age of an individual with better accuracy than previously published methods.


The effect of head and neck suction on G tolerance.
A device was constructed which allowed subatomospheric pressures of up to -50 mm Hg to be applied to the neck, or to the head plus neck, of volunteer subjects riding on the USAFSAM centrifuge. Breathing pressures were always atmospheric. The G tolerance was measured during gradual (0.1 G.s-1) and rapid onset (1.0 G.s-1) runs and heart rate was monitored. Neck suction decreased tolerance to an extent explicable by carotid sinus activation (about -0.8 G at -50 mm Hg), while combined head and neck suction of -25 mm Hg increased tolerance to an extent greater than predicted from pressure effects on the eye and carotid sinus. Neck suction of -50 mm Hg induced less bradycardia when applied at +3 Gz than under 1-G conditions. These results were discussed in relation to intraocular tension, baroreceptor responsiveness, and jugular venous siphon effect.


An association between exposure to Middle East Respiratory Syndrome (MERS) and mortality rate of Coronavirus Disease 2019 (COVID-19).
Our objective was to find an association between exposure of a population to Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and mortality rate due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) across different countries worldwide. To find the relationship between exposure to MERS-CoV and mortality rate due to SARS-CoV-2, we collected and analyzed data of three possible factors that may have resulted in an exposure of a population to MERS-CoV: (1) the number of Middle East Respiratory Syndrome (MERS) cases reported among 16 countries since 2012; (2) data of MERS-CoV seroprevalence in camels across 23 countries, as working with camels increase risk of exposure to MERS-CoV; (3) data of travel history of people from 51 countries to Saudi Arabia was collected on the assumption that travel to a country where MERS is endemic, such as, Saudi Arabia, could also lead to exposure to MERS-CoV. We found a significantly lower number of Coronavirus disease 2019 (COVID-19) deaths per million (deaths/M) of a population in countries that are likely to be exposed to MERS-CoV than otherwise (t-stat=3.686, p<0.01). In addition, the number of COVID-19 deaths/M of a population was significantly lower in countries that reported a higher seroprevalence of MERS-CoV in camels than otherwise (t-stat=4.5077, p<0.01). Regression analysis showed that increased travelling history to Saudi Arabia is likely to be associated with a lower mortality rate due to COVID-19. This study provides empirical evidence that a population that was at an increased risk of exposure to MERS-CoV had a significantly lower mortality rate due to SARS-CoV-2, which might be due to cross-protective immunity against SARS-CoV-2 in that population because of an earlier exposure to MERS-CoV.


Absorption, Pharmacokinetics, Tissue Distribution, and Excretion Profiles of Sea Cucumber-Derived Sulfated Sterols in Mice.
Sea cucumber-derived sulfated sterols exhibited more significant bioactivities compared to plant sterols due to the distinctive structure of the sulfate group at the C-3 position; however, their absorption, pharmacokinetics, tissue distribution, and excretion profiles are unknown, which limits the analysis of molecular mechanisms related to their unique activities. In this study, the absorption characteristics of sea cucumber sterols were determined by oral gavage administration, and their pharmacokinetics, excretion, and tissue distribution were studied by tail vein injection. The results showed that SS1 and SS2 reached the peak at 3 h (20.14 ± 1.2 μg/mL) and 4 h (13.32 ± 0.9 μg/mL) in serum, respectively, after oral gavage administration, suggesting the faster absorption rate of SS1 than SS2 due to the difference in the side-chain groups. Besides, lipid-containing food media improved the digestion and absorption rates of sea cucumber sterols. Moreover, SS1 exhibited a relatively longer duration of efficacy than SS2, and they were almost completely excreted within 9 h through urine. Additionally, sea cucumber sterols were found to be mainly accumulated in the liver (P < 0.05), followed by the kidney and spleen. These findings might provide a theoretical basis for the research and development of functional foods and nutraceuticals associated with sea cucumber sterols.


Amphotericin B delays the incubation period of scrapie in intracerebrally inoculated hamsters.
The scrapie-infected hamster has been considered an excellent model for the study of slow virus diseases of man (Creutzfeldt-Jakob disease) and animals. At the moment no therapy is available for the cure of these fatal central nervous system diseases, although several drugs have been tested. We found that amphotericin B (AmB), a polyene antibiotic, increased the incubation time of scrapie disease in animals infected by either the intraperitoneal or intracerebral route. Hamsters inoculated with a 10% brain suspension of the 263K strain of scrapie showed clinical signs of disease in 54.6 +/- 4.7 days. Under AmB treatment (1 mg/kg for 6 days a week) the incubation time increased with the length of treatment, up to a maximum delay of 45 days. AmB may interact with the scrapie agent on cell plasma membranes and may thereby decrease the rate of scrapie replication. However, AmB did not have any effect when administered after the clinical onset of scrapie disease.


Phylogeny of the gall midges (Diptera, Cecidomyiidae, Cecidomyiinae): Systematics, evolution of feeding modes and diversification rates.
Gall midges (Cecidomyiidae) constitute one of the largest and most diverse families of Diptera, with close to 6600 described species and thousands of undescribed species worldwide. The family is divided into six subfamilies, the five basal ones comprising only fungivorous taxa, whereas the largest, youngest and most diverse subfamily Cecidomyiinae includes fungivorous as well as herbivorous and predatory species. The currently accepted classification of the Cecidomyiinae is morphology-based, and the few phylogenetic inferences that have previously been suggested for it were based on fragmentary or limited datasets. In a first comprehensive phylogenetic analysis of the Cecidomyiinae we sampled 142 species representing 88 genera of 13 tribes from all feeding guilds and zoogeographic regions in order to test the validity of the systematic division of the subfamily and gain insight into patterns of diversification and the evolution of feeding modes. We used sequences from five mitochondrial and nuclear genes to reconstruct maximum likelihood and Bayesian, time-calibrated phylogenies and conducted ancestral state reconstruction of feeding modes. Our results corroborate to a great extent the morphology-based classification of the Cecidomyiinae, with strong support for all supertribes and tribes, all were apparently established in the Upper Cretaceous concordant with the major radiation of angiosperms. We infer that transitions from fungus-feeding to plant-feeding occurred only once or twice in the evolution of the subfamily and that predation evolved only once, contrary to previous hypotheses. All herbivorous clades in the subfamily are very species rich and have diversified at a significantly greater rate than expected, but we found no support for the assertion that herbivorous clades associated with symbiotic fungi in their galls diversify faster than clades that do not have such associations. Currently available data also do not support the hypothesis that symbiotic clades have broader host ranges than non-symbiotic clades.


Chylomicrons against light scattering: The battle for characterization.
Chylomicrons (CMs) are lipoprotein particles circulating in blood and transporting dietary lipids. Optically speaking, CMs are small compared to the wavelength of visible light and widely distributed by the size and refractive index (RI). Consequently, intensity of light scattered by the CMs scales with up to the sixth power of their size, hampering simultaneous analysis of 60 and 600 nm CMs. We present an accurate method for quantitative characterization of large-size CM subpopulation by the distributions over size and RI. For the first time the CM characteristics have been determined at a single particle level based on angle-resolved light-scattering measurements. We applied the developed method to 2 key processes relating to CM metabolism, namely in vivo dynamics of CMs in blood plasma after a meal and in vitro lipolysis of CMs by the lipoprotein lipase in postheparin plasma. We have observed the substantial variations in CM concentration, size and RI distributions. This opens the way for a multitude of medical applications involving screening of CM metabolism, which we exemplified by revealing large differences in CM characteristics after a 12-hour fast between a healthy volunteer and a patient with atherosclerosis.


Coaching, truth induction, and young maltreated children's false allegations and false denials.
This study examined the effects of coaching (encouragement and rehearsal of false reports) and truth induction (a child-friendly version of the oath or general reassurance about the consequences of disclosure) on 4- to 7-year-old maltreated children's reports (N = 198). Children were questioned using free recall, repeated yes-no questions, and highly suggestive suppositional questions. Coaching impaired children's accuracy. For free-recall and repeated yes-no questions, the oath exhibited some positive effects, but this effect diminished in the face of highly suggestive questions. Reassurance had few positive effects and no ill effects. Neither age nor understanding of the meaning and negative consequences of lying consistently predicted accuracy. The results support the utility of truth induction in enhancing the accuracy of child witnesses' reports.


p38alpha mitogen-activated protein kinase plays a critical role in cardiomyocyte survival but not in cardiac hypertrophic growth in response to pressure overload.
The molecular mechanism for the transition from cardiac hypertrophy, an adaptive response to biomechanical stress, to heart failure is poorly understood. The mitogen-activated protein kinase p38alpha is a key component of stress response pathways in various types of cells. In this study, we attempted to explore the in vivo physiological functions of p38alpha in hearts. First, we generated mice with floxed p38alpha alleles and crossbred them with mice expressing the Cre recombinase under the control of the alpha-myosin heavy-chain promoter to obtain cardiac-specific p38alpha knockout mice. These cardiac-specific p38alpha knockout mice were born normally, developed to adulthood, were fertile, exhibited a normal life span, and displayed normal global cardiac structure and function. In response to pressure overload to the left ventricle, they developed significant levels of cardiac hypertrophy, as seen in controls, but also developed cardiac dysfunction and heart dilatation. This abnormal response to pressure overload was accompanied by massive cardiac fibrosis and the appearance of apoptotic cardiomyocytes. These results demonstrate that p38alpha plays a critical role in the cardiomyocyte survival pathway in response to pressure overload, while cardiac hypertrophic growth is unaffected despite its dramatic down-regulation.


The relation between prepregnancy sexuality and sexual function during pregnancy and the postpartum period: a prospective study.
This study examined the relation between sexual functions of women in prepregnancy (before conception) and during pregnancy and the postpartum period. This study was conducted on 59 healthy pregnant women. Participants were followed from the eighth week of gestation to 6 months after delivery. Sexual function during pregnancy and the postpartum period was shown to have a significant linear correlation with prepregnancy sexuality. There was no relation between pregnancy and postpartum sexuality. All of the participants who had prepregnancy sexual dysfunction continued to experience it during pregnancy, and the majority of them had a significant level of sexual dysfunction in the postpartum period. Our results showed that prepregnancy sexuality plays an important role in maintaining sexuality during pregnancy and the postpartum period.


Tuning of regioselectivity in the coupling reaction involving allenic/propargylic palladium species.
Two different types of coupling patterns for the Pd(0)-catalyzed coupling reaction of allenic/propargylic zinc reagents with organic halides or propargylic carbonates (acetate) with the corresponding organometallic reagents were observed. After studying the controlling factors on the regioselectivity of this reaction, we demonstrated that the steric hindrance of both reactants and the types of organic halides determine the regioselectivity of this coupling reaction. By subtle choosing of the substrates, the regioselectivity can be tuned. On the basis of these results, new methodologies for the highly regio- and stereoselective synthesis of 6-substituted hex-5-yn-2-enoates and 4,6-dialkylhexa-2,4,5-trienoates have been developed. Some of the products synthesized by the carbonate protocol cannot be prepared by the lithiation protocol because the regioselectivity of lithiation of dialkyl-substituted internal alkynes is an intrinsic problem.


Neither dichotomous nor split, but schema-related negative interpersonal evaluations characterize borderline patients.
Cognitive models explain extreme thoughts, affects, and behaviors of patients with Borderline Personality Disorder (BPD) by specific mal-adaptive schemas and dichotomous thinking. Psychodynamic theories ascribe these to splitting. This study expanded the study of Veen and Arntz (2000) and investigated whether extreme evaluations in BPD are (1) dichotomous, negativistic, or split; (2) limited to specific (schema-related) interpersonal situations; and (3) related to traumatic childhood experiences. BPD (n = 18), cluster C personality disorder (n = 16), and nonpatient (n = 17) groups were asked to judge 16 characters portrayed in film fragments in a specific or nonspecific context and with negative, positive, or neutral roles on visual analogue scales. These scales were divided in negative-positive trait opposites related to BPD schemas, negative-positive trait opposites unrelated to BPD schemas, and neutral trait opposites. Interpersonal evaluations of patients with BPD were (1) negativistic; (2) schema related; and (3) partially related to traumatic childhood experiences. Negative evaluations of caring characters in an intimate context particularly characterized BPD. No evidence was found for dichotomous thinking or splitting in BPD.


Stress-Induced Cardiomyopathy in Cancer Patients.
Takotsubo syndrome, also known as stress-induced cardiomyopathy (SC), is underrecognized in cancer patients. This study aims to investigate the incidence, natural history, and triggers of SC in cancer patients and its impact on cancer therapy and overall survival. A total of 30 subjects fulfilled the diagnostic criteria for SC at MD Anderson Cancer Center over a 6-year period. Clinical presentation, electrocardiogram, laboratory data, and transthoracic echocardiogram results registered during the acute phase and follow-up were collected. All patients underwent coronary angiography. The most frequent presenting symptoms were chest pain in 63.3% of the patients and shortness of breath/dyspnea on exertion in 27% of the patients. T-wave inversion was a more common electrocardiographic presentation (60%) than ST elevation (13.3%). The median and interquartile range of peak creatine kinase MB fraction, troponin I, and brain natriuretic peptide were creatine kinase MB fraction 8.9, 4.6 to 21.1; troponin I 1.31, 0.7 to 3.3; and brain natriuretic peptide 1,124, 453.5 to 2,369.5. The most common complication of SC was cardiogenic shock requiring inotropic agents (20%). Of the 21 patients who required ongoing cancer treatment, 16 were able to resume chemotherapy, 5 underwent surgery, and 4 received radiation treatment. Median time to resume cancer treatment was 20 days after SC. None of the patients experienced recurrence of SC and other cardiac events. In conclusion, SC should be considered in the differential diagnosis of cancer patients who present with chest pain and ECG findings characteristic of acute coronary syndrome. Most of these patients normalize ejection fraction and may resume cancer therapy early.


Transscleral resection versus iodine brachytherapy for choroidal malignant melanomas 6 millimeters or more in thickness: a matched case-control study.
To assess differences in treatment outcome after transscleral resection (TSR) and iodine brachytherapy (IBT) of choroidal melanomas too thick for ruthenium brachytherapy. Matched case-control study. Two national ocular oncology services. Forty-nine pairs of patients with choroidal melanoma 6 mm thick or more (range = 6-14), treated within 3 years of each other by either TSR or IBT, and retrospectively matched by age, visual acuity at diagnosis, largest basal tumor diameter, and posterior extension of the tumor. Iodine brachytherapy in Finland or TSR in United Kingdom. Prospectively collected time-to-event data were compared with parametric Weibull regression, adjusting for matching. Tumor control, complications, and visual acuity. Risk of local recurrence after IBT was smaller than that after TSR (hazard ratio [HR] = 0.02, 95% confidence interval [CI] = 0.01-0.11, P<0.001, Weibull regression adjusted for matching), but the 8-year all-cause and melanoma-specific (HR = 0.81, 95% CI = 0.30-2.22, P = 0.69) survivals did not differ. The risks of cataract (HR = 2.05, 95% CI = 1.08-3.89, P = 0.029), maculopathy (HR = 2.28, 95% CI = 0.96-5.43, P = 0.062), and vitreous hemorrhage (HR = 2.30, 95% CI = 0.95-5.57, P = 0.064) were higher after IBT. Rubeosis, neovascular glaucoma, and optic neuropathy developed only after IBT. Risk of retinal detachment, exudative after IBT and rhegmatogenous after TSR (HR = 0.84, 95% CI = 0.40-1.75, P = 0.63), and risk of losing 20/60 vision (HR = 1.37, 95% CI 0.76-2.45, P = 0.29) were comparable between the groups, but risk of losing 20/200 vision was higher after IBT (HR = 2.38, 95% CI = 1.48-3.83, P<0.001). No overall difference in quality of life was found. This study suggests that TSR preserves 20/200 vision better than IBT and avoids some of its major complications, but increases the risk of local recurrence. About 350 patients would need to be randomized to prove that TRS preserves 20/60 vision better than IBT.


A rare case of hyperpigmented torpedo maculopathy.
To describe a rare presentation of torpedo maculopathy (TM). A 25-year-old male was examined in the retina clinic for a macular scar in the left eye. His visual acuity was 20/20, N6 in both eyes and no past history of ocular trauma or any medical or ocular history. The anterior segment was quiet and intraocular pressure was normal. The patient's left eye on 78D slit lamp biomicroscopy revealed a flat, diffusely hyperpigmented fusiform torpedo-like lesion with sharp margins and surrounding hypopigmentation located predominantly temporal to the fovea, with its tip pointing towards it and just crossing the vertical foveal midline. Dilated fundus examination with binocular indirect ophthalmoscopy revealed no peripheral chorioretinal lesions or vitritis in both eyes. OCT scan through the lesion revealed gross damage to the outer retinal layers, as well as thickening of the retinal pigment epithelium and underlying shadowing, as well as a hyporeflective subretinal cleft involving the lesion. OCT also revealed outer retinal layer damage with an intact retinal pigment epithelium through the lesion's hypopigmented margins. Fundus autofluorescence image revealed a globally hypoautofluorescent lesion in the left eye, with surrounding patchy hyperautofluoroscent areas. Based on the patient history, clinical and imaging findings, other differential diagnoses such as atypical congenital hypertrophy of retinal pigment epithelium (RPE), choroidal nevus, RPE hamartoma, trauma and inflammatory conditions were ruled out. The diagnosis of TM was confirmed based on the typical lesion shape and location. A torpedo lesion with diffuse hyperpigmentation is an unusually rare presentation.


Foliar delta(13)C and delta(18)O reveal differential physiological responses of canopy foliage to pre-planting weed control in a young spotted gum (Corymbia citriodora subsp. Variegata) plantation.
Weed control may improve the growth of forest plantations by influencing soil water and nutrient availability, but our knowledge of leaf-level physiological responses to weed control at different within-canopy positions is limited for tropical and subtropical plantations. Foliar carbon (delta(13)C) and oxygen (delta(18)O) isotope compositions, gas exchange, and nitrogen (N(mass)) and phosphorus (P(mass)) concentrations at four canopy positions were assessed in a young spotted gum (Corymbia citriodora subsp. Variegata (F. Muell.) A.R. Bean & M.W. McDonald) plantation subjected to either weed control or no weed control treatment, to test if leaves at different positions within the tree canopy had the same physiological responses to the weed control treatment. Weed control increased foliar delta(13)C but lowered delta(18)O in the upper-outer and upper-inner canopy, indicating that weed control resulted in a higher foliar photosynthetic capacity at upper-canopy positions, a conclusion confirmed by gas exchange measurements. The increased photosynthetic capacity resulting from weed control can be explained by an increase in foliar N(mass). In the lower-outer canopy, weed control reduced foliar delta(13)C while lowering delta(18)O even more than in the upper-canopy, suggesting strong enhancement of the partial pressure of CO(2) in the leaf intercellular spaces and of foliar stomatal conductance in lower-canopy foliage. This conclusion was supported by gas exchange measurements. Foliar photosynthesis in the lower-inner canopy showed no significant response to weed control. The finding that leaves at different canopy positions differ in their physiological responses to weed control highlights the need to consider the canopy position effect when examining competition for soil nutrient and water resources between weeds and trees.


Interface engineering of two-dimensional transition metal dichalcogenides towards next-generation electronic devices: recent advances and challenges.
Over the past decade, two-dimensional (2D) transition metal dichalcogenides (TMDCs) have attracted tremendous research interest for future electronics owing to their atomically thin thickness, compelling properties and various potential applications. However, interface engineering including contact optimization and channel modulations for 2D TMDCs represents fundamental challenges in ultimate performance of ultrathin electronics. This article provides a comprehensive overview of the basic understanding of contacts and channel engineering of 2D TMDCs and emerging electronics benefiting from these varying approaches. In particular, we elucidate multifarious contact engineering approaches such as edge contact, phase engineering and metal transfer to suppress the Fermi level pinning effect at the metal/TMDC interface, various channel treatment avenues such as van der Waals heterostructures, surface charge transfer doping to modulate the device properties, and as well the novel electronics constructed by interface engineering such as diodes, circuits and memories. Finally, we conclude this review by addressing the current challenges facing 2D TMDCs towards next-generation electronics and offering our insights into future directions of this field.


Metabolic Insights into Iron Deposition in Relapsing-Remitting Multiple Sclerosis via 7 T Magnetic Resonance Spectroscopic Imaging.
To investigate the metabolic pattern of different types of iron accumulation in multiple sclerosis (MS) lesions, and compare metabolic alterations within and at the periphery of lesions and newly emerging lesions in vivo according to iron deposition. 7 T MR spectroscopic imaging and susceptibility-weighted imaging was performed in 31 patients with relapsing-remitting MS (16 female/15 male; mean age, 36.9 ± 10.3 years). Mean metabolic ratios of four neuro-metabolites were calculated for regions of interest (ROI) of normal appearing white matter (NAWM), "non-iron" (lesion without iron accumulation on SWI), and three distinct types of iron-laden lesions ("rim": distinct rim-shaped iron accumulation; "area": iron deposition across the entire lesions; "transition": transition between "area" and "rim" accumulation shape), and for lesion layers of "non-iron" and "rim" lesions. Furthermore, newly emerging "non-iron" and "iron" lesions were compared longitudinally, as measured before their appearance and one year later. Thirty-nine of 75 iron-containing lesions showed no distinct paramagnetic rim. Of these, "area" lesions exhibited a 65% higher mIns/tNAA (p = 0.035) than "rim" lesions. Comparing lesion layers of both "non-iron" and "rim" lesions, a steeper metabolic gradient of mIns/tNAA ("non-iron" +15%, "rim" +40%) and tNAA/tCr ("non-iron" -15%, "rim" -35%) was found in "iron" lesions, with the lesion core showing +22% higher mIns/tNAA (p = 0.005) and -23% lower tNAA/tCr (p = 0.048) in "iron" compared to "non-iron" lesions. In newly emerging lesions, 18 of 39 showed iron accumulation, with the drop in tNAA/tCr after lesion formation remaining significantly lower compared to pre-lesional tissue over time in "iron" lesions (year 0: p = 0.013, year 1: p = 0.041) as opposed to "non-iron" lesions (year 0: p = 0.022, year 1: p = 0.231). 7 T MRSI allows in vivo characterization of different iron accumulation types each presenting with a distinct metabolic profile. Furthermore, the larger extent of neuronal damage in lesions with a distinct iron rim was reconfirmed via reduced tNAA/tCr concentrations, but with metabolic differences in lesion development between (non)-iron-containing lesions. This highlights the ability of MRSI to further investigate different types of iron accumulation and suggests possible implications for disease monitoring.


Protease-activated receptor-1 down-regulation: a mutant HeLa cell line suggests novel requirements for PAR1 phosphorylation and recruitment to clathrin-coated pits.
Protease-activated receptor-1 (PAR1), a G protein-coupled receptor (GPCR) for thrombin, is irreversibly activated by a proteolytic mechanism, then internalized and degraded in lysosomes. The latter is critical for temporal fidelity of thrombin signaling. Toward understanding PAR1 down-regulation, we first investigated the pathway of PAR1 internalization. Activated PAR1 was rapidly recruited to clathrin-coated pits, where it colocalized with transferrin receptor (TfnR). Dominant-negative dynamin and clathrin hub mutants both blocked PAR1 internalization. Blockade of PAR1 internalization with dynamin K44A also inhibited activation-dependent PAR1 degradation. Thus activated PAR1 internalizes via clathrin-coated pits together with receptors that recycle and is then sorted away from such receptors and delivered to lysosomes. In the course of these studies we identified a mutant HeLa cell line, designated JT1, that was defective in PAR1 internalization. PAR1 signaled robustly in JT1 cells but was not phosphorylated or recruited to clathrin-coated pits after activation. Internalization of TfnR was intact in JT1 cells and internalization of beta(2)-adrenergic receptor, a GPCR that internalizes and recycles, was present but perhaps reduced. Taken together, these studies suggest that PAR1 is internalized in a dynamin- and clathrin-dependent manner like TfnR and beta(2)-adrenergic receptor but requires a distinct gene product for recruitment into this pathway.


Long-term survival after liver transplantation for alcoholic liver disease.
Currently, alcoholic cirrhosis is the second leading indication for liver transplantation in the United States and Europe. The quality of life and survival after a liver transplantation (LT) in patients with alcoholic liver disease (ALD) are similar to those in patients with other cirrhosis etiologies. The alcoholic relapse rate after a LT varies from 10%-50%, and these relapse patients are the ones who present a reduced long-term survival, mainly due to cardiovascular diseases and the onset of de novo neoplasms, including lung and upper aerodigestive tract. Nearly 40% of ALD recipients resume smoking and resume it early post-LT. Therefore, our pre-and post-LT follow-up efforts regarding ALD should be focused not only on alcoholic relapse but also on treating and avoiding other modifiable risk factors such as tobacco. The psychiatric and psychosocial pre-LT evaluation and the post-LT follow-up with physicians, psychiatrists and addiction specialists are important for reversing these problems because these professionals help to identify patients at risk for relapse as well as those patients who have relapsed, thus enabling responsive actions.


In vivo screening for anti-osteoporotic fraction from extract of herbal formula Xianlinggubao in ovariectomized mice.
Traditional Chinese Medicine (TCM) Fufang or formula Xianlinggubao (XLGB) is a prescribed TCM drug in China registered for prevention and treatment of osteoporosis. Fufang in TCM is comprised of a group of herbal compounds contributing in group to the treatment efficacy. The present study aims to identify the bioactive fraction(s) in XLGB extract that account(s) dominantly for its osteogenic effects. The extract of XLGB formula was separated into three fractions using chromatography, i.e., XLGB-A, XLGB-B and XLGB-C. They were administrated to 4-month old ovariectomized (OVX) mice for 6 weeks to determine which bioactive fraction(s) were more effective for preventing OVX-induced bone loss evaluated by microCT, biomechanical testing and biochemical markers. The main peaks of the key fraction were identified using reference compounds isolated from the fraction. In addition, the effects of the composite compounds in XLGB-B on osteoblasts' proliferation and mineralization were evaluated in UMR 106 cells. XLGB-B with a yield of 13.0% from herbal Fufang XLGB was identified as the most potential one among the three fractions for prevention of OVX-induced bone loss confirmed with bone mass, bone microarchitecture, bone strength and bone turnover markers. Nine compounds in HPLC fingerprint were identified in the XLGB-B fraction, including phenylpropanoids from Herba Epimedii, terpenes from Radix Dipsaci and coumarins from Fructus Psoraleae. In addition, the identified compounds effectively promoted proliferation and/or mineralization of osteoblast-like UMR 106 cells in vitro. XLGB-B with defined phytochemical structures was screened as the key fraction that demonstrated preventive effects on OVX-induced bone loss in mice. The present study laid down a foundation towards a new generation of herbal Fufang characterized with "less herbal materials for achieving equal treatment efficacy" in development strategy of TCM for prevention of OVX-induced osteoporosis.


Novel advances in drug delivery to brain cancer.
The therapy of brain tumors has been limited by a lack of effective methods of drug delivery to the brain. Systemic administration is often associated with toxic side effects and ultimately fails to achieve therapeutic concentrations within a tumor. An attractive strategy that has gained importance in brain tumor therapy has relied on local and controlled delivery of chemotherapeutic agents by biodegradable polymers. This technique allows direct exposure of tumor cells to a therapeutic agent for a prolonged period of time and has been shown to prolong the survival of patients with malignant brain tumors. The use of polymers for local drug delivery greatly expands the spectrum of drugs available for the treatment of malignant brain tumors. This review discusses the rationale for local drug delivery, describes the development of currently available polymer-based therapeutic agents, and highlights examples of promising non-polymer based drug delivery methods for use in the treatment of malignant brain tumors.


Causal Inference for Hypertension Prediction.
Hypertension is a leading cause of cardiovascular disease and premature death worldwide and it puts a heavy burden on the healthcare system. It is, therefore, very important to detect and evaluate hypertension and related cardiovascular events as to for efficient diagnosis, treatment and management. Hypertension can be evaluated with noninvasive cardiac signals, such as electrocardiogram (ECG) and photoplethysmogram (PPG) signals. Most of the previous studies predicted hypertension from ECG and PPG signals with extracted features that are correlated with hypertension. However, correlation is sometimes unreliable and may be affected by confounding factors. In this study, we propose a causal inference based approach to identify feature variables from ECG and PPG signals that are potentially causally related with hypertension. The method of greedy equivalence search was employed to construct the causal graph of features and hypertension. With causal features identified from the causal graph, we used machine learning models to diagnose hypertension. The machine learning classification models achieve great classification performance, among which random forest model has the best classification performance, with accuracy being 0.987, precision being 0.990, recall being 0.981, and F1-score being 0.985. The results show that the causal inference based approach can effectively predict hyper-tension.Clinical relevance- This paper proposes a new hypertension risk prediction method, which uses causality instead of correlation as the feature screening criteria to establish a causal graph of hypertension, which can predict the hypertension more reliably.


Cardiac effects of muscarinic receptor antagonists used for voiding dysfunction.
Antimuscarinic agents are the main drugs used to treat patients with the overactive bladder (OAB) syndrome, defined as urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia. Since the treatment is not curative and since OAB is a chronic disease, treatment may be life-long. Antimuscarinics are generally considered to be 'safe' drugs, but among the more serious concerns related to their use is the risk of cardiac adverse effects, particularly increases in heart rate (HR) and QT prolongation and induction of polymorphic ventricular tachycardia (torsade de pointes). An elevated resting HR has been linked to overall increased morbidity and mortality, particularly in patients with cardiovascular diseases. QT prolongation and its consequences are not related to blockade of muscarinic receptors, but rather linked to inhibition of the hERG potassium channel in the heart. However, experience with terodiline, an antimuscarinic drug causing torsade de pointes in patients, has placed the whole drug class under scrutiny. The potential of the different antimuscarinic agents to increase HR and/or prolong the QT time has not been extensively explored for all agents in clinical use. Differences between drugs cannot be excluded, but risk assessments based on available evidence are not possible.


Preparing Learners for Learning in the Engaged Learning Classroom.
This article was migrated. The article was marked as recommended. This set of Tips is written to make the best use of an Engaged Learning Classroom (ELC), which some may refer to as the 'flipped classroom.' Strategies for the ELC include Team-Based Learning (TBL), Peer Instruction (PI), Case-Based Learning (CBL). Our focus will be on the design and implementation of the out-of-class phase for any ELC activity since this is as important as the in-class phase, but often neglected. Experience has shown that the quality of learning from the ELC is highly dependent on the preparation before, and follow-up to the class session. The instructor's designation of material (written, audio-visual, other potential learning resources and activities) and guidance on how to approach these materials generates engagement and enhances learning. We provide important contextual information on the learners of today (Generation Z), highlights of current learning theory applicable to self-directed learning, and the unique ingredients for the linkage between out-of-class and in-class learning that makes for the fullest student engagement. Each Tip addresses frequent questions by both instructors and learners who are embarking on the ELC and/or lessons that we have learned from the literature and designing, facilitating, and evaluating sessions.


Hospice delivery models and survival differences in the terminally ill: a large cohort study.
A common difficulty at the end of life (EOL) is to determine an appropriate service model, such as hospice share care (HSC), hospice inpatient care (HIC) and hospice home care (HHC). This study aimed to recommend the appropriate hospice delivery model based on the physical, psychosocial and spiritual needs of patients referred for hospice care. This cohort study included patients who received only one kind of hospice delivery model between 2006 and 2020. Data were analysed with descriptive statistics, Fisher's exact test, non-parametric analysis of variance, Kaplan-Meier curves and Cox proportional hazards model that determined the patients' clinical characteristics for a hospice delivery model and overall survival. A total of 8874 hospice patients were recruited, of which 7076 (79.7%) were HSC patients, 918 (10.4%) were HIC patients and 880 (9.9%) were HHC patients. There were significant differences in the physical symptoms and demographic, psychosocial and spiritual factors among the three groups (p<0.001). The patients who received the HHC were less to have dyspnoea (18.5%) and dysphagia (28.7%). The HIC patients showed higher severity of symptoms and experienced greater psychosocial distress (73.2%). The HSC is appropriate for noncancer patients . Patients with cancer were associated with less dyspnoea (32.4%) and dysphagia (46.5%). Patients with lung cancer who received the HHC had better survival than those who received other types of hospice care (HR=0.75, 95% CI: 0.66 to 0.86, p<0.001). This study provides guidance regarding the appropriate hospice service model, based on individualised palliative needs, targeting improvement in EOL care.


Provably Secure Symmetric Private Information Retrieval with Quantum Cryptography.
Private information retrieval (PIR) is a database query protocol that provides user privacy in that the user can learn a particular entry of the database of his interest but his query would be hidden from the data centre. Symmetric private information retrieval (SPIR) takes PIR further by additionally offering database privacy, where the user cannot learn any additional entries of the database. Unconditionally secure SPIR solutions with multiple databases are known classically, but are unrealistic because they require long shared secret keys between the parties for secure communication and shared randomness in the protocol. Here, we propose using quantum key distribution (QKD) instead for a practical implementation, which can realise both the secure communication and shared randomness requirements. We prove that QKD maintains the security of the SPIR protocol and that it is also secure against any external eavesdropper. We also show how such a classical-quantum system could be implemented practically, using the example of a two-database SPIR protocol with keys generated by measurement device-independent QKD. Through key rate calculations, we show that such an implementation is feasible at the metropolitan level with current QKD technology.


Transactivation of the Brassica napus napin promoter by ABI3 requires interaction of the conserved B2 and B3 domains of ABI3 with different cis-elements: B2 mediates activation through an ABRE, whereas B3 interacts with an RY/G-box.
The transcriptional activator ABI3 is a key regulator of gene expression during embryo maturation in crucifers. In monocots, the related VP1 protein regulates the Em promoter synergistically with abscisic acid (ABA). We identified cis-elements in the Brassica napus napin napA promoter mediating regulation by ABI3 and ABA, by analyzing substitution mutation constructs of napA in transgenic tobacco plantlets ectopically expressing ABI3. In transient analysis using particle bombardment of tobacco leaf sections, a tetramer of the distB ABRE (abscisic acid-responsive element) mediated transactivation by ABI3 and ABI3-dependent response to ABA, whereas a tetramer of the composite RY/G complex, containing RY repeats and a G-box, mediated only ABA-independent transactivation by ABI3. Deletion of the conserved B2 and B3 domains of ABI3 abolished transactivation of napA by ABI3. The two domains of ABI3 interact with different cis-elements: B2 is necessary for ABA-independent and ABA-dependent activations through the distB ABRE, whereas B3 interacts with the RY/G complex. Thus B2 mediates the interaction of ABI3 with the protein complex at the ABRE. The regulation of napA by ABI3 differs from Em regulation by VP1, in that the B3 domain of ABI3 is essential for the ABA-dependent regulation of napA.


Annular intubation with pigtail probe for canalicular lacerations.
Pigtail probe as a procedure of choice for canalicular laceration. Retrospective, consecutive interventional case series of patients with eyelid laceration involving the canaliculus undergoing repair. All patients were subjected to repair with pigtail probe as first choice and only if this was not possible, they were repaired by other method. Outcome was analyzed in terms of cosmetic, functional, and anatomic success. A total of 35 patients (mean age, 10.88 years) underwent eyelid and canaliculus repair by a single surgeon (RM). In all, 32 (91.42%) canalicular lacerations were repaired by annular intubation using a pigtail probe, while the remaining 3 (8.58%) lacerations in which pigtail probe intubation was not possible, were repaired by an alternative method. Upper canaliculus was involved in 6 (17.14%) and lower canaliculus in 29 (82.86%) eyes. Mean follow-up was 8.2 months (range 3-13 months). Intubation tubes were removed after at least 3 months (range 12-20 weeks). None of the patients had complaints of epiphora. All the patients had good cosmesis, anatomic alignment and functional success as assessed by dye disappearance test in younger children and lacrimal irrigation in older children and adults. Bicanalicular annular repair with pigtail probe achieved excellent functional and cosmetic results. The loop minimizes the chances of extrusion of the tube, maintains natural anatomic alignment of the cut ends of the canaliculus and thus retains the integrity of the delicate canalicular system. Pigtail probe intubation can be considered as the first choice in canalicular lacerations.


Application of genomic SSR locus polymorphisms on the identification and classification of chrysanthemum cultivars in China.
The Chinese traditional chrysanthemum is a notable group of chrysanthemums (Chrysanthemum×morifolium Ramat.) in which the phenotypic characteristics richly vary. At present, there is a serious controversy regarding homonyms and synonyms within this group. Moreover, the current international chrysanthemum classification systems are not comprehensive enough to be used on Chinese traditional chrysanthemums. Thus, we first identified a broad collection of 480 Chinese traditional chrysanthemum cultivars using the unique DNA fingerprints and molecular identities that were established by 20 simple sequence repeat markers. Five loci, which distinguished all of the selected cultivars, were identified as the core loci to establish unique fingerprints and molecular identities with 19 denary digits for each cultivar. A cluster analysis based on Nei's genetic distance indicated that the selected cultivars were clustered according to their horticultural classification. Population structure analysis was subsequently performed with K values ranging from 2 to 14, and the most likely estimate for the population structure was ten subpopulations, which was nearly consistent with the clustering result. Principal component analysis was further performed to verify the classification results. On the basis of the Q-matrices of K = 10, a total of 19 traits were found to be associated with 42 markers. Taken together, these results can serve as starting points for the identification and classification of chrysanthemums based on the polymorphism of microsatellite markers, which is beneficial to promote the marker-assisted breeding and international communication of this marvelous crop.


Multiple endocrine neoplasia syndrome type 1: institution, management, and data analysis of a nationwide multicenter patient database.
The aim of this study was to integrate European epidemiological data on patients with multiple endocrine neoplasia type 1 by creating an Italian registry of this syndrome, including clinical and genetic characteristics and therapeutic management. Clinical, familial and genetic data of patients with multiple endocrine neoplasia type 1, diagnosed, treated, and followed-up for a mean time of 11.3 years, in 14 Italian referral endocrinological centers, were collected, over a 3-year course (2011-2013), to build a national electronic database. The Italian multiple endocrine neoplasia type 1 database includes 475 patients (271 women and 204 men), of whom 383 patients (80.6%) were classified as familial cases (from 136 different pedigrees), and 92 (19.4%) patients were sporadic cases. A MEN1 mutation was identified in 92.6% of familial cases and in 48.9% of sporadic cases. Four hundred thirty-six patients were symptomatic, presenting primary hyperparathyroidism, gastroenteropancreatic neuroendocrine tumors and pituitary tumors in 93, 53, and 41% of cases, respectively. Thirty-nine subjects, belonging to affected pedigrees positive for a MEN1 mutation, were asymptomatic at clinical and biochemical screening. Age at diagnosis of multiple endocrine neoplasia type 1 probands was similar for both familial and simplex cases (mean age 47.2 ± 15.3 years). In familial cases, diagnosis of multiple endocrine neoplasia type 1 in relatives of affected probands was made more than 10 years in advance (mean age at diagnosis 36.5 ± 17.6 years). The analysis of Italian registry of multiple endocrine neoplasia type 1 patients revealed that clinical features of Italian multiple endocrine neoplasia type 1 patients are similar to those of other western countries, and confirmed that the genetic test allowed multiple endocrine neoplasia type 1 diagnosis 10 years earlier than biochemical or clinical diagnosis.


An atlas of type I MADS box gene expression during female gametophyte and seed development in Arabidopsis.
Members of the plant type I MADS domain subfamily have been reported to be involved in reproductive development in Arabidopsis (Arabidopsis thaliana). However, from the 61 type I genes in the Arabidopsis genome, only PHERES1, AGAMOUS-LIKE80 (AGL80), DIANA, AGL62, and AGL23 have been functionally characterized, which revealed important roles for these genes during female gametophyte and early seed development. The functions of the other genes are still unknown, despite the fact that the available single T-DNA insertion mutants have been largely investigated. The lack of mutant phenotypes is likely due to a considerable number of recent intrachromosomal duplications in the type I subfamily, resulting in nonfunctional genes in addition to a high level of redundancy. To enable a breakthrough in type I MADS box gene characterization, a framework needs to be established that allows the prediction of the functionality and redundancy of the type I genes. Here, we present a complete atlas of their expression patterns during female gametophyte and seed development in Arabidopsis, deduced from reporter lines containing translational fusions of the genes to green fluorescent protein and beta-glucuronidase. All the expressed genes were revealed to be active in the female gametophyte or developing seed, indicating that the entire type I subfamily is involved in reproductive development in Arabidopsis. Interestingly, expression was predominantly observed in the central cell, antipodal cells, and chalazal endosperm. The combination of our expression results with phylogenetic and protein interaction data allows a better identification of putative redundantly acting genes and provides a useful tool for the functional characterization of the type I MADS box genes in Arabidopsis.


Nested species-rich networks of scavenging vertebrates support high levels of interspecific competition.
Disentangling the processes that shape the organization of ecological assemblages and its implications for species coexistence is one of the foremost challenges of ecology. Although insightful advances have recently related community composition and structure with species coexistence in mutualistic and antagonistic networks, little is known regarding other species assemblages, such as those of scavengers exploiting carrion. Here we studied seven assemblages of scavengers feeding on ungulate carcasses in mainland Spain. We used dynamical models to investigate if community composition, species richness and structure (nestedness) affect species coexistence at carcasses. Scavenging networks showed a nested pattern in sites where highly efficient, obligate scavengers (i.e., vultures) were present and a non-nested pattern everywhere else. Griffon Vulture (Gyps fulvus) and certain meso-facultative mammalian scavengers (i.e., red fox, Vulpes vulpes, and stone marten, Martes foina) were the main species contributing to nestedness. Assemblages with vultures were also the richest ones in species. Nested species-rich assemblages with vulture presence were associated with high carcass consumption rates, indicating higher interspecific competition at the local scale. However, the proportion of species stopping the consumption of carrion (as derived from the competitive dynamic model) stabilized at high richness and nestedness levels. This suggests that high species richness and nestedness may characterize scavenging networks that are robust to high levels of interspecific competition for carrion. Some facilitative interactions driven by vultures and major facultative scavengers could be behind these observations. Our findings are relevant for understanding species' coexistence in highly competitive systems.


Isolation and characterization of plasmin-generated bioactive fragments of IGFBP-3.
Insulin-like growth factor-binding protein-3 (IGFBP-3) was digested with plasmin, and the proteolytic fragments were isolated by HPLC and tested for bioactivity as measured by stimulation of glucose uptake in microvessel endothelial cells. Two of the pooled fractions of the digest stimulated glucose uptake. The major bioactive pool, at an estimated protein concentration <50 ng/ml, stimulated glucose uptake to 150% of control with greater stimulation and 220% of control at approximately 250 ng/ml. Two fragments were present in the bioactive fraction, the dominant one migrating at approximately 20,000 and the other at approximately 8,000. Both fragments bound 125I-labeled insulin-like growth factor and [3H]heparin. NH2-terminal amino acid analysis of the bioactive peak yielded two sequences. One, representing the majority of the material, had an NH2-terminal sequence identical to IGFBP-3; the second fragment began at amino acid 202 of IGFBP-3. In contrast to the bioactive fragments, intact IGFBP-3, at concentrations up to 130 microgram/ml, had no bioactivity. These findings demonstrate that IGFBP-3 can be degraded into fragments that have potent bioactivities that are not present in the intact IGFBP-3 molecule.


Neuronal ER-plasma membrane junctions organized by Kv2-VAP pairing recruit Nir proteins and affect phosphoinositide homeostasis.
The association of plasma membrane (PM)-localized voltage-gated potassium (Kv2) channels with endoplasmic reticulum (ER)-localized vesicle-associated membrane protein-associated proteins VAPA and VAPB defines ER-PM junctions in mammalian brain neurons. Here, we used proteomics to identify proteins associated with Kv2/VAP-containing ER-PM junctions. We found that the VAP-interacting membrane-associated phosphatidylinositol (PtdIns) transfer proteins PYK2 N-terminal domain-interacting receptor 2 (Nir2) and Nir3 specifically associate with Kv2.1 complexes. When coexpressed with Kv2.1 and VAPA in HEK293T cells, Nir2 colocalized with cell-surface-conducting and -nonconducting Kv2.1 isoforms. This was enhanced by muscarinic-mediated PtdIns(4,5)P2 hydrolysis, leading to dynamic recruitment of Nir2 to Kv2.1 clusters. In cultured rat hippocampal neurons, exogenously expressed Nir2 did not strongly colocalize with Kv2.1, unless exogenous VAPA was also expressed, supporting the notion that VAPA mediates the spatial association of Kv2.1 and Nir2. Immunolabeling signals of endogenous Kv2.1, Nir2, and VAP puncta were spatially correlated in cultured neurons. Fluorescence-recovery-after-photobleaching experiments revealed that Kv2.1, VAPA, and Nir2 have comparable turnover rates at ER-PM junctions, suggesting that they form complexes at these sites. Exogenous Kv2.1 expression in HEK293T cells resulted in significant differences in the kinetics of PtdIns(4,5)P2 recovery following repetitive muscarinic stimulation, with no apparent impact on resting PtdIns(4,5)P2 or PtdIns(4)P levels. Finally, the brains of Kv2.1-knockout mice had altered composition of PtdIns lipids, suggesting a crucial role for native Kv2.1-containing ER-PM junctions in regulating PtdIns lipid metabolism in brain neurons. These results suggest that ER-PM junctions formed by Kv2 channel-VAP pairing regulate PtdIns lipid homeostasis via VAP-associated PtdIns transfer proteins.


DiTing: A Pipeline to Infer and Compare Biogeochemical Pathways From Metagenomic and Metatranscriptomic Data.
Metagenomics and metatranscriptomics are powerful methods to uncover key micro-organisms and processes driving biogeochemical cycling in natural ecosystems. Databases dedicated to depicting biogeochemical pathways (for example, metabolism of dimethylsulfoniopropionate (DMSP), which is an abundant organosulfur compound) from metagenomic/metatranscriptomic data are rarely seen. Additionally, a recognized normalization model to estimate the relative abundance and environmental importance of pathways from metagenomic and metatranscriptomic data has not been organized to date. These limitations impact the ability to accurately relate key microbial-driven biogeochemical processes to differences in environmental conditions. Thus, an easy-to-use, specialized tool that infers and visually compares the potential for biogeochemical processes, including DMSP cycling, is urgently required. To solve these issues, we developed DiTing, a tool wrapper to infer and compare biogeochemical pathways among a set of given metagenomic or metatranscriptomic reads in one step, based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) and a manually created DMSP cycling gene database. Accurate and specific formulae for over 100 pathways were developed to calculate their relative abundance. Output reports detail the relative abundance of biogeochemical pathways in both text and graphical format. DiTing was applied to simulated metagenomic data and resulted in consistent genetic features of simulated benchmark genomic data. Subsequently, when applied to natural metagenomic and metatranscriptomic data from hydrothermal vents and the Tara Ocean project, the functional profiles predicted by DiTing were correlated with environmental condition changes. DiTing can now be confidently applied to wider metagenomic and metatranscriptomic datasets, and it is available at https://github.com/xuechunxu/DiTing.


HYPER: A New Approach for the Recognition and Positioning of Two-Dimensional Objects.
A new method has been designed to identify and locate objects lying on a flat surface. The merit of the approach is to provide strong robustness to partial occlusions (due for instance to uneven lighting conditions, shadows, highlights, touching and overlapping objects) thanks to a local and compact description of the objects boundaries and to a new fast recognition method involving generation and recursive evaluation of hypotheses named HYPER (HY potheses Predicted and Evaluated Recursively). The method has been integrated within a vision system coupled to an indutrial robot arm, to provide automatic picking and repositioning of partially overlapping industrial parts.


Transcranial direct current stimulation of dorsolateral prefrontal cortex improves dual-task gait performance in patients with Parkinson's disease: A double blind, sham-controlled study.
Despite advances in pharmacological treatments and surgical processes, the problem of impaired dual-tasking persists in people with Parkinson's disease (PD). Recently, transcranial direct current stimulation (tDCS) applied to the dorsolateral prefrontal cortex (DLPFC) has shown the potential to improve dual-task walking. Can combining left DLPFC stimulation using tDCS with dual-task performance reduce the cost of dual-tasking in individuals with PD? We conducted a sham-controlled, cross-over, and double-blind study to investigate the effect of combining tDCS with the dual-task walk and its sustained effects among people with PD. Twenty participants with PD completed two sessions (anodal or sham tDCS) with at least a 1-week gap. Stimulation involved transferring 2 mA current through the left DLPFC for 30 min. Single- and dual-task gait was assessed before, during, immediately after, 15, and 30 min after stimulation ceased. Phoneme verbal fluency task was given as the cognitive distractor during dual task. The results of this study show that in the dual-task condition, participants walked faster at fifteen minutes (p = 0.017) and thirty minutes (p < 0.01) after anodal tDCS ceased compared to sham. Similarly, participants generated a higher number of words per minute at fifteen minutes (p = 0.017), and thirty minutes (p < 0.01) after anodal tDCS ceased compared to sham. Furthermore, the dual-task cost (DTC) associated with gait speed was significantly lower (p = 0.022) at fifteen minutes after anodal tDCS compared to sham tDCS. However, no significant effect of tDCS was observed on gait and cognitive performance under the single-task condition. In conclusion, left DLPFC stimulation can improve dual-tasking in participants with PD and the peaking of the tDCS effect was observed at fifteen minutes after stimulation ceased.


Mass Media and the Contagion of Fear: The Case of Ebola in America.
In the weeks following the first imported case of Ebola in the U. S. on September 29, 2014, coverage of the very limited outbreak dominated the news media, in a manner quite disproportionate to the actual threat to national public health; by the end of October, 2014, there were only four laboratory confirmed cases of Ebola in the entire nation. Public interest in these events was high, as reflected in the millions of Ebola-related Internet searches and tweets performed in the month following the first confirmed case. Use of trending Internet searches and tweets has been proposed in the past for real-time prediction of outbreaks (a field referred to as "digital epidemiology"), but accounting for the biases of public panic has been problematic. In the case of the limited U. S. Ebola outbreak, we know that the Ebola-related searches and tweets originating the U. S. during the outbreak were due only to public interest or panic, providing an unprecedented means to determine how these dynamics affect such data, and how news media may be driving these trends. We examine daily Ebola-related Internet search and Twitter data in the U. S. during the six week period ending Oct 31, 2014. TV news coverage data were obtained from the daily number of Ebola-related news videos appearing on two major news networks. We fit the parameters of a mathematical contagion model to the data to determine if the news coverage was a significant factor in the temporal patterns in Ebola-related Internet and Twitter data. We find significant evidence of contagion, with each Ebola-related news video inspiring tens of thousands of Ebola-related tweets and Internet searches. Between 65% to 76% of the variance in all samples is described by the news media contagion model.


AutoDesigner, a De Novo Design Algorithm for Rapidly Exploring Large Chemical Space for Lead Optimization: Application to the Design and Synthesis of d-Amino Acid Oxidase Inhibitors.
The lead optimization stage of a drug discovery program generally involves the design, synthesis, and assaying of hundreds to thousands of compounds. The design phase is usually carried out via traditional medicinal chemistry approaches and/or structure-based drug design (SBDD) when suitable structural information is available. Two of the major limitations of this approach are (1) difficulty in rapidly designing potent molecules that adhere to myriad project criteria, or the multiparameter optimization (MPO) problem, and (2) the relatively small number of molecules explored compared to the vast size of chemical space. To address these limitations, we have developed AutoDesigner, a de novo design algorithm. AutoDesigner employs a cloud-native, multistage search algorithm to carry out successive rounds of chemical space exploration and filtering. Millions to billions of virtual molecules are explored and optimized while adhering to a customizable set of project criteria such as physicochemical properties and potency. Additionally, the algorithm only requires a single ligand with measurable affinity and a putative binding model as a starting point, making it amenable to the early stages of an SBDD project where limited data are available. To assess the effectiveness of AutoDesigner, we applied it to the design of novel inhibitors of d-amino acid oxidase (DAO), a target for the treatment of schizophrenia. AutoDesigner was able to generate and efficiently explore over 1 billion molecules to successfully address a variety of project goals. The compounds generated by AutoDesigner that were synthesized and assayed (1) simultaneously met not only physicochemical criteria, clearance, and central nervous system (CNS) penetration (Kp,uu) cutoffs but also potency thresholds and (2) fully utilize structural data to discover and explore novel interactions and a previously unexplored subpocket in the DAO active site. The reported data demonstrate that AutoDesigner can play a key role in accelerating the discovery of novel, potent chemical matter within the constraints of a given drug discovery lead optimization campaign.