In situ remineralization of early caries by a new high-fluoride dentifrice.
The present study evaluated the ability of a high-fluoride dentifrice containing tricalcium phosphate to remineralize white spot lesions and inhibit lesion formation. Three demineralized enamel blocks and three healthy blocks (cut from a group of 30 molars), were exposed in pairs (one demineralized, one sound) via an appliance worn by 30 adults in a three-phase crossover study lasting 28 days per phase. The pairs were exposed to three dentifrices: one contained 5,000 ppm fluoride with tricalcium phosphate, one contained 5,000 ppm fluoride alone, and one contained no fluoride at all. Lesion status was analyzed using surface microhardness and transverse microradiography. Surface microhardness showed that the two dentifrices containing fluoride significantly inhibited enamel demineralization (p < 0.05) and significantly remineralized white spot lesions (p < 0.05), while the fluoride-free dentifrice did not. The results indicate that combining fluoride with tricalcium phosphate could provide more anti-caries benefits compared to using fluoride alone.


The effect of extracellular matrix on the differentiation of mouse embryonic stem cells.
Embryonic stem cells (ESCs) are promising research materials to investigate cell fate determination since they have the capability to differentiate. Stem cell differentiation has been extensively studied with various microenvironment mimicking structures to modify cellular dynamics associated with the cell-extracellular matrix (ECM) interactions and cell-cell communications. In the current study, our aim was to determine the effect of microenvironmental proteins with different concentrations on the capacity and differentiation capability of mouse ESCs (mESCs), combining the biochemical assays, imaging techniques, Fourier transform infrared (FTIR) spectroscopy, and unsupervised multivariate analysis. Based on our data, coating the surface of mESCs with Matrigel, used as an acellular matrix substrate, resulted in morphological and biochemical changes. mESCs exhibited alterations in their phenotype after growing on the Matrigel-coated surfaces, including their differentiation capacity, cell cycle phase pattern, membrane fluidity, and metabolic activities. In conclusion, mESCs can be stimulated physiologically, chemically, or mechanically to convert them a new phenotype. Thus, identification of ESCs' behavior in the acellular microenvironment could be vital to elucidate the mechanism of diseases. It might also be promising to control the cell fate in the field of tissue engineering.


Linking albinism and immunity: the secrets of secretory lysosomes.
Lysosomes are membrane-bound organelles that are found in all mammalian cells and contain hydrolases and lipases required for protein and membrane degradation. In many cells of the immune system, lysosomes also contain secretory proteins that can be released by regulated exocytosis in response to an external stimulus, providing different cell types with a wide range of effector functions. Melanosomes also use a lysosome-related organelle to secrete melanin for pigmentation. Links between albinism and immunity in patients have uncovered a number of key proteins required for lysosomal secretion and have revealed a versatile secretory mechanism that can be fine-tuned by distinct interactions in different cell types.


Interaction of α-taxilin localized on intracellular components with the microtubule cytoskeleton.
Intracellular vesicle traffic plays an essential role in the establishment and maintenance of organelle identity and biosynthetic transport. We have identified α-taxilin as a binding partner of the syntaxin family, which is involved in intracellular vesicle traffic. Recently, we have found that α-taxilin is over-expressed in malignant tissues including hepatocellular carcinoma and renal cell carcinoma. However, a precise role of α-taxilin in intracellular vesicle traffic and carcinogenesis remains unclear. Then, we first investigated here the intracellular distribution of α-taxilin in Hela cells. Immunofluorescence studies showed that α-taxilin distributes throughout the cytoplasm and exhibits a tubulo-vesicular pattern. Biochemical studies showed that α-taxilin is abundantly localized on intracellular components as a peripheral membrane protein. Moreover, we found that α-taxilin distributes in microtubule-dependent and syntaxin-independent manners, that α-taxilin directly binds to polymerized tubulin in vitro, and that N-ethylmaleimide but not brefeldin A affects the intracellular distribution of α-taxilin. These results indicate that α-taxilin is localized on intracellular components in a syntaxin-independent manner and that the α-taxilin-containing intracellular components are associated with the microtubule cytoskeleton and suggest that α-taxilin functions as a linker protein between the α-taxilin-containing intracellular components and the microtubule cytoskeleton.


Block-iterative frequency-domain methods for Maxwell's equations in a planewave basis.
We describe a fully-vectorial, three-dimensional algorithm to compute the definite-frequency eigenstates of Maxwell's equations in arbitrary periodic dielectric structures, including systems with anisotropy (birefringence) or magnetic materials, using preconditioned block-iterative eigensolvers in a planewave basis. Favorable scaling with the system size and the number of computed bands is exhibited. We propose a new effective dielectric tensor for anisotropic structures, and demonstrate that O Delta x;2 convergence can be achieved even in systems with sharp material discontinuities. We show how it is possible to solve for interior eigenvalues, such as localized defect modes, without computing the many underlying eigenstates. Preconditioned conjugate-gradient Rayleigh-quotient minimization is compared with the Davidson method for eigensolution, and a number of iteration variants and preconditioners are characterized. Our implementation is freely available on the Web.


Executive function and mental health in adopted children with a history of recreational drug exposures.
Adoptive children are at increased risk for problematic behaviors but the origin of these individual differences in neurobehavioral function is unclear. This investigation examined whether adopted children with prenatal exposure to a wide variety of recreational drugs exhibited higher scores (i.e. more problems) with executive function and psychiatric symptomology. Caregivers of children ages 5 to 18 completed an online survey with items about use of alcohol, nicotine, or methamphetamine during pregnancy followed by the Behavior Rating Inventory of Executive Function (BRIEF, N = 437 including 59 adoptive parents) or the Child Behavior Checklist (CBCL, N = 549 including 54 adoptive parents). Relative to a comparison group of children raised by their biological parents, adoptive children that were polysubstance exposed during prenatal development exhibited higher rates of academic difficulties and were behind their classmates in math and reading. Adoptive children had statistically and clinically significant higher BRIEF ratings and this pattern was similar for boys and girls. CBCL ratings were significantly increased in adoptive children, particularly for Externalizing and Attention problems. Adoptive children with a history of polysubstance exposures including alcohol, nicotine, and methamphetamine are at heightened risk for difficulties with executive function as well as various psychopathologies. These findings suggest that increased monitoring to identify and implement remediation strategies may be warranted for adopted children with a history of in utero drug exposures.


Barriers to lose weight from the perspective of children with overweight/obesity and their parents: a sociocultural approach.
There are not enough studies about the barriers to lose weight from the perspective of children and their parents. Children and adolescents diagnosed with overweight/obesity in the Department of Endocrinology and their parents were invited to participate in a series of focus group discussions (FGD). Twenty-nine children 10-16 years old and 22 parents participated in 7 focus groups; 2 mothers and 2 adolescents participated in depth interviews. All interviews were recorded, transcribed, and analyzed through grounded theory. Parents went to the hospital only when their children presented any obesity complication; for them, overweight was not a health problem. Parents referred to lack of time to supervise about a healthy diet and exercise; besides, the same parents, relatives, friends, and the mass media encourage the consumption of junk food. Children accepted eating a lot, not doing exercise, skipping meals, and not understanding overweight consequences. Both, parents and children, demanded support to do the time recommended for exercise inside the schools. They also suggested getting information from schools and mass media (TV) about overweight consequences, exercise, and healthy food by health workers; they recommended prohibiting announcements about junk food and its sale. The barriers detected were lack of perception of being overweight, its identification as a disease and its consequences, lack of time to supervise a healthy lifestyle, and a big social influence to eat junk food.


Andrographolide suppresses epithelial mesenchymal transition by inhibition of MAPK signalling pathway in lens epithelial cells.
Epithelial mesenchymal transition (EMT) of lens epithelial cells (LECs) may contribute to the development of posterior capsular opacification (PCO), which leads to visual impairment. Andrographolide has been shown to have therapeutic potential against various cancers. However, its effect on human LECs is still unknown. The purpose of this study is to evaluate the effect of andrographolide on EMT induced by growth factors in the fetal human lens epithelial cell line (FHL 124). Initially the LECs were treated with growth factors (TGF-beta 2 and bFGF) to induce EMT. Subsequently these EMT-induced cells were treated with andrographolide at 100 and 500 nM concentrations for 24 h. Our results showed that FHL 124 cells treated with growth factors had a significant decrease in protein and m-RNA levels of epithelial markers pax6 and E-Cadherin. After administering andrographolide, these levels significantly increased. It was noticed that EMT markers alpha-SMA, fibronectin and collagen IV significantly decreased after treatment with andrographolide when compared to the other group. Treatment with andrographolide significantly inhibited phosphorylation of ERK and JNK. Cell cycle analysis showed that andrographolide did not arrest cells at G0/G1 or G2/M at tested concentrations. Our findings suggest that andrographolide helps sustain epithelial characteristics by modulating EMT markers and inhibiting the mitogen-activated protein kinase (MAPK) signalling pathway in LECs. Hence it can prove to be useful in curbing EMT-mediated PCO.


Exposure-response relationships for hexahydrophthalic and methylhexahydrophthalic anhydrides with total plasma protein adducts as biomarkers.
This study investigated the exposure-response relationships of hexahydrophthalic anhydride (HHPA) and methylhexahydrophthalic anhydride (MHHPA) and evaluated the applicability of the total plasma protein adducts (TPPA) of these anhydrides as biomarkers of exposure and risk. In a cross-sectional study of 139 workers in a plant manufacturing electrical capacitors, the long-term exposure to HHPA and MHHPA was assessed through the quantification of TPPA using gas chromatography-mass spectrometry. Smoking and medical histories were obtained through questionnaires. Work-related symptoms of the eyes and airways were recorded. Specific immunoglobulin (Ig) E (radioallergosorbent test) and IgG (enzyme-linked immunosorbent assay) were determined in serum. The mean level of the TPPA of HHPA was 840 fmol/ml and that of the TPPA of MHHPA was 1700 fmol/ml. There was no correlation between the TPPA of HHPA and the TPPA of MHHPA. Of all the workers, 19% were found to be positive for specific IgE and 17-19% for IgG. Positive associations were observed between HHPA exposure and specific IgE and IgG and between MHHPA exposure and specific IgG. Regarding work-related symptoms, 27% of the workers had symptoms of the nose, 21% had symptoms of the eyes, 11% had symptoms of the lower airways, and 8% had nose bleeding. There were significant exposure-response relationships for symptoms of the eyes and nose for HHPA exposure. The results show that there is an exposure-response relationship for HHPA both with specific antibodies and with work-related symptoms and down to adduct levels of 40 fmol/ml plasma. In addition, the results elucidate the potential power of TPPA as a relevant index of exposure and risk.


Method for determining distribution of reflection sites in the arterial system.
We developed a new method to determine the location and importance of reflection sites in the arterial system. The method is based on the decomposition of the aortic pressure wave into its forward and backward components, and it provides the reflection profile of the arterial system as a wave reflection site amplitude versus distance from the heart. The reflection profile can be seen as the response of the arterial system to a pressure delta pulse where reflections upstream from the measurement location have been eliminated. The method was successfully tested on a simple model loaded with a pure resistor, a two-element windkessel, and a bifurcating tube system. It was then applied to the aortic pressure and flow signals measured in six mongrel dogs whose aorta was occluded at different levels. The profiles obtained from measurements at control showed two main reflection regions, one located in the vicinity (0.1-0.2 m) of the heart and the other located in the region of the iliac bifurcation. All occlusions, even the most distant one at the iliac bifurcation, could be identified in both amplitude (amount of reflections) and distance from the heart. The spatial resolution of the profiles was approximately 0.1 m as a result of the limited power spectrum contained in the arterial pulse, and the identification of reflection sites decreased rapidly with the distance.


Myoelectric Control Based on a Generic Musculoskeletal Model: Toward a Multi-User Neural-Machine Interface.
This paper aimed to develop a novel electromyography (EMG)-based neural-machine interface (NMI) that is user-generic for continuously predicting coordinated motion betweenmuscle contractionmetacarpophalangeal (MCP) and wrist flexion/extension. The NMI requires a minimum calibration procedure that only involves capturing maximal voluntary muscle contraction for themonitoredmuscles for individual users. At the center of the NMI is a user-generic musculoskeletal model based on the experimental data collected from six able-bodied (AB) subjects and nine different upper limb postures. The generic model was evaluated on-line on both AB subjects and a transradial amputee. The subjectswere instructed to performa virtual hand/wrist posture matching task with different upper limb postures. The on-line performanceof the genericmodelwas also compared with that of the musculoskeletal model customized to each individual user (called "specific model"). All subjects accomplished the assigned virtual tasks while using the user-generic NMI, although the AB subjects produced better performance than the amputee subject. Interestingly, compared with the specific model, the generic model produced comparable completion time, a reduced number of overshoots, and improved path efficiency in the virtual hand/wrist posture matching task. The results suggested that it is possible to design an EMG-driven NMI based on a musculoskeletalmodelthat could fit multiple users, including upper limb amputees, for predicting coordinated MCP and wrist motion. The present new method might address the challenges of existing advanced EMG-based NMI that require frequent and lengthy customization and calibration. Our future research will focus on evaluating the developed NMI for powered prosthetic arms.


Percutaneous endovascular retrieval of an intravascular foreign body in five dogs, a goat, and a horse.
CASE DESCRIPTION-5 Dogs, 1 goat, and 1 horse underwent percutaneous endovascular retrieval of intravascular foreign bodies between 2002 and 2007. CLINICAL FINDINGS-Foreign bodies were IV catheters in 4 dogs, the horse, and the goat and a piece of a balloon valvuloplasty catheter in 1 dog. Location of the foreign bodies included the main pulmonary artery (1 dog), a branch of a pulmonary artery (4 dogs), the right ventricle (the goat), and a jugular vein (the horse). TREATMENT AND OUTCOME-The procedure of percutaneous endovascular retrieval of the foreign body was easy to perform in all instances. One dog was euthanized 41 days after retrieval because of worsening of another disease process, and 1 dog had abnormal neurologic signs secondary to a brain mass. All other animals were clinically normal during the follow-up period (follow-up duration, 3 to 57 months). None of the animals developed long-term complications secondary to the foreign body retrieval procedure. CLINICAL RELEVANCE-Intravascular foreign bodies that result from catheters or devices used during minimally invasive techniques are rare but may cause substantial morbidity. Percutaneous endovascular retrieval of intravascular foreign bodies was easily and safely performed in the 7 animals reported here. Use of percutaneous endovascular retrieval techniques should be considered for treatment of animals with intravascular foreign bodies because morbidity can be substantially decreased; however, proper selection of patients for the procedure is necessary.


Establishing minimal clinically important differences for scores on the pediatric evaluation of disability inventory for inpatient rehabilitation.
Standardized pediatric assessment tools such as the Pediatric Evaluation of Disability Inventory (PEDI) numerically quantify changes during rehabilitation through test scores, but they are unable to provide client-specific information regarding important changes in function. The purpose of this study was to identify the smallest change in PEDI scores during inpatient rehabilitation that was considered to be a minimal clinically important difference (MCID) by physical therapists and other clinicians. A retrospective review was done of the medical charts of 53 children and youth (1-19 years of age) discharged from an inpatient rehabilitation hospital. Fifteen clinicians (5 physical therapists, 6 occupational therapists, and 4 speech and language pathologists) who were masked to the PEDI scores provided ratings of the magnitude of functional changes during inpatient rehabilitation using a Likert scale and a visual analog scale (VAS). Ratings by clinicians were reduced to 4 categories, including the MCID, and compared with PEDI change scores. The MCIDs ranged from 6 to 15 points (X=11.5, 95% confidence interval= +/- 2.8) for all PEDI scales. Likert scale and VAS ratings were correlated (tau =.73-.80). Across all scales, PEDI change scores on the order of about 11% (0-100 scale) appear to be meaningful to clinicians during a child's or adolescent's inpatient rehabilitation. These data can serve as a starting point for interpreting group and individual changes on the PEDI during physical therapy intervention in inpatient rehabilitation.


Binge eating and binge eating disorder in a small-scale, indigenous society: the view from Fiji.
Although the cross-cultural prevalence of anorexia and bulimia nervosa has been investigated in multiple studies, little is known about the prevalence and correlates of binge eating and binge eating disorder (BED) cross-culturally. No published studies to date have explored BED in small-scale, indigenous, or developing societies. The current study investigated the prevalence and correlates of binge eating in a community sample of Fijian women living in rural Fiji. Fifty ethnic Fijian women completed a self-report measure developed for this study on dieting and attitudes toward body shape and change, a Nadroga-language questionnaire on body image, and the Questionnaire on Eating and Weight Patterns-Revised (QEWP-R). Their height and weight were also measured. Patterns of dieting, high body mass index (BMI), and attitudes toward eating and body image were compared between women with and without a history of binge eating. Ten percent of respondents reported at least weekly episodes of binge eating during the past 6 months and 4% endorsed symptoms consistent with BED. Binge eating in this sample was associated significantly with a BMI value above 35, a history of dieting, and a high concern with body shape. Binge eating was not associated with several markers of acculturation in this sample, although it was associated with a key, nontraditionally Fijian (i.e., acculturated) attitude toward the body. Binge eating occurred in a social context with traditions concerning weight and diet widely disparate from Western populations. However, correlates of binge eating in this sample suggest that nontraditional Fijian attitudes toward weight and body shape play a contributory role.


Sexual dimorphisms in genetic loci linked to body fat distribution.
Obesity is a chronic condition associated with increased morbidity and mortality and is a risk factor for a number of other diseases including type 2 diabetes and cardiovascular disease. Obesity confers an enormous, costly burden on both individuals and public health more broadly. Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes. Body fat distribution is distinct from overall obesity in measurement, but studies of body fat distribution can yield insights into the risk factors for and causes of overall obesity. Sexual dimorphism in body fat distribution is present throughout life. Though sexual dimorphism is subtle in early stages of life, it is attenuated in puberty and during menopause. This phenomenon could be, at least in part, due to the influence of sex hormones on the trait. Findings from recent large genome-wide association studies (GWAS) for various measures of body fat distribution (including waist-to-hip ratio, hip or waist circumference, trunk fat percentage and the ratio of android and gynoid fat percentage) emphasize the strong sexual dimorphism in the genetic regulation of fat distribution traits. Importantly, sexual dimorphism is not observed for overall obesity (as assessed by body mass index or total fat percentage). Notably, the genetic loci associated with body fat distribution, which show sexual dimorphism, are located near genes that are expressed in adipose tissues and/or adipose cells. Considering the epidemiological and genetic evidence, sexual dimorphism is a prominent feature of body fat distribution. Research that specifically focuses on sexual dimorphism in fat distribution can provide novel insights into human physiology and into the development of obesity and its comorbidities, as well as yield biological clues that will aid in the improvement of disease prevention and treatment.


Sirtuins: the 'magnificent seven', function, metabolism and longevity.
The sirtuin family of histone deacetylases (HDACs) was named after their homology to the Saccharomyces cerevisiae gene silent information regulator 2 (Sir2). In the yeast, Sir2 has been shown to mediate the effects of calorie restriction on the extension of life span and high levels of Sir2 activity promote longevity. Like their yeast homologs, the mammalian sirtuins (SIRT1-7) are class III HDACs and require NAD(+) as a cofactor to deacetylate substrates ranging from histones to transcriptional regulators. Through this activity, sirtuins are shown to regulate important biological processes ranging from apoptosis, adipocyte and muscle differentiation, and energy expenditure to gluconeogenesis. We review here the current knowledge regarding the role of sirtuins in metabolism, longevity, and discuss the possible therapeutic applications that could result from the understanding of their function in different organs and pathologies.


Are There Circadian Clocks in Non-Photosynthetic Bacteria?
Circadian clocks in plants, animals, fungi, and in photosynthetic bacteria have been well-described. Observations of circadian rhythms in non-photosynthetic Eubacteria have been sporadic, and the molecular basis for these potential rhythms remains unclear. Here, we present the published experimental and bioinformatical evidence for circadian rhythms in these non-photosynthetic Eubacteria. From this, we suggest that the timekeeping functions of these organisms will be best observed and studied in their appropriate complex environments. Given the rich temporal changes that exist in these environments, it is proposed that microorganisms both adapt to and contribute to these daily dynamics through the process of temporal mutualism. Understanding the timekeeping and temporal interactions within these systems will enable a deeper understanding of circadian clocks and temporal programs and provide valuable insights for medicine and agriculture.


Transforming lignin into porous graphene via direct laser writing for solid-state supercapacitors.
Cost-effective valorization of lignin into carbon-based electrode materials remains a challenge. Here we reported a facile and ultrafast laser writing technique to convert lignin into porous graphene as active electrode material for solid-state supercapacitors (SCs). During laser writing, alkaline lignin experienced graphitization. By controlling laser parameters such as power the porous structure and graphitization degree can be well modulated. Graphene obtained at 80% of laser power setting (LIG-80) had higher graphene quality and more porous structure than that obtained at the lower power levels (i.e., 50%, 70%). TEM images revealed that LIG-80 had few-layer graphene structure with fringe-like patterns. LIG-80 proved to be an active electrode material for SCs with a specific capacitance as high as 25.44 mF cm-2 in a H2SO4/PVA gel electrolyte, which is comparable or even superior to SCs based on pristine LIG obtained from other carbon precursors. Taken together, our proposed technical route for lignin-based LIG and subsequent application in SCs would not only open a new avenue to lignin valorization, but also produce porous graphene from a renewable carbon precursor for energy storage applications.


Candida albicans outbreak associated with total parenteral nutrition in the neonatal unit.
The most frequently isolated fungi in patients using TPN belongs to the Candida genus. Various infections including venous catheter infections, fungemia, endocarditis and ophthalmitis may be encountered. Upon growth of Candida in the blood cultures from the pediatric (neonatal) unit of our hospital, a surveillance was performed in this unit and involving the health care workers. Clonal relationships of the isolates were investigated with molecular tests. Blood samples obtained from the patients in pediatric neonatal unit were studied with automatized blood culture [BacT/Alert (Bio Mιrioux, France)]. Yeast isolates from environmental surveillance cultures (TPN solutions, hands of healthcare personnel, ιtagθre, etc) and patients were identified as C. albicans with conventional methods and ID 32 C and ATB TM Fungus 3 (Biomerieux, France) kits. Clonal similarity was determined by using AP-PCR as initial method and we have also typified all strains by the method of REP-PCR (diversilab system,bioMιrieux). Finally; Pulsed Field Gel Electrophoresis (PFGE) was used for confirmation. C. albicans was isolated in blood cultures of seven patients. Similar antifungal susceptibility patterns were observed in all isolates. AP-PCR and REP-PCR showed that the C. albicans isolates grown in the TPN solution and from the patients' blood cultures were clonally same strains. PFGE analysis further confirmed this clonality. According to results of the molecular methods, we thought that a C. albicans outbreak had occurred in the neonatal pediatric unit, due to contamination of TPN solution.


Fruit flies in biomedical research.
Many scientists complain that the current funding situation is dire. Indeed, there has been an overall decline in support in funding for research from the National Institutes of Health and the National Science Foundation. Within the Drosophila field, some of us question how long this funding crunch will last as it demotivates principal investigators and perhaps more importantly affects the long-term career choice of many young scientists. Yet numerous very interesting biological processes and avenues remain to be investigated in Drosophila, and probing questions can be answered fast and efficiently in flies to reveal new biological phenomena. Moreover, Drosophila is an excellent model organism for studies that have translational impact for genetic disease and for other medical implications such as vector-borne illnesses. We would like to promote a better collaboration between Drosophila geneticists/biologists and human geneticists/bioinformaticians/clinicians, as it would benefit both fields and significantly impact the research on human diseases.


The genome of the chicken DT40 bursal lymphoma cell line.
The chicken DT40 cell line is a widely used model system in the study of multiple cellular processes due to the efficiency of homologous gene targeting. The cell line was derived from a bursal lymphoma induced by avian leukosis virus infection. In this study we characterized the genome of the cell line using whole genome shotgun sequencing and single nucleotide polymorphism array hybridization. The results indicate that wild-type DT40 has a relatively normal karyotype, except for whole chromosome copy number gains, and no karyotype variability within stocks. In a comparison to two domestic chicken genomes and the Gallus gallus reference genome, we found no unique mutational processes shaping the DT40 genome except for a mild increase in insertion and deletion events, particularly deletions at tandem repeats. We mapped coding sequence mutations that are unique to the DT40 genome; mutations inactivating the PIK3R1 and ATRX genes likely contributed to the oncogenic transformation. In addition to a known avian leukosis virus integration in the MYC gene, we detected further integration sites that are likely to de-regulate gene expression. The new findings support the hypothesis that DT40 is a typical transformed cell line with a relatively intact genome; therefore, it is well-suited to the role of a model system for DNA repair and related processes. The sequence data generated by this study, including a searchable de novo genome assembly and annotated lists of mutated genes, will support future research using this cell line.


Mortality rates in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors: drug-specific comparisons in the Swedish Biologics Register.
To determine whether the differences in the modes of action and safety profiles of individual tumor necrosis factor inhibitors (TNFi) translate into differential mortality risks, as investigated in etanercept, infliximab, and adalimumab. Data on patients with rheumatoid arthritis (RA) identified in the Swedish Biologics Register (Anti-Rheumatic Therapy in Sweden [ARTIS]) in whom first-ever treatment with a biologic agent (etanercept [n = 2,686], infliximab [n = 2,027], or adalimumab [n = 1,609]) was initiated between 2003 and 2008 were linked to national Swedish registers to get information on deaths from any cause, demographic features, RA characteristics, comorbid conditions, and concurrent treatment at the start of TNFi treatment. Hazard ratios (HRs) were modeled using multivariable adjusted and weighted Cox models. During 19,118 person-years of followup, 211 patients died (3.3%; 1.1 deaths per 100 person-years); 85% of the deaths occurred among patients who had been exposed to only one TNFi. We found no statistically significant difference in overall mortality rates across the exposure groups, regardless of adjustment and modeling approach (for infliximab versus etanercept, HR 1.1 [95% confidence interval (95% CI) 0.7-1.7], and for adalimumab versus etanercept, HR 1.3 [95% CI 0.9-2.0]). Overall, we noted no statistically significant difference in mortality rates between the 3 TNF inhibitors under study. Further studies need to examine whether certain subsets of patients are at increased risk of death with specific TNFi.


Direct exposure to animal enteric pathogens.
Humans have very close interactions with working, food-producing, and companion animals. According to the American Veterinary Medical Association, there are more than one hundred million cat and dog pets in the United States. Furthermore, non-traditional pets like reptiles and exotic birds are not unusual companion animals in households. In addition to sharing with animals our living and/or working space and time, we also share, unfortunately, many disease causing microorganisms. In the past few years, we have become aware that several enteric pathogens that were thought to be mostly restricted to animals are a major cause of human disease. Examples of such pathogens include the protozoan parasite Cryptosporidium parvum and bacteria such as Campylobacter spp. This review will examine the characteristics of zoonotic enteric pathogens including bacterial (Helicobacter spp., Campylobacter spp., Salmonella spp., and verotoxin-producing Escherichia coli); parasitic (Toxoplasma gondii, Giardia spp., Cryptosporidium spp.); and viral (rotavirus, norwalk-like virus, hepatitis E virus), and the status of our knowledge with regard to the impact of such pathogens on human health.


13. Sacroiliac joint pain.
The sacroiliac joint accounts for approximately 16% to 30% of cases of chronic mechanical low back pain. Pain originating in the sacroiliac joint is predominantly perceived in the gluteal region, although pain is often referred into the lower and upper lumbar region, groin, abdomen, and/ or lower limb(s). Because sacroiliac joint pain is difficult to distinguish from other forms of low back pain based on history, different provocative maneuvers have been advocated. Individually, they have weak predictive value, but combined batteries of tests can help ascertain a diagnosis. Radiological imaging is important to exclude "red flags" but contributes little in the diagnosis. Diagnostic blocks are the diagnostic gold standard but must be interpreted with caution, because false-positive as well as false-negative results occur frequently. Treatment of sacroiliac joint pain is best performed in the context of a multidisciplinary approach. Conservative treatments address the underlying causes (posture and gait disturbances) and consist of exercise therapy and manipulation. Intra-articular sacroiliac joint infiltrations with local anesthetic and corticosteroids hold the highest evidence rating (1 B+). If the latter fail or produce only short-term effects, cooled radiofrequency treatment of the lateral branches of S1 to S3 (S4) is recommended (2 B+) if available. When this procedure cannot be used, (pulsed) radiofrequency procedures targeted at L5 dorsal ramus and lateral branches of S1 to S3 may be considered (2 C+).


Removal of nonionic surfactants from wastewater using a constructed wetland.
Removal of nonionic surfactants from municipal wastewater using a constructed wetland with a horizontal subsurface flow was studied in 2009 and 2010. Extraction spectrophotometry with 3',3″,5',5″-tetrabromophenolphthalein ethyl ester and KCl served to determine the analyte concentrations. Triton(®) X-100 was used as a standard to express the nonionic-surfactant concentrations. Anionic and cationic surfactants were shown not to interfere during the determination. Nonionic surfactants were degraded (to products undeterminable by the method) with a high average efficiency that reached 98.1% in 2009 and 99.1% in 2010, respectively. The average concentration of nonionic surfactants at the inflow was 0.978 mg/l, while it was close to the limit of quantification at the outflow (0.014 mg/l). A significant fraction of nonionic surfactants (38.7%) was already degraded during the pretreatment, and only 14.0% of the nonionic surfactants remained in the interstitial H(2) O taken in the vegetation bed at a distance of 1 m from the inflow zone at a 50-cm depth. Nonionic surfactants were degraded both under aerobic and anaerobic conditions.


Varied Rates of Implementation of Patient-Centered Medical Home Features and Residents' Perceptions of Their Importance Based on Practice Experience.
Little is known about how the patient-centered medical home (PCMH) is being implemented in residency practices. We describe both the trends in implementation of PCMH features and the influence that working with PCMH features has on resident attitudes toward their importance in 14 family medicine residencies associated with the P4 Project. We assessed 24 residency continuity clinics annually between 2007-2011 on presence or absence of PCMH features. Annual resident surveys (n=690) assessed perceptions of importance of PCMH features using a 4-point scale (not at all important to very important). We used generalized estimating equations logistic regression to assess trends and ordinal-response proportional odds regression models to determine if resident ratings of importance were associated with working with those features during training. Implementation of electronic health record (EHR) features increased significantly from 2007-2011, such as email communication with patients (33% to 67%), preventive services registries (23% to 64%), chronic disease registries (63% to 82%), and population-based quality assurance (46% to 79%). Team-based care was the only process of care feature to change significantly (54% to 93%). Residents with any exposure to EHR-based features had higher odds of rating the features more important compared to those with no exposure. We observed consistently lower odds of the resident rating process of care features as more important with any exposure compared to no exposure. Residencies engaged in educational transformation were more successful in implementing EHR-based PCMH features, and exposure during training appears to positively influence resident ratings of importance, while exposure to process of care features are slower to implement with less influence on importance ratings.


Platelet-RBC interaction mediated by FasL/FasR induces procoagulant activity important for thrombosis.
Red blood cells (RBCs) influence rheology, and release ADP, ATP, and nitric oxide, suggesting a role for RBCs in hemostasis and thrombosis. Here, we provide evidence for a significant contribution of RBCs to thrombus formation. Anemic mice showed enhanced occlusion times upon injury of the carotid artery. A small population of RBCs was located to platelet thrombi and enhanced platelet activation by a direct cell contact via the FasL/FasR (CD95) pathway known to induce apoptosis. Activation of platelets in the presence of RBCs led to platelet FasL exposure that activated FasR on RBCs responsible for externalization of phosphatidylserine (PS) on the RBC membrane. Inhibition or genetic deletion of either FasL or FasR resulted in reduced PS exposure of RBCs and platelets, decreased thrombin generation, and reduced thrombus formation in vitro and protection against arterial thrombosis in vivo. Direct cell contacts between platelets and RBCs via FasL/FasR were shown after ligation of the inferior vena cava (IVC) and in surgical specimens of patients after thrombectomy. In a flow restriction model of the IVC, reduced thrombus formation was observed in FasL-/- mice. Taken together, our data reveal a significant contribution of RBCs to thrombosis by the FasL/FasR pathway.


Suppression of FoxO1 activity by long-chain fatty acyl analogs.
Overactivity of the Forkhead transcription factor FoxO1 promotes diabetic hyperglycemia, dyslipidemia, and acute-phase response, whereas suppression of FoxO1 activity by insulin may alleviate diabetes. The reported efficacy of long-chain fatty acyl (LCFA) analogs of the MEDICA series in activating AMP-activated protein kinase (AMPK) and in treating animal models of diabesity may indicate suppression of FoxO1 activity. The insulin-sensitizing and anti-inflammatory efficacy of a MEDICA analog has been verified in guinea pig and in human C-reactive protein (hCRP) transgenic mice, respectively. Suppression of FoxO1 transcriptional activity has been verified in the context of FoxO1- and STAT3-responsive genes and compared with suppression of FoxO1 activity by insulin and metformin. Treatment with MEDICA analog resulted in total body sensitization to insulin, suppression of lipopolysaccharide-induced hCRP and interleukin-6-induced acute phase reactants and robust decrease in FoxO1 transcriptional activity and in coactivation of STAT3. Suppression of FoxO1 activity was accounted for by its nuclear export by MEDICA-activated AMPK, complemented by inhibition of nuclear FoxO1 transcriptional activity by MEDICA-induced C/EBPβ isoforms. Similarly, insulin treatment resulted in nuclear exclusion of FoxO1 and further suppression of its nuclear activity by insulin-induced C/EBPβ isoforms. In contrast, FoxO1 suppression by metformin was essentially accounted for by its nuclear export by metformin-activated AMPK. Suppression of FoxO1 activity by MEDICA analogs may partly account for their antidiabetic anti-inflammatory efficacy. FoxO1 suppression by LCFA analogs may provide a molecular rational for the beneficial efficacy of carbohydrate-restricted ketogenic diets in treating diabetes.


A hyperpolarizing component of the receptor potential in the median ocellus of Limulus.
There are two classes of photoreceptor cells in the median ocellus of Limulus. One class of cells respond to long wavelength (visible) stimuli with a depolarizing receptor potential and to near ultraviolet light with a biphasic, initially hyperpolarizing, receptor potential. The other class of receptors respond with a depolarization to near ultraviolet and with a biphasic response to visible light. In the latter type of cell, visible light can counteract the depolarization elicited by near ultraviolet light. The evidence suggests that there are two photopigments in each cell and that both are involved in the generation of receptor potential.


Differential magnocellular versus parvocellular pathway contributions to the combinatorial processing of facial threat.
Recently, speed of presentation of facially expressive stimuli was found to influence the processing of compound threat cues (e.g., anger/fear/gaze). For instance, greater amygdala responses were found to clear (e.g., direct gaze anger/averted gaze fear) versus ambiguous (averted gaze anger/direct gaze fear) combinations of threat cues when rapidly presented (33 and 300ms), but greater to ambiguous versus clear threat cues when presented for more sustained durations (1, 1.5, and 2s). A working hypothesis was put forth (Adams et al., 2012) that these effects were due to differential magnocellular versus parvocellular pathways contributions to the rapid versus sustained processing of threat, respectively. To test this possibility directly here, we restricted visual stream processing in the fMRI environment using facially expressive stimuli specifically designed to bias visual input exclusively to the magnocellular versus parvocellular pathways. We found that for magnocellular-biased stimuli, activations were predominantly greater to clear versus ambiguous threat-gaze pairs (on par with that previously found for rapid presentations of threat cues), whereas activations to ambiguous versus clear threat-gaze pairs were greater for parvocellular-biased stimuli (on par with that previously found for sustained presentations). We couch these findings in an adaptive dual process account of threat perception and highlight implications for other dual process models within psychology.


Gender differences in physical activity and sedentary behavior: Results from over 200,000 Latin-American children and adolescents.
More physical activity and less sedentary behavior is beneficial for children and adolescents. Worldwide, gender differences are >8% favorable for men and the Latin-American region presents an even higher level of insufficient physical activity among women, with a lack of information in young population. Thus, the aim of the current study was to describe the gender differences in physical activity and recreational sedentary behavior in children and adolescents from Latin-American countries. The targeted age range was 5 to 17 years and included 219,803 participants (106,698 boys and 113,105 girls) from 33 out of 47 Latin-American countries identified. Physical activity guidelines from the World Health Organization (≥60 minutes of moderate-to-vigorous physical activity seven days of the week) and <3 hours recreational sedentary behavior daily were the references. In general, boys showed a higher prevalence of meeting physical activity guidelines in comparison with girls. A higher proportion of girls met the <3 hours recreational sedentary behavior cut-point in only ten countries. Thirty percent of the identified countries had no available data. The majority had data from the Global School-based Student Health Survey with data principally on adolescents and only 11/33 countries reported data in the last 5-year period. In conclusion, gender differences in the compliance with physical activity guidelines and the <3 hours recreational sedentary behavior cut-point are evident among children and adolescents from Latin-American countries, with boys being more active than girls.


Interactions between nodes in a physical gel network of telechelic polymers; self-consistent field calculations beyond the cell model.
Triblock copolymers, with associative end-groups and a soluble middle block, form flower-like micelles in dilute solutions and a physical gel at higher concentrations. In a gel the middle blocks form bridges between domains/nodes that contain the ends. We combine the self-consistent field theory with a simple molecular model to evaluate the pair potential between the nodes. In this model the end-groups are forced to remain in nodes and the soluble middle blocks are in solution. When the distance between the centres of the nodes is approximately the corona diameter, loops can transform into bridges, and the pair potential is attractive. Due to steric hindrance, the interaction is repulsive at smaller distances. Till now a cell-model has been used wherein a central node interacts through reflecting boundary conditions with its images in a spherical geometry. This artificial approach to estimate pair potentials is here complemented by more realistic three-gradient SCF models. We consider the pair interactions for (i) two isolated nodes, (ii) nodes positioned on a line (iii) a central node surrounded by its neighbours in simple cubic ordering, and (iv) a central node in a face centred cubic configuration of its neighbours. Qualitatively, the cell model is in line with the more refined models, but quantitative differences are significant. We also notice qualitative differences for the pair potentials in the specified geometries, which we interpret as a breakdown of the pairwise additivity of the pair potential. This implies that for course grained Monte Carlo or molecular dynamics simulations the best choice for the pair potentials depends on the expected node density.


Global malnutrition overlaps with pollinator-dependent micronutrient production.
Pollinators contribute around 10% of the economic value of crop production globally, but the contribution of these pollinators to human nutrition is potentially much higher. Crops vary in the degree to which they benefit from pollinators, and many of the most pollinator-dependent crops are also among the richest in micronutrients essential to human health. This study examines regional differences in the pollinator dependence of crop micronutrient content and reveals overlaps between this dependency and the severity of micronutrient deficiency in people around the world. As much as 50% of the production of plant-derived sources of vitamin A requires pollination throughout much of Southeast Asia, whereas other essential micronutrients such as iron and folate have lower dependencies, scattered throughout Africa, Asia and Central America. Micronutrient deficiencies are three times as likely to occur in areas of highest pollination dependence for vitamin A and iron, suggesting that disruptions in pollination could have serious implications for the accessibility of micronutrients for public health. These regions of high nutritional vulnerability are understudied in the pollination literature, and should be priority areas for research related to ecosystem services and human well-being.


Association between common alcohol dehydrogenase gene (ADH) variants and schizophrenia and autism.
Humans express at least seven alcohol dehydrogenase (ADH) isoforms that are encoded by ADH gene cluster (ADH7-ADH1C-ADH1B-ADH1A-ADH6-ADH4-ADH5) at chromosome 4. ADHs are key catabolic enzymes for retinol and ethanol. The functional ADH variants (mostly rare) have been implicated in alcoholism risk. In addition to catalyzing the oxidation of retinol and ethanol, ADHs may be involved in the metabolic pathways of several neurotransmitters that are implicated in the neurobiology of neuropsychiatric disorders. In the present study, we comprehensively examined the associations between common ADH variants [minor allele frequency (MAF) >0.05] and 11 neuropsychiatric and neurological disorders. A total of 50,063 subjects in 25 independent cohorts were analyzed. The entire ADH gene cluster was imputed across these 25 cohorts using the same reference panels. Association analyses were conducted, adjusting for multiple comparisons. We found 28 and 15 single nucleotide polymorphisms (SNPs), respectively, that were significantly associated with schizophrenia in African-Americans and autism in European-Americans after correction by false discovery rate (FDR) (q < 0.05); and 19 and 6 SNPs, respectively, that were significantly associated with these two disorders after region-wide correction by SNPSpD (8.9 × 10(-5) ≤ p ≤ 0.0003 and 2.4 × 10(-5) ≤ p ≤ 0.0003, respectively). No variants were significantly associated with the other nine neuropsychiatric disorders, including alcohol dependence. We concluded that common ADH variants conferred risk for both schizophrenia in African-Americans and autism in European-Americans.


George Lyman Duff memorial lecture. Progression and regression of atherosclerotic lesions. Insights from lipid physical biochemistry.
This review summarizes the evidence that the physical properties of lipids which accumulate in the intima play major roles in the progression and regression of lesions of atherosclerosis. All of the three major classes of lipids that accumulate in lesions (phospholipids, cholesterol, and cholesterol esters) are water insoluble. Phospholipids and cholesterol esters are almost mutually insoluble, but cholesterol, a crystalline solid at 37 degrees C, has considerable solubility in phospholipid bilayers and cholesterol esters. In normal infant intima, cholesterol is solubilized by phospholipid membranes. During fatty streak development, groups of cells are stimulated to take up more cholesterol than they excrete. The excess cholesterol is biochemically converted to cholesterol ester, which separates as droplets to form foam cells. Some fatty streaks then undergo a transition to an intermediate lesion containing excess cholesterol which is carried in cholesterol-supersaturated membranes and droplets. When nucleation of this excess cholesterol occurs, it precipitates as crystals; their formation coincides with the onset of necrosis and plaque formation. The hallmark of plaque is the presence of inert cholesterol crystals. They appear to form from hydrolysis of the older deposits of cholesterol esters in the base of intermediate lesions. Thus, the lipids in plaques are stratified, with recently deposited cholesterol esters present in the luminal part of the intima and older deposits in the deeper regions. When plasma cholesterol is lowered below about 150 mg/dl, lipids are mobilized from lesions and regression gradually occurs. Early in the regression process, cholesterol esters are reduced at least partly by hydrolysis to yield cholesterol, some of which may crystallize and inhibit rapid regression. After prolonged periods of low plasma cholesterol, cholesterol esters and foam cells disappear and crystalline cholesterol gradually dissolves, leading to true regression.


Crystal Structures of Anti-apoptotic BFL-1 and Its Complex with a Covalent Stapled Peptide Inhibitor.
BCL-2 family proteins are high-priority cancer targets whose structures provide essential blueprints for drug design. Whereas numerous structures of anti-apoptotic BCL-2 protein complexes with α-helical BH3 peptides have been reported, the corresponding panel of apo structures remains incomplete. Here, we report the crystal structure of apo BFL-1 at 1.69-Å resolution, revealing similarities and key differences among unliganded anti-apoptotic proteins. Unlike all other BCL-2 proteins, apo BFL-1 contains a surface-accessible cysteine within its BH3-binding groove, allowing for selective covalent targeting by a NOXA BH3-based stapled peptide inhibitor. The crystal structure of this complex demonstrated the sulfhydryl bond and fortuitous interactions between the acrylamide-bearing moiety and a newly formed hydrophobic cavity. Comparison of the apo and BH3-liganded structures further revealed an induced conformational change. The two BFL-1 structures expand our understanding of the surface landscapes available for therapeutic targeting so that the apoptotic blockades of BFL-1-dependent cancers can be overcome.


Canker and decline diseases caused by soil- and airborne Phytophthora species in forests and woodlands.
Most members of the oomycete genus Phytophthora are primary plant pathogens. Both soil- and airborne Phytophthora species are able to survive adverse environmental conditions with enduring resting structures, mainly sexual oospores, vegetative chlamydospores and hyphal aggregations. Soilborne Phytophthora species infect fine roots and the bark of suberized roots and the collar region with motile biflagellate zoospores released from sporangia during wet soil conditions. Airborne Phytophthora species infect leaves, shoots, fruits and bark of branches and stems with caducous sporangia produced during humid conditions on infected plant tissues and dispersed by rain and wind splash. During the past six decades, the number of previously unknown Phytophthora declines and diebacks of natural and semi-natural forests and woodlands has increased exponentially, and the vast majority of them are driven by introduced invasive Phytophthora species. Nurseries in Europe, North America and Australia show high infestation rates with a wide range of mostly exotic Phytophthora species. Planting of infested nursery stock has proven to be the main pathway of Phytophthora species between and within continents. This review provides insights into the history, distribution, aetiology, symptomatology, dynamics and impact of the most important canker, decline and dieback diseases caused by soil- and airborne Phytophthora species in forests and natural ecosystems of Europe, Australia and the Americas.


p53 Protein overexpression in cholangiocarcinoma arising in primary sclerosing cholangitis.
The protein encoded by the p53 tumour suppressor gene plays an important part in the regulation of cell growth. Abnormalities of this gene represent one of the most common genetic changes in the development of human cancers. This study investigated the expression of p53 protein in cholangiocarcinoma arising in association with primary sclerosing cholangitis (PSC). Of the 14 patients with cholangiocarcinoma studied, 13 had underlying PSC. The expression of p53 protein was detected immunohistochemically in paraffin wax embedded liver specimens, after microwave pretreatment. The expression of p53 protein was shown in the cholangiocarcinoma tissue of 11 of 14 (78.5%) patients. In five of 10 patients, the accumulation of p53 protein highlighted the presence of neoplastic cells in biliary tissue separate from the main tumour. These cells were mainly located in the septal bile ducts or in the accessory glands, or both, but occasionally also in large portal areas at the periphery of nerves and lymphatics, and in one case in the mucosa of an extrahepatic bile duct. No p53 protein was detectable in liver tissue obtained at the time of transplantation in 15 patients with PSC but not cholangiocarcinoma. These results show that cholangiocarcinoma development in PSC is commonly associated with abnormalities of p53 and that these occur at a late stage in the development of the malignant process. Staining for p53 protein could represent an additional criterion for the diagnosis of cholangiocarcinoma development in patients with PSC.


Intake of folate, vitamins B6, B12 and methionine and risk of pancreatic cancer in a large population-based case-control study.
Folate and other methyl-group nutrients may play a key role in pancreatic carcinogenesis through their effects on DNA integrity. We examined the association between pancreatic cancer and intake of folate, vitamins B(6), B(12) and methionine in a large population-based case-control study. Risk factor data were collected during in-person interviews with 532 pancreatic cancer cases diagnosed in 1995-1999 and 1,701 frequency-matched controls in the San Francisco Bay Area. Dietary history and supplement use were obtained using a semi-quantitative food-frequency questionnaire developed at Harvard University. Adjusted unconditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CI) as estimates of the relative risk. Total folate intake was inversely associated with pancreatic cancer (5th vs. 1st quintile: OR = 0.67, 95% CI = 0.48-0.93, p (trend) = 0.04). Increased vitamin B(12) from food was positively associated with pancreatic cancer although risk estimates for quintiles 3-5 were similar (5th vs. 1st quintile: OR = 1.9, 95% CI = 1.3-2.6, p (trend) = 0.001). Intake of vitamin B(6) or methionine was not associated with pancreatic cancer risk. Our study provided some support for an inverse association between folate intake and pancreatic cancer risk. The increased pancreatic cancer risk with vitamin B(12) intake from food warrants further investigation.


The phagotrophic origin of eukaryotes and phylogenetic classification of Protozoa.
Eukaryotes and archaebacteria form the clade neomura and are sisters, as shown decisively by genes fragmented only in archaebacteria and by many sequence trees. This sisterhood refutes all theories that eukaryotes originated by merging an archaebacterium and an alpha-proteobacterium, which also fail to account for numerous features shared specifically by eukaryotes and actinobacteria. I revise the phagotrophy theory of eukaryote origins by arguing that the essentially autogenous origins of most eukaryotic cell properties (phagotrophy, endomembrane system including peroxisomes, cytoskeleton, nucleus, mitosis and sex) partially overlapped and were synergistic with the symbiogenetic origin of mitochondria from an alpha-proteobacterium. These radical innovations occurred in a derivative of the neomuran common ancestor, which itself had evolved immediately prior to the divergence of eukaryotes and archaebacteria by drastic alterations to its eubacterial ancestor, an actinobacterial posibacterium able to make sterols, by replacing murein peptidoglycan by N-linked glycoproteins and a multitude of other shared neomuran novelties. The conversion of the rigid neomuran wall into a flexible surface coat and the associated origin of phagotrophy were instrumental in the evolution of the endomembrane system, cytoskeleton, nuclear organization and division and sexual life-cycles. Cilia evolved not by symbiogenesis but by autogenous specialization of the cytoskeleton. I argue that the ancestral eukaryote was uniciliate with a single centriole (unikont) and a simple centrosomal cone of microtubules, as in the aerobic amoebozoan zooflagellate Phalansterium. I infer the root of the eukaryote tree at the divergence between opisthokonts (animals, Choanozoa, fungi) with a single posterior cilium and all other eukaryotes, designated 'anterokonts' because of the ancestral presence of an anterior cilium. Anterokonts comprise the Amoebozoa, which may be ancestrally unikont, and a vast ancestrally biciliate clade, named 'bikonts'. The apparently conflicting rRNA and protein trees can be reconciled with each other and this ultrastructural interpretation if long-branch distortions, some mechanistically explicable, are allowed for. Bikonts comprise two groups: corticoflagellates, with a younger anterior cilium, no centrosomal cone and ancestrally a semi-rigid cell cortex with a microtubular band on either side of the posterior mature centriole; and Rhizaria [a new infrakingdom comprising Cercozoa (now including Ascetosporea classis nov.), Retaria phylum nov., Heliozoa and Apusozoa phylum nov.], having a centrosomal cone or radiating microtubules and two microtubular roots and a soft surface, frequently with reticulopodia. Corticoflagellates comprise photokaryotes (Plantae and chromalveolates, both ancestrally with cortical alveoli) and Excavata (a new protozoan infrakingdom comprising Loukozoa, Discicristata and Archezoa, ancestrally with three microtubular roots). All basal eukaryotic radiations were of mitochondrial aerobes; hydrogenosomes evolved polyphyletically from mitochondria long afterwards, the persistence of their double envelope long after their genomes disappeared being a striking instance of membrane heredity. I discuss the relationship between the 13 protozoan phyla recognized here and revise higher protozoan classification by updating as subkingdoms Lankester's 1878 division of Protozoa into Corticata (Excavata, Alveolata; with prominent cortical microtubules and ancestrally localized cytostome--the Parabasalia probably secondarily internalized the cytoskeleton) and Gymnomyxa [infrakingdoms Sarcomastigota (Choanozoa, Amoebozoa) and Rhizaria; both ancestrally with a non-cortical cytoskeleton of radiating singlet microtubules and a relatively soft cell surface with diffused feeding]. As the eukaryote root almost certainly lies within Gymnomyxa, probably among the Sarcomastigota, Corticata are derived. Following the single symbiogenetic origin of chloroplasts in a corticoflagellate host with cortical alveoli, this ancestral plant radiated rapidly into glaucophytes, green plants and red algae. Secondary symbiogeneses subsequently transferred plastids laterally into different hosts, making yet more complex cell chimaeras--probably only thrice: from a red alga to the corticoflagellate ancestor of chromalveolates (Chromista plus Alveolata), from green algae to a secondarily uniciliate cercozoan to form chlorarachneans and independently to a biciliate excavate to yield photosynthetic euglenoids. Tertiary symbiogenesis involving eukaryotic algal symbionts replaced peridinin-containing plastids in two or three dinoflagellate lineages, but yielded no major novel groups. The origin and well-resolved primary bifurcation of eukaryotes probably occurred in the Cryogenian Period, about 850 million years ago, much more recently than suggested by unwarranted backward extrapolations of molecular 'clocks' or dubious interpretations as 'eukaryotic' of earlier large microbial fossils or still more ancient steranes. The origin of chloroplasts and the symbiogenetic incorporation of a red alga into a corticoflagellate to create chromalveolates may both have occurred in a big bang after the Varangerian snowball Earth melted about 580 million years ago, thereby stimulating the ensuing Cambrian explosion of animals and protists in the form of simultaneous, poorly resolved opisthokont and anterokont radiations.


Are there sex differences in neuropsychological functions among patients with obsessive-compulsive disorder?
The purpose of this study was to examine whether men and women with obsessive-compulsive disorder (OCD) demonstrate differences in neuropsychological functioning compared to healthy men and women. Participants were 56 consecutive patients (33 male, 23 female) and 40 healthy control participants (20 male, 20 female) of comparable characteristics. Male and female patients had comparable symptom severity, illness duration, comorbidity, in- or out-patient status, and medication usage. An extensive neuropsychological test battery was administered including tests of general nonverbal intelligence, attention, verbal and nonverbal memory, and executive functions. Male and female OCD patients showed comparable neuropsychological performances on most cognitive domains. However, we found some evidence for cross-sex shifts in verbal fluency tasks (FAS and Category Alternation Test [CAT]), the reading component of the Stroop test, and the Wechsler Adult Intelligence Scale-Revised (WAIS-R) Digit Span-Forward test. Post hoc analyses revealed that female patients showed reduced performance on these tests compared to healthy women, in the male-typical direction. Among OCD women only, there were significant negative correlations between OCD symptom severity and performance on the CAT and the reading Stroop. We conclude that sex does not seem to be a major determinant of neuropsychological function in OCD, but the observed cross-sex shifts on some tasks deserve further examination.


Proximal Femoral Deformity Following Threaded Prophylactic Fixation for Slipped Capital Femoral Epiphysis: Risk Stratification Using the Modified Oxford Score.
This study assesses the effect of skeletal maturity on the development of iatrogenic proximal femoral deformity following threaded prophylactic screw fixation in patients presenting with unilateral slipped capital femoral epiphysis (SCFE). Children who underwent threaded screw prophylaxis of the uninvolved hip (Group P) and those who were observed with no prophylaxis (Group N) on presentation with unilateral SCFE were compared. Skeletal maturity was assessed with the Modified Oxford Score (MOS). Proximal femoral morphology was characterized by femoral neck length, femoral neck width, neck shaft angle, and trochanteric femoral head overlap percentage (TFHOP). Femoral head deformity at final follow-up was characterized as spherical (Type 1), mildly aspherical (Type 2), or ovoid (Type 3). Analysis of variance and t test were used to compare the groups. Thirty-eight patients in Group P and 17 patients in Group N met inclusion criteria. The average follow-up was 2.6 years. Group P was younger than Group N by an average of 9.6 months (P=0.04), but the MOS for skeletal maturity was not different between groups (P=0.15). Group P had significantly diminished neck length (P=0.008) and significantly increased relative trochanteric overgrowth as evidenced by increased trochanteric femoral head overlap percentage (P<0.001), but there was no difference between groups in neck shaft angle and neck width. No patient in Group N developed femoral head deformity (all Type 1). In Group P, 14 patients (37%) developed Types 2 and 3 deformity. In patients with MOS 16 in Group P, 60% (3/5) developed Type 2 deformity and 40% (2/5) developed Type 3 deformity. In patients with MOS 17 in Group P, 45% (5/11) had Type 2 deformity. Skeletally immature patients with an MOS of 16 and 17 are at high risk for developing the triad of relative trochanteric overgrowth, coxa breva, and femoral head asphericity with prophylactic threaded screw fixation for SCFE. When prophylactic surgery is indicated, consideration should be given to growth friendly fixation strategies to avoid iatrogenic proximal femoral deformity. Level III-therapeutic retrospective comparative study.


Intruder in a two-dimensional granular system: Effects of dynamic and static basal friction on stick-slip and clogging dynamics.
We present simulation results for an intruder pulled through a two-dimensional granular system by a spring using a model designed to mimic the experiments described by Kozlowski et al. [Phys. Rev. E 100, 032905 (2019)2470-004510.1103/PhysRevE.100.032905]. In that previous study the presence of basal friction between the grains and the base was observed to change the intruder dynamics from clogging to stick-slip. Here we first show that our simulation results are in excellent agreement with the experimental data for a variety of experimentally accessible friction coefficients governing interactions of particles with each other and with boundaries. We then use simulations to explore a broader range of parameter space, focusing on the friction between the particles and the base. We consider both static and dynamic basal friction coefficients, which are difficult to vary smoothly in experiments. The simulations show that dynamic friction strongly affects the stick-slip behavior when the coefficient is decreased below 0.1, while static friction plays only a marginal role.


Shared neural resources between music and language indicate semantic processing of musical tension-resolution patterns.
Harmonic tension-resolution patterns have long been hypothesized to be meaningful to listeners familiar with Western music. Even though it has been shown that specifically chosen musical pieces can prime meaningful concepts, the empirical evidence in favor of such a highly specific semantic pathway has been lacking. Here we show that 2 event-related potentials in response to harmonic expectancy violations, the early right anterior negativity (ERAN) and the N500, could be systematically modulated by simultaneously presented language material containing either a syntactic or a semantic violation. Whereas the ERAN was reduced only when presented concurrently with a syntactic language violation and not with a semantic language violation, this pattern was reversed for the N500. This is the first piece of evidence showing that tension- resolution patterns represent a route to meaning in music.


Quantitative proteomics of heat-treated human cells show an across-the-board mild depletion of housekeeping proteins to massively accumulate few HSPs.
Classic semiquantitative proteomic methods have shown that all organisms respond to a mild heat shock by an apparent massive accumulation of a small set of proteins, named heat-shock proteins (HSPs) and a concomitant slowing down in the synthesis of the other proteins. Yet unexplained, the increased levels of HSP messenger RNAs (mRNAs) may exceed 100 times the ensuing relative levels of HSP proteins. We used here high-throughput quantitative proteomics and targeted mRNA quantification to estimate in human cell cultures the mass and copy numbers of the most abundant proteins that become significantly accumulated, depleted, or unchanged during and following 4 h at 41 °C, which we define as mild heat shock. This treatment caused a minor across-the-board mass loss in many housekeeping proteins, which was matched by a mass gain in a few HSPs, predominantly cytosolic HSPCs (HSP90s) and HSPA8 (HSC70). As the mRNAs of the heat-depleted proteins were not significantly degraded and less ribosomes were recruited by excess new HSP mRNAs, the mild depletion of the many housekeeping proteins during heat shock was attributed to their slower replenishment. This differential protein expression pattern was reproduced by isothermal treatments with Hsp90 inhibitors. Unexpectedly, heat-treated cells accumulated 55 times more new molecules of HSPA8 (HSC70) than of the acknowledged heat-inducible isoform HSPA1A (HSP70), implying that when expressed as net copy number differences, rather than as mere "fold change" ratios, new biologically relevant information can be extracted from quantitative proteomic data. Raw data are available via ProteomeXchange with identifier PXD001666.


Light assisted antibody immobilization for bio-sensing.
Ultrashort UV pulses at 258 nm with repetition rate of 10 kHz have been used to irradiate buffer solution of antibody. The tryptophan residues strongly absorb this radiation thus becoming capable to disrupt the disulfide bridges located next to them. Due to their high reactivity the opened bridges can anchor a gold plate more efficiently than other sites of the macromolecule giving rise to preferential orientations of the variable part of the antibody. UV irradiation has been applied to anchor antiIgG antibody to the electrode of a Quartz Crystal Microbalance (QCM) that lends itself as a sensor, the antibody acting as the bio-receptor. An increase of the QCM sensitivity and of the linear range has been measured when the antibody is irradiated with UV laser pulses. The photo-induced reactions leading to disulfide bridge breakage have been analyzed by means of a chemical assay that confirms our explanation. The control of disulfide bridges by UV light paves the way to important applications for sensing purpose since cysteine in combination with tryptophan can act as a hook to link refractory bio-receptors to surfaces.


Left-sided mouse intubation: description and evaluation.
A method of left main bronchus intubation was developed based on a wire guide-based microscopic endotrachael mouse intubation technique. The authors used a 22 G x 1 inch catheter elongated by a 38-mm silicone tube, and a wire guide with a tag to assign the length of the wire completely covered by the silicon tube. The isoflurane-anesthetized mouse was hung perpendicularly with its incisors on a thread and transorally intubated under strict vision with the wire guide tip advanced 3 mm out of the catheter. Then the catheter was advanced about 6 to 8 mm into the trachea. Afterwards the wire guide was redrawn to the level of the catheter tip (blue tag on the wire guide appeared at the upper end of catheter) to prevent injury. Then the neck was pushed into a right lateral flexion with one finger against a foam block fixed on the vertical plate, causing a straight distance between mouth and left main bronchus. This positioning allows to gently advance the catheter into the left main bronchus by another about 20 mm, using the wire guide with its tip just within the tube, to achieve there a wedge position with gentle pressure.The technique had a success rate of more than 80% in 81 mice weighing 23 to 48 g. It may be of interest for unilateral lung intervention, e.g., with injurious substances or with drugs.


Ozone air pollution is associated with acute myocardial infarction.
Despite the diversity of the studied health outcomes, types and levels of pollution, and various environmental settings, there is substantial evidence for a positive link between urban air pollution and cardiovascular diseases. The objective of this study was to test the associations between air pollutants and the occurrence of acute myocardial infarction (AMI). Pollutant concentrations (SO2, NO2, and O3) were measured hourly as part of the automated air quality network. Since 1985, an AMI registry (the Toulouse MONICA Project) has been collecting data in the southwest of France. All cases of AMI and sudden and probable cardiac deaths are recorded for subjects 35 to 64 years of age. We studied the short-term exposure effect of pollution on the risk of AMI (from January 1, 1997, to June 30, 1999) using a case-crossover design method. We performed a conditional logistic regression analysis to calculate relative risks (RRs) and their 95% CIs. After adjustment for temperature, relative humidity, and influenza epidemics, the RRs (for an increase of 5 microg/m3 of O3 concentration) for AMI occurrence were significant for the current-day and 1-day-lag measurements (RR, 1.05; 95% CI, 1.01 to 1.08; P=0.009; and RR, 1.05; 95% CI, 1.01 to 1.09; P=0.007, respectively). Subjects 55 to 64 years of age with no personal history of ischemic heart disease were the most susceptible to develop an AMI (RR, 1.14; 95% CI, 1.06 to 1.23). NO2 and SO2 exposures were not significantly associated with the occurrence of AMI. Observational data confirm that short-term O3 exposure within a period of 1 to 2 days is related to acute coronary events in middle-aged adults without heart disease, whereas NO2 and SO2 are not.


Biodistribution, excretion, and toxicity of polyethyleneimine modified NaYF4:Yb,Er upconversion nanoparticles in mice via different administration routes.
Upconversion nanoparticles (UCNPs) have drawn much attention in biomedicine, and the clinical translation of UCNPs is closely related to their toxicity and metabolism in vivo. In this study, we chose polyethyleneimine modified NaYF4:Yb,Er upconversion nanoparticles (abbreviated as PEI@UCNPs) to systematically study the biodistribution in mice using intravenous (i.v.), intraperitoneal (i.p.), and intragastric (i.g.) administration. The i.p. injected PEI@UCNPs exhibited obvious accumulation in the spleen within 30 days. Comparably, PEI@UCNPs via i.g. administration exhibited an accumulation that decreased with time in various body tissues and were found mainly in the ileum and cecum but were rather low in concentration in the other examined organs. For the i.v. injected group, the UCNPs exhibited an obvious clearance from the body within 30 days and the accumulation in the spleen gradually decreased. Furthermore, 64Cu labeled PEI@UCNPs were i.v. injected for real-time photon emission computed tomography (PET) imaging to further confirm the biodistribution in mice. Afterward, the excretion routes of the PEI@UCNPs were evaluated. For i.p. injected groups, the UCNPs were slowly and partly excreted via feces and urine for 30 days, and a large number of the UCNPs were steadily excreted via feces for the i.v. group, suggesting that the UCNPs via i.v. injection can be potentially used for imaging and therapy studies in vivo. However, for the i.g. administrated group, most of the UCNPs were excreted through feces within 48 h. Hematology, body weight, and biochemical analysis were used to further quantify the potential toxicity of the UCNPs, and results indicated that there was no over toxicity of the UCNPs in mice at the tested period. This work suggests that the clearance and excretion capabilities of PEI@UCNPs are particularly dependent on their administration routes.


Eco-evolutionary experience in novel species interactions.
A better understanding of how ecological novelty influences interactions in new combinations of species is key for predicting interaction outcomes, and can help focus conservation and management efforts on preventing the introduction of novel organisms or species (including invasive species, GMOs, synthetic organisms, resurrected species and emerging pathogens) that seem particularly 'risky' for resident species. Here, we consider the implications of different degrees of eco-evolutionary experience of interacting resident and non-resident species, define four qualitative risk categories for estimating the probability of successful establishment and impact of novel species and discuss how the effects of novelty change over time. Focusing then on novel predator-prey interactions, we argue that novelty entails density-dependent advantages for non-resident species, with their largest effects often being at low prey densities. This is illustrated by a comparison of predator functional responses and prey predation risk curves between novel species and ecologically similar resident species, and raises important issues for the conservation of endangered resident prey species.


Intracerebral hemorrhage after fibrinolytic therapy for acute myocardial infarction.
Intracerebral hematoma may complicate treatment of acute myocardial infarction in patients treated with fibrinolytic agents. We studied the clinical presentation and computed tomographic characteristics. We studied eight patients with lobar intracerebral hematomas after fibrinolytic treatment of acute coronary occlusion. All patients had electrocardiographic and laboratory evidence of acute myocardial infarction and were treated with tissue plasminogen activator or streptokinase followed by heparin infusion to prevent reocclusion. Computed tomography scans of 17 patients with cerebral hemorrhage from other causes were used for comparison. For most patients, outcome was fatal within hours of the ictus. Computed tomography scans showed superficially large lobar hematomas in six patients. One patient had a putaminal hemorrhage, and one had a vermis hemorrhage. Multiple sites of intracerebral hemorrhage were noted in three patients. Fluid levels inside the hematoma suggesting continuing hemorrhage into multiple compartments were common. Radiologically, fluid levels in hematomas, multiple hematomas, and blood in multiple compartments served to differentiate fibrinolysis-induced hemorrhage from hemorrhage of other causes. Severe amyloid angiopathy was found in one patient who was operated on. Hemorrhages in multiple compartments and the presence of fluid levels inside the hematoma suggest fibrinolysis-associated cerebral hematomas. Severe amyloid angiopathy may be a crucial factor in this clinical entity. Outcome is poor, and a high proportion of patients have rapid progression to brain death. Therefore, emergency neurosurgical evacuation will probably be unsuccessful.


The acute and temporary modulation of PERIOD genes by hydrocortisone in healthy subjects.
The physiological stress system and the circadian clock system communicate with each other at different signaling levels. The steroid hormone cortisol, the end-effector of the hypothalamus-pituitary-adrenal axis, is released in response to stress and acts as a mediator in circadian rhythms. We determined the effect of escalating cortisol doses on the expression of PERIOD genes (PER1, PER2 and PER3) in healthy subjects and analyzed whether the glucocorticoid receptor (GR) is involved in the cortisol-mediated PERIOD gene expression. Forty participants (50% males and 50% females) were randomly assigned to groups receiving a saline placebo solution or 3 mg, 6 mg, 12 mg and 24 mg of hydrocortisone. Blood was drawn every 15 min to measure quantitative gene expression of PER1, PER2 and PER3. A potential role of the GR was determined by an ex vivo study stimulating whole blood with hydrocortisone and RU486 (a GR antagonist). As a result, moderate doses of hydrocortisone produced an acute and temporary induction of PER1 and PER3 mRNA levels, whereas PER2 was not responsive to the hormone administration. The cortisol-dependent induction of PER1 was blocked by the GR antagonist in whole blood after treatment with hydrocortisone and RU486 ex vivo. In conclusion, acute pharmacological stress modulated the expression of PER1 and PER3 in whole blood temporarily in our short-term sampling design, suggesting that these circadian genes mediate stable molecular mechanisms in the periphery.


Evidence for altered cholesterol metabolism in Huntington's disease post mortem brain tissue.
Cholesterol plays an essential role in membrane structure and function, being especially important in the brain. Alteration of brain cholesterol synthesis and metabolism has been demonstrated in several Huntington's disease (HD) mouse and cell models; however, less is known about these alterations in human tissue. This study aimed to identify alterations to cholesterol synthetic and metabolic pathways in human HD brain tissue. A broad range of cholesterol synthetic precursors, metabolites and oxidation products were measured by gas chromatography-tandem mass spectrometry in five regions of human post mortem HD brain and compared with age- and sex-matched control tissues. The level of enzymes that regulate cholesterol homeostasis, cholesterol 24-hydroxylase and delta(24)-sterol reductase were investigated by Western blotting and qPCR in putamen. The most significant changes were localized to the putamen, where a 60% decrease in 24(S)-hydroxycholesterol, 30% increase in cholesterol and 100-200% increase in synthetic precursors (lathosterol, zymosterol and desmosterol) was detected. The enzymes cholesterol 24-hydroxylase and delta(24)-sterol reductase were also significantly decreased in HD putamen as compared with control tissues. Free radical-generated cholesterol oxidation products 7-keto cholesterol and 7β-hydroxycholesterol were also increased by 50-70% in HD putamen. Human HD brain has significantly decreased cholesterol metabolism and disrupted cholesterol homeostasis. Our data also indicate that lipid oxidative stress accompanies HD pathology.


Variation in the human immune system is largely driven by non-heritable influences.
There is considerable heterogeneity in immunological parameters between individuals, but its sources are largely unknown. To assess the relative contribution of heritable versus non-heritable factors, we have performed a systems-level analysis of 210 healthy twins between 8 and 82 years of age. We measured 204 different parameters, including cell population frequencies, cytokine responses, and serum proteins, and found that 77% of these are dominated (>50% of variance) and 58% almost completely determined (>80% of variance) by non-heritable influences. In addition, some of these parameters become more variable with age, suggesting the cumulative influence of environmental exposure. Similarly, the serological responses to seasonal influenza vaccination are also determined largely by non-heritable factors, likely due to repeated exposure to different strains. Lastly, in MZ twins discordant for cytomegalovirus infection, more than half of all parameters are affected. These results highlight the largely reactive and adaptive nature of the immune system in healthy individuals.


The role of tobacco and alcohol use in the interaction of social determinants of non-communicable diseases in Nepal: a systems perspective.
Tobacco and alcohol use are major behavioural risks in developing countries like Nepal, which are contributing to a rapid increase in non-communicable diseases (NCDs). This causal relationship is further complicated by the multi-level social determinants such as socio-political context, socio-economic factors and health systems. The systems approach has potential to facilitate understanding of such complex causal mechanisms. The objective of this paper is to describe the role of tobacco and alcohol use in the interaction of social determinants of NCDs in Nepal. The study adopted a qualitative study design guided by the Systemic Intervention methodology. The study involved key informant interviews (n = 63) and focus group discussions (n = 12) at different levels (national, district and/or community) and was informed by the adapted Social Determinants of Health Framework. The data analysis involved case study-based thematic analysis using framework approach and development of causal loop diagrams. The study also involved three sense-making sessions with key stakeholders. Three key themes and causal loop diagrams emerged from the data analysis. Widespread availability of tobacco and alcohol products contributed to the use and addiction of tobacco and alcohol. Low focus on primary prevention by health systems and political influence of tobacco and alcohol industries were the major contributors to the problem. Gender and socio-economic status of families/communities were identified as key social determinants of tobacco and alcohol use. Tobacco and alcohol use facilitated interaction of the social determinants of NCDs in the context of Nepal. Socio-economic status of families was both driver and outcome of tobacco and alcohol use. Health system actions to prevent NCDs were delayed mainly due to lack of system insights and commercial influence. A multi-sectoral response led by the health system is urgently needed.


Nerve growth factor treatment after brain injury prevents neuronal death.
Cholinergic neuronal degeneration after axotomy has been proposed to be due to the loss of a retrogradely transported neurotrophic factor, possibly nerve growth factor (NGF). To test this hypothesis, NGF was continuously infused into the lateral ventricles of adult rats that had received bilateral lesions of all cholinergic axons projecting from the medial septum to the dorsal hippocampus. After 2 weeks of NGF treatment, identification of cholinergic neurons by the presence of the biosynthetic enzyme choline acetyltransferase revealed a dramatic increase (350%) in the survival of the axotomized septal cholinergic neurons. Thus, NGF or an NGF-like molecule can act as a neurotrophic factor for these neurons.


Core Length: An Alternative Method for Increasing Cancer Detection Rate in Patients with Prostate Cancer.
We determine whether the lengths of benign and malignant cores affect cancer detection rates in patients with prostate cancer (PCa). We evaluated retrospectively 512 patients in our clinic who had undergone 12 core transrectal ultrasound (TRUS)-guided prostate biopsies. The cores were divided into two groups: one with cancer (group 1) and one without cancer (group 2). We also classified Gleason scores as poorly differentiated (scores of 7-10) and moderately differentiated (scores of 5-6); these scores were compared with each other in terms of the core length. The core lengths of the groups were compared using a Student's t-test. A P value of less than .05 was considered to be statistically significant. Of the 512 patients, 76 (15%) had PCa. In total, we evaluated 912 cores of prostate biopsy samples from the 76 patients. Since 92 cores included insufficient tissue and rectal mucosa, we were not able to evaluate them. The remaining 820 cores were divided into two groups. Cancer was detected in 302 cores; 518 cores were benign in nature. The average core length in group 1 was 11.9 ± 4.4 mm, and the average core length in group 2 was 11.1 ± 5.1 mm (P = .015). The core lengths of poorly differentiated and moderately differentiated cancers were similar: 12.3 ± 4.2 mm and 11.7 ± 4.5 mm, respectively (P = .25). Increasing cancer detection rates in cores may be related to core length in TRUS-guided prostate biopsies in PCa patients.


Myocardin regulates BMP10 expression and is required for heart development.
Myocardin is a muscle lineage-restricted transcriptional coactivator that has been shown to transduce extracellular signals to the nucleus required for SMC differentiation. We now report the discovery of a myocardin/BMP10 (where BMP10 indicates bone morphogenetic protein 10) signaling pathway required for cardiac growth, chamber maturation, and embryonic survival. Myocardin-null (Myocd) embryos and embryos harboring a cardiomyocyte-restricted mutation in the Myocd gene exhibited myocardial hypoplasia, defective atrial and ventricular chamber maturation, heart failure, and embryonic lethality. Cardiac hypoplasia was caused by decreased cardiomyocyte proliferation accompanied by a dramatic increase in programmed cell death. Defective chamber maturation and the block in cardiomyocyte proliferation were caused in part by a block in BMP10 signaling. Myocardin transactivated the Bmp10 gene via binding of a serum response factor-myocardin protein complex to a nonconsensus CArG element in the Bmp10 promoter. Expression of p57kip2, a BMP10-regulated cyclin-dependent kinase inhibitor, was induced in Myocd-/- hearts, while BMP10-activated cardiogenic transcription factors, including NKX2.5 and MEF2c, were repressed. Remarkably, when embryonic Myocd-/- hearts were cultured ex vivo in BMP10-conditioned medium, the defects in cardiomyocyte proliferation and p57kip2 expression were rescued. Taken together, these data identify a heretofore undescribed myocardin/BMP10 signaling pathway that regulates cardiomyocyte proliferation and apoptosis in the embryonic heart.


BCL-6 protein is expressed in germinal-center B cells.
Structural alterations of the 5' noncoding region of the BCL-6 gene have been found in 40% of diffuse large cell lymphoma (DLCL) and 5% to 10% of follicular lymphomas (FL), suggesting that deregulated BCL-6 expression may play a role in lymphomagenesis. Nucleotide sequencing of BCL-6 cDNA predicted a protein containing six zinc-finger domains, suggesting that it may function as a transcription factor. Using antisera raised against N- and C-terminal BCL-6 synthetic oligopeptides in immunoprecipitation, immunoblot, and immunocytochemical assays, this study identifies the BCL-6 gene product as a 95-kD nuclear protein. Western blot analysis of human tumor cell lines representative of various hematopoietic lineages/stages of differentiation showed that the BCL-6 protein is predominantly expressed in the B-cell lineage where it was found in mature B cells. Immunohistochemical analysis of normal human lymphoid tissues indicated that BCL-6 expression is topographically restricted to germinal centers including all centroblasts and centrocytes. The BCL-6 protein was also detectable in inter- and intra-follicular CD4+ T cells, but not in other follicular components including mantle-zone B cells, plasma cells, dendritic cells, and macrophages. Immunohistochemical analysis of DLCL and FL biopsy samples showed that the BCL-6 protein is detectable in these tumors independent of the presence of BCL-6 gene rearrangements. These results indicate that the expression of the BCL-6 gene is specifically regulated during B-cell differentiation and suggest a role for BCL-6 in germinal center development or function. Because DLCL derive from germinal-center B cells, deregulated BCL-6 expression may contribute to lymphomagenesis by preventing postgerminal center differentiation.


The role of looming and attention capture in drivers' braking responses.
This study assessed the ability of drivers to detect the deceleration of a preceding vehicle in a simulated vehicle-following task. The size of the preceding vehicles (car, van, or truck) and following speeds (50, 70, or 100 km/h) were systematically varied. Participants selected a preferred following distance by engaging their vehicle's cruise control and when the preceding vehicle began decelerating (no brake lights were illuminated), the participant's braking latency and distances to the lead vehicle were recorded. The experiment also employed a secondary task condition to examine how the attention-capturing properties of a looming vehicle were affected by driver distraction. The results indicated that a looming stimulus is capable of redirecting a driver's attention in a vehicle following task and, as with detection of brake lights, a driver's detection of a looming vehicle is compromised in the presence of a distracting task. Interestingly, increases in vehicle size had the effect of decreasing drivers' braking latencies and drivers engaged in the secondary task were significantly closer to the lead vehicle when they began braking, regardless of the size of the leading vehicle. Performance decrements resulting from the secondary task were reflected in a time-to-collision measure but not in optic expansion rate, lending support to earlier arguments that time-to-collision estimates require explicit cognitive judgements while perception of optic expansion may function in a more automatic fashion to redirect a driver's attention when cognitive resources are low or collision is imminent.


Subcutaneous administration of D-luciferin is an effective alternative to intraperitoneal injection in bioluminescence imaging of xenograft tumors in nude mice.
Currently, intraperitoneal (IP) injection of D-luciferin is the preferred method of providing substrate for bioluminescent imaging (BLI); however it has a failure rate of 3-10% due to accidental intestinal injection. The present study evaluates the quality of BLI after subcutaneous (SC) injection of D-luciferin and demonstrates the effectiveness of SC injection in anatomically disparate tumor models. Mice bearing luciferase-expressing tumors underwent BLI after SC or IP injection of D-luciferin. The average time to maximal luminescence was 6 min (range 5-9 min) after SC injection and 8 min (range 5-8 min) after IP injection. Within 7 minutes of injection, SC and IP routes yielded similar luminescence in subcutaneous, intracranial, tongue, and lung xenograft tumor models. In a model of combined subcutaneous and intracranial xenografts, SC injection resulted in proportional luminescence at all sites, confirming that preferential delivery of substrate does not occur. While tumors were occasionally not visualized with IP injection, all tumors were visualized reliably with SC injection. Thus, SC injection of D-luciferin is a convenient and effective alternative to IP injection for BLI in nude mice. It may be a preferable approach, particularly for tumors with weaker signals and/or when greater precision is required.


BTG-AC: Break-the-Glass Access Control Model for Medical Data in Wireless Sensor Networks.
Wireless sensor networks (WSNs) have recently attracted much interest in the research community because of their wide range of applications. An emerging application for WSNs involves their use in healthcare where they are generally termed wireless medical sensor networks. In a hospital, outfitting every patient with tiny, wearable, wireless vital sign sensors would allow doctors, nurses, and other caregivers to continuously monitor the state of their patients. In such a scenario, patients are expected to be treated in reasonable time, so an access control model is needed, which will provide both real-time access to comprehensive medical records and detect unauthorized access to sensitive data. In emergency situations, a doctor or nurse needs to access data immediately. The loss in data availability can result in further decline in the patient's condition or can even lead to death. Therefore, the availability of data is more important than any security concern in emergency situations. To address that research issue for medical data in WSNs, we propose the break-the-glass access control (BTG-AC) model that is a modified and redesigned version of the break-the-glass role-based access control (BTG-RBAC) model to address data availability issue and to detect the security policy violations from both authorized and unauthorized users. Several changes within the access control engine are made in BTG-RBAC in order to make the new BTG-AC to apply and fit in WSNs. This paper presents the detailed design and development of the BTG-AC model based on a healthcare scenario. The evaluation results show that the concepts of BTG, prevention and detection mechanism, and obligation provide more flexible access than other current access control models in WSNs. Additionally, we compare the BTG-AC model with an adaptive access control (A2C) model, which has similar properties, for further evaluation. Alongside with the comparison, the advantages and disadvantages of BTG-AC over current WSN access control models are presented.