Mediating artificial intelligence developments through negative and positive incentives.
The field of Artificial Intelligence (AI) is going through a period of great expectations, introducing a certain level of anxiety in research, business and also policy. This anxiety is further energised by an AI race narrative that makes people believe they might be missing out. Whether real or not, a belief in this narrative may be detrimental as some stake-holders will feel obliged to cut corners on safety precautions, or ignore societal consequences just to "win". Starting from a baseline model that describes a broad class of technology races where winners draw a significant benefit compared to others (such as AI advances, patent race, pharmaceutical technologies), we investigate here how positive (rewards) and negative (punishments) incentives may beneficially influence the outcomes. We uncover conditions in which punishment is either capable of reducing the development speed of unsafe participants or has the capacity to reduce innovation through over-regulation. Alternatively, we show that, in several scenarios, rewarding those that follow safety measures may increase the development speed while ensuring safe choices. Moreover, in the latter regimes, rewards do not suffer from the issue of over-regulation as is the case for punishment. Overall, our findings provide valuable insights into the nature and kinds of regulatory actions most suitable to improve safety compliance in the contexts of both smooth and sudden technological shifts.


Excessive EP4 Signaling in Smooth Muscle Cells Induces Abdominal Aortic Aneurysm by Amplifying Inflammation.
Excessive prostaglandin E2 production is a hallmark of abdominal aortic aneurysm (AAA). Enhanced expression of prostaglandin E2 receptor EP4 (prostaglandin E receptor 4) in vascular smooth muscle cells (VSMCs) has been demonstrated in human AAAs. Although moderate expression of EP4 contributes to vascular homeostasis, the roles of excessive EP4 in vascular pathology remain uncertain. We aimed to investigate whether EP4 overexpression in VSMCs exacerbates AAAs. Approach and Results: We constructed mice with EP4 overexpressed selectively in VSMCs under an SM22α promoter (EP4-Tg). Most EP4-Tg mice died within 2 weeks of Ang II (angiotensin II) infusion due to AAA, while nontransgenic mice given Ang II displayed no overt phenotype. EP4-Tg developed much larger AAAs than nontransgenic mice after periaortic CaCl2 application. In contrast, EP4fl/+;SM22-Cre;ApoE-/- and EP4fl/+;SM22-Cre mice, which are EP4 heterozygous knockout in VSMCs, rarely exhibited AAA after Ang II or CaCl2 treatment, respectively. In Ang II-infused EP4-Tg aorta, Ly6Chi inflammatory monocyte/macrophage infiltration and MMP-9 (matrix metalloprotease-9) activation were enhanced. An unbiased analysis revealed that EP4 stimulation positively regulated the genes binding cytokine receptors in VSMCs, in which IL (interleukin)-6 was the most strongly upregulated. In VSMCs of EP4-Tg and human AAAs, EP4 stimulation caused marked IL-6 production via TAK1 (transforming growth factor-β-activated kinase 1), NF-κB (nuclear factor-kappa B), JNK (c-Jun N-terminal kinase), and p38. Inhibition of IL-6 prevented Ang II-induced AAA formation in EP4-Tg. In addition, EP4 stimulation decreased elastin/collagen cross-linking protein LOX (lysyl oxidase) in both human and mouse VSMCs. Dysregulated EP4 overexpression in VSMCs promotes inflammatory monocyte/macrophage infiltration and attenuates elastin/collagen fiber formation, leading to AAA exacerbation.


Unusual polysaccharide rheology of aqueous dispersions of soft phytoglycogen nanoparticles.
Phytoglycogen is a natural polysaccharide produced in the form of dense, 35 nm diameter nanoparticles by some varieties of plants such as sweet corn. The highly-branched, dendrimeric structure of phytoglycogen leads to interesting and useful properties such as softness and deformability of the particles, and a strong interaction with water. These properties make the particles ideal for use as unique additives in personal care, nutrition and biomedical formulations. In the present study, we describe rheology measurements of aqueous dispersions of phytoglycogen nanoparticles. The viscosity of the dispersions remained Newtonian up to large concentrations (∼20% w/w). For higher concentrations, the zero-shear viscosity increased dramatically, reaching values that exceeded that of the water solvent by six orders of magnitude at a concentration of 30% w/w and were well described by the Vogel-Fulcher-Tammann relation of glassy dynamics. The very large values of the zero-shear viscosity are coupled with significant deformation of the soft nanoparticles. We quantified the softness of the particles by performing osmotic pressure measurements on concentrated dispersions, obtaining a value of 15 kPa for the compressional modulus. For the most concentrated samples, we observed flow at stresses less than the apparent yield stress value determined by fitting the high strain rate data to the Herschel-Bulkley model. This behavior, similar to that of star polymer glasses, suggests the possibility of a hairy colloid particle geometry. Remarkably, phytoglycogen nanoparticles dispersed in water provide a very simple experimental realization of glass-forming dispersions of soft colloidal particles that can be used to validate theoretical models in detail.


The loss of cellular junctions in epithelial lung cells induced by cigarette smoke is attenuated by corilagin.
Cigarette smoke (CS) contains over 4700 compounds, many of which can affect cellular redox balance through free radicals production or through the modulation of antioxidant enzymes. The respiratory tract is one of the organs directly exposed to CS and it is known that CS can damage the integrity of lung epithelium by affecting cell junctions and increasing epithelium permeability. In this study, we have used a human lung epithelial cell line, Calu-3, to evaluate the effect of CS on lung epithelial cell junctions levels, with special focus on the expression of two proteins involved in intercellular communication: connexins (Cx) 40 and 43. CS exposure increased Cx40 gene expression but not of Cx43. CS also induced NFκB activation and the formation of 4HNE-Cxs adducts. Since corilagin, a natural polyphenol, is able to inhibit NFκB activation, we have determined whether corilagin could counteract the effect of CS on Cxs expression. Corilagin was able to diminish CS induced Cx40 gene expression, 4HNE-Cx40 adducts formation, and NFκB activation. The results of this study demonstrated that CS induced the loss of cellular junctions in lung epithelium, possibly as a consequence of Cx-4HNE adducts formation, and corilagin seems to be able to abolish these CS induced alterations.


Benchmarking Outpatient Rehabilitation Clinics Using Functional Status Outcomes.
To utilize functional status (FS) outcomes to benchmark outpatient therapy clinics. Outpatient therapy data from clinics using Focus on Therapeutic Outcomes (FOTO) assessments. Retrospective analysis of 538 clinics, involving 2,040 therapists and 90,392 patients admitted July 2006-June 2008. FS at discharge was modeled using hierarchical regression methods with patients nested within therapists within clinics. Separate models were estimated for all patients, for those with lumbar, and for those with shoulder impairments. All models risk-adjusted for intake FS, age, gender, onset, surgery count, functional comorbidity index, fear-avoidance level, and payer type. Inverse probability weighting adjusted for censoring. Functional status was captured using computer adaptive testing at intake and at discharge. Clinic and therapist effects explained 11.6 percent of variation in FS. Clinics ranked in the lowest quartile had significantly different outcomes than those in the highest quartile (p < .01). Clinics ranked similarly in lumbar and shoulder impairments (correlation = 0.54), but some clinics ranked in the highest quintile for one condition and in the lowest for the other. Benchmarking models based on validated FS measures clearly separated high-quality from low-quality clinics, and they could be used to inform value-based-payment policies.


Effects of smoking cessation on body composition in postmenopausal women.
Smoking cessation is associated with weight gain, but the effects of smoking cessation on measures of body composition (BC) have not been adequately evaluated. The purpose of this study is to examine the effects of 16 months of cigarette abstinence on areas of BC measured by dual-energy x-ray absorptiometry (DXA). One hundred fifty-two postmenopausal women participated in a smoking cessation study using the nicotine patch. Secondary analyses were conducted on data from 119 subjects (age 56 +/- 7 years, range 41-78 years) who had had DXA scans at baseline and 16 months later. Participants were classified either as quitters (self-reported cigarette abstinence confirmed with exhaled carbon monoxide [co] <or=8 ppm at 3 and 16 months after quit date) or as continued smokers. BC was assessed using a General Electric Lunar DXA IQ machine. Four areas of BC (kg) were measured: whole body weight, fat mass, muscle mass, and functional skeletal muscle mass in arms and legs (ASM/ht(2)). Multivariate analysis of covariance (MANCOVA) assessed changes in BC in quitters vs. continued smokers between baseline and 16 months of follow-up. Increases in BC measures were evaluated as a function of increased calorie intake or change in physical activity, using linear regression. Quitters significantly increased body weight (p < 0.001), fat mass (p < 0.001), muscle mass (p = 0.04), and functional muscle mass (p = 0.004) over time, when baseline BC measures and other confounding factors were controlled. Regression analysis indicated change in BC could not be accounted for by calorie intake or physical activity. Smoking cessation may be associated with increased fat and muscle mass in postmenopausal women. The novel finding of an increase in functional muscle mass suggests that smoking cessation could increase functional capacity. Further studies need to replicate these findings and examine mechanisms of these effects.


Antenatal risk factors for peanut allergy in children.
Prenatal factors may contribute to the development of peanut allergy. We evaluated the risk of childhood peanut allergy in association with pregnancy exposure to Rh immune globulin, folic acid and ingestion of peanut-containing foods. We conducted a web-based case-control survey using the Anaphylaxis Canada Registry, a pre-existing database of persons with a history of anaphylaxis. A total of 1300 case children with reported peanut allergy were compared to 113 control children with shellfish allergy. All were evaluated for maternal exposure in pregnancy to Rh immune globulin and folic acid tablet supplements, as well as maternal avoidance of dietary peanut intake in pregnancy. Receipt of Rh immune globulin in pregnancy was not associated with a higher risk of peanut allergy (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.51 to 1.45), nor was initiation of folic acid tablet supplements before or after conception (OR 0.53, 95% CI 0.19 to 1.48). Complete avoidance of peanut-containing products in pregnancy was associated with a non-significantly lower risk of peanut allergy (OR 0.53, 95% CI 0.27 to 1.03). The risk of childhood peanut allergy was not modified by the following common maternal exposures in pregnancy: Rh immune globulin, folic acid or peanut-containing foods. Rh immune globulin, folic acid supplement use and peanut avoidance in pregnancy have yet to be proven to modulate the risk of childhood anaphylaxis to peanuts. Identification of prenatal factors that contribute to peanut allergy might allow for prevention of this life-threatening condition. This article explores the role of three such factors.


Spin contribution to the ponderomotive force in a plasma.
The concept of a ponderomotive force due to the intrinsic spin of electrons is developed. An expression containing both the classical as well as the spin-induced ponderomotive force is derived. The results are used to demonstrate that an electromagnetic pulse can induce a spin-polarized plasma. Furthermore, it is shown that, for certain parameters, the nonlinear backreaction on the electromagnetic pulse from the spin magnetization current can be larger than that from the classical free current. Suitable parameter values for a direct test of this effect are presented.


Evaluation of neurologic deficit without apparent cause: the importance of a multidisciplinary approach.
A patient presenting with an acute neurologic deficit with no apparent etiology presents a diagnostic dilemma. A broad differential diagnosis must be entertained, considering both organic and psychiatric causes. A case report and thorough literature review of acute paraplegia after a low-energy trauma without a discernible organic etiology. Diagnostic imaging excluded any bony malalignment or fracture and any abnormality on magnetic resonance imaging. When no organic etiology was identified, a multidisciplinary approach using neurology, psychiatry, and physical medicine and rehabilitation services was applied. Neurophysiologic testing confirmed the absence of an organic disorder, and at this juncture, diagnostic efforts focused on identifying any psychiatric disorder to facilitate appropriate treatment for this individual. The final diagnosis was malingering. The full psychiatric differential diagnosis should be considered in the evaluation of any patient with an atypical presentation of paralysis. A thorough clinical examination in combination with the appropriate diagnostic studies can confidently exclude an organic disorder. When considering a psychiatric disorder, the differential diagnosis should include conversion disorder and malingering, although each must remain a diagnosis of exclusion. Maintaining a broad differential diagnosis and involving multiple disciplines (neurology, psychiatry, social work, medical specialists) early in the evaluation of atypical paralysis may facilitate earlier diagnosis and initiation of treatment for the underlying etiology.


Improving the quality of healthcare in Japan: a systematic review of procedural volume and outcome literature.
Though some policies have been implemented based on volume-outcome relationships in Japan, no studies systematically reviewed volume-outcome research conducted in Japan. Original data used in this study were obtained from MEDLINE searches using PubMed or from searches of the Ichushi database and complemented with manual searches. Two investigators reviewed and scored 13 articles, using a standard form to extract information regarding key study characteristics and results. Of the 13 studies we reviewed, 11 studies sought to detect the effects of hospital volume on outcomes while 2 examined the influence of individual physician volumes. Of the 13 studies, 9 studies (69.2%) indicated a statistically significant association between higher hospital volumes and better health outcomes. No study documented a statistically significant association between higher volumes and poorer outcomes. Higher review score is considered to be associated with significant association. The definition of low volume differed widely in each of the studies we reviewed. The 95%CI of healthcare outcomes is considerable even in studies that revealed a significant difference between volumes and outcomes. Higher hospital volumes are thought to be associated with better aggregate healthcare outcomes in Japan. For this reason, minimal-case-number standards might be effective to some extent. However, volume alone is not sufficient to predict the quality of healthcare. In addition, outcome-based evaluation might also be needed.


Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability.
Vagus nerve stimulation (VNS) is effective in refractory epilepsy and depression and is being investigated in heart failure, headache, gastric motility disorders and asthma. The first VNS device required surgical implantation of electrodes and a stimulator. Adverse events (AEs) are generally associated with implantation or continuous on-off stimulation. Infection is the most serious implantation-associated AE. Bradycardia and asystole have also been described during implantation, as has vocal cord paresis, which can last up to 6 months and depends on surgical skill and experience. The most frequent stimulation-associated AEs include voice alteration, paresthesia, cough, headache, dyspnea, pharyngitis and pain, which may require a decrease in stimulation strength or intermittent or permanent device deactivation. Newer non-invasive VNS delivery systems do not require surgery and permit patient-administered stimulation on demand. These non-invasive VNS systems improve the safety and tolerability of VNS, making it more accessible and facilitating further investigations across a wider range of uses.


Maternal Sildenafil vs Placebo in Pregnant Women With Severe Early-Onset Fetal Growth Restriction: A Randomized Clinical Trial.
Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes. To determine whether sildenafil reduces perinatal mortality or major morbidity. This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants. Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo. The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge. Out of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weight, 464 [186] g). In July 2018, the trial was halted owing to concerns that sildenafil may cause neonatal pulmonary hypertension, whereas benefit on the primary outcome was unlikely. The primary outcome, perinatal mortality or major neonatal morbidity, occurred in the offspring of 65 participants (60.2%) allocated to sildenafil vs 58 participants (54.2%) allocated to placebo (relative risk, 1.11; 95% CI, 0.88-1.40; P = .38). Pulmonary hypertension, a predefined outcome important for monitoring safety, occurred in 16 neonates (18.8%) in the sildenafil group vs 4 neonates (5.1%) in the placebo group (relative risk, 3.67; 95% CI, 1.28-10.51; P = .008). These findings suggest that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal mortality or major neonatal morbidity. The results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension. ClinicalTrials.gov Identifier: NCT02277132.


Correlated Heterospectral Lipidomics for Biomolecular Profiling of Remyelination in Multiple Sclerosis.
Analyzing lipid composition and distribution within the brain is important to study white matter pathologies that present focal demyelination lesions, such as multiple sclerosis. Some lesions can endogenously re-form myelin sheaths. Therapies aim to enhance this repair process in order to reduce neurodegeneration and disability progression in patients. In this context, a lipidomic analysis providing both precise molecular classification and well-defined localization is crucial to detect changes in myelin lipid content. Here we develop a correlated heterospectral lipidomic (HSL) approach based on coregistered Raman spectroscopy, desorption electrospray ionization mass spectrometry (DESI-MS), and immunofluorescence imaging. We employ HSL to study the structural and compositional lipid profile of demyelination and remyelination in an induced focal demyelination mouse model and in multiple sclerosis lesions from patients ex vivo. Pixelwise coregistration of Raman spectroscopy and DESI-MS imaging generated a heterospectral map used to interrelate biomolecular structure and composition of myelin. Multivariate regression analysis enabled Raman-based assessment of highly specific lipid subtypes in complex tissue for the first time. This method revealed the temporal dynamics of remyelination and provided the first indication that newly formed myelin has a different lipid composition compared to normal myelin. HSL enables detailed molecular myelin characterization that can substantially improve upon the current understanding of remyelination in multiple sclerosis and provides a strategy to assess remyelination treatments in animal models.


Initiation and extent of skin-to-skin care at two Swedish neonatal intensive care units.
To describe initiation and extent of parents' application of skin-to-skin care (SSC) with their preterm infants at two Swedish neonatal intensive care units. The duration of SSC was recorded in 104 infants' medical charts during their hospital stay, and the parents answered a questionnaire. Both parents were involved in the practice of SSC. Three infants experienced SSC directly after birth, 34 within 1 h, 85 within 24 h and the remaining 19 at 24-78 h postbirth. SSC commenced earlier (median age of 50 min) in infants whose first SSC was with their father instead of with their mother (median age of 649 min: p < 0.001). The earlier the SSC was initiated, the longer the infant was cared for skin-to-skin per day during his/her hospital stay (p < 0.001). The median daily duration of SSC was 403 min. Early initiation of SSC had positive impact on the extent of parents' application of SSC. Even though the infants in this study were cared for skin-to-skin to a high extent, there is a potential for extended use of SSC in this type of hospital setting for reducing separation between infants and parents.


Similar dysregulation of lupus-associated miRNAs in peripheral blood mononuclear cells and splenic lymphocytes in MRL/lpr mice.
MicroRNAs (miRNAs) play an important role in the pathogenesis of various autoimmune diseases including systemic lupus erythematosus (SLE; lupus). We have previously reported a common pattern of miRNA dysregulation in splenic lymphocytes from several mouse models of lupus. In this study, we investigated whether there is a similar miRNAs expression dysregulation in peripheral blood mononuclear cells (PBMCs) and splenocytes in a classical murine lupus model, MRL/lpr. PBMCs were isolated from blood samples of control MRL and lupus MRL/lpr mice aged 14-15 weeks by gradient centrifugation with Histopaque 1083 density media. miRNA TaqMan assays were performed to analyse the expression of 10 lupus-associated miRNAs including miR-182-96-183 cluster, miR-146a, miR-148a, miR-21, miR-31, miR-127, miR-155, and miR-411 in MRL and MRL/lpr PBMCs. In this study, we found that 8 out of 10 examined miRNAs (miR-21, miR-31, miR-127, miR-155, miR-96, miR-182, miR-183 and miR-411) were similarly dysregulated in both PBMCs and splenocytes of MRL/lpr mice when compared with MRL control mice. Only two miRNAs (miR-146a and miR-148a) showed different dysregulation pattern in the PBMCs and splenocytes of MRL/lpr mice. By comparing with the published miRNA data in human lupus, we demonstrated similarity in miRNA dysregulation in murine and human lupus PBMCs. The findings in this study suggest that the miRNA changes observed in PBMCs largely reflect the miRNA dysregulation in cells from the lymphoid organ spleen. Analysis of miRNAs in PBMCs has an advantage over the splenocytes since it allows for monitoring the kinetics of lupus-associated miRNAs expression with peripheral blood cell samples during the development of the disease or after instituting treatment. The similar dysregulation of miRNAs in murine and human lupus PBMCs supports the importance and the feasibility of using murine lupus models to study the pathogenic and therapeutic function of miRNAs in human lupus.


The granzyme B inhibitor, protease inhibitor 9, is mainly expressed by dendritic cells and at immune-privileged sites.
Granzyme B is released from CTLs and NK cells and an important mediator of CTL/NK-induced apoptosis in target cells. The human intracellular serpin proteinase inhibitor (PI)9 is the only human protein able to inhibit the activity of granzyme B. As a first step to elucidate the physiological role of PI9, PI9 protein expression in various human tissues was studied. A mAb directed against human PI9 was developed, which specifically stained PI9-transfected COS-7 cells, and was used for immunohistochemistry. Both in primary lymphoid organs and in inflammatory infiltrates, PI9 was present in different subsets of dendritic cells. Also T-lymphocytes in primary and organ-associated lymphoid tissues were PI9 positive. Endothelial cells of small vessels in most organs tested as well as the endothelial layer of large veins and arteries showed strong PI9 staining. Surprisingly, high PI9 protein expression was also found at immune-privileged sites like the placenta, the testis, the ovary, and the eye. These data fit with the hypothesis that PI9 is expressed at sites where degranulation of CTL or NK cells is potentially deleterious.


Human keratinocyte ATP2C1 localizes to the Golgi and controls Golgi Ca2+ stores.
Hailey-Hailey disease (MIM16960) is a blistering skin disease caused by mutations in the Ca2+ ATPase ATP2C1. We found that the abnormal Ca2+ signaling seen in Hailey-Hailey disease keratinocytes correlates with decreased protein levels of ATP2C1. Human ATP2C1 protein approximated 115 kDa in size. The ATP2C1 is localized to the Golgi apparatus in human keratinocytes, similar to its localization in yeast and Caenorhabditis elegans. To test whether the ATP2C1 controls Golgi Ca2+ stores, we measured intraorganelle Ca2+ concentrations using specifically targeted aequorins. Whereas normal keratinocytes display Golgi Ca2+ levels comparable to other epithelial cells, Hailey-Hailey disease keratinocyte Golgi Ca2+ refill is slower, and the maximum Ca2+ concentration reached is significantly lower. These findings were replicated in vivo, because clinically normal Hailey-Hailey disease epidermis contained lower Ca2+ stores and displayed an abnormal Ca2+ gradient. In this report we localize the ATP2C1, demonstrate its physiologic relevance in mammalian cells, and measure intraorganelle Golgi Ca2+ in keratinocytes.


Access to in-patient stroke services and multidisciplinary team (MDT) rehabilitation: current demands and capacity.
The objective of this project was to analyse the current access to in-patient stroke services and MDT rehabilitation in an acute stroke centre and to compare these services to the recommended "National Clinical Guidelines and Recommendations for the Care of People with Stroke and TIA" (IHF 2010). A retrospective chart review was carried out, recording activity statistics of all patients admitted with acute stroke over a three-month period. 73 patients (male = 40, 54.8%) were included. Patients were discharged from the stroke service after a mean stay of 20.2 days (SD = 19.3). 76.7% (N = 56) of patients were admitted to the acute stroke unit (ASU). The mean length of time from admission to first assessment 3.4 days (SD. = 2.68), with an average of 138 minutes of treatment received per day across all disciplines. This is compared to the IHF's recommendation of patients being assessed within 24-48 hours of admission and receiving 180 minutes of treatment across all disciplines. As demands for stroke MDT services increase, it is important to recognise the benefits of increasing staff and resources to maintain and continue to improve standards of care.


Carcinogenesis Bioassay of Tara Gum (CAS No. 39300-88-4) in F344 Rats and B6C3F1 Mice (Feed Study).
A carcinogenesis bioassay of tara gum, a potential stabilizer for cosmetics and foods, was conducted by feeding diets containing 25,000 or 50,000 ppm of the test substance to 50 F344 rats and 50 B6C3F1 mice of either sex for 103 weeks. Groups of 50 untreated rats and mice of either sex served as controls. In the chronic bioassay, mean body weights of dosed and control rats of either sex were comparable over the course of the study. Feed consumption by low-and high-dose male rats was 92% and 95% that of the controls, and feed consumption by low-and high-dose female rats was 87% and 79% that of the controls. Mean body weights of high-dose mice of either sex were lower than those of controls; feed consumption by dosed mice was comparable with that of controls. Although the rats and mice might have been able to tolerate higher doses, 50,000 ppm (5%) is the recommended maximum concentration of a test substance mixed in feed, according to the guidelines of the Bioassay Program. No tumors were observed in increased incidences that were considered to be related to administration of tara gum to either species. Interstitial cell tumors of the testis in male rats were observed in a statistically significant (P </= 0.003 for trend and group comparisons) positive relationship (40/48 controls; 46/46 low dose; 48/48 high dose); because these tumors are present in almost all aged F344 male rats and because of the marginal statistical significance when time-adjusted analyses are applied, these increases are not regarded as being related to tara gum administration. A significant (P<0.05) negative trend was observed in the proportion of male rats with pancreatic islet cell adenoma (5/45 controls, 1/44 low dose, 0/45 high dose), of female mice with alveolar/bronchiolar adenomas (7/50, 2/49, 2/50), and of female mice with hepatocellular adenomas (9/49, 4/49, 1/50). Under the conditions of this bioassay, tara gum was not carcinogenic for F344 rats or B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative


Overview of "bumper car" disease--impact on the North American lobster fishery.
Recent (1993) landings of American lobsters (Homarus americanus) were valued at $294 million (Can.) in Canada and $213 million (Can.) in the United States. However, post-harvest losses are estimated at $50-75 million (10-15%) annually. The lobster fishery is one of the few remaining viable traditional fisheries in eastern North America. "Bumper car" disease of lobsters, caused by the scuticociliate Anophryoides haemophila, can cause significant losses in coldwater impoundments. Apparently epidemics now occur more frequently and with greater severity; surprisingly the epidemiology and economic impacts of "bumper car" disease are not well documented. The ciliate A. haemophila is easily maintained in a cell-free, chemically defined, seawater-based medium at 5 degrees C. Cultured ciliates require longer and more parasites to kill lobsters than those transmitted by intrahaemocoelic injection from lobster-to-lobster. Regardless of source of ciliates, the larger the inoculum, the more rapid the death of lobsters. The pathogenesis of "bumper car" disease is unknown. Horizontal transmission could occur across the thin cuticle of gills or via wounds in the exoskeleton present during moulting of lobsters. Because ciliates are initially sequestered in lobster tissues for an extended period, they are detectable sooner by histological examination of tissues than by direct examination or culture of haemolymph. Additional to indirect fluorescent antibody testing and immunoperoxidase staining of tissues, utilizing monoclonal antibodies prepared to sonicated ciliates, the parasites are readily detected with oligonucleotide probes based on ssu-rDNA of A. haemophila. The prevalence of A. haemophila should be re-evaluated. Ciliates sequester in gill, heart and muscle tissues. Several disinfectants and chemotherapeutants, licensed in North America for veterinary use in food-producing animals, are efficacious against A. haemophila in vitro. A definition of healthy vs ciliate-infected lobsters is being prepared, based on haematology and clinical chemistry of haemolymph. Our novel bar-coded labelling system for aquatic organisms facilitates experimental design and randomization protocols of lobsters. The model of "bumper car" disease will aid study of health and infectious disease processes of lobsters and other crustaceans.


Melanin and nicotine: A review of the literature.
The role of melanin in nicotine uptake and metabolism has received little attention. Because nicotine has been shown to accumulate in tissues containing melanin, exploring links between melanin and nicotine may provide additional clues to understanding smoking behavior and disease effects. To examine the scientific literature on the relationship between melanin and nicotine, we conducted a PubMed search. We also searched online archives of internal tobacco industry documents. We retrieved and reviewed 82 published research papers related to melanin and nicotine or melanin and metabolism of other drugs, and 150 relevant internal tobacco industry documents. The published literature suggests that nicotine may accumulate in human tissues containing melanin and this retention may increase melanin synthesis. Existing research on the relationship between melanin and nicotine lacks an adequate consideration of this relationship's potential impact, if any, on nicotine metabolism, level of nicotine dependence, and ability to quit smoking. Differential accumulation of nicotine in melanin-containing tissues could have implications for individuals with high levels of melanin.


Effect of ovarian hormones on promotion of bactericidal activity by uterine secretions of ovariectomized mares.
The bactericidal and phagocytic activities of blood neutrophils suspended in uterine washings and the mobilization of neutrophils into the uterine lumen were studied in ovariectomized mares receiving oestradiol benzoate (N = 4), progesterone (N = 4) or oily vehicle (N = 4). Uterine lavage was performed sequentially up to 144 h after induction of endometritis by intrauterine infusion of glycogen (1%). There was no significant difference between the 3 groups in speed of mobilization of neutrophils into the uterus in the first 6 h after infusion but there were significantly more uterine luminal neutrophils in progesterone-treated than in oestradiol-treated mares by 24 h after infusion (P less than 0.01). Uterine washings collected from progesterone-treated mares at 0, 24 and 144 h were significantly worse at promoting bactericidal activity by neutrophils than washings from oestradiol-treated and control mares (P less than 0.001). In oestrogen-treated and control mares bactericidal activity had increased by 144 h but in progesterone-treated mares bactericidal activity remained low. Neither treatment nor time affected the ability of washings to opsonize yeast blastospores. Elevated concentrations of progesterone in plasma were therefore associated with decreased bactericidal activity of neutrophils suspended in uterine washings but the generation of C3b in washings did not appear to be affected by hormone treatment.


Fractal properties of human muscle sympathetic nerve activity.
Muscle sympathetic nerve activity (MSNA) in resting humans is characterized by cardiac-related bursts of variable amplitude that occur sporadically or in clusters. The present study was designed to characterize the fluctuations in the number of MSNA bursts, interburst interval, and burst amplitude recorded from the peroneal nerve of 15 awake, healthy human subjects. For this purpose, we used the Allan and Fano factor analysis and dispersional analysis to test whether the fluctuations were time-scale invariant (i.e., fractal) or random in occurrence. Specifically, we measured the slopes of the power laws in the Allan factor, Fano factor, and dispersional analysis curves. In addition, the Hurst exponent was calculated from the slope of the power law in the Allan factor curve. Whether the original time series contained fractal fluctuations was decided on the basis of a comparison of the values of these parameters with those for surrogate data blocks. The results can be summarized as follows. Fluctuations in the number of MSNA bursts and interburst interval were fractal in each of the subjects, and fluctuations in burst amplitude were fractal in four of the subjects. We also found that fluctuations in the number of heartbeats and heart period (R-R interval) were fractal in each of the subjects. These results demonstrate for the first time that apparently random fluctuations in human MSNA are, in fact, dictated by a time-scale-invariant process that imparts "long-term memory" to the sequence of cardiac-related bursts. Whether sympathetic outflow to the heart also is fractal and contributes to the fractal component of heart rate variability remains an open question.


pDOCK: a new technique for rapid and accurate docking of peptide ligands to Major Histocompatibility Complexes.
Identification of antigenic peptide epitopes is an essential prerequisite in T cell-based molecular vaccine design. Computational (sequence-based and structure-based) methods are inexpensive and efficient compared to experimental approaches in screening numerous peptides against their cognate MHC alleles. In structure-based protocols, suited to alleles with limited epitope data, the first step is to identify high-binding peptides using docking techniques, which need improvement in speed and efficiency to be useful in large-scale screening studies. We present pDOCK: a new computational technique for rapid and accurate docking of flexible peptides to MHC receptors and primarily apply it on a non-redundant dataset of 186 pMHC (MHC-I and MHC-II) complexes with X-ray crystal structures. We have compared our docked structures with experimental crystallographic structures for the immunologically relevant nonameric core of the bound peptide for MHC-I and MHC-II complexes. Primary testing for re-docking of peptides into their respective MHC grooves generated 159 out of 186 peptides with Cα RMSD of less than 1.00 Å, with a mean of 0.56 Å. Amongst the 25 peptides used for single and variant template docking, the Cα RMSD values were below 1.00 A for 23 peptides. Compared to our earlier docking methodology, pDOCK shows upto 2.5 fold improvement in the accuracy and is ~60% faster. Results of validation against previously published studies represent a seven-fold increase in pDOCK accuracy. The limitations of our previous methodology have been addressed in the new docking protocol making it a rapid and accurate method to evaluate pMHC binding. pDOCK is a generic method and although benchmarks against experimental structures, it can be applied to alleles with no structural data using sequence information. Our outcomes establish the efficacy of our procedure to predict highly accurate peptide structures permitting conformational sampling of the peptide in MHC binding groove. Our results also support the applicability of pDOCK for in silico identification of promiscuous peptide epitopes that are relevant to higher proportions of human population with greater propensity to activate T cells making them key targets for the design of vaccines and immunotherapies.


Co-creating a psychiatric resident program with Ethiopians, for Ethiopians, in Ethiopia: the Toronto Addis Ababa Psychiatry Project (TAAPP).
Globalization in medical education often means a "brain drain" of desperately needed health professionals from low- to high-income countries. Despite the best intentions, partnerships that simply transport students to Western medical schools for training have shockingly low return rates. Ethiopia, for example, has sent hundreds of physicians abroad for specialty training over the past 30 years, the vast majority of whom have not returned. This represents a highly problematic net transfer of financial and human resources from the Ethiopian people to Western countries that have failed to develop their own adequate health human resource plans. With this background in mind, in 2003 Addis Ababa University invited the University of Toronto to collaborate on the first Ethiopian psychiatric residency program to be run entirely in Ethiopia. Called the Toronto Addis Ababa Psychiatry Project (TAAPP), it was established on the principle of supplementing the ability of the small Addis Ababa University Department of Psychiatry to teach, provide clinical supervision, and to help develop educational capacity. Over the last 6 years the model has involved a large number of University of Toronto faculty and residents who have spent blocks of 1 month each in Addis Ababa. This article describes the first three phases of TAAPP (I) Development of a model residency program; (II) Enhancing clinical, educational and leadership capacity; and (III) Sustainability, faculty development, and continuing education. Between 2003 and 2009, the number of psychiatrists in Ethiopia increased from 11 to 34; the Addis Ababa University Department of Psychiatry faculty increased members from three to nine. There are new departments of psychiatry established in four other university hospitals in Ethiopia outside the capital city. Mental health services are now being integrated within the national system of primary care. An important issue that underscores such a partnership is the risk of simply exporting Western, America-centric psychiatric training versus creating culturally appropriate models of education.


Preferential attachment of membrane glycoproteins to the cytoskeleton at the leading edge of lamella.
The active forward movement of cells is often associated with the rearward transport of particles over the surfaces of their lamellae. Unlike the rest of the lamella, we found that the leading edge (within 0.5 microns of the cell boundary) is specialized for rearward transport of membrane-bound particles, such as Con A-coated latex microspheres. Using a single-beam optical gradient trap (optical tweezers) to apply restraining forces to particles, we can capture, move and release particles at will. When first bound on the central lamellar surface, Con A-coated particles would diffuse randomly; when such bound particles were brought to the leading edge of the lamella with the optical tweezers, they were often transported rearward. As in our previous studies, particle transport occurred with a concurrent decrease in apparent diffusion coefficient, consistent with attachment to the cytoskeleton. For particles at the leading edge of the lamella, weak attachment to the cytoskeleton and transport occurred with a half-time of 3 s; equivalent particles elsewhere on the lamella showed no detectable attachment when monitored for several minutes. Particles held on the cell surface by the laser trap attached more strongly to the cytoskeleton with time. These particles could escape a trapping force of 0.7 X 10(-6) dyne after 18 +/- 14 (sd) s at the leading edge, and after 64 +/- 34 (SD) s elsewhere on the lamella. Fluorescent succinylated Con A staining showed no corresponding concentration of general glycoproteins at the leading edge, but cytochalasin D-resistant filamentous actin was found at the leading edge. Our results have implications for cell motility: if the forces used for rearward particle transport were applied to a rigid substratum, cells would move forward. Such a mechanism would be most efficient if the leading edge of the cell contained preferential sites for attachment and transport.


Multiplexed imaging of high-density libraries of RNAs with MERFISH and expansion microscopy.
As an image-based single-cell transcriptomics approach, multiplexed error-robust fluorescence in situ hybridization (MERFISH) allows hundreds to thousands of RNA species to be identified, counted and localized in individual cells while preserving the native spatial context of RNAs. In MERFISH, RNAs are identified via a combinatorial labeling approach that encodes RNA species with error-robust barcodes followed by sequential rounds of single-molecule FISH (smFISH) to read out these barcodes. The accuracy of RNA identification relies on spatially separated signals from individual RNA molecules, which limits the density of RNAs that can be measured and makes the multiplexed imaging of a large number of high-abundance RNAs challenging. Here we report an approach that combines MERFISH and expansion microscopy to substantially increase the total density of RNAs that can be measured. Using this approach, we demonstrate accurate identification and counting of RNAs, with a near 100% detection efficiency, in a ~130-RNA library composed of many high-abundance RNAs, the total density of which is more than 10 fold higher than previously reported. In parallel, we demonstrate the combination of MERFISH with immunofluorescence in expanded samples. These advances increase the versatility of MERFISH and will facilitate its application to a wide range of biological problems.


Results From Ghana's 2016 Report Card on Physical Activity for Children and Youth.
Currently, there is limited evidence on estimates for physical activity (PA) behavior and sedentary behavior (SB) in Ghana. This report card (RC) is intended to increase awareness and sensitivity about issues surrounding PA and SB in Ghana. Data were collected from peer-reviewed literature, graduate students' theses, physical education and sports documents, and a survey of opinions of stakeholders covering the 10 key RC indicators and benchmarks. The principal investigator harmonized all grades. A consensus meeting of the RC team was held to assign the final grades. School and Community grades declined from a D in 2014 to an F in 2016. SB declined from B to D. Family and Active Play were not graded in 2014 and now received an F and a B, respectively. Family and Built Environment were graded F, Active Transportation received a C, and Government and Overall PA were graded D. A conscious national investment effort can increase overall PA among children.


Iron-binding antioxidant potential of plasma albumin.
1. The extracellular proteins caeruloplasmin and transferrin have important antioxidant properties by virtue of the fact that they inhibit iron-dependent free radical production, and ensuing damage to cells. 2. Albumin is a plasma protein which can loosely bind iron, but the redox activity of this iron has not been fully investigated. 3. The ability of albumin to bind iron and to prevent iron-dependent lipid peroxidation in vitro was investigated using liposomes and a rat brain homogenate system. 4. The iron-binding capacity of albumin was found to be substantial, and albumin inhibited lipid peroxidation in a concentration-dependent manner in both systems used. 5. This antioxidant property of albumin may be especially important in the plasma of babies born prematurely, in whom transferrin and caeruloplasmin concentrations are often very low, and in whom non-transferrin-bound iron has been detected in the plasma.


Implementation of an indium-tin-oxide (ITO) direct-Ohmic contact structure on a GaN-based light emitting diode.
A GaN-based light-emitting diode (LED) with a direct-Ohmic contact structure, formed by an indium-tin-oxide (ITO) transparent film and Au thermal-diffused and removed layer, is studied. By depositing an Au metallic film on the Mg-doped GaN layer followed by thermal annealing and removed processes, an ITO direct-Ohmic contact at p-GaN/ITO interface is formed. An enhanced light output power of 18.0% is also found at this condition. This is mainly attributed to the larger and more uniform light-emission area resulted from the improved current spreading capability by the use of an ITO direct-Ohmic contact structure.


Transfusion and chelation practices in sickle cell disease: a regional perspective.
Although most common in tropical regions, population migration has meant that sickle cell disease is now one of the most prevalent genetic diseases worldwide. The issues and challenges faced by physicians and patients have been discussed by an international group of experts representing 4 key regions: the USA, Europe, Latin America, and the Middle East/Africa. Conclusive evidence to support the use of transfusion therapy for the prevention of stroke has resulted in key changes to patient management in all regions, and increasing numbers of patients are benefiting from this management approach. However, it is apparent that transfusion therapy is still under-utilized, largely due to concerns over iron overload, alloimmunization, limited blood supplies, and, sometimes, due to parental refusal. Once transfused, assessment and management of body iron levels can be poor, particularly in patients who are intermittently transfused. Compliance with chelation therapy regimens is a significant challenge, but new therapeutic options are likely to overcome some of the current barriers. Key requirements in all regions were considered to be the following: to provide greater physician, patient, and family education; to ensure effective transition from pediatric to adult care; and to establish national guidelines in order to ensure best practice is consistently applied.


The thick left ventricular wall of the giraffe heart normalises wall tension, but limits stroke volume and cardiac output.
Giraffes--the tallest extant animals on Earth--are renowned for their high central arterial blood pressure, which is necessary to secure brain perfusion. Arterial pressure may exceed 300 mmHg and has historically been attributed to an exceptionally large heart. Recently, this has been refuted by several studies demonstrating that the mass of giraffe heart is similar to that of other mammals when expressed relative to body mass. It thus remains unexplained how the normal-sized giraffe heart generates such massive arterial pressures. We hypothesized that giraffe hearts have a small intraventricular cavity and a relatively thick ventricular wall, allowing for generation of high arterial pressures at normal left ventricular wall tension. In nine anaesthetized giraffes (495±38 kg), we determined in vivo ventricular dimensions using echocardiography along with intraventricular and aortic pressures to calculate left ventricular wall stress. Cardiac output was also determined by inert gas rebreathing to provide an additional and independent estimate of stroke volume. Echocardiography and inert gas-rebreathing yielded similar cardiac outputs of 16.1±2.5 and 16.4±1.4 l min(-1), respectively. End-diastolic and end-systolic volumes were 521±61 ml and 228±42 ml, respectively, yielding an ejection fraction of 56±4% and a stroke volume of 0.59 ml kg(-1). Left ventricular circumferential wall stress was 7.83±1.76 kPa. We conclude that, relative to body mass, a small left ventricular cavity and a low stroke volume characterizes the giraffe heart. The adaptations result in typical mammalian left ventricular wall tensions, but produce a lowered cardiac output.


Modification of the serotonergic systems and phenotypes by gestational micronutrients.
Micronutrients consumed in excess or imbalanced amounts during pregnancy may increase the risk of metabolic diseases in offspring, but the mechanisms underlying these effects are unknown. Serotonin (5-hydroxytryptamine, 5-HT), a multifunctional indoleamine in the brain and the gut, may have key roles in regulating metabolism. We investigated the effects of gestational micronutrient intakes on the central and peripheral serotonergic systems as modulators of the offspring's metabolic phenotypes. Pregnant Wistar rats were fed an AIN-93G diet with 1-fold recommended vitamins (RV), high 10-fold multivitamins (HV), high 10-fold folic acid with recommended choline (HFolRC), or high 10-fold folic acid with no choline (HFolNC). Male and female offspring were weaned to a high-fat RV diet for 12 weeks. We assessed the central function using the 5-HT2C receptor agonist, 1-(3-chlorophenyl)piperazine (mCPP), and found that male offspring from the HV- or HFolRC-fed dams were less responsive (P < 0.05) whereas female HFolRC offspring were more responsive to mCPP (P < 0.01) at 6 weeks post-weaning. Male and female offspring from the HV and HFolNC groups, and male HFolRC offspring had greater food intake (males P < 0.001; females P < 0.001) and weight gain (males P < 0.0001; females P < 0.0001), elevated colon 5-HT (males P < 0.01; females P < 0.001) and fasting glucose concentrations (males P < 0.01; females P < 0.01), as well as body composition toward obesity (males P < 0.01; females P < 0.01) at 12 weeks post-weaning. Colon 5-HT was correlated with fasting glucose concentrations (males R2=0.78, P < 0.0001; females R2=0.71, P < 0.0001). Overall, the serotonergic systems are sensitive to the composition of gestational micronutrients, with alterations consistent with metabolic disturbances in offspring.


Study on the Significance of Folate Receptor-Mediated Staining Solution (FRD) Staining in Screening High Grade Cervical Lesions.
BACKGROUND The aim of this study was to investigate the significance of folate receptor-mediated staining solution (FRD) in examination of cervical lesions during gynecological examination. MATERIAL AND METHODS A total of 404 patients participated in this study. FRD staining was applied to screen high grade cervical lesions. ThinPrep cytology test (TCT) and human papillomavirus (HPV) testing were also used for screening high grade cervical lesions. Coincidence rate and KAPPA value of different methods were compared by SPSS software. RESULTS As for CIN2+ and CIN3+, sensitivities for HPV testing were (96.92% and 97.78%) >TCT classification 1 (90.77% and 91.11%) >FRD staining (80.00% and 86.67%) >TCT classification 2 (70.77% and 77.78%), respectively. While specificities for HPV testing were (7.08% and 6.44%) <TCT classification 1 (39.53% and 37.88%) <FRD staining (51.92% and 50.97%) <TCT classification 2 (70.80% and 69.36%), respectively. Coincidence rate and KAPPA value of FRD staining, TCT classification 1, TCT classification 2, and HPV testing for detecting CIN2+ results were 56.44% and 16.52%, 47.77% and 13.54%, 70.79% and 27.76%, and 21.53% and 1.36%, respectively. Coincidence rate and KAPPA value of FRD staining, TCT classification 1, TCT classification 2, and HPV testing versus CIN3+ results were 54.95% and 14.19%, 43.81% and 9.27%, 70.30% and 23.91%, and 17.08% and 1.12%, respectively. CONCLUSIONS FRD staining was capable of detecting cervical lesions rapidly and is a cost-effective method for routine cervical lesions screening.


Clinical and design factors influence the survivorship of custom flange acetabular components.
Custom flange acetabular components (CFACs) are a patient-specific option for addressing large acetabular defects at revision total hip arthroplasty (THA), but patient and implant characteristics that affect survivorship remain unknown. This study aimed to identify patient and design factors related to survivorship. A retrospective review of 91 patients who underwent revision THA using 96 CFACs was undertaken, comparing features between radiologically failed and successful cases. Patient characteristics (demographic, clinical, and radiological) and implant features (design characteristics and intraoperative features) were collected. There were 74 women and 22 men; their mean age was 62 years (31 to 85). The mean follow-up was 24.9 months (sd 27.6; 0 to 116). Two sets of statistical analyses were performed: 1) univariate analyses (Pearson's chi-squared and independent-samples Student's t-tests) for each feature; and 2) bivariable logistic regressions using features identified from a random forest analysis. Radiological failure and revision rates were 23% and 12.5%, respectively. Revisions were undertaken at a mean of 25.1 months (sd 26.4) postoperatively. Patients with radiological failure were younger at the time of the initial procedure, were less likely to have a diagnosis of primary osteoarthritis (OA), were more likely to have had ischial screws in previous surgery, had fewer ischial screw holes in their CFAC design, and had more proximal ischial fixation. Random forest analysis identified the age of the patient and the number of locking and non-locking screws used for inclusion in subsequent bivariable logistic regression, but only age (odds ratio 0.93 per year) was found to be significant. We identified both patient and design features predictive of CFAC survivorship. We found a higher rate of failure in younger patients, those whose primary diagnosis was not OA, and those with more proximal ischial fixation or fewer ischial fixation options. Cite this article: Bone Joint J 2019;101-B(6 Supple B):68-76.


Increased susceptibility to ethylmercury-induced mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines.
The association of autism spectrum disorders with oxidative stress, redox imbalance, and mitochondrial dysfunction has become increasingly recognized. In this study, extracellular flux analysis was used to compare mitochondrial respiration in lymphoblastoid cell lines (LCLs) from individuals with autism and unaffected controls exposed to ethylmercury, an environmental toxin known to deplete glutathione and induce oxidative stress and mitochondrial dysfunction. We also tested whether pretreating the autism LCLs with N-acetyl cysteine (NAC) to increase glutathione concentrations conferred protection from ethylmercury. Examination of 16 autism/control LCL pairs revealed that a subgroup (31%) of autism LCLs exhibited a greater reduction in ATP-linked respiration, maximal respiratory capacity, and reserve capacity when exposed to ethylmercury, compared to control LCLs. These respiratory parameters were significantly elevated at baseline in the ethylmercury-sensitive autism subgroup as compared to control LCLs. NAC pretreatment of the sensitive subgroup reduced (normalized) baseline respiratory parameters and blunted the exaggerated ethylmercury-induced reserve capacity depletion. These findings suggest that the epidemiological link between environmental mercury exposure and an increased risk of developing autism may be mediated through mitochondrial dysfunction and support the notion that a subset of individuals with autism may be vulnerable to environmental influences with detrimental effects on development through mitochondrial dysfunction.


EP3R-Expressing Glutamatergic Preoptic Neurons Mediate Inflammatory Fever.
Fever is a common phenomenon during infection or inflammatory conditions. This stereotypic rise in body temperature (Tb) in response to inflammatory stimuli is a result of autonomic responses triggered by prostaglandin E2 action on EP3 receptors expressed by neurons in the median preoptic nucleus (MnPOEP3R neurons). To investigate the identity of MnPOEP3R neurons, we first used in situ hybridization to show coexpression of EP3R and the VGluT2 transporter in MnPO neurons. Retrograde tracing showed extensive direct projections from MnPOVGluT2 but few from MnPOVgat neurons to a key site for fever production, the raphe pallidus. Ablation of MnPOVGluT2 but not MnPOVgat neurons abolished fever responses but not changes in Tb induced by behavioral stress or thermal challenges. Finally, we crossed EP3R conditional knock-out mice with either VGluT2-IRES-cre or Vgat-IRES-cre mice and used both male and female mice to confirm that the neurons that express EP3R and mediate fever are glutamatergic, not GABAergic. This finding will require rethinking current concepts concerning the central thermoregulatory pathways based on the MnPOEP3R neurons being GABAergic.SIGNIFICANCE STATEMENT Body temperature is regulated by the CNS. The rise of the body temperature, or fever, is an important brain-orchestrated mechanism for fighting against infectious or inflammatory disease, and is tightly regulated by the neurons located in the median preoptic nucleus (MnPO). Here we demonstrate that excitatory MnPO neurons mediate fever and examine a potential central circuit underlying the development of fever responses.


Convergent patterns of long-distance nocturnal migration in noctuid moths and passerine birds.
Vast numbers of insects and passerines achieve long-distance migrations between summer and winter locations by undertaking high-altitude nocturnal flights. Insects such as noctuid moths fly relatively slowly in relation to the surrounding air, with airspeeds approximately one-third of that of passerines. Thus, it has been widely assumed that windborne insect migrants will have comparatively little control over their migration speed and direction compared with migrant birds. We used radar to carry out the first comparative analyses of the flight behaviour and migratory strategies of insects and birds under nearly equivalent natural conditions. Contrary to expectations, noctuid moths attained almost identical ground speeds and travel directions compared with passerines, despite their very different flight powers and sensory capacities. Moths achieved fast travel speeds in seasonally appropriate migration directions by exploiting favourably directed winds and selecting flight altitudes that coincided with the fastest air streams. By contrast, passerines were less selective of wind conditions, relying on self-powered flight in their seasonally preferred direction, often with little or no tailwind assistance. Our results demonstrate that noctuid moths and passerines show contrasting risk-prone and risk-averse migratory strategies in relation to wind. Comparative studies of the flight behaviours of distantly related taxa are critically important for understanding the evolution of animal migration strategies.


Knowledge and attitude of parents/caregivers towards hearing loss and screening in newborns - a systematic review.
The parents/caregivers of a newborn play a pivotal role in the process of hearing screening and intervention. The decisions taken by them depend on their knowledge and attitude. The purpose of this study was to review the literature systematically on knowledge and attitude of parents/caregivers towards infant hearing loss and newborn hearing screening. A systematic search was conducted using electronic databases for the periods from 1990 to March 2016. Two authors scrutinized the studies and extracted the data based on predetermined criteria. Ten studies. Ear discharge was correctly identified as a risk factor for hearing loss along with measles, drugs/medication, family history, congenital causes and noise exposure. The studies revealed mixed results for knowledge about newborn hearing screening. Overall, the parents/caregivers showed positive attitudes towards hearing screening and intervention options. However, due to heterogeneity in the studies, it's hard to derive a conclusion. The present review sheds light on the common areas of misconception among parents/caregivers about risk factors of infant hearing loss and newborn hearing screening. The review also draws attention to the need to have more studies exploring this knowledge and attitude of parents/caregivers among diverse populations.


Mortality and recovery of runt white sturgeon (Acipenser transmontanus) in a commercial farm in California, USA.
We investigated the effect of raising runt white sturgeon (Acipenser transmontanus) separately from dominant fish during the initial stages of grow-out in a commercial farm. Runt fish are poor-growers, have underdeveloped muscle mass, swim slowly and are more-frequently found at the top of the water column. The objective of the study was to describe the mortality and recovery rates (and their determinants) of white-sturgeon runts after separating them from dominant fish. Runt white sturgeon were stocked into twelve 2 m x 2 m rectangular tanks and graded periodically during a follow-up of 46-102 days. Overall mortality rates ranged from 0.3 to 7 dead fish per 1000 sturgeon-days at risk and overall recovery rates from 3.9 to 13.5 recovered fish per 1000 sturgeon-days at risk. Period-specific mortality and recovery rates increased over time. The period-specific mortality rates for all three periods were significantly higher for tanks of runts originating from grow-out tanks with high mortality (p-values: first period = 0.06; second period = 0.09; third period = 0.03), but were similar for tanks of runts of high- and low-mean initial weight. The period-specific recovery rates were significantly higher in runts originating from high-mortality grow-out tanks only for the third period (p = 0.05) but not the first and second periods (p-values = 0.33 and 0.25, respectively). Recovery rates were significantly higher in the higher-mean-weight runts tanks for the first and third period but not for the second (p-values: first period = 0.02; second period = 0.65; third period = 0.06). We concluded that the proportion of runts that recover during a 46-89 day period is substantial (16-58%); therefore, it might be worthwhile growing such fish separately in a fish farm for about three months. Financial analysis showed that this practice was profitable, if the value of white sturgeon fish for the farm exceeded $2.05 per kg.


Incorporation of resident macrophages in engineered tissues: Multiple cell type response to microenvironment controlled macrophage-laden gelatine hydrogels.
The success of tissue engineering strategy is strongly related to the inflammatory response, mainly through the activity of macrophages that are key cells in initial immune response to implants. For engineered tissues, the presence of resident macrophages can be beneficial for maintenance of homeostasis and healing. Thus, incorporation of macrophages in engineered tissues can facilitate the integration upon implantation. In this study, an in-vitro model of interaction was developed between encapsulated naive monocytes, macrophages induced with M1/M2 stimulation and incoming cells for immune assisted tissue engineering applications. To mimic the wound healing cascade, naive THP-1 monocytes, endothelial cells and fibroblasts were seeded on the gels as incoming cells. The interaction was first monitored in the absence of the gels. To mimic resident macrophages, THP-1 cells were encapsulated in the presence or absence of IL-4 to control their phenotype and then these hydrogels were seeded with incoming cells. Without encapsulation, activated macrophages induce apoptosis in endothelial cells. Once encapsulated no adverse effects were seen. Macrophage-laden hydrogels attracted more endothelial cells and fibroblasts compared to monocytes-laden hydrogels. The induction (M2 stimulation) of encapsulated macrophages did not change the overall number of attracted cells; but significantly affected their morphology. M1 stimulation by a defined media resulted in more secretion of both pro- and anti-inflammatory cytokines compared to M2 stimulation. It was demonstrated that there is a distinct effect of encapsulated macrophages on the behaviour of the incoming cells; this effect can be harnessed to establish a microenvironment more prone to regeneration upon implantation.


Amyloid formation: functional friend or fearful foe?
Amyloid formation has been most studied in the context of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, as well as in amyloidosis. However, it is becoming increasingly clear that amyloid is also present in the healthy setting; for example nontoxic amyloid formation is important for melanin synthesis and in innate immunity. Furthermore, bacteria have mechanisms to produce functional amyloid structures with important roles in bacterial physiology and interaction with host cells. Here, we will discuss some novel aspects of fibril-forming proteins in humans and bacteria. First, the amyloid-forming properties of the antimicrobial peptide human defensin 6 (HD6) will be considered. Intriguingly, unlike other antimicrobial peptides, HD6 does not kill bacteria. However, recent data show that HD6 can form amyloid structures at the gut mucosa with strong affinity for bacterial surfaces. These so-called nanonets block bacterial invasion by entangling the bacteria in net-like structures. Next, the role of functional amyloid fibrils in human semen will be discussed. These fibrils were discovered through their property to enhance HIV infection but they may also have other yet unknown functions. Finally, the role of amyloid formation in bacteria will be reviewed. The recent finding that bacteria can make amyloid in a controlled fashion without toxic effects is of particular interest and may have implications for human disease. The role of amyloid in health and disease is beginning to be unravelled, and here, we will review some of the most recent findings in this exciting area.


Use of warfarin in people with low glomerular filtration rate or on dialysis.
Atrial fibrillation, venous thromboembolism, and access malfunction are common clinical problems in dialysis patients that prompt consideration of warfarin therapy. Atrial fibrillation appears to be more common in people with low glomerular filtration rate (GFR) or on dialysis than in the general population, but the risk of stroke in this population is not known. No randomized trials have addressed the safety and efficacy of warfarin in these patients. Deep venous thrombosis and pulmonary embolism are also more common in this population and, again, no randomized trials have addressed the safety and efficacy of warfarin in this group. Pending such information, we suggest an approach that generalizes from large randomized controlled trials in the general population, modifying the assessment of risks and benefits for individual patients using the CHADS(2) and HEMORR(2)HAGES scores. A single randomized trial reported a clinically important benefit in prevention of catheter malfunction from warfarin and low-molecular weight heparin started within 12 hours of catheter insertion, in the prevention of catheter thrombosis, in people treated with ticlopidine. Trials of low-intensity anticoagulation for people with grafts and of fixed 1 mg daily warfarin dosing in people with catheters showed no benefit. Warfarin substantially increases the risk of bleeding in patients on dialysis. It is possible that it may contribute also to accelerated vascular calcification. Large randomized studies are needed to assess the risk-benefit ratio of warfarin in people with low GFR or on dialysis for a range of indications.


Role of endogenous CCK in the inhibition of gastric emptying by peptone and Intralipid in rats.
To assess the role of endogenous cholecystokinin in the control of gastric emptying of peptone solutions and Intralipid suspensions, we examined the ability of a dose range of the CCK-A antagonist, devazepide to accelerate the gastric emptying of various caloric concentrations of peptone and Intralipid in rats. In the absence of devazepide, both peptone and Intralipid emptying slowed with increasing concentration. Devazepide's effect on peptone gastric emptying diminished with increasing peptone concentration. The threshold dose for accelerating the emptying of 0.2 kcal/ml peptone was lower than the threshold dose for affecting 0.5 kcal/ml peptone and devazepide had no effect on the gastric emptying of 1.0 kcal/ml peptone. In contrast, devazepide affected Intralipid gastric emptying at all three Intralipid concentrations and the threshold dose decreased with increasing Intralipid concentration. However, the magnitude of the effect of devazepide on peptone or Intralipid gastric emptying was partial and did not increase as a function of concentration. These data demonstrate a role for endogenous CCK in the emptying of peptone and Intralipid but suggest that endogenous CCK does not account for the increased slowing of gastric emptying evident with increased caloric concentration.


Decadal trends in the north atlantic oscillation: regional temperatures and precipitation.
Greenland ice-core data have revealed large decadal climate variations over the North Atlantic that can be related to a major source of low-frequency variability, the North Atlantic Oscillation. Over the past decade, the Oscillation has remained in one extreme phase during the winters, contributing significantly to the recent wintertime warmth across Europe and to cold conditions in the northwest Atlantic. An evaluation of the atmospheric moisture budget reveals coherent large-scale changes since 1980 that are linked to recent dry conditions over southern Europe and the Mediterranean, whereas northern Europe and parts of Scandinavia have generally experienced wetter than normal conditions.


Life under quartz: Hypolithic mosses in the Mojave Desert.
Several species of dryland cyanobacteria are known to occur as hypoliths under semi-translucent rocks. In the Mojave Desert, these organisms find refuge from intense solar radiation under milky quartz where moisture persists for a longer period of time than in adjacent soil surface habitat. Desert mosses, which are extremely desiccation-tolerant, can also occur in these hypolithic spaces, though little is known about this unique moss microhabitat and how species composition compares to that of adjacent soil surface communities. To address this question, we deployed microclimate dataloggers and collected moss samples from under and adjacent to 18 milky quartz rocks (quartz mean center thickness 26 ± 15 mm) in a western high elevation Mojave Desert site. Light transmission through Mojave quartz rocks may be as low as 1.2%, and data from microclimate loggers deployed for five months support the hypothesis that quartz provides thermal buffering and higher relative humidity compared to the soil surface. Of the 53 samples collected from hypolith and surface microhabitats, 68% were Syntrichia caninervis, the dominant bryophyte of the Mojave Desert biological soil crust. Tortula inermis accounted for 28% of the samples and 4% were Bryum argenteum. In a comparison of moss community composition, we found that S. caninervis was more likely to be on the soil surface, though it was abundant in both microhabitats, while T. inermis was more restricted to hypoliths, perhaps due to protection from temperature extremes. In our study site, the differences between hypolithic and surface microhabitats enable niche partitioning between T. inermis and S. caninervis, enhancing alpha diversity. This work points to the need to thoroughly consider microhabitats when assessing bryophyte species diversity and modelling species distributions. This focus is particularly important in extreme environments, where mosses may find refuge from the prevailing macroclimatic conditions in microhabitats such as hypoliths.


The effect of extended sensory range via the EyeCane sensory substitution device on the characteristics of visionless virtual navigation.
Mobility training programs for helping the blind navigate through unknown places with a White-Cane significantly improve their mobility. However, what is the effect of new assistive technologies, offering more information to the blind user, on the underlying premises of these programs such as navigation patterns? We developed the virtual-EyeCane, a minimalistic sensory substitution device translating single-point-distance into auditory cues identical to the EyeCane's in the real world. We compared performance in virtual environments when using the virtual-EyeCane, a virtual-White-Cane, no device and visual navigation. We show that the characteristics of virtual-EyeCane navigation differ from navigation with a virtual-White-Cane or no device, and that virtual-EyeCane users complete more levels successfully, taking shorter paths and with less collisions than these groups, and we demonstrate the relative similarity of virtual-EyeCane and visual navigation patterns. This suggests that additional distance information indeed changes navigation patterns from virtual-White-Cane use, and brings them closer to visual navigation.


Anatomical factors associated with femoral neck fractures of elderly Beijing women.
Analyses using newly developed structural measures of minimal model (aBMD, W, Sigma, Delta) in a Chinese female age-matched cohort of femoral neck fracture patients and non-fracture community controls resulted in improved fracture prediction, suggesting the usefulness of new variables, extending the value of widely available DXA technology. We have developed a new approach to evaluate 2D femoral neck (FN) structure, the minimal model (MM). This model includes FNaBMD and FNWidth with two new internal structural measures, the standard deviation of normalized mineral mass projection profile distribution (FNSigma) and the displacement between center of mineral (CoM) mass and geometric center of mineral mass projection profile (FNDelta). Differences in these four structural measurements together with age, weight, and height were compared in the contralateral hip of 285 FN fracture Chinese female patients and 261 age-matched community controls. Structural variables were calculated from DXA equivalent 2D images obtained from QCT scans analyzed using Mindways Software. Review of FN scanned profiles of fracture patients and controls identified substantial reduction in mineral mass in the superior segment of FN. Fracture participants were taller, weighed less, and had lower FNaBMD and larger FNDelta, due to a larger inferior displacement in the CoM, consistent with greater reduction in superior segment bone. Logistic regression identified increased height, reduced FNaBMD, increased FNDelta, and reduced FNSigma per SD as significant independent contributors to differentiating fracture from non-fracture. Area under ROC analysis identified significant improvement in discrimination with the addition of FNDelta and FNSigma to the model including age, height, weight, and FNaBMD (C statistic 0.87 and 0.84 respectively). These data extend previous data that identified the benefit of 2D FN internal structural information in discriminating those at increased future fracture risk from recently fractured individuals. These data support continuing investigation of MM analysis as a straightforward analytical approach adding value to DXA hip aBMD in predicting fracture risk.


Inverse association between circulating vitamin D and mortality--dependent on sex and cause of death?
In various populations, vitamin D deficiency is associated with chronic diseases and mortality. We examined the association between concentration of circulating 25-hydroxyvitamin D [25(OH)D], a marker of vitamin D status, and all-cause as well as cause-specific mortality. The study included 3404 participants of the general adult Swiss population, who were recruited between November 1988 and June 1989 and followed-up until the end of 2008. Circulating 25(OH)D was measured by protein-bound assay. Cox proportional hazards regression was used to examine the association between 25(OH)D concentration and all-cause and cause-specific mortality adjusting for sex, age, season, diet, nationality, blood pressure, and smoking status. Per 10 ng/mL increase in 25(OH)D concentration, all-cause mortality decreased by 20% (HR = 0.83; 95% CI 0.74-0.92). 25(OH)D concentration was inversely associated with cardiovascular mortality in women (HR = 0.68, 95% CI 0.46-1.00 per 10 ng/mL increase), but not in men (HR = 0.97; 95% CI 0.77-1.23). In contrast, 25(OH)D concentration was inversely associated with cancer mortality in men (HR = 0.72, 95% CI 0.57-0.91 per 10 ng/mL increase), but not in women (HR = 1.14, 95% CI 0.93-1.39). Multivariate adjustment only slightly modified the 25(OH)D-mortality association. 25(OH)D was similarly inversely related to all-cause mortality in men and women. However, we observed opposite effects in women and men with respect to cardiovascular and cancer mortality.


Mindfulness-based stress reduction for people with multiple sclerosis - a feasibility randomised controlled trial.
Multiple sclerosis (MS) is a stressful condition. Mental health comorbidity is common. Stress can increase the risk of depression, reduce quality of life (QOL), and possibly exacerbate disease activity in MS. Mindfulness-Based Stress Reduction (MBSR) may help, but has been little studied in MS, particularly among more disabled individuals. The objective of this study was to test the feasibility and likely effectiveness of a standard MBSR course for people with MS. Participant eligibility included: age > 18, any type of MS, an Expanded Disability Status Scale (EDSS) </= 7.0. Participants received either MBSR or wait-list control. Outcome measures were collected at baseline, post-intervention, and three-months later. Primary outcomes were perceived stress and QOL. Secondary outcomes were common MS symptoms, mindfulness, and self-compassion. Fifty participants were recruited and randomised (25 per group). Trial retention and outcome measure completion rates were 90% at post-intervention, and 88% at 3 months. Sixty percent of participants completed the course. Immediately post-MBSR, perceived stress improved with a large effect size (ES 0.93; p < 0.01), compared to very small beneficial effects on QOL (ES 0.17; p = 0.48). Depression (ES 1.35; p < 0.05), positive affect (ES 0.87; p = 0.13), anxiety (ES 0.85; p = 0.05), and self-compassion (ES 0.80; p < 0.01) also improved with large effect sizes. At three-months post-MBSR (study endpoint) improvements in perceived stress were diminished to a small effect size (ES 0.26; p = 0.39), were negligible for QOL (ES 0.08; p = 0.71), but were large for mindfulness (ES 1.13; p < 0.001), positive affect (ES 0.90; p = 0.54), self-compassion (ES 0.83; p < 0.05), anxiety (ES 0.82; p = 0.15), and prospective memory (ES 0.81; p < 0.05). Recruitment, retention, and data collection demonstrate that a RCT of MBSR is feasible for people with MS. Trends towards improved outcomes suggest that a larger definitive RCT may be warranted. However, optimisation changes may be required to render more stable the beneficial treatment effects on stress and depression. ClinicalTrials.gov Identifier NCT02136485 ; trial registered 1st May 2014.


Bronchial responsiveness, lung mechanics, gas transfer, and corticosteroid response in patients with chronic airflow obstruction.
Thirty patients with stable chronic airflow obstruction receiving regular bronchodilator treatment were studied to determine whether the level of bronchial responsiveness, transfer factor for carbon monoxide (TLCO), or the mechanical properties of the lung predicted a bronchodilator response to oral corticosteroid treatment. Before treatment mean (SD) FEV1 was 48% (16%) of the predicted value (% pred); the geometric mean concentration of methacholine required to produce a 20% fall in FEV1 (PC20) was 0.44 (range 0.07-3.32) mg/ml; and TLCO was 59% (21%) predicted. The exponential constant (k) defining the shape of the static volume-pressure curve was 146% (66%) predicted and pulmonary conductance relative to predicted lung volume at a transpulmonary pressure of 5 cm H2O (sGL5) was 72% (37%) predicted. After prednisolone treatment (0.6 mg kg-1 day-1 for two weeks) FEV1 increased by 8% (19%) (p less than 0.05) and daily mean peak flow (PEF) by 3% (10%) (p less than 0.01) over pretreatment values. Three patients had an increase in FEV1 of more than 30%, two of whom had sputum eosinophilia (p less than 0.05). The three were among the 13 patients with a reduced sGL5. The increase in FEV1 did not correlate with initial PC20 (r = 0.16), k (r = -0.12), or TLCO (r = -0.14). Thus measurements of bronchial responsiveness, lung distensibility, and TLCO did not predict corticosteroid response in patients with stable chronic airflow obstruction. Patients with sputum eosinophilia or reduced pulmonary conductance may be more likely to respond.


Gut Microbiota Features Associated With Campylobacter Burden and Postnatal Linear Growth Deficits in a Peruvian Birth Cohort.
Campylobacter infection is associated with impaired growth of children, even in the absence of symptoms. To examine the underlying mechanisms, we evaluated associations between Campylobacter infection, linear growth, and fecal microbial community features in a prospective birth cohort of 271 children with a high burden of diarrhea and stunting in the Amazonian lowlands of Peru. Campylobacter was identified using a broadly reactive, genus-specific enzyme-linked immunosorbent assay. 16S rRNA-based analyses were used to identify bacterial taxa in fecal samples at ages 6, 12, 18, and 24 months (N = 928). Associations between infection, growth, and gut microbial community composition were investigated using multiple linear regression adjusting for within-child correlations, age, and breastfeeding. Indicator species analyses identified taxa specifically associated with Campylobacter burden. Ninety-three percent (251) of children had Campylobacter present in asymptomatic fecal samples during the follow-up period. A 10% increase in the proportion of stools infected was associated with mean reductions of 0.02 length-for-age z scores (LAZ) at 3, 6, and 9 months thereafter (P < .01). We identified 13 bacterial taxa indicative of cumulative Campylobacter burden and 14 taxa significantly associated with high or low burden of enteroaggregative Escherichia coli, norovirus, or Giardia. Campylobacter infection is common in this cohort and associated with changes in microbial community composition. These results support the notion that disruptions to the fecal microbiota may help explain the observed effects of asymptomatic infections on growth in early life.


Ammonia oxidation coupled to CO2 fixation by archaea and bacteria in an agricultural soil.
Ammonia oxidation is an essential part of the global nitrogen cycling and was long thought to be driven only by bacteria. Recent findings expanded this pathway also to the archaea. However, most questions concerning the metabolism of ammonia-oxidizing archaea, such as ammonia oxidation and potential CO(2) fixation, remain open, especially for terrestrial environments. Here, we investigated the activity of ammonia-oxidizing archaea and bacteria in an agricultural soil by comparison of RNA- and DNA-stable isotope probing (SIP). RNA-SIP demonstrated a highly dynamic and diverse community involved in CO(2) fixation and carbon assimilation coupled to ammonia oxidation. DNA-SIP showed growth of the ammonia-oxidizing bacteria but not of archaea. Furthermore, the analysis of labeled RNA found transcripts of the archaeal acetyl-CoA/propionyl-CoA carboxylase (accA/pccB) to be expressed and labeled. These findings strongly suggest that ammonia-oxidizing archaeal groups in soil autotrophically fix CO(2) using the 3-hydroxypropionate-4-hydroxybutyrate cycle, one of the two pathways recently identified for CO(2) fixation in Crenarchaeota. Catalyzed reporter deposition (CARD)-FISH targeting the gene encoding subunit A of ammonia monooxygenase (amoA) mRNA and 16S rRNA of archaea also revealed ammonia-oxidizing archaea to be numerically relevant among the archaea in this soil. Our results demonstrate a diverse and dynamic contribution of ammonia-oxidizing archaea in soil to nitrification and CO(2) assimilation and that their importance to the overall archaeal community might be larger than previously thought.


A novel biosynthetic pathway of archaetidyl-myo-inositol via archaetidyl-myo-inositol phosphate from CDP-archaeol and D-glucose 6-phosphate in methanoarchaeon Methanothermobacter thermautotrophicus cells.
Ether-type inositol phospholipids are ubiquitously distributed in Archaea membranes. The present paper describes a novel biosynthetic pathway of the archaeal inositol phospholipid. To study the biosynthesis of archaetidylinositol in vitro, we prepared two possible substrates: CDP-archaeol, which was chemically synthesized, and myo-[(14)C]inositol 1-phosphate, which was enzymatically prepared from [(14)C]glucose 6-phosphate with the inositol 1-phosphate (IP) synthase of this organism. The complete structure of the IP synthase reaction product was determined to be 1l-myo-inositol 1-phosphate, based on gas liquid chromatography with a chiral column. When the two substrates were incubated with the Methanothermobacter thermautotrophicus membrane fraction, archaetidylinositol phosphate (AIP) was formed along with a small amount of archaetidylinositol (AI). The two products were identified by fast atom bombardment-mass spectrometry and chemical analyses. AI was formed from AIP by incubation with the membrane fraction, but AIP was not formed from AI. This finding indicates that archaeal AI was synthesized from CDP-archaeol and d-glucose 6-phosphate via myo-inositol 1-phosphate and AIP. Although the relevant enzymes were not isolated, three enzymes are implied: IP synthase, AIP synthase, and AIP phosphatase. AIP synthase was homologous to yeast phosphatidylinositol synthase, and we confirmed AIP synthase activity by cloning the encoding gene (MTH1691) and expressing it in Escherichia coli. AIP synthase is a newly found member of the enzyme superfamily CDP-alcohol phosphatidyltransferase, which includes a wide range of enzymes that attach polar head groups to ester- and ether-type phospholipids of bacterial and archaeal origin. This is the first report of the biosynthesis of ether-type inositol phospholipids in Archaea.


Do computer-generated summaries, "The Bottom Line (TBL)" accurately reflect published journal abstracts?
txt2MEDLINE allows users to search and retrieve MEDLINE/PubMed citations using SMS text messages. "The Bottom Line" (TBL) concept was developed because of the 160-character limitation of text messages. TBL algorithm generates a shortened version of the published abstract thereby decreasing the number of characters while attempting to maintain the key points of the full-length, author-generated abstract. The data seems to indicate that the TBL generally conveys the essential elements of the full abstract.


Landscape-level variation in disease susceptibility related to shallow-water hypoxia.
Diel-cycling hypoxia is widespread in shallow portions of estuaries and lagoons, especially in systems with high nutrient loads resulting from human activities. Far less is known about the effects of this form of hypoxia than deeper-water seasonal or persistent low dissolved oxygen. We examined field patterns of diel-cycling hypoxia and used field and laboratory experiments to test its effects on acquisition and progression of Perkinsus marinus infections in the eastern oyster, Crassostrea virginica, as well as on oyster growth and filtration. P. marinus infections cause the disease known as Dermo, have been responsible for declines in oyster populations, and have limited success of oyster restoration efforts. The severity of diel-cycling hypoxia varied among shallow monitored sites in Chesapeake Bay, and average daily minimum dissolved oxygen was positively correlated with average daily minimum pH. In both field and laboratory experiments, diel-cycling hypoxia increased acquisition and progression of infections, with stronger results found for younger (1-year-old) than older (2-3-year-old) oysters, and more pronounced effects on both infections and growth found in the field than in the laboratory. Filtration by oysters was reduced during brief periods of exposure to severe hypoxia. This should have reduced exposure to waterborne P. marinus, and contributed to the negative relationship found between hypoxia frequency and oyster growth. Negative effects of hypoxia on the host immune response is, therefore, the likely mechanism leading to elevated infections in oysters exposed to hypoxia relative to control treatments. Because there is considerable spatial variation in the frequency and severity of hypoxia, diel-cycling hypoxia may contribute to landscape-level spatial variation in disease dynamics within and among estuarine systems.


DNA methylation in the developing marsupial embryo.
Marsupial development differs from early development of placental mammals in that the blastocyst is unilaminar, so that both embryonic and extraembryonic cells are derived from a single layer of cells (protoderm) which faces the blastocyst cavity. Also, all cells in female marsupial conceptuses so far examined show preferential paternal X-inactivation. To test for a possible correlation between cell position, paternal X-inactivation and DNA hypomethylation, marsupial DNA preparations from three regions, embryo, vascular yolk sac and avascular yolk sac, were digested with methyl-specific restriction endonucleases, separated on agarose gels and end-labelled with 32P-dCTP. The size distribution of the fragments obtained indicated three levels of methylation: high methylation of embryonic DNA, intermediate levels of methylation of vascular yolk sac DNA and hypomethylation of avascular yolk sac DNA. The degree of methylation of repeat sequences, observed as discrete bands in end-labelled HpaII digests, was correlated with the overall methylation of tissue DNA. Thus, the difference in methylation in embryonic and extraembryonic DNA was similar to that described for the mouse conceptus, and the outside cell position of marsupial fetal precursor cells did not correlate with hypomethylation. HpaII tiny fragments, which indicate the presence of CpG-rich islands of DNA, were evident in the marsupial digests. In the mouse DNA, these islands are associated with gene transcription and provide one route to cloning of unique gene sequences.


Patterns of variation in feeding strike kinematics of juvenile ghost praying mantis (Phyllocrania paradoxa): are components of the strike stereotypic?
Functional systems, such as feeding mechanics, often involve the evolution of several components of the musculoskeletal system that are moved in coordination to capture prey. Because these systems often involve the quick movement of several structures, some feeding systems have been hypothesized to be stereotypic. While the motor activity patterns are often stereotyped, the subsequent kinematics can be variable, many times in response to variation in prey stimulus (e.g. prey position). Patterns of feeding kinematics have been well studied among vertebrates, with less attention on invertebrate systems. The goal of this study was to examine the amount of stereotypy in the feeding strike kinematics of praying mantises. We filmed eight juvenile ghost praying mantises (Phyllocrania paradoxa) at 1000 Hz across several days within instar 7. We digitized several points that represent the movement of the coxa, trochanter-femur and tibia of the raptorial foreleg to obtain a set of kinematics including angles and angular velocities of the joint, as well as body lunge. Using the coefficient of variation, we found less stereotypy in the approach stage of the strike compared with the sweep. Using Bonferroni-corrected Pearson's correlations of kinematics with prey position, we found few traits related to prey position with the exception of some kinematics of the coxa joint and the amount of lunge used during the strike. Our results suggest that several components of the praying mantis strike are stereotypic, while others exhibit flexibility to ensure successful capture of the prey.


Compensatory and excess retrieval: two types of endocytosis following single step depolarizations in bovine adrenal chromaffin cells.
1. Endocytosis following exocytosis evoked by single step depolarizations was examined in bovine adrenal chromaffin cells using high resolution capacitance measurements in perforated-patch voltage clamp recordings. 2. Endocytosis was detected as a smooth exponential decline in membrane capacitance to either the pre-stimulus level ('compensatory retrieval') or far below the pre-stimulus level ('excess retrieval'). During excess retrieval, > 10% of the cell surface could be internalized in under 5 s. 3. Compensatory retrieval was equal in magnitude to stimulus-evoked exocytosis for membrane additions > 100 fF (about fifty large dense-cored vesicles). In contrast, excess retrieval surpassed both the stimulus-evoked exocytosis, and the initial capacitance level recorded at the onset of phase-tracking measurements. Cell capacitance was not maintained at the level achieved by excess retrieval but slowly returned to pre-stimulus levels, even in the absence of stimulation. 4. A large percentage of capacitance increases < 100 fF, usually evoked by 40 ms depolarizations, were not accompanied by membrane retrieval. 5. Compensatory retrieval could occur with any amount of Ca2+ entry, but excess retrieval was never triggered below a threshold Ca2+ current integral of 70 pC. 6. The kinetics of compensatory and excess retrieval differed by an order of magnitude. Compensatory retrieval was usually fitted with a single exponential function that had a median time constant of 5.7 s. Excess retrieval usually occurred with double exponential kinetics that had an extremely fast first time constant (median, 670 ms) and a second time constant indistinguishable from that of compensatory retrieval. 7. The speed of compensatory retrieval was Ca2+ dependent: the largest mono-exponential time constants occurred for the smallest amounts of Ca2+ entry and decreased with increasing Ca2+ entry. The Ca2+ dependence of mono-exponential time constants was disrupted by cyclosporin A (CsA), an inhibitor of the Ca(2+)- and calmodulin-dependent phosphatase calcineurin. 8. CsA also reduced the proportion of responses with excess retrieval, but this action was caused by a shift in Ca2+ entry values below the threshold for activation. The lower total Ca2+ entry in the presence of CsA was due to an increase in the rate of Ca2+ current inactivation rather than a reduction in peak amplitude. 9. Our data suggest that compensatory and excess retrieval represent two independent, Ca(2+)-regulated mechanisms of rapid membrane internalization in bovine adrenal chromaffin cells. Alternatively, there is a single membrane internalization mechanism that can switch between two distinct modes of behaviour.