Modeling and computational analysis of EGF receptor-mediated cell communication in Drosophila oogenesis.
Autocrine signaling through the Epidermal Growth Factor Receptor (EGFR) operates at various stages of development across species. A recent hypothesis suggested that a distributed network of EGFR autocrine loops was capable of spatially modulating a simple single-peaked input into a more complex two-peaked signaling pattern, specifying the formation of a pair organ in Drosophila oogenesis (two respiratory appendages on the eggshell). To test this hypothesis, we have integrated genetic and biochemical information about the EGFR network into a mechanistic model of transport and signaling. The model allows us to estimate the relative spatial ranges and time scales of the relevant feedback loops, to interpret the phenotypic transitions in eggshell morphology and to predict the effects of new genetic manipulations. We have found that the proposed mechanism with a single diffusing inhibitor is sufficient to convert a single-peaked extracellular input into a two-peaked pattern of intracellular signaling. Based on extensive computational analysis, we predict that the same mechanism is capable of generating more complex patterns. At least indirectly, this can be used to account for more complex eggshell morphologies observed in related fly species. We propose that versatility in signaling mediated by autocrine loops can be systematically explored using experiment-based mechanistic models and their analysis.


Comparison of motility characteristics and normal sperm morphology of human semen samples separated by percoll density gradient centrifugation.
The aim of this study was twofold: to investigate the ability of Percoll gradient centrifugation (52, 68, 84%) to fractionate semen samples according to motility quality and percentage normal morphology and to determine whether there is an association between sperm motility quality and percentage normal morphology. Sperm motility was evaluated using a Hamilton Thorn analyzer and normal sperm morphology was manually assessed according to the strict criteria (< or = 4, 5-14, and >14%). The majority of motility parameters and the percentage normal morphology were found to be significantly improved in the 84% Percoll fraction. The greatest effect was on the < or = 4% group, shifting the mean normal morphology percentage from 2.6 to 5.2%. Curvilinear velocity (VCL) and average path velocity (VAP) were the only two motility parameters that were significantly associated with the percentage normal morphology. Using a combined VCL, VAP vector the >14% group was found to have a significantly different value as compared to the 5-14 and < or = 4% groups. Percoll (discontinuous) gradient centrifugation can therefore play a significant role in the improvement of semen samples for use in assisted reproduction procedures. The VCL, VAP vector identified may also serve as an additional tool in the prediction of the fertility potential of sperm samples.


Tumor control and QoL outcomes of very young children with atypical teratoid/rhabdoid tumor treated with focal only chemo-radiation therapy using pencil beam scanning proton therapy.
The aim of this analysis was to assess the early clinical results of pencil beam scanning proton therapy (PT) in the treatment of young children with non-metastatic atypical teratoid/rhabdoid tumor (ATRT) of the CNS. Fifteen children (male, n = 8, 53 %) were treated with PT between May 2008 and January 2013. Mean age at diagnosis was 17.4 ± 7.0 months. The localization was infratentorial in 9 (60 %) patients. Gross total resection of the primary tumors was achieved in 7 (47 %) patients. The dose administered focally under sedation was 54 Gy (RBE). After a median follow-up of 33.4 months (range 9.7-69.2), 3 (20 %), 4 (27 %) and 2 (13 %) patients presented with local failure (LF), distant brain failure (DBF) and spinal failure (SF), respectively. Six patients died, all of tumor progression. The 2-year overall- and progression-free survival was 64.6 and 66.0 %. Tumor location (supratentorial) and the extent of surgical resection (non-gross total resection) were negative prognostic factors for both OS and PFS. PT was well tolerated. No grade >2 acute toxicity was observed. The estimated 2-year toxicity-free survival was 90 %. As assessed by the PedsQoL proxy, no decrease in QoL was observed after PT. We conclude that PBS PT is an effective treatment for young children with ATRT. After PT, with or without concomitant chemotherapy, two third of the patients survived >2 years. Acute toxicity was manageable. Longer follow-up and larger numbers of patients are needed to assess long-term outcomes and treatment-induced toxicity.


[Neurological manifestation and genetic diagnosis of Angelman, Rett and Fragile-X syndromes]
OBJECTIVE: To discuss clinical and electroencephalographic aspects and the genetic mechanisms of three neurogenic syndromes that can be related to nosologic entities in the heterogenic pathological group presenting symptoms of mental retardation and autism. SOURCES: The authors carried out a bibliographic review on each syndrome involved, correlating and characterizing the neurological manifestations, as well as describing genetic mechanisms and identifying biological markers. SUMMARY OF THE FINDINGS: The authors were able to confirm that Rett Sydrome is a genetic disease resulting from the mutation of the MECP2 gene and clinical variations can be explained by different mutations in this gene. Angelman syndrome has four genetic mechanisms responsible for phenotypic variations and different risks of recurrence. In Fragile-X syndrome, the degree of cognitive impairment is related to the number of trinucleotide repeats. CONCLUSIONS: Different genetic mechanisms of the three syndromes are responsible for clinical variability. By identifying the biological markers, the diagnosis will be performed earlier and it will be possible to identify new subtle expressions of the disease.


Digital Mental Health Interventions for Young People in Rural South Africa: Prospects and Challenges for Implementation.
Globally, most young people living with mental health conditions lack access to mental health care but have access to a mobile device. The growing access to mobile devices in South Africa has the potential to increase access to mental health care services through digital platforms. However, uptake of digital mental health interventions may be hampered by several factors, such as privacy, confidentiality, informed consent, and affordability. This study identified the prospects and challenges of implementing a mobile phone-based mental health intervention for young people in Ingwavuma area. Data were collected from 93 young people in three villages purposefully selected in Ingwavuma area. Participants included in the study were aged 16-24. Data were collected through a questionnaire. Thematic and descriptive analysis was performed on the qualitative and quantitative data, respectively. Mental health education was low, with only 22% of participants having received prior education on mental health. About 50% of the participants had come across a mental health app, but none of them had used any of these apps; 87% of participants had Internet access; 60% preferred to use social media to contact a health worker; and 92% suggested that use of digital apps would improve mental health literacy among young people. Barriers to access of digital mental health interventions were identified as the high cost of data, restrictive religious beliefs, limited privacy, lack of native languages on most digital platforms, low digital literacy, and complicated user interface. In uMkhanyakude, uptake of digital mental health apps among the young people was low. We recommend that, developers create context-specific digital applications catered for young people from different cultural backgrounds. Socio-economic issues such as affordability also need to be addressed in developing these tools.


Patient demographics and health plan paid costs in chronic inflammatory demyelinating polyneuropathy.
We determined health plan paid costs and healthcare resource usage of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). CIDP patients from 9 U.S. commercial health plans with claims in 2011 were identified from the Accordant Health Services claims database. We examined demographics, prevalence of comorbidities, prescribed drugs, place of service, and mean annual health plan paid costs per patient. From 6.5 million covered lives, 73 (56% men; mean age 47) met study entry criteria. The most prescribed therapies were intravenous immunoglobulin (IVIg) (26% of patients), gabapentin (26%), and prednisone (16%). The annual health plan paid cost was $56,953. Pharmacy cost was the major cost driver (57% of the total), and IVIg totaled 90% of the pharmacy costs. Healthcare costs for CIDP patients are substantial, with a large burden in pharmacy usage. Studies are needed to determine optimal long-term treatment strategies for CIDP, particularly related to IVIg.


Growth trajectories of exercise self-efficacy in older adults: influence of measures and initial status.
This study examined differential trajectories of exercise-related self-efficacy beliefs across a 12-month randomized controlled exercise trial. Previously inactive older adults (N = 144; M age = 66.5) were randomly assigned to one of two exercise conditions (walking, flexibility-toning-balance) and completed measures of barriers self-efficacy (BARSE), exercise self-efficacy (EXSE), and self-efficacy for walking (SEW) across a 12-month period. Changes in efficacy were examined according to efficacy type and interindividual differences. Latent growth curve modeling was employed to (a) examine average levels and change in each type of efficacy for the collapsed sample and by intervention condition and (b) explore subpopulations (i.e., latent classes) within the sample that differ in their baseline efficacy and trajectory. Analyses revealed two negative trends in BARSE and EXSE at predicted transition points, in addition to a positive linear trend in SEW. Two subgroups with unique baseline efficacy and trajectory profiles were also identified. These results shed new light on the relationship between exercise and self-efficacy in older adults. They also highlight the need for strategies for increasing and maintaining efficacy within interventions, namely targeting participants who start with a disadvantage (lower efficacy) and integrating efficacy-boosting strategies for all participants prior to program end.


Total synthesis of phorboxazole A via de novo oxazole formation: strategy and component assembly.
The phorboxazole natural products are among the most potent inhibitors of cancer cell division, but they are essentially unavailable from natural sources at present. Laboratory syntheses based upon tri-component fragment coupling strategies have been developed that provide phorboxazole A and analogues in a reliable manner and with unprecedented efficiency. This has been orchestrated to occur via the sequential or simultaneous formation of both of the natural product's oxazole moieties from two serine-derived amides, involving oxidation-cyclodehydrations. The optimized preparation of three pre-assembled components, representing carbons 3-17, 18-30, and 31-46, has been developed. This article details the design and syntheses of these three essential building blocks. The convergent coupling approach is designed to facilitate the incorporation of structural changes within each component to generate unnatural analogues, targeting those with enhanced therapeutic potential and efficacy.


Maturation trade-offs in octopus females and their progeny: energy, digestion and defence indicators.
Sexual maturation and reproduction influence the status of a number of physiological processes and consequently the ecology and behaviour of cephalopods. Using Octopus mimus as a study model, the present work was focused in the changes in biochemical compound and activity that take place during gonadal maturation of females and its consequences in embryo and hatchlings characteristics. To do that, a total of 31 adult females of O. mimus were sampled to follow metabolites (ovaries and digestive gland) and digestive enzyme activities (alkaline and acidic proteases) during physiological and functional maturation. Levels of protein (Prot), triacylglyceride (TG), cholesterol (Chol), glucose (Glu), and glycogen (Gly) were evaluated. Groups of eggs coming from mature females were also sampled along development and after hatching (paralarvae of 1 and 3 days old) to track metabolites (Prot, TG, Glu, Gly, TG, Chol), digestive enzymes activity (Lipase, alkaline proteases, and acidic proteases), and antioxidant/detoxification defence indicators with embryos development. Based on the data obtained, we hypothesized that immature females store Chol in their ovaries, probably from the food they ingested, but switch to TG reserves at the beginning of the maturation processes. At the same time, results suggest that these processes were energetically supported by Glu, obtained probably from Gly breakdown by gluconeogenic pathways. Also, was observed that embryos metabolites and enzyme activities (digestive and antioxidant/detoxification enzymes) where maintained without significant changes and in a low activity during the whole organogenesis, meaning that organogenesis is relatively not energetically costly. In contrast, after organogenesis, a mobilization of nutrients and activation of the metabolic and digestive enzymes was observed, together with increments in consumption of yolk and Gly, and reduction in lipid peroxidation. Derived from our results, we also have the hypothesis that reactive oxygen species (ROS) were produced during the metabolic processes that occurs in ovarian maturation. Those ROS may be in part transferred to the egg provoking a ROS charge to the embryos. The elimination of ROS in embryos started when the activity of the heart and the absorption of the yolk around stages XIV and XV were evident. Altogether, these processes allowed the paralarvae to hatch with buffered levels of ROS and with the antioxidant defence mechanisms ready to support further ROS production derived from paralarvae higher life stage requirements (feeding and metabolic demands).


Gifts and influence: Conflict of interest policies and prescribing of psychotropic medications in the United States.
The pharmaceutical industry spends roughly 15 billion dollars annually on detailing - providing gifts, information, samples, trips, honoraria and other inducements - to physicians in order to encourage them to prescribe their drugs. In response, several states in the United States adopted policies that restrict detailing. Some states banned gifts from pharmaceutical companies to doctors, other states simply required physicians to disclose the gifts they receive, while most states allowed unrestricted detailing. We exploit this geographic variation to examine the relationship between gift regulation and the diffusion of four newly marketed medications. Using a dataset that captures 189 million psychotropic prescriptions written between 2005 and 2009, we find that uptake of new costly medications was significantly lower in states with marketing regulation than in areas that allowed unrestricted pharmaceutical marketing. In states with gift bans, we observed reductions in market shares ranging from 39% to 83%. Policies banning or restricting gifts were associated with the largest reductions in uptake. Disclosure policies were associated with a significantly smaller reduction in prescribing than gift bans and gift restrictions. In states that ban gift-giving, peer influence substituted for pharmaceutical detailing when a relatively beneficial drug came to market and provided a less biased channel for physicians to learn about new medications. Our work suggests that policies banning or limiting gifts from pharmaceutical representatives to doctors are likely to be more effective than disclosure policies alone.


The metallothionein and RCAS1 expression analysis in breast cancer and adjacent tissue regarding the immune cells presence and their activity.
The generation of proper immune response in the tumor environment seems to be essential in antitumor defense. RCAS1 expression has been shown to participate in the regulation of immune cytotoxic activity, metallothionein participates in the protection of cells against immune mediated apoptosis. Since MT and RCAS1 expression is observed within healthy tumor environment we aimed to focus on the proteins expression in tumor and its healthy adjacent tissue in invasive ductal breast cancer regarding the immune cells presence and activity. RCAS1, metallothionein, CD3, CD56, CD4, CD25, CD69, CD68 and CD16 antigens expression was assessed by immunohistochemistry in invasive ductal breast cancer. Tissue samples were obtained from 45 patients and were grouped according to the presence of lymph nodes metastases. Two groups were obtained: with and without lymph nodes metastases. Significant differences were observed in RCAS1 and metallothionein expression in tumor and significant differences in metallothionein expression in healthy stroma regarding the presence of lymph nodes metastases. The significantly higher RCAS1 expression was noticed in tumor in comparison to stroma in patients with the presence of lymph nodes metastases. No such difference was observed in patients without the metastases. Significantly higher metallothionein expression was identified in tumor than in stroma in both groups of patients, with and without lymph nodes metastases. These changes in RCAS1 and metallothionein expression were significantly related with the changes in the number and activity of immune cells. RCAS1 and metallothionein expression in breast cancer healthy stroma seems to be essential for the coexistence of cytotoxic immune cells and normal epithelial cells. The loss of the ability to compensate the growing cytotoxic immune response in the environment might participate in the development of tumor spread.


Isolation and characterization of light-regulated phycobilisome linker polypeptide genes and their transcription as a polycistronic mRNA.
Several cyanobacteria adjust both the phycobiliprotein and linker protein composition of the phycobilisome, a light-harvesting complex in cyanobacteria and some eucaryotic algae, to maximize absorption of prevalent wavelengths of light. This process is called complementary chromatic adaptation. We sequenced the amino terminus of a linker polypeptide which is associated with phycocyanin and accumulates to high levels during growth of the cyanobacterium Fremyella diplosiphon in red light. A mixed oligonucleotide encoding a region of this amino terminus was synthesized and used to identify a fragment of F. diplosiphon genomic DNA encoding the linker polypeptide. This linker gene was located between two other linker genes and contiguous to the red-light-induced phycocyanin gene set. Sequences of all three linker genes are presented. These genes were transcribed together onto a large polycistronic mRNA which also encoded the red-light-induced phycocyanin subunits. The relationship of this transcript to the biogenesis of the phycobilisome when F. diplosiphon is grown under different conditions of illumination is discussed.


Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain.
The inhibitor-of-apoptosis proteins (IAPs) regulate programmed cell death by inhibiting members of the caspase family of enzymes. Recently, a mammalian protein called Smac (also named DIABLO) was identified that binds to the IAPs and promotes caspase activation. Although undefined in the X-ray structure, the amino-terminal residues of Smac are critical for its function. To understand the structural basis for molecular recognition between Smac and the IAPs, we determined the solution structure of the BIR3 domain of X-linked IAP (XIAP) complexed with a functionally active nine-residue peptide derived from the N terminus of Smac. The peptide binds across the third beta-strand of the BIR3 domain in an extended conformation with only the first four residues contacting the protein. The complex is stabilized by four intermolecular hydrogen bonds, an electrostatic interaction involving the N terminus of the peptide, and several hydrophobic interactions. This structural information, along with the binding data from BIR3 and Smac peptide mutants reported here, should aid in the design of small molecules that may be used for the treatment of cancers that overexpress IAPs.


Activation of Escherichia coli F1-ATPase by lauryldimethylamine oxide and ethylene glycol: relationship of ATPase activity to the interaction of the epsilon and beta subunits.
The stimulation of the ATPase activity of Escherichia coli F1-ATPase by the detergent lauryldimethylamine oxide (LDAO) and the relationship of this activation to removal of the inhibitory epsilon subunit were studied. The detergent caused a dramatic decrease in the affinity of epsilon-depleted enzyme for epsilon subunit, suggesting that release of epsilon is involved in LDAO activation. However, even in the absence of any epsilon subunit, the detergent caused a 140% increase in activity, indicating activation by effects independent of epsilon. In contrast, the addition of 30% ethylene glycol to the reaction buffer caused a modest inhibition of the ATPase activity of epsilon-depleted F1-ATPase but rendered the enzyme insensitive to inhibition by epsilon subunit. This solvent prevented the cross-linking of epsilon to beta by a water-soluble carbodiimide, although epsilon remained linkable to both beta and gamma by dithiobis(succinimidyl propionate). Thus, epsilon was not dissociated from F1-ATPase, but its intimate interaction with the beta subunit was altered. These results suggest that the inhibitory action of epsilon is expressed through its interaction with beta. Kinetic analysis revealed that LDAO activated hydrolysis at both the high- and low-affinity promotional sites, with little change in Km values. Ethylene glycol caused a substantial increase in Km at the low-affinity promotional site and made the enzyme resistant to inhibition by aurovertin D.


Familial dilated cardiomyopathy associated with pathogenic TBX5 variants: Expanding the cardiac phenotype associated with Holt-Oram syndrome.
Holt-Oram syndrome (HOS) is a rare, autosomal dominant disorder caused by heterozygous pathogenic variants in cardiac T-box transcription factor, TBX5. Classically, it is associated with upper limb malformations and variable cardiac abnormalities. Limb manifestations are considered to be invariably present, ranging in severity from limitation in movement, to triphalangeal thumbs, absent thumbs, shortened forearms, or phocomelia. Cardiac involvement is characterized by congenital heart defects, most commonly septal structural malformations, and conduction system disease. Recently, novel TBX5 variants have also been reported in association with dilated cardiomyopathy (DCM). In this context, we report eight individuals from four unrelated families, in whom pathogenic variants in TBX5 segregated with an atypical HOS phenotype. Affected individuals exhibit relatively mild skeletal features of HOS, with a predominant cardiac phenotype, which includes several individuals affected by non-ischaemic DCM. To our knowledge, these represent the first reported cases of DCM in families with skeletal features of HOS, some of whom also harbored variants previously linked to a classical HOS phenotype (p. Arg279* and p.Arg237Gln). This finding supports diverse roles of TBX5 in cardiovascular development and function, and confirms the importance of long-term cardiac surveillance for individuals affected by HOS. Furthermore, these families highlight the wide phenotypic variability of HOS, which may include comparatively mild upper limb findings in respect to cardiac manifestations.


Average medical cost of fatal and non-fatal injuries by type in the USA.
To estimate the average medical care cost of fatal and non-fatal injuries in the USA comprehensively by injury type. The attributable cost of injuries was estimated by mechanism (eg, fall), intent (eg, unintentional), body region (eg, head and neck) and nature of injury (eg, fracture) among patients injured from 1 October 2014 to 30 September 2015. The cost of fatal injuries was the multivariable regression-adjusted average among patients who died in hospital emergency departments (EDs) or inpatient settings as reported in the Healthcare Cost and Utilization Project Nationwide Emergency Department Sample and National Inpatient Sample, controlling for demographic (eg, age), clinical (eg, comorbidities) and health insurance (eg, Medicaid) factors. The 1-year attributable cost of non-fatal injuries was assessed among patients with ED-treated injuries using MarketScan medical claims data. Multivariable regression models compared total medical payments (inpatient, outpatient, drugs) among non-fatal injury patients versus matched controls during the year following injury patients' ED visit, controlling for demographic, clinical and insurance factors. All costs are 2015 US dollars. The average medical cost of all fatal injuries was approximately $6880 and $41 570 per ED-based and hospital-based patient, respectively (range by injury type: $4764-$10 289 and $31 912-$95 295). The average attributable 1-year cost of all non-fatal injuries per person initially treated in an ED was approximately $6620 (range by injury type: $1698-$80 172). Injuries are costly and preventable. Accurate estimates of attributable medical care costs are important to monitor the economic burden of injuries and help to prioritise cost-effective public health prevention activities.


Leucettines, a class of potent inhibitors of cdc2-like kinases and dual specificity, tyrosine phosphorylation regulated kinases derived from the marine sponge leucettamine B: modulation of alternative pre-RNA splicing.
We here report on the synthesis, optimization, and biological characterization of leucettines, a family of kinase inhibitors derived from the marine sponge leucettamine B. Stepwise synthesis of analogues starting from the natural structure, guided by activity testing on eight purified kinases, led to highly potent inhibitors of CLKs and DYRKs, two families of kinases involved in alternative pre-mRNA splicing and Alzheimer's disease/Down syndrome. Leucettine L41 was cocrystallized with CLK3. It interacts with key residues located within the ATP-binding pocket of the kinase. Leucettine L41 inhibits the phosphorylation of serine/arginine-rich proteins (SRp), a family of proteins regulating pre-RNA splicing. Indeed leucettine L41 was demonstrated to modulate alternative pre-mRNA splicing, in a cell-based reporting system. Leucettines should be further explored as pharmacological tools to study and modulate pre-RNA splicing. Leucettines may also be investigated as potential therapeutic drugs in Alzheimer's disease (AD) and in diseases involving abnormal pre-mRNA splicing.


Structural crossover in a model fluid exhibiting two length scales: Repercussions for quasicrystal formation.
We investigate the liquid state structure of the two-dimensional model introduced by Barkan et al. [Phys. Rev. Lett. 113, 098304 (2014)10.1103/PhysRevLett.113.098304], which exhibits quasicrystalline and other unusual solid phases, focusing on the radial distribution function g(r) and its asymptotic decay r→∞. For this particular model system, we find that as the density is increased there is a structural crossover from damped oscillatory asymptotic decay with one wavelength to damped oscillatory asymptotic decay with another distinct wavelength. The ratio of these wavelengths is ≈1.932. Following the locus in the phase diagram of this structural crossover leads directly to the region where quasicrystals are found. We argue that identifying and following such a crossover line in the phase diagram towards higher densities where the solid phase(s) occur is a good strategy for finding quasicrystals in a wide variety of systems. We also show how the pole analysis of the asymptotic decay of equilibrium fluid correlations is intimately connected with the nonequilibrium growth or decay of small-amplitude density fluctuations in a bulk fluid.


Chaos in voice, from modeling to measurement.
Chaos has been observed in turbulence, chemical reactions, nonlinear circuits, the solar system, biological populations, and seems to be an essential aspect of most physical systems. Chaos may also be central to the interpretation of irregularity in voice disorders. This presentation will summarize the results from a series of our recent studies. These studies have demonstrated the prescence of chaos in computer models of vocal folds, experiments with excised larynges, and human voices. Methods based on nonlinear dynamics can be used to quantify chaos and irregularity in vocal fold vibration. Studies have suggested that disordered voices from laryngeal pathologies such as laryngeal paralysis, vocal polyps, and vocal nodules might exhibit chaotic behaviors. Conventional parameters, such as jitter and shimmer, may be unreliable for analysis of periodic and chaotic voice signals. Nonlinear dynamic methods, however, have differentiated between normal and pathological phonations and can describe the aperiodic or chaotic voice. Chaos theory and nonlinear dynamics can enchance our understanding and therefore our assessment of pathological phonation.


Dual-template cascade synthesis of highly multi-branched Au nanoshells with ultrastrong NIR absorption and efficient photothermal therapeutic intervention.
With the rapid development of photothermal therapy (PTT) in cancer treatment, it is necessary to obtain effective plasma-responsive tunable photothermal transducing agents. Inspired by the peptide-directed hierarchical mineralized Ag nanocages (Ag NCs), scientists designed a new duel-template cascade preparation method, and novel unique multi-branched gold nanoshells (BGSs) were successfully prepared under mild conditions using green strategy. The length, density and diameter of the branches were tuned, which led to the adjustment of the surface plasma response of the nanostructure. Because of the hierarchical structure and anisotropic surface, an obvious red shift of the local surface plasmon resonance spectrum was observed for the branched Au nanoshells. The excellent photothermal conversion efficiency (70.9%) and photo-induced heating responsive curves proved the superior photothermal conversion performance and photothermal stability of BGSs. The in vitro and in vivo results indicated that the heat generated by the intense NIR absorption of BGSs can selectively destroy cancer cells under laser irradiation. The nanostructures with ultrastrong absorption have promising prospects in tumor therapy.


Megaloblastic anaemia: prevalence and causative factors.
Megaloblastic anaemia is not uncommon in India, but data are insufficient regarding its prevalence, and causative and precipitating factors. We did a prospective study to document such data for patients of megaloblastic anaemia. All patients presenting to our hospital over a period of 6 months with a haemoglobin < 10 g/dl and/or mean corpuscular volume > 95 fL and blood film findings consistent with megaloblastosis were included in the study. Demographic data, diet, drug intake, previous blood transfusion and presenting symptoms were recorded. Clinical findings were obtained from medical records of patients. Complete blood counts, blood film examination, reticulocyte count and cobalamin and folate assays were done. Results of liver function tests and bone marrow slides were available for review. Megaloblastic anaemia was diagnosed in 175 patients with anaemia. Assays were done on 120 patients (55 were lost to follow up) and results showed cobalamin deficiency in 78 patients (65%), combined cobalamin and folate deficiency in 20 patients (12%) and pure folate deficiency in 8 patients (6%). Fifteen per cent of patients had normal or high values of both vitamins, having received blood or haematinics before the diagnosis was established. The peak incidence of megaloblastic anaemia was in the age group of 10-30 years (48%), with female preponderance (71%). The predominant symptoms were fatigue, anorexia and gastritis, low grade fever, shortness of breath, palpitations and mild jaundice. Twenty-five per cent of patients were on acid-suppressing medication and 15% had previous transfusion for anaemia. Eighty-seven per cent of patients with cobalamin deficiency and 75% with folate deficiency were lactovegetarians. In the combined deficiency cohort, 71% were vegetarians and 29% were occasional non-vegetarians. Physical findings were pallor (85%), glossitis (29%), mild icterus (25%) and hyperpigmentation (18%). Abnormal haematological findings were mean corpuscular volume 77-123 fL (9 patients had iron deficiency), red cell distribution width 16%-44%, pancytopenia in 62% of patients, reticulocyte count > 2% in 42% of patients and typical megaloblastic blood films in all patients. Bone marrow smears available in 22 patients showed moderate-to-severe megaloblastosis. Thirty-two per cent of patients in whom liver function tests were done showed indirect bilirubinaemia with normal enzymes. Megaloblastic anaemia was diagnosed from complete blood counts, red cell indices, blood film examination and assays of the two vitamins. Bone marrow examination was not essential for diagnosis. Cobalamin deficiency was the major cause of megaloblastosis. Aetiological factors were a diet poor in cobalamin or folate, increased requirements during the growth period and pregnancy, and the use of acid-suppressing medication. Physicians managing these patients need to be aware of the timing of blood sampling for assays, that haematinics and transfusions provide only short term benefits, and that long term follow up and diet counselling is crucial.


The Horizontal Root Fractures. Diagnosis, Clinical Management and Three-Year Follow-Up.
The aim of this retrospective analysis is to describe and to evaluate the middle third horizontal root fractures, long term clinical management results and to estimate the effect of treatments factors upon healing and survival rate. Our clinical study included 42 patients presenting a middle third horizontal root fracture in permanent dentition. For each patient at t0 the parameters recorded were: diastasis, mobility, sensibility, periodontal inflammation, pulpal pathology, associated fracture and dislocation of the coronal fragment. The follow-up was performed after 6 (t1), 12 (t2) and 36 (t3) months after the trauma, both clinically and radiologically. Clinical examination, vitality tests and a radiological evaluation (periapical x-ray) were performed. At t0 it was observed: diastasis (14, 3%), mobility (28, 6%), thermal sensibility (61, 9%), periodontal inflammation (4, 8%), pulpal pathology (38, 1%) and dislocation of the coronal fragment (47, 6%) of the patients. The treatment plan started with the coronal fragment repositioning and the blockage (splint) with the adjacent teeth in 47, 6% of cases.A root canal treatment was performed at t0 in 52,4% of the fractured teeth. Statistical analysis showed the highest level of significance between pulpal lesions (t0) and associated fractures. The mobility, sensibility and pulpar lesions parameters, showed a reduction in relation to the follow up timing, with a main variation remarkably evident between t0 and t1. The ratio between observation time and the presence of diastasis was statistically significant. The analysis of the clinical results exhibits the high success rate of a conservative approach in the treatment of teeth fractured in the middle third of the root.


Peer Coaching as a Faculty Development Tool: A Mixed Methods Evaluation.
In the era of competency-based assessment, medical education faculty are frequently challenged to develop unique teaching approaches. One method to address faculty development needs in a real-time clinical learning environment is peer coaching. We implemented and evaluated a faculty development program involving peer observation and feedback for attending physicians. Hospital internal medicine faculty assigned to a teaching service were recruited for the study. Participants voluntarily agreed to observe and be observed by a peer attending physician during a 2-week block of teaching rounds. When serving in the coaching role, faculty were asked to observe 4 separate occasions using an observation tool based on the Stanford Faculty Development Program framework to guide feedback. An outside consultant facilitated a focus group and completed a qualitative content analysis to categorize all participants' experiences during the faculty development activity. Of the 22 eligible faculty, 14 (64%) agreed to participate by committing to 6 to 8 hours observing another faculty member during rounds, 2 feedback sessions, and 90 minutes to provide program feedback during a focus group. The analysis of the focus group revealed favorable reactions to the faculty development program, including (1) observed attending awareness of unrecognized habits; (2) personalized teaching tips for the observed attending to improve teaching quality based on individual style/preferences; and (3) exposure to new teaching techniques. An inpatient-based peer-coaching faculty development program was acceptable and feasible for a majority of faculty and may improve individual teaching effectiveness among conventionally trained physicians.


Proposed measurement of spatial correlations at the Berezinski-Kosterlitz-Thouless transition of superconducting thin films.
The Berezinski-Kosterlitz-Thouless transition is a unique two-dimensional phase transition, separating two phases with exponentially and power-law decaying correlations, respectively. In disordered systems, these correlations propagate along favorable paths, with the transition marking the point where global coherence is lost. Here we propose an experimental method to probe locally these particular paths in superconducting thin films, which exhibit this transition, and demonstrate theoretically that close to the transition the coherence propagates along a ramified network, reminiscent of a percolation transition. We suggest and calculate experimentally accessible quantities that can shed light on the spatial correlations in the system as it approaches the critical point. This approach can be applicable to a variety of phase transitions in disordered systems.


Disease and the dynamics of extinction.
Invading infectious diseases can, in theory, lead to the extinction of host populations, particularly if reservoir species are present or if disease transmission is frequency-dependent. The number of historic or prehistoric extinctions that can unequivocally be attributed to infectious disease is relatively small, but gathering firm evidence in retrospect is extremely difficult. Amphibian chytridiomycosis and Tasmanian devil facial tumour disease (DFTD) are two very different infectious diseases that are currently threatening to cause extinctions in Australia. These provide an unusual opportunity to investigate the processes of disease-induced extinction and possible management strategies. Both diseases are apparently recent in origin. Tasmanian DFTD is entirely host-specific but potentially able to cause extinction because transmission depends weakly, if at all, on host density. Amphibian chytridiomycosis has a broad host range but is highly pathogenic only to some populations of some species. At present, both diseases can only be managed by attempting to isolate individuals or populations from disease. Management options to accelerate the process of evolution of host resistance or tolerance are being investigated in both cases. Anthropogenic changes including movement of diseases and hosts, habitat destruction and fragmentation and climate change are likely to increase emerging disease threats to biodiversity and it is critical to further develop strategies to manage these threats.


Communicating interest in sex: verbal and nonverbal initiation of sexual activity in young adults' romantic dating relationships.
Relatively little is known about the day-to-day initiation of sexual activity between young adults in committed relationships, notably the ways in which young people communicate interest in sexual activity. Sexual script theory (Simon and Gagnon, Society 22:53-60, 1984) posits that men are traditionally the initiators and women the restrictors of sexual activity early in relationships. However, research suggests that these patterns may be different for individuals in committed relationships. The current study used a diary method to examine verbal/nonverbal and indirect/direct initiation strategies, responses to initiations, and patterns between initiations and responses. Participants included 31 men and 32 women between the ages of 18 and 24 years who were involved in committed heterosexual relationships. Men initiated more frequently than did women and most initiations were nonverbal initiation (91%) rather than verbal (65%). Responses to initiations tended to match the initiators' choice of strategies, suggesting that synchrony plays an important role in initiation patterns. The findings have implications for understanding sexual communication as well as relationship and sexual satisfaction among young adults.


TRV120027, a novel β-arrestin biased ligand at the angiotensin II type I receptor, unloads the heart and maintains renal function when added to furosemide in experimental heart failure.
TRV120027 is a novel β-arrestin biased ligand of the angiotensin II type 1 receptor; it antagonizes canonical G-protein-mediated coupling while, in contrast to classical angiotensin II type 1 receptor antagonists, it engages β-arrestin-mediated signaling. Consequently, TRV120027 inhibits angiotensin II-mediated vasoconstriction while, via β-arrestin coupling, it increases cardiomyocyte contractility. We hypothesized that TRV120027 would elicit beneficial cardiorenal actions when added to furosemide in experimental heart failure. Two groups of anesthetized dogs (n=6 each) with tachypacing-induced heart failure were studied. After a baseline clearance, 1 group (F+V) received furosemide (1 mg/kg per hour) plus saline for 90 minutes, whereas the other (F+T) received the same dose of furosemide plus TRV120027 (0.3 and 1.5 µg/kg per minute for 45 minutes each); 2 clearances were done during drug infusion. After a washout, a postinfusion clearance was done; *P<0.05 between groups. F+V and F+T increased diuresis and natriuresis to a similar extent during drug administration, but urine flow* and urinary sodium excretion* were higher in the postinfusion clearance with F+T. Glomerular filtration rate was preserved in both groups. Renal blood flow increased with F+T but this was not significant versus F+V. Compared with F+V, F+T decreased mean arterial pressure*, systemic* and pulmonary* vascular resistances, and atrial natriuretic peptide*. Pulmonary capillary wedge pressure* decreased to a larger extent with F+T than with F+V. When added to furosemide, TRV120027, a novel β-arrestin biased angiotensin II type 1 receptor ligand, preserved furosemide-mediated natriuresis and diuresis, while reducing cardiac preload and afterload. These results provide support for TRV120027 as a promising novel therapeutic for the treatment of heart failure.


Cell cycle dependence of laminar determination in developing neocortex.
The neocortex is patterned in layers of neurons that are generated in an orderly sequence during development. This correlation between cell birthday and laminar fate prompted an examination of how neuronal phenotypes are determined in the developing cortex. At various times after labeling with [3H]thymidine, embryonic progenitor cells were transplanted into older host brains. The laminar fate of transplanted neurons correlates with the position of their progenitors in the cell cycle at the time of transplantation. Daughters of cells transplanted in S-phase migrate to layer 2/3, as do host neurons. Progenitors transplanted later in the cell cycle, however, produce daughters that are committed to their normal, deep-layer fates. Thus, environmental factors are important determinants of laminar fate, but embryonic progenitors undergo cyclical changes in their ability to respond to such cues.


Comparison of kaolin and tissue factor activated thromboelastography in haemophilia.
A limitation of bypassing agent therapy for haemophilia patients with inhibitors is the absence of a laboratory assay, which predicts the clinical response to treatment. Recent investigations have demonstrated the potential for thromboelastography to assess the effects of bypassing agent therapy in this patient population. While tissue factor activation has been used in several prior studies, a recent multicentre study failed to demonstrate an expected concentration-response effect of rFVIIa and called into question the tissue factor activation methods that have been employed. A comparison of kaolin to two concentrations of tissue factor as the activation method for thromboelastography was investigated in patients with haemophilia. We performed kaolin and tissue factor activated thromboelastography on blood from inhibitor and non-inhibitor patients with and without addition of rFVIIa and rFVIII. The results demonstrate that kaolin leads to a longer R, K and angle than the higher dilution of tissue factor (1:17 000) at baseline (no factor) and after addition of rFVIIa for both the inhibitor and non-inhibitor patients. Kaolin led to a longer R and K in comparison to a low dilution of tissue factor (1:42 000) following the addition of rFVIIa in the inhibitor patients. The longer R and K allows for better discrimination of the effects of rFVIIa thus making kaolin the most sensitive activation method in this setting. Thus kaolin activated thromboelastography should be considered an effective, perhaps the most effective, activator when utilizing thromboelastography to assess the effects of rFVIIa in haemophilia patients with inhibitors.


A two-photon fluorescent probe for ratiometric imaging of endogenous hypochlorous acid in live cells and tissues.
A fluorescent probe that enables ratiometric imaging of endogenous hypochlorous acid (HOCl) in cells and tissues by two-photon microscopy is developed based on a red-emitting acetyl-benzocoumarin (AcBC) dye. An oxathiolane group in the probe reacts with HOCl to generate the AcBC dye, which involves a ratiometric fluorescence change only toward HOCl along with high sensitivity.


Potentially harmful advantage to athletes: a putative connection between UGT2B17 gene deletion polymorphism and renal disorders with prolonged use of anabolic androgenic steroids.
With prolonged use of anabolic androgenic steroids (AAS), occasional incidents of renal disorders have been observed. Independently, it has also been established that there are considerable inter-individual and inter-ethnic differences, in particular with reference to the uridine diphosphate-glucuronosyltransferase 2B17 (UGT2B17) gene, in metabolising these compounds. This report postulates the association of deletion polymorphism in the UGT2B17 gene with the occurrence of renal disorders on chronic exposure to AAS. The major deactivation and elimination pathway of AASs is through glucuronide conjugation, chiefly catalyzed by the UGT2B17 enzyme, followed by excretion in urine. Excretion of steroids is affected in individuals with a deletion mutation in the UGT2B17 gene. We hypothesize that UGT2B17 deficient individuals are more vulnerable to developing renal disorders with prolonged use of AAS owing to increases in body mass index and possible direct toxic effects of steroids on the kidneys. Elevated serum levels of biologically active steroids due to inadequate elimination can lead to prolonged muscle build up. An increase in body mass index may cause renal injuries due to sustained elevated glomerular pressure and flow rate. In the absence of controlled clinical trials in humans, observational studies can be carried out. Real time PCR with allelic discrimination should be employed to examine the prevalence of different UGT2B17 genotypes in patients with impaired renal function and AAS abuse. In individuals with the UGT2B17 deletion polymorphism, blood tests, biofluid analyses, urinalysis, and hair analyses following the administration of an anabolic steroid can be used to determine the fate of the substance once in the body. If the hypothesis is upheld, anabolic steroid users with a deletion mutation in the UGT2B17 gene may be exposed to an increased risk of developing renal disorders. In the current detecting - sanctioning anti-doping system, athletes motivated by the potential to evade detection owing to their unique genetic make-up could subject themselves to a serious health consequence. More research on AAS metabolism in the presence of UGT2B17 gene deletion is required. Benefit - harm evaluations in therapeutic use of anabolic steroids should also consider this potential link between UGT2B17 gene deletion polymorphism and renal disorders.


Internal limiting membrane contrast after staining with indocyanine green and brilliant blue G during macular surgery.
To evaluate the difference in color contrast by performing a color contrast ratio (CR) analysis and resulting visibility of the internal limiting membrane (ILM) when stained with indocyanine green and brilliant blue G (BBG) during macular surgery by performing a color CR analysis. The authors analyzed 40 consecutive cases in which vitrectomy with ILM removal was performed to treat a macular hole or an epiretinal membrane. The surgical procedure was performed in 21 patients (21 eyes) after staining with indocyanine green and in 19 patients (19 eyes) after staining with BBG. The color CRs were estimated based on digital analysis of the red, green, and blue data of the digital images captured, and the CRs obtained with the two dyes were compared. Color contrast analysis was performed in all 40 eyes, in which the ILM was removed after staining with indocyanine green or BBG, and the CRs were estimated in every eye. The CR (mean ± SD) obtained with indocyanine green and BBG was 4.3 ± 0.3 and 2.4 ± 0.1, respectively. Indocyanine green provided a significantly higher CR than BBG (P = 0.015). Digital color contrast analysis can be used to evaluate the visibility of digital images, and it may be useful when choosing the dye to use for staining the ILM better.


Malignancy and mortality in a population-based cohort of patients with coeliac disease or "gluten sensitivity".
To determine the risk of malignancy and mortality in patients with a positive endomysial or anti-gliadin antibody test in Northern Ireland. A population-based retrospective cohort study design was used. Laboratory test results used in the diagnosis of coeliac disease were obtained from the Regional Immunology Laboratory, cancer statistics from the Northern Ireland Cancer Registry and mortality statistics from the General Registrar Office, Northern Ireland. Age standardized incidence ratios of malignant neoplasms and standardized mortality ratios of all-cause and cause-specific mortality were calculated. A total of 13 338 people had an endomysial antibody and/or an anti-gliadin antibody test in Northern Ireland between 1993 and 1996. There were 490 patients who tested positive for endomysial antibodies and they were assumed to have coeliac disease. There were 1133 patients who tested positive for anti-gliadin antibodies and they were defined as gluten sensitive. Malignant neoplasms were not significantly associated with coeliac disease; however, all-cause mortality was significantly increased following diagnosis. The standardized incidence and mortality ratios for non-Hodgkin's lymphoma were increased in coeliac disease patients but did not reach statistical significance. Lung and breast cancer incidence were significantly lower and all-cause mortality, mortality from malignant neoplasms, non-Hodgkin's lymphoma and digestive system disorders were significantly higher in gluten sensitive patients compared to the Northern Ireland population. Patients with coeliac disease or gluten sensitivity had higher mortality rates than the Northern Ireland population. This association persists more than one year after diagnosis in patients testing positive for anti-gliadin antibodies. Breast cancer is significantly reduced in the cohort of patients with gluten sensitivity.


Ecological genomics of tropical trees: how local population size and allelic diversity of resistance genes relate to immune responses, cosusceptibility to pathogens, and negative density dependence.
In tropical forests, rarer species show increased sensitivity to species-specific soil pathogens and more negative effects of conspecific density on seedling survival (NDD). These patterns suggest a connection between ecology and immunity, perhaps because small population size disproportionately reduces genetic diversity of hyperdiverse loci such as immunity genes. In an experiment examining seedling roots from six species in one tropical tree community, we found that smaller populations have reduced amino acid diversity in pathogen resistance (R) genes but not the transcriptome in general. Normalized R gene amino acid diversity varied with local abundance and prior measures of differences in sensitivity to conspecific soil and NDD. After exposure to live soil, species with lower R gene diversity had reduced defence gene induction, more cosusceptibility of maternal cohorts to colonization by potentially pathogenic fungi, reduced root growth arrest (an R gene-mediated response) and their root-associated fungi showed lower induction of self-defence (antioxidants). Local abundance was not related to the ability to induce immune responses when pathogen recognition was bypassed by application of salicylic acid, a phytohormone that activates defence responses downstream of R gene signalling. These initial results support the hypothesis that smaller local tree populations have reduced R gene diversity and recognition-dependent immune responses, along with greater cosusceptibility to species-specific pathogens that may facilitate disease transmission and NDD. Locally rare species may be less able to increase their equilibrium abundance without genetic boosts to defence via immigration of novel R gene alleles from a larger and more diverse regional population.


EphA2 receptor tyrosine kinase regulates endothelial cell migration and vascular assembly through phosphoinositide 3-kinase-mediated Rac1 GTPase activation.
Angiogenesis is critical for vascular remodeling during development and contributes to the pathogenesis of diseases such as cancer. Targeted disruption of several EphB class receptor tyrosine kinases results in vascular remodeling defects during embryogenesis. The role of EphA class receptors in vascular remodeling, however, is not well-characterized. We recently demonstrated that global inhibition of EphA receptors disrupts endothelial migration induced by ephrin, VEGF or tumor-derived signals, though the specific target remained undefined. Here, we report that EphA2 regulates endothelial cell assembly and migration through phosphoinositide (PI) 3-kinase-mediated activation of Rac1 GTPase in two model systems: primary bovine and murine pulmonary microvascular endothelial cells. EphA2-deficient endothelial cells fail to undergo vascular assembly and migration in response to ephrin-A1 in vitro. Ephrin-A1 stimulation induces PI3-kinase-dependent activation of Rac1 in wild-type endothelial cells, whereas EphA2-deficient cells fail to activate Rac1 upon stimulation. Expression of dominant negative PI3-kinase or Rac1 inhibits ephrin-A1-induced endothelial cell migration. Consistent with in vitro data, EphA2-deficient mice show a diminished angiogenic response to ephrin-A1 in vivo. Moreover, EphA2-deficient endothelial cells fail to assemble in vivo when transplanted into recipient mice. These data suggest that EphA2 is an essential regulator of post-natal angiogenesis.


Pride displays communicate self-interest and support for meritocracy.
The present studies examined how observers infer moral attributes and beliefs from nonverbal pride displays. Pride is a self-focused positive emotion triggered by appraisals of the self's success, status, and competence. We hypothesized that when a target emits nonverbal cues of pride, he or she will be viewed by observers as higher in self-interest and therefore more likely to endorse ideologies that would benefit the self-specifically, merit-based resource distributions (meritocracy) as opposed to equality-based resource distributions (egalitarianism). Across studies, experimentally manipulated pride displays (Studies 1 and 3) and naturally occurring expressions of pride (Study 4) led observers to infer heightened support for meritocracy as opposed to egalitarianism. Analyses also revealed that people intuitively associate higher self-interest with enhanced support for meritocracy as opposed to egalitarianism (Study 2), and this association mediates the pathway from pride displays to inferences of heightened support for meritocracy and reduced support for egalitarianism (Studies 3 and 4). Across studies, we compare pride to expressions of joy or no emotion and demonstrate these effects using thin slices as well as static images.


Negative Predictive Value of Multiparametric Magnetic Resonance Imaging in the Detection of Clinically Significant Prostate Cancer in the Prostate Imaging Reporting and Data System Era: A Systematic Review and Meta-analysis.
Prebiopsy multiparametric magnetic resonance imaging (mpMRI) is increasingly used in prostate cancer diagnosis. The reported negative predictive value (NPV) of mpMRI is used by some clinicians to aid in decision making about whether or not to proceed to biopsy. We aim to perform a contemporary systematic review that reflects the latest literature on optimal mpMRI techniques and scoring systems to update the NPV of mpMRI for clinically significant prostate cancer (csPCa). We conducted a systematic literature search and included studies from 2016 to September 4, 2019, which assessed the NPV of mpMRI for csPCa, using biopsy or clinical follow-up as the reference standard. To ensure that studies included in this analysis reflect contemporary practice, we only included studies in which mpMRI findings were interpreted according to the Prostate Imaging Reporting and Data System (PIRADS) or similar Likert grading system. We define negative mpMRI as either (1) PIRADS/Likert 1-2 or (2) PIRADS/Likert 1-3; csPCa was defined as either (1) Gleason grade group ≥2 or (2) Gleason grade group ≥3. We calculated NPV separately for each combination of negative mpMRI and csPCa. A total of 42 studies with 7321 patients met our inclusion criteria and were included for analysis. Using definition (1) for negative mpMRI and csPCa, the pooled NPV for biopsy-naïve men was 90.8% (95% confidence interval [CI] 88.1-93.1%). When defining csPCa using definition (2), the NPV for csPCa was 97.1% (95% CI 94.9-98.7%). Calculation of the pooled NPV using definition (2) for negative mpMRI and definition (1) for csPCa yielded the following: 86.8% (95% CI 80.1-92.4%). Using definition (2) for both negative mpMRI and csPCa, the pooled NPV from two studies was 96.1% (95% CI 93.4-98.2%). Multiparametric MRI of the prostate is generally an accurate test for ruling out csPCa. However, we observed heterogeneity in the NPV estimates, and local institutional data should form the basis of decision making if available. The negative predictive values should assist in decision making for clinicians considering not proceeding to biopsy in men with elevated age-specific prostate-specific antigen and multiparametric magnetic resonance imaging reported as negative (or equivocal) on Prostate Imaging Reporting and Data System/Likert scoring. Some 7-10% of men, depending on the setting, will miss a diagnosis of clinically significant cancer if they do not proceed to biopsy. Given the institutional variation in results, it is of upmost importance to base decision making on local data if available.


Cyclical expression of the Notch/Wnt regulator Nrarp requires modulation by Dll3 in somitogenesis.
Delta-like 3 (Dll3) is a divergent ligand and modulator of the Notch signaling pathway only identified so far in mammals. Null mutations of Dll3 disrupt cycling expression of Notch targets Hes1, Hes5, and Lfng, but not of Hes7. Compared with Dll1 or Notch1, the effects of Dll3 mutations are less severe for gene expression in the presomitic mesoderm, yet severe segmentation phenotypes and vertebral defects result in both human and mouse. Reasoning that Dll3 specifically disrupts key regulators of somite cycling, we carried out functional analysis to identify targets accounting for the segmental phenotype. Using microdissected embryonic tissue from somitic and presomitic mesodermal tissue, we identified new genes enriched in these tissues, including Limch1, Rhpn2, and A130022J15Rik. Surprisingly, we only identified a small number of genes disrupted by the Dll3 mutation. These include Uncx, a somite gene required for rib and vertebral patterning, and Nrarp, a regulator of Notch/Wnt signaling in zebrafish and a cycling gene in mouse. To determine the effects of Dll3 mutation on Nrarp, we characterized the cycling expression of this gene from early (8.5 dpc) to late (10.5 dpc) somitogenesis. Nrarp displays a distinct pattern of cycling phases when compared to Lfng and Axin2 (a Wnt pathway gene) at 9.5 dpc but appears to be in phase with Lfng by 10.5 dpc. Nrarp cycling appears to require Dll3 but not Lfng modulation. In Dll3 null embryos, Nrarp displayed static patterns. However, in Lfng null embryos, Nrarp appeared static at 8.5 dpc but resumed cycling expression by 9.5 and dynamic expression at 10.5 dpc stages. By contrast, in Wnt3a null embryos, Nrarp expression was completely absent in the presomitic mesoderm. Towards identifying the role of Dll3 in regulating somitogenesis, Nrarp emerges as a potentially important regulator that requires Dll3 but not Lfng for normal function.


Pineal opsin: a nonvisual opsin expressed in chick pineal.
Pineal opsin (P-opsin), an opsin from chick that is highly expressed in pineal but is not detectable in retina, was cloned by the polymerase chain reaction. It is likely that the P-opsin lineage diverged from the retinal opsins early in opsin evolution. The amino acid sequence of P-opsin is 42 to 46 percent identical to that of the retinal opsins. P-opsin is a seven-membrane spanning, G protein-linked receptor with a Schiff-base lysine in the seventh membrane span and a Schiff-base counterion in the third membrane span. The primary sequence of P-opsin suggests that it will be maximally sensitive to approximately 500-nanometer light and produce a slow and prolonged phototransduction response consistent with the nonvisual function of pineal photoreception.


Temporal dynamics of emotional responding: amygdala recovery predicts emotional traits.
An individual's affective style is influenced by many things, including the manner in which an individual responds to an emotional challenge. Emotional response is composed of a number of factors, two of which are the initial reactivity to an emotional stimulus and the subsequent recovery once the stimulus terminates or ceases to be relevant. However, most neuroimaging studies examining emotional processing in humans focus on the magnitude of initial reactivity to a stimulus rather than the prolonged response. In this study, we use functional magnetic resonance imaging to study the time course of amygdala activity in healthy adults in response to presentation of negative images. We split the amygdala time course into an initial reactivity period and a recovery period beginning after the offset of the stimulus. We find that initial reactivity in the amygdala does not predict trait measures of affective style. Conversely, amygdala recovery shows predictive power such that slower amygdala recovery from negative images predicts greater trait neuroticism, in addition to lower levels of likability of a set of social stimuli (neutral faces). These data underscore the importance of taking into account temporal dynamics when studying affective processing using neuroimaging.


Brain mechanisms of expectation associated with insula and amygdala response to aversive taste: implications for placebo.
The experience of aversion is shaped by multiple physiological and psychological factors including one's expectations. Recent work has shown that expectancy manipulation can alter perceptions of aversive events and concomitant brain activation. Accruing evidence indicates a primary role of altered expectancies in the placebo effect. Here, we probed the mechanism by which expectation attenuates sensory taste transmission by examining how brain areas activated by misleading information during an expectancy period modulate insula and amygdala activation to a highly aversive bitter taste. In a rapid event-related fMRI design, we showed that activations in the rostral anterior cingulate cortex (rACC), orbitofrontal cortex (OFC), and dorsolateral prefrontal cortex to a misleading cue that the taste would be mildly aversive predicted decreases in insula and amygdala activation to the highly aversive taste. OFC and rACC activation to the misleading cue were also associated with less aversive ratings of that taste. Additional analyses revealed consistent results demonstrating functional connectivity among the OFC, rACC, and insula. Altering expectancies of upcoming aversive events are shown here to depend on robust functional associations among brain regions implicated in prior work on the placebo effect.


Protective effect of Foeniculum vulgare essential oil and anethole in an experimental model of thrombosis.
In a previous screening work, Foeniculum vulgare essential oil emerged from a pool of 24 essential oils for its antiplatelet properties and its ability to destabilize the retraction of the coagulum. In the present work the main component of the oil, anethole, tested in guinea pig plasma was as potent as fennel oil in inhibiting arachidonic acid-, collagen-, ADP- and U46619-induced aggregation (IC(50) from 4 to 147 microg ml(-1)). It also prevented thrombin-induced clot retraction at concentrations similar to fennel oil. The essential oil and anethole, tested in rat aorta with or without endothelium, displayed comparable NO-independent vasorelaxant activity at antiplatelet concentrations which have been proved to be free from cytotoxic effects in vitro. In vivo, both F. vulgare essential oil and anethole orally administered in a subacute treatment to mice (30 mg kg(-1)day(-1) for 5 days) showed significant antithrombotic activity preventing the paralysis induced by collagen-epinephrine intravenous injection (70% and 83% protection, respectively). At the antithrombotic dosage they were free from prohemorrhagic side effect at variance with acetylsalicylic acid used as reference drug. Furthermore, both F. vulgare essential oil and anethole (100 mg kg(-1) oral administration) provided significant protection toward ethanol induced gastric lesions in rats. In conclusion, these results demonstrate for F. vulgare essential oil, and its main component anethole, a safe antithrombotic activity that seems due to their broad spectrum antiplatelet activity, clot destabilizing effect and vasorelaxant action.


Trends in incident hemodialysis access and mortality.
Based on evidence of survival benefit when initiating hemodialysis (HD) via arteriovenous fistula (AVF) or arteriovenous graft (AVG) vs hemodialysis catheter (HC), the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative published practice guidelines in 1997 recommending 50% or greater AVF rates in incident HD patients. A decade after, lapses exist and the impact on HD outcomes is uncertain. To assess the achievement of the practice goals for incident vascular access and the effects on HD outcomes. This retrospective cohort study was conducted using the US Renal Data System. All patients with end-stage renal disease in the United States without prior renal replacement therapy who had incident vascular access for HD created between January 1, 2006, and December 31, 2010 (N = 510 000) were included. Incident vascular access use rates and mortality. Relative mortality was quantified using multivariable Cox proportional hazard models. Coarsened exact matching and propensity score-matching techniques were used to better account for confounding by indication. Of 510 000 patients included in this study, 82.6% initiated HD via HC, 14.0% via AVF, and 3.4% via AVG. Arteriovenous fistula use increased only minimally, from 12.2% in 2006 to 15.0% in 2010. Patients initiating HD with AVF had 35% lower mortality than those with HC (adjusted hazard ratio, 0.65; 95% CI, 0.64-0.66; P < .001). Those initiating HD with AVF had 23% lower mortality than those initiating with an HC while awaiting maturation of an AVF (adjusted hazard ratio, 0.77; 95% CI, 0.76-0.79; P < .001). Current incident AVF practice falls exceedingly short years after recommendations were made in 1997. The impact of this shortcoming on mortality for patients with end-stage renal disease is enormous. Functioning permanent access at initiation of HD confers lower mortality even compared with patients temporized with an HC while awaiting maturation of permanent access. A change of current policies and structured multidisciplinary efforts are required to establish matured fistulae prior to HD to ameliorate this deficit in delivering care.


Reduced levels of neuraminidase of influenza A viruses correlate with attenuated phenotypes in mice.
We have previously obtained four transfectant influenza A viruses containing neuraminidase (NA) genes with mutated base pairs in the conserved double-stranded RNA region of the viral promoter by using a ribonucleoprotein transfection system. Two mutant viruses (D2 and D1/2) which share a C-G-->A-U mutation at positions 11 and 12 of the 3' and 5' ends, respectively, of the NA gene, showed an approximate 10-fold reduction of NA-specific mRNA and protein levels (Fodor et al., Journal of Virology 72, 6283-6290, 1998). These viruses have now allowed us to determine the effects of decreased NA levels on virus pathogenicity. Both D2 and D1/2 viruses were highly attenuated in mice, and their replication in mouse lungs was highly compromised as compared with wild-type influenza A/WSN/33 virus. The results highlight the importance of the level of NA activity in the biological cycle and virulence of influenza viruses. Importantly, mice immunized by a single intranasal administration of 10(3) infectious units of D2 or D1/2 viruses were protected against challenge with a lethal dose of wild-type influenza virus. Attenuation of influenza viruses by mutations resulting in the decreased expression of a viral protein represents a novel strategy which could be considered for the generation of live attenuated influenza virus vaccines.


Mechanoreceptors distribution in the human medial collateral ligament of the elbow.
The human elbow maintains its stability mainly through its bony structure. Stability is enhanced by ligamentous structures. To allow the ligamento-muscular reflex, which protects against strain and stress, mechanoreceptors are embedded in the ligament. This report describes the existence and the distribution of the elbow medial collateral ligaments (MCLs) mechanoreceptors. The bony attachment site has the highest density of mechanoreceptors, and the anterior part has the highest density of mechanoreceptors. Eight MCLs of elbow from fresh frozen cadavers were used. The MCLs were harvested deep to the periosteum from the medial epicondyle to the ulna. The fan-shaped ligaments were divided into six regions of interest (ROI) and stained with modified gold chloride stain. Specimens were evaluated under a light microscope. Golgi, Ruffini, and Pacinian corpuscles were found in every specimen. The number and the distribution of each mechanoreceptor in each ROI were recorded. The density of each mechanoreceptor was calculated in regards to its volume. Golgi, Ruffini, and Pacinian corpuscles were seen in the ligament with small nerve fibers. Ruffini corpuscles had the highest median density of all three corpuscles. The median corpuscle density was higher in the anterior than in the posterior part and higher in the bony attachment than in the mid-substance site except for Golgi corpuscle. The three typical types of mechanoreceptors were identified in human MCL with the anterior part and bony attachment as the dominant distribution site. Basic Science Study.


Successful transmission and transcriptional deployment of a human chromosome via mouse male meiosis.
Most human aneuploidies originate maternally, due in part to the presence of highly stringent checkpoints during male meiosis. Indeed, male sterility is common among aneuploid mice used to study chromosomal abnormalities, and male germline transmission of exogenous DNA has been rarely reported. Here we show that, despite aberrant testis architecture, males of the aneuploid Tc1 mouse strain produce viable sperm and transmit human chromosome 21 to create aneuploid offspring. In these offspring, we mapped transcription, transcriptional initiation, enhancer activity, non-methylated DNA, and transcription factor binding in adult tissues. Remarkably, when compared with mice derived from female passage of human chromosome 21, the chromatin condensation during spermatogenesis and the extensive epigenetic reprogramming specific to male germline transmission resulted in almost indistinguishable patterns of transcriptional deployment. Our results reveal an unexpected tolerance of aneuploidy during mammalian spermatogenesis, and the surprisingly robust ability of mouse developmental machinery to accurately deploy an exogenous chromosome, regardless of germline transmission.


A histological positive margin after surgery is correlated with high local re-recurrence rate in patients with recurrent myxofibrosarcoma.
Myxofibrosarcoma has high frequency of local recurrence after surgery. To determine an optimal treatment for recurrent tumors, clinical features of recurrent cases should be characterized. We performed a retrospective analysis of 30 patients with recurrent myxofibrosarcoma who underwent surgery between 1999 and 2008. A negative margin after surgery was achieved in only 12 patients (40.0%). The 5-year re-recurrence free-survival rate was 31.7%. The 5-year re-recurrence free survival for those with positive histological margin and those with negative margin were 9.8% and 62.3%, respectively, which indicated that a positive margin was the significant predictor of poor prognosis (P = 0.006). In 21 patients with recurrent myxofibrosarcoma in the extremities, 10 patients (47.6%) ultimately underwent amputation in the follow-up period and the 5-year amputation-free survival rate was 62.5%. The 5-year metastasis-free survival rates and the 5-year overall survival rates were 84.8% and 83.6%, respectively. In this study, the majority of recurrent cases could not achieve negative margins; notably, a positive margin is a significant poor prognostic indicator of local re-recurrence in patients with recurrent myxofibrosarcoma. To control local recurrence of myxofibrosarcoma was extremely difficult and amputation is often needed in the extremity cases.


Incidence of metal sensitivity in patients with total joint replacements.
Sensitivity to chromium, cobalt, nickel, molybdenum, vanadium, and titanium was studied by patch tests in 50 patients who had received total joint replacements. Nineteen (38%) were sensitive to one or more of the metals. In 23 patients non-traumatic failure of the prosthesis had occurred, and 15 of these patients were sensitive to metal. Out of 27 patients with no evidence of prosthesis loosening, four were sensitive to nickel and cobalt or nickel only. Dermatological reactions occurred in 13 patients after surgery; in only eight, however, was there evidence of metal sensitivity. These findings indicate that metal-on-metal total joint replacements may sensitise the patient to metals contained in the prosthesis. Although there is a high incidence of prosthesis failure among metal-sensitive patients it remains uncertain whether the loosening causes the sensitisation or vice versa.


A large nosocomial outbreak of hepatitis C virus infections at a hemodialysis center.
To identify modes of HCV transmission during an outbreak of HCV infection in a hemodialysis unit. An epidemiologic study, virologic analysis, assessment of infection control practices and procedures, and technical examination of products and dialysis machines. A private hemodialysis unit treating approximately 70 patients. Detection of HCV RNA by PCR was performed among patients receiving dialysis in 2001. Case-patients were patients who had a first positive result for HCV RNA between January 2001 and January 2002 and either acute hepatitis, a seroconversion for HCV antibodies, or a previous negative result. Three control-patients were randomly selected per case-patient. Of the 61 patients treated in the unit in 2001 and not infected with HCV, 22 (36.1%) became case-patients with onset from May 2001 to January 2002 for an incidence density rate of 70 per 100 patient-years. Phylogenic analysis identified four distinct HCV groups and an index case-patient for each with a similar virus among patients already known to be infected. No multidose medication vials or material was shared between patients. Connection to a dialysis machine by a nurse who had connected an HCV-infected patient "just before" or "one patient before" increased the risk of HCV infection, whereas using the same dialysis machine after a patient infected with HCV did not. Understaffing, lack of training, and breaches in infection control were documented. Direct observation of practices revealed frequent flooding of blood into the double filter on the arterial pressure tubing set. During this outbreak, HCV transmission was mainly patient to patient via healthcare workers' hands. However, transmission via dialysis machines because of possible contamination of internal components could not be excluded.


Quantifying the health impacts of air pollution under a changing climate-a review of approaches and methodology.
Climate change has been predicted to affect future air quality, with inevitable consequences for health. Quantifying the health effects of air pollution under a changing climate is crucial to provide evidence for actions to safeguard future populations. In this paper, we review published methods for quantifying health impacts to identify optimal approaches and ways in which existing challenges facing this line of research can be addressed. Most studies have employed a simplified methodology, while only a few have reported sensitivity analyses to assess sources of uncertainty. The limited investigations that do exist suggest that examining the health risk estimates should particularly take into account the uncertainty associated with future air pollution emissions scenarios, concentration-response functions, and future population growth and age structures. Knowledge gaps identified for future research include future health impacts from extreme air pollution events, interactions between temperature and air pollution effects on public health under a changing climate, and how population adaptation and behavioural changes in a warmer climate may modify exposure to air pollution and health consequences.


Generation of high curvature membranes mediated by direct endophilin bilayer interactions.
Endophilin 1 is a presynaptically enriched protein which binds the GTPase dynamin and the polyphosphoinositide phosphatase synptojanin. Perturbation of endophilin function in cell-free systems and in a living synapse has implicated endophilin in endocytic vesicle budding (Ringstad, N., H. Gad, P. Low, G. Di Paolo, L. Brodin, O. Shupliakov, and P. De Camilli. 1999. Neuron. 24:143-154; Schmidt, A., M. Wolde, C. Thiele, W. Fest, H. Kratzin, A.V. Podtelejnikov, W. Witke, W.B. Huttner, and H.D. Soling. 1999. Nature. 401:133-141; Gad, H., N. Ringstad, P. Low, O. Kjaerulff, J. Gustafsson, M. Wenk, G. Di Paolo, Y. Nemoto, J. Crun, M.H. Ellisman, et al. 2000. Neuron. 27:301-312). Here, we show that purified endophilin can directly bind and evaginate lipid bilayers into narrow tubules similar in diameter to the neck of a clathrin-coated bud, providing new insight into the mechanisms through which endophilin may participate in membrane deformation and vesicle budding. This property of endophilin is independent of its putative lysophosphatydic acid acyl transferase activity, is mediated by its NH2-terminal region, and requires an amino acid stretch homologous to a corresponding region in amphiphysin, a protein previously shown to have similar effects on lipid bilayers (Takei, K., V.I. Slepnev, V. Haucke, and P. De Camilli. 1999. Nat. Cell Biol. 1:33-39). Endophilin cooligomerizes with dynamin rings on lipid tubules and inhibits dynamin's GTP-dependent vesiculating activity. Endophilin B, a protein with homology to endophilin 1, partially localizes to the Golgi complex and also deforms lipid bilayers into tubules, underscoring a potential role of endophilin family members in diverse tubulovesicular membrane-trafficking events in the cell.


Pattern of melatonin secretion mediates transfer of photoperiod information from mother to fetus in mammals.
Studies performed over the past 20 years have revealed that mother rodents can provide photoperiod information to their developing fetuses. In adult mammals, the pattern of pineal melatonin secretion changes in relation to changes in day length, and the melatonin pattern is a key part of the photoperiodic mechanism. Melatonin crosses the placenta, and fetal rodents can respond to the maternal melatonin rhythm. Thus, the mother's melatonin rhythm provides day-length information to the fetus, and this information is used, along with photoperiod information that is obtained after birth, to influence juvenile development. The transfer of photoperiod information from mother to fetus may be part of an adaptive system. When young are born early in the spring or summer breeding season, the increase in day length between the times of fetal and postnatal life results in rapid reproductive maturation, allowing these early-born animals to reproduce later during the same breeding season. In contrast, for young born late in the breeding season, the decrease in photoperiod between fetal and postnatal life results in delayed maturation of the gonads, and reproduction is delayed until the beginning of the next year's breeding season.


Incidence of insomnia and obstructive sleep apnea in active duty United States military service members.
Epidemiologic studies of obstructive sleep apnea (OSA) and insomnia in the U.S. military are limited. The primary aim of this study was to report and compare OSA and insomnia diagnoses in active duty the United States military service members. Data and service branch densities used to derive the expected rates of diagnoses on insomnia and OSA were drawn from the Defense Medical Epidemiology Database. Single sample chi-square goodness of fit tests and independent samples t-tests were conducted to address the aims of the study. Between 2005 and 2019, incidence rates of OSA and insomnia increased from 11 to 333 and 6 to 272 (per 10,000), respectively. Service members in the Air Force, Navy, and Marines were diagnosed with insomnia and OSA below expected rates, while those in the Army had higher than expected rates (p < .001). Female service members were underdiagnosed in both disorders (p < .001). Comparison of diagnoses following the transition from ICD 9 to 10 codes revealed significant differences in the amounts of OSA diagnoses only (p < .05). Since 2005, incidence rates of OSA and insomnia have markedly increased across all branches of the U.S. military. Despite similar requirements for overall physical and mental health and resilience, service members in the Army had higher rates of insomnia and OSA. This unexpected finding may relate to inherent differences in the branches of the military or the role of the Army in combat operations. Future studies utilizing military-specific data and directed interventions are required to reverse this negative trend.


Evidence for geographic isolation and signs of endemism within a protistan morphospecies.
The possible existence of endemism among microorganisms resulting from and preserved by geographic isolation is one of the most controversial topics in microbial ecology. We isolated 31 strains of "Spumella-like" flagellates from remote sampling sites from all continents, including Antarctica. These and another 23 isolates from a former study were characterized morphologically and by small-subunit rRNA gene sequence analysis and tested for the maximum temperature tolerance. Only a minority of the Spumella morpho- and phylotypes from the geographically isolated Antarctic continent follow the worldwide trend of a linear correlation between ambient (air) temperature during strain isolation and heat tolerance of the isolates. A high percentage of the Antarctic isolates, but none of the isolates from locations on all other continents, were obligate psychrophilic, although some of the latter were isolated at low ambient temperatures. The drastic deviation of Antarctic representatives of Spumella from the global trend of temperature adaptation of this morphospecies provides strong evidence for geographic transport restriction of a microorganism; i.e., Antarctic protistan communities are less influenced by transport of protists to and from the Antarctic continent than by local adaptation, a subtle form of endemism.


Quantitative structure-activity relationships for green algae growth inhibition by polymer particles.
After use and disposal of chemical products, many types of polymer particles end up in the aquatic environment with potential toxic effects to primary producers like green algae. In this study, we have developed Quantitative Structure-Activity Relationships (QSARs) for a set of highly structural diverse polymers which are capable to estimate green algae growth inhibition (EC50). The model (N = 43, R2 = 0.73, RMSE = 0.28) is a regression-based decision tree using one structural descriptor for each of three polymer classes separated based on charge. The QSAR is applicable to linear homo polymers as well as copolymers and does not require information on the size of the polymer particle or underlying core material. Highly branched polymers, non-nitrogen cationic polymers and polymeric surfactants are not included in the model and thus cannot be evaluated. The model works best for cationic and non-ionic polymers for which cellular adsorption, disruption of the cell wall and photosynthesis inhibition were the mechanisms of action. For anionic polymers, specific properties of the polymer and test characteristics need to be known for detailed assessment. The data and QSAR results for anionic polymers, when combined with molecular dynamics simulations indicated that nutrient depletion is likely the dominant mode of toxicity. Nutrient depletion in turn, is determined by the non-linear interplay between polymer charge density and backbone flexibility.


Functional, electrophysiologic, and morphometric evaluation of nerve regeneration from coaptation on regenerated nerve fibers: experimental study in rabbits.
The importance of a sufficient number of nerve fibers at a proximal coaptation site is indisputable for the successful repair of nerves; however, the quality of nerve fibers required at this site has yet to be defined. The present study deals with the question of whether it is necessary to trim nerves back to unaffected neuronal tissue or whether the coaptation on recently regenerated nerve fibers, commonly believed to produce a poor quality of repair can, in fact, produce adequate nerve regeneration. Twenty New Zealand White rabbits received a standardized crush lesion on the peroneal nerves of both hind legs. Four weeks later, the nerves of the left hind legs (n = 20) were transected 10 mm distal to the previous crush lesion and coapted to the freshly regenerated nerve fibers. For comparison, on 10 right hind legs, the nerves were transected at the site of previous crushing (Group A, superimposition) or 10 mm proximal to the site of crushing on unscathed nerve fibers (Group B). Eleven weeks later, the quality of nerve regeneration was assessed by the toe-spreading reflex, electrophysiologic data, muscle weight, and histomorphologic evaluation. In the animals of Group A, the quality of nerve regeneration following coaptation on the regrown axons did not differ in any of the examined parameters from the quality of nerve fibers outgrown from the site of the superimposed lesion. Both lesions led to a completely functional reinnervation. Also in Group B, nerve action potential recording and histologic data on both sides did not reveal a significant difference between the number and maturation of nerve fibers equidistant from the suture site, shortly before muscle entrance. With this coaptation model, it could be demonstrated in the peroneal nerve of rabbits, that coaptation to recently regenerated nerve fibers leads to a significant functional regeneration.


Event-related brain dynamics.
Event-related potentials (ERPs) provide evidence of a direct link between cognitive events and brain electrical activity in a wide range of cognitive paradigms. It has generally been held that an ERP is the result of a set of discrete stimulus-evoked brain events. A recent study, however, provides new evidence to suggest that some ERP components might be generated by stimulus-induced changes in ongoing brain dynamics. This is consistent with views emerging from several neuroscientific fields, suggesting that phase synchronization of ongoing rhythms across different spatio-temporal scales mediates the functional integration necessary to perform higher cognitive tasks.


Identity Development and Forgivingness: Tests of Basic Relations and Mediational Pathways.
Adaptive identity development leads to increases in personality traits that allow for social well-being. The current study tested this claim with respect to forgivingness, a dispositional tendency to forgive others. In a sample of university undergraduates (N = 214), we examined the relations between forgivingness and two indicators of identity development: commitment and exploration. Forgivingness uniquely positively related with both identity variables, controlling for the other. Next, we tested mediational models to examine the mechanisms underlying these relationships. Our results suggest that, in part, the association between identity development and forgivingness is mediated by levels of agreeableness and neuroticism, as measured by the Big Five Inventory.


Channeling of fusion alpha-particle power using minority ion catalysis.
Maintaining fuel ions hotter than electrons would greatly facilitate controlled nuclear fusion. The parameter range for achieving this temperature disparity is shown here to be enhanced by catalyzing the α-channeling effect (wave-induced simultaneous expulsion and cooling of α particles) through minority-ion heating. Specifically, a wave can extract energy from hot α particles and transfer it to colder minority ions, which act as a catalyst, eventually forwarding the energy to still colder fuel ions through collisions. In comparison with the traditional α-channeling mechanism, the requirements are thereby relaxed on the waves that accomplish the α channeling, which no longer have to interact simultaneously with α particles and fuel ions. Numerical simulations illustrate how the new scheme may increase, for example, the effective fusion reactivity of mirror-confined plasmas.


The Dutch version of the Oxford Cognitive Screen (OCS-NL): normative data and their association with age and socio-economic status.
The Oxford Cognitive Screen (OCS) is a screening tool designed for stroke patients, assessing attention, executive functions, language, praxis, numeric cognition and memory. Here we present norms for the two parallel versions of the Dutch OCS (OCS-NL, acquired in 246 participants for version A and a subset of 179 participants for version B. We evaluated the association of age and socio-economic status (i.e. education, income, occupation) with OCS-NL performance There were no systematic performance differences between income groups, nor between manual and non-manual workers. There were small differences between education groups. The association of education and performance did not vary across subtests. The association of age and performance varied across subtests, with the strongest associations for the naming, praxis, verbal memory and executive task. Thus, OCS-NL norms do not need to be stratified on income and occupation and age-specific norms are recommended for some subtests.


Electrostatic interaction of particles trapped at fluid interfaces: effects of geometry and wetting properties.
The electrostatic interaction between pairs of spherical or macroscopically long, parallel cylindrical colloids trapped at fluid interfaces is studied theoretically for the case of small inter-particle separations. Starting from the effective interaction between two planar walls and by using the Derjaguin approximation, we address the issue of how the electrostatic interaction between such particles is influenced by their curvatures and by the wetting contact angle at their surfaces. Regarding the influence of curvature, our findings suggest that the discrepancies between linear and nonlinear Poisson-Boltzmann theory, which have been noticed before for planar walls, also occur for spheres and macroscopically long, parallel cylinders, though their magnitude depends on the wetting contact angle. Concerning the influence of the wetting contact angle θ simple relations are obtained for equally sized particles which indicate that the inter-particle force varies significantly with θ only within an interval around 90°. This interval depends on the Debye length of the fluids and on the size of the particles but not on their shape. For unequally sized particles, a more complicated relation is obtained for the variation of the inter-particle force with the wetting contact angle.


Animal Farm: Considerations in Animal Gastrointestinal Physiology and Relevance to Drug Delivery in Humans.
"All animals are equal, but some are more equal than others" was the illustrious quote derived from British writer George Orwell's famed work, Animal Farm. Extending beyond the remit of political allegory, however, this statement would appear to hold true for the selection of appropriate animal models to simulate human physiology in preclinical studies. There remain definite gaps in our current knowledge with respect to animal physiology, notably those of intra- and inter-species differences in gastrointestinal (GI) function, which may affect oral drug delivery and absorption. Factors such as cost and availability have often influenced the choice of animal species without clear justification for their similarity to humans, and lack of standardization in techniques employed in past studies using various animals may also have contributed to the generation of contradictory results. As it stands, attempts to identify a single animal species as appropriately representative of human physiology and which may able to adequately simulate human in vivo conditions are limited. In this review, we have compiled and critically reviewed data from numerous studies of GI anatomy and physiology of various animal species commonly used in drug delivery modeling, commenting on the appropriateness of these animals for in vivo comparison and extrapolation to humans.


Nutrients versus emerging contaminants-Or a dynamic match between subsidy and stress effects on stream biofilms.
Freshwater ecosystems are threatened by multiple anthropogenic stressors, which might be differentiated into two types: those that reduce biological activity at all concentrations (toxic contaminants), and those that subsidize biological activity at low concentrations and reduce it at high concentrations (assimilable contaminants). When occurring in mixtures, these contaminants can have either antagonistic, neutral or synergistic effects; but little is known on their joint effects. We assessed the interaction effects of a mixture of assimilable and toxic contaminants on stream biofilms in a manipulative experiment using artificial streams, and following a factorial design with three nutrient levels (low, medium or high) and either presence or absence of a mixture of emerging contaminants (ciprofloxacin, erythromycin, diclofenac, methylparaben, and sulfamethoxazole). We measured biofilm biomass, basal fluorescence, gross primary production and community respiration. Our initial hypotheses were that biofilm biomass and activity would: increase with medium nutrient concentrations (subsidy effect), but decrease with high nutrient concentrations (stress effect) (i); decrease with emerging contaminants, with the minimum decrease at medium nutrient concentrations (antagonistic interaction between nutrients subsidy and stress by emerging contaminants) and the maximum decrease at high nutrient concentrations (synergistic interaction between nutrients and emerging contaminants stress) (ii). All the measured variables responded linearly to the available nutrients, with no toxic effect at high nutrient concentrations. Emerging contaminants only caused weak toxic effects in some of the measured variables, and only after 3-4 weeks of exposure. Therefore, only antagonistic interactions were observed between nutrients and emerging contaminants, as medium and high nutrient concentrations partly compensated the harmful effects of emerging contaminants during the first weeks of the experiment. Our results show that contaminants with a subsidy effect can alleviate the effects of toxic contaminants, and that long-term experiments are required to detect stress effects of emerging contaminants at environmentally relevant concentrations.