Protective Effects of Crocus Sativus L. Extract and Crocin against Chronic-Stress Induced Oxidative Damage of Brain, Liver and Kidneys in Rats.
Chronic stress has been reported to induce oxidative damage of the brain. A few studies have shown that Crocus Sativus L., commonly known as saffron and its active constituent crocin may have a protective effect against oxidative stress. The present work was designed to study the protective effects of saffron extract and crocin on chronic - stress induced oxidative stress damage of the brain, liver and kidneys. Rats were injected with a daily dose of saffron extract (30 mg/kg, IP) or crocin (30 mg/kg, IP) during a period of 21 days following chronic restraint stress (6 h/day). In order to determine the changes of the oxidative stress parameters following chronic stress, the levels of the lipid peroxidation product, malondialdehyde (MDA), the total antioxidant reactivity (TAR), as well as antioxidant enzyme activities glutathione peroxidase (GPx), glutathione reductase (GR) and superoxide dismutase (SOD) were measured in the brain, liver and kidneys tissues after the end of chronic stress. In the stressed animals that receiving of saline, levels of MDA, and the activities of GPx, GR, and SOD were significantly higher (P<0.0001) and the TAR capacity were significantly lower than those of the non-stressed animals (P<0.0001). Both saffron extract and crocin were able to reverse these changes in the stressed animals as compared with the control groups (P<0.05). These observations indicate that saffron and its active constituent crocin can prevent chronic stress-induced oxidative stress damage of the brain, liver and kidneys and suggest that these substances may be useful against oxidative stress.


Selective pressures on genomes in molecular evolution.
We describe the evolution of macromolecules as an information transmission process and apply tools from Shannon information theory to it. This allows us to isolate three independent, competing selective pressures that we term compression, transmission, and neutrality selection. The first two affect genome length: the pressure to conserve resources by compressing the code, and the pressure to acquire additional information that improves the channel, increasing the rate of information transmission into each offspring. Noisy transmission channels (replication with mutations) give rise to a third pressure that acts on the actual encoding of information; it maximizes the fraction of mutations that are neutral with respect to the phenotype. This neutrality selection has important implications for the evolution of evolvability. We demonstrate each selective pressure in experiments with digital organisms.


Phytophthora infestans effector SFI3 targets potato UBK to suppress early immune transcriptional responses.
The potato blight agent Phytophthora infestans secretes a range of RXLR effectors to promote disease. Recent evidence indicates that some effectors suppress early pattern-triggered immunity (PTI) following perception of microbe-associated molecular patterns (MAMPs). Phytophthora infestans effector PiSFI3/Pi06087/PexRD16 has been previously shown to suppress MAMP-triggered pFRK1-Luciferase reporter gene activity. How PiSFI3 suppresses immunity is unknown. We employed yeast-two-hybrid (Y2H) assays, co-immunoprecipitation, transcriptional silencing by RNA interference and virus-induced gene silencing (VIGS), and X-ray crystallography for structure-guided mutagenesis, to investigate the function of PiSFI3 in targeting a plant U-box-kinase protein (StUBK) to suppress immunity. We discovered that PiSFI3 is active in the host nucleus and interacts in yeast and in planta with StUBK. UBK is a positive regulator of specific PTI pathways in both potato and Nicotiana benthamiana. Importantly, it contributes to early transcriptional responses that are suppressed by PiSFI3. PiSFI3 forms an unusual trans-homodimer. Mutation to disrupt dimerization prevents nucleolar localisation of PiSFI3 and attenuates both its interaction with StUBK and its ability to enhance P. infestans leaf colonisation. PiSFI3 is a 'WY-domain' RXLR effector that forms a novel trans-homodimer which is required for its ability to suppress PTI via interaction with the U-box-kinase protein StUBK.


Self-referenced photonic molecule bio(chemical)sensor.
We report a new type of optical biosensor capable of differentiating between bulk and surface perturbations of the ambient refractive index as well as between specific and nonspecific binding of molecules on the sensor surface. The proposed detection scheme is based on tracking the shifts of hybridized bonding and antibonding optical modes in coupled optical microcavities (photonic molecules). We demonstrate that by using two measurements of spectral shifts it is possible to discriminate between surface and volume index perturbation, to detect specific target molecules in a complex environment and to estimate the thickness of thin layers of adsorbed molecules.


Approach to interfacial and intramolecular electron transfer of the diheme protein cytochrome c4 assembled on Au(111) surfaces.
Intramolecular electron transfer (ET) between metal centers is a core feature of large protein complexes in photosynthesis, respiration, and redox enzyme catalysis. The number of microscopic redox potentials and ET rate constants is, however, prohibitive for experimental cooperative ET mapping, but two-center proteins are simple enough to offer complete communication networks. At the same time, multicenter redox proteins operate in membrane environments where conformational dynamics may lead to gated ET features different from conditions in homogeneous solution. The bacterial respiratory diheme protein Pseudomonas stutzeri cytochrome c(4) has been a target for intramolecular, interheme ET. We report here voltammetric and in situ scanning tunneling microscopy (STM) data for P. stutzeri cyt c(4) at single-crystal, atomically planar Au(111)-electrode surfaces modified by variable-length omega-mercapto-alkanoic carboxylic acids. As evidenced by in situ STM, the strongly dipolar protein is immobilized in a close to vertical orientation at this surface with the positively charged high-potential heme domain adjacent to the electrode. This orientation gives asymmetric voltammograms with two one-ET peaks in the cathodic direction and a single two-ET peak in the anodic direction. Intramolecular, interheme ET with high, 8,000-30,000 s(-1), rate constants is notably an essential part of this mechanism. The high rate constants are in striking contrast to ET reactions of P. stutzeri cyt c(4) with small reaction partners in homogeneous solution for which kinetic analysis clearly testifies to electrostatic cooperative effects but no intramolecular, interheme ET higher than 0.1-10 s(-1). This difference suggests a strong gating feature of the process. On the basis of the three-dimensional structure of P. stutzeri cyt c(4), gating is understandable due to the through-space, hydrogen-bonded electronic contact between the heme propionates which is highly sensitive to environmental configurational fluctuations.


Results from the Workshop "Problem Formulation for the Use of Gene Drive in Mosquitoes".
Reducing the incidence of malaria has been a public health priority for nearly a century. New technologies and associated vector control strategies play an important role in the prospect of sustained reductions. The development of the CRISPR/Cas9 gene editing system has generated new possibilities for the use of gene-drive constructs to reduce or alter vector populations to reduce malaria incidence. However, before these technologies can be developed and exploited, it will be necessary to understand and assess the likelihood of any potential harms to humans or the environment. To begin this process, the Foundation for the National Institutes of Health and the International Life Sciences Institute Research Foundation organized an expert workshop to consider the potential risks related to the use of gene drives in Anopheles gambiae for malaria control in Africa. The resulting discussion yielded a series of consensus points that are reported here.


Renal agenesis and the absence of enteric neurons in mice lacking GDNF.
Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor for dopaminergic neurons and motor neurons in culture. It also protects these neurons from degeneration in vitro, and improves symptoms like Parkinson's disease induced pharmacologically in rodents and monkeys. Thus GDNF might have beneficial effects in the treatment of Parkinson's disease and amyotrophic lateral sclerosis. To examine the physiological role of GDNF in the development of the mammalian nervous system, we have generated mice defective in GDNF expression by using homologous recombination in embryonic stem cells to delete each of its two coding exons. GDNF-null mice, regardless of their targeted mutation, display complete renal agencies owing to lack of induction of the ureteric bud, an early step in kidney development. These mice also have no enteric neurons, which probably explains the observed pyloric stenosis and dilation of their duodenum. However, ablation of the GDNF gene does not affect the differentiation and survival of dopaminergic neurons, at least during embryonic development.


Chronic Immune Activation and CD4+ T Cell Lymphopenia in Healthy African Individuals: Perspectives for SARS-CoV-2 Vaccine Efficacy.
Chronic immune activation has been considered as the driving force for CD4+ T cell depletion in people infected with HIV-1. Interestingly, the normal immune profile of adult HIV-negative individuals living in Africa also exhibit chronic immune activation, reminiscent of that observed in HIV-1 infected individuals. It is characterized by increased levels of soluble immune activation markers, such as the cytokines interleukin (IL)-4, IL-10, TNF-α, and cellular activation markers including HLA-DR, CD-38, CCR5, coupled with reduced naïve and increased memory cells in CD4+ and CD8+ subsets. In addition, it is accompanied by low CD4+ T cell counts when compared to Europeans. There is also evidence that mononuclear cells from African infants secrete less innate cytokines than South and North Americans and Europeans in vitro. Chronic immune activation in Africans is linked to environmental factors such as parasitic infections and could be responsible for previously observed immune hypo-responsiveness to infections and vaccines. It is unclear whether the immunogenicity and effectiveness of anti-SARS-CoV-2 vaccines will also be reduced by similar mechanisms. A review of studies investigating this phenomenon is urgently required as they should inform the design and delivery for vaccines to be used in African populations.


Electrophysiological classes of layer 2/3 pyramidal cells in monkey prefrontal cortex.
The activity of supragranular pyramidal neurons in the dorsolateral prefrontal cortex (DLPFC) neurons is hypothesized to be a key contributor to the cellular basis of working memory in primates. Therefore, the intrinsic membrane properties, a crucial determinant of a neuron's functional properties, are important for the role of DLPFC pyramidal neurons in working memory. The present study aimed to investigate the biophysical properties of pyramidal cells in layer 2/3 of monkey DLPFC to create an unbiased electrophysiological classification of these cells. Whole cell voltage recordings in the slice preparation were performed in 77 pyramidal cells, and 24 electrophysiological measures of their passive and active intrinsic membrane properties were analyzed. Based on the results of cluster analysis of 16 independent electrophysiological variables, 4 distinct electrophysiological classes of monkey pyramidal cells were determined. Two classes contain regular-spiking neurons with low and high excitability and constitute 52% of the pyramidal cells sampled. These subclasses of regular-spiking neurons mostly differ in their input resistance, minimum current that evoked firing, and current-to-frequency transduction properties. A third class of pyramidal cells includes low-threshold spiking cells (17%), which fire a burst of three-five spikes followed by regular firing at all suprathreshold current intensities. The last class consists of cells with an intermediate firing pattern (31%). These cells have two modes of firing response, regular spiking and bursting discharge, depending on the strength of stimulation and resting membrane potential. Our results show that diversity in the functional properties of DLPFC pyramidal cells may contribute to heterogeneous modes of information processing during working memory and other cognitive operations that engage the activity of cortical circuits in the superficial layers of the DLPFC.


Rare benign mixed tumour of the upper lip: A case report.
Chondroid syringomas (CS) are rare benign mixed tumours. Clinical differentiation can be misleading due to the silent presentation, with only histopathological findings confirming the diagnosis. A 23-year-old Caucasian gentleman presented with an eighteen month history of increasing size of his exophytic upper lip mass. The initial clinical impression was thought to be related to the skin. Following a punch biopsy, histopathology confirmed appearance in keeping with part of a chondroid syringoma with subsequent excision of the lesion. CS present as a slow-growing, asymptomatic, non-tender, nonulcerated, smooth, firm subcutaneous, or intradermal nodule and can range from 0.5 to 3.0 cm, predominantly occurring in the head and neck region in patients aged above 35 years with a male predication. The most effective diagnostic method is microscopic examination. The gold standard treatment modality is by complete excision with a margin of normal tissue in order to examine the histopathologic features and prevent recurrence. CS should be included as a differential diagnosis of facial subcutaneous skin lesions in middle aged male patients. Careful evaluation, with a view of total excision and adequate surgical margin will enable diagnostic confirmation, whilst maintaining the aesthetic and functional unit.


Symbolic or utilitarian? Juggling interpretations of Neanderthal behavior: new inferences from the study of engraved stone surfaces.
Different categories of finds reveal how Neanderthals have manifested at different moments behaviors not ascribable to the utilitarian sphere, but to the aesthetic or symbolic. When the majority of this evidence dates to the few millennia that preceded the spread of Anatomically Modern Humans in Europe, these are grounds to continue the debate regarding the emergence of complex behavior, seen as an autonomous phenomenon of Neanderthal man or as the result of contact with immigrant populations. Re-examination of pebbles or flaked stones, a large part of such evidence, using a rigorous technological and taphonomic approach integrated with experimental tests, has already revealed these materials to be insignificant or natural, rather than anthropic, in origin. The following work seeks to shed light on the uncertainty existing around those stones and lithic artefacts bearing surface lines and scratches; these are of doubtful anthropic origin, but have not, as yet, been definitively interpreted. Generally, these findings are occasional in Mousterian sites, and when they are recovered with an excellent degree of preservation, different methods and levels of observation can be used for investigating them. The case studies taken into account are three sites in north Italy, where the surfaces of pebbles and flakes reveal a variety of signs and modifications attributable to various utilitarian acts. Of these, preventive cleaning of flint nodules has not been excluded, even if the traces on some tools reveal intentionality and repetition of gestures applied to the construction of a curated artifact.


Ultrafast and widely tuneable vertical-external-cavity surface-emitting laser, mode-locked by a graphene-integrated distributed Bragg reflector.
We report a versatile way of controlling the unsaturated loss, modulation depth and saturation fluence of graphene-based saturable absorbers (GSAs), by changing the thickness of a spacer between a single layer graphene (SLG) and a high-reflection mirror. This allows us to modulate the electric field intensity enhancement at the GSA from 0 up to 400%, due to the interference of incident and reflected light at the mirror. The unsaturated loss of the SLG-mirror-assembly can be reduced to ∼0. We use this to mode-lock a vertical-external-cavity surface-emitting laser (VECSEL) from 935 to 981 nm. This approach can be applied to integrate SLG into various optical components, such as output coupler mirrors, dispersive mirrors or dielectric coatings on gain materials. Conversely, it can also be used to increase the absorption (up to 10%) in various graphene based photonics and optoelectronics devices, such as photodetectors.


Epitope exposure on functional, oligomeric HIV-1 gp41 molecules.
We have used cells infected with the HIV-1 molecular clone HX10 to study the binding of monoclonal antibodies (mAbs) to different epitopes within the extracellular domain of the HIV-1 transmembrane glycoprotein gp41. Gp41 mAb binding to the infected cells at 4 degrees was variable but weaker than the binding of an anti-gp120/V3 loop mAb and increased substantially for three of the gp41 antibodies at 37 degrees. Treatment of the cells with soluble CD4 (sCD4) at 37 degrees increased gp41 mAb binding to epitopes spanning residues 521-663, implying that these regions had probably been masked by gp120, which following interaction with sCD4 had subsequently dissociated from gp41. By contrast, the binding of a mAb to residues 662-667 which form a neutralization epitope was reduced by sCD4 binding. Another region which has been described as containing a neutralization epitope spans residues 725-750. MAbs to this region bound equally well to noninfected and HIV-infected cells, and binding was not increased in the presence of sCD4. These data strongly imply that this epitope is not exposed on the external surface of the membrane, a finding in accord with the proposed cytoplasmic localization of this region.


The sentinel within: exploiting the immune system for cancer biomarkers.
The release of proteins from tumors triggers an immune response in cancer patients. These tumor antigens arise from several mechanisms including tumor-specific alterations in protein expression, mutation, folding, degradation, or intracellular localization. Responses to most tumor antigens are rarely observed in healthy individuals, making the response itself a biomarker that betrays the presence of underlying cancer. Antibody immune responses show promise as clinical biomarkers because antibodies have long half-lives in serum, are easy to measure, and are stable in blood samples. However, our understanding of the specificity and the impact of the immune response in early stages of cancer is limited. The immune response to cancer, whether endogenous or driven by vaccines, involves highly specific T lymphocytes (which target tumor-derived peptides bound to self-MHC proteins) and B lymphocytes (which generate antibodies to tumor-derived proteins). T cell target antigens have been identified either by expression cloning from tumor cDNA libraries, or by prediction based on patterns of antigen expression ("reverse immunology"). B cell targets have been similarly identified using the antibodies in patient sera to screen cDNA libraries derived from tumor cell lines. This review focuses on the application of recent advances in proteomics for the identification of tumor antigens. These advances are opening the door for targeted vaccine development, and for using immune response signatures as biomarkers for cancer diagnosis and monitoring.


Foot pressure distributions during walking in African elephants (Loxodonta africana).
Elephants, the largest living land mammals, have evolved a specialized foot morphology to help reduce locomotor pressures while supporting their large body mass. Peak pressures that could cause tissue damage are mitigated passively by the anatomy of elephants' feet, yet this mechanism does not seem to work well for some captive animals. This study tests how foot pressures vary among African and Asian elephants from habitats where natural substrates predominate but where foot care protocols differ. Variations in pressure patterns might be related to differences in husbandry, including but not limited to trimming and the substrates that elephants typically stand and move on. Both species' samples exhibited the highest concentration of peak pressures on the lateral digits of their feet (which tend to develop more disease in elephants) and lower pressures around the heel. The trajectories of the foot's centre of pressure were also similar, confirming that when walking at similar speeds, both species load their feet laterally at impact and then shift their weight medially throughout the step until toe-off. Overall, we found evidence of variations in foot pressure patterns that might be attributable to husbandry and other causes, deserving further examination using broader, more comparable samples.


Bradykinin induces tubulin phosphorylation and nuclear translocation of MAP kinase in mesangial cells.
Glomerular hypertension and glomerular hypertrophy act early and synergistically to promote glomerular injury in diabetes. We have previously shown that increased renal kinin production contributes to the glomerular hemodynamic abnormalities associated with diabetes. Glomerulosclerosis, characterized by mesangial cell proliferation and matrix expansion, is the final pathway leading to renal failure. The signal(s) initiating mesangial cell proliferation is ill defined. In the present study, we utilized immunofluorescence, immunoprecipitation, and immunoblotting techniques to identify substrates that are tyrosine phosphorylated in response to bradykinin action in mesangial cells. Immunofluorescence microscopy of mesangial cells stained with anti-phosphotyrosine (anti-PY) antibodies following bradykinin treatment (10(-9)-10(-6) M) revealed a dose-dependent increase in the labeling of cytoplasmic and nuclear proteins. Immunoprecipitation with anti-PY, followed by immunoblot revealed bradykinin-induced tyrosyl phosphorylation of tubulin and mitogen-activated protein kinase (MAPK). Confocal microscopy of mesangial cells stained for MAPK indicated that bradykinin stimulation resulted in translocation of MAPK from the cytoplasm to the nucleus by 2 h. These data demonstrate that bradykinin action results in the tyrosine phosphorylation of cellular proteins in mesangial cells and suggest a role for tubulin and MAPK in the signaling cascade of bradykinin leading to altered mesangial function.


Opioid Analgesic Prescribing Practices of Dental Professionals in the United States.
The prescription of opioid analgesics by dental professionals is widespread in the United States. Policy makers, government agencies, and professional organizations consider this phenomenon a growing public health concern. This study examined trends in the prescription of opioid analgesics for adults by dental professionals and associated factors in the United States. Data from the Medical Expenditure Panel Survey (1996-2013) were analyzed. Descriptive statistics were calculated separately for each year. Logistic regression analyses were conducted to estimate the overall trend during the period with and without adjusting for dental procedures and personal characteristics. Survey weights were incorporated to handle the sampling design. The prescription of opioid analgesics following dental care increased over time. After adjusting for sociodemographic factors, source of payment, and type of dental procedure, the odds ratio (OR) of prescribing opioid analgesics following a dental visit per each decade difference was 1.28 (95% confidence interval [CI], 1.19-1.38). Surgical, root canal, and implant procedures had the highest rates of opioid prescriptions and the greatest increases in rates over the study period. After adjusting for personal characteristics and type of dental procedure, the OR of receiving a prescription for opioids comparing blacks, Asians, and Hispanics to whites was 1.29 (95% CI, 1.17-1.41), 0.57 (95% CI, 0.47-0.70), and 0.84 (95% CI, 0.75-0.95), respectively. Opioid analgesic prescriptions following dental visits increased over time after adjusting for personal characteristics and type of dental procedure. The odds of receiving a prescription for opioids were higher for certain racial/ethnic minority groups. Knowledge Transfer Statement: This study highlights dental professionals prescribing practices of opioid analgesics by following dental treatments in the United States. With this knowledge, appropriate guidelines, protocols, and policies can be developed and implemented to address any inappropriate prescribing practices of opioid analgesics. In addition, this information could lead to an improvement in the prescribing practices of dental professionals and to evidence-based therapeutic decision making.


First Report of Chrysanthemum stunt viroid in Various Cultivars of Argyranthemum frutescens in France.
Described for the first time in Chrysanthemum indicum in the United States, Chrysanthemum stunt viroid (CSVd) was reported to naturally infect species in the Asteraceae family (1,3), as well a few hosts in other families. In May 2010 in a nursery in southwest France, the occurrence of stunted A. frutescens plantlets of cv. Butterfly showing yellow deformed leaves with terminal necrosis, which resembled the growth reduction, flower distortion or leaf necrosis symptoms reported for CSVd in Argyranthemum spp. (3), was reported. Mother plants from which the plantlets originated were asymptomatic. Reverse transcription (RT)-PCR with universal pospiviroid primers Pospi1-FW/RE (4) was performed on five symptomatic plants. A fragment of expected size (197 bp) was obtained in all cases. Viroid infection was confirmed by RT-PCR with two sets of primers: Vid-FW/RE using a 59°C annealing temperature instead of the recommended 62°C (4) and Vir-plus/minus that allows the amplification of the full-length viroid genome (2). Sequences of the three different uncloned amplicons were determined and a 355-nt contig was assembled (GenBank No. JF938538). A BLAST analysis of this full-length sequence revealed 99% identity with CSVd isolates from Chrysanthemum from Korea and Germany (GenBank Accession Nos. AF394452 and X16408). The Argyranthemum CSVd sequence differed from the Chrysanthemum ones by an A insertion at position 289 and substitutions (A to T) at positions 65 and 299. The insertion at position 289 is currently unique among CSVd sequences in GenBank. Thirty-five symptomless mother plants of A. frutescens cv. Butterfly were tested by PCR and all were shown to be infected. The difference in symptomatology observed between the mother plants and the commercial potting plants cannot be explained at this stage, but may reflect the different physiologies or growing conditions of the two kinds of plants, since these are known to affect CSVd symptoms in other hosts (1). To estimate the extent of CSVd contamination in A. frutescens, samples of 11 other cultivars originating from different nurseries were similarly analyzed. In addition to Butterfly, cvs. Sonnenstral, Maya Bofinger, Lili, Blanc Double, and Daisy Solenio were found to be infected by CSVd in the absence of clear symptomatology. The CSVd-free cultivars were Angelic Bordeaux, Dark Pink, Pink Delight, Angelic White, Dana, and Summer. The Pospi1-FW/RE amplicons from Blanc Double, Lili, and Daisy Solenio were identical to the Butterfly isolate sequence while the Maya Bofinger sequence showed one substitution (C to T) at position 256 and Sonnenstral had one substitution (T to A) at position 254. Although CSVd infection of Butterfly had been reported from Germany (3), to our knowledge, the results reported here represent the first report of CSVd in Argyranthemum for France and implicate a range of cultivars. CSVd being classified as a quarantine pest in Chrysanthemum spp. in the European Union, the finding of its significant prevalence in A. frutescens cultivars, frequently in the absence of clear symptomatology, raises the possibility that contaminated Argyranthemum may constitute a reservoir for future Chrysanthemum contamination. References: (1) I. Bouwnen and A. van Zaayen. Page 281 in: Viroids. Science Publishers, Enfield, NH, 2003. (2) T. Candresse et al. Plant Dis. 91:330, 2007. (3) W. Mentzel and E. Maiss. Z. Pflanzenk. Pfanzenschutz 107:548, 2000. (4) J. Th. J. Verhoeven et al. Eur. J. Plant Pathol. 110:823, 2004.


Positive tendency toward synchronous use of acetaminophen and ibuprofen in treating patients with patent ductus arteriosus.
Spontaneous closure of the ductus arteriosus often fails to occur in premature newborns and this condition can be associated with increased morbidity and mortality. The initial treatment to achieve closure of the opening is pharmacological, and various nonsteroidal anti-inflammatory drugs may be used. The aim of this study was to determine whether combining acetaminophen with ibuprofen is more effective than the individual use of these drugs to treat patent ductus arteriosus (PDA). The present randomized, controlled trial study included 154 premature newborns with PDA. The patients were randomized into 3 groups: the acetaminophen group (n=67), ibuprofen group (n=68), and combination drug group (n=19). Echocardiography was performed before initiating the medication and after completing a first and second course of treatment. Blood markers were measured to assess the safety of the 3 types of therapy. After the first course of treatment, PDA closure was seen in 76.1% of the infants in the acetaminophen group, 76.4% of those in the ibuprofen group, and 78.9% of the combination therapy group (p=0.97). The closure rate after a second course of treatment was 43.7% in the acetaminophen group, 62.5% in the ibuprofen group, and 100% in the combination group. There were no complications attributed to the 3 methods of treatment used. Concomitant use of acetaminophen and ibuprofen can be an effective option for closure of PDA. Other studies with a larger sample size are recommended in order to confirm these results.


The effect of training for a participatory ergonomic intervention on physical exertion and musculoskeletal pain among childcare workers (the TOY project) - a wait-list cluster-randomized controlled trial.
Objective Many employees have high physical exertion at work and suffer from musculoskeletal pain (MSP) leading to sickness absence with large costs. Participatory ergonomics is a potentially effective intervention for reducing physical exertion, MSP and sickness absence. The main aim of this study was to investigate the effectiveness of a 20-week workplace participatory ergonomic intervention among childcare workers on physical exertion and MSP. Methods In a two-arm cluster-randomized trial, 190 workers were recruited from 16 childcare institutions and randomly assigned to either a 20-week participatory ergonomics intervention consisting of three training workshops or a control group receiving usual care. Primary outcomes were physical exertion during work, maximal pain intensity, number of pain regions, and pain-related work interference. Secondary outcomes were MSP-related sickness absence, need for recovery (NFR), employee involvement, and self-efficacy. We followed the intention-to-treat principle and adhered to the registered study protocol (ISRCTN10928313). Results After 20 weeks, half the workers noticed some positive changes in their work. However, there were no statistically discernible effects in physical exertion, maximum pain intensity, pain-related work interference, or number of pain regions. We found a significant reduction of MSP-related sickness absence in the intervention compared to the control group [-0.48 days per month (95% confidence interval (CI), -0.8- -0.1]. We found no significant effects in NRF or involvement of employees, but self-efficacy was reduced in the intervention compared to the control group [-0.2 (95% CI, -0.3- -0.0)]. Conclusion This 20-week training for a participatory ergonomic intervention in childcare workers did not show effects on physical exertion and MSP, but was both feasible and effective in reducing MSP-related sickness absence.


Effects of feed restriction and prolactin-release inhibition at drying-off on susceptibility to new intramammary infection in cows.
A cow's risk of acquiring a new intramammary infection during the dry period increases with milk production at drying-off. A method commonly used to reduce milk production is a drastic reduction in feed supply in the days that precede drying-off. Milk production can also be reduced by inhibiting the lactogenic signal driven by prolactin (PRL). This study aimed to compare the effects of these 2 drying-off procedures on milk production, metabolism, and susceptibility to intramammary infection in cows. A total of 21 Holstein cows in late lactation were assigned to 1 of 3 treatments based on milk yield, somatic cell count, and parity. The cows were fed a lactation diet until drying-off (control), only dry hay during the last 5 d before drying-off (DH), or the same diet as the control cows but with twice-daily i.m. injections of 4mg of quinagolide, a specific inhibitor of PRL release, from 5 d before drying-off until 13 d after (QN). On d 1 to 7 after the last milking, the cows were challenged by daily teat dipping in a solution containing Streptococcus agalactiae at 5×10(7) cfu/mL. Quinagolide induced a decrease in PRL concentration in blood on all the injection days. Blood PRL was also depressed in the hay-fed cows before drying-off. Both the QN and DH treatments induced a decrease in milk production, which at drying-off averaged 12.0, 10.0, and 21.7kg/d for the QN, DH, and control cows, respectively. The DH treatment decreased blood concentration of glucose and increased blood concentrations of β-hydroxybutyrate and nonesterified fatty acids before drying-off. Somatic cell count at drying-off was greater in the milk of the QN cows than in that of the control cows but after drying-off was greater in the mammary secretions of the control cows than in those of the QN cows. The number of S. agalactiae colonies found in mammary secretions on d 8 and 14 after the last milking was lower for the QN cows than for the control cows. The percentage of S. agalactiae-infected quarters was also lower in the QN cows than in the control cows and on d 14 averaged 17.2, 33.7, and 57.5% in the QN, DH, and control cows, respectively. No differences between the DH and control groups were observed for either bacterial count or infection rate. In conclusion, this experiment shows that PRL-release inhibition could be an alternative for reducing milk production and improving resistance to intramammary infection at drying-off.


Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family.
Aggrecan is responsible for the mechanical properties of cartilage. One of the earliest changes observed in arthritis is the depletion of cartilage aggrecan due to increased proteolytic cleavage within the interglobular domain. Two major sites of cleavage have been identified in this region at Asn(341)-Phe(342) and Glu(373)-Ala(374). While several matrix metalloproteinases have been shown to cleave at Asn(341)-Phe(342), an as yet unidentified protein termed "aggrecanase" is responsible for cleavage at Glu(373)-Ala(374) and is hypothesized to play a pivotal role in cartilage damage. We have identified and cloned a novel disintegrin metalloproteinase with thrombospondin motifs that possesses aggrecanase activity, ADAMTS11 (aggrecanase-2), which has extensive homology to ADAMTS4 (aggrecanase-1) and the inflammation-associated gene ADAMTS1. ADAMTS11 possesses a number of conserved domains that have been shown to play a role in integrin binding, cell-cell interactions, and extracellular matrix binding. We have expressed recombinant human ADAMTS11 in insect cells and shown that it cleaves aggrecan at the Glu(373)-Ala(374) site, with the cleavage pattern and inhibitor profile being indistinguishable from that observed with native aggrecanase. A comparison of the structure and expression patterns of ADAMTS11, ADAMTS4, and ADAMTS1 is also described. Our findings will facilitate the study of the mechanisms of cartilage degradation and provide targets to search for effective inhibitors of cartilage depletion in arthritic disease.


The effects of insomnia and internet addiction on depression in Hong Kong Chinese adolescents: an exploratory cross-sectional analysis.
The negative association of insomnia and internet addiction with mental health is widely documented in the literature, yet little is known about their inter-relationships. The primary aim of this study was to examine the inter-relationships between insomnia, internet addiction and depression. A total of 719 Chinese adolescents in Hong Kong participated in this school-based cross-sectional study. Participants completed the Chinese version of the Pittsburgh Sleep Quality Index (PSQI), the Chinese Internet Addiction Scale (CIAS), the 12-item version of General Health Questionnaire (GHQ-12) and questions assessing internet use pattern and sociodemographic characteristics. The classification of internet addiction and insomnia was based on the CIAS cutoff global score >63 and PSQI cutoff global score >5, respectively. Multiple regression analyses tested the effects of insomnia and internet addiction on depression. Among students with internet addiction (17.2%), 51.7% were also identified as insomniacs. Internet addicts scored significantly poorer on all PSQI components, except sleep duration, than their non-addicted counterparts. After adjustment for gender and internet use time, both internet addiction (β=0.05; Sobel test Z=6.50, P<0.001) and insomnia (β=0.59; Sobel test Z=4.49, P<0.001) demonstrated a significant association with depression. Overall, there is high comorbidity between internet addiction and insomnia. Both insomnia and internet addiction emerged as significant explanatory factors, but they exerted differential effects on depression. Future research should be directed at determining the causal relationship between internet addiction and insomnia, and its underlying mechanism with depression.


Challenges in residential fall prevention: insight from apprentice carpenters.
Falls remain a serious source of morbidity and mortality in residential construction despite considerable knowledge of risk factors and prevention strategies. While training is universally viewed as positive, we know little about its effectiveness in preventing residential falls. A series of focus groups were conducted with union apprentice carpenters (n = 36) at varied levels of training to elicit input on factors that might influence the effectiveness of residential fall prevention training, including hazard awareness, timing of elements of formal instruction, jobsite mentoring, and workplace norms. While apprentices identified many residential fall hazards, they voiced little concern about work near unprotected vertical or horizontal openings such as stairwells, window openings or leading edges. On residential jobs, apprentices worked at heights immediately and were often exposed to hazards they had not yet been trained to handle. The quality of mentoring varied tremendously, and things they had been taught in school were often not the norm on these small worksites. Use of fall arrest equipment was uncommon. Job insecurity in this fast-paced work environment influenced behaviors even when apprentices reported knowledge of safe procedures; this was more of a problem for less experienced apprentices. These data provide compelling evidence that apprentices often do not apply safety principles they have been taught in school in the actual work environment, illuminating how attempts to empower workers through training alone can fall short. The findings have policy implications and demonstrate the importance of measuring more than knowledge when evaluating effectiveness of training.


Rapid and sensitive determination of phytosterols in functional foods and medicinal herbs by using UHPLC-MS/MS with microwave-assisted derivatization combined with dual ultrasound-assisted dispersive liquid-liquid microextraction.
In this work, a hyphenated technique of dual ultrasound-assisted dispersive liquid-liquid microextraction combined with microwave-assisted derivatization followed by ultra high performance liquid chromatography tandem mass spectrometry has been developed for the determination of phytosterols in functional foods and medicinal herbs. Multiple reaction monitoring mode was used for the tandem mass spectrometry detection. A mass spectrometry sensitive reagent, 4'-carboxy-substituted rosamine, has been used as the derivatization reagent for five phytosterols, and internal standard diosgenin was used for the first time. Parameters for the dual microextraction, microwave-assisted derivatization, and ultra high performance liquid chromatography tandem mass spectrometry were all optimized in detail. Satisfactory linearity, recovery, repeatability, accuracy and precision, absence of matrix effect, extremely low limits of detection (0.005-0.015 ng/mL) and limits of quantification (0.030-0.10 ng/mL) were achieved. The proposed method was compared with previously reported methods. It showed better sensitivity, selectivity, and accuracy. The matrix effect was also significantly reduced. The proposed method was successfully applied to the determination of five phytosterols in vegetable oil (sunflower oil, olive oil, corn oil, peanut oil), milk and orange juice (soymilk, peanut milk, orange juice), and medicinal herbs (Ginseng, Ganoderma lucidum, Cordyceps, Polygonum multiflorum) for the quality control of functional foods and medicinal herbs.


Active site remodeling during the catalytic cycle in metal-dependent fructose-1,6-bisphosphate aldolases.
Crystal structures of two bacterial metal (Zn2+)-dependent d-fructose-1,6-bisphosphate (FBP) aldolases in complex with substrate, analogues, and triose-P reaction products were determined to 1.5-2.0 Å resolution. The ligand complexes cryotrapped in native or mutant Helicobacter pylori aldolase crystals enabled a novel mechanistic description of FBP C3-C4 bond cleavage. The reaction mechanism uses active site remodeling during the catalytic cycle, implicating relocation of the Zn2+ cofactor that is mediated by conformational changes of active site loops. Substrate binding initiates conformational changes triggered upon P1 phosphate binding, which liberates the Zn2+-chelating His-180, allowing it to act as a general base for the proton abstraction at the FBP C4 hydroxyl group. A second zinc-chelating His-83 hydrogen bonds the substrate C4 hydroxyl group and assists cleavage by stabilizing the developing negative charge during proton abstraction. Cleavage is concerted with relocation of the metal cofactor from an interior to a surface-exposed site, thereby stabilizing the nascent enediolate form. Conserved residue Glu-142 is essential for protonation of the enediolate form prior to product release. A d-tagatose 1,6-bisphosphate enzymatic complex reveals how His-180-mediated proton abstraction controls stereospecificity of the cleavage reaction. Recognition and discrimination of the reaction products, dihydroxyacetone-P and d-glyceraldehyde 3-P, occurs via charged hydrogen bonds between hydroxyl groups of the triose-Ps and conserved residues, Asp-82 and Asp-255, respectively, and are crucial aspects of the enzyme's role in gluconeogenesis. Conformational changes in mobile loops β5-α7 and β6-α8 (containing catalytic residues Glu-142 and His-180, respectively) drive active site remodeling, enabling the relocation of the metal cofactor.


In vitro and In vivo Antioxidant Activity of Flavonoid Extracted from Mulberry Fruit (Morus alba L.).
Many plants possess antioxidants that exhibit additive or synergistic activities. In this study, an ethanol-extracted flavonoid extracted from mulberry fruit (FEM) was evaluated for the antioxidant activity in vitro and the hemolysis in red blood cell (RBC) and lipid peroxidation in liver in vivo. Antioxidant activities in vitro were measured by quantifying its 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity, reducing power, and Fe(2+)-chelating ability. FEM inhibits hemolysis in RBCs and effects of lipid peroxidation in the liver were estimated. The total content of flavonoid compounds was 187.23 mg of quercetin equivalents per grams dried material. In the in vitro assays, FEM demonstrated a strong antioxidant effect, especially in DPPH scavenging activity and reducing power. Mouse RBC hemolysis induced by H2O2 was significantly inhibited by FEM in a dose- and time-dependent manner. The effects of FEM on lipid peroxidation in liver, mitochondria, and microsome were investigated. The percentage of inhibition at high concentration (100 μg/mL) of FEM was 45.51%, 39.36%, and 42.78% for liver, mitochondria, and microsomes, respectively. These results suggest that the FEM possesses a strong antioxidant activity both in vivo and in vitro. The total content of flavonoid compounds in mulberry fruit was 187.23 mg/g dried materialFEM showed a strong antioxidant effect, especially in 2,2-diphenyl-1-picrylhydrazyl scavenging activity and reducing powerMouse red blood cell hemolysis induced by H2O2 was significantly inhibited by FEM in a dose- and time-dependent mannerThe inhibition percentage at high concentration of FEM was 45.51%, 39.36%, and 42.78% for mouse's liver, mitochondrial, and microsomes, respectively. Abbreviations used: FEM: Flavonoid Extracted from Mulberry fruit, H2O2: Hydrogen peroxide, DPPH: 2,2-diphenyl-1-picrylhydrazyl, EDTA: Ethylene diamine tetraacetic acid, MDA: malondialdehyde, TBA: 2-thiobarbituric acid, RBC: Red blood cells, DNJ: 1-deoxynojirimycin, LDL: low density lipoprotein, ROS: reactive oxygen species, EDTA2Na: Ethylenediaminetetraacetic acid disodium salt.


The role of the southern ocean in uptake and storage of anthropogenic carbon dioxide
An ocean-climate model that shows high fluxes of anthropogenic carbon dioxide into the Southern Ocean, but very low storage of anthropogenic carbon there, agrees with observation-based estimates of ocean storage of anthropogenic carbon dioxide. This low simulated storage indicates a subordinate role for deep convection in the present-day Southern Ocean. The primary mechanism transporting anthropogenic carbon out of the Southern Ocean is isopycnal transport. These results imply that if global climate change reduces the density of surface waters in the Southern Ocean, isopycnal surfaces that now outcrop may become isolated from the atmosphere, tending to diminish Southern Ocean carbon uptake.


Iminodibenzyl class antipsychotics for schizophrenia: a systematic review and meta-analysis of carpipramine, clocapramine, and mosapramine.
We conducted a meta-analysis of the iminodibenzyl antipsychotics carpipramine, clocapramine, and mosapramine, which are classified as second-generation antipsychotics (SGAs) for schizophrenia treatment. We searched data that had been published in PubMed, the Cochrane Library databases, PsycINFO, CiNii, and the Japan Medical Abstracts Society up to August 29, 2014. Randomized controlled trials that compared iminodibenzyl antipsychotics with other antipsychotics in patients with schizophrenia were included. Odds ratios and standardized mean differences were evaluated. We included four randomized controlled trials on carpipramine (number of patients [n]=290), six on clocapramine (n=1,048), and five on mosapramine (n=986) in the meta-analysis. There were no significant differences in the response rates or in the discontinuation rates either between carpipramine and the other pooled antipsychotics or between clocapramine and the other pooled antipsychotics. On the Positive and Negative Syndrome Scale, mosapramine's positive subscale scores were superior to those of the other pooled antipsychotics (standard mean of difference =-0.22); however, on that same scale, there were no significant differences in total scores, negative scores, general subscale scores, response rates, or the discontinuation rates between mosapramine and the other pooled antipsychotics. Furthermore, the incidences of extrapyramidal symptoms and of hyperprolactinemia were significantly greater with mosapramine than with the other pooled antipsychotics. The pharmacological profiles of carpipramine and clocapramine, which are classified as SGAs, were similar to those of first-generation antipsychotics because there were no significant differences in efficacy and safety outcomes. However, mosapramine was associated with a greater risk of extrapyramidal symptoms and hyperprolactinemia than the other SGAs were, although it may be beneficial for the improvement of positive symptoms.


Solution structure of oxidized Saccharomyces cerevisiae iso-1-cytochrome c.
The solution structure of oxidized Saccharomycescerevisiae Cys102Ser iso-1-cytochromechas been determined using 1361 meaningful NOEs (of 1676 total) after extending the published proton assignment [Gao, Y., et al. (1990) Biochemistry 29, 6994-7003] to 77% of all proton resonances. The NOE patterns indicate that secondary structure elements are maintained upon oxidation in solution with respect to the solid state and solution structures of the reduced species. Constraints derived from the pseudocontact shifts [diamagnetic reference shift values are those of the reduced protein [Baistrocchi, P., et al. (1996) Biochemistry 35, 13788-13796]] were used in the final stages of structure calculations. After restrained energy minimization with constraints from NOEs and pseudocontact shifts, a family of 20 structures with rmsd values of 0.58 +/- 0.08 and 1.05 +/- 0.10 A (relative to the average structure) for the backbone and all heavy atoms, respectively, was obtained. The solution structure is compared with the crystal structure and the structures of related systems. Twenty-six amide protons were detected in the NMR spectrum 6 days after the oxidized lyophilized protein was dissolved in D2O (pH 7.0 and 303 K); in an analogous experiment, 47 protons were observed in the spectrum of the reduced protein. The decrease in the number of nonexchanging amide protons, which mainly are found in the loop regions 14-26 and 75-82, confirms the greater flexibility of the structure of oxidized cytochrome c in solution. Our finding of increased solvent accessibility in these loop regions is consistent with proposals that an early step in unfolding the oxidized protein is the opening of the 70-85 loop coupled with dissociation of the Met80-iron bond.


Fatal scedosporiosis in multiple solid organ allografts transmitted from a nearly-drowned donor.
Scedosporium spp. is the most common mold infection in pneumonia resulting from near-drowning. Three fatal scedosporiosis cases developed after solid organ transplantation, probably transmitted from the nearly-drowned donor. One heart transplant recipient and two kidney transplant recipients developed fatal scedosporiosis following deceased donor transplantation from the same donor, a nearly-drowned victim of a suicide attempt. Genotypically, indistinguishable strains of Scedosporium auratiacum were recovered from the three recipients. Two liver transplant recipients from the same donor received prophylactic voriconazole without any subsequent signs of infection. To determine the safety of donation from nearly-drowned donors, a national traceback investigation was also performed of the causes of deaths in all transplant recipients who received organs from drowned donors between 2001 and 2013. Over 13 years, 2600 deceased donor transplants were performed in Korea. Among these 2600 deceased donor transplants, 27 (1%) victims of drowning donated their organs. From these 27 donors, 84 patients received organ transplants and 18 died, including the above three. We found no microbiologic evidence of invasive mold transmission from the nearly-drowned donors to the other 15 recipients. Although disseminated infection in the donor could not be demonstrated by culture, undiagnosed disseminated donor infection and transmission of Scedosporium spp. should be considered in near-drowning events.


Self-monitoring in weight loss: a systematic review of the literature.
Self-monitoring is the centerpiece of behavioral weight loss intervention programs. This article presents a systematic review of the literature on three components of self-monitoring in behavioral weight loss studies: diet, exercise, and self-weighing. This review included articles that were published between 1993 and 2009 that reported on the relationship between weight loss and these self-monitoring strategies. Of the 22 studies identified, 15 focused on dietary self-monitoring, one on self-monitoring exercise, and six on self-weighing. A wide array of methods was used to perform self-monitoring; the paper diary was used most often. Adherence to self-monitoring was reported most frequently as the number of diaries completed or the frequency of log-ins or reported weights. The use of technology, which included the Internet, personal digital assistants, and electronic digital scales were reported in five studies. Descriptive designs were used in the earlier studies whereas more recent reports involved prospective studies and randomized trials that examined the effect of self-monitoring on weight loss. A significant association between self-monitoring and weight loss was consistently found; however, the level of evidence was weak because of methodologic limitations. The most significant limitations of the reviewed studies were the homogenous samples and reliance on self-report. In all but two studies, the samples were predominantly white and women. This review highlights the need for studies in more diverse populations, for objective measures of adherence to self-monitoring, and for studies that establish the required dose of self-monitoring for successful outcomes.


Randomized trial of group interventions to reduce HIV/STD risk and change theoretical mediators among detained adolescents.
Criminally involved adolescents engage in high levels of risky sexual behavior and alcohol use, and alcohol use may contribute to lack of condom use. Detained adolescents (n = 484) were randomized to (1) a theory-based sexual risk reduction intervention (GPI), (2) the GPI condition with a group-based alcohol risk reduction motivational enhancement therapy component (GPI + GMET), or (3) an information-only control (INFO). All interventions were presented in same-sex groups in single sessions lasting from 2 to 4 hr. Changes to putative theoretical mediators (attitudes, perceived norms, self-efficacy, and intentions) were measured immediately following intervention administration. The primary outcomes were risky sexual behavior and sexual behavior while drinking measured 3 months later (65.1% retention). The GPI + GMET intervention demonstrated superiority over both other conditions in influencing theoretical mediators and over the INFO control in reducing risky sexual behavior. Self-efficacy and intentions were significant mediators between condition and later risky sexual behavior. This study contributes to an understanding of harm reduction among high-risk adolescents and has implications for understanding circumstances in which the inclusion of GMET components may be effective.


Multiple genetic variations confer risks for obesity and type 2 diabetes mellitus in arab descendants from UAE.
The United Arab Emirates (UAE) is one of the countries most threatened with obesity. Here we investigated associations between hundreds of single-nucleotide polymorphisms (SNPs) and the following obesity indicators: body mass index (BMI), waist circumference (WC), and height. We also investigated the associations between obesity-related genes with type 2 diabetes mellitus (T2DM). We tested 87, 58, and 586 SNPs in a previous genome-wide significance level for associations with BMI (n = 880), WC (n = 455), and height (n = 897), respectively. For each trait, we used normally transformed Z scores and tested them with SNPs using linear regression models that incorporated age and gender as covariates. The weighted polygenic risk scores for significant SNPs for each trait were tested with the corresponding Z scores using linear regression models with the same covariates. We further tested 145 obesity loci with T2DM (464 cases, 415 controls) using a logistic regression model including age, gender, and BMI Z scores as covariates. The Mean BMI was 29.39 kg/m2, and mean WC was 103.66 cm. Hypertension and dyslipidemia were common obesity comorbidities (>60%). The best associations for BMI was in FTO, LOC284260 and USP37, and for WC in RFX7 and MYEOV. For height, the best association was in NSD1 followed by MFAP2 and seven other loci. The polygenic scores revealed stronger associations for each trait than individual SNPs; although they could only explain <1% of the traits' Z scores variations. For T2DM, the strongest associations were with the TCF7L2 and MC4R loci (P < 0.01, OR ~1.70), with novel associations detected with KCNK3 and RARB. In this first study of Arab descendants, we confirmed several known obesity (FTO, USP37, and RFX7), height (NSD1, MFAP2), and T2DM (TCF7L2, MC4R) associations; and report novel associations, like KCNK3 and RARB for T2DM.


Cross-sectional and longitudinal construct validity of two rotator cuff disease-specific outcome measures.
Disease-specific Quality Of Life (QOL) measures are devised to assess the impact of a specific disease across a spectrum of important domains of life. The purpose of this study was to examine the cross-sectional and longitudinal construct validity (sensitivity to change) of two rotator cuff disease-specific measures, the Rotator Cuff-Quality Of Life (RC-QOL) and the Western Ontario Rotator Cuff (WORC) index, in relation to one another and to other joint and limb specific measures in the same population of the patients suffering from rotator cuff pathology. Participants enrolled were consecutive patients who received physical therapy for management of impingement syndrome or received treatment following rotator cuff repair, acromioplasty or decompression surgeries. All subjects received physical therapy treatment and completed four outcome measures at 3 single points (initial, interim, and final). Cross-sectional convergent validity was assessed at each of the 3 time-points by correlating the WORC and RC-QOL's scores to each other and to two alternative scales; a joint-specific scale, the American Shoulder and Elbow Surgeons (ASES) standardized shoulder assessment form and a limb-specific measure, the Upper Extremity Functional Index (UEFI). Non-parametric statistics (Spearman's rho and Wilcoxon-Mann-Whitney tests) examined the construct validity. The standardized response mean (SRM) was used to examine sensitivity to change. Forty-one participants entered the study and their scores were compared at 3 cross sectional single points. The correlation coefficients among the 4 measures varied from 0.60 to 0.91. Correlation between corresponding domains of the WORC and RC-QOL varied from 0.45 to 0.85. The known group validity was not significantly different among individual sub-scores and total scores. The final SRMs were (1.42), (1.43), (1.44), and (1.54) for the ASES, RCQOL, WORC, and UEFI respectively. The WORC and RC-QOL exhibit similar cross-sectional convergent validity in patients suffering from rotator cuff pathology. The sensitivity to change was very close among all scores, with the UEFI having the highest sensitivity. Further research is needed to examine the extent to which each physical or emotional domain contributes to prognostic or therapeutic decision-making.


GenomeGraphR: A user-friendly open-source web application for foodborne pathogen whole genome sequencing data integration, analysis, and visualization.
Food safety risk assessments and large-scale epidemiological investigations have the potential to provide better and new types of information when whole genome sequence (WGS) data are effectively integrated. Today, the NCBI Pathogen Detection database WGS collections have grown significantly through improvements in technology, coordination, and collaboration, such as the GenomeTrakr and PulseNet networks. However, high-quality genomic data is not often coupled with high-quality epidemiological or food chain metadata. We have created a set of tools for cleaning, curation, integration, analysis and visualization of microbial genome sequencing data. It has been tested using Salmonella enterica and Listeria monocytogenes data sets provided by NCBI Pathogen Detection (160,000 sequenced isolates in 2018). GenomeGraphR presents foodborne pathogen WGS data and associated curated metadata in a user-friendly interface that allows a user to query a variety of research questions such as, transmission sources and dynamics, global reach, and persistence of genotypes associated with contamination in the food supply and foodborne illness across time or space. The application is freely available (https://fda-riskmodels.foodrisk.org/genomegraphr/).


The Interconnections Project: development and evaluation of a community-based depression program for African American violence survivors.
Multi-faceted depression care programs based within the healthcare system have been found to be effective, but may not fully address the needs of African American Intimate Partner Violence (IPV) survivors, many of whom are not seeking depression care in healthcare settings. To develop and evaluate a multifaceted, community-based depression care program (the Interconnections Project) for African American women with a history of IPV. We used a community-based participatory research (CBPR) approach to develop, implement, and evaluate the intervention. Participants were African American women who had current depressive symptoms and a lifetime history of IPV. They participated in a 6-month intervention where a peer advocate provided education, skills training, and case management services, and used Motivational Interviewing to support self-management behaviors. We conducted pre-intervention and post-intervention assessments using quantitative and qualitative data. Fifty-nine women participated, with 92 % attending any sessions and 51 % attending at least 6 h of intervention activities. Intervention changes made to better accommodate participants' unpredictable schedules improved participation rates. Participants noted high levels of satisfaction with the program. There were significant improvements in depression severity (PHQ-9 13.9 to 7.9, p < 0.001), self-efficacy, self-management behaviors, and self-esteem (all p < 0.001), but no increase in use of antidepressants. Common themes related to why the program was helpful included that the program was by and for African American women, that it fostered trust, and that it taught self-management strategies with practical, lasting value. Culturally specific, community-based interventions led by peer advocates may be a promising way to help African American IPV survivors effectively address depression.


Duchenne muscular dystrophy in one of monozygotic twin girls.
Monozygotic twin girls are reported, one of whom has the typical clinical features of Duchenne muscular dystrophy despite a normal female karyotype. Although certain features of the biopsy were atypical, the clinical diagnosis was supported by persistent markedly raised blood creatine kinase levels and findings typical of DMD on electromyography and magnetic resonance spectroscopy. Analysis of an X linked DNA polymorphism in 16 independent somatic cell hybrids made between cells derived from each girl and a mouse line suggest that in one twin only the maternal X chromosome is active, whereas in the other the active X was paternally derived. More data are needed to exclude sampling error. These preliminary experimental results support the hypothesis that both girls are heterozygous for Duchenne muscular dystrophy. X inactivation, by chance, resulted in two contrasting cell masses with different active X chromosomes. This segregation was followed by, and may even have resulted in, twinning into a female pair, one normal and one with the full clinical features of the disease.


Pathway-based analysis of GWAs data identifies association of sex determination genes with susceptibility to testicular germ cell tumors.
Genome-wide association (GWA) studies of testicular germ cell tumor (TGCT) have identified 18 susceptibility loci, some containing genes encoding proteins important in male germ cell development. Deletions of one of these genes, DMRT1, lead to male-to-female sex reversal and are associated with development of gonadoblastoma. To further explore genetic association with TGCT, we undertook a pathway-based analysis of SNP marker associations in the Penn GWAs (349 TGCT cases and 919 controls). We analyzed a custom-built sex determination gene set consisting of 32 genes using three different methods of pathway-based analysis. The sex determination gene set ranked highly compared with canonical gene sets, and it was associated with TGCT (FDRG = 2.28 × 10(-5), FDRM = 0.014 and FDRI = 0.008 for Gene Set Analysis-SNP (GSA-SNP), Meta-Analysis Gene Set Enrichment of Variant Associations (MAGENTA) and Improved Gene Set Enrichment Analysis for Genome-wide Association Study (i-GSEA4GWAS) analysis, respectively). The association remained after removal of DMRT1 from the gene set (FDRG = 0.0002, FDRM = 0.055 and FDRI = 0.009). Using data from the NCI GWA scan (582 TGCT cases and 1056 controls) and UK scan (986 TGCT cases and 4946 controls), we replicated these findings (NCI: FDRG = 0.006, FDRM = 0.014, FDRI = 0.033, and UK: FDRG = 1.04 × 10(-6), FDRM = 0.016, FDRI = 0.025). After removal of DMRT1 from the gene set, the sex determination gene set remains associated with TGCT in the NCI (FDRG = 0.039, FDRM = 0.050 and FDRI = 0.055) and UK scans (FDRG = 3.00 × 10(-5), FDRM = 0.056 and FDRI = 0.044). With the exception of DMRT1, genes in the sex determination gene set have not previously been identified as TGCT susceptibility loci in these GWA scans, demonstrating the complementary nature of a pathway-based approach for genome-wide analysis of TGCT.


Nutrition in early life and risk of childhood leukemia: a case-control study in Greece.
There is a paucity of findings concerning the role of diet in childhood leukemogenesis, whereas the results are equivocal and the studies heterogeneous with regard to food items examined. This case-control study investigates the association of childhood leukemia with food groups, macronutrient consumption, total energy intake and adherence to Mediterranean diet among children aged 5-14 years in Greece. A total of 139 consecutive, incident leukemia cases out of which 121 were acute lymphoblastic leukemia were derived from the Nationwide Registry for Childhood Hematological Malignancies along with one : one age- and gender-matched hospital controls. Information on socio-demographic, maternal and child variables and dietary habits was obtained through in-person interviews with the guardians/children. Multiple logistic regression was performed with adjustment for birth weight and possible confounding variables. Higher consumption of added lipids was associated with an increased risk of childhood leukemia, whereas consumption of milk and dairy products with reduced risk. From the macronutrient analysis, a borderline trend linking high protein intake with reduced childhood leukemia risk was observed. Consumption of milk and dairy products in the first year of life may protect against childhood leukemia possibly through vitamin D actions, while added lipids may increase the risk through various mechanisms. These results offer a holistic evaluation of children's nutrition and suggest that dietary habits in the early years of life may contribute to the prevention of childhood leukemia.


Vaccination recommendations for the hematology and oncology and post-stem cell transplant populations.
Vaccination is a simple yet important process used to prevent many infections in the general population. For patients with suppressed immune systems, especially those who are undergoing chemotherapy or who have undergone stem cell transplant, repeat vaccination or boosters may be crucial in prolonging and/or extending immunity. The purpose of this review is to examine the need for each vaccine in two separate oncology populations: patients receiving concurrent chemotherapy and post-stem cell transplant patients. In addition, the importance of avoiding live vaccines and criteria for reconsideration at a future time will also be discussed.


Fine structural distribution of acetylcholine receptors at developing mouse neuromuscular junctions.
The distribution of acetylcholine receptors (AChRs) in neuromuscular junctions of embryonic and newborn mice (strain 129/ReJ) was examined on the fine structural level using [125I]alpha-bungarotoxin labeling and quantitative electron microscope autoradiography. Changes in junctional receptor site density were related to changes in the structure of the postjunctional membrane, in particular the differentiation of morphologically distinct regions of thickened membrane and the formation of junctional folds. The following sequence of development is described: (1) At the earliest age examined, embryonic day 16 of gestation (i.e., at approximately the time when junctional receptor accumulations are first detected), subneural receptor aggregates have poorly defined boundaries and seem to extend beyond the region of direct axonal or Schwann cell contact. At that time the subneural AChR site density is somewhat variable but averages approximately 2000 to 3000 sites/micron 2, and the subneural muscle membrane shows discontinuous membrane specialization (membrane thickening plus a cytoplasmic amorphous layer). There seems to be no preferential labeling of contact regions rich in such specialization compared with those where membrane thickening was less obvious or absent. (2) By birth, junctional AChRs are strongly correlated with morphologically specialized membrane, at a constant density of approximately 9000/micron 2 (comparable to that in adult animals of this strain of mouse). During the first postnatal week, a large fraction of the primary cleft is covered by Schwann cell rather than axon terminal. Receptor-rich dense membrane and incipient junctional folds are found under axon terminals and, to a lesser extent, under Schwann cell extensions, but they are not seen beyond the edge of the "junctional complex." Coated vesicles are a prominent feature of the subjunctional sarcoplasm in neonatal junctions, and their number declines sharply during the first week. (3) Junctional folds differentiate mainly after the first postnatal week. Development of folds is associated with a 1.5- to 1.8-fold increase in length of specialized thickened membrane and a parallel increase in number of receptor sites per endplate. Since this is also a period of rapid overall endplate growth (Steinbach, J.H. (1981) Dev. Biol. 84: 267-276) the total number of endplate receptors increases greater than 30-fold during the maturation period following the first week while the concentration of receptors/micron 2 of thickened membrane remains constant.


Intelligent Word Embeddings of Free-Text Radiology Reports.
Radiology reports are a rich resource for advancing deep learning applications in medicine by leveraging the large volume of data continuously being updated, integrated, and shared. However, there are significant challenges as well, largely due to the ambiguity and subtlety of natural language. We propose a hybrid strategy that combines semantic-dictionary mapping and word2vec modeling for creating dense vector embeddings of free-text radiology reports. Our method leverages the benefits of both semantic-dictionary mapping as well as unsupervised learning. Using the vector representation, we automatically classify the radiology reports into three classes denoting confidence in the diagnosis of intracranial hemorrhage by the interpreting radiologist. We performed experiments with varying hyperparameter settings of the word embeddings and a range of different classifiers. Best performance achieved was a weighted precision of 88% and weighted recall of 90%. Our work offers the potential to leverage unstructured electronic health record data by allowing direct analysis of narrative clinical notes.


Clinical features and genotyping analysis of community-acquired methicillin-resistant Staphylococcus aureus infections in Taiwanese children.
Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infection in children without health care-associated risk factors has emerged. To evaluate the clinical features and genotyping analysis of CA-MRSA in children in Taiwan, we conducted this study. Between July 2000 and June 2001, 198 episodes of S. aureus infection were identified in 191 children hospitalized at Chang-Gung Children's Hospital. The medical records of these children were retrospectively reviewed. The MRSA clinical isolates from each episode of infection, if available, were collected for pulsed-field gel electrophoresis (PFGE) typing and staphylococcal cassette chromosome mec (SCCmec) type determination. Among the 198 episodes of S. aureus infection, MRSA accounted for 47% of 114 CA infections and 62% of 84 hospital-acquired (HA) infections, respectively. Among 54 CA-MRSA infections, 32 episodes (59%) occurred in children without risk factors. Similar to HA-MRSA isolates, these CA-MRSA isolates were also multiresistant, with a high rate of resistance to clindamycin (93%) and erythromycin (94%), but 91% of them were susceptible to trimethoprim/sulfamethoxazole. Superficial soft tissue infection was the most common presentation, accounting for 65% of CA-MRSA infections. All 54 children with CA-MRSA infection recovered without sequelae, though 63% of 35 children with superficial soft tissue infection were treated with in vitro nonsusceptible antibiotics. Of the 83 clinical isolates (40 CA, 22 with no identified risk) available for analysis, 6 genotypes with 30 subtypes were identified. Three major PFGE patterns were identified, accounting for 94% of the isolates (92.5% for CA isolates, 95% for HA isolates). Type IV SCCmec was carried by 25 and 40% of CA and HA isolates, respectively. In Taiwan, MRSA was prevalent among pathogens of CA infections in children, and these CA isolates were multiresistant and genetically associated with HA isolates. In an area with a high prevalence of methicillin resistance, for children with putative S. aureus infection, even community-acquired, a glycopeptide-containing regimen should be considered for initial empirical therapy in the case of serious infection.


Functional implications of ubiquitous semicircular canal non-orthogonality in mammals.
The 'canonical model' of semicircular canal orientation in mammals assumes that 1) the three ipsilateral canals of an inner ear exist in orthogonal planes (i.e., orthogonality), 2) corresponding left and right canal pairs have equivalent angles (i.e., angle symmetry), and 3) contralateral synergistic canals occupy parallel planes (i.e., coplanarity). However, descriptions of vestibular anatomy that quantify semicircular canal orientation in single species often diverge substantially from this model. Data for primates further suggest that semicircular canal orthogonality varies predictably with the angular head velocities encountered in locomotion. These observations raise the possibility that orthogonality, symmetry, and coplanarity are misleading descriptors of semicircular canal orientation in mammals, and that deviations from these norms could have significant functional consequences. Here we critically assess the canonical model of semicircular canal orientation using high-resolution X-ray computed tomography scans of 39 mammal species. We find that substantial deviations from orthogonality, angle symmetry, and coplanarity are the rule for the mammals in our comparative sample. Furthermore, the degree to which the semicircular canals of a given species deviate from orthogonality is negatively correlated with estimated vestibular sensitivity. We conclude that the available comparative morphometric data do not support the canonical model and that its overemphasis as a heuristic generalization obscures a large amount of functionally relevant variation in semicircular canal orientation between species.


High-Resolution Time-Frequency Spectrum-Based Lung Function Test from a Smartphone Microphone.
In this paper, a smartphone-based lung function test, developed to estimate lung function parameters using a high-resolution time-frequency spectrum from a smartphone built-in microphone is presented. A method of estimation of the forced expiratory volume in 1 s divided by forced vital capacity (FEV₁/FVC) based on the variable frequency complex demodulation method (VFCDM) is first proposed. We evaluated our proposed method on 26 subjects, including 13 healthy subjects and 13 chronic obstructive pulmonary disease (COPD) patients, by comparing with the parameters clinically obtained from pulmonary function tests (PFTs). For the healthy subjects, we found that an absolute error (AE) and a root mean squared error (RMSE) of the FEV₁/FVC ratio were 4.49% ± 3.38% and 5.54%, respectively. For the COPD patients, we found that AE and RMSE from COPD patients were 10.30% ± 10.59% and 14.48%, respectively. For both groups, we compared the results using the continuous wavelet transform (CWT) and short-time Fourier transform (STFT), and found that VFCDM was superior to CWT and STFT. Further, to estimate other parameters, including forced vital capacity (FVC), forced expiratory volume in 1 s (FEV₁), and peak expiratory flow (PEF), regression analysis was conducted to establish a linear transformation. However, the parameters FVC, FEV1, and PEF had correlation factor r values of 0.323, 0.275, and -0.257, respectively, while FEV₁/FVC had an r value of 0.814. The results obtained suggest that only the FEV1/FVC ratio can be accurately estimated from a smartphone built-in microphone. The other parameters, including FVC, FEV1, and PEF, were subjective and dependent on the subject's familiarization with the test and performance of forced exhalation toward the microphone.


Fibroblast heterogeneity: Keystone of tissue homeostasis and pathology in inflammation and ageing.
Fibroblasts, derived from the embryonic mesenchyme, are a diverse array of cells with roles in development, homeostasis, repair, and disease across tissues. In doing so, fibroblasts maintain micro-environmental homeostasis and create tissue niches by producing a complex extracellular matrix (ECM) including various structural proteins. Although long considered phenotypically homogenous and functionally identical, the emergence of novel technologies such as single cell transcriptomics has allowed the identification of different phenotypic and cellular states to be attributed to fibroblasts, highlighting their role in tissue regulation and inflammation. Therefore, fibroblasts are now recognised as central actors in many diseases, increasing the need to discover new therapies targeting those cells. Herein, we review the phenotypic heterogeneity and functionality of these cells and their roles in health and disease.


Spoof four-wave mixing for all-optical wavelength conversion.
We present for the first time an all-optical wavelength conversion (AOWC) scheme supporting modulation format independency without requiring phase matching. The new scheme is named "spoof" four wave mixing (SFWM) and in contrast to the well-known FWM theory, where the induced dynamic refractive index grating modulates photons to create a wave at a new frequency, the SFWM is different in that the dynamic refractive index grating is generated in a nonlinear Bragg Grating (BG) to excite additional reflective peaks at either side of the original BG bandgap in reflection spectrum. This fundamental difference enable the SFWM to avoid the intrinsic shortcoming of stringent phase matching required in the conventional FWM, and allows AOWC with modulation format transparency and ultrabroad conversion range, which may have great potential applications for next generation of all-optical networks.


An extremely luminous panchromatic outburst from the nucleus of a distant galaxy.
Variable x-ray and γ-ray emission is characteristic of the most extreme physical processes in the universe. We present multiwavelength observations of a unique γ-ray-selected transient detected by the Swift satellite, accompanied by bright emission across the electromagnetic spectrum, and whose properties are unlike any previously observed source. We pinpoint the event to the center of a small, star-forming galaxy at redshift z = 0.3534. Its high-energy emission has lasted much longer than any γ-ray burst, whereas its peak luminosity was ∼100 times higher than bright active galactic nuclei. The association of the outburst with the center of its host galaxy suggests that this phenomenon has its origin in a rare mechanism involving the massive black hole in the nucleus of that galaxy.


GAD2 on chromosome 10p12 is a candidate gene for human obesity.
The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on Chromosome 10p11-12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of gamma-aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects) analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs) +61450 C>A and +83897 T>A (OR = 0.81, 95% CI [0.681-0.972], p = 0.0049) and an at-risk SNP (-243 A>G) for morbid obesity (OR = 1.3, 95% CI [1.053-1.585], p = 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype (chi(2) = 7.637, p = 0.02). In the murine insulinoma cell line betaTC3, the G at-risk allele of SNP -243 A>G increased six times GAD2 promoter activity (p < 0.0001) and induced a 6-fold higher affinity for nuclear extracts. The -243 A>G SNP was associated with higher hunger scores (p = 0.007) and disinhibition scores (p = 0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic beta cells, we analyzed GAD65 antibody level as a marker of beta-cell activity and of insulin secretion. In the control group, -243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of beta-cell function (p = 0.009 and 0.01, respectively). These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity.


Triptan-induced enhancement of neuronal nitric oxide synthase in trigeminal ganglion dural afferents underlies increased responsiveness to potential migraine triggers.
Migraine is a common neurological disorder often treated with triptans. Triptan overuse can lead to increased frequency of headache in some patients, a phenomenon termed medication overuse headache. Previous preclinical studies have demonstrated that repeated or sustained triptan administration for several days can elicit persistent neural adaptations in trigeminal ganglion cells innervating the dura, prominently characterized by increased labelling of neuronal profiles for calcitonin gene related peptide. Additionally, triptan administration elicited a behavioural syndrome of enhanced sensitivity to surrogate triggers of migraine that was maintained for weeks following discontinuation of drug, a phenomenon termed 'triptan-induced latent sensitization'. Here, we demonstrate that triptan administration elicits a long-lasting increase in identified rat trigeminal dural afferents labelled for neuronal nitric oxide synthase in the trigeminal ganglion. Cutaneous allodynia observed during the period of triptan administration was reversed by NXN-323, a selective inhibitor of neuronal nitric oxide synthase. Additionally, neuronal nitric oxide synthase inhibition prevented environmental stress-induced hypersensitivity in the post-triptan administration period. Co-administration of NXN-323 with sumatriptan over several days prevented the expression of allodynia and enhanced sensitivity to stress observed following latent sensitization, but not the triptan-induced increased labelling of neuronal nitric oxide synthase in dural afferents. Triptan administration thus promotes increased expression of neuronal nitric oxide synthase in dural afferents, which is critical for enhanced sensitivity to environmental stress. These data provide a biological basis for increased frequency of headache following triptans and highlight the potential clinical utility of neuronal nitric oxide synthase inhibition in preventing or treating medication overuse headache.


Negotiating identity: a qualitative analysis of stigma and support seeking for individuals with cerebral palsy.
The current research investigates how adults with cerebral palsy construct their personal and social identities in the face of stigma when support seeking, and considers the dilemmas they might face when doing so. Participants were 28 adults with cerebral palsy who completed an online survey reporting on their identity as a person with cerebral palsy and their experiences of stigma when seeking and accessing support. Qualitative analyses indicated that the majority of participants sought support to help manage their cerebral palsy. Of these, half reported experiencing stigma in these environments, although they largely continued seeking support despite this. The majority viewed both their personal identity (i.e. as a unique individual) and their social identity (i.e. as a person with cerebral palsy) as important to their sense of self. However, how participants constructed their identity also appeared to vary according to context. While they appeared to value being seen as an individual to receive support that was unique to their needs (their personal identity), they also reported valuing the group to facilitate coping with stigma (their social identity). Yet, despite their utilities, enacting their identity in each of these ways was associated with costs. In order to access desired support, they had to incorporate their social identity as similar to other disabled people, which led to stigmatization through feelings of difference to the non-disabled. Conversely emphasizing individuality and difference from the disabled stereotype was associated with concerns about the degree to which their suitability for support might be questioned by their care provider. As has been observed in many fields, stigma can complicate identity. In this domain, people with cerebral palsy face a number of threats in how they construe their identity, both in navigating stigma and maintaining access to needed support. Implications for Rehabilitation Stigma in help and support settings remains a significant problem for adults with cerebral palsy (CP). This creates dilemmas regarding how they view and construct their identity in the contexts of stigma and support-seeking. It is important for specialists to recognize that the needs of adults with CP are unique, and so provided services should be tailored to the individual. Healthcare providers should also encourage their patients to actively engage with online disability support groups in order to build a meaningful social identity with other people with CP.


Coupling Between and Among Ammonia Oxidizers and Nitrite Oxidizers in Grassland Mesocosms Submitted to Elevated CO2 and Nitrogen Supply.
Many studies have assessed the responses of soil microbial functional groups to increases in atmospheric CO2 or N deposition alone and more rarely in combination. However, the effects of elevated CO2 and N on the (de)coupling between different microbial functional groups (e.g., different groups of nitrifiers) have been barely studied, despite potential consequences for ecosystem functioning. Here, we investigated the short-term combined effects of elevated CO2 and N supply on the abundances of the four main microbial groups involved in soil nitrification: ammonia-oxidizing archaea (AOA), ammonia-oxidizing bacteria (AOB), and nitrite-oxidizing bacteria (belonging to the genera Nitrobacter and Nitrospira) in grassland mesocosms. AOB and AOA abundances responded differently to the treatments: N addition increased AOB abundance, but did not alter AOA abundance. Nitrobacter and Nitrospira abundances also showed contrasted responses to the treatments: N addition increased Nitrobacter abundance, but decreased Nitrospira abundance. Our results support the idea of a niche differentiation between AOB and AOA, and between Nitrobacter and Nitrospira. AOB and Nitrobacter were both promoted at high N and C conditions (and low soil water content for Nitrobacter), while AOA and Nitrospira were favored at low N and C conditions (and high soil water content for Nitrospira). In addition, Nitrobacter abundance was positively correlated to AOB abundance and Nitrospira abundance to AOA abundance. Our results suggest that the couplings between ammonia and nitrite oxidizers are influenced by soil N availability. Multiple environmental changes may thus elicit rapid and contrasted responses between and among the soil ammonia and nitrite oxidizers due to their different ecological requirements.


Salesperson knowledge of teen-specific vehicle safety features.
Teen drivers experience elevated crash risk compared with experienced adult drivers. Active parental oversight can improve teen driving safety, and several manufacturers have released teen-focused safety features over the past decade. Still, parents don't always use these systems and often don't even know their vehicle is equipped. A recent survey found that parents who do know about such systems on their vehicle first learned of them from a salesperson at a dealership. The current study examined how salespeople discuss and sell teen-specific safety systems on vehicles to parents shopping for a new teen driver. The study focused on four vehicle brands. Two researchers posed as the parents of a new teen driver who were shopping for a vehicle for their teen. They entered dealerships and conducted semistructured interviews with the salesperson that approached them, using prompts of increasing specificity about their teen driver and their interest in safety, and tracking at what point each salesperson mentioned their brand's teen-specific systems, what features they mentioned, and how accurate those mentions were. Thirty of the 40 participating salespeople were able to mention their brand's teen-specific system at some point during the procedure. Hyundai salespeople most consistently brought up their brand's teen features, and Chevy salespeople mentioned the most features while Ford salespeople mentioned the fewest. Salespeople often mentioned speed-related features, although the most commonly mentioned features varied by brand. No participating salespeople reported receiving training specifically about their brand's teen features. Most salespeople approached did mention their brand's teen-focused safety systems, but did not usually do so until they had received more targeted prompts. Information these salespeople did share was often vague and general. Salespeople are a key source of information about a vehicle's specific and relevant safety features, and parents without at least some vague preexisting knowledge about the systems or features that could be available on a vehicle of interest are not likely to leave a dealership with a clear idea of all available features that could aid their efforts to keep their teen drivers safe.


Requirement for a beta 2-microglobulin-associated Fc receptor for acquisition of maternal IgG by fetal and neonatal mice.
There is considerable evidence to suggest that an FcR similar in structure to class I MHC Ags, neonatal Fc receptor (FcRn), transports IgG across the intestinal epithelium of suckling mice. However, this has not previously been shown definitively, nor has it been shown whether FcRn is the only, or even the major, IgG transporter in the neonatal mouse gut. We report here that neonatal mice homozygous for a targeted disruption of the beta 2microglobulin (beta 2m) gene, which encodes one subunit of FcRn, had reduced FcRn alpha-chain at the lumenal plasma membrane of intestinal cells. These mice had strikingly lower serum IgG levels during the first month after birth than littermates that possessed functional FcRn. Furthermore, we found by fostering mice on mothers with a different IgG allotype that all of the IgG in sera of beta 2m-/- mice was endogenous, and that none was obtained from milk. We conclude that FcRn is the only transporter of IgG from mother to young in the mouse. The onset of IgG synthesis in mice that received no milk IgG lagged behind that in siblings with normal IgG transport, suggesting that maternal IgG stimulates Ab production in the neonate. We noted no difference between the IgG concentrations in the milk of beta 2m-/- and beta 2m+/- mice, indicating that FcRn is not involved in the secretion of IgG into milk.


Rare SF3B1 R625 mutations in cutaneous melanoma.
RNA splicing is the cellular process that has only recently been found to be an important target for various cancers. Among the spliceosome genes that are involved in cancers, SF3B1 is most frequently mutated. Recurrent mutation in codon 625 has been found in uveal melanoma, but this mutation has not been identified in cutaneous melanoma. We used whole-exome sequencing to explore the mutational landscape of 295 melanoma samples, 231 of which are cutaneous melanoma. Among these cutaneous melanoma samples, we found two samples with R625 mutation in SF3B1 gene. The results were validated by Sanger sequencing. We conclude that SF3B1 R625 mutation does occur in cutaneous melanoma, although with a low frequency (∼1%).


Stroke recurrence rates among patients with symptomatic intracranial vertebrobasilar stenoses: systematic review and meta-analysis.
A recent randomized trial of patients with primarily anterior circulation intracranial artery stenosis showed that intensive medical therapy was superior to intracranial stenting in preventing recurrent stroke. The rate of stroke recurrence or death in symptomatic intracranial vertebrobasilar stenosis with medical therapy alone may be especially high, and rates compared with endovascular therapy need further study. We conducted a systematic review and meta-analysis of studies reporting the rates of stroke recurrence or death (the primary outcome) in symptomatic intracranial vertebrobasilar stenosis with medical or endovascular treatment over a minimum follow-up period of 6 months. We included all studies in any language indexed in MEDLINE or EMBASE, supplemented by bibliography searches and by contacting the authors. The secondary endpoints were stroke recurrence, and basilar artery and vertebral artery stroke recurrence rates. 23 studies (592 medical treatment patients and 480 endovascular treatment patients) were included. The risk of combined stroke recurrence or death was 14.8 per 100 person-years (95% CI 9.5 to 20.1) in the medical group compared with 8.9 per 100 person-years (95% CI 6.9 to 11.0) in the endovascular group. The incidence rate ratio was 1.3 (95% CI 1.0 to 1.7). The stroke recurrence rate was 9.6 per 100 person-years (95% CI 5.1 to 14.1) in the medical group compared with 7.2 per 100 person-years (95% CI 5.5 to 9.0) in the endovascular group. Our results showed that the risk of stroke recurrence or death or the risk of stroke recurrence alone was comparable between the medical and endovascular therapy groups. A small preventive effect of endovascular therapy may exist, particularly if the 30 day postprocedural risk is reduced.