Cancer of childhood in sub-Saharan Africa.
Measurement of incidence rates of childhood cancer in Africa is difficult. The study 'Cancer of Childhood in sub Saharan Africa' brings together results from 16 population-based registries which, as members of the African Cancer Registry Network (AFCRN), have been evaluated as achieving adequate coverage of their target population. The cancers are classified according to the third revision of the International Classification of Childhood Cancer (ICCC-3) and recorded rates in Africa are compared with those in childhood populations in the UK, France, and the USA. It is clear that, in many centres, lack of adequate diagnostic and treatment facilities leads to under-diagnosis (and enumeration) of leukaemias and brain cancers. However, for several childhood cancers, incidence rates in Africa are higher than those in high-income countries. This applies to infection-related cancers such as Kaposi sarcoma, Burkitt lymphoma, Hodgkin lymphoma and hepatocellular carcinoma, and also to two common embryonal cancers - retinoblastoma and nephroblastoma. These (and other) observations are unlikely to be artefact, and are of considerable interest when considering possible aetiological factors, including ethnic differences in risk (and hence genetic/familial antecedents). The data reported are the most extensive so far available on the incidence of cancer in sub Saharan Africa, and clearly indicate the need for more resources to be devoted to cancer registration, especially in the childhood age range, as part of an overall programme to improve the availability of diagnosis and treatment of this group of cancers, many of which have-potentially-an excellent prognosis.


A highly efficient g-C3N4/SiO2 heterojunction: the role of SiO2 in the enhancement of visible light photocatalytic activity.
SiO2, an insulator, hardly has any photocatalytic acitivity due to its intrinsic property, and it is generally used as a hard template to increase the surface area of catalysts. However, in this work, we found that the surface state of the insulator SiO2 can promote the migration of photogenerated charge carriers, leading to the enhancement of the photooxidation ability of graphitic carbon nitride (g-C3N4). A one-pot calcination method was employed to prepare g-C3N4/SiO2 composites using melamine and SiO2 as precursors. The composites present considerably high photocatalytic degradation activities for 2,4-dichlorophenol (2,4-DCP) and rhodamine B (RhB) under visible light (λ > 420 nm) irradiation, which are about 1.53 and 4.18 times as high as those of bulk g-C3N4, respectively. The enhancement of the photocatalytic activity is due to the fact that the introduction of the insulator SiO2 in g-C3N4/SiO2 composites can greatly improve the specific surface area of the composites; more importantly, the impurity energy level of SiO2 can help accelerate the separation and transfer of electron-hole pairs of g-C3N4. Electron paramagnetic resonance (EPR) spectroscopy and trapping experiments with different radical scavengers show that the main active species of g-C3N4 are superoxide radicals, while holes also play a role in photodegradation. For g-C3N4/SiO2-5, besides superoxide radicals and holes, the effect of hydroxyl radicals was greatly improved. Finally, a possible mechanism for the photogenerated charge carrier migration of the g-C3N4/SiO2 photocatalyst was proposed.


Unusually extensive networks of vocal recognition in African elephants.
Research on acoustic communication has often focused on signalling between territorial individuals or static neighbouring groups. Under these circumstances, receivers have the opportunity to learn to recognize the signals only of the limited number of conspecifics with which they are in auditory contact. In some mammals, however, social units move freely with respect to one another and range widely, providing individuals with opportunities to learn to recognize the signals of a wide range of conspecifics in addition to those of their immediate neighbours. We conducted playback experiments on African elephants, Loxodonta africana, in Amboseli National Park, Kenya, to determine the extent to which adult female elephants, which have a highly fluid social system, can recognize others in the population through infrasonic contact calls. Female elephants could distinguish the calls of female family and bond group members from those of females outside of these categories; moreover, they could also discriminate between the calls of family units further removed than bond group members, on the basis of how frequently they encountered them. We estimated that subjects would have to be familiar with the contact calls of a mean of 14 families in the population (containing around 100 adult females in total), in order to perform these discriminations. Female elephants thus appear to have unusually extensive networks of vocal recognition, which may prove to be typical of long-lived species that have both fluid social systems and the means for long-distance vocal communication. Copyright 2000 The Association for the Study of Animal Behaviour.


Very low pressures drive ventilatory flow in chimaeroid fishes.
Chimaera (Holocephali) are cartilaginous fishes with flexible operculi rather than external gill slits, suggesting ventilation occurs in a manner different from other fishes. We examined holocephalan ventilation morphology, behavior, and performance by anatomical investigations, high-speed video, and in vivo pressure measurements from the buccal and parabranchial cranial cavities in Hydrolagus colliei and Callorhinchus callorynchus. Ventilatory modes ranged from quiet resting breathing to rapid "active" breathing, yet external cranial movements-excepting the passive movement of the opercular flap-were always extremely subtle, and pressures generated were one to two orders of magnitude lower than those of other fishes. To explain ventilation with such minimal pressure generation and cranial motion, we propose an "accordion" model, whereby rostrocaudal movement of the visceral arches drives pressure differentials, albeit with little lateral or ventral movement. Chimaeroids have comparatively large oropharyngeal cavities, which can move fluid with a smaller linear dimension change than the comparatively smaller cavities of other fishes. Orobranchial pressures are often less than parabranchial pressures, suggesting flow in the "wrong" direction; however, the long gill curtains of chimaeroids may passively restrict backflow. We suggest that constraints on holocephalan jaw and hyoid movements were compensated for evolutionarily by novel visceral arch mechanics and kinematics.


Ligand stimulation of CD95 induces activation of Plk3 followed by phosphorylation of caspase-8.
Upon interaction of the CD95 receptor with its ligand, sequential association of the adaptor molecule FADD (MORT1), pro-forms of caspases-8/10, and the caspase-8/10 regulator c-FLIP leads to the formation of a death-inducing signaling complex. Here, we identify polo-like kinase (Plk) 3 as a new interaction partner of the death receptor CD95. The enzymatic activity of Plk3 increases following interaction of the CD95 receptor with its ligand. Knockout (KO) or knockdown of caspase-8, CD95 or FADD prevents activation of Plk3 upon CD95 stimulation, suggesting a requirement of a functional DISC for Plk3 activation. Furthermore, we identify caspase-8 as a new substrate for Plk3. Phosphorylation occurs on T273 and results in stimulation of caspase-8 proapoptotic function. Stimulation of CD95 in cells expressing a non-phosphorylatable caspase-8-T273A mutant in a rescue experiment or in Plk3-KO cells generated by CRISPR/Cas9 reduces the processing of caspase-8 prominently. Low T273 phosphorylation correlates significantly with low Plk3 expression in a cohort of 95 anal tumor patients. Our data suggest a novel mechanism of kinase activation within the Plk family and propose a new model for the stimulation of the extrinsic death pathway in tumors with high Plk3 expression.


High-resolution vibration-rotational spectra and rotational perturbation of the OO-stretching (ν6) band of CH2OO between 879.5 and 932.0 cm-1.
We report the observation of a rotationally resolved ν6 band associated with the OO-stretching mode of the simplest Criegee intermediate, CH2OO, in the range of 879.5-932.0 cm-1 (11.37-10.73 μm) at an optical resolution of 0.0015 cm-1. The spectra were recorded with a tunable cw external-cavity quantum-cascade laser (EC-QCL) system coupled with a Herriott multipass absorption cell. Over one thousand lines were assigned to determine the rovibrational parameters of the ν6 band. Rotational parameters A', B', and C' and higher-order parameters ΔJ, ΔJK, ΔK, δJ, and δK were determined precisely. Rotational perturbations for Ka' = 3, Ka' = 6, and Ka' ≥ 11 on high-J levels were observed. In particular, for Ka' = 6, frequency shifts as a function of J' showed an avoided crossing; the shifts were analyzed in terms of a Coriolis interaction between modes ν6 and ν8 of CH2OO. According to the distinct temporal profiles, lines of a hot band near 899.5 cm-1 were also identified.


In vitro and in vivo antifungal activities of ER-30346, a novel oral triazole with a broad antifungal spectrum.
ER-30346 is a novel oral triazole with a broad spectrum of potent activity against a wide range of fungi. ER-30346, with MICs at which 90% of the strains tested are inhibited (MIC90s) ranging from 0.025 to 0.78 microgram/ml, was 4 to 32 times more active than itraconazole, fluconazole, and amphotericin B against Candida albicans, Candida parapsilosis, and Candida glabrata. Against Candida tropicalis, ER-30346, with an MIC90 of 12.5 micrograms/ml, was 2 to > 8 times more active than itraconazole and fluconazole, but was 16 times less active than amphotericin B. ER-30346 (MIC90, 0.78 microgram/ml) was four to eight times more active than fluconazole and amphotericin B and had activity comparable to that of itraconazole against Trichosporon beigelli. The MIC90s of ER-30346 were 0.10 microgram/ml for Cryptococcus neoformans and 0.39 microgram/ml for Aspergillus fumigatus. ER-30346 was 2 to 8 times more active than itraconazole and amphotericin B and 32 to > 256 times more active than fluconazole. ER-30346 also showed good activity against dermatophytes, with MICs ranging from 0.05 to 0.39 microgram/ml, and its activity was comparable to or 2 to 16 times higher than those of itraconazole and amphotericin B and > 32 times higher than that of fluconazole. In vivo activity was evaluated with systemic infections in mice. Against systemic candidiasis and cryptococcosis, ER-30346 was comparable in efficacy to fluconazole and was more effective than itraconazole. Of the drugs tested, ER-30346 was the most effective drug against systemic aspergillosis. We studied the levels of ER-30346 in mouse plasma. The maximum concentration of drug in plasma and the area under the concentration-time curve for ER-30346 showed good linearity over a range of doses from 2 to 40 mg/kg of body weight.


Tumor imprint cytology of ovarian ependymoma. A case report.
Ependymoma is a tumor that usually develops in the central nervous system and is extremely rare in the ovary. The first case of ovarian ependymoma was reported by Kleinman et al. (Kleinman GM, Young RH, Scully RE. Ependymoma of the ovary: report of three cases. Hum Pathol 1984;15:632-8.) in 1984, and only eight cases have been reported since then. Criteria for the histopathologic diagnosis of ependymoma are already established, but there has been no investigation of the cytologic diagnosis of ovarian ependymoma. An imprint cytologic specimen was obtained from a recurrent ovarian ependymoma. The imprint cytologic features were compared with the findings of histologic examination, immunostaining, and electron microscopy. Imprint cytology revealed clusters of small cells with tapering cytoplasmic processes and a round nucleus. On the basis of these features, a neurogenic tumor could be included in the differential diagnosis. Furthermore, many rosette-like collections of cells that were suggestive of ependymal rosettes or perivascular pseudorosettes, characteristic of ependymoma, were found. The presence of ependymal rosettes and perivascular pseudorosettes also were confirmed by the histopathologic examination. Together with positive immunostaining for glial fibrillary acidic protein, this led to the diagnosis of ependymoma, which also was supported by the electron microscopic findings. Careful observation of the imprint cytologic specimen of an ovarian ependymoma should reveal numerous rosette-like collections of cells that were suggestive of ependymal rosettes or perivascular pseudorosettes. In addition, if we remember that ependymoma can develop in the ovary and find cells with tapering processes that suggest a neurogenic tumor, it may be possible to detect histologic features characteristic of ependymoma by the imprint cytology. To our knowledge, this is the first report on the imprint cytologic diagnosis of ependymoma originating in the ovary.


Cogniphobia in Mild Traumatic Brain Injury.
Cogniphobia refers to avoidance of mental exertion out of a fear of developing or exacerbating a headache. Headaches are very common after mild traumatic brain injury (mTBI) and often become chronic. Cogniphobia is hypothesized to contribute to poor cognitive test performance and persistent disability in some patients with mTBI. Eighty patients with mTBI and post-traumatic headaches were recruited from specialty outpatient clinics. They completed a battery of questionnaires (including a cogniphobia scale) and neuropsychological tests (the National Institutes of Health Toolbox Cognition Battery and the Medical Symptom Validity Test) at 2-3 months post injury, in a cross-sectional design. Participants with more severe headaches reported higher levels of cogniphobia. Cogniphobia was associated with lower performance on memory testing (but not other cognitive tests), independent of headache severity. Participants who avoided mental exertion also tended to avoid physical activity and traumatic stress triggers. The findings provide preliminary support for the role of cogniphobia in persistent cognitive difficulties after mTBI, and suggest that cogniphobia may reflect a broader avoidant coping style.


Annular beam scintillations in strong turbulence.
A scintillation index formulation for annular beams in strong turbulence is developed that is also valid in moderate and weak turbulence. In our derivation, a modified Rytov solution is employed to obtain the small-scale and large-scale scintillation indices of annular beams by utilizing the amplitude spatial filtering of the atmospheric spectrum. Our solution yields only the on-axis scintillation index for the annular beam and correctly reduces to the existing strong turbulence results for the Gaussian beam--thus plane and spherical wave scintillation indices--and also correctly yields the existing weak turbulence annular beam scintillations. Compared to collimated Gaussian beam, plane, and spherical wave scintillations, collimated annular beams seem to be advantageous in the weak regime but lose this advantage in strongly turbulent atmosphere. It is observed that the contribution of annular beam scintillations comes mainly from the small-scale effects. At a fixed primary beam size, the scintillations of thinner collimated annular beams compared to thicker collimated annular beams are smaller in moderate turbulence but larger in strong turbulence; however, thinner annular beams of finite focal length have a smaller scintillation index than the thicker annular beams in strong turbulence. Decrease in the focal length decreases the annular beam scintillations in strong turbulence. Examining constant area annular beams, smaller primary sized annular structures have larger scintillations in moderate but smaller scintillations in strong turbulence.


Nonlinear trimer resonators for compact ultra-fast switching.
We propose and numerically verify a scheme for compact optical modulation which can enable complex directional switching of signals in integrated micro-optical circuits within hundreds of femtoseconds. The scheme is based on a trimer comprised of two identical silica whispering gallery mode (WGM) microresonators spaced by a central non-linear WGM resonator. The non-linear resonator is in the form of a silica cylinder with a thin coating of an ultrafast Kerr nonlinear material (a J-aggregate of cyanine dye). Using a two-dimensional finite-difference time-domain method and realistic material and structural parameters, we investigated the near-field coupling from a waveguide to the trimer and the subsequent switching process. In our scheme the sandwiched central control resonator has a resonant frequency that is mismatched to that of the input and output resonators. Therefore the optical energy is coupled from the waveguide into only the primary resonator in linear operation. However, for control light intensities of more than approximately 10(-2) W/microm the effective index and hence eigenfrequency of the central resonator can be shifted to match that of its neighbors and hence the optical energy can be redirected.


Predictions of species interactions from consumer-resource theory: experimental tests with grasshoppers and plants.
We tested the ability of consumer-resource theory to predict direct and indirect interactions among species, using an experimental system of insect herbivores and herbaceous plants. Specifically, we examined interactions among three species of grasshoppers (Melanoplus femur-rubrum, Spharagemon collare, andPhoetaliotes nebrascensis; Orthoptera, Acrididae) and herbaceous plants in experimental field cages placed over existing fertilized or unfertilized vegetation in a Minnesota old field. For the conditions inside these cages, we addressed whether (1) grasshopper diet predicted the presence of competition among grasshopper species, and (2) direct effects of grasshoppers on plants produced indirect interactions among plants, grasshoppers and soil nitrogen. Overall,M. femur-rubrum ate a greater proportion of forbs in cages, while the other two species ate primarily grasses. As expected, a pair of grasshopper species competed if they had similar diets. However, there were important exceptions that could be explained from observed indirect effects, although alternative explanations were also possible. First, all three grasshopper species significantly shifted their diets in the presence of other species, and these shifts occurred most often when competition was expected or occurred. Second, the two grassfeeding species reduced the biomass of the dominant grass (Schizachyrium scoparium) and increased available soil nitrogen and biomass of forbs. This effect may explain why the grass-feedingP. nebrascensis had a positive effect on the forb-feedingM. femur-rubrum on unfertilized plots. Overall, we show that direct effects of consumers on resources can predict competition and other important indirect interactions within a community.


HUMAN IMPACTS. The unique ecology of human predators.
Paradigms of sustainable exploitation focus on population dynamics of prey and yields to humanity but ignore the behavior of humans as predators. We compared patterns of predation by contemporary hunters and fishers with those of other predators that compete over shared prey (terrestrial mammals and marine fishes). Our global survey (2125 estimates of annual finite exploitation rate) revealed that humans kill adult prey, the reproductive capital of populations, at much higher median rates than other predators (up to 14 times higher), with particularly intense exploitation of terrestrial carnivores and fishes. Given this competitive dominance, impacts on predators, and other unique predatory behavior, we suggest that humans function as an unsustainable "super predator," which—unless additionally constrained by managers—will continue to alter ecological and evolutionary processes globally.


Updated therapeutic strategy for adult low-grade glioma stratified by resection and tumor subtype.
The importance of surgical resection for patients with supratentorial low-grade glioma (LGG) remains controversial. This retrospective study of patients (n = 153) treated between 2000 to 2010 at a single institution assessed whether increasing the extent of resection (EOR) was associated with improved progression-free survival (PFS) and overall survival (OS). Histological subtypes of World Health Organization grade II tumors were as follows: diffuse astrocytoma in 49 patients (32.0%), oligoastrocytoma in 45 patients (29.4%), and oligodendroglioma in 59 patients (38.6%). Median pre- and postoperative tumor volumes and median EOR were 29.0 cm(3) (range 0.7-162 cm(3)) and 1.7 cm(3) (range 0-135.7 cm(3)) and 95%, respectively. Five- and 10-year OS for all LGG patients were 95.1% and 85.4%, respectively. Eight-year OS for diffuse astrocytoma, oligoastrocytoma, and oligodendroglioma were 70.7%, 91.2%, and 98.3%, respectively. Five-year PFS for diffuse astrocytoma, oligoastrocytoma, and oligodendroglioma were 42.6%, 71.3%, and 62.7%, respectively. Patients were divided into two groups by EOR ≥90% and <90%, and OS and PFS were analyzed. Both OS and PFS were significantly longer in patients with ≥90% EOR. Increased EOR resulted in better PFS for diffuse astrocytoma but not for oligodendroglioma. Multivariate analysis identified age and EOR as parameters significantly associated with OS. The only parameter associated with PFS was EOR. Based on these findings, we established updated therapeutic strategies for LGG. If surgery resulted in EOR <90%, patients with astrocytoma will require second-look surgery, whereas patients with oligodendroglioma or oligoastrocytoma, which are sensitive to chemotherapy, will be treated with chemotherapy.


How effective is orthotic treatment in patients with recurrent diabetic foot ulcers?
We assessed the efficacy of customized foot orthotic therapy by comparing reulceration rates, minor amputation rates, and work and daily living activities before and after therapy. Peak plantar pressures and peak plantar impulses were compared with the patients not wearing and wearing their prescribed footwear. One hundred seventeen patients with diabetes were prescribed therapeutic insoles and footwear based on the results of a detailed biomechanical study and were followed for 2 years. All of the patients had a history of foot ulcers, but none had undergone previous orthotic therapy. Before treatment, the reulceration rate was 79% and the amputation rate was 54%. Two years after the start of orthotic therapy, the reulceration rate was 15% and the amputation rate was 6%. Orthotic therapy reduced peak plantar pressures in patients with reulcerations and in those without (P < .05), although a significant decrease in peak plantar impulses was achieved only in patients not experiencing reulceration. Sick leave was reduced from 100% to 26%. Personalized orthotic therapy targeted at reducing plantar pressures by off-loading protects high-risk patients against reulceration. Treatment reduced the reulceration rate and peak plantar pressures, leading to patients' return to work or other activities.


Life satisfaction in association with self-efficacy and stressor experience in adolescents - self-efficacy as a potential moderator.
This paper reports associations among socio-demographic variables, stressor experience, self-efficacy and life satisfaction among Norwegian adolescents aged 15-21 years and the potential moderating role of self-efficacy on the association between stressor experience and life satisfaction. The cross-sectional school-based survey study involved 1816 upper-secondary school students from Mid-Norway. Data were analysed with independent samples t test, Pearson's product moment correlation and multiple linear regression analysis. Bivariate results showed that boys scored higher than girls on life satisfaction and self-efficacy, whereas girls scored higher than boys on all stressor domains. Multiple linear regression analysis showed that life satisfaction declined weakly with age, whereas stronger family economy and having parents who work full-time associated with higher life satisfaction. Stress with teacher interaction, peer pressure, home life, school attendance, school-leisure conflict and school performance were all negatively associated with life satisfaction, whereas self-efficacy associated positively and strongly with life satisfaction. Self-efficacy moderated the association between both interpersonal and school-related stressors and life satisfaction. The results provide support for the unique role of stressor experience and self-efficacy in association with adolescents' life satisfaction as well as self-efficacy as a stress moderator in relation to life satisfaction.


Therapeutic strategies targeting cancer stem cells.
Cancer stem cells (CSCs) are undifferentiated cancer cells with a high tumorigenic activity, the ability to undergo self-renewal, and a multilineage differentiation potential. Cancer stem cells are responsible for the development of tumor cell heterogeneity, a key feature for resistance to anticancer treatments including conventional chemotherapy, radiation therapy, and molecularly targeted therapy. Furthermore, minimal residual disease, the major cause of cancer recurrence and metastasis, is enriched in CSCs. Cancer stem cells also possess the property of "robustness", which encompasses several characteristics including a slow cell cycle, the ability to detoxify or mediate the efflux of cytotoxic agents, resistance to oxidative stress, and a rapid response to DNA damage, all of which contribute to the development of therapeutic resistance. The identification of mechanisms underlying such characteristics and the development of novel approaches to target them will be required for the therapeutic elimination of CSCs and the complete eradication of tumors. In this review, we focus on two prospective therapeutic approaches that target CSCs with the aim of disrupting their quiescence or redox defense capability.


Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates.
The rise of antibiotic resistance in many bacterial pathogens has been driven by the spread of a few successful strains, suggesting that some bacteria are genetically pre-disposed to evolving resistance. Here, we test this hypothesis by challenging a diverse set of 222 isolates of Staphylococcus aureus with the antibiotic ciprofloxacin in a large-scale evolution experiment. We find that a single efflux pump, norA, causes widespread variation in evolvability across isolates. Elevated norA expression potentiates evolution by increasing the fitness benefit provided by DNA topoisomerase mutations under ciprofloxacin treatment. Amplification of norA provides a further mechanism of rapid evolution in isolates from the CC398 lineage. Crucially, chemical inhibition of NorA effectively prevents the evolution of resistance in all isolates. Our study shows that pre-existing genetic diversity plays a key role in shaping resistance evolution, and it may be possible to predict which strains are likely to evolve resistance and to optimize inhibitor use to prevent this outcome.


Opioid Prescribing in the Pediatric Orthopaedic Trauma Population.
The purpose of this article is to describe opioid prescribing patterns for children with orthopaedic injuries. A retrospective chart review was conducted on pediatric orthopaedic trauma patients (n = 124) who were discharged from the hospital or emergency department or had a clinic visit during a 1-month period. Patient demographics, prescription specifics, injury details, and fracture fixation information were collected. Results show that most children received opioids after injury (82.3%). While children undergoing operative fixation typically received opioids, only 39.5% with closed reduction did. Hydrocodone- acetaminophen accounted for 93% of prescriptions, but adolescents were more likely to receive other drugs. There was a significant trend of increasing daily dosage with increased age; 36.73% of adolescents received > 50 morphine milligram equivalents per day. Children with orthopaedic injuries are typically prescribed opioids; older children more commonly receive higher dosages. Further study is needed to define prescribing trends across facility and specialty types to aid in development of standardized prescribing guidelines. (Journal of Surgical Orthopaedic Advances 27(4):269-273, 2018).


Flattened dispersion in silicon slot waveguides.
We propose a silicon strip/slot hybrid waveguide that produces flattened dispersion of 0 ± 16 ps/(nm∙km), over a 553-nm wavelength range, which is 20 times flatter than previous results. Different from previously reported slot waveguides, the strip/slot hybrid waveguide employs the mode transition from a strip mode to a slot mode to introduce unique waveguide dispersion. The flat dispersion profile is featured by three zero-dispersion wavelengths, which is obtained for the first time in on-chip silicon waveguides, to the best of our knowledge. The waveguide exhibits flattened dispersion from 1562-nm to 2115-nm wavelength, which is potentially useful for both telecom and mid-infrared applications.


Experimental validation of novel genes predicted in the un-annotated regions of the Arabidopsis genome.
Several lines of evidence support the existence of novel genes and other transcribed units which have not yet been annotated in the Arabidopsis genome. Two gene prediction programs which make use of comparative genomic analysis, Twinscan and EuGene, have recently been deployed on the Arabidopsis genome. The ability of these programs to make use of sequence data from other species has allowed both Twinscan and EuGene to predict over 1000 genes that are intergenic with respect to the most recent annotation release. A high throughput RACE pipeline was utilized in an attempt to verify the structure and expression of these novel genes. 1,071 un-annotated loci were targeted by RACE, and full length sequence coverage was obtained for 35% of the targeted genes. We have verified the structure and expression of 378 genes that were not present within the most recent release of the Arabidopsis genome annotation. These 378 genes represent a structurally diverse set of transcripts and encode a functionally diverse set of proteins. We have investigated the accuracy of the Twinscan and EuGene gene prediction programs and found them to be reliable predictors of gene structure in Arabidopsis. Several hundred previously un-annotated genes were validated by this work. Based upon this information derived from these efforts it is likely that the Arabidopsis genome annotation continues to overlook several hundred protein coding genes.


Using participatory action research to identify strategies to improve pandemic vaccination.
Developing and implementing effective strategies to increase influenza vaccination rates among health care personnel is an ongoing challenge, especially during a pandemic. We used participatory action research (PAR) methodology to identify targeted vaccination interventions that could potentially improve vaccine uptake in a medical center. Front-line medical center personnel were recruited to participate in 2 PAR teams (clinical and nonclinical staff). Data from a recent medical center survey on barriers and facilitators to influenza (seasonal, pandemic, and combination) vaccine uptake were reviewed, and strategies to increase vaccination rates among medical center personnel were identified. Feasible, creative, and low-cost interventions were identified, including organizational strategies that differed from investigator-identified interventions. The recommended strategies also differed by team. The nonclinical team suggested programs focused on dispelling vaccination-related myths, and the clinical team suggested campaigns emphasizing the importance of vaccination to protect patients. PAR methodology was useful to identify innovative and targeted recommendations for increasing vaccine uptake. By involving representative front-line workers, PAR may help medical centers improve influenza vaccination rates across all work groups.


Electromagnetic cosine-Gaussian Schell-model beams in free space and atmospheric turbulence.
A recently introduced class of scalar cosine-Gaussian Schell-Model [CGSM] beams is generalized to electromagnetic theory. The realizability conditions and the beam conditions on the source parameters are derived. Analytical formulas for the cross-spectral density matrix elements of the electromagnetic cosine-Gaussian Schell-model [EM CGSM] beams propagating in isotropic random medium are derived. It is found that the EM CGSM beams possess single-ring or double-ring intensity profiles, depending of source parameters. As two examples, the statistical characteristics of the EM CGSM beams propagating in free space and non-Kolmogorov turbulent atmosphere are studied numerically. The effects of the fractal constant of the atmospheric spectrum and the refractive-index structure constant on such characteristics are analyzed in detail.


The genome sequence of segmental allotetraploid peanut Arachis hypogaea.
Like many other crops, the cultivated peanut (Arachis hypogaea L.) is of hybrid origin and has a polyploid genome that contains essentially complete sets of chromosomes from two ancestral species. Here we report the genome sequence of peanut and show that after its polyploid origin, the genome has evolved through mobile-element activity, deletions and by the flow of genetic information between corresponding ancestral chromosomes (that is, homeologous recombination). Uniformity of patterns of homeologous recombination at the ends of chromosomes favors a single origin for cultivated peanut and its wild counterpart A. monticola. However, through much of the genome, homeologous recombination has created diversity. Using new polyploid hybrids made from the ancestral species, we show how this can generate phenotypic changes such as spontaneous changes in the color of the flowers. We suggest that diversity generated by these genetic mechanisms helped to favor the domestication of the polyploid A. hypogaea over other diploid Arachis species cultivated by humans.


Reliability of a commercially available threshold loading device in healthy subjects and in patients with chronic obstructive pulmonary disease.
Threshold loading with the Nickerson and Keens' device is frequently applied in the training and assessment of inspiratory muscles. However, this equipment is not easily applied in clinical practice and training. A study was therefore designed to investigate the accuracy and reliability of the Threshold, a commercially available threshold loading device. The resolution (accuracy) of the system was determined by measuring variation of pressure and flow during one minute in an experimental setup. The reproducibility and flow independence were then determined during threshold loading at six different inspiratory loads between 25% and 50% maximal inspiratory pressure (PImax) in 10 patients with chronic obstructive pulmonary disease (COPD) and eight healthy subjects. In the first experiment the mean variation of the sustained pressure for all loads was 1.7%. The mean coefficients of variation for pressure and flow measurements were 0.2% and 3%, respectively. In the second experiment the healthy subjects showed mean coefficients of variation for pressure and flow of 0.8% and 20.5%, respectively, and the patients showed mean coefficients of variation of 0.6% and 14.5%, respectively. During the in vitro experiment as well as during the experiments in patients with COPD and in healthy subjects only small variations in pressure were observed despite large variations in flow. The Threshold is a reliable and reproducible device for loading inspiratory muscles in patients with COPD as well as in healthy subjects.


Galectins in tumor angiogenesis.
The expansion of solid tumors depends on the continuous ingrowth of new blood vessels out of pre-existing capillaries. Consequently, tumor neovascularization or tumor angiogenesis is considered a hallmark of cancer and an attractive target for cancer therapy. Tumor angiogenesis is mainly carried out by endothelial cells (EC), i.e., the cells lining the luminal vessel wall. These cells have to take on different functional activities in order to successfully make new tumor blood vessels. In the last decade it has become apparent that galectins are important regulators of tumor angiogenesis. In the present review we summarize the current knowledge regarding the role galectins in tumor angiogenesis focussing on the endothelial galectins, i.e., gal-1/-3/-8/-9.


Direct Utilization of Organic Nitrogen by Phytoplankton and Its Role in Nitrogen Cycling Within the Southern California Bight.
The new production model attempts to quantify the amount of organic material exported from surface waters based on the form of nitrogen (N) being utilized. Dissolved organic N (DON) is rarely assessed during such investigations and even less is understood about the organisms involved in these different transformations within the complex N cycle. Stable isotope probing (SIP) and uptake activity measurements were combined to investigate the dynamics of new and regenerated production during the spring within the Southern California Bight (SCB). We examined the uptake and assimilation of several nitrogenous substrates at several depths to quantify these processes and identify the active communities across all three domains of life that are driving each transformation. Several reoccurring members closely related to the eukaryotic diatom Chaetoceros, dominated assimilation of NO3 - and urea through the water column, and contributed greatly to the overall production. Prokaryotic growth was predominantly carried out through NH4 + assimilation with transitions from Flavobacteria to Rhodobacteraceae and Marine Group II Euryarchaeota to Marine Group I Thaumarchaeota with increasing depth for bacterial and archaeal clades, respectively. Only urea uptake and SIP activity correlated with each other, likely demonstrating that cellular transport and incorporation of urea were coupled. SIP was therefore able to identify the organisms primarily responsible for urea cycling at each depth during this investigation. The role of diatoms within high nutrient areas are well defined but their part in DON cycling in highly stratified regimes is less well understood. Here we demonstrate their ability to efficiently scavenge urea in situ, allowing certain diatoms to outcompete the rest of the community. This diversion of DON away from the trophically inefficient microbial loop directly back into the larger, particle forming populations would alter the current view of microbial food webs. This proposed "phytoplankton shunt" of organic material could potentially enhance the biological pump by mitigating losses due to trophic transfers while increasing DON flux due to ballasting. Our results provide unique biogeochemical and ecological insight into the dynamics and diversity of N cycling and the organisms involved within the surface waters of the SCB.


Impact of hospital-wide process redesign on clinical outcomes: a comparative study of internally versus externally led intervention.
INTRODUCTION In response to increasing demand for hospital beds, institution-wide clinical process redesign has been advocated for improving efficiency. METHODS This retrospective, before-after study involved five tertiary hospitals in Queensland, Australia and assessed effects of externally led redesign over 6 months within two hospitals, comprising ward-based innovations led by consultancy-led standardised processes, and internally led redesign over 25 months in one hospital which implemented medical assessment and planning unit, 23 h elective surgical ward and new bed management processes. The primary outcome measures were control chart changes in emergency department (ED) access block and overdue category 1 elective surgery waits over 3.5 years involving intervention hospitals and two control hospitals. RESULTS At one externally led redesign hospital, control charts indicated a decrease in ED access block outside control limits which coincided with the intervention, but this was not subsequently sustained. There were no special-cause variations seen in the other hospital. In contrast, at the internally led redesign hospital, there were two decreases in access block outside control limits during the intervention period, resulting in a decrease from a baseline average of 55% to a postintervention average of 22%. All hospitals showed declines in elective surgery waits with oscillations in data indicating the existence of special-cause factors other than redesign. CONCLUSION Internally led compared with externally led redesign led to superior and sustained improvements in ED access block as a result of major structural reforms that were driven by committed clinicians and managers and cut across departmental boundaries.


Purinergic regulation of high-glucose-induced caspase-1 activation in the rat retinal Müller cell line rMC-1.
Chronic activation of proinflammatory caspase-1 in the retinas of diabetic animals and patients in vivo and retinal Müller cells in vitro is well documented. In this study we characterized how elevated glucose and extracellular purines contribute to the activation of caspase-1 in a cultured rat Müller cell (rMC-1) model. The ability of high glucose (25 mM, 24 h) to activate caspase-1 was attenuated by either apyrase, which metabolizes extracellular ATP to AMP, or adenosine deaminase (ADA), which metabolizes extracellular adenosine to inosine. This suggested that autocrine stimulation of ATP-sensing P2 receptors and adenosine-sensing P1 receptors may in part mediate the response to high glucose. Exogenous ATP, 5'-N-ethylcarboxamido-adenosine (NECA), a nonselective P1 receptor agonist, or forskolin (FSK) increased caspase-1 activity in rMC-1 cells cultured in control glucose (5 mM) medium. Accumulation of active caspase-1 was also increased by dipyridamole, which suppresses adenosine reuptake. High-glucose stimulation of caspase-1 was attenuated by suramin, a nonselective P2 antagonist, or A2 adenosine receptor antagonists, but not by antagonism of P2X7 ATP-gated ion channel receptors. Although high glucose increased P2X7 mRNA, neither P2X7 protein nor function was detected in rMC-1 cells. The increased caspase-1 activity stimulated by high glucose, FSK, NECA, or ATP was correlated with increased gene expression of caspase-1 and thioredoxin-interacting-protein (TXNIP). These findings support a novel role for autocrine P1 and P2 purinergic receptors coupled to cAMP signaling cascades and transcriptional induction of caspase-1 in mediating the high-glucose-induced activation of caspase-1 and secretion of IL-1β in a cell culture model of nonhematopoietic retinal Müller cells.


Effects of endurance training and acute exhaustive exercise on antioxidant defense mechanisms in rat heart.
We investigated whether 8-week treadmill training strengthens antioxidant enzymes and decreases lipid peroxidation in rat heart. The effects of acute exhaustive exercise were also investigated. Male rats (Rattus norvegicus, Sprague-Dawley strain) were divided into trained and untrained groups. Both groups were further divided equally into two groups where the rats were studied at rest and immediately after exhaustive exercise. Endurance training consisted of treadmill running 1.5 h day(-1), 5 days week(-1) for 8 weeks. For acute exhaustive exercise, graded treadmill running was conducted. Malondialdehyde level in heart tissue was not affected by acute exhaustive exercise in untrained and trained rats. The activities of glutathione peroxidase and glutathione reductase enzymes decreased by both acute exercise and training. Glutathione S-transferase and catalase activities were not affected. Total and non-enzymatic superoxide scavenger activities were not affected either. Superoxide dismutase activity decreased by acute exercise in untrained rats; however, this decrease was not observed in trained rats. Our results suggested that rat heart has sufficient antioxidant enzyme capacity to cope with exercise-induced oxidative stress, and adaptive changes in antioxidant enzymes due to endurance training are limited.


Protection of Oligodendrocytes Through Neuronal Overexpression of the Small GTPase Ras in Hyperoxia-Induced Neonatal Brain Injury.
Prematurely born infants are highly susceptible to various environmental factors, such as inflammation, drug exposure, and also high environmental oxygen concentrations. Hyperoxia induces perinatal brain injury affecting white and gray matter development. It is well known that mitogen-activated protein kinase signaling is involved in cell survival, proliferation, and differentiation. Therefore, we aim to elucidate cell-specific responses of neuronal overexpression of the small GTPase Ras on hyperoxia-mediated brain injury. Six-day-old (P6) synRas mice (neuronal Ras overexpression under the synapsin promoter) or wild-type littermates were kept under hyperoxia (80% oxygen) or room air (21% oxygen) for 24 h. Apoptosis was analyzed by Western blot of cleaved Caspase-3 and neuronal and oligodendrocyte degeneration via immunohistochemistry. Short-term differentiation capacity of oligodendrocytes was assessed by quantification of myelin basic protein expression at P11. Long-lasting changes of hyperoxia-induced alteration of myelin structures were evaluated via transmission electron microscopy in young adult animals (P42). Western blot analysis of active Caspase-3 demonstrates a significant upregulation in wild-type littermates exposed to hyperoxia whereas synRas mice did not show any marked alteration of cleaved Caspase-3 protein levels. Immunohistochemistry revealed a protective effect of neuronal Ras overexpression on neuron and oligodendrocyte survival. Hyperoxia-induced hypomyelination in wild-type littermates was restored in synRas mice. These short-term protective effects through promotion of neuronal survival translated into long-lasting improvement of ultrastructural alterations of myelin sheaths in mice with neuronal overexpression of Ras compared with hyperoxic wild-type mice. Our data suggest that transgenic increase of neuronal Ras activity in the immature brain results in secondary protection of oligodendrocytes from hyperoxia-induced white matter brain injury.


Conversation Cafés and Conceptual Framework Formation for Research Training and Mentoring of Underrepresented Faculty at Historically Black Colleges and Universities: Obesity Health Disparities (OHD) PRIDE Program.
The development of research training opportunities for investigators from the untapped pool of traditionally underrepresented racial/ethnic groups has gained intense interest at the National Institutes of Health (NIH). The significant and persistent disparity in the likelihood of R01 funding between African American and Whites was highlighted in the groundbreaking 2011 report, Race, Ethnicity, and NIH Research Awards. Disparities in funding success were also shown to exist at the institutional level, as 30 institutions receive a disproportionate share of federal research funding. Historically Black Colleges and Universities (HBCUs) have a dual commitment to education and research; however, the teaching loads at HBCUs may present challenges for research-oriented faculty. Few research training and mentoring programs have been specifically designed for this group. During 2015 and 2016, we held three conversation cafés with 77 participants in Jackson, Mississippi and Baltimore, Maryland. The purpose of this article is to describe findings from these conversation cafés regarding barriers and facilitators to building robust research careers at HBCUs, and to illustrate how these data were used to adapt the conceptual framework for the NHLBI-funded Obesity Health Disparities (OHD) PRIDE program. Identified barriers included teaching and advising loads, infrastructures, and lack of research mentors on campus. The benefit of incorporating research into classroom teaching was a noted facilitator.


Sex-selective effects of neonatal isolation on fear conditioning and foot shock sensitivity.
Our previous work demonstrates enduring effects of the early life stress of neonatal isolation (ISO). ISO facilitates appetitive response learning in adult female, but not male rats, and enhances corticosterone levels and stress responsivity in infant and juvenile rats of both sexes. Corticosterone acts at brain areas such as hippocampus that are rich in glucocorticoid receptors, differentiate postnatally, are sexually dimorphic, and involved in learning. Thus, ISO is hypothesized to alter aversive learning in adult rats in a sex-specific manner. This study tests this hypothesis using context and cue fear conditioning. Pups were isolated for 1h a day on postnatal (PN) days 2-9 or were non-handled and were then tested in adulthood (PN70-90). In Experiment 1, context- and cue-elicited freezing and ultrasonic vocalizations (USVs; 22 kHz range) were measured. Experiments 2-4, respectively, examined three unconditioned foot shock responses (flinch, jump, vocalization), unconditioned fear (time in center of an open, novel arena), and appetitive (stroking-induced; 50 kHz range) USVs. ISO had a sex-selective effect on context-induced USVs that may reflect changes in foot shock sensitivity. ISO increases foot shock sensitivity and tends to enhance context-induced fear in female rats, whereas ISO tends to impair context-induced fear in male rats. Overall, male rats show greater conditioned fear, and female rats show greater unconditioned fear as well as enhanced responses to the aversive and appetitive stimuli. The sex-specific effect of ISO on context fear may reflect neuronal reorganization in stress responsive areas and/or sex differences in some unconditioned responses.


RGS4 inhibits signaling by group I metabotropic glutamate receptors.
Metabotropic glutamate receptors (mGluRs) couple to heterotrimeric G-proteins and regulate cell excitability and synaptic transmission in the CNS. Considerable effort has been focused on understanding the cellular and biochemical mechanisms that underlie regulation of signaling by G-proteins and their linked receptors, including the mGluRs. Recent findings demonstrate that regulators of G-protein signaling (RGS) proteins act as effector antagonists and GTPase-activating proteins for Galpha subunits to inhibit cellular responses by G-protein-coupled receptors. RGS4 blocks Gq activation of phospholipase Cbeta and is expressed broadly in rat brain. The group I mGluRs (mGluRs 1 and 5) couple to Gq pathways to regulate several effectors in the CNS. We examined the capacity of RGS4 to regulate group I mGluR responses. In Xenopus oocytes, purified RGS4 virtually abolishes the mGluR1a- and mGluR5a-mediated but not the inositol trisphospate-mediated activation of a calcium-dependent chloride current. Additionally, RGS4 markedly attenuates the mGluR5-mediated inhibition of potassium currents in hippocampal CA1 neurons. This inhibition is dose-dependent and occurs at concentrations that are virtually identical to those required for inhibition of phospholipase C activity in NG108-15 membranes and reconstituted systems using purified proteins. These findings demonstrate that RGS4 can modulate mGluR responses in neurons, and they highlight a previously unknown mechanism for regulation of G-protein-coupled receptor signaling in the CNS.


Cnidarian and bilaterian promoters can direct GFP expression in transfected hydra.
Complete sexual development is not easily amenable to experimentation in hydra. Therefore, the analysis of gene function and gene regulation requires the introduction of exogenous DNA in a large number of cells of the hydra polyps and the significant expression of reporter constructs in these cells. We present here the procedure whereby we coupled DNA injection into the gastric cavity to electroporation of the whole animal in order to efficiently transfect hydra polyps. We could detect GFP fluorescence in both endodermal and ectodermal cell layers of live animals and in epithelial as well as interstitial cell types of dissociated hydra. In addition, we could confirm GFP protein expression by showing colocalisation between GFP fluorescence and anti-GFP immunofluorescence. Finally, when a FLAG epitope was inserted in-frame with the GFP coding sequence, GFP fluorescence also colocalised with anti-FLAG immunofluorescence. This GFP expression in hydra cells was directed by various promoters, either homologous, like the hydra homeobox cnox-2 gene promoter, or heterologous, like the two nematode ribosomal protein S5 and L28 gene promoters, and the chicken beta-actin gene promoter. This strategy provides new tools for dissecting developmental molecular mechanisms in hydra; more specifically, the genetic regulations that take place in endodermal cells at the time budding or regeneration is initiated.


Antibiotic prophylaxis of postoperative endophthalmitis after cataract surgery: Results of the 2014 ASCRS member survey.
A 2014 online survey of the American Society of Cataract and Refractive Surgery members indicated increasing use of intracameral antibiotic injection prophylaxis compared with a comparable survey from 2007. Forty-seven percent of respondents already used or planned to adopt this measure. One half of all surgeons not using intracameral prophylaxis expressed concern about the risks of noncommercially prepared antibiotic preparations. Overall, the large majority (75%) said they believe it is important to have a commercially available antibiotic approved for intracameral injection. Assuming reasonable cost, the survey indicates that commercial availability of Aprokam (cefuroxime) would increase the overall percentage of surgeons using intracameral antibiotic injection prophylaxis to nearly 84%. Although the majority used topical perioperative antibiotic prophylaxis, and gatifloxacin and moxifloxacin were still the most popular agents, there was a trend toward declining use of fourth-generation fluoroquinolones (60%, down from 81% in 2007) and greater use of topical ofloxacin and ciprofloxacin (21%, up from 9% in 2007).


An anatomical and analytical study of the modiolus: enlightening its relevance to plastic surgery.
This study was designed to evaluate the structures, muscles, and fasciae of which the modiolus is composed. It can aid in the understanding and, therefore, the utilization of plastic surgery for the aesthetic or reconstructive treatment of that region, especially the angle of the mouth. Dissections of the midface were done on five different cadavers. They were of different races (3 males, 2 females). The anatomy of the modiolus was studied in detail. New anatomical observations were classified as type I through type VI. The perifacial artery fascia contributed to the modiolus in four (80%) specimens and was not part of it in 1 (20%) specimen. The facial artery was anterior to it in one (20%) specimen, lateral in four (80%) specimens, and never medial to it. No significant relationship was observed between the perifacial artery fascia contribution to the modiolus and gender or race. Also, the location of the facial artery lateral or anterior to the modiolus was not significantly related to gender or race. In addition, the deep and superficial fasciae of the face converged not anterior to the masseter muscle but actually at the modiolus, which was different from observations made by others. The modiolus is of critical importance in aesthetic and reconstructive plastic surgery of the face.


Allele-selective inhibition of mutant atrophin-1 expression by duplex and single-stranded RNAs.
Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive neurodegenerative disorder that currently has no curative treatments. DRPLA is caused by an expansion of a CAG trinucleotide repeat region within the protein-encoding sequence of the atrophin-1 (ATN-1) gene. Inhibition of mutant ATN-1 protein expression is one strategy for treating DRPLA, and allele-selective gene silencing agents that block mutant expression over wild-type expression would be lead compounds for therapeutic development. Here we develop an assay for distinguishing mutant from wild-type ATN-1 protein by gel electrophoresis. We use this assay to evaluate duplex RNAs and single-stranded silencing RNAs (ss-siRNAs) for allele-selective inhibition of ATN-1 protein expression. We observed potent and allele-selective inhibition by RNA duplexes that contain mismatched bases relative to the CAG target and have the potential to form miRNA-like complexes. ss-siRNAs that contained mismatches were as selective as mismatch-containing duplexes. We also report allele-selective inhibition by duplex RNAs containing unlocked nucleic acids or abasic substitutions, although selectivities are not as high. Five compounds that showed >8-fold allele selectivity for mutant ATN-1 were also selective for inhibiting the expression of two other trinucleotide repeat disease genes, ataxin-3 (ATXN-3) and huntingtin (HTT). These data demonstrate that the expanded trinucleotide repeat within ATN-1 mRNA is a potential target for compounds designed to achieve allele-selective inhibition of ATN-1 protein, and one agent may allow the targeting of multiple disease genes.


System-related interventions to reduce diagnostic errors: a narrative review.
Diagnostic errors (missed, delayed or wrong diagnosis) have recently gained attention and are associated with significant preventable morbidity and mortality. The authors reviewed the recent literature and identified interventions that address system-related factors that contribute directly to diagnostic errors. The authors conducted a comprehensive search using multiple search strategies. First, they performed a PubMed search to identify articles exclusively related to diagnostic error or delay published in English between 2000 and 2009. They then sought papers from references in the initial dataset, searches of additional databases, and subject matter experts. Articles were included if they formally evaluated an intervention to prevent or reduce diagnostic error; however, papers were also included if interventions were suggested and not tested to inform the state of the science on the subject. Interventions were characterised according to the step in the diagnostic process they targeted: patient-provider encounter; performance and interpretation of diagnostic tests; follow-up and tracking of diagnostic information; subspecialty and referral-related issues; and patient-specific care-seeking and adherence processes. 43 articles were identified for full review, of which six reported tested interventions and 37 contained suggestions for possible interventions. Empirical studies, although somewhat positive, were non-experimental or quasi-experimental and included a small number of clinicians or healthcare sites. Outcome measures in general were underdeveloped and varied markedly among studies, depending on the setting or step in the diagnostic process. Despite a number of suggested interventions in the literature, few empirical studies in the past decade have tested interventions to reduce diagnostic errors. Advancing the science of diagnostic error prevention will require more robust study designs and rigorous definitions of diagnostic processes and outcomes to measure intervention effects.


VARIETAL IDENTIFICATION IN HOUSEHOLD SURVEYS: RESULTS FROM THREE HOUSEHOLD-BASED METHODS AGAINST THE BENCHMARK OF DNA FINGERPRINTING IN SOUTHERN ETHIOPIA.
Accurate crop varietal identification is the backbone of any high-quality assessment of outcomes and impacts. Sweetpotato (Ipomoea batatas) varieties have important nutritional differences, and there is a strong interest to identify nutritionally superior varieties for dissemination. In agricultural household surveys, such information is often collected based on the farmer's self-report. In this article, we present the results of a data capture experiment on sweet potato varietal identification in southern Ethiopia. Three household-based methods of identifying varietal adoption are tested against the benchmark of DNA fingerprinting: (A) Elicitation from farmers with basic questions for the most widely planted variety; (B) Farmer elicitation on five sweet potato phenotypic attributes by showing a visual-aid protocol; and (C) Enumerator recording observations on five sweet potato phenotypic attributes using a visual-aid protocol and visiting the field. In total, 20% of farmers identified a variety as improved when in fact it was local and 19% identified a variety as local when it was in fact improved. The variety names given by farmers delivered inconsistent and inaccurate varietal identities. Visual-aid protocols employed in methods B and C were better than those in method A, but greatly underestimated the adoption estimates given by the DNA fingerprinting method. Our results suggest that estimating the adoption of improved varieties with methods based on farmer self-reports is questionable and point towards a wider use of DNA fingerprinting in adoption and impact assessments.


Responsibility taking and role definition in family practice: effect of training and practice setting.
There is evidence that family physicians (FPs) reduce health care costs by reducing patient referral to more expensive secondary and tertiary care facilities. Presumably, the effectiveness of FPs in meeting patients' needs is related to their role definition and willingness to assume responsibility. The purpose of this study was to determine the influence of training and practice setting on responsibility taking and role definition of FPs. A previously developed and validated self-administered questionnaire was completed by 153 certified FPs and FP residents from five departments of family practice in Israel. The main independent variables were previous training and practice setting. The main outcome measures were self-reported data on responsibility taking, role boundaries, and reported role performance. The results showed that certified FPs were more willing to assume responsibility, to define broader role boundaries, and to perform more specialized interventions than residents. Differences in practice setting affected only reported performance, with physicians who practice in rural clinics performing more specialized activities than those in urban clinics. Multiple regression analysis shows that professional development is associated with an increased willingness to assume responsibility; this willingness affects role boundaries definitions, which affects reported performance. Practice setting alters the tendency to perform a wider range of interventions, but does not affect physicians' attitudes.


High salt intake: independent risk factor for obesity?
High salt intake is the major cause of raised blood pressure and accordingly leads to cardiovascular diseases. Recently, it has been shown that high salt intake is associated with an increased risk of obesity through sugar-sweetened beverage consumption. Increasing evidence also suggests a direct link. Our study aimed to determine whether there was a direct association between salt intake and obesity independent of energy intake. We analyzed the data from the rolling cross-sectional study-the UK National Diet and Nutrition Survey 2008/2009 to 2011/2012. We included 458 children (52% boys; age, 10±4 years) and 785 adults (47% men; age, 49±17 years) who had complete 24-hour urine collections. Energy intake was calculated from 4-day diary and misreporting was assessed by Goldberg method. The results showed that salt intake as measured by 24-hour urinary sodium was higher in overweight and obese individuals. A 1-g/d increase in salt intake was associated with an increase in the risk of obesity by 28% (odds ratio, 1.28; 95% confidence interval, 1.12-1.45; P=0.0002) in children and 26% (odds ratio, 1.26; 95% confidence interval, 1.16-1.37; P<0.0001) in adults, after adjusting for age, sex, ethnic group, household income, physical activity, energy intake, and diet misreporting, and in adults with additional adjustment for education, smoking, and alcohol consumption. Higher salt intake was also significantly related to higher body fat mass in both children (P=0.001) and adults (P=0.001) after adjusting for age, sex, ethnic group, and energy intake. These results suggest that salt intake is a potential risk factor for obesity independent of energy intake.


Finasteride to prevent prostate cancer: should all men or only a high-risk subgroup be treated?
PURPOSE Finasteride has been shown to reduce the incidence of prostate cancer. Yet the use of finasteride remains low, likely because of the risk of adverse effects. We sought to determine whether prostate-specific antigen (PSA) levels could identify a high-risk subgroup for which the benefits of finasteride treatment outweigh the potential harms. PATIENTS AND METHODS Raw data from the Prostate Cancer Prevention Trial were used to model chemopreventive treatment strategies: treat all men, treat no men, or treat a high-risk subgroup based on PSA level. We weighted the benefits (reduction in cancer rate) and harms (treatment rate) of each strategy using numbers-needed-to-treat thresholds-the maximum number of men a clinician would treat with finasteride to prevent one cancer. Results Of 9,058 men, 1,957 were diagnosed with prostate cancer during the 7-year study. For the end point of all cancers, including both for-cause and end-of-study biopsies, the optimal strategy is to treat all or nearly all men. To reduce risk of cancers detected through routine care, treating men with PSA > 1.3 or > 2 ng/mL is optimal. For example, treating only men with PSA > 2 ng/mL reduced the treatment rate by 83% and resulted in a cancer rate only 1.1% higher than treating all men. CONCLUSION Clinicians wishing to reduce the risk of any biopsy-detectable prostate cancer should recommend finasteride to all men. Clinicians who believe that it is unnecessary to prevent all cancers, but that preventing those readily detectable by screening would be desirable, would be best off recommending finasteride only to a high-risk subgroup.


The rat Ruby ( R) locus is Rab38: identical mutations in Fawn-hooded and Tester-Moriyama rats derived from an ancestral Long Evans rat sub-strain.
Hermansky-Pudlak syndrome (HPS) is a group of rare, recessive disorders in which oculocutaneous albinism, progressive pulmonary fibrosis, bleeding diathesis, and other abnormalities result from defective biogenesis of multiple cytoplasmic organelles. Seven different HPS genes are known in humans; in mouse, at least 16 loci are associated with HPS-like mutant phenotypes. In the rat, only two HPS models are known, Fawn-hooded (FH) and Tester Moriyama (TM), non-complementing strains in which HPS-like hypopigmentation and platelet storage pool deficiency result from a mutation of the Ruby (red eyed dilution; R) locus on Chromosome (Chr) 1. We have identified the R locus as the Rab38 gene, establishing that rat R is homologous to mouse chocolate ( cht). Further, we show that FH and TM rats have identical Rab38 Met1Ile mutations, occurring on an identical Chr 1 marker allele haplotype, indicating that these two strains derive from a common ancestor. This ancestor appears to have been a sub-strain of the outbred Long Evans (LE) strain, and several modern LE sub-strains carry the Rab38 Met1Ile R mutation on the same Chr 1 marker haplotype. These findings have significant implications for the many past and ongoing studies that involve the FH and LE-derivative rat strains. Hermansky-Pudlak syndrome (HPS; MIM 203300) is a group of autosomal recessive diseases in which oculocutaneous albinism (OCA), progressive and fatal pulmonary fibrosis, and bleeding diathesis due to platelet storage pool deficiency result from defects in the biogenesis of specific cytoplasmic organelles and granules: melanosomes, lysosomes, and platelet dense granules. In humans, seven different HPS genes are known. In the mouse, at least 16 loci associated with HPS-like mutant phenotypes are known, seven of which are homologous to the human HPS loci.


Functional topography of the thalamocortical system in human.
Various studies have indicated that the thalamus is involved in controlling both cortico-cortical information flow and cortical communication with the rest of the brain. Detailed anatomy and functional connectivity patterns of the thalamocortical system are essential to understanding the cortical organization and pathophysiology of a wide range of thalamus-related neurological and neuropsychiatric diseases. The current study used resting-state fMRI to investigate the topography of the human thalamocortical system from a functional perspective. The thalamus-related cortical networks were identified by performing independent component analysis on voxel-based thalamic functional connectivity maps across a large group of subjects. The resulting functional brain networks were very similar to well-established resting-state network maps. Using these brain network components in a spatial regression model with each thalamic voxel's functional connectivity map, we localized the thalamic subdivisions related to each brain network. For instance, the medial dorsal nucleus was shown to be associated with the default mode, the bilateral executive, the medial visual networks; and the pulvinar nucleus was involved in both the dorsal attention and the visual networks. These results revealed that a single nucleus may have functional connections with multiple cortical regions or even multiple functional networks, and may be potentially related to the function of mediation or modulation of multiple cortical networks. This observed organization of thalamocortical system provided a reference for studying the functions of thalamic sub-regions. The importance of intrinsic connectivity-based mapping of the thalamocortical relationship is discussed, as well as the applicability of the approach for future studies.


Postoperative renal failure in thoracoabdominal aortic aneurysm repair with simple cross-clamp technique and 4°C renal perfusion.
Acute renal failure (ARF) is reported in up to 12% of patients after thoracoabdominal aortic aneurysm (TAAA) repair with assisted circulation. ARF increases mortality, reduces quality of life, and increases length of hospital stay. This study analyzes ARF after TAAA repair done without assisted circulation. A retrospective analysis of all patients treated for TAAA from 2000 to 2013 was performed using a concurrently maintained, institutionally approved database. All surgeries used simple cross-clamp technique, with moderate systemic hypothermia (32°-33°C) and renal artery perfusion with 4°C solution. Serum creatinine concentration was measured preoperatively and 1 day, 3 days, 7 days, and 30 days after surgery, and Cockcroft-Gault estimated glomerular filtration rate (eGFR) was calculated. Kidney injury was classified by RIFLE (Risk, Injury, Failure, Loss of kidney function, End-stage renal disease) eGFR criteria. Changes in eGFR, kidney injury, ARF, dialysis, length of stay, mortality, and risk factors for ARF were analyzed with SAS-JMP software (SAS Institute, Cary, NC) for univariate analysis and multivariate modeling. From 2000 to 2013, 455 patients had TAAA surgery; 116 (25.5%) were acute. Mean preoperative eGFR was 62.3 mL/min. Mean renal ischemia time was 58.9 minutes. Eighteen patients (4%) had ARF; nine (2%) required temporary dialysis, and three (0.66%) required permanent dialysis. In univariate analysis, age, renal ischemia time, acuity, baseline eGFR, previous aortic surgery, surgical blood loss, and return to operating room for bleeding complications were significant for ARF (P < .05). Sex, aneurysm extent by Crawford type, cardiac index and mean arterial pressure after reperfusion, and use of loop diuretics were not significant for ARF. In a stepwise deletion model, acute (P = .0377), previous aortic surgery (P = .0167), return to operating room (P = .0213), and age (P = .0478) were significant for ARF. Surgical blood loss (P = .0056) and return to operating room (P = .0024) were significant for postoperative dialysis in multivariate analysis. Only surgical blood loss was significant for permanent dialysis in a multivariate model (P = .0331). Very low ARF after TAAA repair can be achieved by simple cross-clamp technique with moderate systemic hypothermia and profound renal cooling. Age, preoperative eGFR, previous aortic surgery, return to operating room, and surgical blood loss were significant for ARF. Return to operating room for bleeding and surgical blood loss were significant for dialysis. Baseline eGFR <30 mL/min and postoperative dialysis were significant for mortality. Most patients with ARF, even those with temporary dialysis after TAAA repair, recover renal function to near preoperative levels.


Genotoxicity of source, treated and distributed water from four drinking water treatment plants supplied by surface water in Sardinia, Italy.
High levels of disinfection by-products (DBPs) are constantly found in drinking water distributed in Sardinia, an Italian island with a tourist vocation and critical issues related to the drinking water supply. To reduce the concentration of trihalomethanes the disinfectant in use was changed - chlorine dioxide was adopted instead of hypochlorite. However, this caused the appearance of other DBPs (e.g., chlorites) in water distributed to the population. Thus, the use of monochloramine as a secondary disinfectant (associated with chlorine dioxide as the primary disinfectant) was evaluated in four drinking water treatment plants supplied by artificial basins located in the central-northern part of Sardinia. Raw, disinfected and distributed waters were studied for genotoxicity using a battery of in vitro tests on different cells (bacteria, plant and mammalian cells) to detect different genetic endpoints (i.e., point and chromosome mutations and DNA damage). Moreover, a chemical and microbiological characterisation of water samples was performed. All samples of water distributed to the people showed mutagenic or genotoxic effects in different cells/organisms. In particular, chromosome aberrations in plant cells and DNA damage in human cells were observed. In this study, the use of chloramines associated with other disinfectants did not eliminate the mutagenicity present in the raw water and when the raw water was not mutagenic it introduced mutagenic/genotoxic substances. A careful management of drinking water is needed to reduce health hazards associated with the mutagenicity of drinking water.


Preprandial single oral dose of sitagliptin does not affect circulating ghrelin and gastrin levels in normal subjects.
To determine the effect of an oral dose of sitagliptin on the secretion of ghrelin and gastrin hormones. Ten healthy volunteers were recruited in this study. A baseline blood sample was drawn before oral dosing with a 100-mg tablet of sitagliptin. Two blood samples were obtained 0.5 and 1 h after dosing. Three additional postprandial blood samples were drawn at 0.5, 1, and 2 h. Radioimmunoassay was used for determining hormonal levels. A Student's t test, Pearson correlation analysis, and multivariate approach to repeated-measures analysis of variance were used for statistics. After sitagliptin dosing, but before the meal, there was no significant change in circulating ghrelin, gastrin, insulin, and glucose levels. Only after meal loading was there a progressive and persistent decline in ghrelin levels until the end of the study, while a rapid and temporary rise in gastrin, insulin, and glucose levels at 0.5 h was observed. The levels of gastrin, insulin, and glucose then declined progressively. Preprandial oral dose of sitagliptin does not affect circulating ghrelin, gastrin, insulin, and glucose concentrations in normal subjects. Decreased ghrelin and increased gastrin and insulin levels occurred only after meal loading. These results support the theory that sitagliptin might not cause appetite-enhanced body weight gain and insulin-induced hypoglycemia.


Characterization of mutants in Arabidopsis showing increased sugar-specific gene expression, growth, and developmental responses.
Sugars such as sucrose serve dual functions as transported carbohydrates in vascular plants and as signal molecules that regulate gene expression and plant development. Sugar-mediated signals indicate carbohydrate availability and regulate metabolism by co-coordinating sugar production and mobilization with sugar usage and storage. Analysis of mutants with altered responses to sucrose and glucose has shown that signaling pathways mediated by sugars and abscisic acid interact to regulate seedling development and gene expression. Using a novel screen for sugar-response mutants based on the activity of a luciferase reporter gene under the control of the sugar-inducible promoter of the ApL3 gene, we have isolated high sugar-response (hsr) mutants that exhibit elevated luciferase activity and ApL3 expression in response to low sugar concentrations. Our characterization of these hsr mutants suggests that they affect the regulation of sugar-induced and sugar-repressed processes controlling gene expression, growth, and development in Arabidopsis. In contrast to some other sugar-response mutants, they do not exhibit altered responses to ethylene or abscisic acid, suggesting that the hsr mutants may have a specifically increased sensitivity to sugars. Further characterization of the hsr mutants will lead to greater understanding of regulatory pathways involved in metabolite signaling.


Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease.
The very low-density lipoprotein receptor (VLDLR) plays an important role in the development of hepatic steatosis. In this study, we investigated the role of Peroxisome Proliferator-Activated Receptor (PPAR)β/δ and fibroblast growth factor 21 (FGF21) in hepatic VLDLR regulation. Studies were conducted in wild-type and Pparβ/δ-null mice, primary mouse hepatocytes, human Huh-7 hepatocytes, and liver biopsies from control subjects and patients with moderate and severe hepatic steatosis. Increased VLDLR levels were observed in liver of Pparβ/δ-null mice and in Pparβ/δ-knocked down mouse primary hepatocytes through mechanisms involving the heme-regulated eukaryotic translation initiation factor 2α (eIF2α) kinase (HRI), activating transcription factor (ATF) 4 and the oxidative stress-induced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathways. Moreover, by using a neutralizing antibody against FGF21, Fgf21-null mice and by treating mice with recombinant FGF21, we show that FGF21 may protect against hepatic steatosis by attenuating endoplasmic reticulum (ER) stress-induced VLDLR upregulation. Finally, in liver biopsies from patients with moderate and severe hepatic steatosis, we observed an increase in VLDLR levels that was accompanied by a reduction in PPARβ/δ mRNA abundance and DNA-binding activity compared with control subjects. Overall, these findings provide new mechanisms by which PPARβ/δ and FGF21 regulate VLDLR levels and influence hepatic steatosis development.


Comparison of Sociodemographic and Nutritional Characteristics between Self-Reported Vegetarians, Vegans, and Meat-Eaters from the NutriNet-Santé Study.
There is a growing trend for vegetarian and vegan diets in many Western countries. Epidemiological evidence suggesting that such diets may help in maintaining good health is rising. However, dietary and sociodemographic characteristics of vegetarians and vegans are not well known. The aim of this cross-sectional study was to describe sociodemographic and nutritional characteristics of self-reported, adult vegetarians and vegans, compared to meat-eaters, from the French NutriNet-Santé study. Participants were asked if they were following a specific diet. They were then classified into three self-reported diet groups: 90,664 meat-eaters, 2370 vegetarians, and 789 vegans. Dietary data were collected using three repeated 24-h dietary records. Multivariable polytomic logistic regression models were perfomed to assess the association between the sociodemographic characteristics and type of diet. The prevalence of nutrient intake inadequacy was estimated, by sex and age for micronutrients, as well as by type of self-reported diet. Compared with meat-eaters, vegetarians were more likely to have a higher educational level, whereas vegans had a lower education level. Compared with meat-eaters, vegetarians were more likely to be women, younger individuals, and to be self-employed or never employed rather than managerial staff. Vegetarians and vegans substituted animal protein-dense products with a higher consumption of plant protein-dense products (e.g., soy-based products or legumes). Vegetarians had the most balanced diets in terms of macronutrients, but also had a better adherence to French dietary guidelines. Vegetarians exhibited a lower estimated prevalence of inadequacies for micronutrients such as antioxidant vitamins (e.g., for vitamin E, 28.9% for vegetarian women <55 years of age vs. 41.6% in meat-eaters) while vegans exhibited a higher estimated prevalence of inadequacies for some nutrients, in particular vitamin B12 (69.9% in men and 83.4% in women <55 years of age), compared to meat-eaters. Our study highlighted that, overall, self-reported vegetarians and vegans may meet nutritional recommendations.


Underutilisation of the gastroscope for total colonoscopy in adults: a survey of two European countries.
High caecal intubation success rates have been reported with the gastroscope in adults. We surveyed the current use of the gastroscope for total colonoscopy in adults in the UK and Greece. A questionnaire was e-mailed to 952 members of the British Society of Gastroenterology (UK) and 478 members of the Hellenic Society of Gastroenterology (GR), enquiring as to access to a paediatric colonoscope, use of gastroscope for total colonoscopy and estimate of caecal intubation success rate. Valid replies were 17.4% from UK and 19.7% from GR. The paediatric colonoscope was available to 106/138 (77%) UK and to only 18/86 (21%) GR respondents (p = 0.0002). Of all the UK and GR respondents, 109/138 (79%) and 68/86 (79%), respectively, did not use the gastroscope for total colonoscopy. For the use of the gastroscope for total colonoscopy, 26/29 (89%) UK and 9/18 (50%) GR users did so, while a paediatric colonoscope was also available (p = 0.001), and 3/29 (10.3%) UK and 9/18 (50%) GR users did so, whilst they had no access to a paediatric colonoscope (p = 0.001). Estimated gastroscope caecal intubation success rate was 69% (SD 0.26) UK and 46% (SD 0.36) GR, p = 0.008. Only 37% UK and 28% GR respondents used the gastroscope to examine the left colon. The gastroscope is underutilised for total colonoscopy in both the UK and Greece. Use of the gastroscope does not appear to be related to lack of access to a paediatric colonoscope in the UK but may be in GR. Gastroscope caecal intubation success rate justifies its use where the colonoscope fails.


Time-resolved analysis of the matrix metalloproteinase 10 substrate degradome.
Proteolysis is an irreversible post-translational modification that affects intra- and intercellular communication by modulating the activity of bioactive mediators. Key to understanding protease function is the system-wide identification of cleavage events and their dynamics in physiological contexts. Despite recent advances in mass spectrometry-based proteomics for high-throughput substrate screening, current approaches suffer from high false positive rates and only capture single states of protease activity. Here, we present a workflow based on multiplexed terminal amine isotopic labeling of substrates for time-resolved substrate degradomics in complex proteomes. This approach significantly enhances confidence in substrate identification and categorizes cleavage events by specificity and structural accessibility of the cleavage site. We demonstrate concomitant quantification of cleavage site spanning peptides and neo-N and/or neo-C termini to estimate relative ratios of noncleaved and cleaved forms of substrate proteins. By applying this strategy to dissect the matrix metalloproteinase 10 (MMP10) substrate degradome in fibroblast secretomes, we identified the extracellular matrix protein ADAMTS-like protein 1 (ADAMTSL1) as a direct MMP10 substrate and revealed MMP10-dependent ectodomain shedding of platelet-derived growth factor receptor alpha (PDGFRα) as well as sequential processing of type I collagen. The data have been deposited to the ProteomeXchange Consortium with identifier PXD000503.


TCF4 sequence variants and mRNA levels are associated with neurodevelopmental characteristics in psychotic disorders.
TCF4 is involved in neurodevelopment, and intergenic and intronic variants in or close to the TCF4 gene have been associated with susceptibility to schizophrenia. However, the functional role of TCF4 at the level of gene expression and relationship to severity of core psychotic phenotypes are not known. TCF4 mRNA expression level in peripheral blood was determined in a large sample of patients with psychosis spectrum disorders (n = 596) and healthy controls (n = 385). The previously identified TCF4 risk variants (rs12966547 (G), rs9960767 (C), rs4309482 (A), rs2958182 (T) and rs17512836 (C)) were tested for association with characteristic psychosis phenotypes, including neurocognitive traits, psychotic symptoms and structural magnetic resonance imaging brain morphometric measures, using a linear regression model. Further, we explored the association of additional 59 single nucleotide polymorphisms (SNPs) covering the TCF4 gene to these phenotypes. The rs12966547 and rs4309482 risk variants were associated with poorer verbal fluency in the total sample. There were significant associations of other TCF4 SNPs with negative symptoms, verbal learning, executive functioning and age at onset in psychotic patients and brain abnormalities in total sample. The TCF4 mRNA expression level was significantly increased in psychosis patients compared with controls and positively correlated with positive- and negative-symptom levels. The increase in TCF4 mRNA expression level in psychosis patients and the association of TCF4 SNPs with core psychotic phenotypes across clinical, cognitive and brain morphological domains support that common TCF4 variants are involved in psychosis pathology, probably related to abnormal neurodevelopment.


Obesity is associated with macrophage accumulation in adipose tissue.
Obesity alters adipose tissue metabolic and endocrine function and leads to an increased release of fatty acids, hormones, and proinflammatory molecules that contribute to obesity associated complications. To further characterize the changes that occur in adipose tissue with increasing adiposity, we profiled transcript expression in perigonadal adipose tissue from groups of mice in which adiposity varied due to sex, diet, and the obesity-related mutations agouti (Ay) and obese (Lepob). We found that the expression of 1,304 transcripts correlated significantly with body mass. Of the 100 most significantly correlated genes, 30% encoded proteins that are characteristic of macrophages and are positively correlated with body mass. Immunohistochemical analysis of perigonadal, perirenal, mesenteric, and subcutaneous adipose tissue revealed that the percentage of cells expressing the macrophage marker F4/80 (F4/80+) was significantly and positively correlated with both adipocyte size and body mass. Similar relationships were found in human subcutaneous adipose tissue stained for the macrophage antigen CD68. Bone marrow transplant studies and quantitation of macrophage number in adipose tissue from macrophage-deficient (Csf1op/op) mice suggest that these F4/80+ cells are CSF-1 dependent, bone marrow-derived adipose tissue macrophages. Expression analysis of macrophage and nonmacrophage cell populations isolated from adipose tissue demonstrates that adipose tissue macrophages are responsible for almost all adipose tissue TNF-alpha expression and significant amounts of iNOS and IL-6 expression. Adipose tissue macrophage numbers increase in obesity and participate in inflammatory pathways that are activated in adipose tissues of obese individuals.


Most methylation-susceptible DNA sequences in human embryonic stem cells undergo a change in conformation or flexibility upon methylation.
DNA methylation in eukaryotes occurs on the cytosine bases in CG, CHG, and CHH (where H indicates non-G nucleotides) contexts and provides an important epigenetic mark in various biological processes. However, the structural and physical properties of methylated DNA are poorly understood. Using nondenaturing polyacrylamide gel electrophoresis, we performed a systematic study of the influence of DNA methylation on the conformation and physical properties of DNA for all CG, CHG, and CHH contexts. In the CG context, methylated multimers of the CG/CG-containing unit fragment migrated in gels slightly faster than their unmethylated counterparts. In the CHG context, both homo- and hemimethylation caused retarded migration of multimers of the CAG/CTG-containing fragment. In the CHH context, methylation caused or enhanced retarded migration of the multimers of CAA/TTG-, CAT/ATG-, CAC/GTG-, CTA/TAG-, or CTT/AAG-containing fragments. These results suggest that methylation increases DNA rigidity in the CG context and introduces distortions into several CHG and CHH sequences. More interestingly, we found that nearly all of the methylation repertoires in the CHG context and 98% of those in the CHH context in human embryonic stem cells were species that undergo conformational changes upon methylation. Similarly, most of the methylation repertoires in the Arabidopsis CHG and CHH contexts were sequences with methylation-induced distortion. We hypothesize that the methylation-induced properties or conformational changes in DNA may facilitate nucleosome formation, which provides the essential mechanism for alterations of chromatin density.


Development of an infant feeding core outcome set for childhood obesity interventions: study protocol.
Childhood obesity is a significant public health challenge that affects approximately one in five children worldwide. Infant feeding practices are implicated in the aetiology of childhood obesity. Infant feeding interventions for childhood obesity are increasingly popular but outcome reporting is inconsistent across trials. Lack of standardisation limits examination of intervention effects and mechanisms of change. The aim of the current project is to develop a core set of infant feeding outcomes for children ≤ 1 year old, to be evaluated in childhood obesity intervention trials. This project will use similar methodology to previous core outcome development research. An infant feeding core outcome set (COS) will be developed in four stages: (1) a systematic review of the literature, (2) discussion and clarification of outcomes in a meeting involving multiple stakeholder perspectives, (3) prioritisation of outcomes using the Delphi technique with an expert panel of stakeholders, and (4) achieving consensus on the COS using the nominal group technique (NGT) consensus meeting. An online Delphi survey will be conducted following the NGT meeting to prioritise outcomes identified in the systematic review. An NGT meeting will be conducted with groups of health professionals, non-clinician researchers, and parents of infants ≤ 1 year old, to achieve final consensus on the infant feeding COS. This study aims to develop a core outcome set of infant feeding outcomes for randomised infant feeding studies to prevent childhood obesity. This research will improve examination and syntheses of the outcomes of such studies to prevent and reduce childhood obesity.


Golgi-to-phagosome transport of acid sphingomyelinase and prosaposin is mediated by sortilin.
Sortilin, also known as neurotensin receptor 3 (NTR3), is a transmembrane protein with a dual function. It acts as a receptor for neuromediators and growth factors at the plasma membrane, but it has also been implicated in binding and transport of some lysosomal proteins. However, the role of sortilin during phagosome maturation has not been investigated before. Here, we show that in macrophages, sortilin is mainly localized in the Golgi and transported to latex-bead phagosomes (LBPs). Using live-cell imaging and electron microscopy, we found that sortilin is delivered to LBPs in a manner that depends on its cytoplasmic tail. We also show that sortilin participates in the direct delivery of acid sphingomyelinase (ASM) and prosaposin (PS) to the phagosome, bypassing fusion with lysosomal compartments. Further analysis confirmed that ASM and PS are targeted to the phagosome by sortilin in a Brefeldin-A-sensitive pathway. Analysis of primary macrophages isolated from Sort1(-/-) mice indicated that the delivery of ASM and PS, but not pro-cathepsin D, to LBPs was severely impaired. We propose a pathway mediated by sortilin by which selected lysosomal proteins are transported to the phagosome along a Golgi-dependent route during the maturation of phagosomes.


The research and policy importance of nursing sample surveys and minimum data sets.
This article reviews the information gathered by the National Sample Survey of Registered Nurses (NSSRN) and other sources of data on the registered nurse (RN) workforce. It examines how the data have been used to create knowledge about the RN workforce and highlights the relative strengths and weaknesses of different data sets. Recommendations for future data collection affirm the Institute of Medicine's recommendation that both license-record based minimum data and the NSSRN be collected in order to help the United States and states meet current and future nursing needs.


Basin-scale transmissivity and storativity estimation using hydraulic tomography.
While tomographic inversion has been successfully applied to laboratory- and field-scale tests, here we address the new issue of scale that arises when extending the method to a basin. Specifically, we apply the hydraulic tomography (HT) concept to jointly interpret four multiwell aquifer tests in a synthetic basin to illustrate the superiority of this approach to a more traditional Theis analysis of the same tests. Transmissivity and storativity are estimated for each element of a regional numerical model using the geostatistically based sequential successive linear estimator (SSLE) inverse solution method. We find that HT inversion is an effective strategy for incorporating data from potentially disparate aquifer tests into a basin-wide aquifer property estimate. The robustness of the SSLE algorithm is investigated by considering the effects of noisy observations, changing the variance of the true aquifer parameters, and supplying incorrect initial and boundary conditions to the inverse model. Ground water flow velocities and total confined storage are used as metrics to compare true and estimated parameter fields; they quantify the effectiveness of HT and SSLE compared to a Theis solution methodology. We discuss alternative software that can be used for implementing tomography inversion.


The human resource implications of improving financial risk protection for mothers and newborns in Zimbabwe.
A paradigm shift in global health policy on user fees has been evident in the last decade with a growing consensus that user fees undermine equitable access to essential health care in many low and middle income countries. Changes to fees have major implications for human resources for health (HRH), though the linkages are rarely explicitly examined. This study aimed to examine the inter-linkages in Zimbabwe in order to generate lessons for HRH and fee policies, with particular respect to reproductive, maternal and newborn health (RMNH). The study used secondary data and small-scale qualitative fieldwork (key informant interview and focus group discussions) at national level and in one district in 2011. The past decades have seen a shift in the burden of payments onto households. Implementation of the complex rules on exemptions is patchy and confused. RMNH services are seen as hard for families to afford, even in the absence of complications. Human resources are constrained in managing current demand and any growth in demand by high external and internal migration, and low remuneration, amongst other factors. We find that nurses and midwives are evenly distributed across the country (at least in the public sector), though doctors are not. This means that for four provinces, there are not enough doctors to provide more complex care, and only three provinces could provide cover in the event of all deliveries taking place in facilities. This analysis suggests that there is a strong case for reducing the financial burden on clients of RMNH services and also a pressing need to improve the terms and conditions of key health staff. Numbers need to grow, and distribution is also a challenge, suggesting the need for differentiated policies in relation to rural areas, especially for doctors and specialists. The management of user fees should also be reviewed, particularly for non-Ministry facilities, which do not retain their revenues, and receive limited investment in return from the municipalities and district councils. Overall public investment in health needs to grow.